SUPPLEMENTS SUBCOMMITTEE







                       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


  4   LDL cholesterol is a valid--it's a recognized valid


  5   modifiable risk factor or surrogate endpoint for


  6   predicting coronary heart disease.  And so we don't


  7   have to--when we look at the evidence for whether


  8   or not a substance will reduce your risk for


  9   disease, we don't necessarily need--because of


 10   that, we don't need necessarily incidence data in


 11   populations.  We can rely upon evidence of LDL


 12   cholesterol, changes in serum LDL cholesterol, a


 13   reduction in this case.  That was the point of that


 14   slide.  Because we have evidence, ample evidence


 15   that LDL cholesterol is a valid modifiable risk


 16   factor and indeed does predict your risk for


 17   developing disease--and that's been established


 18   with studies where you've measured the incidence of


 19   heart disease, in the same group of people you're


 20   measuring LDL cholesterol in response to the same


 21   intervention.  And so you have that kind of


 22   evidence that essentially tested whether or not it




  1   was predictive, and, in fact, it was predictive.


  2   We have plenty of evidence.


  3             DR. DWYER:  I guess what I was after is:


  4   Does it matter what the level of LDL is?  If it's


  5   outside of the 95 percentile for a population, does


  6   it matter?  Or is it just the causal chain that


  7   matters?


  8             DR. ROWLANDS:  I'm not sure I understand


  9   your question, but I can tell you that we look at


 10   changes, significant changes, so statistically


 11   significant changes, decreases in LDL cholesterol,


 12   as being a beneficial effect, if that answers your


 13   question.


 14             DR. MILLER:  Dr. Russell?


 15             DR. RUSSELL:  A question going back to


 16   healthy population.  I know you gave us a


 17   definition that they don't have diagnosed disease.


 18   But I'm wondering, if a population--if a large


 19   percent of a population, let's say 50 percent of


 20   the population, has some degree of a disease, not


 21   symptomatic, let's say hypertension or let's say


 22   atrophic gastritis--there's any number that we




  1   could pick that sort of accompany aging--are these


  2   people considered healthy?


  3             DR. ROWLANDS:  So what is healthy, right?


  4   I mean, everyone is--


  5             DR. RUSSELL:  Yes, but I think it's an


  6   important question for us to grapple with, because


  7   your definition is, well, they just haven't been--they don't


  8   have diagnosed disease.


  9             DR. ROWLANDS:  Yes, I guess the way to


 10   look at it is when we are given a body of evidence


 11   and it says in the evidence that these individuals


 12   have the disease, well, then, we have to assume


 13   they have the disease.  The question is to the FAC:


 14   Can you base risk reduction on that kind of


 15   evidence?  And our definition in this case of


 16   disease is they have diagnosable osteoarthritis.


 17   Now, they may have other conditions.  They may be


 18   unhealthy for other reasons.  But the point we're


 19   trying to focus on is the disease which is the


 20   subject of the claim is the most important thing we


 21   want to focus on because that is what the claim is


 22   about.




  1             Now, to the extent that other things may


  2   be impacting that process, the experts here can


  3   fill us in.  But that's essentially our definition


  4   for health claims.


  5             DR. MILLER:  Dr. Cush?


  6             DR. CUSH:  So soy and walnuts can be given


  7   to healthy people to alter a surrogate that might


  8   help someone with a disease, and that's a good


  9   health claim.  How would aspirin be classified?


 10   Because aspirin is given to healthy people and has


 11   disease benefits downstream.  Presumably its


 12   surrogate would be by having an antithrombotic


 13   effect.  How would aspirin be handled?


 14             DR. ROWLANDS:  Aspirin, of course, is


 15   already a drug.


 16             DR. CUSH:  Right.


 17             DR. ROWLANDS:  And so once you already


 18   have something as a drug, it cannot be a food.


 19   Health claims are about foods.  But you're getting


 20   into the regulations now, so there's a technical


 21   regulatory reason why that wouldn't matter.


 22             DR. CUSH:  I was trying an example.




  1             DR. ZEISEL:  Just to help us, the question


  2   we're being asked--Steve Zeisel.  The question


  3   we're being asked today, one of them, is:  Can


  4   evidence in patients who already have the diagnosed


  5   disease be used to predict whether something would


  6   prevent the progression of the pre--the things that


  7   have to occur ahead of the disease being diagnosed


  8   from occurring?  So joint degeneration but not to


  9   the point of diagnosable osteoarthritis,


 10   progressing to that point being prevented is--and


 11   the question you're asking is:  Can we use data


 12   from people who already have the diagnosed disease


 13   to make that prediction?


 14             DR. ROWLANDS:  Yes, in a sense, that's


 15   correct.  I would just also point out that risk


 16   reduction and prevention, they sound the same.


 17   They're a little bit different.  We're not saying


 18   that we have to prevent it.  It would lower your


 19   risk for getting it.  So a little bit of a nuance


 20   there.


 21             DR. MILLER:  Dr. Krinsky?


 22             DR. KRINSKY:  Norman Krinsky.  It seems to




  1   me that you're creating a black-and-white


  2   situation, whereas there is a gray area.  For


  3   example, I have prostate cancer, and I was


  4   diagnosed with the disease.  But before I was


  5   diagnosed, was I, therefore, healthy and did not


  6   have prostate cancer?


  7             DR. ROWLANDS:  Based on if they gave us a


  8   paper and the evidence that was given to us said


  9   that you were looked at by a physician and you do


 10   not have prostate cancer, then we will assume you


 11   do not have prostate cancer.  And I realize that is


 12   a simplistic way of looking at it, but flip it


 13   around.  When you have a population that has a


 14   diagnosed disease, which is all the evidence we


 15   have here, what do you do with that?


 16             DR. MILLER:  Dr. Cush?


 17             DR. CUSH:  As a distinction between a


 18   health claim and a drug claim can be difficult in


 19   the kind of product you're talking about, is it


 20   this committee's purview to favor one over the


 21   other as opposed--or we're just here to talk about


 22   the health claim, and, for instance, there may be




  1   not enough evidence to make the health claim, but


  2   could we discuss then the use of a product as a


  3   drug claim?


  4             DR. ROWLANDS:  This meeting is about


  5   health claims, and to the extent you believe the


  6   evidence supports risk reduction, that's what we


  7   would like to hear about.


  8             DR. MILLER:  Actually, let me interrupt.


  9   The way I understood it, this meeting is not about


 10   a health claim, but is about the question of


 11   whether the science supports the relationship


 12   between osteoarthritis--I want to make that


 13   distinction because once you get into the issue of


 14   the regulation and the interpretation of the


 15   regulation, that's a morass.  And I don't think we


 16   have the time to get into that discussion.


 17             DR. ROWLANDS:  That's correct.  I guess I


 18   was thinking more along the lines of Question 2,


 19   which seems to be what your question is directed


 20   at, whether or not you can use what we call


 21   treatment studies to extrapolate to risk reduction.


 22   We're not interested in whether or not there is a




  1   therapeutic benefit for treating the symptoms of a


  2   disease.  That's not what our question is about.


  3             DR. MILLER:  Dr. Dickinson?


  4             DR. DICKINSON:  Annette Dickinson.  It's


  5   typical, I think, for research studies on any given


  6   substance and disease prevention or treatment to be


  7   done in diseased populations because you can expect


  8   with a reasonable number of subjects to get some


  9   kind of a response.


 10             In the case of dietary ingredients, if the


 11   intervention is with a dietary ingredient, like,


 12   for example, calcium or omega-3s, you may also be


 13   able fairly readily to get epidemiological


 14   information or observational information that


 15   indicates that high intakes of that nutrient also


 16   have a preventive effect in the healthy population.


 17             But if you're dealing with a substance


 18   like chondroitin, for example, which might not be


 19   widely consumed in the general population unless


 20   they're supplementing it, then there will be


 21   barriers to drawing conclusions about the healthy


 22   population because it's not something they're




  1   exposed to in meaningful amounts in the regular


  2   diet.  And yet we can point to many examples, like


  3   with omega-3 and calcium, where intervention agents


  4   are also effective prevention agents.  Are we


  5   allowed to take those comparisons into account,


  6   those comparative cases into account?


  7             DR. ROWLANDS:  I'm not in a position to


  8   tell you what you can and cannot take into account.


  9   If you feel it's important, then I guess that


 10   should be something you should bring into your


 11   discussion.


 12             DR. FELSON:  You didn't want this to be a


 13   discussion of glucosamine and chondroitin, so let's


 14   leave it as a discussion of osteoarthritis and


 15   whether risk factors for incident disease and


 16   progressive disease are the same.  There are a


 17   number of studies--and probably Dr. Simon will


 18   review them--that suggest very strongly that the


 19   risk factors differ for incidence and progression.


 20   Bone density, for example, appears to be--increased


 21   bone density appears to be a risk factor for


 22   incident disease, and yet data suggests that it




  1   probably--high bone density protects against


  2   progressive disease.


  3             Vitamin D, what data there are suggest


  4   that it protects against progressive disease and


  5   has no effect on incident disease.  Okay?  So I


  6   think it would be beyond a scientific reasonable


  7   extrapolation to suggest that anything that treats


  8   this disease is likely to have an effect on


  9   incidence.


 10             DR. MILLER:  That was Dr. Felson.


 11             Dr. Lane?


 12             DR. LANE:  Yes, I was just going to


 13   comment further on Dr. Felson's question.  With the


 14   limited data that we now have regarding risk


 15   factors for incident and risk factors for--or


 16   variables associated with progression of disease,


 17   it's limited, but Dr. Felson brings up just about


 18   everything we know.


 19             DR. MILLER:  Any other comments?


 20             [No response.]


 21             DR. MILLER:  We're doing quite well so


 22   far.  I hate to think that my role is to watch the




  1   clock, but I guess that's what it is.


  2             Dr. Bucci?


  3             DR. BUCCI:  Here.


  4             DR. MILLER:  Are you prepared to make your


  5   presentation now?


  6             DR. BUCCI:  Yes, I am.


  7             DR. MILLER:  Why don't we do that and then


  8   we'll take our break after Dr. Bucci's presentation.


  9             DR. BUCCI:  Well, good morning, ladies and


 10   gentlemen, and I wish to thank the Food Advisory


 11   Committee for inviting us to make this


 12   presentation.


 13             My role here is to do several things, and


 14   really what I'm here for is to show evidence,


 15   credible evidence, that glucosamine and chondroitin


 16   sulfate reduces the risk of osteoarthritis, joint


 17   degeneration and/or joint deterioration.


 18             So what I'll do is--I don't think I'll


 19   spend much time reviewing the need for reducing the


 20   risk of osteoarthritis.  I think that is self-evident.


 21   Also, the proposed health claims have




  1   already been listed.  What I would like to do,


  2   though, is spend a wee bit of time on reviewing the


  3   roles of glucosamine and chondroitin in reducing


  4   osteoarthritis risk.  One of the ways I'll do that


  5   is by showing you what they do in normal cartilage


  6   tissue and then get into some of what I feel is


  7   credible evidence that supports these claims.


  8             These are facts and figures taken from the


  9   Centers for Disease Control, and arthritis is the


 10   leading cause of disability in the United States.


 11   I think the numbers speak for themselves here.


 12             What I find of great interest are the


 13   9,500 deaths from a supposedly non-fatal disease.


 14   Now, I realize some of these figures lump


 15   rheumatoid arthritis with osteoarthritis, but


 16   medical textbooks have said that osteoarthritis has


 17   an--or if you have osteoarthritis, you have an 11-percent


 18   higher death rate than the average


 19   population.  And this is from a non-fatal disease.


 20             So obviously there is a need to reduce the


 21   risk of osteoarthritis in the general population,


 22   if for no other reason than to not have people die




  1   needlessly.


  2             But as you can see, there's a huge cost


  3   associated with the treatment of osteoarthritis.


  4   Its impact is enormous, and that's one of the


  5   reasons that we're all here today, is to figure out


  6   if we can reduce this enormous risk and burden to


  7   our health care.


  8             The very bottom part of this figure shows


  9   the age ranges of incidence of osteoarthritis, and


 10   as we all are aware, this is an age-related type of


 11   condition.  However, ages 18 to 44, I think people


 12   in that age group would deny that they're aged, and


 13   one out of five of them has diagnosed arthritis.


 14   Again, some of these are rheumatoid but, still, the


 15   majority is osteoarthritis since that makes up


 16   about 80 percent of the total arthritis.


 17             The point I'm getting at here is that


 18   these people would--these are not considered aged


 19   people.  It is not a completely age-related


 20   disease, and this speaks to the variety of factors.


 21             Okay.  These are the health claims that


 22   have been proposed by Weider Nutrition. 




  1   Glucosamine and chondroitin may reduce the risk of


  2   osteoarthritis, joint degeneration, and joint


  3   deterioration.  I think we've seen these already so


  4   I'll proceed on in the interest of time.


  5             What I'd like to do is give you some


  6   visual reference points so you can put what


  7   glucosamine and chondroitin do into a context and


  8   mental framework.


  9             Uh-oh, I hit the wrong button again.  This


 10   even works behind your back.  Very good.


 11             This is an artist's rendition of articular


 12   cartilage, and the point here is that this is a


 13   different tissue than others in the body, quite


 14   different, in fact.  Cartilage is thought of by


 15   most people as being sort of an inert Teflon washer


 16   for your joints that cushions--makes your joint


 17   lubricated so they can slide easily and you can


 18   have adequate movement.  Obviously, this is an


 19   artist's rendition, so there are a few things out


 20   of scale.  But the point here is that there's no


 21   blood vessels inside of cartilage, except for some


 22   in the menisci; no nerves; no lymphatics.




  1             These chondrocytes, which are the primary


  2   cell type in cartilage, rely on diffusion from


  3   synovial and subchondral bone blood vessels to get


  4   all their nutrients--oxygen, water, carbohydrates,


  5   protein, amino acids, glucosamine, et cetera.


  6             This is a little more of a closeup of


  7   cartilage in a very stick-figure kind of diagram.


  8   Chondrocytes are supposed to be the only cell type


  9   in cartilage, and they manufacture this cartilage


 10   matrix, which is a combination of Type II collagen


 11   mostly, which are represented by these purple


 12   girder-like structures.  And in between all the


 13   very precisely laid out collagen girders are these


 14   proteoglycans, commonly called--aggrecan is the


 15   main one.  And these are composed of--what I'll


 16   show you is mostly chondroitin sulfate.


 17             As you can see in this stick figure, these


 18   little yellow sticks running around randomly,


 19   supposedly randomly, but in between these girders


 20   represent the proteoglycans.  And we'll give you a


 21   little bit better picture in a moment.


 22             But, first of all, these proteoglycans




  1   form around a hyaluronan backbone, HA, and


  2   hyaluronan is a glucosaminoglycan; 50 percent of it


  3   is directly derived from glucosamine.  And we have


  4   these proteoglycan subunits that are attached to


  5   the hyaluronan over and over and over again,


  6   hundreds per hyaluronan.  These proteoglycan


  7   subunits are relatively large molecular structures.


  8   They have a couple hundred, on the average,


  9   chondroitin sulfate chains attached to each core


 10   protein, and you have several hundred of these


 11   proteoglycan--which I've abbreviated here as PG--subunits


 12   per aggrecan or proteoglycan molecule.


 13             Now, I think something that's extremely


 14   important for everyone here to realize and remember


 15   is that the life span of aggrecan proteoglycan in


 16   adult human cartilage is 600 to 1,000 days, two to


 17   three years.  Keep that time frame in mind.  I


 18   think it's important for interpretation of the


 19   results of human studies.


 20             In other words, cartilage is a very slow


 21   tissue, and it responds to stimuli in a very slow


 22   and simple manner.




  1             This is another artist's picture that


  2   gives you a little bit better idea of how space-filling the


  3   proteoglycans are.  The chondroitin


  4   sulfates have a relatively large amount of sulfate


  5   groups that are charged and attract water, and they


  6   fill up all the space between the collagen girders


  7   that make up the shape and the structural integrity


  8   of cartilage.  Various insults can physically


  9   damage and degrade the structures of cartilage,


 10   specifically the chondroitin sulfate, the collagen,


 11   as well as the hyaluronan backbone of


 12   proteoglycans.  These insults are constant,


 13   ongoing, and inescapable.  Free radicals are


 14   probably one of the primary insults, and any type


 15   of other risk factor eventually leads to generation


 16   of free radicals that do actually physically damage


 17   and break off small pieces of cartilage, including


 18   chondroitin sulfate, hyaluronan, and Type II


 19   collagen.  Some of these pieces are actually being


 20   looked at surrogate endpoints or biomarkers for


 21   cartilage damage.


 22             So what I'm trying to do here is give you,




  1   again, a context or a perspective of what


  2   glucosamine and chondroitin are.  I hit the wrong


  3   button again, but here we go.


  4             One thing I didn't mention previously is


  5   that glucosamine is the major precursor for


  6   chondroitin sulfate.  We'll look at that in a


  7   moment.  I'd like to cover some of the human


  8   supplementation studies that have used glucosamine


  9   and chondroitin sulfate and their applicability to


 10   risk reduction of osteoarthritis and joint


 11   degeneration and deterioration.


 12             Again, I want to reiterate the fact that


 13   cartilage turnover, normal maintenance and repair,


 14   is constant and ongoing.  Your cartilage is not an


 15   inert Teflon washer.  Although kind of slow and


 16   best by problems of nutrient diffusion compared to


 17   other perfuse tissues, cartilage does maintain


 18   itself all the time as we go through life.  The


 19   half-life of the major structural components--aggrecan,


 20   proteoglycan, and collagen--is about one


 21   to two years.  Remember the life span was two to


 22   three years.  And as I've already mentioned, normal




  1   wear and tear in healthy people--everybody, for


  2   that matter--produces these degraded fragments


  3   constantly.


  4             Another cause is shear stress, and this is


  5   where things like trauma and injuries can enter


  6   into play.  In other words, just the shear stress


  7   of overload of mechanical forces can literally


  8   break off pieces.


  9             Cartilage does respond via the


 10   chondrocytes in the synovial lining to the


 11   molecular pieces of the most exposed macromolecular


 12   constituent.  That's pretty much obvious, and these


 13   constituents being hyaluronan in synovial fluid and


 14   chondroitin sulfate in cartilage itself, since they


 15   are the space-filling macromolecules that anything


 16   that would be at a molecular level would encounter


 17   first in synovial fluid and collagen.  So it kind


 18   of makes sense that these chondrocytes which are


 19   trapped in their matrix respond to pieces of the


 20   structure.  In other words, the analogy, very


 21   simple analogy, would be that if you start to see


 22   bricks falling around outside your house, you know




  1   you have a problem with the structural integrity of


  2   your house and you need to start patching up your


  3   brickwork again.  It's a very simplistic analogy,


  4   but there are receptors on chondrocytes and


  5   synovial lining cells and, indeed, cells throughout


  6   the body that recognize both intact and various


  7   sizes and fragments of both hyaluronan and


  8   chondroitin sulfate.


  9             So all these things are happening all the


 10   time, whether somebody is five years old, 50 years


 11   old, 90 years old, whether they walk with a limp or


 12   can run marathons.


 13             Supplementation trials also have these


 14   other factors going on.  Joint tissues can only


 15   maintain themselves and, thus, resist degradation,


 16   resist deterioration, and remain normal by


 17   biosynthesis of more matrix.  This is a brick-and-mortar-


 18   type of idea I'm trying to get across.  if


 19   the bricks and mortar start to fall apart, you have


 20   to add more brick and mortar.  So the only way that


 21   joint tissues can make more matrix is to start off


 22   with glucosamine and convert that into chondroitin




  1   and proteoglycans, and that sets the stage for


  2   collagen production on top of that.  There must be


  3   a combination of collagen production and


  4   proteoglycan production to produce cartilage.  It's


  5   a relatively simple tissue structurally.  And


  6   biosynthesis of chondroitin is essential to the


  7   maintenance of cartilage and, thus, to the


  8   prevention of joint deterioration.


  9             I took this quote from a textbook in 1986


 10   called "Articular Cartilage Biochemistry," and I'll


 11   read it for the record.  "The integrity of this


 12   matrix is critical for the unique biochemical


 13   properties of hyaline cartilage and depends on a


 14   maintenance of the quantity and quality of the


 15   matrix components.  Such maintenance must be the


 16   result of a balance between synthetic and


 17   degradative processes within the tissue.  Thus, any


 18   loss of, for example, proteoglycan from the


 19   cartilage matrix due to physiologic or pathologic


 20   processes must be balanced by de novo synthesis of


 21   proteoglycans by the chondrocytes."


 22             So, in other words, if there's anything




  1   going on with the cartilage in terms of structural


  2   damage or loss of any components, the only way to


  3   fix that is to actually make more.  And the only


  4   way to make more is to use glucosamine to


  5   manufacture chondroitin, et cetera, et cetera.


  6             Also, a review of the available


  7   literature, which is, of course, quite extensive,


  8   shows that the same biochemical signals, the same


  9   regulatory, cellular, biosynthetic, anabolic,


 10   catabolic, and metabolic mechanisms that operate in


 11   cartilage in normal health are also operating


 12   during the process of diagnosed osteoarthritis.  So


 13   what I'm trying to say here is that I believe that


 14   normal cartilage is acting the same way that


 15   cartilage does in osteoarthritis to a very large


 16   extent.


 17             Maintenance of cartilage consists of the


 18   same processes and events that occur during normal


 19   wear and tear, that also occur during normal aging,


 20   and also in persons diagnosed with osteoarthritis.


 21   In other words, all three of these situations


 22   involve use of glucosamine and chondroitin to make




  1   more matrix.


  2             In other words, the chondrocyte doesn't


  3   know if you've been labeled osteoarthritic or


  4   elderly or young and growing.  It just does what it


  5   has to do, and that's make more matrix.


  6             Also, I think one thing that's been


  7   alluded to extensively is surrogate markers or


  8   endpoints of progression of disease.  And I think


  9   it's pretty clear from looking at textbooks over


 10   the last five decades that there is an unbroken


 11   continuum of events in cartilage from health to


 12   degenerative disease.  Notice that the official


 13   definition of osteoarthritis from Stedman's Medical


 14   Dictionary really identified a very late stage,


 15   such as eburnation.  That's the progression that


 16   we're trying to stop, that we're trying not to get


 17   to, is losing cartilage and getting bone on bone.


 18   That is what we are trying to reduce the risk of


 19   getting to.


 20             So, therefore, there's no agreed-upon


 21   threshold or marker that clearly defines the onset


 22   of osteoarthritis.  I think Dr. Krinsky's point




  1   about when does diagnosis occur and when are you


  2   considered or diseased is very applicable here.  In


  3   other words, if someone walks into a doctor's


  4   office and gets diagnosed with osteoarthritis that


  5   day, what were they the day before?  They would


  6   have been considered healthy unless they had, of


  7   course, been looked at and determined to be


  8   osteoarthritic.  So that is, I think, the question,


  9   but I think the answer is that there's really not


 10   much difference.  It is a continuum.  If you're


 11   going to say, well, you right there, you're


 12   osteoarthritic, and the next person that you look


 13   at and evaluate whether they're osteoarthritic or


 14   not has similar findings but no symptoms, well, is


 15   that the same thing or not?  They'd be considered


 16   healthy.  So there is a continuum.


 17             There's also considerable overlap of these


 18   biochemical markers as well as the appearance of


 19   cartilage from various diagnostic imaging


 20   techniques between healthy controls and


 21   osteoarthritic subjects.  I think this is well


 22   borne out in the literature.  You look at the




  1   reference ranges for some of these biomarkers in


  2   normal persons and persons with diagnosed


  3   osteoarthritis, and by normal people I mean persons


  4   that have no or very little signs of joint


  5   degeneration or damage visually by diagnostic


  6   imaging techniques, and there is considerable


  7   overlap.


  8             In other words, I think that speaks to the


  9   fact that chondrocytes are doing the same thing in


 10   each condition.  All they know how to do is make


 11   more matrix.  They don't care if they're healthy;


 12   they don't care if they're hurting.  So I'm arguing


 13   that the same type and extent of imbalance between


 14   matrix component synthesis and degradation is seen


 15   in both healthy and osteoarthritic subjects.  If


 16   you're going to start segmenting arbitrarily,


 17   you're going to knock out a significant proportion


 18   of the population.


 19             I'm a Ph.D., not a rheumatologist, but


 20   maybe you can help clarify this for the audience


 21   later on today, but osteoarthritis diagnosis is


 22   based on the clinical signs, subjective clinical




  1   signs of the individual, pain and stiffness in


  2   joints, as well as X-ray evidence of structural


  3   changes in joints.


  4             The staging is relatively arbitrary and


  5   subjective.  In other words, there's no lab test


  6   you can send off to a laboratory for it and it


  7   comes back and says, yes, you have osteoarthritis.


  8   This has to be determined by physicians and by the


  9   signs and symptoms given to them subjectively by


 10   the patient as well as diagnostic imaging.


 11             Human studies with osteoarthritic subjects


 12   have examined a portion of that continuum of joint


 13   health.  They represent one window on that


 14   continuum.


 15             Pre-diagnostic joint damage, therefore,


 16   must exist in greater incidence than diagnosed


 17   osteoarthritis.  And since diagnosis is roughly


 18   about 20 percent of the population over age 50


 19   right now, it's an enormous number.  There are


 20   obviously many more people than that that perhaps


 21   would be diagnosed with osteoarthritis that are


 22   considered healthy right now--again, blurring the




  1   distinction between disease and health.


  2             Just looking at the situation of normal


  3   aging shows that a loss of chondroitin in cartilage


  4   and/or hyaluronan in synovial fluid occurs all the


  5   time.  It happens as we age.  Normal aging


  6   specifically shows decreased length or size of


  7   chondroitin and, thus, the aggrecan proteoglycans


  8   that are synthesized routinely for maintenance and


  9   upkeep.  Obviously, if you live to be 80 years old,


 10   you've gone through 20 to 40 or so cycles of new


 11   cartilage or of turning over cartilage.  And as


 12   those cycles keep going, the macromolecular


 13   components start to get a little bit smaller.


 14   Thus, with less chondroitin around, cartilage holds


 15   a little bit less water and actually reduces in


 16   size.  I think a lot of us realize that we lose


 17   height as we age, and a lot of that is from the


 18   actual diminishing size of intervertebral disks,


 19   whether or not--it is completely unrelated to loss


 20   of bone in the spinal column, but one or two inches


 21   can be lost simply from normal aging, losing the


 22   size of cartilage because of the loss of size of




  1   chondroitin.  And that's considered normal.


  2             So osteoarthritis obviously results from


  3   an imbalance of normal anabolic and catabolic


  4   activities in cartilage, and this is alluded to in


  5   textbooks over and over.  Therefore, osteoarthritis


  6   is a deficiency of normal regulation of cartilage


  7   maintenance.  And I think the data from the human


  8   studies and also from the animal and in vitro


  9   studies shows that both glucosamine and chondroitin


 10   sulfate help to regulate towards normal cartilage


 11   maintenance.  Maintenance of the normal balance of


 12   anabolic and catabolic actions leads to a return to


 13   health and obviously reduces the risk of


 14   osteoarthritis.  So a relatively simplistic concept


 15   here because cartilage is a relatively simplistic


 16   tissue.  It only knows how to make more matrix.


 17             Let's take a closer look at some of the


 18   clinical studies on glucosamine itself.


 19             Again, much work has gone into finding


 20   that the availability of glucosamine is a key rate-limiting


 21   step for synthesis of connective tissue


 22   macromolecules.  This is true not only for




  1   cartilage but other connective tissues as well.


  2   Normally, glucosamine is manufactured from glucose,


  3   which, of course, is readily available all over our


  4   bodies.  But if you supply the synthetic cells with


  5   glucosamine itself, they like it, a lot better than


  6   having to make it themselves.  In other words, it


  7   bypasses several chemical enzymatic steps, and it


  8   kind of--I play Monopoly--does go directly to go--you bypass


  9   the jail and go directly to go, and


 10   straight into synthesis of GAGs or glycosaminoglycans, the


 11   major one being chondroitin sulfate.


 12             So, in other words, glucosamine is a


 13   preferred substrate for repair, maintenance, and


 14   upkeep of cartilage, and also of hyaluronan and


 15   synovial fluid.


 16             I've put together a list of the types of


 17   published evidence in glucosamine.  There's


 18   consensus statements and review articles I've


 19   lumped as independent expert opinions.  There are


 20   14 meta-analyses that I've identified on


 21   glucosamine, all of them supportive.  Large, well-designed


 22   human clinical trials are at least 80




  1   total subjects, and several of those have been


  2   reported more than one time, but the majority of


  3   those do support some benefit for administration of


  4   glucosamine for persons with osteoarthritis.


  5             There are smaller, well-designed human


  6   clinical trials.  Again, the evidence is credible


  7   in that there is much more supportive than non-supportive.


  8   And instead of saying uncontrolled, I


  9   think I should have said unblinded human clinical


 10   trials.  Many of these trials did have control


 11   groups but were open.  And the animal intervention


 12   studies, giving glucosamine and then inducing


 13   arthritis, and in vitro studies, they are all very


 14   supportive, providing credible evidence that


 15   glucosamine has benefits for joint health.  And


 16   this is kind of across the board, anything you can


 17   find.  So 180 original studies, and I was very


 18   light on the animal and in vitro studies since I


 19   obviously, being a trained scientist, also feel


 20   that they have slightly less merit than the human


 21   clinical studies.  So I didn't go crazy with those.


 22   I just listed a few of them.  There's a lot more




  1   than that out there.


  2             These are some of what I call--let's just


  3   call them biomarkers that are affected by


  4   glucosamine.  The biosynthesis of hyaluronan,


  5   glycosaminoglycans, collagen.  It's relatively


  6   obvious this is textbook stuff.  Glucosamine is the


  7   major precursor.  Also, not only being a building


  8   block, but glucosamine does have regulatory effects


  9   and has been called a biological response modifier.


 10   It does enhance gene expression of the enzymatic


 11   machinery that produces chondroitin and other


 12   glycosaminoglycans as well as collagen.


 13             Also, glucosamine is added to collagen,


 14   and I think that's where the glycoprotein confusion


 15   might have arisen from glucosamine being called


 16   glycoprotein.  Obviously, glucosamine is not a


 17   glycoprotein.  It's an amino sugar.  But it does


 18   get added to quite a few proteins, and especially


 19   Type II collagen.  Also, glucosamine is converted


 20   into other sugars that are then glycosylating


 21   proteins throughout cartilage.


 22             Also, glucosamine has been shown to




  1   inhibit cartilage breakdown.  There have been two


  2   large, three-year human clinical studies, and I'm


  3   sure that my compatriots from Rotta will address


  4   those.  They both showed the prevention of joint


  5   space loss in knee osteoarthritis in humans.


  6             One interesting point that I think has


  7   been overlooked in the second of these studies by


  8   Pavelka from 2002 is that when you do these types


  9   of studies, you pretty much focus on one knee that


 10   has definite signs of osteoarthritis and is causing


 11   all the symptoms.  Well, what about the other knee?


 12   They actually stated that the contralateral or non-


 13   osteoarthritic knees looked better, and actually


 14   people reported that they felt better.  And those


 15   weren't the knees that were diagnosed with


 16   osteoarthritis.  So I propose that that's a


 17   definition of normalcy and that glucosamine in a


 18   long-term study has been documented to benefit a


 19   normal joint.


 20             Also, there have been correlations with


 21   some of the molecular biomarkers associated with


 22   joint damage.  Osteocalcium, which I didn't list on




  1   this slide, and the chondroitin sulfate 3B3


  2   epitope, which is one of those fragments of


  3   chondroitin that are produced from damage, have


  4   correlated with the radiological images in humans.


  5   There is one case report of an intervertebral disk


  6   actually regenerating after six months of


  7   glucosamine and chondroitin sulfate, verified by


  8   MRIs.  And one of the earlier studies from Italy by


  9   Drovanti in 1980 actually looked at cartilage


 10   biopsies after the study in a couple of people


 11   given glucosamine sulfate and found that the


 12   surfaces were smooth and almost normal.  But they


 13   also looked at a couple biopsies of cartilage from


 14   normal subjects to compare it to.  They chose a


 15   couple of people from the placebo group that were


 16   happening to have surgery, looked at their


 17   cartilage biopsies, and they showed the typical


 18   surface fibrillation and damage associated with


 19   osteoarthritis.


 20             So, therefore, there are indications in


 21   the literature that giving glucosamine does affect


 22   the structure of cartilage.  It brings it more back




  1   to normal.


  2             I think the cases of joint degeneration in


  3   healthy animals that are induced to become


  4   osteoarthritic being prevented by glucosamine is


  5   relevant.  It shows that glucosamine does have the


  6   ability, if it is present before any joint damage,


  7   to actually slow down, delay, and prevent the


  8   progression or incident of osteoarthritis once


  9   osteoarthritis is definitely administered.  And


 10   obviously from in vitro studies, glucosamine can be


 11   added, and, again, that data supports glucosamine


 12   improving cartilage by inhibiting breakdown.


 13             One interesting study by Braham in 2003,


 14   published in the British Journal of Sports


 15   Medicine, looked at people with knee pain.  They


 16   said they specifically did not include people with


 17   osteoarthritis diagnosis.  They just had knee pain


 18   and decreased function.  After 2000 mg per day for


 19   12 weeks, these subjects noted less pain and


 20   improved function.  Most of these people were


 21   younger and had sports injuries.  In fact, I think


 22   that this mirrors the continuum of joint health to




  1   disease, that some of these people may probably


  2   have become osteoarthritic in the future.  Injuries


  3   to joints are obviously a etiological cause of


  4   osteoarthritis.  So, again, more evidence that


  5   glucosamine can help prevent the progression of


  6   joint damage and deterioration.


  7             Okay.  I need to move along.  I will just


  8   kind of quickly go through some of the other


  9   mechanisms of glucosamine.  There are anti-inflammatory


 10   effects that actually are not so


 11   immediate.  They work via regulation, not direct


 12   inhibition of inflammatory events.  So, in other


 13   words, glucosamine is not an aspirin, it's not an


 14   NSAID.  It doesn't work like that.  It works by


 15   regulating the cells to stop doing all those


 16   things, is the simplest way I can put it.  And in


 17   human studies, giving glucosamine with NSAIDs has


 18   shown a synergy in the effects of the NSAIDs.


 19   Downregulation of inducible nitric oxide in joints,


 20   in cartilage; some antioxidant protective effects,


 21   perhaps by being converted into hyaluronan; and


 22   other immune modulation effects have been




  1   demonstrated as well.  Yes, these are animal and in


  2   vitro studies, but they speak to the mechanism of


  3   how glucosamine can accomplish the findings seen in


  4   the human studies.


  5             Now on to chondroitin sulfate.  Again, a


  6   list of the various types of published evidence


  7   shows, again, an overwhelming amount of credible


  8   evidence in favor of chondroitin supporting joint


  9   health.  Eight meta-analyses, all in one form or


 10   another expressed that there were benefits derived


 11   from chondroitin sulfate administration to people


 12   with osteoarthritis or joint damage.


 13             Again, the large, well-designed human


 14   clinical trials, of which there are a pretty good


 15   number here, were unanimous.  Again, similar for


 16   glucosamine, chondroitin shows a high preponderance


 17   of beneficial evidence.


 18             And as I mentioned for glucosamine, I was


 19   very partial in listing animal and in vitro


 20   studies.  This is but a sampling of the many


 21   studies that are available.  Chondroitin has been


 22   around for a long time, has been widely studied for




  1   other health conditions as well.  But I'm limiting


  2   these to joint health.


  3             Let me back up one second.  On the


  4   consensus statements, one of those is from the


  5   Arthritis Foundation in which they said that for


  6   both glucosamine and chondroitin, it does reduce


  7   the signs and symptoms of osteoarthritis.  So for


  8   someone as conservative as the Arthritis Foundation


  9   to make that statement in their public writings and


 10   also to allow sponsorship of dietary supplements


 11   containing glucosamine and chondroitin by allowing


 12   placement of their logo on approved products I


 13   think speaks very highly that there is a consensus


 14   of medical experts somewhere that glucosamine and


 15   chondroitin do affect osteoarthritis and in a very


 16   positive manner.


 17             One of the other consensus statement is


 18   from EULAR, the European Union League Against


 19   Rheumatism, where they list glucosamine and also


 20   chondroitin sulfate as part of the primary


 21   treatment of osteoarthritis, as part of a multi-modality


 22   approach.  So, in other words, it is




  1   considered standard therapy in certain countries.


  2             Again, chondroitin can be--in other words,


  3   how does it work?  Obviously it is a building


  4   block, and, again, it's also a regulatory building


  5   block.  More chondroitin means more stimulation.


  6   And it actually works on gene expression of the


  7   enzymes involved in chondroitin sulfate and, thus,


  8   cartilage production.


  9             A lot of work has focused on the


 10   inhibition of cartilage breakdown.  One study in


 11   particular from 1986 in France looked at sports


 12   overuse injuries.  It used kneecap cartilage


 13   biopsies, and after 16 weeks of 1500 mg per day of


 14   chondroitin sulfate, they noticed thicker, smoother


 15   cartilage appearance from these kneecap cartilage


 16   biopsies.  So these were in people with sports


 17   overuse injuries.


 18             This type of finding was also mirrored by


 19   glucosamine sulfate in an open-label study from


 20   Germany in the early 1980s in people around 20


 21   years old or so that their chondropathia also


 22   improved after a few months of glucosamine.




  1             There were at least four studies showing


  2   the prevention of new lesions in finger


  3   osteoarthritis.  Okay.  There it is.  Two of these


  4   studies were two years in length; one of the


  5   studies was three years in length.  And erosive


  6   finger osteoarthritis has a large genetic


  7   component.  Causes are presumed to be genetically


  8   mediated, which means that it may be impossible to


  9   stop it.  But if the progression--in other words,


 10   the progression to erosion can be prevented, then I


 11   would say that's reducing the risk of


 12   osteoarthritis.  And that's been shown in these


 13   two- and three-year studies by Rovetta and


 14   VerBruggen.


 15             Likewise, there have been at least eight


 16   studies of preventing joint space loss in knee


 17   osteoarthritis from chondroitin sulfate.  These


 18   studies range from one to two years in length, and,


 19   again, with eight studies showing the same thing,


 20   the magnitude of joint space protection was about


 21   0.3 millimeters after a one- to two-year period.


 22   In other words, the magnitude of preservation of




  1   joint space was virtually identical to that seen by


  2   the glucosamine studies.  So we are seeing that


  3   glucosamine and chondroitin both prevent the loss


  4   of joint cartilage during mild to moderate


  5   osteoarthritis.  And I think another interesting


  6   point is that most of the investigators stated that


  7   the people with earlier stages and, thus, more


  8   towards normal stages appeared to have better


  9   results.  Again, this speaks directly to reducing


 10   the risk of osteoarthritis and in my mind makes


 11   this more relevant to "normal" or healthy


 12   population that may have joint damage already


 13   ongoing and just being diagnosed.


 14             Again, the biomarkers of cartilage loss


 15   were shown to correlate some of the time--not all


 16   of the time, but some of the time to the diagnostic


 17   imaging pictures.  In other words, less signs of


 18   joint damage and degeneration, such as cartilage


 19   oligomeric protein, keratan sulfate, urine


 20   pyridinoline/creatinine ratios, and the


 21   deoxypyridinoline/creatine ratios.  Those are


 22   markers of collagen damage and destruction.  These




  1   were reduced as the joint space loss was halted.


  2   So although I'm not going to sit here and say that


  3   glucosamine and chondroitin will rebuild cartilage,


  4   I think stopping the progression seen over a


  5   several-year period is pretty close to the same


  6   thing.


  7             Likewise, with chondroitin, prevention of


  8   osteoarthritis in animal models being induced to


  9   have arthritis showed that it could prevent the


 10   signs of damage, degeneration, and deterioration.


 11             There are some other interesting human


 12   studies on chondroitin sulfate.  After


 13   administering 800 mg for five or ten days, the


 14   levels and the size of hyaluronan and synovial


 15   fluid were increased in subjects with knee


 16   osteoarthritis.  Also, the elastase inhibitor


 17   complex levels were reduced, which means that


 18   chondroitin had a direct inhibition of degradative


 19   enzymes, as was the collagenase activity and N-acetyl-


 20   glucosaminidase activity levels.  And


 21   there's at least three human studies looking at


 22   joint fluid to show direct inhibition of enzyme




  1   activity with typical oral dosages, and that's over


  2   a short term.


  3             Now, if you can extrapolate the effects of


  4   doing that over and over and over and over and over


  5   again for years, I think that can easily explain


  6   the cessation of loss of cartilage.  If you're


  7   stopping the inhibition and improving the


  8   synthesis, what else can happen?


  9             How much more time do I have?  I want to


 10   make sure not to run over.  Okay, thank you.


 11             I also wanted to mention other biomarkers


 12   affected by chondroitin, one of which is mechanostructural


 13   or tensegrity for tension integrity.


 14   Chondroitin being a highly charged molecule and


 15   accounting for a lot of the structural integrity of


 16   cartilage itself, when it is lost, that structural


 17   integrity is lost, more mechanical forces are


 18   transmitted to chondrocytes.  They do have mechano-receptors


 19   as part of what their cytoskeleton is


 20   there for.  So when cartilage is lost, chondrocytes


 21   have another way to determine that.  They don't


 22   need the fragments.  They can just see the overall




  1   structure or mechanical load, and that also


  2   influences the synthesis of chondroitin.  More


  3   load, more synthesis.


  4             Other immune modulation effects for


  5   chondroitin in human, animal, and in vitro studies,


  6   downregulation of inducible nitric oxide antitoxin


  7   effects, and, again, some nonsteroidal type of


  8   anti-inflammatory effects, but not like


  9   nonsteroidal anti-inflammatory drugs.


 10             Chondroitin and glucosamine are working on


 11   the cells to stop making these signals that


 12   maintain and exacerbate the catabolic cascade


 13   rather than actually knocking out a cytooxygenase


 14   enzyme, for example.


 15             So I'd like to summarize as quickly as I


 16   can.  I did want to mention that the oral


 17   bioavailability of each of these two ingredients


 18   has been well worked out.  The chondroitin


 19   especially has been an issue because it's a


 20   macromolecule and, thus, how can it get in.  Well,


 21   it does get in.  A lot of fragments are absorbed


 22   into the bloodstream.  A lot of them are partially




  1   desulfated, and this is expected to account for


  2   some of its actions.  Again, these are similar to


  3   what is seen by the chondrocytes.  Since


  4   chondrocytes get plasma effusions, they see these


  5   fragments.  And both glucosamine and chondroitin,


  6   after oral administration, have been shown to be


  7   incorporated into large macromolecular structures


  8   of cartilage in healthy animals, healthy humans, as


  9   well as osteoarthritic animals and osteoarthritic


 10   humans.  That I think is important to show that the


 11   same processes occur in normal people and


 12   osteoarthritic people.  Giving them glucosamine and


 13   chondroitin does get to the joints, and it does


 14   what chondrocytes and cartilage do, which is make


 15   matrix in both conditions.  So that's why I think


 16   this continuum is just that, a continuum.  And that


 17   is why I feel that normal people would be benefited


 18   from this.


 19             The economic impact, as we have all seen


 20   the billions of dollars of cost and burden.  In


 21   France, they've looked at 11,000 subjects using


 22   chondroitin, and because of their decreased NSAID




  1   use and, thus, also feeling better and less other


  2   therapies, they actually came out, if not equal,


  3   ahead in the price game.  So, in other words, for


  4   socialized medicine such as they have in France,


  5   this is a boon.  They get to safely treat people,


  6   prevent long-term problems with the drugs and with


  7   the illness itself.  That argues very strongly to


  8   me that you are reducing the risk, if not of the


  9   disease, then of the economic burden.


 10             Now, there's also a similar study in


 11   Russia, but I haven't translated it yet, so I can't


 12   give any details.  But their abstract reported that


 13   they did have more efficient economy of treatment


 14   of osteoarthritis.


 15             So to kind of wrap this up, both


 16   glucosamine and chondroitin have been shown to


 17   prevent the loss of cartilage over time.  Remember


 18   the turnover time of cartilage, one to three years.


 19   Look at the length of studies that have shown this,


 20   one to three years.  Earlier stages of


 21   osteoarthritis showed larger effects at reducing


 22   the cartilage loss, indicating prevention of




  1   progression over versus simply treating symptoms.


  2   And the effects were long-lasting after cessation.


  3   In other words, stop taking glucosamine or


  4   chondroitin, and the symptoms are--the reduction of


  5   symptoms and the improvement in the structure are


  6   maintained for months.  This is not just a quick-time, rapid


  7   action type of nutrient.  These are


  8   actually affecting the structural integrity.


  9             There are the biomarkers that are


 10   affected.  These biomarkers have been correlated


 11   with the signs and symptoms of joint degeneration


 12   and deterioration.


 13             I'm going to skip over the animal and in


 14   vitro models.  They do support the human clinical


 15   findings, but I would like to again reiterate that


 16   data from various types of publications for


 17   glucosamine and for chondroitin are very


 18   reproducible and very consistent for benefits that


 19   do support preventing joint degeneration.  I feel


 20   the result is inescapable.  There's not any other


 21   conclusion.


 22             The time course of the findings in humans,




  1   both symptomatic and structural, do fit the


  2   mechanisms of ingredients that work on the


  3   regulation of anabolic and catabolic properties.


  4             We've seen how glucosamine can prevent


  5   progression of joint deterioration in human studies


  6   as well as chondroitin, and that's echoed by animal


  7   studies as well, which can be actually more


  8   controlled to answer the question than human


  9   studies can.


 10             So glucosamine and chondroitin have the


 11   ability to prevent joint deterioration and joint


 12   degeneration by all the lines of evidence that are


 13   out there and, thus, reduce the risk of


 14   osteoarthritis, which has been defined as the


 15   progression of joint deterioration and degeneration


 16   to eburnation.


 17             Thank you very much.


 18             DR. MILLER:  Thank you, Dr. Bucci.


 19             Comments or questions?  Dr. Archer?


 20             DR. ARCHER:  I'm trying to get clear.


 21   You've thrown a lot of information at us.  But are


 22   you saying is joint degeneration a surrogate for




  1   osteoarthritis or does it define osteoarthritis?


  2             Dr. BUCCI:  How about both?  I mean, I


  3   hate to make it a bivalent answer, but how can you


  4   have osteoarthritis without joint degeneration or


  5   joint deterioration?  The endpoint is eburnation


  6   and loss of cartilage, and joint degeneration and


  7   deterioration I think is loss of cartilage at one


  8   point or another.  So I guess that's why I'm saying


  9   yes to both.  Also, that's one of the


 10   characteristics of the radiological staging.


 11             DR. MILLER:  Dr. Krinsky?


 12             DR. KRINSKY:  Norman Krinsky.  I would


 13   assume that in the normal joint, if one exists, the


 14   anabolic and catabolic processes are in


 15   equilibrium.  And under those circumstances, if you


 16   treat that with glucosamine or glucosamine and


 17   chondroitin sulfate and you increase the anabolic


 18   processes and decrease the catabolic processes,


 19   does that, therefore, lead to an increase in


 20   cartilage?  And what are the implications of that


 21   in a normal joint?


 22             DR. BUCCI:  Right, that's an excellent




  1   question because I am--one of my answers is, Have


  2   you seen people with cartilage just pouring out of


  3   a joint?  No.  Even in acromegaly, which is really


  4   a regulatory problem with growth hormone, you do


  5   see extra cartilage, but not otherwise.  And, in


  6   fact, if you give glucosamine and chondroitin into


  7   normal cultures, unless there's a need for


  8   synthesis, you don't make extra cartilage.  You


  9   might synthesize a few more precursors, but they're


 10   not let outside the cell to make matrix.  That's


 11   why I was trying to stress these are regulatory


 12   molecules.  If you don't need them, they won't


 13   overdo it, so to speak.  If you need them, they fit


 14   right in and help restore matrix.


 15             DR. MILLER:  Dr. McBride?


 16             Dr. McBRIDE:  You've mentioned that


 17   there's evidence that chondroitin sulfate and


 18   glucosamine are absorbed into joints.  Is there


 19   evidence that they're absorbed into healthy joints,


 20   not inflamed joints?


 21             DR. BUCCI:  Yes.  In fact, most of the


 22   evidence is in healthy animals and healthy humans




  1   as well.


  2             DR. McBRIDE:  These are marker studies or--


  3             DR. BUCCI:  Yes, these are radiolabeled


  4   glucosamine, radiolabeled chondroitin.  Labels on


  5   the sulfate for chondroitin and also the hydrogens


  6   on the sugar ring for both glucosamine and


  7   chondroitin; also tech-(?)  99 labeling of


  8   chondroitin as well.


  9             DR. McBRIDE:  Are there any comparison


 10   studies of absorption into inflamed joints or those


 11   that might truly have osteoarthritis and those that


 12   would be precursors, probably less inflamed?


 13             DR. BUCCI:  I know that there have been


 14   studies in osteoarthritic animals and even, I


 15   think, one or two in people that have looked at


 16   uptake into joints.  I'm afraid I can't recall if


 17   there's any direct comparison.


 18             DR. McBRIDE:  But those would be


 19   osteoarthritic joints.


 20             DR. BUCCI:  Yes, so we do know that they


 21   can get into osteoarthritic joints and become




  1   incorporated into macromolecules, also the same for


  2   healthy tissues.


  3             Now, the rates of incorporation, I don't


  4   know if that has been quantified.  If it I has, I


  5   just have not picked that up in the literature.


  6   There is obviously a lot here to remember.  But I


  7   know that that has been looked at in animal


  8   studies, and the normal maintenance that is


  9   constantly ongoing is enough to label cartilage


 10   with glucosamine and chondroitin in a normal


 11   setting, if that helps answer your question..


 12             DR. MILLER:  Dr. Russell?


 13             DR. RUSSELL:  Yes, I was interested in the


 14   two studies that may have something to do with


 15   primary prevention of osteoarthritis.  One was the


 16   finger osteoarthritis.  You said that treatment


 17   prevented new finger osteoarthritis.  Does that


 18   mean joints that were previously uninvolved that


 19   remain uninvolved?  And presumably in the untreated


 20   group that there were some new finger lesions?  And


 21   were those statistically significant differences


 22   or--I don't know the detail of the study.




  1             DR. BUCCI:  Okay.  To clarify that, some


  2   of the studies did show a prevention of new


  3   lesions; in other words, no arthritic lesions in a


  4   finger joint, there was less appearance of new


  5   lesions in the chondroitin-treated group versus the


  6   placebo group.  Some studies did not find it and


  7   others did.  But pretty much all the studies did


  8   find that the prevention to the severe erosive


  9   stage from moderate-mild damage was prevented.  I


 10   think that was near universal in each of those


 11   studies.  And the effects were obviously larger and


 12   significant as time went on.  Some studies did not


 13   see it at one year, but at two or three years they


 14   did see it.


 15             DR. RUSSELL:  And I wonder if you could


 16   clarify just a little bit on the knee study that


 17   you mentioned, that the non-osteoarthritic knees in


 18   this 2002 study were improved.  Again, was this--not


 19   improved, but were not involved.  Was this


 20   statistically significant from the non-treated


 21   group?


 22             DR. BUCCI:  I don't think that they looked




  1   at this in a statistical manner because it wasn't


  2   one of the enterprises of measurement.  I think it


  3   was an observation in the discussions.  I think


  4   that my colleagues can speak to that, too.


  5             DR. MILLER:  Dr. Abramson?


  6             DR. ABRAMSON:  That was a very clear


  7   presentation, and I always need to have those fern-like


  8   molecules pointed out to me again.  But I want


  9   to just discuss whether one can sometimes overly


 10   simplify very complicated tissue and talk about the


 11   chondrocyte as making and creating proteoglycans


 12   and collagen, because I think apropos the fact that


 13   this may be a different disease once established


 14   versus early on, these kinds of metabolic changes


 15   may be difficult to extrapolate over.


 16             So, for example, if early OA, we know, is


 17   a proliferative hypertrophic disease where


 18   proteoglycan actually is increased in its


 19   production and not decreased, then it's not clear


 20   that in early disease, at least just playing the


 21   hypothetical here, that a decrease in proteoglycan


 22   synthesis should necessarily be corrected by the




  1   addition of exogenous substrates like glucosamine.


  2   And then the changes occur, you know, through


  3   hypertrophy and the catabolic changes, and then you


  4   get this very complicated disease which is not just


  5   in and out of proteoglycan and collagen, but


  6   there's bone and there's synovial cells and there's


  7   interleukin-1.  And at that point, the in vitro


  8   evidence I think is very intriguing that


  9   glucosamine and chondroitin, as you showed, can


 10   reverse some of these catabolic events.  And that


 11   case is consistent with whatever kind of clinical


 12   evidence we may have that this is a beneficial


 13   treatment.


 14             But I think going back on the table today


 15   of health claims, it's not clear that those


 16   effects, were they true in vivo, in patients, are


 17   necessarily applicable to these early changes.  And


 18   I just--so that's a long statement.  Do you want to


 19   comment on the actual complexity of this biology?


 20             DR. BUCCI:  Yes, I'd love to, and I'll try


 21   to keep it brief, obviously.  But, no, that's a


 22   consideration I've thought about quite a bit,




  1   obviously.  Of course, there is a difference


  2   between osteoarthritis and just normal non-damaged


  3   tissue, and it does get more complex.  But, again,


  4   the reason I made my whole presentation simplistic


  5   on purpose is because, no matter how complex it


  6   became, no matter what biomarkers you were looking


  7   at, no matter what pathways you were looking at, no


  8   matter what disease state, no matter what the state


  9   of cartilage was, whether it's in the increased


 10   production of proteoglycans in the early stages or


 11   the decreased production in later stages, they all


 12   go back to the same point, which is making more


 13   matrix.  Sooner or later, everything points to


 14   that.  It's almost a unified field area or unified


 15   matrix area, if I can coin a term, that regardless


 16   of which stage--normal, early, middle late


 17   osteoarthritis, damage with no signs and symptoms--sooner or


 18   later it's a problem with making the


 19   matrix.  And glucosamine is intimately involved not


 20   only in making the matrix but in regulating it.


 21   And for whatever reason, the catabolic signals


 22   overwhelm the limited ability to increase the




  1   anabolism.  I think that the ability of


  2   chondrocytes to generate more matrix, they can only


  3   increase proteoglycan production from normal upkeep


  4   about 250 percent.  I think that's from human and


  5   animal studies in general.


  6             So, in other words, cartilage has a very


  7   slow, limited response to any of these complex


  8   stimuli.  But that's the response to all of these.


  9             DR. ABRAMSON:  So I would just--I


 10   understand.  I would just point out that there are


 11   two mechanisms of glucosamine and chondroitin that


 12   you're talking about.  One is it's acting as a


 13   substrate to a building block for more


 14   proteoglycan.  The other is a pharmacological


 15   action, which is somehow through receptors it


 16   inhibits the activation of chondrocytes in response


 17   to IL-1, and that probably is via a different


 18   mechanism, or one could possibly--that's two


 19   separate mechanisms:  one is the available


 20   substrate, and the other is what it's doing to


 21   signaling that we really don't understand, except


 22   it does seem to do that, and what happens in




  1   clearly established disease, and separating the


  2   relative importance of that I think is an


  3   interesting question that I think needs more


  4   understanding.


  5             DR. BUCCI:  I agree.  But, conceptually, I


  6   would say that these are physiological roles and


  7   events, and these regulatory roles are trying to


  8   get tissue back to normal.  That's obviously what


  9   our bodies try to do in every tissue.  This is the


 10   way chondrocytes do it.  They use glucosamine and


 11   chondroitin to try to return to normal, keep


 12   normalcy.  If there is anything abnormal, then they


 13   are there to try to restore normality.  And that


 14   really is what I think reducing risk and prevention


 15   of a disease is all about.  How can you prevent


 16   disease if it's not there?  Well, by these


 17   mechanisms you just described.


 18             DR. MILLER:  Dr. Felson?


 19             DR. FELSON:  I guess, once again, sort of


 20   a lovely, comprehensive discussion of many, many


 21   issues.  Unfortunately, perhaps oversimplifying


 22   some difficult ones, which probably if there were a




  1   variety of other osteoarthritis scientists in the


  2   room would take a week to discuss and not resolve.


  3             One of them is I think you sort of


  4   presented the clinical data in a couple of ways


  5   that I think the rest of the audience sort of needs


  6   to comprehend a little bit, which is that my


  7   reading of the clinical data are not that


  8   convincing.  And the reason for that is that there


  9   have been--all of the studies that you commented


 10   on, many of them--all of them, I think, the


 11   positive ones, are industry-supported.  There have


 12   been three publicly supported trials of


 13   glucosamine, and all have been null, one of which


 14   is a very nice Canadian multi-center withdrawal


 15   trial.  And that's one of the reasons why the NIH


 16   is now spending millions of our tax dollars on a


 17   trial to try to definitely determine whether


 18   glucosamine and chondroitin are efficacious.  I


 19   think the jury is still out as far as treatment


 20   goes.  I'm not sure how to interpret all the data


 21   that you described, and I don't disagree with you


 22   that the preponderance of it is supportive.




  1             The other issue that you were--you used a


  2   p