DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
FDA SCIENCE BOARD ADVISORY COMMITTEE
Thursday, April 22, 2004
Advisors and Consultants Staff Conference Room
5630 Fishers Lane
Kenneth I. Shine, M.D., Chair
Jan. N. Johannessen, Ph.D., Executive Secretary
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.
Daniel A. Casciano, Ph.D.
David W. Feigel, Jr., M.D., M.P.H.
Kathy Carbone, M.D.
Robert E. Brackett, Ph.D.
Steven Galson, M.D., M.P.H.
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
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
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 -
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!
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
necessity to find ways to bring new products to
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
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
22 DR. PI-SUNYER:
I am Xavier Pi-Sunyer. I
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
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
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
Ken Shine. I serve currently as
the Executive Vice
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
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
be replaced until he comes back--
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
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
completed but we believe those benchmarks that were
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
Thompson released a new FDA report outlining the
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
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
end of this decade.
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
to the bedside, to the pharmacy, to the hospital
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
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
come up with, but this one has a system to it and
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
encouraging to the committee.
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
in which a particular product is discussed, issues
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
is allotted to them and, at the same time, I would
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
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.
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
obesity initiative, and then following me the next
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
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
nationwide program where it takes the participation
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.
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.
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.
20 They were given a very simple charge, and
21 that was to prepare a report that outlines an
action plan that would cover the critical
1 dimensions of the obesity problem that FDA could
2 participate in with the other agencies as well.
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.
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.
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
actually get consumers to understand that they are
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.
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.
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
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
factors--do contribute to increasing obesity and,
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.
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.
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
obesity, especially FDA's participation. Dr.
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
22 What I am going to use my time on to do
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
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.
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
common in those who are naturally fat than lean.
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.
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
gamut from cardiovascular disease and all of its
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.
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.
Then, as I said, coming at it from the other side,
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.
22 The harsh reality of the state of medical
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.
21 But having said that, opportunities
abound. This is a list of the
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
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
discussion. I will really touch
mostly on just one
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
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.
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
led ultimately to the passage of the 1938 Food,
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
unfortunate case of Redux and the unexpected, but
1 in some cases, frankly malignant cardiac
2 valvulopathy that resulted from the use of those
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.
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
think all these drugs are stimulant anorexigens and
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.
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
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
approximately 5 kg for placebo and a range of
1 placebo-subtracted means across multiple studies of
2 1-10 kg.
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.
22 With this recognition or this casting in a
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.
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
further information on durable efficacy and safety
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.
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
20 Three drugs have been approved for
21 long-term treatment under the current guidelines.
The first, dexfenfluramine, was withdrawn less than
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.
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
on Harmonization E1A document on the development of
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.
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
is our responsibility to be as sure as we can be
1 that drugs are going to be safe and effective when
2 they go out into these millions and millions of
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
17 Long-term safety and efficacy of older
18 drugs also needs better understanding, particularly
21 I show you this slide of drug use data
from 1991-2002 to demonstrate that throughout these
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.
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
long-term individual and population reductions in
1 morbid and mortal sequelae of obesity?
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
we are still on the waxing side of this story.
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.
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
20 With that, diet and exercise remain the
21 mainstays of prevention and treatment of obesity;
drugs are adjunctive to hygienic measures. They
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,
1 Dr. Shine, for that introduction.
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.
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
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.
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",
essentially genomics, proteomics and metabolomics;
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.
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
established worked through the root of focus
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
that if you look at items that are typically
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
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
works into physical activity and choice of food and
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.
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
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,
parents misjudge the weight of their children and
1 will often determine that their children are at
2 healthy weight where, in fact, they may be a little
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
there is emphasis on incremental change. I think
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.
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
indicated that these are important areas. What we
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.
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
food in the home environment versus the fast-food
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
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.
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
that will drive reformulation to develop healthier
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.
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
further explore these barriers.
As I said, there
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.
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.
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
unintentionally contributing to the obesity
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
appropriate animal models.
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"
issue to identify susceptibilities.
This is really
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
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.
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
and develop regulatory policies.
This is obviously
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
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.
22 To conclude, obviously, calories are a
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
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
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
been established as a basis on which they have been
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
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
combination with another product which was still
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
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
is the great hope for obesity, as well as you
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
Rockefeller people, and the question again of
1 whether over some period of time we could identify
2 targets that are more likely to be responsive than
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
the concept of drug cycling, which I gather is
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
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
part of understanding consumer behavior. There is
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
on and so forth. My question is
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
22 That speaks also to developing educational
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
won't. But I think, rather than
be in the second
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
that might respond that might respond in this group
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?
Highlights of the Obesity Working Group Report
1 DR. RULIS: Thank you, Chairman.
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
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.
20 What I would like to focus on in my
21 presentation is a couple of other areas that are
extremely important to the success of FDA's efforts
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
and feedback to us.
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
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
21 With respect to foods eaten away from
home, we imagined putting together a contract for a
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?
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.
22 Should nutrition information be listed for
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.
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.
20 How should restaurants tailor the kinds of
21 nutrition information presented based on expected
clientele? You can imagine the
need there to focus
1 the kinds of information that is presented to the
2 type of restaurant and the clientele that frequent
3 that restaurant.
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.
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
obesity working group report we say as part of the
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
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
absorbed and, once absorbed, it does not
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.
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.
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
pitfalls of trying to create an awareness about
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.
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
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.
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
currently overweight as adults to lose some weight.
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.
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.
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.
But we also do see the value of partnering. A lot
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
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
to the Board, and you have all seen them in your
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.
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
your recommendations about that.
If we haven't hit
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?
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.
22 What advice would you have for a
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?
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.
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?
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.
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.
6 What other questions should FDA be asking
7 a facilitator to explore in order to help the
8 agency develop effective educational strategies?
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?
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.
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
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
and your good guidance to the agency.
That is my
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
seems trivial, but even from personal experience
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
much aware that, yes, indeed, they are not really
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
circumstances. So, I think
industry involvement is
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
research that I have reviewed prior to this do we
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
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
what consumers would buy?
Because I think that
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
heretofore was a major source of discretionary
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
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,
single competition sports.
Nowadays you can't even
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
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
had. I have two doctorate
degrees and I was just
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
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--
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:
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
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
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,
particularly from other campaigns with tobacco and
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
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.
22 It is a very catchy campaign. I am
1 compelled to say so and that is how we get
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
hypertensives, but that depends on turnover.
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
interest of young people about their bodies, and so
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
and do something else for their kids.
So, as far
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
they will do but what they will do--you really
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
add is, is there a way that you can link the
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
are you trying to measure in order to make those
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,
but as you go into this I think you really need to
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