1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

 

 

                  FDA SCIENCE BOARD ADVISORY COMMITTEE

 

 

 

 

 

 

 

                        Thursday, April 22, 2004

 

                               8:00 a.m.

 

 

 

             Advisors and Consultants Staff Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland

                                                                 2

 

                              PARTICIPANTS

 

         Kenneth I. Shine, M.D., Chair

         Jan. N. Johannessen, Ph.D., Executive Secretary

 

      BOARD MEMBERS:

 

         Gail H. Cassell, Ph.D.

         Josephine Grima, Ph.D., Consumer Representative

         Susan Harlander, Ph.D.

         Cato T. Laurencin, M.D., Ph.D.

         Cecil B. Pickett, Ph.D.

         F. Xavier Pi-Sunyer, M.D., M.P.H.

         Jose C. Principe, Ph.D.

         Jim E. Riviere, D.V.M., Ph.D.

         Allen D. Roses, M.D.

         Katherine M.J. Swanson, Ph.D.

         John L. Thomas, Ph.D.

 

      OFFICE OF THE COMMISSIONER:

 

         Lester M. Crawford, D.V.M., Ph.D.,

         Norris E. Alderson, Ph.D.

 

      FDA:

 

         Daniel A. Casciano, Ph.D.

         David W. Feigel, Jr., M.D., M.P.H.

         Kathy Carbone, M.D.

         John Marzilli

         Robert E. Brackett, Ph.D.

         Steven Galson, M.D., M.P.H.

                                                                 3

 

                            C O N T E N T S

 

      Call to Order, Kenneth I. Shine, M.D., Chair,              5

 

      Welcome and Opening Remarks,

        Lester M. Crawford, D.V.M., Ph.D., Acting

          Commissioner of Food and Drugs                         9

 

      Overview of the FDA Initiative on Obesity,

        Robert E. Brackett, Ph.D., CFSAN, FDA                   19

 

      Obesity - Therapeutics, David G. Orloff, M.D.,

        CDER, FDA                                               27

 

      Obesity - Research, David W.K. Acheson, M.D.,

        CFSAN, FDA                                              47

 

      Highlights of the Obesity Working Group Report,

        Alan Rulis, Ph.D., CFSAN, FDA                           76

 

      Questions and Discussion with the

        Board/Presenters                                        96

 

      Update on ORA Peer Review Process,

        John R. Marzilli, Deputy Associate

        Commissioner for Regulatory Affairs, FDA               129

 

        John J. Specchio, Ph.D., ORA Science Advisor           135

 

      Open Public Hearing:

 

        Arthur Frank, M.D., George Washington University       150

        Elizabeth Jacobson, Ph.D., AdvaMed                     158

        Richard Atkinson, M.D., American

          Obesity Association                                  170

 

      Introduction to Critical Path, Janet Woodcock,

        M.D., Acting Deputy Commissioner for

        Operations, FDA                                        175

 

      Perspective on Anti-Infectives and Vaccines,

        Gail H. Cassell, Ph.D., Eli Lilly and Company          220

 

      Perspective on Chronic Disease Therapies,

        Robert M. Califf, M.D., Duke University                241

                                                                 4

 

                            C O N T E N T S

 

      Drug Formulation and Development, and Tissue

        Engineering Issues, Robert S. Langer, Sc.D., MIT       268

 

      Overview of Opportunities - Drugs, Robert Temple,

        M.D., CDER, FDA                                        298

 

      Overview of Opportunities - Devices, Larry G.

        Kessler, Sc.D., CDRH, FDA                              324

 

      Overview of Opportunities - Biologics,

        Jesse Goodman, M.D., M.P.H., CBER, FDA                 339

 

      Questions and Discussion with Board -

        Recommendations                                        363

 

                                                                 5

 

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

 

  2                          Call to Order

 

  3             DR. SHINE:  Good morning, ladies and

 

  4   gentlemen.  We will come to order.  Welcome to this

 

  5   meeting of the FDA Science Board Advisory

 

  6   Committee.  I am Ken Shine.  Mark McClellan, when

 

  7   he was Commissioner, asked me if I would chair this

 

  8   committee then he split!

 

  9             [Laughter]

 

 10             I was a little anxious because our

 

 11   colleague, Dr. Crawford, who is the Acting

 

 12   Commissioner, was scheduled perhaps to be in Japan

 

 13   but it turns out that he is able to be here so I

 

 14   don't feel quite so deserted.  But we are pleased

 

 15   to be able to welcome you to this meeting which

 

 16   will be focused on two major and extremely

 

 17   important issues for all of us, the issues relating

 

 18   to the epidemic of obesity, which is a worldwide

 

 19   epidemic of extraordinary proportions in terms of

 

 20   all of the implications of that epidemic; and then

 

 21   an examination of the Critical Path in terms of the

 

 22   necessity to find ways to bring new products to

 

                                                                 6

 

  1   market in a timely and cost effective way.

 

  2             We have a very distinguished advisory

 

  3   committee and before we ask Dr. Crawford to make

 

  4   his introductory comments, perhaps we could go

 

  5   around, starting with Dr. Pickett, and ask you to

 

  6   identify yourself and then just a sentence or so

 

  7   about your area of interest or perspective that you

 

  8   bring to the committee so that folks have a sense

 

  9   of your approach to things.  Dr. Pickett?

 

 10             DR. PICKETT:  Yes, good morning.  I am

 

 11   Cecil Pickett.  I am President of Research and

 

 12   Development for the Schering-Plough Corporation,

 

 13   which is the pharmaceutical arm of Schering-Plough.

 

 14   I obviously have a fundamental interest in drug

 

 15   discovery and drug development and how we can bring

 

 16   innovative new therapies to patients.

 

 17             DR. PRINCIPE:  Good morning.  My name is

 

 18   Jose Principe.  I am Distinguished Professor of

 

 19   Electrical and Biomedical Engineering at the

 

 20   University of Florida, and my expertise resides in

 

 21   electrical systems and machine and learning

 

 22   algorithms.

 

                                                                 7

 

  1             DR. RIVIERE:  Hello.  I am Jim Riviere.  I

 

  2   am Distinguished Professor of Pharmacology, North

 

  3   Carolina State University, and have expertise in

 

  4   pharmacology and toxicology.

 

  5             DR. GRIMA:  Hi. My name is Josephine

 

  6   Grima.  I am the Director of Research and

 

  7   Legislative Affairs for the National Marfan

 

  8   Foundation, and I am the consumer representative.

 

  9             DR. THOMAS:  Good morning.  I am John

 

 10   Thomas, Vice President, retired, and Professor

 

 11   Emeritus of Pharmacology and Toxicology, University

 

 12   of Texas Health Science Center at San Antonio.

 

 13             DR. SWANSON:  Good morning.  I am Katie

 

 14   Swanson.  I am with the President of KMJ Swanson

 

 15   Food Safety, a food safety consulting firm.

 

 16             DR. LAURENCIN:  I am Cato Laurencin.  I am

 

 17   a Lillian Pratt Distinguished Professor and Chair

 

 18   of Orthopaedic Surgery, and university professor at

 

 19   the University of Virginia.  My areas of expertise

 

 20   are biomaterials, tissue engineering and

 

 21   nanotechnology.

 

 22             DR. PI-SUNYER:  I am Xavier Pi-Sunyer.  I

 

                                                                 8

 

  1   am Professor of Medicine at Columbia University

 

  2   College of Physicians and Surgeons, and I am

 

  3   Director of the Division of Endocrinology and the

 

  4   Obesity Research Center at St. Lukes Roosevelt

 

  5   Hospital.  My area of interest is diabetes and

 

  6   obesity.

 

  7             DR. HARLANDER:  Hello.  My name is Susan

 

  8   Harlander.  I am president of my consulting firm,

 

  9   called BIOrational Consultants.  My background is

 

 10   in food science and nutrition and I work primarily

 

 11   in the areas of genetically modified foods and

 

 12   drugs.

 

 13             DR. ROSES:  I am Allen Roses.  I am Senior

 

 14   Vice President in Genetics Research,

 

 15   GlaxoSmithKline.  I spent 27 years at Duke and the

 

 16   final 20 of those I was Chairman of Neurology.  My

 

 17   expertise is in neurology and genetics, medicine

 

 18   and a variety of other.

 

 19             DR. SHINE:  Thank you.  Have I missed

 

 20   anybody on the committee?  We will be hearing from

 

 21   some of our colleagues at the FDA shortly.  I am

 

 22   Ken Shine.  I serve currently as the Executive Vice

 

                                                                 9

 

  1   Chancellor of Health Affairs at the University of

 

  2   Texas System, after two terms at the Institute of

 

  3   Medicine.  I am interested in health policy.  As a

 

  4   cardiologist, I also recommend the food for

 

  5   breakfast--

 

  6             [Laughter]

 

  7             --and hope that in the interest of

 

  8   controlling obesity we will all have heart healthy

 

  9   lunches.  So, we will see!

 

 10             I think we are very fortunate that Les

 

 11   Crawford can serve as the interim Commissioner.  I

 

 12   have known Dr. Crawford for many years and his

 

 13   leadership in this organization has been manifest

 

 14   over and over again.  He brings wonderful

 

 15   experience and perspective and we will ask him to

 

 16   make a few remarks.  Les?

 

 17                   Welcome and Opening Remarks

 

 18             DR. CRAWFORD:  Well, thanks very much, Dr.

 

 19   Shine, and thank you very much for agreeing to be

 

 20   chairman.  It is one of the lasting legacies of the

 

 21   great Mark McClellan that you are here.  You cannot

 

 22   be replaced until he comes back--

 

                                                                10

 

  1             [Laughter]

 

  2             --it is almost like a biblical thing.

 

  3             DR. SHINE:  Now I am worried!

 

  4             DR. CRAWFORD:  In any case, I want to

 

  5   welcome you as the chairman and also we have four

 

  6   new members, all of whom I have known before except

 

  7   Dr. Allen Roses, and I am particularly grateful for

 

  8   you to agree to serve on this committee.  We expect

 

  9   great things from you and you will have a fun time.

 

 10   I think your particular area of expertise is very

 

 11   much needed by the committee and I hope it is an

 

 12   enjoyable and fruitful thing for you.

 

 13             I have known Dr. Susan Harlander for a

 

 14   long time, and she was been nominated for this

 

 15   committee and turned us down one time before but

 

 16   she can run but she can't hide.  She is right here

 

 17   today, and thank you for that.

 

 18             Xavier Pi-Sunyer and I served on the same

 

 19   committee, another committee which met only one

 

 20   day, Dr. Pi-Sunyer, and went away, some ten years

 

 21   ago.  This one is enduring.  So, thank you also.

 

 22             Gail Cassell--I think Gail is not here yet

 

                                                                11

 

  1   but she is coming.  Also, she is very well

 

  2   recommended because she comes from the University

 

  3   of Alabama, Birmingham.  She and I speak the same

 

  4   language and communicate often.  So, we are

 

  5   grateful to her also.

 

  6             We have had, as I mentioned earlier, the

 

  7   transfer actually of Mark McClellan to the Center

 

  8   for Medicare and Medicaid Services.  That is a blow

 

  9   for us but it is a strengthening of our Department

 

 10   of Health and Human Services, which is our umbrella

 

 11   organization under Tommy Thompson.  So, Dr.

 

 12   McClellan is still available to us and we see him

 

 13   fleetingly but he is very much interested in what

 

 14   is happening here, and we will continue to stay in

 

 15   touch throughout this administration and beyond.

 

 16             We remain focused on his strategic plan

 

 17   that has now become our strategic plan and also on

 

 18   the five goals where were developed during that

 

 19   time, which were shared and worked out to some

 

 20   extent in concert with this committee.  Those have

 

 21   stood the test of time.  All the work is not

 

 22   completed but we believe those benchmarks that were

 

                                                                12

 

  1   established by the committee or commission on the

 

  2   strategic plan which meets monthly in order to do a

 

  3   check of how well we are doing--we think all of

 

  4   that work will be accomplished within this

 

  5   presidential administration.  At that time we will

 

  6   put a ribbon around it, put it in a box and serve

 

  7   it up to the American people.  I think it is a job

 

  8   already well done but a job not quite completed.

 

  9             We are focusing on our mission of

 

 10   protecting and advancing public health.  We face

 

 11   many new challenges and opportunities.  We are

 

 12   proceeding with your help through the most

 

 13   difficult part, which is bringing science to bear

 

 14   on the regulatory process.

 

 15             This session of the FDA Science Advisory

 

 16   Board is scheduled, actually, at a very opportune

 

 17   time.  The agency has undertaken a number of major

 

 18   new initiatives, two of which you will be hearing

 

 19   about in much greater detail during the remainder

 

 20   of the day.

 

 21             On March 12 of last year Secretary

 

 22   Thompson released a new FDA report outlining the

 

                                                                13

 

  1   agency's strategy for combating the major public

 

  2   health problem of obesity, actually initiated it on

 

  3   March 12 of last year and received a report from

 

  4   FDA this year.  In point of fact, three different

 

  5   agencies, under the leadership of Secretary

 

  6   Thompson, did major initiatives on obesity.  These

 

  7   were six-month programs to bring together the

 

  8   expertise in the National Institutes of Health, the

 

  9   Centers for Disease Control and the Food and Drug

 

 10   Administration.

 

 11             During the time that those three

 

 12   committees were working on the problem of obesity,

 

 13   from its very fundamental scientific rationale all

 

 14   the way up to ameliorative steps, the estimated

 

 15   number of deaths from obesity-related diseases in

 

 16   the United States increased from 300,000 per year

 

 17   to 400,000 per year.  A major path-breaking paper

 

 18   by Dr. Julie Gerberding and others at the Centers

 

 19   for Disease Control and Prevention have estimated

 

 20   that obesity is going to overtake smoking as the

 

 21   leading cause of death in the United States by the

 

 22   end of this decade.

 

                                                                14

 

  1             These are chilling figures.  It is a

 

  2   horrible disease, a complex of diseases that is

 

  3   lurching out of control.  FDA, through the

 

  4   authorities it has under the Nutrition, Labeling

 

  5   and Education Act, must do something.  Dr. Bob

 

  6   Brackett is going to detail that for you.  He came

 

  7   in as Director of the Center for Food Safety and

 

  8   Applied Nutrition in the middle of the obesity

 

  9   initiative but his expertise and leadership are

 

 10   very much part and parcel of our accomplishing of

 

 11   this mission.  He will talk about the other people

 

 12   from his Center and elsewhere who were on the

 

 13   committee, but it is a great accomplishment for FDA

 

 14   and I am very pleased that you are going to hear

 

 15   about it in depth from Dr. Brackett himself.

 

 16             The second major thing is the Critical

 

 17   Path initiative which was developed in the last

 

 18   stages of Dr. McClellan's tenure here.  It has

 

 19   stood the test of introduction; it has not stood

 

 20   the test of time yet.  But with your help we will

 

 21   get the Critical Path from the research laboratory

 

 22   to the bedside, to the pharmacy, to the hospital

 

                                                                15

 

  1   and all other places where we need to be sure that

 

  2   FDA is not an impediment to the development and

 

  3   introduction of new drugs and other modalities of

 

  4   therapy, and also fine-tuning our procedures so

 

  5   that we actually encourage by efficiency the

 

  6   development of much needed drugs in much needed

 

  7   areas.

 

  8             One of the things that you will hear about

 

  9   today is a publication, on a regular basis, of

 

 10   Critical Path opportunities that we will list to

 

 11   the public, to the industry that we serve, and also

 

 12   to all other stakeholders about what we think are

 

 13   the opportunities for new development that FDA

 

 14   would like to work with sponsors on, work with

 

 15   research institutions on and anybody and everybody

 

 16   else.  This is something new for FDA and I think we

 

 17   are ready for it, but you will also have some

 

 18   targets of opportunity this morning to help shape

 

 19   and develop that critical initiative.  I believe it

 

 20   will be with us for a long time.  We have had some

 

 21   similar kinds of things in the past that we have

 

 22   come up with, but this one has a system to it and

 

                                                                16

 

  1   we believe, if we do it right, it will be enduring

 

  2   and it will mark a new era for the Food and Drug

 

  3   Administration.  So, your critical attendance to

 

  4   that is very much solicited.  Dr. Woodcock will be

 

  5   talking about that.

 

  6             At this point I would like to turn the

 

  7   floor back over to Ken Shine, with many thanks once

 

  8   again for his leadership on this committee.  I am

 

  9   looking forward to the day, as I hope all of you

 

 10   are.  Thank you.

 

 11             DR. SHINE:  Thank you very much, Dr.

 

 12   Crawford.  One of the responsibilities of this

 

 13   committee is to be the final judges in the FDA

 

 14   scientific achievement awards program.  Those

 

 15   awards apparently will be given in another month or

 

 16   so, but I think one of the parts of our activities

 

 17   has been the opportunity to look at the quality of

 

 18   the science.  I had a great deal of difficulty in

 

 19   choosing in many categories the more outstanding of

 

 20   the proposal because the science was so good.  I

 

 21   think that is an area that has been extremely

 

 22   encouraging to the committee.

 

                                                                17

 

  1             We do have some other business we have to

 

  2   undertake before we begin the program, and Jan

 

  3   Johannessen is going to take care of that.

 

  4             DR. JOHANNESSEN:  Thank you, Dr. Shine.

 

  5   The following announcement addresses the issue of

 

  6   conflict of interest with respect to this meeting,

 

  7   and is made part of the public record to preclude

 

  8   even the appearance of such at the meeting.

 

  9             The Food and Drug Administration has

 

 10   prepared general matters waivers for Drs. Shine,

 

 11   Principe, Pickett, Grima, Riviere, Laurencin,

 

 12   Swanson, Thomas, Roses, Pi-Sunyer, Cassell,

 

 13   Harlander and one of the guest speakers, Dr.

 

 14   Califf.  A copy of the waiver statements may be

 

 15   obtained by submitting a written request to our

 

 16   Freedom of Information office.  The waivers permit

 

 17   them to participate in the committee's discussion

 

 18   of FDA's obesity working group report and Critical

 

 19   Path initiative.

 

 20             Topics of today's meeting are of broad

 

 21   applicability and, unlike issues before a committee

 

 22   in which a particular product is discussed, issues

 

                                                                18

 

  1   of broader applicability involve many industrial

 

  2   sponsors and academic institutions.  The

 

  3   participating committee members have been screened

 

  4   for their financial interests as they may apply to

 

  5   these general topics at hand.  Because general

 

  6   topics impact so many institutions, it is not

 

  7   practical to recite all the potential conflicts of

 

  8   interest as they apply to each participant.  The

 

  9   FDA acknowledges that there may be potential

 

 10   conflicts of interest but, because of the general

 

 11   nature of the discussion before the committee,

 

 12   these potential conflicts are mitigated.

 

 13             We have open public comments scheduled for

 

 14   eleven o'clock.  I would just remind everyone to

 

 15   turn your microphones on when you speak so that the

 

 16   transcriber can pick everything up.  Thank you.

 

 17             DR. SHINE:  Thank you very much, Jan.  I

 

 18   think we are prepared now to go to our program.  I

 

 19   would just make a couple of observations.  This is

 

 20   a very dense program and we are going to have to,

 

 21   on the one hand, hold our speakers to the time that

 

 22   is allotted to them and, at the same time, I would

 

                                                                19

 

  1   urge you to make notes and recognize that if they

 

  2   use their full allotted time we are not going to be

 

  3   able to question them at that time but, rather, we

 

  4   have a specific period at 10:15 for a period of

 

  5   questions.  So, if there are issues where you

 

  6   really need clarification in order to understand

 

  7   what is being proposed, then by all means we ought

 

  8   to do that.  On the other hand, we are going to

 

  9   have to move expeditiously through the

 

 10   presentations if we are going to get today's work

 

 11   done.

 

 12             We are pleased that the overview for the

 

 13   FDA initiative on obesity, as you have heard, will

 

 14   be provided by Dr. Robert Brackett and we invite

 

 15   him to proceed.

 

 16            Overview of the FDA Initiative on Obesity

 

 17             DR. BRACKETT:  Thank you, Dr. Shine.

 

 18             [Slide]

 

 19             Good morning, everybody.  I am Bob

 

 20   Brackett and what I am going to do is give a very

 

 21   brief overview of sort of the major points of the

 

 22   obesity initiative, and then following me the next

 

                                                                20

 

  1   three speakers will actually get into some of the

 

  2   more final details that were part of the

 

  3   initiative, as well as some of the summary of the

 

  4   report.

 

  5             [Slide]

 

  6             I think the background for why we did this

 

  7   is pretty much apparent to most people in that

 

  8   people have sort of rediscovered that obesity in

 

  9   this country and worldwide is, in fact, of epidemic

 

 10   proportions in that in the United States overweight

 

 11   and obese people have increased risks of many other

 

 12   chronic diseases that are relating to the deaths

 

 13   that Dr. Crawford mentioned, including heart

 

 14   disease, diabetes and certain types of cancer.

 

 15   Also, as Dr. Crawford mentioned, it is enough so

 

 16   that there are significant deaths, to the point

 

 17   where that is competing with tobacco as a public

 

 18   health problem.  So, it is something that we do

 

 19   need to address within FDA, something that we have

 

 20   partnered on with other entities within Health and

 

 21   Human Services.  In fact, this is sort of a

 

 22   nationwide program where it takes the participation

 

                                                                21

 

  1   and the partnership of many different groups.  That

 

  2   is one of the things we have attempted to do and

 

  3   will attempt to do.

 

  4             [Slide]

 

  5             One thing that is lost, in addition to the

 

  6   400,000 deaths that are estimated related to

 

  7   obesity, is the economic cost of obesity to this

 

  8   country.  That is estimated at 117 billion dollars

 

  9   per year.  So, that has a major impact on the

 

 10   health costs in this country and does drive the

 

 11   cost for everybody.  So, it is something that we

 

 12   all need to participate in trying to eliminate.

 

 13             [Slide]

 

 14             The obesity working group was actually

 

 15   created in 2003, in August, by Dr. McClellan when

 

 16   he was here.  At that time Dr. Crawford was the

 

 17   chair and my predecessor, Joe Levitt, was the

 

 18   deputy chair at that time.

 

 19             [Slide]

 

 20             They were given a very simple charge, and

 

 21   that was to prepare a report that outlines an

 

 22   action plan that would cover the critical

 

                                                                22

 

  1   dimensions of the obesity problem that FDA could

 

  2   participate in with the other agencies as well.

 

  3             [Slide]

 

  4             During that time the group was very

 

  5   active.  From 2003 to 2004--that is not much time

 

  6   to do all of the activities that they had to and

 

  7   they were very, very active.  It was on a fast

 

  8   track.  The obesity working group met eight times

 

  9   during that short period of time.  They received

 

 10   briefings from a number of different invited

 

 11   experts from the Department of Health and Human

 

 12   Services, as well as and including Centers for

 

 13   Disease Control and NIH.  We did hold one public

 

 14   meeting and one workshop; two round table

 

 15   discussions; and also solicited from the public

 

 16   many different comments on our obesity related

 

 17   issues by docket submissions.  So, in fact, we did

 

 18   try to absorb as much information to put in this

 

 19   report as we possibly could, and then tried to

 

 20   synthesize all of what was provided and provide the

 

 21   report that was required.

 

 22             [Slide]

 

                                                                23

 

  1             This is just a copy of the report, and

 

  2   this has been submitted.  It is called "Calories

 

  3   Count" and it is the report of the working group on

 

  4   obesity.  What the report actually does is to

 

  5   provide a range of both short- and long-term

 

  6   recommendations to address this epidemic.

 

  7             An important part is that we did try to

 

  8   base all of these recommendations on known

 

  9   scientific facts.  So, it did take some teasing

 

 10   apart of what was thought to be contributing to

 

 11   obesity versus what is known from a nutritional

 

 12   standpoint.  The one thing it also attempted to do,

 

 13   and did, is address the multiple facets that

 

 14   contribute to the obesity problem, particularly

 

 15   those that are under FDA's purview.

 

 16             [Slide]

 

 17             Some of the recommendation highlights that

 

 18   were given from it are, first of all, developing

 

 19   appropriate and effective consumer messages to aid

 

 20   consumers in making wiser dietary choices.  That

 

 21   was one of the most important things, that is, to

 

 22   actually get consumers to understand that they are

 

                                                                24

 

  1   in control of their weight problems, and to

 

  2   establish educational strategies and partnerships

 

  3   to support these appropriate methods to teach

 

  4   people, and particularly children with regard to

 

  5   childhood obesity, how they can lead better lives

 

  6   through better nutrition.  So, this is getting back

 

  7   to some really fundamental issues that needed to be

 

  8   addressed to the American people.

 

  9             [Slide]

 

 10             It also involved pursuing improvements to

 

 11   the labeling of packaged foods with respect to

 

 12   caloric and other nutritional information, that is,

 

 13   giving the consumers the information they need to

 

 14   make the judgments that we were trying to educate

 

 15   them about.

 

 16             Then, encouraging and enlisting

 

 17   restaurants in voluntary, collaborative efforts to

 

 18   combat obesity and then also provide nutritional

 

 19   content information to consumers at the point of

 

 20   sale.  Since many of the meals are eaten away from

 

 21   the home, this was particularly important.

 

 22             [Slide]

 

                                                                25

 

  1             It also recommended facilitating the

 

  2   development of new therapeutics that could be used

 

  3   in the treatment of obesity, and then,

 

  4   coincidentally, designing and collaborating with

 

  5   others--and that "others" is very broad--effective

 

  6   research in the fight against obesity.  So, it was

 

  7   really trying to encompass the whole scope of

 

  8   activities that could be done.  Again, the

 

  9   important part was really involving the

 

 10   stakeholders continuously throughout these various

 

 11   processes.  We had to not be dictating what this

 

 12   was but it was actually a very participatory

 

 13   process.

 

 14             [Slide]

 

 15             The conclusions, in summary were, as many

 

 16   of us already know, that the problem of obesity in

 

 17   America really has no single cause.  There is no

 

 18   one thing that you could point to; it is really the

 

 19   result of a variety of different factors that when

 

 20   they act together over time--and this includes the

 

 21   genetic component for consumers and environmental

 

 22   factors--do contribute to increasing obesity and,

 

                                                                26

 

  1   consequently, there also is no single solution to

 

  2   this problem in that the current trends will only

 

  3   be reversed if you have well-coordinated,

 

  4   complementary efforts from virtually all sectors of

 

  5   society to combat this.

 

  6             [Slide]

 

  7             The other thing, and the part that we

 

  8   needed to particularly emphasize to consumers, is

 

  9   that the obesity epidemic is not going to be solved

 

 10   quickly, neither will their individual weight

 

 11   problems be solved quickly.  Any long-lasting

 

 12   reversal of the phenomenon will itself be a

 

 13   long-term process.  We took a long time to get to

 

 14   this point and it is going to take some time to

 

 15   reverse it.

 

 16             [Slide]

 

 17             Just to give you a little bit of update

 

 18   about the obesity working group, Dr. Rulis, who

 

 19   will be speaking this morning as well, has been

 

 20   engaging in a national policy dialogue of what

 

 21   things can and could be done with regard to

 

 22   obesity, especially FDA's participation.  Dr.

 

                                                                27

 

  1   Orloff, who will also be following up, has dealt a

 

  2   lot with the therapeutics aspects of obesity and,

 

  3   of course, the research component, which will be

 

  4   discussed by Dr. Acheson, can provide more details

 

  5   on where the research sort of would be heading in

 

  6   the future.

 

  7             With that, I will end and, again, leave

 

  8   some of the details to the speakers that follow,

 

  9   and with them you will get a lot more of the

 

 10   nitty-gritty of what the obesity working group has

 

 11   accomplished in the last year.

 

 12             DR. SHINE:  Thank you, Dr. Brackett.  Why

 

 13   don't we proceed then to hear from David G. Orloff,

 

 14   who is the Director of the Division of Metabolic

 

 15   and Endocrine Drugs in the Center for Drug

 

 16   Evaluation and Research, to talk about therapeutics

 

 17   involved in obesity?

 

 18                      Obesity - Therapeutics

 

 19             DR. ORLOFF:  Good morning.  Thank you very

 

 20   much.

 

 21             [Slide]

 

 22             What I am going to use my time on to do

 

                                                                28

 

  1   today is to give you a brief overview of what the

 

  2   therapeutics subgroup which largely consisted of

 

  3   members of the Division of Metabolic and Endocrine

 

  4   Drug Products--myself, Dr. Eric Colman and Dr.

 

  5   Patricia Beaston--reported to the overall obesity

 

  6   working group according to our charge from Dr.

 

  7   McClellan and the original charge to the group

 

  8   itself.

 

  9             Specifically, I will give you a sense and

 

 10   an understanding, I hope, of where we are today in

 

 11   our regulatory stance; how we got here; and what

 

 12   our plans are for the immediate future as we

 

 13   participate in this enterprise to address this

 

 14   public health problem.

 

 15             [Slide]

 

 16             Let me start with two quotes which

 

 17   actually are cited by Dr. Bray, who is a leader in

 

 18   this field, in a recent paper that is actually

 

 19   included in a volume edited by Dr. Pi-Sunyer who is

 

 20   with us.

 

 21             The first is that sudden death is more

 

 22   common in those who are naturally fat than lean. 

 

                                                                29

 

  1   This sounds like a contemporary summary statement

 

  2   from a modern epidemiologic study.

 

  3             The second, which is a bit older sounding

 

  4   but perhaps more broadly conclusive in a sense,

 

  5   reads that corpulency, when in an extraordinary

 

  6   degree, may be reckoned a disease, as it in some

 

  7   measure obstructs the free exercise of the animal

 

  8   functions, and has a tendency to shorten life by

 

  9   paving the way to dangerous distempers.

 

 10             Well, as the title of this slide suggests,

 

 11   these are actually not new observations.  The first

 

 12   is a quote from Hippocrates and the second is a

 

 13   quote from Dr. Fleming of the Edinborough School,

 

 14   writing in 1760.

 

 15             [Slide]

 

 16             Today we call these risks associated with

 

 17   obesity co-morbidities.  While they are certainly

 

 18   better enumerated and their pathophysiology better

 

 19   understood, as I have suggested, this is not a new

 

 20   problem.  As you can see and as everyone is aware

 

 21   around the table, these co-morbidities run the

 

 22   gamut from cardiovascular disease and all of its

 

                                                                30

 

  1   manifestations through the big problem of metabolic

 

  2   syndrome and burgeoning epidemic or existing

 

  3   epidemic of type 2 diabetes, to increased risk for

 

  4   a variety of malignancies and a whole host of

 

  5   psychological disorders, including depression and

 

  6   eating disorders.

 

  7             One of the reasons I start with this slide

 

  8   is because, frankly, the drug side of FDA has been,

 

  9   for lack of a better term, accused in the past of

 

 10   being somewhat insensitive to the magnitude of this

 

 11   problem as reflected in all of these risks, and I

 

 12   want to assure everyone that we fully understand

 

 13   the overall metabolic and health consequences of

 

 14   obesity and it drives our interest in ongoing

 

 15   active participation in this initiative.

 

 16             [Slide]

 

 17             So, with that, Dr. McClellan gave us

 

 18   really two charges that asked us to address the

 

 19   problem, we believe, from two different sides.  The

 

 20   first was to assess the real or perceived barriers

 

 21   to development of new or enhanced therapeutics.

 

 22   Then, as I said, coming at it from the other side,

 

                                                                31

 

  1   to make recommendations on ways to encourage

 

  2   development of new or enhanced therapeutics.

 

  3             We took this as a call, on the one hand,

 

  4   to make sure, as always, that we were well informed

 

  5   and up to date in our understanding of obesity and

 

  6   its risks, but also that we really ought to be

 

  7   revisiting our FDA guidance to industry on

 

  8   development of drugs for obesity.  Needless to say,

 

  9   FDA guidance to industry is supposed to represent

 

 10   current thinking and I think it is worth at least

 

 11   considering that 1996 is retreating into the past

 

 12   and we ought to make sure that that is still our

 

 13   current thinking.

 

 14             So, we have an open comment period on that

 

 15   document that is closing in a few weeks.  We have

 

 16   already had face-to-face dialogue with the American

 

 17   Obesity Association of PhRMA, of which Dr. Crawford

 

 18   was president, and we will be convening an advisory

 

 19   committee later this year to discuss potential

 

 20   changes to our guidance.

 

 21             [Slide]

 

 22             The harsh reality of the state of medical

 

                                                                32

 

  1   therapeutics is really where we start.  The fact is

 

  2   that although there are a number of drugs on the

 

  3   market for the treatment of obesity, current

 

  4   therapies are really not the panacea or in any way

 

  5   miracle drugs.  They generally induce only modest

 

  6   degrees of weight loss.  Weight maintenance is

 

  7   really a central problem in addressing this public

 

  8   health issue.

 

  9             It is important to understand, with regard

 

 10   to the state of the evidence, that we have limited

 

 11   data available on the impact of drug-associated

 

 12   weight loss on morbid outcomes.  The Xendos trial

 

 13   with Orlistat in obese patients at risk for type 2

 

 14   diabetes is one recent example of a finding that

 

 15   touches or that addresses the effects of weight

 

 16   loss on that significant outcome.  But we really

 

 17   have no mortality data and we think that that is a

 

 18   big hole.  I think everybody agrees that that is a

 

 19   big hole in our understanding.

 

 20             [Slide]

 

 21             But having said that, opportunities

 

 22   abound.  This is a list of the potential targets

 

                                                                33

 

  1   and mechanistic approaches to the treatment of

 

  2   obesity that are really under development and

 

  3   consideration and research, and the list grows

 

  4   daily with an increasing understanding by those

 

  5   involved in the scientific side of this enterprise,

 

  6   with increasing understanding not only of the

 

  7   physiology of weight maintenance and of energy

 

  8   economy in general, but also the pathophysiology of

 

  9   obesity.

 

 10             [Slide]

 

 11             Let me tell you where we see the path

 

 12   forward to safe and effective obesity drugs from

 

 13   the standpoint of the Center for Drugs.  To do so,

 

 14   I need to tell you a little bit about the modern

 

 15   history of obesity therapeutics; to talk to you

 

 16   about standards of evidence for approval of drugs

 

 17   prior to our 1996 guidance; and the transformation

 

 18   in medical perception of obesity to the way it is

 

 19   looked at today that led ultimately to the

 

 20   development of our standards and rationale in our

 

 21   1996 guidance.  There are multiple areas for

 

 22   discussion.  I will really touch mostly on just one

 

                                                                34

 

  1   of them.

 

  2             These, if you will, constitute some of the

 

  3   barriers which Dr. McClellan asked us to address,

 

  4   as well as a number of unanswered questions that,

 

  5   in our mind, constitute barriers as well, although

 

  6   perhaps not barriers in the same way as regulatory

 

  7   barriers.

 

  8             With regard to the modern history, as I

 

  9   think most people realize, it is a checkered one.

 

 10   It has been fraught with ill-conceived mechanistic

 

 11   approaches, unscrupulous investigators and

 

 12   practitioners and a lot of bad luck along the way,

 

 13   if nothing else.

 

 14             [Slide]

 

 15             It begins in the 1880s with the use of

 

 16   thyroid extract and drug-induced hyperthyroidism as

 

 17   a path to weight loss with its attendant risks,

 

 18   into the 1930s with dinitrophenol which,

 

 19   incidentally, continues to rear its head even today

 

 20   and which, as many of you realize, is one of the

 

 21   poster children in the FDA chamber of horrors that

 

 22   led ultimately to the passage of the 1938 Food,

 

                                                                35

 

  1   Drug and Cosmetic Act, along with the elixir of

 

  2   sulfinamide tragedy, to amphetamines which really

 

  3   came to market in the mid-1930s and, as I will say

 

  4   in a few minutes, dominated the scene with regard

 

  5   to obesity therapeutics over the last half century

 

  6   and their problems related to addiction and CNS and

 

  7   cardiac toxicity.

 

  8             The late 1960s marked really the end of

 

  9   the Rainbow pill problem which had begun some 20 or

 

 10   25 years before.  These were medical regimens which

 

 11   included fixed-dose combinations of digitalis and

 

 12   thyroid hormone but, in the collective, included

 

 13   the addition of thiazide and other diuretics,

 

 14   purgatives as well as amphetamines.  It was that

 

 15   lethal combination of digitalis and thiazides with

 

 16   hypokalemia and accentuated digitalis toxicity that

 

 17   led to numerous tragedies and ultimately to

 

 18   regulatory action against this enterprise.

 

 19             The 1970s saw a mini epidemic in primary

 

 20   pulmonary hypertension, mostly in Europe, related

 

 21   to Aminorex and I think people are aware of the

 

 22   unfortunate case of Redux and the unexpected, but

 

                                                                36

 

  1   in some cases, frankly malignant cardiac

 

  2   valvulopathy that resulted from the use of those

 

  3   drugs.

 

  4             I think it is worth pointing out, and

 

  5   everyone should realize, that in terms of a barrier

 

  6   that this history, on the one hand definitely

 

  7   tempers our approach from a regulatory standpoint

 

  8   to the development of therapeutics in this area,

 

  9   but I also think that it has affected in the past,

 

 10   and continues to affect, the overall integrity of

 

 11   the anti-obesity enterprise and it is something, if

 

 12   you will, that from a public relations standpoint

 

 13   needs to be dealt with.

 

 14             [Slide]

 

 15             This is a list of the centrally-acting

 

 16   anorexigens approved after 1938.  I put it up

 

 17   really to show you that the last 50 years is the

 

 18   half century of amphetamine congeners in obesity

 

 19   research and therapeutics.

 

 20             Two drugs on this list, mazindol and

 

 21   sibutramine, are not amphetamines per se but I

 

 22   think all these drugs are stimulant anorexigens and

 

                                                                37

 

  1   they have all been marketed as controlled

 

  2   substances.  All, except for sibutramine, as I will

 

  3   explain in a moment, were approved and labeled for

 

  4   only short-term use.

 

  5             [Slide]

 

  6             So, what were the standards of evidence

 

  7   that we had to support the use of these drugs prior

 

  8   to 1996?  As I said, all of the drugs approved

 

  9   prior to that time, and so labeled for treatment of

 

 10   obesity were for short-term use.  The trials that

 

 11   supported the efficacy and safety of these products

 

 12   were up to 12 weeks in duration and were limited in

 

 13   size with 200-400 patients.  There were obviously

 

 14   concerns about abuse and addiction potential that I

 

 15   mentioned a moment ago with these products and, as

 

 16   I said, they were labeled for short-term use,

 

 17   really dating back to the late 1960s and early

 

 18   1970s.

 

 19             Their efficacy was modest and, as you will

 

 20   see in a moment, not really all that different from

 

 21   what we have today, with the mean loss of

 

 22   approximately 5 kg for placebo and a range of

 

                                                                38

 

  1   placebo-subtracted means across multiple studies of

 

  2   1-10 kg.

 

  3             [Slide]

 

  4             Although this is an age list epidemic and

 

  5   the observations of its association with chronic

 

  6   morbid and mortal conditions, you know, goes back

 

  7   to the ancients, nevertheless, it took a sort of

 

  8   reexamination to lead to a transformation in the

 

  9   way this disease was perceived and in the way that

 

 10   it ought to be treated.  As I said, today it is

 

 11   looked at as a chronic condition associated with

 

 12   metabolic derangements and conferring the risk for

 

 13   long-term morbid and mortal sequelae.

 

 14             As I said, there is a big problem with the

 

 15   high rate of weight regain following

 

 16   discontinuation of drugs, and there is a

 

 17   recognition that maintenance of healthy weight is

 

 18   critical to reduction in risk for

 

 19   obesity-associated adverse outcomes as opposed to

 

 20   cycling of weight.

 

 21             [Slide]

 

 22             With this recognition or this casting in a

 

                                                                39

 

  1   metabolic light, in 1992 the obesity drugs were

 

  2   transferred to Endocrine and Metabolic, and in

 

  3   1995, before my time, an advisory committee was

 

  4   held to discuss this evolution and a disease model,

 

  5   the standards for lifelong treatment algorithms

 

  6   with these drugs, and discussion of clinical trial

 

  7   design and evidentiary standards.

 

  8             [Slide]

 

  9             In 1996 a draft guidance was issued.  The

 

 10   cardinal features of that draft guidance include

 

 11   the patient populations which are to be targeted,

 

 12   which include those patients who have significant

 

 13   obesity and who are at high risk for sequelae.

 

 14   This is in keeping with the NIH evidence-based

 

 15   treatment guidelines which were issued in that same

 

 16   time frame.

 

 17             The duration of Phase 3 trials which we

 

 18   have adhered to up until now include a first year

 

 19   of placebo-controlled investigation to provide

 

 20   proof or principle of efficacy, followed by an

 

 21   open-label year, in the second year, to provide

 

 22   further information on durable efficacy and safety

 

                                                                40

 

  1   in long-term use.  This harkens back to the

 

  2   historical bad luck to which I referred and,

 

  3   frankly, to the absence of outcomes data with

 

  4   existing drugs and to the fact that we are not

 

  5   requiring any outcomes data for establishing the

 

  6   balance of risk and benefit for these products.

 

  7             [Slide]

 

  8             With regard to the efficacy criteria, it

 

  9   is notable that the FDA's efficacy standard is less

 

 10   rigorous than the European one.  We require either

 

 11   a demonstration of a mean placebo-subtracted weight

 

 12   loss greater than or equal to five percent of

 

 13   baseline body weight, or that the proportion of

 

 14   subjects who lose greater than or equal to five

 

 15   percent of their baseline body weight is greater in

 

 16   the drug than the placebo group.  The EMEA, as you

 

 17   can see, has ten percent cutoffs for both those

 

 18   criteria.

 

 19             [Slide]

 

 20             Three drugs have been approved for

 

 21   long-term treatment under the current guidelines.

 

 22   The first, dexfenfluramine, was withdrawn less than

 

                                                                41

 

  1   18 months after its approval, as I mentioned

 

  2   earlier, related to unexpected cardiac

 

  3   valvulopathy.  Sibutramine, a centrally-acting

 

  4   anorexigen, and Orlistat, a non-absorbed intestinal

 

  5   lipase inhibitor, remain on the market.  These are

 

  6   indicated for long-term use.  As I said before,

 

  7   their efficacy over the loan haul, over the one to

 

  8   two years of exposure in the clinical trials, is

 

  9   about along the lines of the earlier products

 

 10   approved for short-term use.

 

 11             [Slide]

 

 12             With regard to barriers, as I said, I will

 

 13   mention just one, and this relates to the safety

 

 14   exposures that have been required of sponsors

 

 15   working in this area.  The FDA has stated a minimum

 

 16   of 1,500 patients for one year should be exposed to

 

 17   these products prior to submission of an NDA, and

 

 18   that 200-500 patients complete a second year to get

 

 19   an understanding of durable efficacy and safety.

 

 20             Those who have held that this might be too

 

 21   rigorous have evoked the International Conference

 

 22   on Harmonization E1A document on the development of

 

                                                                42

 

  1   drugs for long-term treatment of

 

  2   non-life-threatening conditions which cite 300-600

 

  3   patients for 6 months and 100 for 1 year.  They

 

  4   cite also 1,500 patients total in all of the

 

  5   studies, including Phase I.

 

  6             [Slide]

 

  7             But that document also explains that

 

  8   longer and larger exposures are readily

 

  9   rationalized and perhaps necessary if the benefit

 

 10   of the drug is noted or expected to be small,

 

 11   experienced only by a fraction of treated patients

 

 12   and of uncertain magnitude as in reliance on a

 

 13   surrogate, such as weight loss.

 

 14             I think this characterizes the state of

 

 15   the evidence and the state of the efficacy with

 

 16   these products and it is really our rationale

 

 17   behind requiring larger exposures.  Also, I think

 

 18   we all understand, as has been said many times

 

 19   today, that the magnitude of this epidemic is such

 

 20   that the anticipated target populations in

 

 21   open-market use is absolutely astronomical and it

 

 22   is our responsibility to be as sure as we can be

 

                                                                43

 

  1   that drugs are going to be safe and effective when

 

  2   they go out into these millions and millions of

 

  3   patients.

 

  4             [Slide]

 

  5             With regard to therapeutic gaps and

 

  6   unanswered questions, one of the issues that really

 

  7   we believe bears further investigation is

 

  8   head-to-head comparisons of approved agents.  This

 

  9   is an issue that comes up in a lot of different

 

 10   fields of medical therapeutics and is certainly one

 

 11   in which I think patients and physicians are

 

 12   under-served by the pharmaceutical and clinical

 

 13   investigational communities as a means of providing

 

 14   evidence for individualized, rational choices in

 

 15   treatment.

 

 16             [Slide]

 

 17             Long-term safety and efficacy of older

 

 18   drugs also needs better understanding, particularly

 

 19   phentermine.

 

 20             [Slide]

 

 21             I show you this slide of drug use data

 

 22   from 1991-2002 to demonstrate that throughout these

 

                                                                44

 

  1   last 12-plus years phentermine leads the pack with

 

  2   regard to U.S. prescriptions.  These were projected

 

  3   prescriptions for 2002 but I think they were borne

 

  4   out, and also projected for 2003.  Phentermine

 

  5   prescriptions are double those for sibutramine and

 

  6   Orlistat, yet, this is a drug that is approved only

 

  7   for short-term use.  It is likely that in this

 

  8   context it is being used for long-term use and we

 

  9   really are poorly informed as to its long-term

 

 10   safety and efficacy.

 

 11             [Slide]

 

 12             Studies of combination therapy, in order

 

 13   that we can better label these drugs, are also

 

 14   necessary and, parenthetically, studies of drug

 

 15   cycling which I believe are commonplace in

 

 16   therapeutic interventions in obesity--more

 

 17   information is required for purposes of drug

 

 18   labeling.   Finally, the "Holy Grail" that is the

 

 19   question that we all yearn for an answer about, and

 

 20   that is, do the drugs that we are going to use in

 

 21   this area, both today's and tomorrow's, confer

 

 22   long-term individual and population reductions in

 

                                                                45

 

  1   morbid and mortal sequelae of obesity?

 

  2             [Slide]

 

  3             Finally, or actually next to finally, I

 

  4   want to read you another quote, and this is from J.

 

  5   Diamond, writing an interesting piece that he

 

  6   published in Nature last year.  The piece is really

 

  7   about the worldwide epidemic of type 2 diabetes,

 

  8   diabetes and obesity that humans generally,

 

  9   although some more than others, are programmed as a

 

 10   result of energy economy genes in the aggregate to

 

 11   develop when food is overly abundant.  That is

 

 12   obviously why we are here today.  In discussing

 

 13   this problem he states that an epidemic of a

 

 14   genetic disease waxes because of a rise in

 

 15   environmental risk factors, and then wanes when the

 

 16   number of susceptible potential victims falls, but

 

 17   only because of the preferential deaths of those

 

 18   who are genetically more susceptible.

 

 19             This is a sobering concept and that is why

 

 20   I wanted to bring it to our attention.  However

 

 21   long obesity has been a problem, it is clear that

 

 22   we are still on the waxing side of this story. 

 

                                                                46

 

  1   When the obesity and type 2 diabetes epidemics

 

  2   begin to wane we want it to be because of the

 

  3   success of our interventions and not because of a

 

  4   culling of the susceptibles.

 

  5             [Slide]

 

  6             In conclusion, from the standpoint of the

 

  7   therapeutic subgroup the magnitude of the obesity

 

  8   epidemic, its contribution to chronic disease, its

 

  9   costs to individuals and society, and the absence

 

 10   of broadly effective therapeutics constitute a call

 

 11   to action by the collective medical community,

 

 12   including FDA, and we are certainly committed in

 

 13   that regard.

 

 14             Resolution of issues around real or

 

 15   perceived barriers to development is paramount to

 

 16   advancing the field of obesity therapeutics, though

 

 17   we want to emphasize that this must be without

 

 18   sacrificing the overall quality of the obesity

 

 19   armamentarium.

 

 20             With that, diet and exercise remain the

 

 21   mainstays of prevention and treatment of obesity;

 

 22   drugs are adjunctive to hygienic measures.  They

 

                                                                47

 

  1   were yesterday, they are today and they will be

 

  2   tomorrow we believe.

 

  3             Precedent with older as well as newer

 

  4   drugs, reliance on weight loss alone as a measure

 

  5   of health effects of these products directs a

 

  6   cautious, measured approach in obesity

 

  7   therapeutics.  Questions, among others, of

 

  8   comparative efficacy and safety, long-term clinical

 

  9   outcomes of treatment and effects of combination

 

 10   therapy regimens must be addressed sooner rather

 

 11   than later.  Thank you very much.

 

 12             DR. SHINE:  Thank you very much.  I think

 

 13   we will go ahead and have Dr. Acheson make his

 

 14   presentation and then it looks like we may have a

 

 15   few minutes before the break to inquire about both

 

 16   of these presentations.

 

 17             David Acheson is Director of Food Safety

 

 18   and Security Staff in the Center for Food Safety

 

 19   and Applied Nutrition, and he is going to discuss

 

 20   issues related to obesity and research.

 

 21                        Obesity - Research

 

 22             DR. ACHESON:  Good morning and thank you,

 

                                                                48

 

  1   Dr. Shine, for that introduction.

 

  2             [Slide]

 

  3             What I am proposing to do over the next

 

  4   few minutes is really to describe the process that

 

  5   the obesity subgroup of the FDA obesity work group

 

  6   underwent to begin to address the issue of obesity

 

  7   research.  This clearly is an enormous area and so

 

  8   I want to begin with really just a focus on what

 

  9   the overall approach was for this.  One of the

 

 10   mandates for the obesity work group was to identify

 

 11   the applied basic research needs that include the

 

 12   development of healthier foods, as well as a better

 

 13   understanding of consumer behavior and motivation.

 

 14             [Slide]

 

 15             The overall approach that we took here was

 

 16   really to begin with focusing on research topics

 

 17   that were mission-relevant to FDA.  When we began

 

 18   to think about research in the context of obesity,

 

 19   clearly, there is an enormous amount of research

 

 20   going on and we needed to focus it down and target

 

 21   it towards FDA relevant issues.

 

 22             The approach that we took to try to do

 

                                                                49

 

  1   this was to think through and to document current

 

  2   and relevant research that was related to these

 

  3   mission-relevant topics, and I am going to go

 

  4   through some of those, and based on that, then to

 

  5   identify knowledge gaps.  Essentially, my

 

  6   presentation is set up to look at some of the

 

  7   research issues and subsequent knowledge gaps.

 

  8             [Slide]

 

  9             As we discussed this, we really tried to

 

 10   narrow this down and came up with three principal

 

 11   areas.  The first was in relation to labeling and I

 

 12   would say this is probably one of the largest areas

 

 13   that we discussed.  The labeling was broken down

 

 14   into labeling in relation to restaurants and

 

 15   labeling in relation to the Nutrition Facts Panel.

 

 16             We also considered translational research,

 

 17   and where I am going there is in relation to some

 

 18   of the translation between the basic science and

 

 19   the mission-relevant issues for FDA.  We identified

 

 20   three areas there that are of potential relevance:

 

 21   the first, neonatal imprinting; second, "omics",

 

 22   essentially genomics, proteomics and metabolomics;

 

                                                                50

 

  1   and, thirdly, the impact of caloric restriction and

 

  2   what research there was going on in FDA and other

 

  3   areas that was related to that.

 

  4             The third point was just to consider the

 

  5   other areas.  You just heard from Dr. Orloff

 

  6   extensive discussion about drugs in relation to

 

  7   obesity.  But we also wanted to consider drugs and

 

  8   devices, food additives and dietary supplements

 

  9   and, essentially, those areas were largely excluded

 

 10   from our consideration because they weren't mission

 

 11   relevant research for FDA.  I am not saying that

 

 12   they are not relevant to the quest of tackling the

 

 13   obesity problem but, as you will see, my

 

 14   presentation doesn't cover those in any great

 

 15   detail and the explanation is really that the

 

 16   research in those areas is not relevant to the

 

 17   mission of FDA.

 

 18             [Slide]

 

 19             So, to focus firstly on the labeling

 

 20   research, the current research and some research

 

 21   that was undertaken once the obesity work group was

 

 22   established worked through the root of focus

 

                                                                51

 

  1   groups.  One of the areas that was addressed was

 

  2   restaurant labeling and to determine consumer

 

  3   reactions to menus that include caloric information

 

  4   and, essentially, to ask the question whether, if

 

  5   you provide caloric information on a menu, it makes

 

  6   a difference to consumers' choice.

 

  7             The second area in relation to the food

 

  8   label was to consider consumer reactions to the

 

  9   nutrition facts panel.  Obviously, there is a

 

 10   limited amount of information you can get on a

 

 11   facts panel, but what are the critical elements

 

 12   that one needs to get on?  Some of the areas that

 

 13   were addressed there were the issue of calories of

 

 14   the daily value, what did the consumers understand

 

 15   by that; what the impact would be of eliminating

 

 16   the calories from the fat section of the nutrition

 

 17   facts panel; and then to consider what the impact

 

 18   would be on adding more information on

 

 19   multi-serving packages to show the actual calories

 

 20   and the percent daily value in the package.

 

 21             Where we were going there was essentially

 

 22   that if you look at items that are typically

 

                                                                52

 

  1   consumed in a single serving, such as a muffin, it

 

  2   may be labeled in such a way that it is considered

 

  3   that a muffin is two servings and not many of us

 

  4   going to consume just half a muffin and put it on

 

  5   the side for consuming later.  So, it was more

 

  6   logical to think through the total amount of

 

  7   calories of the serving.

 

  8             Obviously, the third point was to consider

 

  9   messages and to determine what is the most

 

 10   effective message for conveying these nutritional

 

 11   issues.

 

 12             [Slide]

 

 13             As part of this, FDA has been involved in

 

 14   the development of a social sciences model to help

 

 15   determine the factors that influence dietary and

 

 16   weight management.  That has really involved three

 

 17   areas  The first is the review of literature to try

 

 18   to identify factors that affect food behavior and

 

 19   to catalog existing data; the second, to develop a

 

 20   quantitative model really to get at what an

 

 21   individual's decisions are affecting weight.  This

 

 22   works into physical activity and choice of food and

 

                                                                53

 

  1   that, obviously, involves attitudes, behaviors and

 

  2   environmental factors.  Then, to get into the issue

 

  3   of cost benefit analysis and the role of food

 

  4   labeling regulation and the development of policy.

 

  5             [Slide]

 

  6             Some of the consumer perceptions and

 

  7   attitudes--and this is just a brief summary--are

 

  8   listed on this slide.  Some of the things that we

 

  9   learned from this brief study of the research

 

 10   environment was the perception of overweight versus

 

 11   obesity and the fact that, in fact, most or many

 

 12   consumers don't consider overweight as a "problem"

 

 13   and indicate that it is of little consequence to

 

 14   consumers.  It is different with obesity, but just

 

 15   simply being overweight is not a significant

 

 16   consequence.

 

 17             Secondly, the perception of a person's

 

 18   weight and typically adults and teenagers

 

 19   mis-perceive their weight.  Men tend to

 

 20   underestimate their weight and healthy, underweight

 

 21   women tend to overestimate their weight.  Also,

 

 22   parents misjudge the weight of their children and

 

                                                                54

 

  1   will often determine that their children are at

 

  2   healthy weight where, in fact, they may be a little

 

  3   overweight.

 

  4             The third point is what consumers'

 

  5   perception is of their diet, and there is a

 

  6   tendency to think that generally you are eating a

 

  7   more healthy diet than you actually are.  If you

 

  8   analyze the content of the diet, the perception

 

  9   certainly is that you are eating better than, in

 

 10   fact, you are eating.

 

 11             Some of the recent focus groups have

 

 12   really tried to target parents and children.

 

 13   Obviously, part of our thinking here was the

 

 14   research in relation to product obesity and trying

 

 15   to work on that angle of it.

 

 16             The second point there is the perception

 

 17   of obesity, which I have alluded to, in terms of

 

 18   access for information and the perceived barriers

 

 19   and the motivating factors that will allow people

 

 20   to alter these perceptions.

 

 21             The conclusion of all of this was that

 

 22   there is emphasis on incremental change.  I think

 

                                                                55

 

  1   as you have already heard, nothing is going to

 

  2   happen here quickly.  Also, we have to be cautious

 

  3   of over-saturation of consumers.  They obviously

 

  4   want to receive health information but we have to

 

  5   do this in a targeted, judged and careful way.

 

  6   Finally, the focus on child education, I think, was

 

  7   a very clear message as an area of research in

 

  8   relation to this whole consumer aspect that has to

 

  9   be considered as an important focus.

 

 10             [Slide]

 

 11             The knowledge gaps: the first knowledge

 

 12   gap that comes out of this is information used to

 

 13   facilitate consumers' weight management decisions.

 

 14   There is a very clear need for research in this in

 

 15   both a qualitative and quantitative fashion.  I

 

 16   have just summarized three points there.  Firstly,

 

 17   the consumer reaction to the food label.  I have

 

 18   gone over some of the issues there, but what are

 

 19   the advantages of highlighting the calories, or

 

 20   listing the quantitative amounts of nutrients in

 

 21   multi-size packages?  Our initial focus groups

 

 22   indicated that these are important areas.  What we

 

                                                                56

 

  1   need now is to take this into quantitative research

 

  2   to really document the impact that we might get

 

  3   from some of these changes.

 

  4             The second point, the consumer reaction to

 

  5   and the effectiveness of restaurant nutrition

 

  6   information.  Does it make a difference if we list

 

  7   the information about the calories, the fat, the

 

  8   sodium next to the items on the menu list when you

 

  9   go to a fast-food environment?

 

 10             Finally, the consumer's dietary behavior

 

 11   and attitudes toward weight management, which

 

 12   obviously encompasses what I have already talked

 

 13   about but gets into the area of physical activity

 

 14   as well.

 

 15             [Slide]

 

 16             The second knowledge gap is the

 

 17   relationship between obesity and food consumption

 

 18   patterns.  Where we are going there is essentially

 

 19   the relationship between obesity and the frequency

 

 20   of foods consumed in different locations.  The

 

 21   target there is to examine the impact of consuming

 

 22   food in the home environment versus the fast-food

 

                                                                57

 

  1   environment versus a restaurant environment, and

 

  2   does it make a difference in terms of the frequency

 

  3   and the types of foods that are consumed in those

 

  4   environments?

 

  5             Also, we recognize that there is an

 

  6   important impact of both socioeconomic status in

 

  7   this as well as ethnic background, and there is a

 

  8   very clear need to generate data in relation to

 

  9   both of those issues.

 

 10             Finally in this second knowledge gap are

 

 11   the factors that actually contribute to overeating.

 

 12   Obviously, those are encompassed with many of the

 

 13   things I have already discussed, but what is the

 

 14   role of the super-size portion in all of this, and

 

 15   that really needs to be investigated.  I am just

 

 16   using that as an example of factors that would

 

 17   contribute to overeating.

 

 18             [Slide]

 

 19             The second area is in relation to

 

 20   formulation research, and really what this was

 

 21   addressing was what do we know about the factors

 

 22   that will drive reformulation to develop healthier

 

                                                                58

 

  1   foods?  The questions that were posed there were

 

  2   whether current regulations offer a barrier or an

 

  3   incentive to the production of healthier foods.

 

  4   The research that is currently ongoing there is

 

  5   that there are currently discussions with key

 

  6   industry personnel, and this is being done through

 

  7   a third-party contractor, so that we can get some

 

  8   insight into the barrier and regulatory hurdles

 

  9   that may be present that could impact product

 

 10   reformulation to develop healthier food.

 

 11             The third bullet there gets into the

 

 12   issues focused on manufacturers--what they can put

 

 13   on the label; what claims they can make; possible

 

 14   changes in regulations that would facilitate

 

 15   healthier foods; and what incentives we may be able

 

 16   to put in place, as a regulatory agency, that would

 

 17   encourage the development of healthier foods.

 

 18             [Slide]

 

 19             So, the third knowledge gap in relation to

 

 20   this product reformulation is where do we need to

 

 21   go?  What do we need to do?  We really need to

 

 22   further explore these barriers.  As I said, there

 

                                                                59

 

  1   is research that is going to give some pointers but

 

  2   the three key areas there are, firstly, do

 

  3   incentives, e.g., label prominence, impact industry

 

  4   on the development of healthier foods.  What is

 

  5   going to drive them to do that?  Do the barriers,

 

  6   e.g., regulatory hurdles, have an impact on the

 

  7   development of healthier foods?  We really need to

 

  8   understand that, understand what those hurdles are

 

  9   and, if possible, see what we can do to get around

 

 10   them.  Obviously, the third point there, once we

 

 11   have tried to balance the incentives and the

 

 12   hurdles, is how can these be addressed.

 

 13             [Slide]

 

 14             The next area in relation to drugs,

 

 15   devices, food additives and dietary supplements--as

 

 16   I mentioned, this was not a primary focus for the

 

 17   reasons that I have already given.

 

 18             [Slide]

 

 19             However, we did identify one knowledge gap

 

 20   here that we thought was important.  That was the

 

 21   potential for FDA-regulated products to be

 

 22   unintentionally contributing to the obesity

 

                                                                60

 

  1   problem.  The two points there were to consider

 

  2   whether weight gain may be an unintended and

 

  3   unrecognized complication of certain medications.

 

  4   Obviously, there are examples of that.  A research

 

  5   gap here or a research need is that this has not

 

  6   been consistently measured.  It has not been

 

  7   consistently evaluated, and we need to consider

 

  8   whether this should be an adverse effect that has

 

  9   to be taken into account in the approval of a drug.

 

 10             So the sub-bullets there are that, first

 

 11   of all, we have to determine if this is a problem.

 

 12   We identified it as a knowledge gap, and I

 

 13   emphasize knowledge gap.  We have to figure out

 

 14   whether it is a problem that needs to be addressed.

 

 15             Then, obviously, the corollary of that is

 

 16   to develop animal models to study the long-term

 

 17   effects on weight management and medications.

 

 18   Obviously, animal models can go in many other

 

 19   directions too but the issue of unintended

 

 20   consequences of a drug that is taken for a

 

 21   completely unrelated reason could be tested through

 

 22   appropriate animal models.

 

                                                                61

 

  1             [Slide]

 

  2             Finally, there is the basic science

 

  3   component of this.  I mentioned the three areas:

 

  4   Neonatal imprinting, and where we were going there

 

  5   was to try to get a better understanding of the

 

  6   impact of developmental programming, particularly

 

  7   during early development so, obviously, fetal

 

  8   exposure, neonatal exposure, infant exposure when

 

  9   these metabolic pathways are being

 

 10   established--does what mommy eats when she is

 

 11   pregnant, does what the neonate is fed or the young

 

 12   infant fed, what is the impact of that on

 

 13   subsequent development of obesity?  Part of our

 

 14   thinking on neonatal imprinting was the impact of

 

 15   infant formula often on childhood obesity and

 

 16   subsequent adult obesity.  Certainly, an area there

 

 17   that is of interest is the push towards different

 

 18   types of formula, without really I think major

 

 19   consideration on the impact of the obesity issue in

 

 20   relation to new formulas.

 

 21             The second area is obviously the "omics"

 

 22   issue to identify susceptibilities.  This is really

 

                                                                62

 

  1   getting at linking genetic susceptibilities.

 

  2   Obviously, this goes beyond just the susceptibility

 

  3   to obesity but the susceptibility of obese people

 

  4   to develop other problems such as type 2 diabetes.

 

  5   A clear area there is through genomics and

 

  6   subsequently proteomics and then metabolomics to

 

  7   really get a better handle on how that all fits

 

  8   together.

 

  9             Finally, the effects of caloric

 

 10   restriction, and over the last ten years NCTR has

 

 11   placed some emphasis on this.  They have been

 

 12   working on that and have been looking at the effect

 

 13   of caloric restriction, and this is in relation to

 

 14   free radical formation, malignant tumor rates and

 

 15   "less than ad lib" feeding on rapid weight

 

 16   reduction.  so, there is also a need there in terms

 

 17   of further research.

 

 18             [Slide]

 

 19             The fifth knowledge gap relates to this

 

 20   area of translational research, and we felt that it

 

 21   was essential that FDA use basic research to drive

 

 22   and develop regulatory policies.  This is obviously

 

                                                                63

 

  1   going to be especially with NIH but also many or

 

  2   the other stakeholders.

 

  3             Just as a small aside there, I was

 

  4   recently at a meeting at NIH where I presented some

 

  5   of what we have been doing and, interestingly,

 

  6   while there was a lot of discussion about the basic

 

  7   metabolic pathways and many of the potential drug

 

  8   therapies that Dr. Orloff discussed were raised,

 

  9   the group really was beginning to focus on that

 

 10   obviously a lot of this is about calories, and to

 

 11   get a better understanding of caloric management

 

 12   and some of the "social" sciences around food

 

 13   intake.

 

 14             But the knowledge gaps here include

 

 15   obviously the area of getting a better

 

 16   understanding of developmental imprinting, the use

 

 17   of "omics" and the development of animal models for

 

 18   the effects of diet, drug therapy and long-term

 

 19   weight maintenance.  So, there are some common

 

 20   themes there.

 

 21             [Slide]

 

 22             To conclude, obviously, calories are a

 

                                                                64

 

  1   critical element and the research that we were

 

  2   focused on was really how can we, having taken that

 

  3   basic premise that calories are what this is all

 

  4   about--how can we focus our research to get at

 

  5   that.  Probably the most critical element of all of

 

  6   this is understanding consumers.  We need to

 

  7   understand food labeling and how the consumers

 

  8   react to it; their eating habits and their weight

 

  9   management.  When we have a better understanding of

 

 10   that, we can then use food labels, education

 

 11   programs or whatever to try to move in the right

 

 12   direction.

 

 13             The third point there is the development

 

 14   of healthier foods.  I have already discussed that

 

 15   obviously in the context of what can we do as a

 

 16   regulatory agency to encourage healthier food

 

 17   development, and then, finally, the input from

 

 18   basic research in the development of regulatory

 

 19   policy which is always an underpinning, the good

 

 20   science has to be there first to move forward.

 

 21   Thank you very much.

 

 22             DR. SHINE:  Thank you very much.  We have

 

                                                                65

 

  1   an opportunity now, before our break, to engage our

 

  2   three speakers on any issues that the committee

 

  3   would like to raise.  What kinds of questions or

 

  4   issues would you like to inquire about?  Xavier?

 

  5             DR. PI-SUNYER:  I would just like to ask

 

  6   Dr. Orloff--I agree with him completely about the

 

  7   need to do studies of combination therapy to look

 

  8   at either the safety or the efficacy of combination

 

  9   drugs, but as he knows and I know, the drug

 

 10   companies only want to test their own drug and not

 

 11   a combination because of the expense of doing that.

 

 12   So, how would he propose that this get done?

 

 13             DR. ORLOFF:  Well, the first thing is that

 

 14   this is a problem obviously, as you point out,

 

 15   during the patent life of drugs.  I suppose, to

 

 16   some extent, the community would have to give

 

 17   thought to really how large and long the

 

 18   combination therapy trials might actually have to

 

 19   be.  Again, I am just thinking off the top of my

 

 20   head here but it occurs to me that if the long-term

 

 21   safety and efficacy of the individual products has

 

 22   been established as a basis on which they have been

 

                                                                66

 

  1   approved by the FDA, then that principle stands

 

  2   and, obviously, on a case-by-case basis this would

 

  3   have to be considered but it seems reasonable to

 

  4   think that we might be able to prove principle of

 

  5   efficacy and acceptable safety of combinations,

 

  6   perhaps not to the standards of directing labeling

 

  7   but certainly to a standards that would provide

 

  8   some guidance to physicians in this field, thus,

 

  9   standards for publication in peer-reviewed journals

 

 10   which, for better or for worse, is not always the

 

 11   same as standards for labeling.  So, that is one

 

 12   possibility.

 

 13             FDA cannot force drug companies to do

 

 14   trials with drugs other than their own unless, I

 

 15   suppose, there was some clear-cut rationale, for

 

 16   example, that the combination of drug with another

 

 17   was such that it spared toxicity of the proprietary

 

 18   drug and FDA stated that they would be really

 

 19   unwilling to approve--and this would be precedent

 

 20   setting--the proprietary drug at its optimal

 

 21   effective dose but would consider approving it in

 

 22   combination with another product which was still

 

                                                                67

 

  1   effective, the two together, but where the toxicity

 

  2   was spared.  Those are just a few thoughts.

 

  3             DR. SHINE:  Dr. Orloff, just to follow-up

 

  4   on another element here, you quite appropriately

 

  5   showed that obesity is a chronic illness and that

 

  6   it is likely that one might have to think about it

 

  7   much like hypertension in that it may require

 

  8   lifetime treatment.  What do we know about the

 

  9   capacity to select individuals who, in fact, might

 

 10   be most effectively treated with drugs long term in

 

 11   terms of either their behavioral characteristics or

 

 12   their genetic characteristics?  That is, could one

 

 13   stratify the obese population into categories where

 

 14   it would make more sense to make major efforts with

 

 15   drug therapy as opposed to other kinds of

 

 16   approaches?

 

 17             DR. ORLOFF:  I don't think we have that

 

 18   information available to us.  I am certainly not

 

 19   the expert to give the definitive answer but what

 

 20   you have touched on is clearly a problem that is

 

 21   active in all areas of medical therapeutics, and it

 

 22   is the great hope for obesity, as well as you

 

                                                                68

 

  1   suggested for hypertension and other sort of risk

 

  2   factor modification approaches to disease

 

  3   prevention, that we would be better up-front at

 

  4   identifying patients, on the one hand, who are at

 

  5   greatest risk for the sequelae--and we are better

 

  6   and better at doing that for cardiovascular disease

 

  7   risk based on biomarkers and such--but, on the

 

  8   other hand, are likely to benefit most from the

 

  9   drug from the standpoint of, for example,

 

 10   pharmacogenomic directed responsiveness.  I don't

 

 11   know if anybody else around the table--Dr.

 

 12   Pi-Sunyer, if you have any thoughts on where the

 

 13   state of the science is there.

 

 14             DR. PI-SUNYER:  No, I think that is a very

 

 15   good point but I think we are not there in terms of

 

 16   knowledge that we can select people who we know

 

 17   will get a better effect or are less likely to have

 

 18   safety problems with a drug than others.

 

 19             DR. SHINE:  I am fascinated by the

 

 20   implications of the fat gene argument made by Jerry

 

 21   Diamond and a number of other people, including the

 

 22   Rockefeller people, and the question again of

 

                                                                69

 

  1   whether over some period of time we could identify

 

  2   targets that are more likely to be responsive than

 

  3   others.

 

  4             Both of you touched on this, but in terms

 

  5   of the science one of the biggest gaps we have is

 

  6   the research on behavior and how and in what way we

 

  7   can influence behavior.  We know that for a whole

 

  8   variety of other addictions the only way that one

 

  9   is usually successful in dealing with tobacco or

 

 10   alcohol, or whatever, is total cessation.

 

 11   Unfortunately, that doesn't work for obesity.

 

 12             DR. ORLOFF:  Yes, I think it is an

 

 13   interesting point that overall poor or less than

 

 14   satisfactory outcomes in obesity treatment, even in

 

 15   patients who remain on drugs, is a combination

 

 16   likely of at least two factors.  One is perhaps

 

 17   that in truth the efficacy of the drug wanes but

 

 18   probably more than likely because the behavioral

 

 19   components that determine the ultimate success of

 

 20   the intervention are, you know, that the patient

 

 21   falls off the wagon, if you will.  I talked about

 

 22   the concept of drug cycling, which I gather is

 

                                                                70

 

  1   utilized by a number of obesity docs.  The degree

 

  2   to which it is successful after the first couple of

 

  3   cycles I think is in question.

 

  4             DR. SHINE:  Dr. Swanson?

 

  5             DR. SWANSON:  This is a question for Dr.

 

  6   Acheson.  Building on the behavioral issue, we all

 

  7   know that part of the issue is that calories count

 

  8   but it is an intake-output balance that is

 

  9   necessary.  Was the consideration of how to

 

 10   motivate people to expend more energy or some kind

 

 11   of a link between X number of calories--to eat this

 

 12   thing that contains X number of calories you would

 

 13   need to expend so many steps?  Or, was that out of

 

 14   scope because it is kind of out of FDA's purview?

 

 15             DR. ACHESON:  Well, it certainly was

 

 16   discussed, Dr. Swanson.  The issue of caloric

 

 17   balance is obviously input-output.  Unfortunately

 

 18   FDA can't regulate exercise.  If we could, maybe we

 

 19   would solve the problem.  But what we did there, we

 

 20   had a number of presentations from people who are

 

 21   involved in that.

 

 22             For example, the VA has a program that

 

                                                                71

 

  1   they are just initiating called "Move" in which

 

  2   they are essentially identifying their obese at

 

  3   various points through their healthcare system and

 

  4   enrolling them, as much as possible, in some kind

 

  5   of exercise and weight management program.  So,

 

  6   they are trying to tackle it from both sides.  Our

 

  7   approach was, well, what can we do on a label, etc.

 

  8   that is going to have an impact, and that is half

 

  9   the story.  You are right, it is not just

 

 10   understanding caloric intake; it is also output.

 

 11   So, we didn't ignore it.  We need to partner with

 

 12   people to try to get that piece across.

 

 13             DR. SWANSON:  I just think that,

 

 14   considered from a prevention aspect, rather than

 

 15   targeting obese or overweight people and this is

 

 16   what you need to get the pounds off, another

 

 17   approach that I really haven't seen is how do you

 

 18   prevent the pounds from going on, and you can have

 

 19   the super-size meal if you walk to a certain

 

 20   restaurant versus driving.

 

 21             DR. ACHESON:  I totally agree and that is

 

 22   part of understanding consumer behavior.  There is

 

                                                                72

 

  1   no question that that is important.  Also, I think

 

  2   let's try and get in there and prevent the problem

 

  3   before it ever starts.

 

  4             DR. SHINE:  Let me follow-up on that.  The

 

  5   experience with tobacco is that you can do

 

  6   substantial amounts of public education.  You can

 

  7   probably change the overall attitudes of a subject

 

  8   but, in fact, much of the progress made in tobacco

 

  9   was related to taxing tobacco; to changing the

 

 10   environment in which people could smoke, and so

 

 11   forth.  In the case of obesity, clearly there is no

 

 12   population that is at greater risk than children

 

 13   where, on the one hand as Dr. Swanson points out,

 

 14   physical exercise--gym is often gone from the

 

 15   curriculum but, on the other hand, they are being

 

 16   exposed to a substantial amount of fast foods.

 

 17             I was impressed by the way in which in

 

 18   your focus groups you identified that consumers

 

 19   like to get the information about a group of foods

 

 20   that they would likely eat together, the burger

 

 21   example of the combination of fries, Cokes, and so

 

 22   on and so forth.  My question is whether an

 

                                                                73

 

  1   appropriate target would be schools and school

 

  2   administrators around the combination of what kids

 

  3   are eating in school to try to educate them and

 

  4   their parents as to what the risks are in having

 

  5   access to what in many institutions is just awful.

 

  6   Now, some school districts are clearly making an

 

  7   attempt to modify that but changing the environment

 

  8   by virtue of changing what is available to kids

 

  9   might be a very important strategy here, and there

 

 10   the FDA might be able to come up with some labeling

 

 11   activities, similar to the way in which you have

 

 12   grouped the information about burgers, in a way

 

 13   that would be useful to administrators and PTAs.

 

 14             DR. ACHESON:  I agree with you.  It does

 

 15   focus on the product population which is possibly

 

 16   the primary target here.  I think that is one

 

 17   avenue to pursue.  Obviously, schools have many

 

 18   things that they have to deal with and think about,

 

 19   and this would just be one component of managing a

 

 20   child's life, so to speak, to try to control their

 

 21   diet.

 

 22             That speaks also to developing educational

 

                                                                74

 

  1   programs to help parents understand the importance

 

  2   of caloric balance for their children.  Maybe that

 

  3   could be done through the schools as well,

 

  4   potentially working with the school lunch program,

 

  5   for example, to try to think about healthier foods

 

  6   in that context.  So, I agree with you.  It is

 

  7   certainly an avenue that one should consider.

 

  8             DR. SHINE:  What I am arguing about is not

 

  9   just about the education; it is actually changing

 

 10   the environment in a substantial way.  Dr. Roses?

 

 11             DR. ROSES:  I was also going to make the

 

 12   point about the only reason that we eat is so we

 

 13   can burn the calories, and if you are only

 

 14   measuring one side of the equation as part of the

 

 15   studies that are done and as part of the advice we

 

 16   give we may be just dealing with, one might say, a

 

 17   minor part of the problem.

 

 18             I was pleased to hear that there is now an

 

 19   acceptability that we are genetically different and

 

 20   we have different susceptibilities, and some of us

 

 21   will gain weight on different calories and others

 

 22   won't.  But I think, rather than be in the second

 

                                                                75

 

  1   point about "omics" as if there were some magic in

 

  2   applying techniques to biological problems, there

 

  3   is some evidence already that we can stratify

 

  4   populations by their genetic polymorphisms.  For

 

  5   instance, this room could be stratified by your

 

  6   blood types.  However, just in the beginning state,

 

  7   the science called pharmacogenetics is applying

 

  8   that to responders versus non-responders the

 

  9   extremes of a drug trial.

 

 10             With our experience with a recent

 

 11   candidate, in a very small study which is in the

 

 12   public domain and I can show it if you like in a

 

 13   single slide, we were able to put stratifying

 

 14   markers in a very simple way on people who were the

 

 15   big responders and people who could not respond and

 

 16   people who, by the way, had a difference in weight

 

 17   gain if they gained weight on the drug.

 

 18             The third part has to do with head-to-head

 

 19   trials.  Head-to-head trials take the average group

 

 20   of patients and they test them against a drug.  But

 

 21   in the world of stratification comparing one third

 

 22   that might respond that might respond in this group

 

                                                                76

 

  1   with the one third that might respond in this group

 

  2   is not really head-to-head, and it is now possible

 

  3   to stratify people by their metabolic enzymes, by

 

  4   their markers, by a variety of other things so that

 

  5   we can truly do, if you are interested in making

 

  6   that a gold standard, head-to-head trials that at

 

  7   least have some common denominators.

 

  8             DR. SHINE:  Any comments?  If not, I am

 

  9   going to take the chair's prerogative and go to a

 

 10   break.  We are going to have an opportunity after

 

 11   the next speaker to have a continued discussion,

 

 12   and I presume you will be available for further

 

 13   conversation.  Let's go ahead and take a break.  We

 

 14   will reconvene at 9:45.  Thank you.

 

 15             [Brief recess]

 

 16             DR. SHINE:  We will come back to our

 

 17   discussion after the next presentation.  We are

 

 18   pleased that Alan Rulis, Senior Advisor for Special

 

 19   Projects in the Center for Food Safety and Applied

 

 20   Nutrition, will tell us about the highlights of the

 

 21   obesity working group report.  Alan?

 

 22          Highlights of the Obesity Working Group Report

 

                                                                77

 

  1             DR. RULIS:  Thank you, Chairman.

 

  2             [Slide]

 

  3             I am Alan Rulis.  I am currently Senior

 

  4   Advisor for Special Projects in the Center for Food

 

  5   Safety and Applied Nutrition.  I have been involved

 

  6   with the obesity working group writing team and

 

  7   throughout the process of putting that report

 

  8   together.

 

  9             To summarize very briefly, the report

 

 10   recommends a number of thrusts in several different

 

 11   areas that you are all aware of now, in particular

 

 12   the food label and in particular there calories,

 

 13   serving size, claims and so forth, even the issue

 

 14   of carbohydrates.  We have recommendations in the

 

 15   report about enforcement against products with

 

 16   misleading weight loss claims and, as you have

 

 17   heard this morning, there are sections that deal

 

 18   with therapeutics and research.

 

 19             [Slide]

 

 20             What I would like to focus on in my

 

 21   presentation is a couple of other areas that are

 

 22   extremely important to the success of FDA's efforts

 

                                                                78

 

  1   to stem the tide of obesity.  They relate to

 

  2   education and restaurants, under the rubric of

 

  3   trying to find means by which we can get around the

 

  4   table the people involved in these issues, not just

 

  5   the agency but stakeholders, educators, industry,

 

  6   consumer groups, and so forth, to discuss next

 

  7   steps and to move forward, to make some sort of

 

  8   forward progress.

 

  9             In that regard, the report does recommend

 

 10   in fact that the FDA use a third-party facilitator

 

 11   as a convener to essentially create a national

 

 12   dialogue on obesity.  So, what I would like to

 

 13   cover in my remarks this morning are some slides

 

 14   that relate to development of that national

 

 15   dialogue by means of a facilitator to get the

 

 16   discussion going.

 

 17             I looked over my slides and realized that

 

 18   25 of my 30 slides are really questions.  Of the

 

 19   last 12, 9 of them are questions to the Board.  So,

 

 20   my slides will be primarily in that vein, looking

 

 21   forward to your insights, comments, recommendations

 

 22   and feedback to us.

 

                                                                79

 

  1             As I said, the report does in fact

 

  2   recommend that FDA work through a facilitator to

 

  3   provide a forum for stakeholders to seek a

 

  4   consensus-based approach that addresses two

 

  5   specific aspects of obesity in the United States,

 

  6   in particular, developing options for providing

 

  7   voluntary nutrition information for foods consumed

 

  8   away from home, for example in the restaurant

 

  9   setting and, secondly, education to combat product

 

 10   obesity.

 

 11             The reasons are quite obvious.  We know

 

 12   that Americans now spend about 46 percent of their

 

 13   food budget on food eaten outside the home, as our

 

 14   report states.  We also know that body weight and

 

 15   trends towards obesity that begin at puberty or in

 

 16   adolescence are often propagated through adulthood

 

 17   and are very difficult to reverse.  So, we think

 

 18   that those are two prime areas for establishing a

 

 19   dialogue.

 

 20             [Slide]

 

 21             With respect to foods eaten away from

 

 22   home, we imagined putting together a contract for a

 

                                                                80

 

  1   facilitator to start the dialogue and we imagined

 

  2   having the facilitator address the following

 

  3   questions:  What nutrition information would be the

 

  4   most helpful for consumers to have before ordering

 

  5   food in a restaurant?

 

  6             [Slide]

 

  7             What are the best options for providing

 

  8   nutrition information in a restaurant setting?  We

 

  9   have had many discussions with the restaurant

 

 10   industry throughout the course of the obesity

 

 11   working group's efforts focused on this question.

 

 12   It is a complicated question because the restaurant

 

 13   industry is very diverse.  There are quick service

 

 14   restaurants where people walk in and get their meal

 

 15   right away and there are others where there are

 

 16   white tablecloths and meals are prepared to order,

 

 17   and there are a lot of specific changes that are

 

 18   made to menu items by the cook.  It is very

 

 19   difficult to say that there is one set of best

 

 20   options, of course.

 

 21             [Slide]

 

 22             Should nutrition information be listed for

 

                                                                81

 

  1   all menu items or just some items?  What are the

 

  2   practical considerations there?  If we do have

 

  3   restaurants put information on some menu items,

 

  4   then what criteria should determine which items

 

  5   should have nutrition information listed?  We have,

 

  6   as a matter of fact, a very interesting menu right

 

  7   now in the agency from a major chain restaurant

 

  8   that has caloric information next to all of the

 

  9   menu items and it is very interesting, very

 

 10   remarkable to look at because you are not used to

 

 11   seeing it but it can be done and it is there.

 

 12             [Slide]

 

 13             When providing nutrition information in

 

 14   the restaurant setting, what consideration should

 

 15   be given to the differences between chain and

 

 16   non-chain restaurants?  Of course, that relates to

 

 17   the whole question of the diversity of that segment

 

 18   of the industry.

 

 19             [Slide]

 

 20             How should restaurants tailor the kinds of

 

 21   nutrition information presented based on expected

 

 22   clientele?  You can imagine the need there to focus

 

                                                                82

 

  1   the kinds of information that is presented to the

 

  2   type of restaurant and the clientele that frequent

 

  3   that restaurant.

 

  4             [Slide]

 

  5             Number six, should nutrition information

 

  6   be presented in context, for example, as a percent

 

  7   of daily value, comparing for example to a 2,000

 

  8   calorie per day diet or, for example, comparing to

 

  9   other menu items?  This is something that I think

 

 10   many consumers would find very helpful, the notion

 

 11   that when you walk into a restaurant and order an

 

 12   item off the menu, you have some sense of whether

 

 13   consuming that item is going to comprise 20 percent

 

 14   or 80 percent or 150 percent of your normal daily

 

 15   caloric intake.  That sort of feel for what that

 

 16   meal represents would be extremely helpful we think

 

 17   to restaurant patrons.

 

 18             [Slide]

 

 19             Number seven, how should FDA proceed to

 

 20   encourage restaurants to participate in a voluntary

 

 21   pilot program to test various options?  In the

 

 22   obesity working group report we say as part of the

 

                                                                83

 

  1   recommendations that we would like to see a pilot

 

  2   study conducted that would get into the question,

 

  3   in specific terms, about how such nutrition

 

  4   information, caloric information for example, could

 

  5   be placed at the point of sale for consumers to

 

  6   use, and we envision the restaurant industry coming

 

  7   with ideas about this.  We don't envision the FDA

 

  8   funding and creating such a pilot study out of thin

 

  9   air.  This is the kind of thing that would need to

 

 10   be done around the table, in communication with the

 

 11   industry and, thus, again the idea of a third-party

 

 12   facilitator.

 

 13             [Slide]

 

 14             Number eight, how can industry and Food

 

 15   and Drug Administration measure the effectiveness

 

 16   of providing nutrition information to consumers in

 

 17   restaurants?  One of the things we learned in our

 

 18   deliberations in the obesity working group is that

 

 19   information itself doesn't really necessarily

 

 20   answer the concern; that imparting information to

 

 21   people can be done but it is not necessarily

 

 22   absorbed and, once absorbed, it does not

 

                                                                84

 

  1   necessarily change behavior.  So, I think a

 

  2   pertinent question that we would pose to our

 

  3   third-party facilitator would be to get at the

 

  4   answer to this question.

 

  5             [Slide]

 

  6             On the subject of pediatric

 

  7   nutrition/obesity education, we have similar

 

  8   questions that we would like a facilitator to help

 

  9   us address.  On what age groups is it most

 

 10   appropriate for Food and Drug Administration to

 

 11   focus education efforts?  This is a sociological

 

 12   question as much as a pharmacodynamic one.

 

 13             [Slide]

 

 14             What are the most appropriate settings,

 

 15   for example school or home, health settings, social

 

 16   organizations or clubs, for such educational

 

 17   efforts?  Again, those of us who were on the

 

 18   obesity working group are well aware that there are

 

 19   many groups which have spent years working on these

 

 20   kinds of issues and know a lot about imparting

 

 21   information to children, to families and the

 

 22   pitfalls of trying to create an awareness about

 

                                                                85

 

  1   such subjects as obesity and then to change

 

  2   behavior.  It is very complicated.  It is almost an

 

  3   art form.  It is something that I think many of us

 

  4   at the agency are feeling like we really do need to

 

  5   have a participatory discussion about and, again,

 

  6   is another reason for having a third-party

 

  7   facilitator bring in people with different areas of

 

  8   expertise to get around this question.

 

  9             [Slide]

 

 10             Another question on the pediatric

 

 11   nutrition/obesity education issue is how important

 

 12   is it for education efforts to be conducted using

 

 13   mass media, for example television, radio and

 

 14   print?  When I think of adolescents today, they are

 

 15   wired, they are electronic, they are not reading

 

 16   newspapers; they are plugged in and they can be

 

 17   reached very effectively in many ways through the

 

 18   Internet, through the media, through the various

 

 19   things that they are tuned into constantly.  So, we

 

 20   need to be contemporaneous here.  We can't be

 

 21   thinking in terms of 20th century communication

 

 22   tools.

 

                                                                86

 

  1             [Slide]

 

  2             Over what time period should an education

 

  3   effort be extended to achieve optimal impact and

 

  4   lasting effects?  Another thing we learned in our

 

  5   deliberations in the group was that education is

 

  6   really not a short-term phenomenon.  It is possible

 

  7   to generate messages, to send them out and, you

 

  8   know, clean the dust off your hands and walk away

 

  9   and affect absolutely nothing.  What has to happen

 

 10   is that there needs to be a long-term effort that

 

 11   is continuous, that is reinforced and that has

 

 12   mid-course corrections to make it more effective.

 

 13             [Slide]

 

 14             What types of messages are the most

 

 15   effective, and in which age groups, for educating

 

 16   children about nutrition and health?  Again, this

 

 17   ties back into the question of prevention, the

 

 18   notion that if we can prevent adolescents or young

 

 19   people from starting on a path of being overweight

 

 20   we have done a whale of a lot more than we can do

 

 21   by worrying about how to get people who are

 

 22   currently overweight as adults to lose some weight.

 

                                                                87

 

  1   That is also important but it is extremely

 

  2   important to realize that once that pattern is set

 

  3   it is very hard to reverse.

 

  4             [Slide]

 

  5             To what extent should education and/or

 

  6   other types of messages be tailored to different

 

  7   ethnic and/or socioeconomic groups?  This is

 

  8   another issue we heard strong signals on in our

 

  9   facilitated discussions during the course of our

 

 10   obesity working group.  We are a heterogeneous

 

 11   nation, extremely so and becoming more so.  We have

 

 12   large numbers of immigrants coming to our country

 

 13   from different cultures where eating patterns and

 

 14   signals about what is right to eat and what is

 

 15   appropriate to eat, what is appropriate to feed

 

 16   your family are very, very different.  Even those

 

 17   of us who have been here a number of generations

 

 18   across our country have very different views about

 

 19   how we eat and what is appropriate.  So, we need to

 

 20   be able to tailor our efforts and I think our

 

 21   facilitator needs to be able to help us to do that.

 

 22             [Slide]

 

                                                                88

 

  1             Then, what are the effective means that we

 

  2   might be able to find for partnering in the public

 

  3   and private sectors to develop and deliver obesity

 

  4   education?  The Department of Health and Human

 

  5   Services has published a proposal in the Federal

 

  6   Register, last summer, that invited comments and

 

  7   suggestions on how to create public/private

 

  8   partnerships on a number of health issues that face

 

  9   the country, and this is one of them.  We are I

 

 10   think open to the question.  We would put the

 

 11   question to our third-party facilitator.  Let's get

 

 12   to the essential factors that help us partner with

 

 13   those stakeholder segments out there, the industry

 

 14   segment and the consumer segment and the citizen

 

 15   segment of our country, to get everybody around the

 

 16   table to chew on this issue.

 

 17             It is not simple because the FDA, as a

 

 18   regulatory agency, needs to be careful about how it

 

 19   does those things so it does not present either the

 

 20   appearance or the actuality of favoritism to any

 

 21   one company over other companies, and so forth.

 

 22   But we also do see the value of partnering.  A lot

 

                                                                89

 

  1   can be done that isn't regulatory in the

 

  2   traditional sense.  Talking to and working with

 

  3   effective partners on the outside can be extremely

 

  4   effective, and we would like our facilitator to

 

  5   help us uncover effective examples that are

 

  6   currently operating, and there are some.  We, at

 

  7   the FDA, are very familiar with the "Fight Back"

 

  8   campaign that was addressing the issue of microbial

 

  9   contamination of food and that is a very effective

 

 10   program that has educated a lot of people and

 

 11   prevented a lot of illness in this country.  It is

 

 12   a nice example of how that can work.  There are

 

 13   undoubtedly many others and we want to find out

 

 14   what they are, learn about what makes them

 

 15   successful and then adopt the aspects of them that

 

 16   make them successful to the programs that we would

 

 17   generate.

 

 18             [Slide]

 

 19             That brings me then to my last dozen

 

 20   slides or so on which there are still nine more

 

 21   questions, and these are really questions that go

 

 22   to the Board, and you have all seen them in your

 

                                                                90

 

  1   materials and I hope you have given them some

 

  2   thought.  They are focused on the two prongs of the

 

  3   issue as I have presented them here, namely, the

 

  4   scope of work that we would present to our

 

  5   contractor or third-party facilitator relating to

 

  6   food eaten away from home, and work on pediatric

 

  7   obesity education.

 

  8             Chairman, I would I guess defer to you in

 

  9   terms of how you want to proceed.  I can go through

 

 10   these questions quickly if you would like me to

 

 11   just to remind folks of what they are, and then we

 

 12   can kind of revisit them.

 

 13             DR. SHINE:  Why don't you go through them?

 

 14             DR. RULIS:  Okay.

 

 15             [Slide]

 

 16             Number one, are FDA's proposed questions

 

 17   and issues likely to provide appropriate

 

 18   information to proceed with a pilot program with

 

 19   restaurants?  In other words, are we asking the

 

 20   right questions here?  Are we missing something

 

 21   obvious?  We really need your thoughtful input and

 

 22   your recommendations about that.  If we haven't hit

 

                                                                91

 

  1   the target right on the head, then can you think of

 

  2   some other questions or issues that should be

 

  3   addressed and that we should have our facilitator

 

  4   focus on?

 

  5             [Slide]

 

  6             Secondly, what kind of evaluation is

 

  7   appropriate to assess the effectiveness of a pilot

 

  8   program?  As I mentioned, we wanted to get together

 

  9   and have the restaurant industry create some sort

 

 10   of program by which this can occur.  I should say

 

 11   very quickly that these programs are already going

 

 12   on out there.  You know, McDonalds and other

 

 13   companies have been in the news recently about

 

 14   programs that they are putting together to move the

 

 15   country in the right direction in terms of

 

 16   increased physical activity and wise food choices.

 

 17   So, we are well aware of that.  We want to engage

 

 18   with them on something specific in this context and

 

 19   so how do you evaluate the effectiveness of such a

 

 20   program?  I think we need your help on that.

 

 21             [Slide]

 

 22             What advice would you have for a

 

                                                                92

 

  1   facilitator?  If we were to go forward and contract

 

  2   out this work, what advice would you have for a

 

  3   facilitator concerning the basis for evaluating

 

  4   recommendations on providing nutrition information

 

  5   in a restaurant setting?  Again, are we targeting

 

  6   this right?  Have we asked the right questions or

 

  7   are we missing something obvious?

 

  8             [Slide]

 

  9             Fourth, what research would be helpful for

 

 10   a facilitator to know about to help them provide

 

 11   the best guidance to the agency on this subject?

 

 12   Again, you all, on the Board, have many different

 

 13   areas of research that you are familiar with.

 

 14   Perhaps you are aware of some that could be of

 

 15   value for us to hear about on the record today that

 

 16   could help us focus this in the right direction.

 

 17             [Slide]

 

 18             Fifth, in view of the materials that you

 

 19   have been provided, is there any other advice or

 

 20   information you believe is important to give the

 

 21   FDA on this issue?

 

 22             [Slide]

 

                                                                93

 

  1             That also goes for the pediatric obesity

 

  2   issues as well, and I will go through those

 

  3   questions briefly.  Are FDA's proposed questions

 

  4   and issues likely to provide appropriate

 

  5   information to guide the development of useful and

 

  6   understandable nutrition/obesity education efforts?

 

  7             I will tell you why I put

 

  8   nutrition/obesity on this slide.  In our

 

  9   discussions with people who have been doing this

 

 10   for years, they say one of the things you don't do

 

 11   when you talk to adolescents about obesity is use

 

 12   the word "obesity."  As I say, it is an art form

 

 13   and children are extremely interested in knowing

 

 14   how to live healthy lives, and they are very

 

 15   conscious of their bodies, their body weights and

 

 16   their physical appearance, and they very definitely

 

 17   want to be healthy.  But if you come at them with

 

 18   information that talks about obesity, it is a

 

 19   turnoff.  These are things that are sort of the

 

 20   subtleties of this issue that we have to get around

 

 21   and understand.

 

 22             [Slide]

 

                                                                94

 

  1             What research would be helpful for a

 

  2   facilitator to know about?  Again, this is the same

 

  3   as in the other aspect, to provide the best

 

  4   guidance to the agency on this subject.

 

  5             [Slide]

 

  6             What other questions should FDA be asking

 

  7   a facilitator to explore in order to help the

 

  8   agency develop effective educational strategies?

 

  9             [Slide]

 

 10             In view of the materials you have been

 

 11   provided, is there any other advice or information

 

 12   you believe is important to give FDA on this issue?

 

 13             [Slide]

 

 14             Let me finish by saying just two things

 

 15   here.  I have a couple of quotes.  One is from Dr.

 

 16   Crawford: "We're going back to basics, designing a

 

 17   comprehensive effort to attack obesity through an

 

 18   aggressive, science-based, consumer-friendly

 

 19   program with the simple message that 'Calories

 

 20   Count.'"  That really in a sentence summarizes what

 

 21   it is all about on that subject.

 

 22             [Slide]

 

                                                                95

 

  1             Our Secretary, Tommy Thompson:  "Counting

 

  2   calories is critical for people trying to achieve

 

  3   and maintain a healthy weight.  This new report

 

  4   highlights FDA's overall strategy for getting

 

  5   consumers accurate, helpful information that allows

 

  6   them to make wise food choices at home, at

 

  7   supermarkets and in restaurants.  Taking small

 

  8   steps to eat a more balanced diet and to stay

 

  9   physically active can go a long way to reversing

 

 10   the epidemic of obesity that harms far too many

 

 11   Americans."

 

 12             I think we are at a point where we have

 

 13   written the report and we have delivered the

 

 14   report.  The report has recommendations and we now

 

 15   want to move forward with those recommendations to

 

 16   take the next steps.  What I have described by way

 

 17   of third-party facilitated national dialogue on

 

 18   these two main issues about restaurants and

 

 19   pediatric obesity are concrete first steps that I

 

 20   think we can take beyond just delivering a report.

 

 21   We look forward to your feedback on these questions

 

 22   and your good guidance to the agency.  That is my

 

                                                                96

 

  1   presentation.  Thank you.

 

  2        Questions and Discussion with the Board/Presenters

 

  3             DR. SHINE:  Thank you very much, Dr.

 

  4   Rulis.  I know there are a couple of questions that

 

  5   we were going to come back to with our first two

 

  6   speakers, and we will do that at the end of this

 

  7   session, but I would like to focus over the next

 

  8   few minutes on the challenge from Dr. Rulis with

 

  9   regard to commenting on the charge to the

 

 10   facilitator.  I gather he is not asking us the

 

 11   answer to those questions.  He is asking us are

 

 12   those the right questions and are there other

 

 13   questions or other approaches that would be

 

 14   important for FDA to undertake.  We also have a

 

 15   written copy of these questions.  Jim, why don't

 

 16   you go ahead?

 

 17             DR. RIVIERE:  I just have one comment.

 

 18   Focus groups seems to be the primary mechanism that

 

 19   you are going to ask this facilitator to address

 

 20   these questions, and just that there be a lot of

 

 21   concern about the makeup of those focus groups.  It

 

 22   seems trivial, but even from personal experience

 

                                                                97

 

  1   with focus groups, people who will go to focus

 

  2   groups, there is a selection process in that area,

 

  3   especially for some of the questions on teens--and

 

  4   I still have two teenagers.  One has a problem in

 

  5   this area and the other one doesn't.  You know,

 

  6   same environment; obviously different genetics--but

 

  7   the point really is in looking at who would

 

  8   participate in this and how you would get them to

 

  9   participate because otherwise your results are

 

 10   going to be strongly biased to people who may not

 

 11   even have a problem to begin with.  And I agree, if

 

 12   you say it is an obesity focus group you are not

 

 13   going to get the right target population you want,

 

 14   but just to try to look at some clinical trial

 

 15   sampling protocols to make sure you have a

 

 16   representative group.

 

 17             DR. RULIS:  Thank you.  Let me just add in

 

 18   response, if I might, that in the course of our

 

 19   deliberations we did have the opportunity to do

 

 20   some focus groups and we did them, and they

 

 21   contributed to the report.  But we were all very

 

 22   much aware that, yes, indeed, they are not really

 

                                                                98

 

  1   research; they are focus groups, and that what

 

  2   needs to happen is research that has a much broader

 

  3   and deeper sort of foundation and a long-term

 

  4   lasting effect.  So, yes, thank you.  I think it is

 

  5   a very important point and we need to keep that

 

  6   very clearly in front of us.

 

  7             DR. SHINE:  Susan?

 

  8             DR. HARLANDER:  When you mentioned that

 

  9   you were going to get a third-party facilitator

 

 10   involved, I am assuming that that is going to go

 

 11   way beyond consumer-based focus groups.  My

 

 12   understanding is that that facilitator would also

 

 13   be engaging the other stakeholders, like the

 

 14   restaurant industry or the food industry--

 

 15             DR. RULIS:  Very definitely.

 

 16             DR. HARLANDER:  --and I think it is

 

 17   critically important to involve stakeholders

 

 18   because food companies and restaurants understand

 

 19   their consumer base and they do a tremendous amount

 

 20   of proprietary research internally that they might

 

 21   be quite willing to share with you under certain

 

 22   circumstances.  So, I think industry involvement is

 

                                                                99

 

  1   critical.

 

  2             Personally, I tend to believe that the

 

  3   market is going to sort itself out on this issue.

 

  4   You already see that certain restaurants, if they

 

  5   perceive that their consumers are interested in

 

  6   more healthy alternatives, are including them on

 

  7   the menu already.  So, you know, I think that they

 

  8   can bring a tremendous amount of knowledge to what

 

  9   you are trying to do.  I guess my understanding is

 

 10   we are going way beyond consumers and will involve

 

 11   the affected industry as well.  That is true?

 

 12             DR. RULIS:  Yes, thank you.

 

 13             DR. SHINE:  Susan, given your background

 

 14   in food science, what is your general reaction to

 

 15   the set of questions that have been raised?  Are

 

 16   these the right questions, do you think?

 

 17             DR. HARLANDER:  Well, there is one

 

 18   critical question that I would add.  I would agree

 

 19   with all the questions that you have but I think

 

 20   one key area is that all of this information that

 

 21   will be provided is not free, and nowhere in the

 

 22   research that I have reviewed prior to this do we

 

                                                               100

 

  1   ask consumers if they are willing to pay for

 

  2   additional information.  If we are going to expect

 

  3   the food industry to change their labels, we have

 

  4   to understand that that is not free.  You know, it

 

  5   costs money to make all those changes, particularly

 

  6   if analytical work is going to be required.  The

 

  7   same will be true for restaurants.  They are not

 

  8   typically giving that kind of information to

 

  9   consumers so either they are going to have to use

 

 10   some sort of software package that is going to

 

 11   predict this, which they haven't typically used in

 

 12   the past, or they are going to have to do

 

 13   analytical--they are going to have concerns about

 

 14   liability.

 

 15             So, I think one question I would add is if

 

 16   there are costs associated with that, are consumers

 

 17   willing to pay.  I just spoke with one gentleman

 

 18   and we talked about, you know, maybe consumers

 

 19   would be willing to pay more for a smaller bag of

 

 20   French fries than for a larger bag of French fries.

 

 21   If those costs were there, would that influence

 

 22   what consumers would buy?  Because I think that

 

                                                               101

 

  1   kind of information would be very helpful as you

 

  2   approach restaurants to try to get them involved.

 

  3   So, I think if there is a cost associated with

 

  4   this, we need to understand that.

 

  5             DR. SHINE:  Other comments?  Yes, John?

 

  6             DR. THOMAS:  I would like to make some

 

  7   comments with respect to focusing on our youngsters

 

  8   and the various inequities in school systems across

 

  9   the country.  Certainly, it seems to me, and I am

 

 10   generalizing now because I am sure some schools are

 

 11   much more advanced than others and maybe this is

 

 12   more detail than you are really searching for at

 

 13   this point in time, but establishing under the

 

 14   rubric of PTAs, for example, some sort of

 

 15   nutritional council where, in fact, they bring the

 

 16   PE teacher, the health educator, other dieticians,

 

 17   assuming that particular school board has access to

 

 18   that because I realize there are going to be some

 

 19   small schools that may not have those--I know, for

 

 20   example, a lot of schools have begun to put

 

 21   restrictions on school vending machines which

 

 22   heretofore was a major source of discretionary

 

                                                               102

 

  1   monies for the school principal where he or she

 

  2   could go out and buy books, or whatever, which

 

  3   otherwise was not funded by their particular

 

  4   budgets.

 

  5             Also, building into that overall concept

 

  6   some sort of notion of nutritional incentive.

 

  7   Weigh these kids at the beginning of the year and

 

  8   see what happens at the end of the year.  You know,

 

  9   give them a goal to shoot for.  Don't just talk

 

 10   about it on the first day and then forget about it.

 

 11             We can't change the busing system with

 

 12   respect to physical activities.  We all live in the

 

 13   suburbs now so that one is taken away from the

 

 14   pediatric cohort.

 

 15             Finally, I think there needs to be a

 

 16   reemphasis on individual sports in our school

 

 17   systems.  Team sports have obviously taken

 

 18   precedence but they need to have lifelong physical

 

 19   activities and we need to encourage them through

 

 20   the physical education departments and whatever

 

 21   structure they have to go forth with lifelong,

 

 22   single competition sports.  Nowadays you can't even

 

                                                               103

 

  1   get kids to run out to the ball field because it

 

  2   has to be organized.  There is no such thing as

 

  3   getting a group of youngsters just to play ball for

 

  4   the fun of it.  It has to be a lesson or it has to

 

  5   be a league.  Somehow we need to encourage tennis,

 

  6   golf and other things that they are going to do for

 

  7   the rest of their life.  Again, I am sure there are

 

  8   schools that are already doing this but it has to

 

  9   be a coordinated effort for these various skill

 

 10   sets.

 

 11             DR. SHINE:  Thank you.  Other comments?

 

 12   Yes, Cato?

 

 13             DR. LAURENCIN:  Well, I would like to echo

 

 14   some of the thoughts that were said earlier.  I

 

 15   think that a number of groups are already trying to

 

 16   do this; a number of large chains are already doing

 

 17   this.  My one comment is that I think the FDA can

 

 18   be very helpful in terms of young people by trying

 

 19   to keep it simple.  I went to one restaurant where

 

 20   the place mats actually had all the nutritional

 

 21   information for all the different foods that they

 

 22   had.  I have two doctorate degrees and I was just

 

                                                               104

 

  1   about able to get through it, so I think that a

 

  2   young person might have a difficult time getting

 

  3   through it.

 

  4             We are trying a pilot program at our

 

  5   university where we are labeling the foods in the

 

  6   vending machines with green, yellow and red.  The

 

  7   foods that are labeled red have actually five

 

  8   percent surcharge that goes to research.  So, these

 

  9   sorts of methodologies are where perhaps the FDA

 

 10   can be helpful in terms of being able to decide

 

 11   what is green, what is yellow and what is red and

 

 12   also, of course, the possibility of recommendations

 

 13   in terms of how we can disseminate this sort of

 

 14   information in terms of what the different levels

 

 15   are, and things like that.

 

 16             One, I think it is important to try and

 

 17   keep it simple in terms of actually trying to help

 

 18   young people.  Number two, we can even place some

 

 19   monetary incentives and make that a part of it, and

 

 20   I think it would be good.

 

 21             DR. SHINE:  Thank you.  Josephine?

 

 22             DR. GRIMA:  In recent years the public has

 

                                                               105

 

  1   been bombarded with information about low

 

  2   carbohydrate diets, and although this is not a

 

  3   trend that has been endorsed by the AMA or

 

  4   government associations, the fact of the matter is

 

  5   that that information is out there in the public.

 

  6   I think one of the important things to address is

 

  7   how much information is really the consumer taking

 

  8   in, and I think the facilitator has to use that in

 

  9   their plans in order to educate the public on this.

 

 10             DR. RULIS:  Yes, I will just respond

 

 11   briefly on the carbs issue.  The carbs issue is

 

 12   front and center right now.  It is on a lot of

 

 13   packages we see in the stores and we are well aware

 

 14   that this is an issue that is really crying out for

 

 15   some clarification.  As we have stated in our

 

 16   report, we are currently in possession of some

 

 17   petitions that are intending to try to clarify some

 

 18   of these statements on labels and we are working

 

 19   very hard.  Those of us who have spent many years

 

 20   at FDA, we relish the opportunity to beat our head

 

 21   against hard problems--

 

 22             [Laughter]

 

                                                               106

 

  1             --and this is a difficult one because, you

 

  2   know, what is a carb, first of all, and then how do

 

  3   you impart information in a way that is not

 

  4   misleading and, yet, doesn't impinge on people's

 

  5   right to say things under the First Amendment?

 

  6   These are difficult questions but we look forward

 

  7   to trying to solve them.

 

  8             DR. SHINE:  Susan?

 

  9             DR. HARLANDER:  I just have one reaction

 

 10   to what Cato brought up.  I think that there is a

 

 11   lot of concern about labeling foods as good foods

 

 12   or bad foods, and that you will get a lot more

 

 13   cooperation from the food industry and the

 

 14   restaurant industry if any food, whether it is a

 

 15   green dot, yellow dot or a red dot, can fit into a

 

 16   balanced diet, and it has a lot to do with how much

 

 17   you are going to consume of that.  But I think

 

 18   there is a lot of concern about is something going

 

 19   to be categorized as a bad food as a result of some

 

 20   of these efforts, and it might create some lack of

 

 21   willingness to cooperate.

 

 22             DR. SHINE:  Yes, Xavier?

 

                                                               107

 

  1             DR. PI-SUNYER:  I think you get around

 

  2   that by talking about total calories, and you get

 

  3   around the carbohydrate issue also by talking about

 

  4   total calories, which I think is what the FDA is

 

  5   trying to do.  I think the really important thing

 

  6   is how many calories people are eating in relation

 

  7   to how much exercise they are doing.

 

  8             I would just like to say a couple of

 

  9   things.  Number one is that I think it would be

 

 10   nice if the FDA would collaborate with other HHS

 

 11   agencies on these campaigns.  For instance, CDC is

 

 12   very much involved with the physical activity

 

 13   aspect of trying to educate the public, and it

 

 14   would seem to me that eventually, if and when the

 

 15   FDA goes out with an educational program for

 

 16   raising the consciousness of the American people or

 

 17   to raise the consciousness of the restaurants, or

 

 18   whatever, that there be kind of a concerted effort

 

 19   with agencies like the CDC which are working on the

 

 20   other side, which is the expenditure side.  That is

 

 21   number one.

 

 22             Number two, I think that the main emphasis

 

                                                               108

 

  1   really ought to be on prevention.  I agree with Dr.

 

  2   Swanson completely that weight loss is extremely

 

  3   difficult, and it is expensive, and it is hard to

 

  4   do and it is hard to maintain.  What I think the

 

  5   message needs to be for children and for adults is

 

  6   to control their weight.  The average American is

 

  7   gaining an enormous amount of weight every year and

 

  8   over a decade they are gaining between 10 and 20

 

  9   pounds.  So, what we want to do is to prevent that

 

 10   weight gain from age 21 or age 18 on, and I think

 

 11   that is where the focus really ought to be of the

 

 12   campaign.

 

 13             DR. SHINE:  Dr. Crawford is going to

 

 14   comment, but again, looking at the questions that

 

 15   you were asked, are these the right questions for a

 

 16   facilitator?  Are you comfortable with the

 

 17   direction that this is taking?

 

 18             DR. PI-SUNYER:  Well, I am comfortable

 

 19   with that direction.  I think we need to know more

 

 20   about behavior but, you know, the trouble is that

 

 21   we do know quite a bit about behavior already,

 

 22   particularly from other campaigns with tobacco and

 

                                                               109

 

  1   other substances of abuse, and I think changing

 

  2   behavior is very hard.  I am not sure that these

 

  3   focus groups are going to give you the answers

 

  4   totally that you are looking for.

 

  5             I do think talking to the focus groups,

 

  6   particularly about the labeling, is very important

 

  7   because clearly, as Cato says, you don't want to

 

  8   give them a label that they are not going to be

 

  9   able to read or that they are going to throw up

 

 10   their hands and say I don't understand this.  So, I

 

 11   think the whole label reading aspect of this focus

 

 12   group initiative is very good.

 

 13             DR. CRAWFORD:  Your question about

 

 14   coordination within HHS was a good one.  The way

 

 15   Secretary Thompson dealt with this as he moved this

 

 16   towards the top of his priority list was that, as I

 

 17   mentioned, about a year ago he caused NIH, CDC and

 

 18   FDA to put together these in-depth studies, headed

 

 19   up by working groups chaired by the deputies at

 

 20   each one of those organizations.  I was the one who

 

 21   chaired the FDA one.

 

 22             Then, one week about three months ago each

 

                                                               110

 

  1   of the agencies presented their findings to the

 

  2   public.  It was obesity week for Secretary Thompson

 

  3   and he had three separate and then one unified

 

  4   press conference.  At that point, the Department of

 

  5   Health and Human Services took over the public

 

  6   education initiative.  FDA's role will be to feed

 

  7   into that, as will the CDC's.  That initiative of

 

  8   education has begun with an ad council campaign.

 

  9   Then it will be followed up with some more in-depth

 

 10   approach as we attempt to reach all strata of

 

 11   American society.  The message will be refined.  It

 

 12   will be more sophisticated as it moves forward from

 

 13   the base, which is like a cartoon type presentation

 

 14   which is called sometimes the "body parts"

 

 15   presentation because in the most famous one of

 

 16   those ads someone is walking through a supermarket

 

 17   aisle and there is some protoplasm on the floor,

 

 18   and a little girl asks her parent what is that on

 

 19   the floor, and the parent responds it looks like

 

 20   someone lost their double chin from eating well.

 

 21             [Laughter]

 

 22             It is a very catchy campaign.  I am

 

                                                               111

 

  1   compelled to say so and that is how we get

 

  2   coordinated.

 

  3             DR. SHINE:  Let me just follow-up on this

 

  4   for a minute.  I think there is a real question

 

  5   here to understand the niche of the FDA in this

 

  6   area.  I think one needs to explore very carefully,

 

  7   not only in terms of the federal agencies but state

 

  8   health departments, medical associations and others

 

  9   who are confronting this problem at local

 

 10   communities.  Changing this with national publicity

 

 11   creates a certain kind of environment, if you will.

 

 12   But where the rubber hits the road is going to be

 

 13   concerted efforts in communities that will address

 

 14   all of the elements.  We have talked about

 

 15   restaurants and schools but what about company

 

 16   cafeterias and the whole question of whether, in

 

 17   fact, it is economically desirable to a company

 

 18   which has X amount of turnover to be paying Y

 

 19   amount of dollars in order to minimize the obesity

 

 20   that goes on in that company because it might help

 

 21   them save healthcare costs with diabetics and

 

 22   hypertensives, but that depends on turnover.

 

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  1             So, the kinds of programs that we are

 

  2   talking about are going to be partnerships.  They

 

  3   are going to be efforts to get the media, to get

 

  4   the schools, to get industry to relate to this

 

  5   issue of everything from bike lanes to exercise or

 

  6   fitness programs in companies.

 

  7             My point is that I think the extent to

 

  8   which the facilitator can really hone in--the

 

  9   agency is famous for its capacity to analyze

 

 10   science and to find science-based information which

 

 11   could form the basis of all of these programs.

 

 12   Articulating that, modifying that, working on that

 

 13   so that it is part of these overall programs is

 

 14   going to be key.  Therefore, I would urge them to

 

 15   look fairly broadly as to what we are talking about

 

 16   and I think, again, I would not exclude state

 

 17   health departments.  I wouldn't exclude both urban

 

 18   and rural environments as places to understand what

 

 19   the niche is.

 

 20             I would also suggest to you that

 

 21   increasingly in 8th grade biology there is an

 

 22   interest of young people about their bodies, and so

 

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  1   forth.  Anorexia-bulimia has been a major target

 

  2   for those educational programs.  The question is

 

  3   whether those educational programs could provide a

 

  4   balanced view of diet, exercise, and so forth, and

 

  5   is the FDA an ideal source of information packages

 

  6   and materials that could be used in public schools?

 

  7   With all due respect to USDA, I worry about the

 

  8   USDA's way of presenting that.  Perhaps between the

 

  9   two agencies one might be able to come up with

 

 10   material that would be part of the curriculum in

 

 11   terms of that.

 

 12             Finally, I want to emphasize, as I

 

 13   mentioned before about tobacco, that everything we

 

 14   have learned about changing behavior has to do with

 

 15   not just the information but changing the

 

 16   environment, whether it is because you pay more or

 

 17   whether because something is accessible or not.

 

 18   Therefore, when you talk about children, I happen

 

 19   to think that is where an enormous amount of the

 

 20   focus should be.  I think the public cares about

 

 21   their kids.  I think they will often do one thing

 

 22   and do something else for their kids.  So, as far

 

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  1   as they are concerned, starting in kindergarten,

 

  2   the environment in which they are living will make

 

  3   an enormous difference as to what their lifetime

 

  4   habits are.  So, I don't think you can start too

 

  5   early.  Although I have focused on the 8th grade

 

  6   biology course, the fact is that if a second grader

 

  7   sees vending machines all around with high cal food

 

  8   or high fat food, they are going to assume that it

 

  9   is part of the environment in which they live.  So,

 

 10   I think the emphasis on pediatrics is extremely

 

 11   important but that one ought to think about it in

 

 12   terms of how and in what way you can use the data

 

 13   that you have to change the environment in terms of

 

 14   what is available to people.  Katherine?

 

 15             DR. SWANSON:  Kind of building on the

 

 16   notion that behavior is important, I personally

 

 17   think that your question related to how do you

 

 18   measure effectiveness is the most important one.

 

 19   If you go down the path of trying all of these

 

 20   different concepts and you don't have a way to

 

 21   measure behavior change--not just what people say

 

 22   they will do but what they will do--you really

 

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  1   won't be able to target what is going to have the

 

  2   biggest impact.  So, I would make sure that that

 

  3   question might be thought of first with every

 

  4   strategy that you are looking at, how would we

 

  5   impact the magnitude of the change.

 

  6             Another thing to consider with regard to

 

  7   the restaurants, listing the calories I think is

 

  8   very interesting.  The segregation out of healthy

 

  9   choices is another.  Another option that would be

 

 10   very interesting to explore that would be

 

 11   applicable to the white tablecloth restaurants as

 

 12   well would be smaller portion sizes.  I mean, many

 

 13   of us who are on the road all the time and you go

 

 14   to the restaurant and you simply cannot eat all of

 

 15   the food that is put on your plate, and would you

 

 16   be able to pay not half as much because there are

 

 17   labor costs there, but offering multiple service

 

 18   sizes might be a very interesting thing to study

 

 19   because if you reduce it by half you have cut your

 

 20   calory intake in half.

 

 21             One more question that you might want to

 

 22   add is, is there a way that you can link the

 

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  1   caloric intake piece to the caloric output piece in

 

  2   some kind of a message?

 

  3             DR. SHINE:  Thank you, Katherine.  I would

 

  4   suggest that I would like a facilitator to create a

 

  5   model for continuous quality improvement in this

 

  6   area.  What I mean by that is we don't know what

 

  7   works.  We don't know what will not work.  We need

 

  8   a concept that there is a lot of experimentation

 

  9   going on to learn from that what impact it has, and

 

 10   then constantly reassess how and in what way we are

 

 11   using our activity.  I think the notion is that it

 

 12   is for the long haul.  I think that looking at that

 

 13   in terms of socioeconomic status, ethnic groups,

 

 14   and so forth, is going to be pretty central

 

 15   because, in fact, they may behave very differently

 

 16   and it is not at all clear to me, once you get the

 

 17   data and put something in place, that it will work

 

 18   in the same way in a variety of settings.  So, I

 

 19   think that notion of what is the long-term model

 

 20   for constantly reassessing where one is and where

 

 21   do you get the data, how do you get the data, what

 

 22   are you trying to measure in order to make those

 

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  1   decisions would be an important part of how to

 

  2   conceptualize this.

 

  3             Incidentally, we were talking at the break

 

  4   about differences in terms of environment and

 

  5   culture.  You might be interested to know that the

 

  6   Japanese, about a year or two ago, redid the

 

  7   height/weight tables for boys because the boys are

 

  8   getting so much bigger and putting on more weight.

 

  9   They are also getting higher cholesterol levels,

 

 10   incidentally.  But girls are not.  The culture in

 

 11   Japan is so focused on young women being thin that

 

 12   they have shown no change in the height/weight

 

 13   environment.  So, these cultural elements make an

 

 14   enormous difference in terms of how people behave.

 

 15   Other comments?

 

 16             DR. THOMAS:  Just a couple of follow-up

 

 17   points, and these are certainly not revelations but

 

 18   I would strongly urge as you look at behavioral

 

 19   profiles that you make every effort to get a

 

 20   quantifiable endpoint.  That is almost a

 

 21   contradiction when you are dealing with behavior,

 

 22   but as you go into this I think you really need to

 

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  1   look at those endpoints.

 

  2             The other thing, I was struck by the

 

  3   simplicity of the color coding that Cato mentioned.

 

  4   While it has a downside and you can get into the

 

  5   good and bad foods, I think the general public