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                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                   ENDOCRINOLOGIC AND METABOLIC DRUGS

 

                         ADVISORY SUBCOMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                      Wednesday, September 8, 2004

 

                               8:00 a.m.

 

 

                              Holiday Inn

                          Versailles Ballrooms

                         8120 Wisconsin Avenue

                           Bethesda, Maryland

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                              PARTICIPANTS

 

         Glenn Braunstein, M.D., Acting Chair

         LCDR Dornette Spell-LeSane, M.H.A.,

         Executive Secretary

 

         MEMBERS:

 

         Lynne L. Levitsky, M.D.

         Louis J. Aronne, M.D.

         Katherine Flegal, Ph.D., M.P.H.

         Melanie G. Coffin (Patient Representative)

         Frank L. Greenway, M.D.

         Jules Hirsch, M.D.

         Jack A. Yanovski, M.D., Ph.D.

         Susan Z. Yanovski, M.D.

         Paul D. Woolf, M.D.

         Thomas O. Carpenter, M.D.

         Dean A. Follmann, Ph.D.

         Steven W. Ryder, M.D.

         David S. Schade, M.D.

         Morris Schambelan, M.D.

         Nelson B. Watts, M.D.

         Margaret E. Wierman, M.D.

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                            C O N T E N T S

 

      Call to Order and Introductions, Glenn Braunstein,

        M.D., Cedars-Sinai Medical Center, UCLA School

        of Medicine                                              4

 

      Conflict of Interest Statement,

         LCDR Dornette Spell-LeSane, Executive Secretary         6

      Welcome and Introductory Comments, David Orloff,

        M.D., Director, DMEDP                                    9

 

      The Regulatory History of Weight-Loss Drugs,

         Eric Colman, M.D., Medical Team Leader, DMEDP          14

 

      The Epidemiology of Overweight and Obesity,

         Katherine Flegal, Ph.D., Senior Research

         Scientist, National Center for Health Statistics       38

 

      Current Status of Weight-Loss Drugs, Frank

        Greenway, M.D., Director, Pennington Biomedical

        Research Center                                         71

 

      Patterns of Weight-Loss Drug Use,

         Laura A. Governale, Pharm.D., MBA, Drug

         Utilization Specialist, Team Leader, Division of

         Surveillance Research and Communications

         Support, ODS                                           87

 

      Role of  Drugs in the Treatment of Obesity:

         Current and Future, Richard L. Atkinson, M.D.,

         Director, Obetech Obesity Research Center             106

 

      Charge to the Committee, David Orloff, M.D.,

         Director, DMEDP                                       150

 

      Committee Discussion                                     186

 

                                                                 4

 

                         P R O C E E D I N G S

 

                    Call to Order and Introductions

 

                DR. BRAUNSTEIN:  We will call the meeting

 

      to order.  This is the Food and Drug

 

      Administration, Center for Drug Evaluation and

 

      Research, Endocrinologic and Metabolic Drugs

 

      Advisory Committee meeting, on September 8, 2004.

 

      The agenda today is to discuss the FDA draft

 

      guidance document entitled, "Guidance for the

 

      Clinical Evaluation of Weight Control Drugs."  The

 

      original guidance was dated September 24, 1996.

 

                I am Glenn Braunstein, Professor and

 

      Chair, Department of Medicine, Cedars-Sinai Medical

 

      Center.  I am an endocrinologist.  I would like to

 

      go around the table and ask people to introduce

 

      themselves and tell us where they are from.  We

 

      will start with Dr. Orloff.

 

                DR. ORLOFF:  I am David Orloff.  I am

 

      Director, Division of Metabolic and Endocrine Drugs

 

      at FDA.

 

                DR. COLMAN:  I am Eric Colman, a medical

 

      officer from Metabolic and Endocrine Drugs at FDA.

 

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                DR. HIRSCH:  Jules Hirsch, Rockefeller

 

      University, New York.

 

                DR. SCHAMBELAN:  Morris Schambelan, from

 

      the University of California, San Francisco.

 

                DR. FOLLMANN:  Dean Follmann, from NIH.

 

                DR. YANOVSKI:  Jack Yanovski, from NIH.

 

                DR. LEVITSKY:  Lynne Levitsky, Pediatric

 

      Endocrinology Unit, Massachusetts General.

 

                MS. COFFIN:  I am Melanie Coffin, patient

 

      representative.

 

                LCDR SPELL-LESANE:  Dornette Spell-LeSane,

 

      executive secretary for the committee.

 

                DR. GREENWAY:  I am Frank Greenway, from

 

      the Pennington Center.

 

                DR. FLEGAL:  I am Katherine Flegal, from

 

      CDC's National Center for Health Statistics.

 

                DR. YANOVSKI:  Susan Yanovski, NIH.

 

                DR. CARPENTER:  Tom Carpenter, pediatric

 

      endocrinology at Yale University.

 

                DR. WIERMAN:  I am Maggie Wierman,

 

      endocrinologist at the University of Colorado.

 

                DR. WOOLF:  Paul Woolf, endocrinologist,

 

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      Crozer Chester Medical Center.

 

                DR. WATTS:  Nelson Watts, endocrinology,

 

      University of Cincinnati.

 

                DR. SCHADE:  Dave Schade, endocrinology,

 

      University of New Mexico.

 

                DR. ARONNE:  Louis Aronne, New York City,

 

      Weill Cornell Medical Center.

 

                DR. RYDER:  Steve Ryder, Pfizer Research

 

      and Development.  I am the industry representative.

 

                DR. BRAUNSTEIN:  Thank you.  I will now

 

      turn the meeting over to LCDR Dornette

 

      Spell-LeSane.

 

                     Conflict of Interest Statement

 

                LCDR SPELL-LESANE:  Good morning.  The

 

      following announcement addresses the issue of

 

      conflict of interest with respect to this meeting

 

      and is made a part of the record to preclude even

 

      the appearance of such at this meeting.

 

                Based on the agenda, it has been

 

      determined that the topic of today's meeting is an

 

      issue of broad applicability, and there are no

 

      products being approved at this meeting.  Unlike

 

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      issues before a committee in which a particular

 

      product is discussed, issues of broader

 

      applicability involve many industrial sponsors and

 

      academic institutions.

 

                All special government employees have been

 

      screened for their financial interests as they may

 

      apply to the general topic at hand.  To determine

 

      if any conflict of interest existed, the agency has

 

      reviewed the agenda and all relevant financial

 

      interests reported by the meeting participants.

 

      The Food and Drug Administration has granted

 

      general matters waivers to the special government

 

      employees participating in this meeting who require

 

      a waiver under Title 18, United States Code,

 

      Section 208.

 

                A copy of the waiver statements may be

 

      obtained by submitting a written request to the

 

      agency's Freedom of Information Office, Room 12A-30

 

      of the Parklawn Building.

 

                Because general topics impact so many

 

      entities, it is not practical to recite all

 

      potential conflicts of interest as they apply to

 

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      each member, consultant and guest speaker.

 

                FDA acknowledges that there may be

 

      potential conflicts of interest but, because of the

 

      general nature of the discussion before the

 

      committee, these potential conflicts are mitigated.

 

                With respect to FDA's invited industry

 

      representative, we would like to disclose that Dr.

 

      Steven Ryder is participating in this meeting as a

 

      non-voting industry representative, acting on

 

      behalf of regulated industry.  Dr. Ryder is

 

      employed by Pfizer Global Research and Development

 

      as senior vice president and global

 

      cardiovascular/metabolism/GI/GU development head.

 

      And, although Pfizer conducts research in

 

      therapeutic areas possibly covered by today's

 

      discussion, Dr. Ryder's role on this committee is

 

      to represent industry interests in general and not

 

      any one particular company.

 

                In the event that the discussions involve

 

      any other products or firms not already on the

 

      agenda for which FDA participants have a financial

 

      interest, the participant's involvement and their

 

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      exclusion will be noted for the record.

 

                With respect to all other participants, we

 

      ask in the interest of fairness, that they address

 

      any current or previous financial involvement with

 

      any firm whose product they may wish to comment

 

      upon.  Thank you.

 

                DR. BRAUNSTEIN:  Thank you.  Dr. David

 

      Orloff with give the welcome and introductory

 

      comments.

 

                   Welcome and Introductory Comments

 

                DR. ORLOFF:  Good morning.  The first

 

      thing I want to say actually before I get to the

 

      introductory comments is that I believe, Dornette,

 

      if I am not mistaken, we do not have any speakers

 

      for the open public hearing.  Is that correct?

 

                LCDR SPELL-LESANE:  That is correct.

 

                DR. ORLOFF:  As a result of that, time

 

      permitting, we may try to push Dr. Atkinson's talk

 

      up to the morning before we break for lunch.  I

 

      leave that up to Dr. Braunstein and to the clock.

 

                I want to wish everyone a good morning and

 

      welcome our advisors, our guest consultants, FDA

 

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      staff and interested public.

 

                The purpose of today's meeting of the

 

      Metabolic and Endocrine Advisory Committee is to

 

      revisit the division's 1996 draft guidance on the

 

      development of drugs for the treatment of obesity.

 

      As everyone present knows, the FDA's public health

 

      mission includes the charge to assure that safe and

 

      effective drugs are efficiently, but without

 

      cutting crucial corners, brought forward through

 

      development to the marketplace in order to

 

      diagnose, cure, treat, prevent or mitigate disease.

 

      That, broadly speaking, explains our purpose here

 

      today.

 

                More specifically, in August of 2003 the

 

      then Commissioner McClellan established the FDA

 

      obesity working group and asked that group to

 

      develop a plan of action to address critical

 

      aspects of the burgeoning obesity problem in the

 

      U.S. within the authorities of the Food and Drug

 

      Administration.

 

                Germane to our work here today, he charged

 

      the so-called therapeutic subgroup, which was led

 

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      by our division, to assess real or perceived

 

      barriers to obesity drug development and to make

 

      recommendations on ways to encourage the

 

      development of new or enhanced therapeutics for

 

      obesity.

 

                In the face of this growing public health

 

      problem, advances in the understanding of the

 

      physiology and pathophysiology of obesity and the

 

      activity within the pharmaceutical industry in this

 

      therapeutic area, we took the opportunity to plan a

 

      discussion of the current guidance and its

 

      potential modification.  Today's meeting is further

 

      timely in light of the recent release by NIH,

 

      announced on August 24th, of the final version of

 

      its own strategic plan for obesity research which

 

      includes intensification of efforts on

 

      pharmacologic approaches to the prevention and

 

      treatment of obesity in both children and adults.

 

                In early 2004 we published a formal call

 

      for comments on the guidance in the Federal

 

      Register, with an open comment period until late

 

      April.  Today, with the help of our advisors and

 

                                                                12

 

      consultants, we will review what we consider to be

 

      the salient issues raised in the comments we

 

      received, as well as others that we believe are

 

      critical to ensuring that FDA's evidentiary

 

      standards for safety and efficacy of obesity drugs

 

      are, to the extent possible, in line with the

 

      science of the day.

 

                We look forward to the formal

 

      presentations and what we trust will be a fruitful

 

      discussion to follow.  I should make clear, as I

 

      believe is apparent from the agenda, that this

 

      meeting is not intended to discuss any specific

 

      drug products, approved or in development.

 

      Furthermore, in a manner distinct from a meeting of

 

      that type, we will not ask the committee and guests

 

      to vote per se on the questions we will pose.

 

      These are intended to raise the issues that we wish

 

      to hear discussed.  We, the FDA staff, will listen

 

      and contribute as we see fit and, of course,

 

      respond to questions directed at us as we are able.

 

      We intend to take the information we have gleaned

 

      today back for consideration in drafting possible

 

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      revisions to our guidance for industry.

 

                It is important for those participating

 

      and listening today to understand that by this

 

      meeting we make no formal commitment to changes in

 

      the guidance.  We view this as an information

 

      gathering step in a process that may lead to

 

      changes.  I know you all have the agenda and I will

 

      not review it.  I have already announced the

 

      potential changes.

 

                Finally, before we start, I would like to

 

      thank Dr. Lynne Levitsky, valued advisor

 

      particularly on pediatric matters whose term has

 

      recently expired, for service to us over the last

 

      term.  She is here today formally speaking as a

 

      consultant.  By her agreement to stay on in that

 

      capacity, we hope to continue to engage her in the

 

      future and look forward to her additional input

 

      into the work of the division and the agency.

 

                Finally, special recognition goes to Dr.

 

      Glenn Braunstein who has kindly agreed to serve as

 

      the chair of today's meeting.  Dr. Braunstein's

 

      second term as a member expired in June, and having

 

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      him here today is particularly fitting given that

 

      he chaired the 1995 meeting that led to the

 

      drafting of the '96 guidance under discussion.

 

      Glenn's association with the committee and the

 

      division dates to late 1991, including two stints

 

      as an extremely effective chair.  We thank him once

 

      again for his invaluable service.  Indeed, we are

 

      not releasing him.  He too has agreed to remain a

 

      consultant.  Glenn, thank you for your generosity

 

      with your precious time and for your contributions

 

      over many years to this committee, to the division

 

      and to the work of the agency.  With that, I will

 

      turn it over to you.

 

                DR. BRAUNSTEIN:  Thank you, David.  I

 

      appreciate that.  The first speaker this morning as

 

      far as presentations are concerned is Dr. Eric

 

      Colman, who is medical team leader, and he is going

 

      to speak about the regulatory history of weight

 

      loss drugs.

 

              The Regulatory History of Weight-Loss Drugs

 

                DR. COLMAN:  What I plan to do for the

 

      next 20 minutes or so is to give you an overview of

 

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      the FDA regulation of obesity drugs from roughly

 

      the years 1938 through 1999.  Before I get to that,

 

      I did want to mention two milestones in the history

 

      of drug regulatory.

 

                These were, first, the signature in 1906

 

      of the original Food and Drugs Act and that was

 

      signed by President Teddy Roosevelt.  Roughly

 

      30-plus years later another Roosevelt, Franklin,

 

      signed the Food, Drug and Cosmetic Act of 1938.

 

      This Act has quite an influence on drug regulation.

 

      It affected the labeling provisions, the

 

      advertising provisions for drugs, and it was also

 

      the first time that drug companies had to submit

 

      evidence of a drug's safety before it was allowed

 

      to go onto the market.  It also marked the

 

      beginning of the new drug application, or NDA,

 

      process that we have all come to appreciate over

 

      the years.

 

                Getting started with the obesity drugs, in

 

      1938 Myerson and colleagues reported the paper in

 

      The New England Journal of Medicine, "Benzedrine

 

      sulfate as an aid in the treatment of obesity." 

 

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      These two colleagues treated roughly 17 obese

 

      patients with 30 mg of amphetamine sulfate, which

 

      is what Benzedrine is.  They reported that the

 

      patients lost anywhere from 9-54 lbs.  This was

 

      just one of a number of studies that started to

 

      appear in the medical literature that suggested

 

      that amphetamines may be an effective way to treat

 

      obesity.

 

                The following year, in 1939, the agency

 

      approved Benzedrine for a host of different

 

      indications, however, obesity was not one of them.

 

      Several years later the agency approved another

 

      amphetamine.  This one was desoxyephedrine.  Again,

 

      there was a list of indications--narcolepsy, mild

 

      depression, alcoholism, even hay fever at one

 

      point, but again obesity was not in the list.

 

                Now, it took four more years before the

 

      agency finally felt comfortable and granted an

 

      obesity indication for desoxyephedrine.  To the

 

      best of my knowledge, this was the first drug that

 

      the agency approved for the treatment of obesity.

 

                I have shown you here some of the language

 

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      from the labeling at that time to give you a flavor

 

      of what people were thinking.  For this drug the

 

      labeling stated that the sympathomimetic amines

 

      have been found of value, when administered under

 

      the supervision of a physician, as an adjunct to

 

      the dietary management of obesity.  That was the

 

      indication section.

 

                The labeling also warned, however, against

 

      its use in persons with cardiovascular disease,

 

      hypertension or insomnia, and in those who were

 

      neurotic or hyperexcitable.  So, clearly, there was

 

      an awareness that these drugs were stimulatory to

 

      the central nervous system, to the cardiovascular

 

      system.

 

                On this last point regarding the

 

      amphetamines I want to just highlight--this is just

 

      to remind you that I will be talking a lot about

 

      amphetamines and I will be talking about

 

      amphetamine-like drugs in a moment.  But when I

 

      refer to the amphetamines I am including a large

 

      number of compounds which include amphetamine

 

      sulfate, desoxyephedrine, also referred to as

 

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      methamphetamine, dextroamphetamine and a number of

 

      amphetamine-barbiturate combinations.

 

                Soon after the amphetamines were approved

 

      in the '40s and early '50s companies began to work

 

      to try to develop compounds that, on the one hand,

 

      maintained the anorectic properties of the

 

      amphetamines but had less of the stimulatory

 

      properties.  They were successful to varying

 

      degrees.

 

                By 1960 the agency had approved five new

 

      what I refer to as amphetamine-like drugs.  These

 

      are also referred to as the amphetamine cogeners.

 

      These drugs were phenmetrazine, phendimetrazine,

 

      phentermine, benzphetamine and diethylpropion.

 

                Again to give you a sense of what people

 

      were thinking during this time, I have shown you

 

      some of the language from the labeling for

 

      diethylpropion.  This drug was indicated for any

 

      obese patient, including the adolescent, the

 

      geriatric and the gravid, as well as the special

 

      high-risk situations of the cardiac, hypertensive

 

      and diabetic patient.   That is probably an

 

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      indication section that most drug companies would

 

      die for at this point.

 

                The labeling also stated that because

 

      tolerance, habituation or addiction did not

 

      develop, this drug was ideal for long-term use.

 

      Again, it is interesting to look at the labeling

 

      language from back in the late '50s.

 

                Against the backdrop of the approval of

 

      the amphetamines and amphetamine-like drugs, there

 

      was a problem growing in this country and some

 

      people were referring to it as an epidemic.  That

 

      was an epidemic of the abuse of amphetamines.

 

                I have shown three figures here to give

 

      you a sense of the amount of use of these

 

      compounds.  In 1958 there were approximately 3.5

 

      billion tablets of amphetamines manufactured

 

      legally in this country.  Approximately a decade

 

      later that had more than doubled to 8 billion

 

      tablets.  Expressed another way, in 1967 there were

 

      approximately 23 million prescriptions for

 

      amphetamines, 80 percent were for women and of all

 

      the indications, these drugs were most commonly

 

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      prescribed for obesity.

 

                The government tried to intervene to slow

 

      or stop the spread of this abuse by passing two

 

      laws, one was the Drug Abuse Control Amendments, in

 

      1965.  The second was the Controlled Substances Act

 

      of 1970.  This is when the scheduling of drugs was

 

      introduced.

 

                Moving from 1970 back to the early '60s,

 

      in 1962 there was a very important addition made to

 

      the '38 Food, Drug and Cosmetic Act.  These were

 

      the Kefauver-Harris Amendments, also known as the

 

      Drug Efficacy Amendments.  This legislation for the

 

      first time mandated that new drug applications

 

      contain substantial evidence of a dug's

 

      effectiveness.

 

                You recall, I mentioned that in '38 the

 

      law said you had to have evidence of safety.  This

 

      law now said you had to have evidence of efficacy.

 

      So the loop had now been closed.  And, this

 

      effectiveness was to come from adequate and

 

      well-controlled investigations.

 

                This raised a problem however.  This

 

                                                                21

 

      legislation took care of drugs approved in '62

 

      forward but there were literally thousands of drugs

 

      that were approved between '38 and '62.  The

 

      question came up what do we do about the efficacy

 

      assessment of these drugs approved before 1962?

 

      The answer came when the Commissioner called upon

 

      the National Research Council of the National

 

      Academy of Sciences to take this task on.  This

 

      endeavor became known as the Drug Efficacy Study

 

      Implementation, or the DESI review process.

 

                The formal portion of the Drug Efficacy

 

      Study was conducted between 1966 and 1969.  There

 

      were a host of different drug panels, depending on

 

      expertise, and it was the psychiatric drug panel

 

      that was charged with reviewing the available data

 

      on the efficacy of the amphetamines and

 

      amphetamine-like drugs.  They were told after they

 

      completed their analyses of the available data that

 

      they should classify the efficacy using one of

 

      these five descriptors, starting at the top with

 

      effective; effective but; probably effective;

 

      possibly effective; or ineffective.

 

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                They completed their analyses in 1969 and

 

      sent the results outcome the FDA Commissioner, and

 

      this is what they concluded.  They felt the

 

      efficacy data supported a statement saying that the

 

      amphetamines were possibly effective for the

 

      treatment of obesity.

 

                Regarding the amphetamine-like drugs, a

 

      little bit better--they thought that this was

 

      effective but... so, again, one step below

 

      effective.  The reasons they cited for not

 

      classifying these compounds as effective were the

 

      following:  Many of the studies that they looked at

 

      were of short duration.  There was no evidence

 

      available that the drugs altered the natural

 

      history of obesity.  There was some evidence that

 

      the anorectic effects may have been strongly

 

      influenced by the suggestibility of the patient.

 

      And, there were concerns about the adequacy of the

 

      controls in some of the clinical studies.

 

                What were the regulatory consequences of

 

      DESI review of the obesity drugs?  In 1970 the FDA

 

      concluded that the amphetamines were, indeed,

 

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      possibly effective in the treatment of obesity, and

 

      basically mimicked what the DESI review panel

 

      recommended.  However, because this was short of

 

      the category of effective, the FDA directed

 

      industry to submit evidence of weight-loss efficacy

 

      from adequate and well-controlled trials and,

 

      ideally, of more than a few weeks duration.  I

 

      would point out here that at this time the FDA made

 

      no comment about the efficacy of the

 

      amphetamine-like drugs.  That wouldn't come for a

 

      few more years.

 

                After the DESI review process was finished

 

      in '69, in the early 1970s the Division of

 

      Neuropharmacology Drug Products at the agency--that

 

      was a division that had the regulatory purview of

 

      these agents--clearly felt the need to develop a

 

      policy whereby they could develop and regulate

 

      obesity drugs.  So, flowing from the DESI review

 

      process, three important actions occurred in the

 

      early '70s.  These were the Prout Consultant Group,

 

      the Neuropharmacology Drugs Advisory Committee, and

 

      the conduct of the Amphetamine-Anorectic Drug

 

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      Project.  Let me go through each one of those

 

      briefly.

 

                The Prout Consultant Group was put

 

      together by folks in the Neuropharmacology Drug

 

      Division at the FDA.  It consisted of eight

 

      external consultants and was headed by a physician

 

      named Thaddeus Prout who was an endocrinologist

 

      from Johns Hopkins.  This group of eight

 

      individuals met in April of 1071 to discuss

 

      specific issues related to obesity drugs and

 

      regulation and development of these compounds.

 

                They issued these four statements back to

 

      the Neuropharmacology Division:  They felt that, in

 

      fact, weight-loss drugs did have some potential

 

      value.  They felt that the efficacy trials for

 

      these drugs should be at least 12 weeks in

 

      duration; that the long-term follow-up of patients

 

      was not the responsibility of drug companies; and

 

      that the efficacy of the weight-loss drugs should

 

      be defined as statistical superiority of drug to

 

      placebo.  This is an interesting point.  This group

 

      was specifically asked to define clinically

 

                                                                25

 

      significant weight loss.  Either they could not do

 

      it or they did not want to do it but, in any event,

 

      they said you should consider this as efficacy.  In

 

      other words, if the weight loss on a drug is more

 

      than the weight on the placebo and the difference

 

      is statistically significant, then you have a drug

 

      that works .

 

                About five months after the Prout Group

 

      met and made their recommendations, the

 

      Neuropharmacology Drug Division convened its own

 

      advisory committee, in September of '71, and again

 

      they wanted to get input about how to develop and

 

      regulate the obesity drugs.  They were also asked

 

      to provide a definition of clinically significant

 

      weight loss.  They did not venture an answer.

 

      Instead, they referred back to Prout's

 

      recommendation that efficacy be defined as

 

      statistical superiority of drug to placebo.  This

 

      was another group that could not define clinically

 

      significant weight loss.

 

                So, after two groups deliberated on this

 

      the agency still had no working definition of

 

                                                                26

 

      clinically significant weight loss.  The

 

      Amphetamine-Anorectic Drug Project somewhat

 

      approached this problem in a backward direction.

 

      This was a meta-analysis conducted by members of

 

      the Neuropharmacology Drug Division, along with

 

      agency statisticians.  The overall goal was to try

 

      to, once and for all, quantitate the efficacy of

 

      the amphetamine and the amphetamine-like drugs.  At

 

      this point there were data available for

 

      fenfluramine and sanorex.

 

                This meta-analysis was quite large.  It

 

      included 200 clinical studies.  These studies

 

      ranged in duration from one month to six months.  I

 

      would say that the average study was six to 8 weeks

 

      in duration.  There were about 10,000 patients

 

      involved in the whole analysis.  At the end of the

 

      day, when they got done analyzing these data, they

 

      issued two conclusions.  The first one doesn't

 

      sound very impressive but this is what they said:

 

      Patients treated with active medication did, in

 

      fact, lose some fraction of a pound a week more

 

      than those on placebo.  The second conclusion was

 

                                                                27

 

      that the data did not suggest that one drug was

 

      superior to another, nor that the amphetamines as a

 

      class were more effective than the amphetamine-like

 

      drugs.  This would have major implications, as we

 

      will see in a few minutes.

 

                What were the consequences of this

 

      meta-analysis?  In 1973 the agency officially

 

      declared that the amphetamines and the

 

      amphetamine-like drugs were effective for the

 

      treatment of obesity.  You will recall that in 1970

 

      they said amphetamines were possibly effective and

 

      they didn't say anything about the amphetamine-like

 

      drugs.  So, from doing this meta-analysis, they

 

      felt comfortable in declaring that these two sets

 

      of compounds were both effective for the treatment

 

      of obesity.

 

                The second thing that came out of this

 

      project was class labeling.  I mentioned the abuse

 

      problem, the speed epidemic that had continued

 

      through the '60s and into the '70s.  So, the abuse

 

      of the amphetamines was still very much on the

 

      minds of the senior leadership at the FDA.  So,

 

                                                                28

 

      people started to reason, well, if you limit the

 

      use of these drugs just for a few weeks you can't

 

      get abuse.  So, if we limit their use to only a few

 

      weeks we take care of the abuse problem and that

 

      way we tidy up the risk/benefit profile for these

 

      drugs.  So, they made a blanket case and not only

 

      were the amphetamines indicated for short term and

 

      a few weeks actually shows up in the label.  People

 

      have often referred to this as a few months but the

 

      label actually says a few weeks.

 

                Instead of just limiting it to the

 

      amphetamines, they threw it over to the

 

      amphetamine-like-like drugs as well so at this

 

      point all these drugs became indicated only for

 

      short-term use, a few weeks use, and I would submit

 

      that was largely driven by concerns about abuse,

 

      street abuse.

 

                The next notable event in this history

 

      came in 1979 when the agency announced its plans to

 

      remove the obesity indication from the

 

      amphetamines.  They still hadn't had enough; they

 

      wanted more.  They felt that they had good reason

 

                                                                29

 

      to propose this removal.  One of the things that

 

      backed them up, they believed, is that there was

 

      continued evidence of abuse of amphetamines.  They

 

      knew it was largely coming from this database

 

      referred to as DAWN, which stands for the Drug

 

      Abuse Warning Network.

 

                The other point has to do with, as I just

 

      mentioned, the risk/benefit profile of the

 

      amphetamines relative to the amphetamine-like

 

      drugs.  The FDA had clearly said that they don't

 

      think the efficacy is any different for the

 

      amphetamines than the amphetamine-like drugs but we

 

      do believe that the abuse potential was more of a

 

      problem for the amphetamines than the

 

      amphetamine-like drugs.  Therefore, amphetamines

 

      have a less favorable risk/benefit profile versus

 

      the amphetamine-like drugs.  If you took the

 

      obesity indication away from the amphetamines

 

      people in this country would not suffer at all;

 

      they had have the amphetamine-like drugs that

 

      worked just as well.

 

                The industry had a chance to respond to

 

                                                                30

 

      this proposal and they did so.  I have listed four

 

      of their rebuttals here.  For one thing, industry

 

      felt that the FDA analyses of the DAWN data were

 

      incorrect.  They just didn't believe that there was

 

      evidence of continued abuse.

 

                Secondly, they argued that if illicit

 

      production and use of the amphetamines was a real

 

      problem, that was the purview of the state medical

 

      boards and the Department of Justice; it wasn't

 

      something the FDA should get involved in.

 

                Thirdly, they said, wait a minute, abuse

 

      requires use beyond a few weeks and our drugs are

 

      only approved for a few weeks.  So, if this is a

 

      problem we are talking about off-label drug use

 

      and, once again, that is not something the FDA gets

 

      involved in.

 

                Finally, the risk/benefit issue--they felt

 

      that the risk/benefit equation should be made on

 

      its own merits, in other words, relative to

 

      placebo.  In this case, the agency was saying that

 

      the risk/benefit profile of the amphetamines was

 

      less favorable than the risk/benefit profile for

 

                                                                31

 

      the amphetamine-like drugs.  According to industry,

 

      they didn't think that was a legitimate or legal or

 

      regulatorily tenable reason to take away the

 

      indication.

 

                I have to say that after all this

 

      bickering the industry won out because this planned

 

      action never took place.  The agency never removed

 

      the obesity indication from the amphetamines and,

 

      to this day, I know of one amphetamine that still

 

      has in its label its use for short-term treatment

 

      of obesity.

 

                We now enter the 1980s, and I think the

 

      1980s in terms of obesity drug development really

 

      should focus on one particular happening, and that

 

      was the start of the phen-fen studies.  In the

 

      early 1980s, a clinical pharmacologist from the

 

      University of Rochester reasoned that the stimulant

 

      effects of phentermine would counter the sedative

 

      effects of fenfluramine such that the two together

 

      would provide a very tolerable combination that

 

      could be used over long-term use.  So, he and his

 

      colleagues started these studies in the '80s.

 

                                                                32

 

                In 1992 they published a number of papers

 

      citing the main results of these trials.  They

 

      concluded that yes, indeed, the combination was

 

      tolerable and that people could take these drugs

 

      over the course of years, and that it was safe and

 

      effective.

 

                Again, these were published in 1992.  They

 

      had a major impact on subsequent use of these

 

      drugs, as I have shown here, in this table.  These

 

      are the estimated total number of prescriptions for

 

      phentermine in 1992, 2 million.  For fenfluarmine

 

      there were about 70,000 prescriptions in

 

      1992--again, the year the papers were published.

 

      Four years later these numbers had gone from 2

 

      million to 11 million and from 69,000 to 7 million.

 

      I am not saying all of this was due to these papers

 

      but a large part of it was.

 

                There was another event that happened

 

      around 1992, and that was the transfer of the

 

      regulatory responsibility of the obesity drugs from

 

      neuropharmacology to the Division of Metabolic and

 

      Endocrine Drugs, where they are now.  When the new

 

                                                                33

 

      drugs arrived in the new division there was fairly

 

      strong feeling that effective drug treatment

 

      required long-term or indefinite treatment.

 

      Therefore, why don't we have long-term pre-approval

 

      trials?  There were other thoughts within the

 

      division.  There was a strong sense that we need to

 

      get this formulated into a guidance policy.  They

 

      convened their advisory committee in a two-day

 

      meeting in 1995 to discuss how to develop and

 

      regulate obesity drugs, with an eye to issuing an

 

      obesity guidance document.

 

                They had a successful meeting.  The

 

      obesity draft guidance was issue in 1996.  I just

 

      show you two of the more important components of

 

      that guidance document, and these will be issues

 

      that we will be discussing later today.

 

                In terms of efficacy, a 5 percent

 

      benchmark was chosen.  At that time, people could

 

      point to the fact that if people lose as little as

 

      5 percent of weight they could get improvements in

 

      lipids, blood pressure and cholesterol and,

 

      therefore, this was a clinically significant weight

 

                                                                34

 

      loss.  So, now we finally have a definition for

 

      clinically significant weight loss.

 

                On the other side, in terms of the size

 

      and duration of phase 3 trials, I think most people

 

      felt comfortable that we had agreed that one year

 

      of a placebo-controlled trial would be an adequate

 

      exposure to assess efficacy and some degree of

 

      safety.  A lot of people felt though that of these

 

      1500 patients who made it out to a year, 200-500

 

      should be rolled over into an open-label exposure

 

      for a following year, again, to get another sense

 

      of safety.  We will be talking about these issues

 

      as well later today.

 

                Just briefly, long-term treatment of

 

      obesity, from FDA's perspective, came about when

 

      dexfenfluramine was approved in 1996.  We all know

 

      it was removed from the market the following year

 

      because of valvulopathy.  A couple of months after

 

      the removal, sibutramine, or Meridia, was approved.

 

      I have shown you here the actual labeling for the

 

      indication.  Meridia is indicated for weight loss

 

      and weight maintenance.  Xenical, the most recently

 

                                                                35

 

      approved drug, in 1999, has the same indications,

 

      weight loss and weight maintenance, but it also has

 

      an additional indication and that is to reduce the

 

      risk for weight regain after prior weight loss.

 

      These are issues that we hope committee members

 

      will engage in a dialogue later this afternoon in

 

      terms of what these terms mean; how they should be

 

      defined, etc.

 

                So, if I could provide you with a global

 

      summary, I think it is safe to say that defining or

 

      quantitating the efficacy of weight-loss drugs has

 

      been problematic.  It certainly has been a

 

      challenge from a regulatory perspective.  It wasn't

 

      until the mid-1990s that we had a workable

 

      definition of clinically significant weight loss,

 

      and that is the 5 percent benchmark.  We still

 

      don't have a definition of clinically significant

 

      drug-induced weight loss--that is a different

 

      issue.

 

                On the other side of the coin, I also

 

      think it is safe to say that the regulatory history

 

      of the obesity drugs has seen its share of highly

 

                                                                36

 

      publicized safety problems.  Beginning with the

 

      abuse of the amphetamines in the '40s, '50s, '60s

 

      and beyond, primary hypertension became an issue

 

      with a drug called aminorex that was used in Europe

 

      in the '60s.  It was never in this country.

 

                But this condition was subsequently linked

 

      to fenfluramine and it was a major issue at the

 

      time that dexfenfluramine was approved.  It was

 

      well-known that this drug increased the risk of BPH

 

      in people who took dexfenfluramine.  That was

 

      before dexfenfluramine was approved.  These

 

      concerns were only later overshadowed by the

 

      cardiac valvulopathy that showed up a year after

 

      their approval.  These were all very, very highly

 

      publicized events, basically so many in the

 

      population were exposed to these drugs.

 

                Finally, the approval of Meridia or

 

      sibutramine, back in '97, was accompanied by very

 

      strong warnings, precautions and concerns regarding

 

      the effect of that drug on blood pressure and

 

      pulse.

 

                Let me close.  Since the topic of today's

 

                                                                37

 

      discussion is the obesity guidance document, I

 

      thought I would just provide a visual reminder of

 

      the goals of not only this guidance document but I

 

      think of all guidance documents, and that is

 

      obviously, on the one hand, to facilitate

 

      industry's development of safe and effective drugs

 

      but, just as importantly, to provide regulators

 

      with the best available evidence upon which to

 

      judge a new drug's risk/benefit profile before the

 

      drug is approved.  Obviously, those two things

 

      require a certain amount of compromise and juggling

 

      but I will leave you today with that thought.  Keep

 

      that in the back of your mind as we deliberate the

 

      various proposals to change the guidance document.

 

      Thank you.

 

                DR. BRAUNSTEIN:  Thank you, Dr. Colman.

 

      Are there any questions from the panel for Dr.

 

      Colman?

 

                [No response]

 

                Thank you.  We will move on then to Dr.

 

      Katherine Flegal's discussion of the epidemiology

 

      of overweight and obesity.

 

                                                                38

 

               The Epidemiology of Overweight and Obesity

 

                DR. FLEGAL:  This is the outline.  I am

 

      going to give a very brief overview of trends in

 

      obesity and overweight in the United State,; a

 

      history of regulation of weight-loss drugs, a brief

 

      history of definitions of overweight; some

 

      population estimates; prevalence of overweight

 

      categories and comorbidities; and kind of a brief

 

      discussion of some of the aspects of possible

 

      benefits and risks of weight change in mildly

 

      overweight people with comorbid conditions.

 

                Most of the data I am going to present

 

      today come from the series of National Health and

 

      Nutrition examination surveys in the U.S., NHANES.

 

      Many of you are familiar with this but I know some

 

      of you aren't.  These are a series of

 

      cross-sectional national representative surveys,

 

      conducted by CDC's National Center for Health

 

      Statistics, in which weight and height are measured

 

      and many other actual measurements are taken.  We

 

      have a series of these dating back to the 1960s up

 

      until today.  So, we have a little over 40 years of

 

                                                                39

 

      data on the U.S. population from these surveys.

 

      The most recent one began in 1999 and is

 

      continuous, representing some data from 1999 up to

 

      2002 in that survey.

 

                This slide shows the age-adjusted trends

 

      in obesity, defined as a body mass index of 30 or

 

      above in the United States.  Starting back in 1960,

 

      the prevalence was only about 10 percent for men

 

      and today it has gone up to almost 30 percent.  As

 

      you see, the prevalence was really fairly constant

 

      from 1960.  In '71 to '74 and '76 to '80 there were

 

      not large changes for either men or women.  In the

 

      '89 to '94 survey the prevalence went up sharply

 

      and somewhat unexpectedly, and in the most recent

 

      survey it has gone up again so we see this

 

      continuing trend.

 

                This is the same setup.  This is for

 

      overweight defined as a body mass index of 25 or

 

      above so it includes the obesity data I just showed

 

      you.  Again, the prevalence was relatively stable

 

      over the first three surveys and then increased.

 

      One thing to note is that the prevalence of

 

                                                                40

 

      overweight with these definitions has been pretty

 

      high since 1960.  Almost 50 percent of men and 40

 

      percent of women were overweight in 1960 according

 

      to this definition.

 

                As you have just seen, the definitions of

 

      overweight and obesity that I am using are based on

 

      body mass index which is calculated as weight in

 

      kilograms divided by height in meters squared.

 

      There are two definitions of overweight in this

 

      system.  One is a body mass index of 25 up to 29.9

 

      or a body mass index of 25 or above.  Obesity is

 

      then defined as a body mass index of 30 or above

 

      and a healthy weight as a BMI of 18.5 but less than

 

      25.

 

                These definitions have been a long time

 

      getting systematized and standardized.  This is a

 

      very brief overview, but basically definitions of

 

      overweight up to the early '80s really were not

 

      systematized and there were very wide international

 

      variations.  In the United States there was a lot

 

      of use of weight-height tables like the insurance

 

      company tables that you have probably seen.  There

 

                                                                41

 

      is a whole set of issues of skinfolds measurements,

 

      different kinds of prediction equations; a lot of

 

      different kinds of weight-height indices.  There is

 

      the Broca index, ponderal index.  You can see these

 

      used in different literature and they are used in

 

      different metric systems as well so you never knew

 

      whether it would be kilograms and meters or

 

      centimeters or pounds and inches.  So, if you look

 

      at the literature back in the '70s, say, and before

 

      it is very difficult to make any comparisons.

 

      There are a lot of different definitions that were

 

      being used and there were a lot of differences

 

      between countries as well.

 

                I think during the 1980s epidemiologic

 

      consensus began to form around body mass index,

 

      which is also called Quetelet index after the great

 

      Belgian statistician in the 19th century.  So, you

 

      can see that this index has been around for a long

 

      time and has been used somewhat, but it began to be

 

      really more the index of choice.  An NIH consensus

 

      conference in 1985 recommended the use of body mass

 

      index.  But at that point the cut-off values still

 

                                                                42

 

      were somewhat varied.

 

                The 1959 Metropolitan Life tables in the

 

      U.S. had a range of desirable weights for a given

 

      height.  There was a practice that had grown up of

 

      taking the midpoint of that range as kind of the

 

      ideal weight and then saying if you are at or about

 

      120 percent of that midpoint, then that was the

 

      beginning of the definition of overweight of the

 

      median frame weight range.

 

                At the NIH consensus conference, in '85,

 

      there was data presented from NHANES, as I have

 

      already shown you, about the 85th percentile values

 

      for men and women age 20 to 29.  Those were a value

 

      of 27.8 for men, 27.3 for women.  The consensus

 

      conference decided to adopt those as some kind of

 

      definition of overweight because they actually

 

      correspond pretty closely to the Met Life, to the

 

      120 percent definition based on Met Life.  We, in

 

      fact, used these values as recently as 10 years

 

      ago.  We would have been publishing data using

 

      those particular cut-off points.

 

                Meanwhile, BMI cut-points of 25 and 30

 

                                                                43

 

      began to be recommended by expert committees.

 

      These were not suggested originally by these expert

 

      committees.  I think the earliest suggestions I am

 

      aware of were by George Bray and George Garrow,

 

      back around 1980 probably or perhaps before.  But

 

      these were thought to be more systematized.  There

 

      was a 1995 report from an expert committee of the

 

      World Health Organization that suggested these

 

      cut-off points.  That was followed in 1998 by the

 

      Clinical Guidelines on the Identification,

 

      Evaluation and Treatment of Overweight and Obesity

 

      in Adults that NHLBI put out, which is really more

 

      or less the basis for our current use of these

 

      values.

 

                Why these values?  Here is what it says in

 

      the 1995 expert committee report that they proposed

 

      a classification with cut-off points of 25, 30 and

 

      40.  This is based principally on the association

 

      between BMI and mortality.

 

                They go on to say the method used to

 

      establish these kind of points has been largely

 

      arbitrary.  In essence, it has been based on visual

 

                                                                44

 

      inspection of the relationship between BMI and

 

      mortality: the cut-off of 30 is based on the point

 

      of flexion of the curve.

 

                So, in this report and in others there is

 

      not a careful study of the criteria for using

 

      exactly 25 or 30 as opposed to, say, using 30.5 or

 

      27.8.  These are kind of general and, as I say,

 

      largely arbitrary.  Here is kind of a typical

 

      relation between mortality and BMI curve that would

 

      have been available to that committee.  This is

 

      from the American Cancer Society studies.

 

                You see a couple of things here.  First of

 

      all, the point of lowest mortality tends to hover

 

      around a BMI of 25.  You see this curvolinear,

 

      somewhat U-shaped relationship with much higher

 

      risk out here.  Also, body mass index is not a

 

      physiologic measure; it is just an index and you

 

      can kind of intuit that the choice of cut points of

 

      20,  25, 30, 35 and 40 are because these are round

 

      numbers and they vary by 5.  These are not really

 

      physiologically based cut points.  So, these are

 

      approximations.  They are very useful

 

                                                                45

 

      approximations, by the way.  We are very glad to

 

      have internationally standardized definitions that

 

      we can all use.  Now you can compare one person's

 

      data with another person's data so these are quite

 

      valuable to have.

 

                The 1998 NHLBI clinical guidelines also

 

      offer the same definitions.  Here overweight is 25

 

      to 29.9 and they say the rationale was based on

 

      epidemiological data that show increases in

 

      mortality with BMIs above 25.  This increase tends

 

      to be modest until a BMI of 30 is reached.  So, you

 

      see that this language also is somewhat imprecise.

 

                I think this is on the following page.

 

      They describe quite a few studies.  Very often the

 

      point of minimum mortality is around a BMI of 25.

 

      This is a study of NHANES I where they show the

 

      lowest mortality in the range of 25-30, and they

 

      found, by race and sex, the lowest mortality at

 

      24.5 for white men, 26.5 for white women, and even

 

      higher values for black men and women.  There is

 

      other information presented in the same NHLBI

 

      report which also has somewhat similar analyses.

 

                                                                46

 

                So, definitions of overweight have changed

 

      quite a bit over time.  We have pretty much settled

 

      down now to using these standard definitions but

 

      that is a little bit of the history.

 

                Getting back to definitions, overweight is

 

      a BMI of 25-29.9.  These are slides like the ones I

 

      showed you but now these are really just that

 

      range.  There are two things you can see from this.

 

      One is that the prevalence of overweight by these

 

      definitions has really changed very little over

 

      time.  It is almost constant.  Another thing you

 

      can see is that the prevalence of overweight by

 

      these definitions is quite a bit higher in men than

 

      it is in women, which is less true of the

 

      prevalence of obesity.  It is about 38-40 percent

 

      for men and about 25 percent for women.

 

                Just looking at the numbers of people, and

 

      I am going to try to divide this by separate

 

      categories.  One is BMI to under 27 and 27 up to 30

 

      because that is one of the cut points used in the

 

      current guidance document.  This is just to show

 

      you the number of people in the U.S. population who

 

                                                                47

 

      fall into these various categories.  I also

 

      included the next lowest category as kind of a

 

      comparison point.  In this lowest category of 23 to

 

      less than 25 the numbers of men and women are

 

      approximately equal, about 14 million in each.  In

 

      the range of 25 to under 27 there are a few more

 

      men than women.  There are about 16 million men and

 

      12 million women.  As you go up to the range of 27

 

      to 30 there are more people in this category, which

 

      is actually a broader category, of course, also.

 

      There are 21 million men and about 17 million

 

      women.

 

                Looking at that by age as well, I have

 

      divided this into 4 age groups, 29-29, 40-59, 60-79

 

      and 80 and above.  You can see that for a BMI of 25

 

      to 27, men and women both in that BMI range are in

 

      the age groups 20 up to 59.  When you get to the

 

      60-79 year-old age range there are fewer people but

 

      you see that in the younger ranges there are more

 

      men than women in these categories.  When you get

 

      up to this age range there are actually almost

 

      equal numbers of men and women in the older ages. 

 

                                                                48

 

      The same is true for the next category of a BMI of

 

      27-30.  So, there is a definite age pattern with

 

      these numbers.

 

                Now I am going to talk about

 

      comorbidities.  There are five listed plus "other"

 

      in the guidance document: hypertension,

 

      hyperlipidemia, glucose intolerance, cardiovascular

 

      disease, sleep apnea and other obesity-related

 

      conditions.  I don't really have good data to show

 

      you on cardiovascular disease or on sleep apnea or

 

      the other conditions so I am just going to talk

 

      about these three from what we have, hypertension,

 

      high cholesterol and glucose intolerance.

 

                One thing I was asked to do is to consider

 

      the question of the point of inflection of the

 

      curve of the relationship of these comorbidities to

 

      BMI.  So, I have presented the data this way and I

 

      have a whole series of slides, all laid out the

 

      same way.

 

                The yellow line is men--this is for men,

 

      20-39; the green line, 40-59; the pink line, 60-79;

 

      and then 80 and above.  This shows the body mass

 

                                                                49

 

      index categories along this axis and the

 

      prevalence.  There are a couple of things you can

 

      see from this.  First of all, you don't see a very

 

      clear point of inflection, for example, between

 

      23-25, 25-27.  Here you see a little increase but

 

      in this case it was a decrease here and an increase

 

      there so these bounce around somewhat.  So, you see

 

      a gradual increase in the prevalence of these

 

      conditions with the BMI level in all age groups.

 

      You don't visually see an obvious point of

 

      inflection.

 

                The other thing to notice is that although

 

      we talk about these as obesity-related

 

      comorbidities, this shows you pretty clearly that

 

      they are also age-related comorbidities and, in

 

      fact, the prevalence of any of these conditions in

 

      people with a BMI of 30 who are young is far, far

 

      lower than the prevalence even in people at the

 

      lowest BMI level who are older.  So, you need to

 

      keep that in mind.  Again, there are other risk

 

      factors for these conditions and age, in

 

      particular, is a very strong risk factor.

 

                                                                50

 

                This is the same picture now for women.

 

      Again, you see at the old age range a very high

 

      prevalence of hypertension at all BMI levels.  You

 

      see in most age groups a slight increase in the

 

      prevalence by BMI level and you don't see a strong

 

      inflection point.  By the way, I defined

 

      hypertension as a measure of blood pressure

 

      systolic  over 140 or diastolic over 90, or using

 

      medications for hypertension.

 

                This is for high cholesterol, which I

 

      defined for this purpose as total cholesterol of

 

      above 240 mg/dl or using medication.  Here you see

 

      a somewhat similar picture.  The prevalence is not

 

      as high even in the oldest age group and our data

 

      are somewhat sparse in the older age group.  It may

 

      be one of the reasons this curve is not estimated

 

      that well.  Again, you see some tendency for

 

      increase in cholesterol with BMI, also a tendency

 

      to increase with age--not a terribly clear

 

      inflection point.

 

                Here is the same information for women.

 

      Again, sort of the same comments would apply.

 

                                                                51

 

                Finally diabetes--this is just based on

 

      diagnosed diabetes and this is self-report of

 

      diagnosed diabetes so this is not based on

 

      measurements of glucose tolerance or looking at

 

      undiagnosed diabetes.  This is people who say that

 

      they have been told that they have diabetes.  I

 

      also excluded people who had age at onset below 30

 

      and have used insulin since diagnosis,

 

      approximately since diagnosis, to try to limit this

 

      proximally to type 2 diabetes.  Again you see the

 

      increase with BMI.  You see the age differential

 

      and you, again, don't really see a strong

 

      inflection point.  The same thing for women.

 

                This is just the prevalence of any

 

      comorbidity.  I should say any selected comorbidity

 

      because I am only looking at three.  This is by age

 

      and body mass index group for men.  This has

 

      somewhat smoothed out the lines because there are

 

      more comorbidities involved.  Again, there is this

 

      big age differential--you know, fairly smooth

 

      curves; they go up and down some but there is no

 

      obvious inflection point between 25-27 and 27-30 or

 

                                                                52

 

      23-25.

 

                This is the same diagram for women.

 

      Again, big age differences; increasing prevalence

 

      of comorbidity with BMI group; fairly smooth lines.

 

                So, how many millions of people are we

 

      talking about?  I will show you some other data but

 

      this is when people have 2 or more comorbidities by

 

      BMI categories.  For comparison purposes, I put a

 

      lot of BMI levels in here.  In this range, which is

 

      the range of interest for this purpose I think,

 

      there are roughly speaking about 4 million people

 

      in the U.S. who have a BMI at that level and have 2

 

      or more comorbidities.  That is in contrast to

 

      about 6 million in the 27-30 range who have 2 or

 

      more comorbidities.  So, there is a ratio here.

 

      This is about two-thirds of that.  I have left out

 

      some comorbidities so presumably these numbers

 

      could be higher so this is just selected

 

      comorbidities.

 

                For comparison, even at the next lower

 

      level there are almost 3 million people who would

 

      fall into that category, even the lowest BMI

 

                                                                53

 

      category.  So, these comorbidities, again, are not

 

      limited only to people in these overweight and

 

      obese ranges.  At the BMI level of 30-35 the

 

      numbers are really much higher.  Also, the numbers

 

      of men and women are pretty equal in these

 

      categories of interest in the overweight range.

 

                There is a difference by age again.  This

 

      shows the same slide but now it is just limited to

 

      people in the age range of 20-59.  Here there is

 

      about one and a half million people who fall into

 

      this category, which is BMI 25-27 and one or more

 

      comorbidities, and now the numbers of men and women

 

      are no longer equal.  There are about twice as many

 

      men as women in this younger category.

 

                This is for ages 60 and above.  Remember,

 

      the total here is a little under 4 million so

 

      almost 2.5 million of those people are in the age

 

      range of 60-70 and now we see that there are, not

 

      unexpectedly in this case, more women than men in

 

      this age range in this BMI category with

 

      comorbidities.  That is true along the whole

 

      spectrum of BMI levels.

 

                                                                54

 

                This is sort of changing the design here

 

      but this shows you the number of million of people

 

      with 1 or more, 2 or more or 3 comorbidities.  This

 

      is for BMI 25-27 so this is 1 or more, 2 or more or

 

      3, and this shows the total with the different

 

      components of the bar showing the age ranges.  So,

 

      what you can see is that, for example, is people

 

      with one or more comorbidity about equal numbers of

 

      people in the 40-59 and 60-70 age ranges and those

 

      make up the majority of people with a smaller

 

      contribution from people 20-39, even though many

 

      people in the population in this 20-39 age range

 

      don't fall into the comorbidity range.

 

                So, we see about 12 million total with one

 

      or more comorbidities as compared to 18 million in

 

      the higher BMI range.  When we get down to 2 or

 

      more comorbidities, which is the number I just

 

      showed you, this is approximately 4 million.  The

 

      largest group is going to be people in the 60-79

 

      age range and people above 60 make up the majority

 

      of this group, although not everybody in this

 

      group.  That is true also for BMI 27-29.  So, the

 

                                                                55

 

      age structure of these age groups is not the same

 

      as the age structure of the population.

 

                What about weight loss for people with BMI

 

      25-27?  I have tried to review the literature.  I

 

      have probably not reviewed everything, by a long

 

      shot.  As far as I can discern, there is not very

 

      much information about the benefits of weight loss

 

      in this particular BMI range.  Most studies of

 

      weight loss don't include that many people in this

 

      level.  Again, up to 10 years ago we would not have

 

      considered people in this range to be overweight so

 

      that might be one of the reasons why they were not

 

      really going to be included.  Some of them may

 

      actually explicitly exclude people when they study

 

      a BMI of 27 or a BMI or 28.

 

                That is also true of studies of the

 

      benefits of weight loss in the control of

 

      conditions such as hypertension or hyperlipidemia.

 

      They may explicitly exclude people who have BMIs as

 

      low, so to speak, as 25-27 or may include few, if

 

      any, participants.

 

                In kind of a mirror image, I also read an

 

                                                                56

 

      article which was complaining that drug trials for

 

      hypertension are conducted in people who are

 

      overweight but not obese so we know very little

 

      about it.  So, basically, trials of weight loss and

 

      hypertension are conducted in obese people and in

 

      trials of drug use and hypertension are studied in

 

      overweight people but not the converse.  So, we may

 

      have missing information on both sides of that.

 

                The NHLBI clinical guidelines

 

      recommendations for a BMI of 25-29 overweight

 

      recommend treatment only when patients have 2 or

 

      more risk factors or a high waist circumference.

 

      Other than that, weight maintenance is actually

 

      recommended.  So, the guidelines here for

 

      overweight treatment do not recommend treatment for

 

      everybody but just for people with other risk

 

      factors.  They also mention--I didn't put this on

 

      the slide--that treatment of the other risk factors

 

      is also just as important and should also be

 

      considered.

 

                You will see this statement on another

 

      slide, but there are a lot of studies that show

 

                                                                57

 

      that short-term weight loss has beneficial effects

 

      on risk factors such as high blood pressure and

 

      cholesterol.  That is really very well established.

 

      Most studies suggest that these are monotonic

 

      relations but there is no obvious threshold.  So,

 

      you would infer from this that weight loss is very

 

      likely to improve blood pressure and other risk

 

      factors, certainly in the range of BMI of 25-27 as

 

      well and perhaps at any weight level.  We don't

 

      really know but there is not that much evidence on

 

      the specific BMI range.  This is a fairly

 

      reasonable inference.

 

                How much benefit would that have?  What

 

      would be the net result?  That is very hard to

 

      judge in the literature.  This is one very

 

      approximate way of looking at it.  You have already

 

      seen these data but in a different format.  What is

 

      the prevalence of having 2 or more comorbidities by

 

      age group for BMI 23-25 versus 25-27?  If you think

 

      that weight loss in the BMI group 25-27 puts you

 

      into this next lower group, which is a very

 

      plausible assumption, roughly speaking what would

 

                                                                58

 

      the expected prevalence be?

 

                You can see that effect--this is an

 

      approximation again--by just comparing these 2 bars

 

      which show the prevalence in the 23-25 BMI group

 

      versus the prevalence in the 25-27 for different

 

      age groups.  In the youngest age group in which BMI

 

      is probably a stronger risk factor, relative risk

 

      for hypertension associated with BMI stronger are

 

      stronger in the youngest group, you see a pretty

 

      big potential difference of about half the number

 

      of people in this lower BMI group.  The number with

 

      2 or more comorbidities is about half.  So, that

 

      would suggest that you get a fairly noticeable

 

      prevalence effect by this kind of change in weight.

 

      At the older age ranges the prevalence is high.

 

                So, just looking at these data you would

 

      suspect that if you had people with a BMI of 25-27

 

      and they reduced their weight to 23-25 it is not

 

      likely that they are going to end up down here

 

      where the 20-39 year-olds are.  They are more

 

      likely to be approximately where people in their

 

      same age group are.  So, the prevalence of having 2

 

                                                                59

 

      or more comorbidities is likely to be high even

 

      after weight reduction.  So, while there is likely

 

      to be a beneficial effect, the net effect on

 

      prevalence may not be that great.

 

                Weight loss is just kind of part of the

 

      therapeutic armamentarium for treatment of various

 

      conditions.  There is a whole non-pharmacologic

 

      treatment or therapeutic lifestyle changes which

 

      include weight loss, physical activity and

 

      healthful eating habits, which may mean more fruits

 

      and vegetables, less sodium, less saturated fat, a

 

      whole different range of possible changes.  These

 

      are an important part of the treatment of diabetes

 

      and cardiovascular risk factors obviously.  Drug

 

      treatment is also often used in managing these

 

      conditions.

 

                So, you might ask what is the relative

 

      contribution of weight loss in this panoply of

 

      treatments.  As far as I can find out, that is not

 

      well established.  For example, what would be the

 

      probability that non-pharmacologic treatment alone

 

      versus drug treatment would have on management of

 

                                                                60

 

      hypertension?  There are review articles and

 

      summary data on this but they tend to start at a

 

      higher BMI level, at BMI of 27 or above or 28 or

 

      above.  So, it is somewhat difficult to assess.

 

                Also, for example, there is one paper by

 

      Ed Gregg using the national health interview survey

 

      data that suggests that the intention to lose

 

      weight is associated with improved mortality

 

      regardless of actual weight loss, and the intention

 

      to lose weight may be accompanied by some of these

 

      other changes, such as increased physical activity

 

      and changes in eating habits.  So, it is hard to

 

      judge and usually weight loss by itself is not the

 

      only part of it.  Therapeutic lifestyle changes

 

      include more, and clinical trials will also look at

 

      lifestyle changes.  So, they include more than

 

      weight change and try to assess where weight change

 

      itself falls in the pictures.  I couldn't find any

 

      data that really spoke very clearly to this issue.

 

                There are a couple of concerns.  This is

 

      from the Look Ahead Action for Health and Diabetes

 

      study, I guess.  This is from their website.  This

 

                                                                61

 

      is the sentence I already had on the other slide.

 

      Although we know that weight loss improves risk

 

      factors and clearly improves blood pressure and

 

      glucose tolerance, there are these observational

 

      studies that suggest some association of weight

 

      loss with increased rather than decreased

 

      mortality.

 

                These studies do not differentiate

 

      intentional from unintentional weight loss so they

 

      definitely have limitations but they can't be

 

      completely ignored either.  Because of this, there

 

      is actually a randomized clinical trial of

 

      intentional weight loss going on.  There are some

 

      questions we don't really have the answers to about

 

      this possibility of increased mortality with weight

 

      loss so that is one concern, looking at weight loss

 

      in this BMI range.

 

                Another possible concern is, again, that a

 

      lot of the people who are in this BMI range who

 

      have comorbid conditions are elderly and more of

 

      the elderly, not surprisingly, are women rather

 

      than men and there are, you know, some possible

 

                                                                62

 

      adverse effects of weight loss in this age range in

 

      the elderly and particularly perhaps for women.

 

      One of these is the possibility that weight loss as

 

      adverse effects on bone health and can result in

 

      lower bone density or greater risk of hip fracture.

 

                This is a report from the study of

 

      osteoporotic fractures where these women were close

 

      to this range and the median and they had an

 

      increased risk of hip fracture with weight loss.

 

      In fact, this study found also an increase in thin

 

      women as well, although the increase was not as

 

      great.  They did look at intentionality versus

 

      unintentionality or lack of intention to lose

 

      weight.  In this study, and this is not the only

 

      study on this topic but just something to kind of

 

      keep in mind as a possible issue, regardless of

 

      current weight or intention to lose weight there

 

      was an association of weight loss with hip bone

 

      loss and risk of hip fracture.  So, they concluded

 

      that even voluntary weight loss in overweight women

 

      increases hip fracture risk.

 

                Just to summarize, definitions of

 

                                                                63

 

      overweight have varied a lot over time, and

 

      epidemiologically useful consensus definitions do

 

      not necessarily represent physiological

 

      differences.

 

                The prevalence of selected comorbidities

 

      rises with BMI and doesn't have, at least in my

 

      analysis, clear inflection points.  There are about

 

      12 million adults with a BMI 25-27 with at least

 

      one selected comorbidity and about 4 million have

 

      at least 2 selected comorbidities.  So, it is a

 

      large group of the population.

 

                Half or more of the adults with BMI 25-27

 

      and selected comorbidities are age 60 and above.

 

      Weight loss, lifestyle changes and drugs are all

 

      used to manage these and other comorbidities.  So,

 

      weight loss is part of a whole package of possible

 

      treatment modalities.

 

                Weight loss is associated with some

 

      possible adverse consequences in observational

 

      studies.  So, I would conclude that the benefits

 

      and risks of weight loss for people with BMI 25 to

 

      under 27 have not been clearly established.  Thank

 

                                                                64

 

      you.

 

                DR. BRAUNSTEIN:  Thank you.  Are there any

 

      questions from the panel members?  Dr. Follmann?

 

                DR. FOLLMANN:  I just had a comment.  I

 

      hadn't seen the relationship between BMI and

 

      overall mortality before and I was really struck by

 

      the nadir at 25.  Many of these documents we have

 

      been reading before this meeting were talking about

 

      a cut point of 25-30 for definition of overweight,

 

      and it just strikes me as maybe curious as to why

 

      you would recommend or why people would consider

 

      having someone who has to be above 25.1, which is

 

      close to optimal, lose weight.  So, I was wondering

 

      if you could comment on that.

 

                DR. FLEGAL:  Well, I guess I think of this

 

      from an epidemiological perspective.  We have

 

      prevalence estimates that use 25 and, you know,

 

      different studies show the nadir at different

 

      points so I don't think you can say that it is

 

      exactly at 25.  But the recommendations of NHLBI

 

      are really not to lose weight at a BMI of 25.1

 

      unless you have comorbid conditions.  So, avoidance

 

                                                                65

 

      of weight gain is probably more important in that

 

      range.

 

                DR. BRAUNSTEIN:  Yes?

 

                DR. RYDER:  Yes, I just have one quick

 

      question.  On the two graphs that I you showed

 

      earlier on the age-adjusted trends in obesity, you

 

      used two categorical definitions, one of 25 and one

 

      of 30 with somewhat different patterns.

 

                I have a two-part question.  One is if you

 

      use 27 instead of 25 or 30, because I have seen

 

      that put forward, would the display be more like 30

 

      or more like 25?

 

                DR. FLEGAL:  I think it would be more like

 

      30 but I haven't actually looked at data.

 

                DR. RYDER:  And the second part is the

 

      average weight in the United States over this time

 

      period I believe has been going off in somewhat of

 

      a linear way, or maybe even more than a linear way.

 

      Has the distribution pattern, Poissant

 

      distribution, been maintained or is it just one arm

 

      skewing out?

 

                DR. FLEGAL:  That I can't answer. 

 

                                                                66

 

      Basically, the whole distribution of body mass

 

      index is shifting to the right a little bit.  But

 

      the distribution is becoming much more skewed so

 

      there are much larger changes at the higher tail of

 

      the distribution.  The median has shifted somewhat

 

      but the 90th percentile has shifted a lot.  So, the

 

      distribution is both shifting to the right and

 

      becoming much more skewed.

 

                DR. RYDER:  Thank you.

 

                DR. CARPENTER:  I was struck by the large

 

      impact of age on the comorbidities and, at the same

 

      time, struck by the fact that in your later slides

 

      you demonstrate that the effect on comorbidities

 

      with weight loss is much greater at the young ages.

 

      I wonder if anybody has looked at the duration of

 

      carrying a certain BMI as being more important than

 

      the current BMI as a risk factor for comorbidities.

 

                DR. FLEGAL:  There are studies like that.

 

      I don't think they would explain those age

 

      differences.  I think basically a lot of people,

 

      even at the lowest BMI in the age range of

 

      60-79--you know, a lot of people have hypertension

 

                                                                67

 

      regardless of BMI.  So, any duration or changes

 

      can't affect that.  You know, at every BMI level

 

      you have like 70-80 percent of people with

 

      hypertension so, although duration may very well

 

      have an impact, I don't think that can be the

 

      explanation for those prevalence figures.

 

                DR. BRAUNSTEIN:  Dr. Follmann?

 

                DR. FOLLMANN:  Have there been studies

 

      done that look at the pattern of weight gain over,

 

      say, a 10-year period and how that might affect

 

      mortality?  I am thinking of someone who, say,

 

      weighs 200 lbs at 40 and goes up to 250 lbs in a

 

      steady linear fashion as one kind of trajectory,

 

      and the other where they repeatedly diet and their

 

      weight fluctuates a lot over that 10-year period

 

      but they end up at the same weight.  So, steady

 

      versus erratic weight velocities--have there been

 

      studies looking at the risk associated with those

 

      two possible trajectories?

 

                DR. FLEGAL:  Well, there have been studies

 

      of weight cycling.  Sue Yanovski probably knows

 

      more about that than I do.  But I believe that a

 

                                                                68

 

      kind of consensus is that weight cycling probably

 

      doesn't have a large impact on mortality.  Is that

 

      right, Sue?

 

                DR. S. YANOVSKI:  Yes, the difficulty with

 

      these kinds of studies is that they are all

 

      observational studies, and weight cycling in itself

 

      is associated with a lot of psychiatric morbidity,

 

      a lot of other comorbidities and it is really

 

      difficult to tease out cause and effect in those

 

      kinds of studies.

 

                DR. FLEGAL:  Again, there are

 

      observational studies that suggest that weight loss

 

      is associated with increased mortality.  There are

 

      a lot of questions about intentionality; why do

 

      people change their weight.  As Sue was saying,

 

      there are other issues.  So, this whole area is a

 

      very tangled and confused area to really sort out.

 

                DR. BRAUNSTEIN:  Dr. Hirsch?

 

                DR. HIRSCH:  I think you have just about

 

      answered what I was going to ask.  The 1997

 

      recommendation concerning the issue that a

 

      randomized clinical trial of intentional weight

 

                                                                69

 

      loss is the only way we could prove whether there

 

      are dangers inherent in weight loss--no such trial

 

      that fits any of those issues has been carried out.

 

      Is that true?

 

                DR. FLEGAL:  Of intentional weight loss--

 

                DR. HIRSCH:  Yes, randomized, prospective

 

      trial.  You are saying that is the only way you

 

      could find out what the inherent harms of weight

 

      loss might be.

 

                DR. FLEGAL:  Look Ahead is the only one I

 

      am aware of.  Is that right, Sue?

 

                DR. S. YANOVSKI:  Yes.  NIDDK is

 

      sponsoring the Look Ahead clinical trial, which is

 

      5000 individuals with diabetes who are randomized

 

      to intentional weight loss or a controlled

 

      condition.

 

                DR. HIRSCH:  But no data are available?

 

                DR. S. YANOVSKI:  Not yet.

 

                DR. BRAUNSTEIN:  Why do you think the

 

      mortality curve is J-shaped?  That is, that the

 

      mortality goes up as you start getting to a lower

 

      BMI at a time when all the comorbid risk factors

 

                                                                70

 

      seem to be lowest?

 

                DR. FLEGAL:  Well, again, there are a lot

 

      of issues that are really unresolved.  It could be

 

      that at older ages there is some association--at

 

      all ages there is an association of low BMI with

 

      mortality as well as with high BMI.  It may have to

 

      do with issues like not having adequate nutritional

 

      reserves; people going in for surgery at age 65 and

 

      you lose weight in the course of being in a

 

      hospital and deplete your nutritional reserves.

 

      You may be at a higher risk of hip fracture.  The

 

      pattern of the causes of mortality may be different

 

      at different BMI levels at different ages.  There

 

      are also issues of smoking.  Most of these studies

 

      adjust in some way for smoking but smokers tend to

 

      have lower body mass index and be at higher risk.

 

      So, there are a lot of different issues.  I don't

 

      think it has really been sorted out very clearly in

 

      the literature.

 

                DR. BRAUNSTEIN:  Thank you.  We will move

 

      on to Dr. Frank Greenway's discussion of the

 

      current status of weight-loss drugs.

 

                                                                71

 

                  Current Status of Weight-Loss Drugs

 

                DR. GREENWAY:  I was asked to speak on the

 

      safety and efficacy of the drugs that we have for

 

      weight loss at the present time.  Obesity, before

 

      the 1985 consensus conference, was felt to be bad

 

      habits rather than a chronic disease, which is the

 

      way we now understand it.  At least, it was my

 

      understanding that eating habits can be retrained

 

      over a period of a few weeks and that this at least

 

      was another reason why the older recommendation for

 

      obesity drugs was over a shorter period of time.

 

                The drugs approved before 1985 were,

 

      therefore, approved for periods up to a few weeks,

 

      and tested over that period of time.  Mazindol and

 

      fenfluramine are no longer available; phentermine

 

      and diethylpropion are.  Dr. Colman already

 

      reviewed the analysis of the FDA information on new

 

      drug applications that were reviewed in the 1970s

 

      that showed that these drugs approximately doubled

 

      the weight loss seen with the placebo groups.

 

                Just a few overview comments about

 

      treating obesity as a chronic disease with

 

                                                                72

 

      medications, first of all, the drugs work only when

 

      they are taken and I will show you a slide to

 

      demonstrate that.  The average weight of the

 

      participants in those studies is 100 kg.  So, one

 

      can look at these weight loss graphs as percent

 

      weight losses or kilograms of weight loss since it

 

      is 100 kg.

 

                The placebo group in these trials has

 

      always required some type of treatment because IRBs

 

      feel that placebo groups need to get some form of

 

      treatment as well.  So, people in these trials are

 

      really getting two different treatments.  Weight

 

      loss in these trials usually plateaus at about 6

 

      months.  The primary criteria for approving drugs

 

      in Europe is a 10 percent weight loss that is

 

      greater than placebo.  A primary criterion in the

 

      United States is a weight loss that is 5 percent

 

      greater than placebo and is statistically

 

      significant.

 

                This is a slide of a study done in a

 

      practice situation where patients were given

 

      fenfluramine, a drug no longer approved.  They were

 

                                                                73

 

      seen monthly for a year.  As you can see, the

 

      weight loss plateaus at about 6 months.  The

 

      one-year people in this trial had their drug

 

      discontinued but they would continue to be followed

 

      for the following year.  When they were followed

 

      off the treatment the weight loss just about went

 

      away by the time they got to the second year.

 

                Another point I wanted to make was about

 

      the ancillary treatment that goes on in these

 

      clinical trials.  Back in the early '70s behavior

 

      modification was a new treatment.  There was a

 

      trial that was done to approve mazindol and two of

 

      the sites did it in the standard way, which is

 

      demonstrated on this slide.  Everybody got a

 

      tear-off diet sheet and the placebo and drug groups

 

      were given pills each week and were weighed each

 

      week.  As one can see, the placebo group really

 

      lost no weight over 6 weeks and the mazindol group

 

      lost 6.5 lbs over that period of time.

 

                In another site in that trial behavior

 

      modification was superimposed upon all groups.  The

 

      mazindol group in that site lost 8.5 lbs rather

 

                                                                74

 

      than 6.5 lbs but the difference between drug and

 

      placebo was reduced considerably, to the point

 

      where, at least in this particular site, the

 

      difference was no longer significant.

 

                To sort of carry that forward, because

 

      this is sort of the difference between the European

 

      and U.S. kinds of criteria, here you can see that

 

      an orlistat trial in Europe had 11 percent weight

 

      loss but only a 2 percent difference from placebo.

 

      This is because there was presumably a larger

 

      ancillary program that was superimposed upon this

 

      weight loss program.

 

                This is a sibutramine trial that was done

 

      in the United States where the difference was to

 

      get a spread between the two groups.  You have a 7

 

      percent weight loss with sibutramine and a 2

 

      percent loss with placebo, and there was,

 

      therefore, a 5 percent difference.

 

                In talking about the safety and efficacy

 

      of the drugs that are presently available, the Rand

 

      Corporation was commissioned to prepare an evidence

 

      report on the pharmacologic treatment of obesity by

 

                                                                75

 

      the agency for Health Care Policy and Research of

 

      our federal government.  Some new meta-analyses

 

      were done during that process using the studies

 

      that were at least 6 months in duration.  Although

 

      this hasn't yet been published, they have given me

 

      permission to present some of that data.

 

                There are several categories that one can

 

      put the drugs available into.  One would be

 

      phentermine and diethylpropion which are approved

 

      for obesity but for short-term use.  The second

 

      would be orlistat and sibutramine which are

 

      approved for obesity for long-term use.  Then there

 

      are drugs that are approved for other indications,

 

      not for obesity, things that are approved for

 

      depression, like fluoxetine and bupropion; things

 

      that are approved for epilepsy such as topiramate

 

      and zonisamide which also give weight loss.  Then,

 

      there are 2 drugs that are in phase 3 clinical

 

      trials, Axokine and rimonabant which have some

 

      public information available on them.

 

                The data presented here on efficacy

 

      presents the data in the way the FDA evaluates

 

                                                                76

 

      drugs, that is, the difference between the placebo

 

      group and the drug group.  In trials of phentermine

 

      up to 6 months in duration, using 30 mg/day, the

 

      difference between drug and placebo was about 3.5

 

      kg.  With diethylpropion, in studies that went up

 

      to about a year, the difference was 3 kg.

 

                One might ask how can one, in this day and

 

      age when we understand obesity to be a chronic

 

      disease, find a use for these medications that are

 

      only approved over a period of a few weeks.  This

 

      is a study that was done comparing the green line,

 

      which shows continuous use of phentermine, against

 

      the yellow line, which showed 1 month on 1 month

 

      off; 1 month on, 1 month off.

 

                As you can see, the line is more jagged

 

      but they end up at approximately the same place at

 

      9 months compared to the red line, which is

 

      placebo.  So, there are still ways that these drugs

 

      can be useful.

 

                Orlistat, at 120 mg 3 times a day, gave a

 

      2.5 kg difference compared to placebo at 6 months

 

      in the 11 studies in this meta-analysis, and about

 

                                                                77

 

      2.75 kg at 1 year in 21 studies.

 

                Orlistat is an inhibitor of pancreatic

 

      lipase.  It causes a third of dietary fat to be

 

      lost in the stool.  The relative risks for diarrhea

 

      were 3.4, for flatulence 3.1, and dyspepsia 1.5.

 

      So, one can see that these side effects result from

 

      the mechanism of action.

 

                These trials showed a reduction in total

 

      LDL cholesterol and in blood pressure.  There was a

 

      slight reduction in glucose and glycohemoglobin in

 

      diabetics, and it was shown that one could prevent

 

      diabetes in those with impaired glucose tolerance.

 

                Sibutramine, in doses of 10-20 mg/day,

 

      showed a 3.5 kg difference from placebo at 6 months

 

      in 12 trials, and about a 4.5 kg difference at 1

 

      year in 5 trials.  Sibutramine is a norepinephrine

 

      and serotonin reuptake inhibitor.  It had

 

      dose-related dry mouth, insomnia and nausea

 

      associated with it.  The heart rate went up 4

 

      beats/minute in these trials, and there was no

 

      consistent effect on blood pressure or lipids.

 

      There was a slight improvement in glucose and

 

                                                                78

 

      glycohemoglobin in diabetics.

 

                One could logically ask, since we have

 

      these two drugs that are approved for long-term use

 

      in obesity and they work by different mechanisms,

 

      could one combine them and get better weight loss.

 

      This is one trial that tried to address that issue.

 

      The yellow line shows sibutramine treatment for a

 

      year.  You can see that the weight loss plateau'd

 

      at 6 months and remained stable for the next 6

 

      months.  When orlistat was added to sibutramine

 

      there was no further weight loss.

 

                Fluoxetine is a medication that was

 

      approved for depression, not for obesity.  It was

 

      studied for obesity, however, and at 60 mg/day, a

 

      higher dose than is typically used for depression,

 

      it caused about a 4.5 kg difference from placebo at

 

      6 months.  But, as you probably will notice as

 

      something different compared to the other slides,

 

      there is less difference at 1 year than there was

 

      at 6 months, in this case 3 kg.

 

                Fluoxetine is a reuptake inhibitor of

 

      serotonin.  The relative risks of nervousness,

 

                                                                79

 

      sweating and tremors was 6.6; of nausea and

 

      vomiting 2.7; fatigue and somnolence 2.4; insomnia

 

      2.0; and diarrhea 1.7.  There was regain of weight

 

      between 6 months and a year.  That is presumably

 

      the reason that it was not approved.

 

                This is a slide to graphically demonstrate

 

      that fact.  You can see that the weight loss came

 

      down and plateau'd at around 6 months, but in the

 

      last 6 months of that year there was obvious weight

 

      gain in the fluoxetine group and not in the placebo

 

      group.

 

                Bupropion is a drug that is approved for

 

      depression and smoking cessation.  At 200 mg twice

 

      a day in 2 6-month trials there was about a 2 kg

 

      difference from placebo.  In one trial at 1 year

 

      there was about a 5 kg difference.

 

                Bupropion is a reuptake inhibitor of

 

      dopamine and norepinephrine.  The 6-month studies

 

      were both in depressed patients.  The 12-month

 

      study was in obese patients that were not

 

      depressed.  So, these may represent 2 different

 

      groups in terms of response.  The relative risk for

 

                                                                80

 

      dry mouth was 3.  There was also an increased

 

      incidence in insomnia, and there were no increases

 

      in pulse or blood pressure in those studies.

 

                Topiramate is a drug approved for

 

      epilepsy, not for obesity.  At 192 mg/day there was

 

      a trial that showed a 6.5 kg difference between

 

      that drug and placebo.  The mechanism or weight

 

      loss with this drug is not clear.  The relative

 

      risk of paresthesia was 4.9.  Taste perversions was

 

      9.2.  There were other central nervous system and

 

      gastrointestinal side effects with this medication.

 

                Zonisamide is another anti-epileptic drug,

 

      not approved for use in obesity.  A 16-week trial

 

      showed a 5 kg difference between that drug and

 

      placebo.

 

                Axokine is a large protein that is

 

      injected subcutaneously and is in development in

 

      phase 3 for the treatment of obesity.  There is one

 

      study that is in the public domain that shows a 3.5

 

      kg difference from placebo at 1 year.  Axokine

 

      appears to activate the leptin pathway distal to

 

      the place where leptin acts since it acts in

 

                                                                81

 

      animals that don't have leptin.  It has injection

 

      site reactions, nausea and a dry cough associated

 

      with its use.  Over 30 percent of the people in the

 

      trial that I mentioned developed antibodies to

 

      Axokine.  Those patients who developed these

 

      antibodies lost less than 1 percent of their body

 

      weight compared to placebo at a year.

 

                Rimonabant is the other medication on

 

      which there is public information in the phase 3

 

      trials for the treatment of obesity.  The one trial

 

      that was reported talked about uncomplicated

 

      obesity.  It was a 16-week trial and I took the

 

      liberty of projecting the weight loss consistent

 

      with other weight loss curves of these types of

 

      drugs.  If one projects that out to 6 months, one

 

      gets just slightly less than a 5 kg difference,

 

      assuming no weight loss in the placebo group which

 

      was not reported on that website.

 

                There is a second trial that used

 

      rimonabant in dyslipidemic patients.  The

 

      difference from placebo was 5 kg at 6 months and

 

      6.5 kg at a year.

 

                                                                82

 

                Rimonabant is an antagonist of

 

      cannabinoid-1 receptor.  In other words, it blocks

 

      the receptor that is thought to be effective in

 

      causing the munchies when people smoke marijuana.

 

      Nausea and diarrhea were greater than 5 percent

 

      above placebo.  There was a 10 percent increase in

 

      HDL, a 15 percent reduction in triglycerides and a

 

      reduction in the 2-hour post glucose load insulin,

 

      and no significant effects on pulse or blood

 

      pressure in these dyslipidemic patients.

 

                I put in this slide to put into context

 

      the blue line, which is a typical drug where there

 

      is weight loss of 10 percent, compared with the

 

      gastric bypass which has weight loss of 30 percent

 

      which is durable over 14 years.

 

                In summary, there are short-term weight

 

      loss medications that are approved for treatment of

 

      obesity, such as phentermine and diethylpropion.

 

      There are drugs that are approved for the long-term

 

      use in the treatment of obesity, that is, orlistat

 

      and sibutramine.  There are other medications

 

      approved for epilepsy or depression, i.e.,

 

                                                                83

 

      bupropion, fluoxetine, topiramate and zonisamide,

 

      which are not approved for use in treating obesity

 

      but which seem to give weight loss.  And, there are

 

      two drugs, Axokine and rimonabant, about which

 

      there is public information that are presently in

 

      phase 3 trials for the treatment of obesity.

 

                In conclusion, all these drugs give

 

      between a 2 and 6.5 kg greater weight loss than

 

      placebo in trials that last up to a year, and the

 

      amount of weight loss appears to be medically

 

      significant.  The weight loss between these

 

      different drugs is not different statistically and

 

      the choice, therefore, revolves around side

 

      effects.  The weight loss and the difference from

 

      placebo are two different things, which I hope I

 

      demonstrated, and data beyond 2 years essentially

 

      does not exist, with a couple of exceptions.  Thank

 

      you.

 

                DR. BRAUNSTEIN:  Thank you.  Questions

 

      from the panel?  Yes, Dr. Woolf?

 

                DR. WOOLF:  There was a report in "New

 

      York Times" on Monday, I think it was, of results

 

                                                                84

 

      of a one-year or a two-year trial in Europe with a

 

      drug that they didn't specify, other than saying it

 

      was a receptor blocker of some sort that had, I

 

      think, 19 lbs weight loss and 3.5 inch reduction in

 

      waist and a 24 percent increase in HDL.  Do you

 

      know anything about that?

 

                DR. GREENWAY:  That was rimonabant.  I saw

 

      that article and that was about rimonabant.

 

                DR. WOOLF:  Sorry?

 

                DR. GREENWAY:  I read the article and it

 

      was reporting on rimonabant, a new study of

 

      rimonabant, not the one that was reported by Frank.

 

                DR. WOOLF:  Thank you.

 

                DR. GREENWAY:  Actually,  those results

 

      are on the website.  I checked it yesterday, 1

 

      year, 52 weeks, 5 and 20 mg.

 

                DR. BRAUNSTEIN:  Yes?

 

                DR. ARONNE:  Frank, can you talk a little

 

      bit about the problem with dropouts in weight-loss

 

      drug studies, and some of the pros and cons of the

 

      type of analyses used, last observation carried

 

      forward versus completers?

 

                                                                85

 

                DR. GREENWAY:  Well, it seems as though

 

      people in weight-loss studies appear to have a

 

      feeling of being stigmatized when they drop out of

 

      studies because they don't want to come back.  It

 

      is very difficult to get final data on people who

 

      drop from weight-loss studies.  Weight-loss studies

 

      that go out to a year usually have something like a

 

      30 percent dropout rate.

 

                The traditional way of analyzing these

 

      studies, as Susan suggested, has been the last

 

      observation carried forward, and what that does is

 

      it dilutes the effect of the drug because it

 

      assumes that the reason the people dropped out is

 

      because they didn't lose weight.  Actually, what

 

      the physician treating a patient is interested in

 

      is more what happens to the patient that I treat

 

      who stays in treatment, rather than the more public

 

      health perspective of this last observation carried

 

      forward which looks at the entire group.  If you

 

      treat everybody, what does the total group gain

 

      from this experience?  So, from the way in which

 

      these medications are used, it is much more

 

                                                                86

 

      informative to me, as a clinician, to have the

 

      analysis of completers rather than the last

 

      observation carried forward.

 

                DR. BRAUNSTEIN:  Dr. Schambelan?

 

                DR. SCHAMBELAN:  Just a quick question

 

      about Axokine.  You said it worked distal to

 

      leptin.  Do you know if it works distal to the

 

      leptin receptor or just distal to leptin?  Is its

 

      actual site of action known?

 

                DR. GREENWAY:  The site of action of

 

      Axokine is in the leptin pathway.  It is probably

 

      in that signaling pathway but it is distal to the

 

      site where leptin acts.

 

                DR. BRAUNSTEIN:  Frank, can you describe,

 

      in the studies that were carried out for one year

 

      with these drugs, what the effect was on the

 

      comorbid states and whether there were any

 

      differences among the drugs?  For instance, did

 

      some lead to lowering of blood pressure and others

 

      didn't?  Did some lead to lowering of cholesterol

 

      while others didn't?  Or were they all fairly

 

      consistent?

 

                                                                87

 

                DR. GREENWAY:  You are asking me what was

 

      the effect on comorbidities in these studies?

 

                DR. BRAUNSTEIN:  Yes.

 

                DR. GREENWAY:  Of the two drugs that are

 

      approved for treatment of obesity in the United

 

      States, orlistat seems to have a disproportionate

 

      beneficial effect on lipids, probably because it

 

      enforces a low fat diet.  Sibutramine doesn't have

 

      the expected beneficial effect on blood pressure

 

      that one might expect, probably because of its

 

      norepinephrine reuptake mechanism of action.

 

      Otherwise, one gets the expected benefits that one

 

      would expect with weight loss with these drugs.

 

                DR. BRAUNSTEIN:  Other questions?

 

                [No response]

 

                Thank you.  Our next speaker will be Dr.

 

      Laura Governale, who is going to speak about

 

      patterns of weight-loss drug use.

 

                    Patterns of Weight-Loss Drug Use

 

                DR. GOVERNALE:  Good morning.  To begin, I

 

      would like to briefly state that the Division of

 

      Surveillance Research and Communications Support in

 

                                                                88

 

      the Office of Drug Safety is responsible for the

 

      procurement, management and analysis of drug

 

      utilization databases for the FDA's use.  The

 

      information contained in these slides has been

 

      approved for this meeting.

 

                The topics I will be discussing today are

 

      the patterns of prescription weight-loss drug use

 

      and the patient demographics associated with

 

      weight-loss drug use.  For this presentation

 

      weight-loss drugs are defined as dexfenfluramine,

 

      sibutramine and orlistat and amphetamine congeners

 

      such as phentermine and dimetrazine diethylpropion,

 

      phendimetrazine, diethylpropion, benzphetamine,

 

      mazindol and fenfluramine.  We did not include

 

      amphetamines in this analysis.  Also not covered in

 

      this analysis are over-the-counter drugs and

 

      nutritional supplements.  The analysis is conducted

 

      using proprietary databases at the agency's

 

      disposal.

 

                Two databases were used in this analysis

 

      from IMS Health.  IMS health is a pharmaceutical

 

      marketing usage company that collects prescription

 

                                                                89

 

      drug use information worldwide.  The agency uses

 

      these databases as well in order to obtain drug use

 

      information and trends in the U.S.  The two

 

      databases from IMS Health were the National

 

      Prescription Audit Plus and the National Disease

 

      and Therapeutic Index.

 

                NPA, or the National Prescription Audit

 

      Plus, measures the retail outflow of prescriptions

 

      from pharmacies into the hands of consumers by

 

      formal prescriptions.  The number of dispensed

 

      prescriptions is obtained from a sample of

 

      approximately 22,000 randomly selected pharmacies

 

      around the country and projected nationally.  The

 

      pharmacies in the database account for

 

      approximately 40 percent of all pharmacy stores and

 

      represent approximately 45 percent of prescription

 

      coverage in the U.S.  The pharmacies include the

 

      following retail channels such as chain,

 

      independent, mass merchandisers and food stores

 

      with pharmacies, and also include mail-order and

 

      long-term care pharmacies.

 

                The National Disease and Therapeutic Index

 

                                                                90

 

      is a survey of roughly 3000 office-based physicians

 

      around the country.  The data gathered in NDTI are

 

      designed to provide descriptive information on the

 

      patterns and treatment of disease encountered in

 

      this setting.  The data are collected and projected

 

      to provide a national estimate of use.  However, in

 

      certain instances the small sample size tend to

 

      make these data unstable and sometimes these

 

      results should be interpreted with caution.

 

                Patterns for prescription weight-loss

 

      drugs dispensed were obtained from NPA Plus.  Here

 

      I will present the trends in prescription

 

      weight-loss drug use dispensed from 1966 to 2003

 

      and also the method of payment for these

 

      prescription weight-loss drugs from 1999 to 2003.

 

                This slide, which is based on NPA data,

 

      represents the total number of prescriptions

 

      dispensed for prescription weight-loss products

 

      from 1966 to 2003.  The total number of

 

      prescriptions represents new prescriptions as well

 

      as refill prescriptions.

 

                The yellow-shaded area here represents the

 

                                                                91

 

      total added prescription weight-loss products of

 

      all the individual weight-loss products as shown

 

      here.  The individual lines represent individual

 

      active ingredients in some of these weight-loss

 

      drug products.  Again, this slide does not include

 

      any amphetamine products.

 

                As you can see, over the last 38 years

 

      there have been fluctuations in prescription

 

      weight-loss products.  As you can see, there are

 

      two major spikes in prescription drug use.  These

 

      fluctuations in use have been largely due to two or

 

      three prescription drugs at any given time.

 

                The first spike, which occurred during the

 

      early 1970s, around the decade of the '70s, was

 

      most likely due to the enactment of the Controlled

 

      Substances Act in 1970.  This was also presented by

 

      Dr. Colman in a previous presentation.  This

 

      legislation in essence restricted the production

 

      and distribution of amphetamines which, throughout

 

      the 1960s, were commonly prescribed for weight

 

      loss.  When these restrictions were placed on

 

      amphetamines the amphetamine congeners were used

 

                                                                92

 

      more frequently.

 

                Also in 1973, the agency declared that

 

      amphetamine and amphetamine-like compounds were

 

      effective for the treatment of obesity.  This led

 

      to a large spike in use for diethylpropion and

 

      phentermine products.  The number of prescriptions

 

      here peaked at 12.5 million in 1976.

 

                However, we see a decline in use around

 

      1979.  In 1979 there was a Federal Register notice

 

      calling for the removal of the obesity indication

 

      in amphetamines.  This led to a sharp decline in

 

      use in weight-loss drugs, namely, for phentermine

 

      and diethylpropion.  However, the proposal to

 

      remove the obesity indication from the amphetamines

 

      never materialized.  Since then, the use of

 

      weight-loss products had steadily declined until

 

      the mid-1990s.

 

                I will focus now on the last 13 years for

 

      prescription drug trends.  Looking at the last 13

 

      years, the number of total prescriptions dispensed

 

      for weight-loss drugs reached its lowest point

 

      around the 1990s, early 1990s, with approximately

 

                                                                93

 

      3.3 million prescriptions dispensed.

 

                Then, in early 1995, 1996, we began to

 

      notice an increase in usage.  This was most likely

 

      due to the result of a publication, in 1992, of a

 

      series of papers that concluded that the

 

      combination of phentermine and fenfluramine, or

 

      phen-fen, was safe and effective for long-term

 

      weight loss.  In 1996 the FDA approved

 

      dexfenfluramine for the treatment of obesity.  The

 

      number of anti-obesity prescription drugs dispensed

 

      reached its peak in 1996 with 21 million

 

      prescriptions.  The compounds responsible for this

 

      increase include phentermine, fenfluramine and

 

      dexfenfluramine.

 

                Again, dexfenfluramine was marketed under

 

      the name of Vidoxx and fenfluramine was marketed

 

      under the name of Pondimin.  During its peak use in

 

      1996 fenfluramine held 33 percent of the market

 

      share with 7 million prescriptions dispensed,

 

      whereas dexfenfluramine held 11 percent of the

 

      market share with 2.3 million prescriptions

 

      dispensed.  Phentermine held 52 percent of the

 

                                                                94

 

      market share with approximately 11 million

 

      prescriptions dispensed.

 

                This large spike in use was followed by a

 

      market decline over the next two years when, in

 

      1997, the FDA announced a voluntary withdrawal of

 

      fenfluramine and dexfenfluramine following

 

      increased reports of cardiac valvulopathy in

 

      patients treated for obesity.  The total number of

 

      prescriptions dispensed went from a peak of 21

 

      million prescriptions down to approximately 7

 

      million prescriptions ion 1998, which represents

 

      approximately a 67 percent decline.  Since then the

 

      number of prescriptions dispensed for weight-loss

 

      drugs has declined to approximately 5.8 million

 

      prescriptions in the year 2003.

 

                Orlistat was released into the market

 

      around 1997, and sibutramine in 1999.  Currently,

 

      or in year 2003, they hold second and third place

 

      in the market with 1.3 million prescriptions

 

      dispensed for orlistat or 22 percent of the market

 

      share, and 760,000 prescriptions dispensed for

 

      sibutramine, which represents 13 percent of the

 

                                                                95

 

      market share.

 

                Phentermine continues to predominate the

 

      market with approximately 3 million prescriptions

 

      dispensed, which represents over 50 percent of the

 

      market share.  Other products, such as the

 

      amphetamine congeners, have steadily declined in

 

      use since the mid-1990s and collectively account

 

      for less than a million prescriptions per year.

 

                This slide, in contrast to the previous

 

      slides, represents only new prescriptions

 

      dispensed.  Furthermore, this analysis excludes the

 

      mail-order and long-term care channels.  Therefore,

 

      the numbers of prescriptions reported in this

 

      analysis are smaller than in the previous slides.

 

                This graph is an analysis of method of

 

      payment for prescription weight-loss drugs.  As you

 

      can see, the number of new prescriptions paid by

 

      cash has declined steadily over the past 5 years,

 

      from approximately 5 million in year 1999 to 2.6

 

      million in year 2003.  However, the number of

 

      third-party payment for new prescriptions has

 

      remained steady at approximately 1.1 to 1.6 million

 

                                                                96

 

      prescriptions over the 5-year period surveyed.  The

 

      drop in cash payment, in effect, has increased the

 

      proportion of third-party payment for these drugs

 

      from 20 percent in year 1999 to approximately 30

 

      percent in year 2003.  So, the main message from

 

      this slide is that cash payment remains an

 

      important mechanism for the payment of these

 

      weight-loss prescription drugs.

 

                Next I will discuss the patient

 

      demographics associated with prescription

 

      weight-loss drugs.  The data are based on IMS

 

      Health, National Diseases and Therapeutic Index.

 

      Again, the data are projected nationally.  However,

 

      it does not represent disease burden, nor is it

 

      representative of all disease states in the nation.

 

      Rather, the data reflect a population of ambulatory

 

      patients, visiting physicians and office-based

 

      practice settings during which a weight-loss drug

 

      is mentioned during the visit.  Again, due to the

 

      limitations in data sampling in this database, any

 

      perceived trends must be interpreted with caution.

 

                The topics I will be discussing for

 

                                                                97

 

      patient demographics include the principal

 

      diagnoses associated with prescription weight-loss

 

      drugs, the gender distribution, age distribution

 

      and race distribution.

 

                This table represents the principal

 

      diagnoses associated with prescription weight-loss

 

      products for ambulatory patients.  Not

 

      surprisingly, obesity is the diagnosis most often

 

      mentioned with weight-loss drug products, with

 

      approximately 89 percent or 1.8 million projected

 

      diagnosis visits.

 

                This slide represents the number of

 

      mentions associated with the use of weight-loss

 

      drugs as reported by office-based physician

 

      practice settings.  This is a measure of drug

 

      mentions again and is not reflective of disease

 

      burden in the nation.

 

                As you can see, females account for a

 

      clear majority in use for prescriptions of

 

      weight-loss products, with an average of 2.3

 

      million drug appearances or 85 percent over the

 

      time period surveyed.

 

                                                                98

 

                Taking a closer look at the most recent

 

      calendar year, we see that the adult age group,

 

      18-44, accounts for the largest majority of drug

 

      use for prescription weight-loss products, with

 

      approximately 1.2 million or 62 percent of total

 

      drug appearances.  This is followed next by age

 

      45-64 category, with 624,000 mentions or 32.6

 

      percent of total drug appearances in the year 2003.

 

      In conclusion, the majority of weight-loss drug

 

      products is in the young, female, adult and middle

 

      age adults.

 

                This graph represents the race

 

      distribution of patients associated with the use of

 

      prescription weight-loss drugs as reported by

 

      office-based physician practice settings.  Again,

 

      the reporting in this database, NDTI, is reported

 

      by the physician and not is not self-reported by

 

      the patient.  The key take-away from this graph is

 

      that a proportion represented by each race group

 

      has remained constant over the time period

 

      surveyed.  Approximately three-quarters of use is

 

      from Caucasian patients.

 

                                                                99

 

                Now that I have represented the data, I

 

      will present the limitations on each of these

 

      databases.  The NDA Plus data provide only limited

 

      demographic information on prescription use.

 

      Therefore, we did not use this database for this

 

      analysis.  Instead, we used NDTI to obtain

 

      demographic information which has these

 

      limitations:  As you can see, the small sample size

 

      makes some projections unstable.  Again, the data

 

      are not generalizable to all of these patients.

 

      And, due to the limitations, any perceived trends

 

      must be interpreted with caution.

 

                In conclusion, over the last 38 years

 

      there has been a fluctuation in the total number of

 

      prescriptions dispensed for prescription

 

      weight-loss products.  These fluctuations have been

 

      largely due to two or three drugs at any given

 

      time.

 

                The second point is that cash payment

 

      remains an important mechanism for payment for

 

      these products.  Also the primary users of these

 

      products are Caucasian women between the ages of 18

 

                                                               100

 

      and 44.  That is the end of the presentation.

 

                DR. BRAUNSTEIN:  Thank you.  Any questions

 

      from members of the panel?  Yes?

 

                MS. COFFIN:  On your slide that talks

 

      about the race distribution of the patients you can

 

      see huge differences and, of course, the Caucasian

 

      patients are shown as the largest amount.  How does

 

      that normalize to the population as a whole?  Is

 

      the population as a whole from '98 to 2003 more

 

      greatly Caucasian than it is Asian American or

 

      African American?

 

                DR. GOVERNALE:  Again, this database is

 

      not supposed to represent any epidemiology of

 

      obesity.  It represents patients visiting

 

      office-based physicians and it could reflect just

 

      that there are more Caucasian patients visiting

 

      these physicians.

 

                DR. BRAUNSTEIN:  Dr. Woolf?

 

                DR. WOOLF:  Do you know if the heavy use

 

      of cash for these drugs is because they are being

 

      excluded by drug plans that the patients have?  Are

 

      they being excluded from the formularies that the

 

                                                               101

 

      patients are covered on?  Is that why cash is so

 

      prevalent?

 

                DR. GOVERNALE:  I think if I heard your

 

      question, it is why are most of these products not

 

      covered?

 

                DR. WOOLF:  Yes, is the reason that cash

 

      accounts for three-quarters of the method of

 

      payment because they are being excluded from drug

 

      plans?

 

                DR. GOVERNALE:  Yes, that is the

 

      limitation with these products.  Most of these

 

      products are not covered by third-party payers and,

 

      therefore, that is why they are being paid for by

 

      cash.

 

                DR. BRAUNSTEIN:  Dr. Watts?

 

                DR. WATTS:  I was interested in your

 

      demographics.  I may be making wrong inferences but

 

      it seems to me if the largest use of these drugs in

 

      the real world is by younger white women, that may

 

      be more for cosmetic benefits of weight loss.  This

 

      is a question then for Dr. Greenway.  I didn't get

 

      from your presentation the demographics of the

 

                                                               102

 

      subjects that are studied in the typical weight

 

      loss trial.  Are they different from the people who

 

      are using these drugs as we heard from this

 

      presentation?

 

                DR. GREENWAY:  The patients in the regular

 

      weight-loss trials primarily have a BMI between 30

 

      and 40.  So, they aren't in the trials because they

 

      have just cosmetic concerns, but I think that what

 

      you have observed is correct, that obesity is

 

      stigmatized in our society, particularly

 

      stigmatized in regards to women, and that is

 

      probably the reason that we have 80 percent of

 

      these obesity trials that are composed of women.

 

      Clearly, 80 percent of the population isn't women.

 

                DR. WATTS:  To extend that though, is

 

      there a particular age of the subjects in the

 

      studies that you showed?  Were they different,

 

      older, from the use of these drugs in the real

 

      world?

 

                DR. GREENWAY:  The average age of the

 

      people in the trials is usually around 40.  So,

 

      they may be slightly older than this group but I

 

                                                               103

 

      think they are probably fairly representative.

 

                DR. BRAUNSTEIN:  Dr. Yanovski?

 

                DR. S. YANOVSKI:  These data did not

 

      report out BMI.  They might have the physician

 

      diagnosis for obesity correct but you couldn't tell

 

      how many of the patients in these studies had BMIs

 

      above a certain range.  Is that correct?

 

                DR. GOVERNALE:  Correct.  There is no

 

      linkage of BMIs to the diagnosis of obesity.

 

                DR. S. YANOVSKI:  So, in preparation for

 

      this I pulled an article by Laura Kettle Conning

 

      and colleagues at CDC that looked at use of

 

      prescription weight-loss pills in U.S. adults from

 

      1996-98 that I think addresses your question.  They

 

      used the behavioral risk factors surveillance

 

      survey and they looked at all patients who reported

 

      use of prescription weight-loss drugs.  They then

 

      looked at the proportion of patients who reported

 

      using prescription weight-loss drugs who had a BMI

 

      of less than 27, which was the lower limit for

 

      indication with comorbidities.  What they found was

 

      that 5 million U.S. adults had used prescription

 

                                                               104

 

      weight-loss drugs in that 2-year period.  Of that

 

      group, 25 percent reported that they had a BMI of

 

      less than 25.  So, it looks like there is

 

      substantial use of these medications for cosmetic

 

      purposes.

 

                DR. BRAUNSTEIN:  Dr. Schambelan?

 

                DR. SCHAMBELAN:  I just want to pursue Dr.

 

      Woolf's question about the reason that the cash

 

      payment is decreased.  Do we know that there has

 

      been a systematic change in policy of third-party

 

      payers as to what they will approve for weight-loss

 

      drugs?  Perhaps you don't know but other panelists

 

      may know.

 

                DR. BRAUNSTEIN:  What will the effect of

 

      the recent change in coverage of the drugs by

 

      Medicare have on all this?  I guess that is part of

 

      the question.

 

                DR. SCHAMBELAN:  Well, Medicare or other

 

      payers.

 

                DR. GOVERNALE:  We did not look into the

 

      reasons for why some of these prescription drug

 

      products are being covered or not covered by

 

                                                               105

 

      third-parties, but that could be a very interesting

 

      question to look into for future analyses.

 

                DR. BRAUNSTEIN:  Dr. Aronne?

 

                DR. ARONNE:  While there hasn't been a

 

      systematic change in the number of plans which are

 

      covering drugs, what we have seen is that

 

      practitioners of obesity medicine where we focus on

 

      obesity to treat someone's diabetes, sleep apnea or

 

      other complications, is a steady increase in the

 

      willingness of insurance companies to pay for drug

 

      therapy in an appropriate setting.  So, with prior

 

      approval, if the patient is in a medically

 

      supervised program, the insurance companies will

 

      pay for the drugs.  Right now in the New York area

 

      it is more than 40 percent.  The last number I

 

      heard was that 44 percent of patients who have

 

      insurance get coverage for these types of drugs.

 

                DR. BRAUNSTEIN:  Any further questions?

 

                [No response]

 

                We will take a 15-minute break.  Thank

 

      you.

 

                [Brief recess]

 

                                                               106

 

                DR. BRAUNSTEIN:  We are changing the order

 

      a bit.  We are going to ask Dr. Richard Atkinson,

 

      who is director of Obetech Obesity Research Center,

 

      to speak on the role of drugs in the treatment of

 

      obesity: current and future.  Following that, we

 

      will then move to the open public hearing, followed

 

      by Dr. Orloff's talk.

 

               Role of Drugs in the Treatment of Obesity:

 

                           Current and Future

 

                DR. ATKINSON:  Thank you, Dr. Braunstein.

 

      Thank you, Dr. Orloff and Dr. Colman for inviting

 

      me to speak.  I am coming today wearing two hats.

 

      One is the president of the American Obesity

 

      Association and the second is a physician/clinician

 

      who has literally treated thousands of obese people

 

      over the years.

 

                From that perspective, I have looked into

 

      the eyes of these people and seen the pain and

 

      heard their pain as they talk, and I have failed

 

      them and I think we have all failed them.  The

 

      physicians and scientists have failed them.  The

 

      drug companies have failed them and the government

 

                                                               107

 

      has failed them.  That sounds like a negative

 

      message and I am going to spend a little time

 

      talking about why I think we have all failed.  But

 

      I think the promise of the future is really very

 

      bright and I will try to end up on that.

 

                I always like to start off with something

 

      that is not unique to me; I probably stole it from

 

      someone, but obesity is a chronic disease of

 

      multiple etiologies characterized by the presence

 

      of excess adipose tissue.  Everybody has excess

 

      adipose tissue but the critical word I think here

 

      is "disease."  I think we have heard in this

 

      discussion this morning even some questioning of

 

      the idea of obesity as a disease.  But I believe

 

      obesity is a chronic disease and if you think of

 

      other chronic diseases, try to think of one that is

 

      not treated with drugs.

 

                If obesity is a chronic disease and most

 

      other chronic diseases are treated with drugs, why

 

      not obesity?  We know that the biochemistry of

 

      obese individuals is different from that of lean

 

      people.  That is very well known.  Bob Eckle and

 

                                                               108

 

      others have some data that when obese people lose

 

      weight their biochemistry does not become the same

 

      as lean people's.  For example, lipoprotein lipase,

 

      the major clearer of triglycerides out of the

 

      bloodstream, in adipose tissue lipoprotein lipase

 

      goes up; in muscle it goes down.  So, people who

 

      were formerly obese are poised to regain their fat.

 

      What do we do with drugs?  We change the

 

      biochemistry.  So, the rationale for using drugs is

 

      to change the biochemistry of the bodies of obese

 

      people.

 

                There have been, as you have heard, a

 

      number of barriers to the use of drugs.  The first

 

      one I am going to put up here is discrimination

 

      against obesity.  I am going to spend several

 

      slides talking about this.

 

                When Dr. Orloff asked me to talk, we

 

      talked about the fact that we were going to have a

 

      very nice bunch of scientific presentations and I

 

      am going to come with a more emotional part with

 

      this presentation.  But as president of an

 

      organization that is advocating for these people, I

 

                                                               109

 

      want to point out some of the discrimination

 

      against obesity.  The fact of physician and

 

      clinician ignorance of obesity, an particularly of

 

      obesity drugs; economic factors; policy and

 

      political barriers, and I have come much more to

 

      appreciate that.  We have had several meetings with

 

      people from the FDA, NIH and others and I have come

 

      to appreciate more some of the barriers.  There is

 

      a lack of advocacy about obese people and, finally,

 

      currently there is a modest effectiveness of

 

      obesity drugs, as we have heard.

 

                I am going to talk a little bit about

 

      discrimination.  Obesity is the last bastion of

 

      socially acceptable bigotry.  If you are a radio

 

      announcer or a TV announcer and you tell a joke, a

 

      race joke or an ethnic joke, or a joke directed

 

      against homosexuals, you will get fired.  Fat jokes

 

      are told all the time.  Look in your comic pages

 

      and virtually every day there is some slam against

 

      fat people and nothing is done.

 

                This discrimination against obesity is in

 

      the people who are in our field.  Stan Heshka and

 

                                                               110

 

      David Allison are two very good friends, two very

 

      bright people, good scientists, but "labeling

 

      obesity a disease may be expedient but it is not a

 

      necessary step in a campaign to combat obesity and

 

      it may be interpreted as a self-serving advocacy

 

      without a sound scientific basis."  Well, those are

 

      pretty strong words for somebody who is in the

 

      field.

 

                There is a lack of medicalization of

 

      obesity.  Think about obesity compared with some

 

      other chronic diseases.  For example, newly

 

      diagnosed type 2 diabetes, newly diagnosed

 

      hypertension--a very high percentage of those

 

      patients will respond very well to diet and

 

      exercise.  it goes away.  I did a study about 20

 

      years ago and it goes away in 80 percent of the

 

      people.  But the first words our of the mouth of a

 

      primary care physician are not "I'm going to put

 

      you on a diet and exercise program;" it is "I'm

 

      going to put you on drugs."

 

                The primary treatment for obesity is diet

 

      and exercise and drugs are an adjunct.  As we have

 

                                                               111

 

      heard from Colman's talk, that has been true for

 

      many, many years.  Many patients must demonstrate

 

      that they have failed diet and exercise before they

 

      can get either drugs or surgery.  There is no other

 

      disease where that happens.

 

                Physician and clinician

 

      ignorance--obesity, obviously, is not thought to be

 

      a real disease.  As many of you know, we have been

 

      doing some work on viruses that cause obesity and I

 

      have gotten up and had people shake their fist at

 

      me and say, "you're trying to give these fat people

 

      an excuse."  Wow!  Physicians are uncomfortable

 

      about counseling overweight or obese patients.  I

 

      have a talk on discrimination against obesity to

 

      document many papers in the literature where this

 

      has been shown.

 

                Physicians and clinicians are not

 

      knowledgeable about nutrition, physical activity,

 

      and particularly about obesity drugs.  This is a

 

      disease that is killing 400,000 people per year

 

      according to the CDC.  At the University of

 

      Wisconsin I was able to get a clinical nutrition

 

                                                               112

 

      course on the curriculum and we had exactly three

 

      lectures on obesity.  Since I left, that has now

 

      been cut to one.  That is pretty much all they get

 

      about obesity in the whole curriculum.

 

                Physicians are unaware of referral

 

      information.  If you have a fat person, what do you

 

      do?  They feel helpless and there is a feeling that

 

      if you refer a patient to an obesity physician you

 

      are sort of sending them to a charlatan.  There is

 

      a bias.  We have heard a little bit about that

 

      today, that drug treatments are dangerous,

 

      ineffective and somehow not worthy.

 

                There are economic factors that are

 

      barriers to obesity drugs.  I was flabbergasted to

 

      hear Lou Aronne's comment that in New York 40

 

      percent of third-party payers are starting to pay

 

      for drugs.  That is super.  We looked in Wisconsin

 

      and in our population it was between 10-15 percent.

 

      They had a very high percentage of HMOs and these

 

      HMOs simply didn't cover obesity or obesity drugs.

 

                Some of the reasons for that are that the

 

      treatment is fairly expensive.  This, after all, is

 

                                                               113

 

      a chronic disease.  The insurance companies and

 

      employers are worried about breaking the bank.

 

      There are a large number of overweight and obese

 

      people.  We heard Katherine Flegal's talk.  Over 30

 

      percent of the entire adult population is obese,

 

      has a BMI of 30 or above.  So, one, there is a

 

      large population that might want to use those drugs

 

      or use that treatment and, secondly, given a

 

      choice, they will.

 

                We heard from Susan Yanovski about maybe

 

      as many as 25 percent of people that are using

 

      these drugs are using them for cosmetic purposes.

 

      That is a little bit of a discrimination in itself.

 

      There is a whole industry that makes drugs for

 

      cosmetic purposes, like skin rashes and so forth

 

      and so on.  So, what is so bad about somebody

 

      wanting to lose some weight when, if you are

 

      overweight, you have a harder time getting a job,

 

      getting promoted in a job, finding a spouse.  If

 

      you are a small kid other kids don't want to play

 

      with you.  It is not just a cosmetic problem; this

 

      is a socioeconomic huge discrimination problem

 

                                                               114

 

      against obese people.

 

                For many of the insurance companies and

 

      insurance plans and HMOs savings in the future

 

      costs are too remote compared to current expenses.

 

      Their bottom line is a year or less.  If it doesn't

 

      pay for itself in a year, let's don't pay for it.

 

                Turning to the government, honest to God,

 

      at a Harvard CME course put on by George Blackburn,

 

      I am happy to say a former member of the FDA, he

 

      made the statement, "gaining weight doesn't hurt

 

      you and losing weight doesn't help you."  I am

 

      embarrassed to say I got into a shouting match with

 

      him in front of 400 people.

 

                Obesity drugs I think have been held to a

 

      different standard in the past than drugs for other

 

      diseases.  I will just bring up the phen-fen

 

      debacle versus troglitazone.  Within two months of

 

      the first unconfirmed, uncontrolled case series

 

      that was prematurely reported by The New England

 

      Journal--it wasn't even published yet but what was

 

      released as a press release--within two months of

 

      that fenfluramine and dexfenfluramine were taken

 

                                                               115

 

      off the market.  It was not really sure that anyone

 

      had died from fenfluramine or dexfenfluramine.

 

      Sixty people had died from troglitazone and it

 

      stayed on the market two more years.

 

                Now, the cynic in me says that is because

 

      diabetes is a real disease and obesity is not.

 

      That may not be fair and there are other factors,

 

      but from my side, coming from an advocacy

 

      organization, it looks like that is discrimination

 

      against obesity.  I am not saying that fenfluramine

 

      and dexfenfluramine should not have been taken off

 

      the market, but the timing was interesting.

 

                The recent experience of obesity

 

      drugs--dexfenfluramine had quite a hard time

 

      getting approved.  Sibutramine was initially turned

 

      down and only upon appeal was approved.  Orlistat

 

      had what apparently was a spurious association with

 

      cancer so they had to go back and do a great many

 

      more trials to look at the patients to show that

 

      there was not a correlation with cancer.

 

                As many of you know, and as many of you

 

      here have participated in, the American Obesity

 

                                                               116

 

      Association has sponsored a series of meetings with

 

      people from the FDA, the NIH, other government

 

      agencies, scientists and many representatives of

 

      the pharmaceutical industry who have obesity drugs

 

      or are interested in obesity drugs.  And, one of

 

      the things I have been impressed with is that the

 

      people at FDA have a huge load on their shoulders

 

      because if anything goes wrong, it is their

 

      problem.  We have, you know, 100 million people who

 

      might be wanting to take these drugs and if even a

 

      few of them start to have problems, it is the FDA's

 

      fault for having not been more careful.

 

                Fenfluramine had been on the market since

 

      1973.  It was not until 1997 that it was found to

 

      have cardiac valve problems.  The problem with

 

      pulmonary hypertension, as Eric noted, was there

 

      but it was really pretty rare.  So, I have a much

 

      better understanding of the pressures, both

 

      political and from media and from scientists, on

 

      the FDA and why they simply have to be cautious.

 

                From the Medicare/Medicaid perspective, we

 

      have already heard today that until just a month or

 

                                                               117

 

      so ago the language in the Medicare and Medicaid

 

      regulations was "obesity is not a disease" despite

 

      the fact that it was called a disease in 1985 by an

 

      NIH consensus development conference.  Apparently,

 

      efficacy standards, in contrast to drugs and

 

      treatments for most other chronic diseases, will

 

      have to have some sort of proving that this

 

      treatment works.         Now, as I said earlier, we

 

      have failed these people but obese people fail

 

      themselves.  The expectations and the behavior of

 

      obese people contribute to the problem because many

 

      do not believe they are worthy or respect.  Obese

 

      people discriminate against obese people actually

 

      more than thin people discriminate against obese

 

      people.  They do not bind together for action.

 

      Trying to get people to join this advocacy group

 

      has been absolutely amazing.  I thought everybody

 

      in the world who was obese would sign up.  They

 

      don't.  They are ashamed to be associated with the

 

      world of obesity.  They simply do not act as

 

      advocates.

 

                Other barriers to obesity drugs are

 

                                                               118

 

      limited choices and poor efficacy.  There are only

 

      two drugs still on patent.  Why haven't the drug

 

      companies done more in the past?  They are

 

      certainly doing it now.  There are really only

 

      three categories of drugs, as you have heard, the

 

      adrenergic agents, sibutramine which is in a

 

      category by itself and orlistat which is in a

 

      category by itself.  We still have an infantile

 

      understanding of the etiology of obesity and

 

      mechanisms of action of drugs.  We heard about

 

      topiramate.  We don't have a clue as to how it

 

      works.  It causes weight loss but we don't know how

 

      it works.

 

                As we have heard, typical weight-loss

 

      agents, single agents at least, cause only about a

 

      10 percent loss from initial body weight, and there

 

      has been very limited use of combinations of drugs.

 

      I will come back to that.

 

                This is the data on dexfenfluramine, the

 

      index study from Europe, the best study that

 

      dexfenfluramine had, and there was about a 10

 

      percent weight loss at a year.

 

                                                               119

 

                Sibutramine, about an 8 percent or 9

 

      percent weight loss at a year with 15 mg.

 

      Sibutramine out over 2 years, again over in

 

      Europe--again, this is about a 13 percent weight

 

      loss.  This is the Storm trial.

 

                With orlistat, about a 10 percent weight

 

      loss at one year.  This is a 2-year trial.  The

 

      2-year data was about 8 percent.

 

                If you are a 220 lb woman and you lose 22

 

      lbs, your physician can tell you all he or she

 

      wishes, "oh, you're healthy; your blood pressure's

 

      better; your blood sugar's better, your lipids are

 

      better."  That woman or that man who is obese is

 

      still suffering the slings and arrows of

 

      discrimination by society.  As a matter of fact,

 

      when we showed the data from 2000, John Monroe's

 

      group in BMJ and in Practitioner back a long time

 

      ago, these were 36-week trials and the percent

 

      weight loss was about 13 percent in each.  That is

 

      pretty much all there is with phentermine which is

 

      the most commonly used drug.

 

                That is sort of, if not the bad news, at

 

                                                               120

 

      least the mediocre news.  Let's look at what is

 

      going on for the future.  I apologize, I am sure

 

      some of the companies out there have some areas

 

      that I have left out here.  But we know gut

 

      peptides are a very fierce focus of action with CCK

 

      analogues and enterostatin and so on; opioid

 

      antagonists, the ones in phase 3 trials; various

 

      neurotransmitter agonists and antagonists;

 

      thermogenic agents, the Holy Grail--increase your

 

      metabolic rate, keep eating and increase your

 

      muscle mass and reduce your fat mass.  Growth

 

      hormone and growth factors have been disappointing

 

      to date but maybe there is something there.  Things

 

      that enhance lipid oxidation I think will be of

 

      particular interest; and nutrient partitioning

 

      agents will be very interesting agents for the

 

      future.  I am sure this isn't all.  There are many

 

      more areas in which we may be able to affect food

 

      intake, body weight or body composition.

 

                These are just some of the potential

 

      agents.  Again, several people and particularly

 

      Frank have talked about bupropion, topiramate and

 

                                                               121

 

      zonisamide which are already out there.  There are

 

      several in clinical trials, and then there are a

 

      number of others here.  From my understanding,

 

      there are about 350 different drugs in the

 

      pipeline.

 

                This is the data on bupropion.  Frank

 

      already showed this, about a 10 percent weight loss

 

      at a year.

 

                Topiramate--I put this slide up because it

 

      shows 5-year data in epilepsy patients.  As Frank

 

      showed you, it has a pretty reasonable comparison

 

      against placebo at 6 months.

 

                This is the data from Gadde on zonisamide,

 

      again showing a 32-week weight loss of about 9

 

      percent.

 

                However, single drugs are not likely to be

 

      very effective or much better than about 10 percent

 

      or 15 percent because there are so many redundant

 

      systems regulating food intake and body weight,

 

      something so critical to life as that.  So, I think

 

      I am not sure we are even born yet with our use of

 

      drug combinations.  I talked about the infancy of

 

                                                               122

 

      drubs.  Obesity is a chronic disease.  Most chronic

 

      diseases are treated with drugs.  Most chronic

 

      diseases require more than one drug.  How many

 

      chronic diseases can you think of that are treated

 

      with just one drug?

 

                You heard about phentermine and

 

      fenfluramine.  Combinations of drugs may have

 

      additive or synergistic effects.  As Weintraub

 

      showed with phen-fen, some of the side effects may

 

      even be offset.

 

                Here is the original Weintraub data

 

      showing about a 15 percent weight loss at a year.

 

      As you know, he took those data out to 4 years.  He

 

      had a pretty good dropout rate but still had

 

      efficacy.

 

                Here is another combination of ephedrine

 

      and caffeine.  Either one alone is not terribly

 

      effective but the combination causes about a 16

 

      percent weight loss that persisted out to a year.

 

      That is, of course, not on the market anymore.

 

                Here is some data that we did at the

 

      University of Wisconsin comparing phen-fen to

 

                                                               123

 

      phentermine and fluoxetine and the slope is about

 

      the same.  These are 6-month data.  Again, we had a

 

      pretty good dropout.  We did not have a control

 

      group.

 

                This meeting is all about the guidances

 

      and what is going to happen to the guidances.  So,

 

      let me put on my helmet, get my lance out and tilt

 

      at this windmill for a while to talk about some of

 

      the things that I think would be very useful to

 

      have from an obesity advocacy point of view.

 

                Obesity is a major public health problem.

 

      We have an epidemic here.  There have been 10 times

 

      more people dying of obesity-related causes than

 

      are dying of AIDS in this country alone.  Why

 

      shouldn't obesity drugs be fast track as they are

 

      for many other drugs?  As Dr. Greenway pointed out,

 

      in virtually all the drugs that we see the weight

 

      loss plateaus certainly by 6 months.

 

                Why should we need to show efficacy?  Why

 

      should the trials go out past that?  Why not have

 

      safety?  You know, safety is what is really

 

      important.  If you show efficacy, and almost all

 

                                                               124

 

      the drugs show a 5 percent weight loss in 6 months

 

      or better, virtually all the safety issues have

 

      been seen by then, and when we have a drug on the

 

      market--fenfluramine--for 20-some years and we

 

      don't pick up that it has a problem, it is just a

 

      crap shoot.  Why not go ahead and allow the drug

 

      companies to cut those massive costs of research to

 

      get the drugs on the market earlier, and then have

 

      a much more rigorous long-term safety evaluation as

 

      the drugs are on the market and they can begin to

 

      recover some of their costs?

 

                This extended run-in period--I see very

 

      little usefulness for the run-in period.  I am

 

      raising some of the questions that were brought up

 

      at the discussions that we have had, four

 

      discussions so far.  One of the things that most

 

      people feel is really pretty useless is a run-in

 

      period.  In one of the original guidances people

 

      were supposed to show weight loss and only those

 

      people who showed weight loss would then be allowed

 

      to go on to the clinical trial.  That makes no

 

      sense at all.  We know that long-term diet and

 

                                                               125

 

      exercise don't work.  The question is do drugs work

 

      long term?  Trying to get people to change their

 

      behavior is very, very difficult.  If you can

 

      change their biochemistry maybe we can get

 

      somewhere.

 

                Frank Greenway showed a trial on mazindol

 

      with and without behavior modification, and when

 

      you throw in behavior modification you reduce the

 

      apparent efficacy of the drug but you can only lose

 

      weight so fast.  If you starve yourself you can

 

      only lose weight so fast.  So, as you have a better

 

      diet and exercise program you wash out the effect

 

      of the drug.  Why have a run-in period at all?

 

                Another thing that I think would be

 

      useful--I was quite interested in Eric's comments

 

      about what used to be the acceptable standard, any

 

      statistically significant difference from placebo.

 

      Drugs almost certainly will have to be used in

 

      combination.  Unfortunately, sibutramine and

 

      orlistat don't work in combination but phentermine

 

      and fenfluramine did.  I, and I know others in this

 

      room, have used phentermine and topiramate together

 

                                                               126

 

      and appear to get a little better weight loss than

 

      with either one alone.  That has not been studied

 

      in any organized fashion.  So, if safe, these drugs

 

      not only cause modest weight loss, many hold

 

      promise that they could be used in combination with

 

      other drugs and I would love to see that in the

 

      guidances somehow.       Varied indications for use are

 

      justified.  Others have shown that rapid weight

 

      loss initially is associated with better response

 

      of blood pressure, blood sugar.  Jim Anderson has

 

      done two meta-analyses showing that rapid weight

 

      loss early, no matter what the time period, no

 

      matter what the outcome measure--the people who

 

      have lost a lot initially have at least as good or

 

      better outcome variables.  So, maybe drugs that

 

      only cause a short-term weight loss might be useful

 

      and then you switch to something else.

 

                So, I think there are many varied

 

      indications for use.  Some for short term; some for

 

      long term; some for use after a very low calory

 

      diet, and perhaps the committee could consider some

 

      of those indications.

 

                                                               127

 

                One of the things that David Orloff and I

 

      spent some time talking about on the phone is how

 

      desperate the American public for drugs to treat

 

      obesity.  So, I think rational expectations for the

 

      media and for patients--current drugs are only

 

      modestly effective.  Drugs in the pipeline appear

 

      to be similar in terms of efficacy.  The maximum

 

      weight loss that I have heard is about 17 percent.

 

                When companies over-hype the weight loss

 

      or try to convince people that a 5 percent or 10

 

      percent weight loss is wonderful, it is not.  So, I

 

      think over-hyping is bad on the part of the drug

 

      companies.  On the other hand, over-caution by the

 

      FDA and scientists is detrimental.  Hundreds of

 

      thousands of people are dying of obesity-related

 

      causes.  Some drugs cause some problems.  We have

 

      to be safe but there is that tradeoff and Eric's

 

      balance at the end I thought was particularly

 

      appropriate.  The media has not always been

 

      responsible.  In fact, I would say the media has

 

      been predominantly irresponsible.  I still remember

 

      the Redux revolution--the cover on Time magazine,

 

                                                               128

 

      this is going to solve all your problems, America.

 

      The general public is desperate.  They need

 

      perspective and understanding of obesity as a

 

      disease.  Physicians have not really given them

 

      that perspective.  Unfortunately, I think long-term

 

      lifestyle changes are needed.  Trying to change

 

      behavior is very difficult but that is what we are

 

      stuck we right now.

 

                For the future, I believe drugs of the

 

      future of obesity treatment has the offer of

 

      virtually every other chronic disease.  Obesity is

 

      due to biochemical differences.  Drugs change

 

      biochemistry.  And, why am I so optimistic?  Frank

 

      Greenway showed you the data on obesity surgery is

 

      somewhere between 25-40 percent of anethole body

 

      weight.  Surgery doesn't work because it makes a

 

      little gastric pouch.  It works because it changes

 

      the biochemistry of the body.  There are starting

 

      to be lots of papers on changes in metabolic rate

 

      and multiple different hormones.  And, if surgery

 

      can do it I have no doubt that the smart people at

 

      the drug companies are going to figure out how they

 

                                                               129

 

      can reproduce that kind of weight loss with one

 

      drug or combinations of drugs.  The surgery changes

 

      biochemistry.

 

                At least 350 drugs are in the pipeline, I

 

      understand, and I think that bodes very well for

 

      the future.  Combination treatment I think is going

 

      to be necessary, and I think the future is

 

      extremely bright.

 

                So, I will just end up by showing the

 

      slide for the American Obesity Association.  It is

 

      a lay advocacy group.  Its mission is to improve

 

      the quality of life of obese people.  I guess you

 

      got copies of these slides but this is my contact

 

      information, here.  Thank you very much.

 

                DR. BRAUNSTEIN:  Thank you, Richard.

 

      Questions from the panel?  Let me start off with

 

      one.  You mentioned that fenfluramine had been on

 

      the market for some time before the valvulopathy

 

      was uncovered.  If we look at the previous

 

      speaker's slides on the use of fenfluramine, it

 

      really didn't pick up greatly until the Weintraub

 

      papers had come out.  So, I wonder if what we are

 

                                                               130

 

      talking about in terms of safety is a numbers game;

 

      if you really do need a large number of patients to

 

      pick up some of these potentially disastrous

 

      complications.  I would like your thoughts on that.

 

                DR. ATKINSON:  Yes, I notice there was

 

      something like 70,000 prescriptions of fenfluramine

 

      per year over a long period of time.  That went up

 

      to several million later.  But Weintraub's paper

 

      came out in 1992.  By 1993 those numbers were going

 

      up dramatically and it still took until 1997 before

 

      it was identified, and there were millions of

 

      people taking it obviously, and fenfluramine and

 

      dexfenfluramine had been used in Europe.

 

      Obviously, dexfenfluramine had been approved 10

 

      years earlier.  So, it is not just here.  It was

 

      all over the world that it was being used and it

 

      wasn't picked up.

 

                So, you know, I think drugs are going to

 

      have consequences and obviously we need to look

 

      very carefully at the drugs and study them, but I

 

      would argue for shorter initial trials and more

 

      intensive longer-term trials.  I noticed in one

 

                                                               131

 

      slide that the FDA was not charged with showing the

 

      safety of drugs after they have been approved.

 

      That probably ought to change.

 

                DR. S. YANOVSKI:  I would just like to

 

      comment on your excellent question about

 

      dexfenfluramine and why it hadn't been picked up

 

      earlier with the fenfluramine.  Before the

 

      Weintraub papers came out these drugs were used

 

      only exclusively short term, often 30 days or less

 

      and it was never more than 90 days.  It was only

 

      after the Weintraub paper came out that they

 

      started getting used for months and months and, in

 

      some cases, even years.  Since there was a length

 

      of treatment response relationship with the

 

      valvulopathy, that is likely why it wasn't seen

 

      earlier.

 

                DR. ATKINSON:  Yes, that is an interesting

 

      point, however, there were a number of people that

 

      were reported that had valvulopathy who used it for

 

      a relatively short period of time.  It is probably

 

      an idiosyncratic reaction.

 

                DR. BRAUNSTEIN:  Dr. Woolf?

 

                                                               132

 

                DR. WOOLF:  I am unclear.  Are you

 

      proposing that drugs for the treatment of obesity

 

      be held to a different standard in terms of

 

      evaluation of efficacy and safety than drugs in

 

      general?  At least the drugs that we discussed in

 

      this committee before have had trials longer than 6

 

      months, and certainly the clinical trials that I

 

      participated in have been longer than 6 months.

 

      So, are you proposing a different standard for

 

      obesity drugs, or that the FDA change its modus

 

      operandi?

 

                DR. ATKINSON:  I couldn't hear that very

 

      well, but what I heard is am I proposing different

 

      standards for obesity drugs?  I think there are

 

      different standards for different drugs.  For

 

      example, drugs for Alzheimer's disease, drugs for

 

      AIDS, after relatively limited safety and efficacy

 

      evaluations, are allowed to go on the market.  The

 

      point I am making is we have an epidemic of obesity

 

      and a third of the population is affected.  I think

 

      it is not unreasonable to say how can we improve

 

      the delivery of drugs, new and better drugs and

 

                                                               133

 

      more drugs so we can try some of those

 

      combinations?  No, I don't want to have different

 

      standards but I think there are different standards

 

      for drugs and I would like to put obesity with sort

 

      of the ones that get handled expediently.

 

                DR. BRAUNSTEIN:  Dr. Schade?

 

                DR. SCHADE:  I have a question about

 

      weight loss.  If one assumes that the drugs overall

 

      result in, let's say--I am going to be

 

      optimistic--10 percent weight loss, if you look at

 

      the mortality or morbidity curve, if somebody has a

 

      BMI of 35 and they lose 10 percent of the weight so

 

      they drop to a BMI of 32, is their mortality then

 

      exactly the same as a group that doesn't lose

 

      weight but has a BMI of 32?

 

                DR. ATKINSON:  Yes, that is a very good

 

      question.  I don't know the answer to that.

 

      Katherine Flegal's data were mainly focused on the

 

      lower BMI groups.  As you start up, when you start

 

      getting to 30 and above, those curves start going

 

      up fairly dramatically I think, if that is right,

 

      Katherine.  But I can't tell you that if you have

 

                                                               134

 

      lost 2, 3 or 5 BMI units, do you then assume the

 

      mortality and the morbidity of people who have

 

      never been above that.  I just don't know that.

 

                DR. SCHADE:  Well, the reason I ask that

 

      is when we treat diabetes we treat hemoglobin A1C

 

      and we assume, through our treatment, that we then

 

      reduce the hemoglobin A1C and we can plot on the

 

      curve the benefit.  I just wondered whether the

 

      curve for obesity is similar.

 

                DR. ATKINSON:  Yes, and I think that is

 

      good.  As you heard, there are some trials that are

 

      ongoing to try to look at these sorts of things.

 

      Again, this is a disease that

 

      affects--what?--100-some million people in the U.S.

 

      and we know almost nothing about it.

 

                DR. BRAUNSTEIN:  Dr. Aronne?

 

                DR. ARONNE:  Can I comment on the last

 

      question?  I think that the benefit from small

 

      amounts of weight loss is disproportionate to the

 

      amount of weight lost because of the initial loss

 

      of visceral fat.  When you look at the composition

 

      of weight that is initially lost, it is the

 

                                                               135

 

      riskiest fat that is lost first so small amounts of

 

      weight loss appear to have disproportionate

 

      benefit, out of proportion of what you would expect

 

      from that small amount.  What some people have

 

      suggested is following something like the

 

      C-reactive protein and that in the future that

 

      could turn out to be our version of the hemoglobin

 

      A1C because it is a measure of the inflammatory

 

      burden of fat, and a lot of people believe that

 

      visceral fat is where a lot of the C-reactive

 

      protein is coming from.

 

                DR. BRAUNSTEIN:  Dr. Orloff?

 

                DR. ORLOFF:  Can you reiterate your

 

      position on the run-in aspect of trial designs, and

 

      specifically address whether you are proposing that

 

      all run-ins of any duration, of any type, be

 

      dispensed with?

 

                DR. ATKINSON:  No, certainly not.  I think

 

      a run-in period in the trials that I have designed

 

      and gone out and done, investigator initiated type

 

      clinical trials, we have put in a 2-week run-in

 

      period that was not a treatment period but we

 

                                                               136

 

      stretched out the initial evaluation.  What that

 

      does is get out the people who are not serious, who

 

      don't want to come or it is too difficult to come,

 

      or whatever.  But in terms of requiring a weight

 

      loss or requiring people to show that they can

 

      adhere to a diet before they are allowed to go on

 

      drugs, that is not true for other kinds of

 

      diseases, for example, diabetes and hypertension,

 

      and there may be companies that would want to do

 

      that and would want to have a run-in, or that would

 

      be what they think their drug is going to be useful

 

      for--in other words, get the weight off and then

 

      this is going to be their weight maintenance drug.

 

      Fine, they can have a run-in.  But I think the

 

      mandate that all companies have to have an extended

 

      run-in I don't agree with.

 

                DR. ORLOFF:  Again, a bit more

 

      clarification.  Do you still advocate diet and

 

      exercise and continued reinforcement of those

 

      lifestyle aspects for treatment of obesity in the

 

      context of the trial?

 

                DR. ATKINSON:  Yes, I guess it was fairly

 

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      dramatically shown here.  Dr. Greenway showed the

 

      difference in weight losses that are achieved in

 

      the United States versus over in Europe.  The

 

      companies design the trial to get well over

 

      whatever the standards are.  So, I think that can

 

      be manipulated.

 

                I make the statement often that everybody,

 

      whether they are skinny or fat, needs to have a

 

      good diet and lifestyle.  I think as people come in

 

      they need to be informed of what is a healthy

 

      lifestyle and the exercise and the vegetables, and

 

      all those things.  Again, I am speaking for myself

 

      not for anybody else, but I think the idea of

 

      allowing the drug companies individually to figure

 

      out where in the spectrum they want to put that is

 

      not unreasonable, but at least some lip service

 

      ought to be given, if for no other reason, because

 

      people will do things very differently.  I mean,