1

FOOD ADVISORY COMMITTEE AND DIETARY

SUPPLEMENTS SUBCOMMITTEE

THE ROLE OF GLUCOSOSAMINE AND CHONDROITIN

SULFATE IN OSTEOARTHRITIS

Monday, June 7, 2004

8:03 a.m.

Bethesda Marriott

5151 Pooks Hill Road

Bethesda, Maryland

P A R T I C I P A N T S

Sanford A. Miller, Ph.D., Chair

Linda Reed, Acting Executive Secretary

Douglas L. Archer, Ph.D.

Patrick S. Callery, Ph.D.

Annette Dickinson, Ph.D.

Goulda A. Downer, Ph.D.

Johanna Dwyer, D.Sc., R.D.

Jean M. Halloran

Norman I. Krinsky, Ph.D.

Daryl B. Lund, Ph.D.

Margaret C. McBride, M.D.

Mark F. Nelson, Ph.D.

Robert M. Russell, M.D.

Carolyn I. Waslien, Ph.D., R.D.

Edward Blonz, Ph.D.

Edward D. Harris, Ph.D.

Harihara M. Mehendale, Ph.D.

Steven Zeisel, M.D., Ph.D.

Temporary Voting Members

Steven Abramson, M.D.

John J. Cush, M.D.

Luis Espinoza, M.D.

David Felson, M.D., M.P.H.

Scott A. Kale, M.D., J.D., M.S.

Nancy E. Lane, M.D.

Also Present:

Jeanne Latham, Executive Secretary, Dietary

Supplements Subcommittee

C O N T E N T S

AGENDA ITEM PAGE

Call to Order, Introductions - Dr. Miller 4

Administrative Matters and Conflict of Interest

Statement - Ms. Reed 9

Opening Remarks, Robert E. Brackett, Ph.D.,

Director, Center for Food Safety and Applied

Nutrition (CFSAN) 20

Background and Questions to Committee - Laura M.

Tarantino, Ph.D. 22

Questions and Clarifications 30

Overview of Legal Framework, Louisa Nickerson,

Office of General Counsel, FDA 33

Questions and Clarifications 38

Overview of petitions: FDA's Review Process and

Issues - Dr. Craig Rowlands, Biologist,

FDA/ONPLDS/CFSAN 42

Questions and Clarifications 57

Petitioner: Weider Nutrition International, Inc.,

Luke R. Bucci, Ph.D., Vice President of Research,

Weider Nutrition Group 69

Questions and Clarifications 105

Petitioner: Rotta Pharmaceutical, Inc.

- Dr. Lucio C. Rovati, Executive Medical Director,

Rotta Research Laboratory 136

- Dr. Roy D. Altman, Professor of Medicine and

Rheumatology, University of Miami and University of

California-Los Angeles 156

Questions and Clarifications 174

Lunch 207

Questions and Comments 250

C O N T E N T S (Continued)

AGENDA ITEM PAGE

Current State of the Science on Etiology of OA and

Modifiable Risk Factors for OA - Dr. Lee Simon,

Harvard University 209

Questions and Clarifications 250

The Role of Animal and in vitro Models in OA Risk

Reduction - Dr. James Witter, Center for Drug

Evaluation and Research, FDA 256

Questions and Clarifications 287

Public Comment 291

- Jason Theodasakis, M.D. 291

- Gayle E. Lester, Ph.D. 299

- Robert Arnot, M.D. 304

- Jose Verges, M.D. 317

- Todd Henderson, D.V.M. 332

- Chuck Filburn, Ph.D. 334

Questions and Clarifications 341

Adjournment 352

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

2 DR. MILLER: Good morning. I want to take

3 this opportunity of welcoming you to this meeting

4 of the Food Advisory Committee. Today and tomorrow

5 the committee is going to deal with two topics, one

6 dealing with the role of glucosamine and

7 chondroitin sulfate in osteoarthritis, and the

8 other having to do with furan contaminants in

9 foods.

10 For that reason, in order to expand the

11 expertise of the committee, we've invited some

12 temporary members to join the committee, several

13 dealing with the glucosamine and chondroitin

14 sulfate issue and several having to do with the

15 issues concerned with furans.

16 As always, we have much too full a

17 schedule, and as always, I'm going to insist that

18 we stick to our time. We have to give everybody an

19 opportunity to speak and speak for the time limits

20 that they've been assigned, and we also have to

21 provide enough time for us to discuss the issues to

22 the extent that the committee needs and feels that

1 discussion is needed. Towards that end, as you

2 make your presentations and you have exceeded your

3 time, I'll let you know. And I'm not sure exactly

4 what I'll do if you continue to talk, but--

5 [Laughter.]

6 DR. MILLER: The very least would be to

7 turn off your microphone and ask questions

8 concerning the meaning of your data.

9 To begin the meeting, I'd like to

10 introduce--or have them introduce themselves, the

11 members of the committee. This morning we will

12 deal with the glucosamine and chondroitin sulfate

13 issues, and tomorrow we'll deal with furans.

14 I'll begin by introducing myself. My name

15 is Sandy Miller. I'm a senior research associate

16 at the Center for Food Nutrition Policy at Virginia

17 Tech University.

18 DR. RUSSELL: I'm Robert Russell. I'm

19 director of the USDA Human Nutrition Research

20 Center on Aging at Tufts.

21 DR. DICKINSON: Annette Dickinson,

22 president of the Council for Responsible Nutrition.

1 DR. ARCHER: I'm Doug Archer, professor,

2 Food Science and Human Nutrition at the University

3 of Florida.

4 DR. CALLERY: Patrick Callery,

5 pharmaceutical chemist, from West Virginia

6 University.

7 DR. DOWNER: Goulda Downer, president and

8 CEO, Metroplex Health and Nutrition Services,

9 Washington, D.C.

10 DR. McBRIDE: Margaret McBride, child

11 neurologist at Akron Children's Hospital.

12 DR. BLONZ: Edward Blonz, nutritional

13 biochemist, from Kensington, California.

14 DR. ABRAMSON: Steve Abramson, Director of

15 Rheumatology at NYU and the Hospital for Joint

16 Diseases and Dean for Clinical Research at NYU.

17 DR. FELSON: David Felson, rheumatologist,

18 from Boston University.

19 DR. ESPINOZA: Luis Espinoza, Chief of

20 Rheumatology, LSU, New Orleans.

21 DR. KALE: Scott Kale. I'm a

22 rheumatologist at Rush Presbyterian and St. Luke's

1 in Chicago.

2 DR. LANE: Nancy Lane, rheumatologist,

3 University of California-San Francisco.

4 DR. ZEISEL: Steve Zeisel. I'm professor

5 and Chair of the Department of Nutrition at the

6 University of North Carolina at Chapel Hill.

7 DR. MEHENDALE: Hari Mehendale, professor

8 of toxicology at the University of Louisiana at

9 Monroe.

10 DR. HARRIS: I'm Ed Harris, professor of

11 biochemistry and nutrition, Texas A&M University.

12 DR. NELSON: Mark Nelson, Vice President

13 for Scientific and Regulatory Policy, Grocery

14 Manufacturers of America.

15 DR. WASLIEN: Carol Waslien, Chair and

16 professor, Nutritional Epidemiology, University of

17 Hawaii.

18 DR. LUND: Daryl Lund, University of

19 Wisconsin-Madison, Food Science, and Executive

20 Directors of the North Central Regional

21 Association.

22 DR. DWYER: Johanna Dwyer, professor at

1 Tufts University, and Director of the Frances Stern

2 Nutrition Center and New England Medical Center,

3 and I'm spending the year in Washington.

4 DR. KRINSKY: Norman Krinsky, emeritus

5 professor of biochemistry, Tufts University School

6 of Medicine.

7 MS. LATHAM: Jeanne Latham, Food and Drug

8 Administration, Executive Secretary of the Dietary

9 Supplements Subcommittee.

10 MS. REED: Linda Reed, Acting Executive

11 Secretary of the Food Advisory Committee.

12 DR. MILLER: Next we have certain

13 administrative things that we need to go through,

14 and Linda Reed, who is the Acting Executive

15 Secretary of the Food Advisory Committee, will

16 present those rules of the road and issues

17 concerning conflict of interest.

18 MS. REED: Good morning, everyone. As

19 you've heard, I'm Linda Reed, the Acting Executive

20 Secretary of the Food Advisory Committee. I was

21 asked to take a few minutes to refresh everyone's

22 memory about a few rules of the road, if you will,

1 in terms of Advisory Committee operations.

2 It is my understanding that all of the

3 committee members have been provided a copy of a

4 Committee Member Guide to FDA Advisory Committees.

5 There is a copy of the Member Guide at the

6 registration desk for anyone who may be interested

7 in looking through it. The Committee Member Guide

8 is in need of updating, but, by and large, it does

9 provide good operational review.

10 FDA relies on Advisory Committees to

11 provide the best possible scientific advice

12 available to assist us in making complex decisions.

13 Our goal is to do that in as open and transparent a

14 manner as possible. Part of that openness carries

15 with it a request that the members try to avoid

16 even the appearance that issues are being decided

17 or conclusions are being reached outside of the

18 meeting.

19 We understand that issues raised during

20 the meeting may well lead to conversation over

21 breaks and during a meal. In fact, we hope the

22 discussions are thought-provoking.

1 We have had instances where members have

2 come back from a break and said, "You know, we were

3 talking over the break, and we would like to

4 request that the FDA provide us with some

5 additional information so we can better understand

6 thus and such." That is perfectly acceptable.

7 What we don't want is to have a situation

8 where, after the break, the members come back and

9 say, "We were talking over the break and decided

10 that an answer to a question is..." From our

11 perspective, that would be particularly troublesome

12 because neither the agency nor the public would

13 have had the benefit of listening to the entire

14 discussion, the question raised, and the responses.

15 In fact, FDA has adopted a policy that

16 only the matters can be reached by a show of hands,

17 procedure matters, for example--I read all that

18 wrong. Excuse me.

19 In fact, FDA has adopted a policy that the

20 only matters that can be decided by a show of hands

21 are procedure matters, for example, break times.

22 All other votes and comments must be placed on the

1 record, attributed to the member making that

2 statement. The policy goes even further. If a

3 member has to leave the meeting early, the member

4 waives that right to vote. You may wonder why the

5 person may lose their right to vote, but the answer

6 is fairly simple. FDA believes that all parts of

7 the meeting and discussions are important.

8 Consequently, voting on issues without having the

9 benefit of the discussion would be premature.

10 The issue of openness is larger than what

11 transpires during the course of the meeting. I

12 would like to call your attention to the section in

13 the Member Guide titled "Member Interaction Before,

14 During, and After a Meeting." In essence, this

15 section underscores the fact that all

16 communications with the members should be routed

17 through the committee's Executive Secretary. That

18 would be myself. No one, not even FDA staff, with

19 the exception of the Executive Secretary, should be

20 contacting the members about upcoming meetings,

21 topics, et cetera. This same guidance applies to

22 consultations between members prior to a meeting.

1 If a member receives an inappropriate

2 contact, the member should feel free to notify

3 myself and/or refer the person making the contact

4 to me. Our goal in having all contacts routed

5 there the Exec. Sec. is to minimize any situations

6 that could be misinterpreted.

7 Appearance issues are always difficult,

8 because, as is true of many things, appearances can

9 be deceiving. We ask that our members, guest

10 speakers, liaisons, and everyone attending the

11 meeting be mindful of how an interaction between a

12 member--and anyone, for that matter--might be

13 perceived.

14 Please let me be clear. It is not my

15 intention to question anyone's integrity or

16 motives. But I'm very sensitive to the issue

17 because I have--and I imagine you all have, too--seen highly

18 respected individuals become an object

19 of negative attention based on a misperception.

20 And I certainly wouldn't want anyone in this room

21 to become such a target.

22 I'm confident that everyone here today is

1 sensitive to these issues and can appreciate that

2 my comments are intended as a gentle reminder.

3 Lastly, as you settle in, please take this

4 opportunity to silent any cell phones or other

5 devices that ring, beep, or play show tunes. And I

6 appreciate your attention for that statement.

7 Now I'd like to read the conflict of

8 interest statement into the record.

9 DR. MILLER: Just to be certain that there

10 are no mistakes, does anybody need any

11 clarification?

12 [No response.]

13 DR. MILLER: If not, why don't we go on.

14 MS. REED: Okay. As Dr. Miller mentioned,

15 we have the pleasure of having two of our

16 subcommittees and several members of our sister

17 center Advisory Committee serving throughout the

18 meeting, and we thank you for being here.

19 And with that, I would like to read the

20 conflict of interest statement into the meeting

21 record. And as with the rules of the road, this is

22 a rather long one, so please bear with me.

1 The authority to appoint temporary voting

2 members to the Food Advisory Committee is granted

3 to the Center Director. Relying on that authority,

4 Dr. Robert Brackett, Director, Center for Food

5 Safety and Applied Nutrition, has signed letters

6 appointing Dr. Luis Espinoza, Dr. Scott Kale, and

7 Dr. Nancy Lane as temporary voting members of the

8 Food Advisory Committee of the June 7-8, 2004,

9 committee meeting. These members will serve on the

10 committee for the first portion of the meeting, the

11 subject of which is osteoarthritis.

12 The authority to grant permission to

13 borrow special government employees currently

14 serving on the Advisory Committee in a sister

15 center, in this case the Center for Drug Evaluation

16 and Research, is granted to the Associate

17 Commissioner for External Relations, Mr. Peter

18 Pitts. Relying on that authority, Mr. Pitts has

19 signed a memorandum granting permission to Dr.

20 Steven Abramson, Dr. John Cush, and Dr. David

21 Felson to serve as temporary voting members on June

22 7-8, 2004, for the first portion of this meeting.

1 They will represent the Arthritis Drugs Advisory

2 Committee.

3 Mr. Pitts in the same memorandum also

4 granted permission for Dr. P. Joan Chesney to serve

5 as a temporary voting member for the second portion

6 of the meeting concerning furan on June 8, 2004.

7 Dr. Chesney will represent the Pediatrics Advisory

8 Subcommittee of the Anti-Infective Drug Advisory

9 Committee.

10 With that said, we have a total of seven

11 temporary voting members who will participate in

12 one of these two parts of this meeting.

13 Because of the breadth of topics to be

14 discussed at this meeting, all of the members and

15 temporary voting members have been screened for any

16 and all financial interests associated with the

17 regulated industry. Based on this review, FDA has

18 determined, in accordance with 18 U.S.C., Section

19 208(b)(3), to grant general matters waivers to Dr.

20 Steven Abramson, Dr. Marian Allen, Dr. Douglas

21 Archer, Dr. Edward Blonz, Dr. John Cush, Dr.

22 Johanna Dwyer, Dr. Luis Espinoza, Dr. David Felson,

1 Dr. George Gray, Dr. Edward Harris, Dr. Scott Kale,

2 Dr. Norman Krinsky, Dr. Nancy Lane, Dr. Harihara

3 Mehendale, Dr. Margaret McBride, Dr. Sanford

4 Miller, Dr. Robert Russell, Dr. Carolyn Waslien,

5 and Dr. Steven Zeisel.

6 The granting of these waivers permits

7 individuals to participate fully in the matters

8 before this committee. Copies of the waiver

9 statements may be obtained by submitting a written

10 request to the agency's Freedom of Information

11 Office, Room 12A-30 of the Parklawn Building.

12 In an effort to enhance consistency within

13 the FDA, the agency has recently adopted a policy

14 whereby all public commenters will be asked to

15 report any personal financial interests that could

16 be affected by the committee's deliberations. A

17 copy of the policy was provided to all individuals

18 who registered to make comments at this meeting.

19 Additional copies of the policy may be obtained

20 from the registration desk.

21 Similarly, we have asked our guest

22 speakers to complete a financial interest and

1 professional relationship certification for guests

2 and guest speakers to identify any potential

3 conflicts of interest. Dr. Luke Bucci, Dr. Lucio

4 Rovati, Dr. Roy Altman, and Dr. Lee Simon will

5 speak at the first portion of the meeting. Dr.

6 Bucci has declared that he has a financial interest

7 in the Weider Nutrition Group. Dr. Lucio Rovati

8 has declared he has a financial interest in the

9 Rotta Research Laboratorium in Monza, Italy. Dr.

10 Roy Altman has declared he has a financial

11 relationship with Rotta Pharm. And Dr. Lee Simon

12 has indicated that he has no financial

13 relationships with dietary supplements or the

14 pharmaceutical industries.

15 Dr. Don Forsythe and Dr. Glenda Moser will

16 be guest speakers at the second portion of the

17 meeting. Both have indicated they have no

18 financial interests in the food industry.

19 I have one final administrative announcement. We

20 have received two written submissions

21 from Nutramax Laboratories, Incorporated. The

22 submissions have been provided to our members, and

1 copies are available at the registration desk for

2 those attending the meeting.

3 Almost done. Lunch will be provided today

4 and tomorrow for our members and guest speakers.

5 We hope this will avoid some of the time crunches

6 we have experienced in the past and facilitate

7 returning to the meeting in a timely fashion, as

8 this meeting is a very full one.

9 I want to thank you again for your

10 attention as I read the statement and welcome all

11 of you again. Thank you very much for being here.

12 DR. MILLER: Thank you, Linda.

13 As many of you know, there was a change in

14 leadership at CFSAN since the beginning of the

15 year. Dr. Robert Brackett was named Director of

16 the Center when Joe Levitt left. At our last

17 meeting, Dr. Brackett had an opportunity of being

18 introduced to the FAC. However, at that time he

19 had not been--he had been named, but he hadn't

20 assumed the position of Center Director. He's with

21 us today, and he's going to make some opening

22 remarks.

1 Bob?

2 DR. BRACKETT: Well, thank you, Dr.

3 Miller, and good morning to all of you. It is a

4 distinct pleasure for me to be able to provide some

5 very brief opening remarks and to welcome you to

6 this Food Advisory Committee.

7 As was mentioned, you have a very, very

8 full schedule, and so I am going to keep my

9 comments brief. But I did want to offer the fact

10 that this is something that I support very highly,

11 the Food Advisory Committee meeting. I think that

12 it enables FDA to enhance the expertise that we

13 have available to us; it allows for a breadth of

14 different views on some important scientific

15 issues. And the two that we've got today and

16 tomorrow--that is, chondroitin sulfate and

17 glucosamine and then, tomorrow, furan--are two that

18 have been in front of us a lot in the last year.

19 So, you know, I myself am going to find the results

20 of the discussions quite interesting.

21 I had originally intended to stay both

22 days all day because I did want to hear some of the

1 scientific discussions, but I have found out that

2 my schedule has changed since I returned from

3 Europe last week, and so I will only be able to

4 stay a little bit today, and unless things change

5 tomorrow, I will not be able to be here tomorrow.

6 But I wish that I could.

7 One of the things I do want to say is in

8 supporting the Food Advisory Committee, the fact

9 that you have scientific discussion in an open,

10 transparent manner, I find that it's enhancing to

11 our experts to be able to hear what outside

12 scientists say. But as a former member of this

13 committee before I came to FDA, I also found that

14 participating from the outside in this also helped

15 sort of give a little more depth and breadth to the

16 scientific expertise for those that come here.

17 As mentioned, we're having some extra

18 experts coming from our Center for Drugs as special

19 government employees, and that is always enriching

20 to the discussion as well.

21 I hope that things can move along on time

22 and that you will have the opportunity to give all

1 of the opinions that you have and all the

2 discussion that is required from this meeting.

3 It's something that, again, as I say, I am looking

4 forward to very much, and I really do want to again

5 wish you here--but I don't want to belabor the

6 point because I do know that you have a lot going.

7 And, again, thank you for coming. Thank you for

8 participating. I know this does take a lot of time

9 out of your professional schedules as well.

10 So good morning and welcome.

11 DR. MILLER: Thank you, Bob.

12 Let us turn now to the basic issues of why

13 we're here. Our first speaker from the FDA will

14 present the background and the questions the

15 committee is being asked to consider. I would like

16 to emphasize how important it is that we listen to

17 this very carefully because if we don't stick to

18 the topics and we allow ourselves to drift and not

19 focus on what we're here for, we're not going to be

20 able to come to any conclusions by the time this

21 meeting has been completed. So please listen to

22 this very carefully.

1 Thank you.

2 DR. TARANTINO: In order to listen to it,

3 I'll have to lower the microphone dramatically.

4 But I have done so.

5 Good morning, everybody, Dr. Miller and

6 members of the committee. I am Laura Tarantino. I

7 am not Barbara Schneeman. Dr. Schneeman, many of

8 you may know, is the newly appointed Director of

9 the Office of Nutritional Products, Labeling, and

10 Dietary Supplements. Unfortunately, she couldn't

11 be here today, so on her behalf, it is my great

12 privilege and pleasure to welcome you. And as Bob

13 Brackett did, once again, thank you for taking time

14 from what I know is a very busy schedule to come

15 here and to allow us to benefit from your expert

16 knowledge.

17 My job, as Sandy mentioned, is to outline

18 the task that we're asking you to focus on over the

19 next day and a half during the part one of this

20 two-part meeting, and perhaps to review and amplify

21 on and actually maybe translate a little bit the

22 questions that we're asking you to consider.

1 As you're aware from the background

2 materials that you got, the agency is evaluating

3 health claim petitions that concern glucosamine and

4 chondroitin sulfate and osteoarthritis. In a few

5 minutes, Louisa Nickerson of FDA is going to give

6 you some brief background concerning health claims

7 to give you context and an idea of the framework in

8 which we are operating. But I want to emphasize

9 that the questions that are in front of you

10 actually are--and the questions that we're asking

11 you to consider are not about health claims per se.

12 Furthermore, as you'll have noted from

13 your background material and the information, the

14 questions are also not about glucosamine and

15 chondroitin sulfate specifically. Rather, what we

16 are asking you and what we're asking your help

17 about is in assessing the science needed to

18 demonstrate reduction in risk of osteoarthritis in

19 healthy people. Health claims have to do with the

20 relationship between a substance and a disease and

21 reduction of risk of a disease in healthy people.

22 What we put in the Federal Register notice

1 about this meeting is actually pretty much on

2 point. In part, it reads, "to receive advice and

3 recommendations relating to the etiology of

4 osteoarthritis, its modifiable risk factors, and

5 the relevance of scientific studies cited in the

6 petitions that substantiate the substance/disease

7 relationship."

8 Okay. Let's see. This is this, and this

9 advances? Yes, it does. Thank you.

10 The first question--and as I say, I am

11 going to try to translate a little bit because they

12 look pretty long and involved on your piece of

13 paper, but this is identical to what you have in

14 your background. It is revised spatially to

15 simplify it a little bit, but same words.

16 The first question really then is about

17 modifiable risk factors. That is, are joint

18 degeneration or cartilage deterioration a valid

19 risk factor for osteoarthritis that can be

20 modified, and can be modified in this case by diet,

21 a dietary substance, leading to a reduction in risk

22 of osteoarthritis in healthy people? That's really

1 what we're asking about.

2 We recognize that there really isn't

3 complete knowledge, as you well know, about the

4 etiology and development of osteoarthritis. But in

5 this case, as is true with the other questions,

6 and, really, as is true generally in the way we do

7 business, the information that's available today is

8 what we're going to have to use to make essentially

9 a binary decision. We recognize that our

10 conclusion could change as information changes, but

11 what we really need to ask you is your views on

12 which way does the needle point on this and the

13 other questions with the information we have in

14 front of us today.

15 The second question really gets to the

16 relevance of studies and information on patients

17 with osteoarthritis, to the questions we need to

18 answer. The petitions cite many intervention

19 studies in patients with osteoarthritis, and this

20 question really is asking about the relevance of

21 that data, and the data and information that could

22 show that a substance treats osteoarthritis or may,

1 for example, slow joint degeneration or cartilage

2 deterioration in osteoarthritis patients. What is

3 the relevance of that information? Can that

4 information be validly extrapolated to the question

5 in front of us, which is reduction of risk in

6 healthy population?

7 And the third question, (a) and (b), has

8 to do with the utility and relevance of in vitro

9 models and of animal models. Some of the data

10 before us are from animal or in vitro models of

11 osteoarthritis. So this question is really asking

12 what's the relevance and utility of these models

13 for assessing disease risk reduction in humans and

14 what sort of data would we really need to be able

15 to base--that we could use these particular studies

16 for, what kinds of information.

17 And later this morning, Dr. Rowlands is

18 going to talk about all of these in much more

19 detail. Furthermore, he's going to present a

20 survey of our review of the issues raised by these

21 questions and going to present the tentative

22 conclusions from our analysis thus far. After

1 that, the petitioners will present their analyses

2 and their rationale for their conclusions. And,

3 finally, you're going to hear from some additional

4 experts who will try to review the state of the

5 science on the issues raised and the questions

6 we've put before you.

7 We're certainly very interested in hearing

8 from this committee your reaction to our and the

9 petitioners' analyses and your responses to each of

10 the questions based on the information available

11 today. Again, what we're really looking for is,

12 based on everything you know, what you've seen in

13 the background packages, and what's there, which

14 way, again, does the needle point on each of these

15 questions.

16 Before I close, I want to make just one

17 brief aside. Some of you may have seen a notice

18 published in the Federal Register last Thursday.

19 That notice is regarding a consumer study that the

20 agency was proposing to carry out related to

21 testing consumer reactions to various types of

22 claim language involving glucosamine and

1 chondroitin sulfate. In the event any of you

2 became aware of it, I just want to make very clear

3 that the notice and the studies described in that

4 notice are in no way relevant to today's

5 proceeding. The study that was discussed is

6 directed at consumer perceptions, and consumer

7 perceptions is an area that the agency is very

8 interested in in terms of the whole claims area,

9 but it does not involve the scientific questions

10 that are before you today. The notice, in fact,

11 was published in error and contains some

12 misstatements and will be corrected. But the

13 timing was unfortunate because there was a

14 possibility that it would get confused with what we

15 are bringing before the Advisory Committee. But it

16 is quite a different issue entirely.

17 So I think I'm going to repeat what Bob

18 Brackett said. We very much look forward to

19 today's and tomorrow's discussions on this subject.

20 I'm sure they'll be very helpful to us, as has been

21 true of other Advisory Committee meetings, in

22 reaching a solid and well-justified and well-documented

1 decision on these petitions. Advisory

2 Committees in the past have helped us enormously in

3 making sure that our decisions benefit from

4 objective, public discussion and examination of

5 issues from all sides.

6 I expect your deliberations will be

7 lively, will help us greatly. Again, welcome and

8 thank you for your attention.

9 DR. MILLER: Thank you.

10 Before we go on, Dr. John Cush joined us.

11 Would you introduce yourself for the record?

12 DR. CUSH: Jack Cush. I'm a

13 rheumatologist from Presbyterian Hospital, Dallas.

14 And I'm on the Arthritis Advisory Board.

15 DR. MILLER: Thank you.

16 Laura, why don't you wait a minute and see

17 if there are any questions. Any questions for

18 clarification? This is very important that we all

19 understand what we're supposed to be doing here and

20 what we're supposed to be working on. So if you

21 have any questions, Laura will be here, of course,

22 throughout the meeting and if questions come up--

1 DR. TARANTINO: We will probably come back

2 to this a couple times, too, but yes.

3 DR. FELSON: "Healthy people" is a hard

4 one to deal with. So if this were to be taken or

5 if something were to be taken for people who

6 already have disease to prevent worsening of

7 disease, does that fit the criterion?

8 DR. TARANTINO: I guess if you could

9 differentiate that from treating the disease--it's

10 not an easy distinction to make. I'd be interested

11 to hear the discussion.

12 DR. ZEISEL: May I ask, just to clarify,

13 because that is the crux, I think, of today's

14 discussion. There can be a stage in which

15 cartilage degeneration or other symptoms occur in

16 which osteoarthritis is not yet diagnosed, and that

17 would be a healthy person preventing progression to

18 the point where the disease is diagnosable? Is

19 that the idea?

20 DR. TARANTINO: Yes, if there is someone

21 who--well, either the general population without

22 symptoms, it's that population, can you show that

1 it would inhibit progression to disease?

2 DR. ABRAMSON: This can go on a long time,

3 but if a person has atherosclerosis--

4 DR. TARANTINO: Yes, I was going to say, I

5 suspect--

6 DR. MILLER: Excuse me. Please identify

7 yourself for the record.

8 DR. ABRAMSON: Steve Abramson. This is a

9 very subjective kind of debate, and I would only

10 have paused at this moment because the analogy of

11 someone having asymptomatic osteoarthritis is not

12 dissimilar from having asymptomatic coronary heart

13 disease, perhaps. And if a person has coronary

14 heart disease and is asymptomatic, are they a

15 healthy person or not a healthy person? I think

16 these are the kinds of things that we have to--not

17 make osteoarthritis a disease that's necessarily

18 different from other common diseases that we take

19 care of.

20 DR. TARANTINO: I would agree.

21 DR. MILLER: Okay. Thank you, Laura.

22 Next is Louisa Nickerson from the Office

1 of General Counsel to give us an overview of the

2 legal framework for this.

3 MS. NICKERSON: Good morning. My name is

4 Louisa Nickerson. I'm a lawyer for the FDA, and

5 I'm here to try to give you a little bit of legal

6 context for what you're being asked to do.

7 I am not going to even attempt to explain

8 the entire regulatory system for health claims

9 because, for one thing, we'd be here all day; and,

10 second, because it's not necessary. As Dr.

11 Tarantino has emphasized, you're here to address

12 scientific issues.

13 Nonetheless, we thought it would be

14 helpful to tell you just a little bit about how FDA

15 regulates health claims and about how FDA defines

16 certain terms that you may have come across in the

17 background materials that were provided to you.

18 Being a lawyer, I'm going to start with a

19 disclaimer. I want to emphasize again that your

20 role is to advise us on scientific issues, and so

21 the information that I'm going to provide is for

22 background only. You should not--we're not asking

1 you to resolve any regulatory issues or to draw any

2 legal conclusions because that's the agency's role,

3 and for us to ask you to do that would not be an

4 appropriate use of the committee.

5 I want to say a little bit about

6 regulatory categories. There are some products

7 that are drugs; there are some products that are

8 dietary supplements. Again, I'm not going to try

9 to go into the ramifications of the full

10 definitions of those terms. But I do want to point

11 out first that there is some overlap between those

12 categories: for products intended to affect the

13 structure or function of the body and also for

14 products that are intended to reduce the risk of

15 disease.

16 The other point that I wanted to make is

17 that if a product is intended to treat, mitigate,

18 or cure disease, there is no overlap. That kind of

19 product is regulated as a drug. And that's true

20 even if it's labeled as a dietary supplement and

21 even if it otherwise qualifies as a dietary

22 supplement.

1 So let me give you a couple of examples in

2 the context of osteoarthritis. The claims for

3 relief of the signs and symptoms of osteoarthritis

4 and effective arthritis pain relief, those are both

5 treatment claims that make the product a drug. In

6 fact, as many of you probably know, those are

7 actual claims that are made for osteoarthritis

8 drugs on the market.

9 I also want to talk a little bit about the

10 definition of "health claim," which I think Dr.

11 Tarantino has already mentioned. Our definition of

12 "health claim" is not the same as the ordinary

13 English meaning of that term. I think when a lot

14 of people hear "health claim," they think it means

15 just any claim about health, and in some contexts,

16 it certainly does mean that. But FDA defines that

17 term in a very specific and narrower way. Our

18 definition of "health claim" is "any claim made on

19 the label or in the labeling of food, including a

20 dietary supplement, that expressly or by

21 implications...characterizes the relationship of

22 any substance to a disease or health-related

1 condition." And if you're wondering the difference

2 between label and labeling, they do mean different

3 things. The label is the immediate product label;

4 whereas, labeling is a broader term that also

5 includes other promotional material that

6 accompanies the product, such as brochures,

7 leaflets, catalogues, that sort of thing. But it

8 does not include advertising.

9 To give you a couple of examples of health

10 claims that FDA has authorized by regulation, there

11 is a claim for foods containing soy protein: "25

12 grams of soy protein a day, as part of a diet low

13 in saturated fat and cholesterol, may reduce the

14 risk of heart disease. A serving of [name of food]

15 supplies __ grams of soy protein." That's a type

16 of claim about a beneficial substance in food.

17 There are also claims that relate to

18 limiting the amount of substances that may be

19 harmful, that may increase the risk of disease if

20 eaten in excess. So, for example, for low-sodium

21 foods, there's a health claim: "Diets low in

22 sodium may reduce the risk of high blood pressure,

1 a disease associated with many factors."

2 So since health claims are about the

3 effect of a food substance on a disease or a

4 health-related condition, it's important to

5 understand how FDA defines those terms. They are

6 defined by regulation: "Disease or health-related

7 condition" means "damage to an organ, part,

8 structure, or system of the body such that it does

9 not function properly...or a state of health

10 leading to such dysfunctioning..." except that

11 nutrient deficiency diseases, such a scurvy and

12 pellagra, are not included in the definition for

13 regulatory purposes.

14 So a couple brief examples. Diabetes

15 would be considered a disease. Insulin resistance

16 would be considered a health-related condition,

17 that is, a state of health leading to disease.

18 It's also important to note that the scope

19 of health claims is limited. Health claims are

20 about reducing the risk of a disease or health-related

21 condition. They're not about treating,

22 mitigating, or curing diseases. That is the

1 position that FDA took in responding to a health

2 claim petition for saw palmetto and relieving the

3 symptoms of benign prostatic hypertrophy a couple

4 years ago, and that position was upheld by a

5 federal appellate court at the beginning of this

6 year in the case of Whitaker v. Thompson.

7 So applying that concept, an example of a

8 claim that would not be a health claim--and this is

9 actually the claim that was proposed for saw

10 palmetto--"Consumption of 320 mg daily of saw

11 palmetto extract may improve urine flow, reduce

12 nocturia and reduce voiding urgency association

13 with mild benign prostatic hyperplasia." And that

14 is not a health claim because it's about treating

15 or mitigating BPH by relieving its symptoms.

16 That's all that I wanted to cover today.

17 As I mentioned, I was not intending to provide a

18 comprehensive view of the regulatory framework, but

19 just touch on a few relevant terms and issues.

20 Are there any questions? Yes?

21 DR. HARRIS: Ed Harris. I would like you

22 to clarify just why a nutrient deficiency, which we

1 know can lead to quite a bit of abnormal

2 metabolism, why is that not considered in your

3 context a health claim--or disease state?

4 MS. NICKERSON: Because--it's not that we

5 don't consider it a disease scientifically. It's

6 that obviously Vitamin C is good for preventing

7 scurvy. We didn't want people to have to go

8 through the health claim regulatory process of

9 coming to us with their data when it was obvious

10 that, you know, Vitamin C would work for that use

11 and other nutrients would solve other--would cure

12 other nutrient deficiency diseases.

13 Yes?

14 DR. DWYER: If this example is not a

15 health claim, is it a drug claim?

16 MS. NICKERSON: Yes. That would be a drug

17 claim.

18 Yes?

19 DR. BLONZ: Edward Blonz. The concept of

20 functioning properly, is this an age-specific

21 dynamic definition?

22 MS. NICKERSON: That's a scientific

1 question, so I'm not going to try to address that.

2 Craig, is that something that you can address

3 later?

4 DR. ROWLANDS: [Inaudible, off

5 microphone.]

6 MS. NICKERSON: Anyone else?

7 DR. MILLER: Dr. Cush?

8 DR. CUSH: This is Jack Cush. Would this

9 be a health claim if it were to stop at "improving

10 urine flow and reduce nocturia" and didn't go into

11 association with BPH? Again, it would be being--use the

12 health claim because it improves symptoms

13 without necessarily trying to comment on

14 relatedness to disease?

15 MS. NICKERSON: Well, I don't think it

16 matters if the disease is mentioned, as long as you

17 have characterizing symptoms of the disease. So

18 one can recognize from what conditions described

19 are that, okay, we're talking about the typical

20 symptom complex of BPH, which is what those are.

21 DR. CUSH: Right.

22 MS. NICKERSON: Then it doesn't make a

1 difference if they use the words BPH or not. It's

2 just the difference between an implied claim and an

3 express claim.

4 DR. MILLER: Dr. Krinsky?

5 DR. KRINSKY: Norman Krinsky. If the

6 definition of a health claim is to reduce the risk

7 of a disease, is that, therefore, limited to a

8 healthy population?

9 MS. NICKERSON: Yes, that's our position.

10 DR. MILLER: Dr. Zeisel?

11 DR. ZEISEL: Again, help me understand.

12 When does a condition become a disease? So

13 prostate being slightly larger, is that a disease?

14 Or does it have to be diagnosed as prostatic

15 hyperplasia by a physician to become a disease?

16 MS. NICKERSON: Again, I really think

17 that's a scientific and medical question that I

18 can't address. But I will say, you know, what a

19 healthy person is is certainly a matter of debate.

20 DR. MILLER: This discussion reminds me

21 why I am always nervous when scientists get

22 involved in regulatory activities.

1 [Laughter.]

2 DR. MILLER: I just want to remind you

3 that the questions we're being asked have nothing

4 to do with the regulation, or to the issue of

5 regulation. The questions being asked is whether

6 or not the science supports a relationship between

7 various biomarkers, among other things, and the

8 disease of osteoarthritis. And I think it's been

9 too much fun trying to understand the morass of

10 regulatory language.

11 All right. Thank you.

12 Next, Dr. Craig Rowlands from FDA will

13 give us an overview of the petitions and say

14 something about the review process.

15 DR. ROWLANDS: I can see I already have my

16 work cut out here. I got three questions before I

17 even got to the podium.

18 First, I just want to thank you, Dr.

19 Miller, and thank you, members of the committee,

20 for being here. I know some of you, perhaps all of

21 you, had to do some gymnastics with your schedules

22 to be here on such short notice, and we do

1 appreciate it. And what you have to say to us is

2 very important, so we're looking forward to these

3 discussions.

4 So my goal this morning is to cover some

5 of the background you've already heard--I'll just

6 reiterate a couple of points--and then provide you

7 a summary of the scientific evidence that was

8 submitted in the petitions, along with the relevant

9 conclusions for the questions we've asked from the

10 petitions' conclusions, provide you with our

11 evaluation of the evidence that raised the issues

12 which were the basis for the questions we gave you,

13 and then I'd like to leave you with the meeting's

14 objectives.

15 So the petitioners are Weider Nutrition

16 International, Incorporated--I'll refer to them as

17 Petitioner A--and Rotta Pharmaceutical, whom I'll

18 refer to as Petitioner B.

19 Petitioner A submitted nine independent

20 health claims based on two different substances.

21 That would be: Glucosamine may reduce the risk of

22 osteoarthritis, may reduce the risk of joint

1 degeneration, and may reduce the risk of cartilage

2 deterioration. Also, chondroitin sulfate may

3 reduce the risk of osteoarthritis, joint

4 degeneration, and cartilage deterioration. And,

5 again, the same three claims for combination

6 products of glucosamine and chondroitin sulfate.

7 Rotta Pharmaceutical, Petitioner B,

8 submitted one health claim: Crystalline

9 glucosamine sulfate may reduce the risk of

10 osteoarthritis.

11 As Louisa has already pointed out, health

12 claims are about a substance-disease relationship.

13 They're about risk reduction in healthy

14 populations, not disease treatment or mitigation;

15 those are regulated as drugs. Let me just go ahead

16 and point out one of the questions is what is

17 healthy, and what we look at for healthy is

18 individuals who do not have the diagnosed disease

19 that is the subject of the health claim. So they

20 would be healthy if they do not have a diagnosed

21 condition, in this case of osteoarthritis.

22 The substances, of course, are glucosamine

1 and chondroitin sulfate. Glucosamine is a

2 glycoprotein and is an endogenous substance. It is

3 derived from marine exoskeletons or produced

4 synthetically for commercial markets. And it is

5 sold as the sulfate sodium chloride, or sulfate,

6 salt, the hydrochloride salt, and N-acetyl-glucosamine.

7 Chondroitin sulfate is a very different

8 kind of substance. It's a glucosaminoglycan, which

9 is a large molecule made of glucuronic acid and

10 galactosamine, and it is manufactured from natural

11 sources such as shark and bovine cartilage.

12 Of course, the disease is osteoarthritis,

13 and Stedman's Medical Dictionary defines this as

14 arthritis which is characterized by erosion of

15 articular cartilage, either primary or secondary to

16 trauma or other conditions, which becomes soft,

17 frayed, and thinned with eburnation of subchondral

18 bone and outgrowths of marginal osteophytes.

19 That's quite a mouthful, but basically what it

20 means is it's a disease of not just the cartilage

21 or just the bone or just the musculature. It is a

1 disease of the whole joint. Dr. Lee Simon will be

2 providing us an overview of osteoarthritis later on

3 this afternoon, where he will talk about the

4 etiology of the disease and some of its modifiable

5 risk factors.

6 The characterized risk factors include

7 genetic predisposition, trauma, anatomic/postural

8 abnormalities, and obesity. However, our reading

9 of the petitions, the literature, and our

10 consultation with experts indicates that there are

11 no biomarkers that are valid modifiable risk

12 factors/surrogate endpoints for osteoarthritis.

13 And this is one of the major goals of the National

14 Institutes of Health's Osteoarthritis Initiative,

15 to identify cartilage and bone metabolism

16 endpoints, biochemical markers that could be

17 validated as modifiable risk factors/surrogate

18 endpoints.

19 The scientific evidence summarized in the

20 petitions include in vitro mechanistic studies,

21 animal studies, and human clinical studies in OA

22 patients. Petitioner A provided a summary of all

1 three types of studies, whereas Petitioner B

2 focused on the glucosamine sulfate studies in human

3 clinical studies in osteoarthritis patients.

4 The in vitro mechanistic data were

5 conducted in human and animal primary cell

6 cultures, established cell culture models, and

7 tissue/organ cultures, and these studies reported

8 that glucosamine and chondroitin sulfate positively

9 affected various biochemical endpoints for

10 inflammation, cartilage degradation, and immune

11 responses, as well as stimulated the production of

12 proteoglycans.

13 The animal studies for glucosamine

14 reported that it reduced kaolin- and adjuvant-induced tibio-

15 tarsal arthritis in rats; glucosamine

16 reduced cartilage degradation in rabbits; and some

17 of these studies also gave chondroitin sulfate; and

18 glucosamine was reported to enhance the rate of new

19 articular cartilage proteoglycan synthesis in mice.

20 Chondroitin sulfate prevented articular

21 cartilage degradation which was induced by

22 chymopapain in rabbits, Freund's adjuvant in mice,

1 and surgery in rabbits.

2 The human clinical studies were all

3 conducted in osteoarthritis patients, and these

4 studies reported that glucosamine and chondroitin

5 sulfate improved symptoms of pain and functionality

6 using things such as Lequesne index, WOMAC's index,

7 visual analog scales. And some of these studies

8 directly compared these substances to the

9 nonsteroidal anti-inflammatory drugs, for example,

10 Ibuprofen.

11 These studies in OA patients also reported

12 that there was improvement in joint degeneration

13 and cartilage deterioration based on radiographic

14 evidence, which were X-rays of joint space

15 narrowing, and some of these studies also reported

16 biochemical evidence for bone and cartilage

17 metabolism in synovium, serum, and urine.

18 So the petitioners concluded from this

19 evidence that human clinical intervention studies

20 in OA patients support OA risk reduction in healthy

21 populations, that is, people without

22 osteoarthritis.

1 Joint degeneration and cartilage

2 deterioration are valid modifiable risk

3 factors/surrogate endpoints for osteoarthritis.

4 And for Petitioner A, animal and in vitro models of

5 OA are relevant to OA risk reduction in humans.

6 We evaluated the evidence and identified

7 several issues which are related to the relevance

8 of OA treatment studies to OA risk reduction in

9 healthy populations; the validity of joint

10 degeneration and cartilage deterioration as

11 modifiable risk factors/surrogate endpoints for

12 osteoarthritis; and the relevance of animal and in

13 vitro models of osteoarthritis to humans.

14 The FDA relies upon two types of outcomes

15 to determine disease risk reduction. The strongest

16 evidence is a reduction in the incidence of

17 disease. These would be intervention and

18 observational studies in healthy people--those

19 without OA--demonstrating that a substance reduces

20 the incidence of osteoarthritis.

21 However, all of the human clinical

22 intervention studies were conducted in OA patients.

1 There were no intervention or observational studies

2 in healthy people demonstrating OA risk reduction.

3 FDA also relies upon studies measuring

4 beneficial changes in valid modifiable risk

5 factors/surrogate endpoints for disease. These

6 would be intervention and observational studies in

7 healthy humans demonstrating that intake of a

8 substance produces beneficial changes in valid

9 modifiable risk factors/surrogate endpoints for

10 osteoarthritis.

11 So then what is a valid modifiable risk

12 factor or surrogate endpoint? This is a biological

13 entity that meets all three of the following

14 conditions: it is associated with disease; it

15 mediates the relationship between intake in healthy

16 people and disease; and its expression is modified

17 by intake of a substance in healthy people.

18 I've tried to represent this with a

19 diagram at the bottom of the slide where the green

20 box represents healthy people, the yellow box

21 represents valid modifiable risk factors/surrogate

22 endpoints, and the red box represents disease or

1 health-related condition.

2 Essentially, there are two relationships.

3 Relationship 1 is between the modifiable risk

4 factor/surrogate endpoint and the disease. And

5 Relationship 2 is between the intervention in

6 healthy subjects and the modifiable risk

7 factor/surrogate endpoint.

8 Relationship 1 must be valid if it is to

9 be relied upon in Relationship 2. That is, there

10 must be evidence that the modifiable risk

11 factor/surrogate endpoint predicts clinical

12 outcome. Only then can intervention studies in

13 healthy subjects rely upon the modifiable risk

14 factor/surrogate endpoint to establish disease risk

15 reduction.

16 The example given is the qualified health

17 claim for walnuts. Because it has been established

18 that LDL cholesterol is a valid modifiable risk

19 factor/surrogate endpoint for coronary heart

20 disease, intervention studies in healthy subjects

21 that observed decreased serum LDL cholesterol were

22 relevant for demonstrating a reduced risk for

1 coronary heart disease.

2 So then are joint degeneration and

3 cartilage deterioration associated with

4 osteoarthritis? I think the answer is obvious.

5 Yes, there is clearly plenty of evidence that

6 they're associated with osteoarthritis.

7 Does joint degeneration and cartilage

8 deterioration mediate the relationship between

9 intake of a substance in healthy people and

10 osteoarthritis? That is, is there evidence that

11 changes in joint degeneration or cartilage

12 deterioration predict clinical outcome for

13 osteoarthritis? Well, the evidence given to us in

14 the petition and our own reviewing of the

15 literature, we did not identify any intervention

16 studies of any substance in healthy individuals

17 that measured both joint degeneration or cartilage

18 deterioration and OA incidence, precisely the type

19 of evidence one would need if you're going to

20 determine whether or not these are predictive of

21 clinical outcome.

22 So then are joint degeneration and

1 cartilage deterioration modified by intake of a

2 substance in healthy people? Again, all of the

3 evidence provided was in OA patients.

4 Then are joint degeneration and cartilage

5 deterioration valid modifiable risk factors/surrogate

6 endpoints for osteoarthritis. As I said,

7 they're clearly associated with osteoarthritis.

8 However, we don't know whether they mediate the

9 relationship between intake in healthy people and

10 OA; we don't know whether their expression is

11 modified by intake of a substance in healthy

12 people.

13 So our tentative conclusion is that, no,

14 these are not valid modifiable risk factors for

15 osteoarthritis. We've given you questions directly

16 asking this, and we're very interested to hear your

17 opinions on this matter.

18 The last issue very quickly then is: Do

19 animal and in vitro models of OA mimic human

20 osteoarthritis? Well, we know that animals have a

21 different physiology, in vitro models are conducted

22 in an artificial environment, and when you combine

1 this with the fact that the etiology of OA in

2 humans is poorly understood, it would seem to

3 indicate that animal and in vitro models of OA

4 cannot be relied upon for predicting human effects.

5 In fact, this was demonstrated a few years ago in a

6 study that reported that nonsteroidal anti-inflammatory

7 drugs inhibit OA in rodents but not in

8 humans.

9 The role of animal and in vitro models of

10 OA risk reduction will be discussed this afternoon

11 by Dr. Jim Witter, who is a rheumatologist with the

12 FDA Center for Drug Evaluation and Research.

13 So these issues served as the basis for

14 our questions. I'll go ahead and read them into

15 the record. Is, for Question (1a), joint

16 degeneration and, for Question (1b), cartilage

17 deterioration a state of health leading to disease,

18 that is, a modifiable risk factor/surrogate

19 endpoint for OA risk reduction? Then we'd like to

20 know what are the strengths and limitations of the

21 scientific evidence on this issue. This question

22 is essentially asking: Are joint degeneration and

1 cartilage deterioration valid modifiable risk

2 factors/surrogate endpoints for osteoarthritis?

3 Question 2 is: If we assume that joint

4 degeneration or cartilage deterioration is a

5 modifiable risk factor/surrogate endpoint for OA

6 risk reduction and we assume that research

7 demonstrates that a dietary substance treats,

8 mitigates, or slows joint degeneration or cartilage

9 deterioration in patients diagnosed with

10 osteoarthritis, is it scientifically valid to use

11 such research to suggest a reduced risk of OA in

12 the general healthy population--again, these would

13 be individuals without osteoarthritis--from

14 consumption of the dietary substance? And this

15 question is essentially asking: Is it

16 scientifically valid to use human OA treatment

17 studies to suggest a reduced risk of OA in the

18 general healthy population?

19 And the final question is: If human data

20 are absent, can the results from animal and in

21 vitro models of OA demonstrate risk reduction of OA

22 in humans? And then we have two subparts: Subpart

1 (a), To the extent that animal or in vitro models

2 of OA may be useful, what animal models, or in

3 vitro models, types of evidence, and endpoints

4 should be used to assess risk reduction of OA in

5 humans? And (b) is: If limited human data are

6 available, what data should be based on human

7 studies and what data could be based on animal and

8 in vitro studies to determine whether the overall

9 data are useful in assessing a reduced risk of OA

10 in humans?

11 This question is simply asking: Are the

12 results from animal and in vitro models relevant

13 for demonstrating OA risk reduction in humans?

14 This meeting then is about the science

15 needed to demonstrate risk reduction. It is not

16 about disease treatment or mitigation. This

17 meeting is about osteoarthritis. It's not about

18 glucosamine and chondroitin sulfate. it's a

19 meeting about the etiology of osteoarthritis, its

20 valid modifiable risk factors/surrogate endpoints,

21 and the relevant models of osteoarthritis. Because

22 it's about risk reduction in osteoarthritis, we

1 also feel that the recommendations of this FAC can

2 apply to other substance-osteoarthritis

3 relationships.

4 Again, I thank you for being here, and I

5 look forward to the discussions over the next day

6 and a half.

7 DR. MILLER: Thank you, Craig.

8 Any questions or comments? Dr. Cush?

9 DR. CUSH: You several times have said

10 this is not about mitigating the disease through a

11 substance. And in Ms. Nickerson's presentation,

12 she stated that a dietary supplement is a product

13 that is intended to treat, mitigate, or cure

14 disease--oh, it's called a drug, sorry. So if it

15 mitigates a disease, it would then be classified as

16 a drug.

17 DR. ROWLANDS: That's correct.

18 DR. CUSH: Okay. I'm sorry.

19 DR. CALLERY: Pat Callery. I understand

20 that it's not about glucosamine or chondroitin

21 sulfate, but you do mention glucosamine as a

22 glycoprotein, and I'm wondering what the rationale

1 is there, because we'll have much discussion later

2 about salts and makeup and the difference between

3 the particular agents or compounds. I don't think

4 it's a glycoprotein.

5 DR. ROWLANDS: If I made an error, I

6 apologize. I was simply quoting the information I

7 was given. But that would be--we'll put on the

8 record what exactly it is.

9 DR. MILLER: Any other questions?

10 [No response.]

11 DR. MILLER: All right. Thank you, Craig.

12 Sorry. Johanna? Craig, just a minute.

13 DR. DWYER: Just a quick one.

14 DR. MILLER: Dr. Johanna Dwyer.

15 DR. DWYER: It's Slide 12, your diagram.

16 The diagram that shows healthy people, valid

17 modifiable risk factors, and you use the example of

18 walnuts, LDL cholesterol, and coronary heart

19 disease. And I'm focusing on the arrow from

20 healthy people to valid modifiable risk. That does

21 not depend, does it, on the level of HDL

22 cholesterol? It's just that it affects that

1 there's a causal chain? Is that what your diagram

2 is saying?

3 DR. ROWLANDS: The diagram is saying that