FOOD ADVISORY COMMITTEE AND DIETARY


                                    SUPPLEMENTS SUBCOMMITTEE













                                   SULFATE IN OSTEOARTHRITIS




                                  FURAN CONTAMINANTS IN FOODS













                                     Tuesday, June 8, 2004


                                           8:00 a.m.









                                       Bethesda Marriott

                                         Grand Ballroom

                                      5150 Pooks Hill Road

                                       Bethesda, Maryland













                  Food Advisory Committee


                  Sanford A. Miller, Ph.D., Chairman

                  Linda Reed, Acting Executive Secretary


                  Douglas L. Archer, Ph.D.

                  Patrick S. Callery, Ph.D.

                  Goulda A. Downer, Ph.D.

                  Johanna Dwyer, D.Sc, RD

                  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.


                  Dietary Supplements Subcommittee Members


                  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.

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

                  Nancy E. Lane, M.D.




                  Jeanne Latham

                  Dr. Craig Rowlands











                                        C O N T E N T S




                  Call to Order

                  Sanford A. Miller, Ph.D., Chair                            4


                  Review of Issues

                  Dr. Craig Rowlands                                         6


                  Committee Discussion                                       8


                  Concluding Comments                                      103


                  Dr. Miller











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


              2                          Call to Order


              3             DR. MILLER:  Good morning.  We are going


              4   to begin the second day of the meetings of the Food



              5   Advisory Committee.  This morning and the first


              6   part of this afternoon will be spent with the


              7   committee deliberating the information that we have


              8   received so far and try to develop a consensus


              9   response to the three questions that were presented



             10   to us by the FDA for us to respond to.


             11             Before we begin our work for today, there


             12   is a couple of issues I need to make and Linda also


             13   has some administrative things that need to be


             14   brought to your attention.



             15             First, two of the members of the


             16   committee, Dr. David Felson and Dr. Annette


             17   Dickinson will not be with us today.  They were


             18   unable to stay for the two days of the meeting, and


             19   I think we will miss them.  But, for the record,



             20   they won't be with us.


             21             Secondly, it is really important that we


             22   stick to the time frame as closely as possible.  We











              1   have another subject to discuss, the Food Advisory


              2   Committee has another subject to discuss, and that


              3   is the contamination of foods with furans, and we


              4   have to be out of this room, I have been informed,



              5   by 6 o'clock at the very latest, otherwise, we will


              6   find ourselves in the middle of a wedding, that


              7   that is not going to help our deliberations to any


              8   great extent.


              9             So, we will do that.  At 1:45, this



             10   section of the meeting will adjourn and the


             11   temporary voting members and the members of the


             12   Supplements Subcommittee that have joined us will


             13   be excused, with our thanks, of course, and we will


             14   continue on with the furan part of the meeting with



             15   a new group of temporary voting members, and so on,


             16   and so forth.


             17             Linda.


             18             MS. REED:  Good morning, everyone.  I just


             19   have a couple of administrative announcements,



             20   information I want to give you.  If anyone needs


             21   transportation back to their respective airports,


             22   please see Sharon Barcelos [ph], who is sitting out











              1   front at the registration desk, and she will get


              2   that arranged for you.


              3             Also, just as a reminder, I believe


              4   checkout is at noon for anybody who needs to check



              5   out.  Also, if you would like to have your briefing


              6   materials Fed Ex'd back to your business or


              7   residence, we have Fed Ex boxes and labels outside


              8   also where Sharon is sitting, if anybody wants to


              9   take advantage of doing that versus carrying it



             10   back with them, so please see Sharon for those


             11   details.


             12             Thank you.


             13             DR. MILLER:  Dr. Craig Rowlands from the


             14   FDA will again present the questions to us.  He is



             15   also available, if anybody has any questions they


             16   need for clarification, or information that they


             17   might need in order to come to some decision on


             18   these questions, please address them to Craig.


             19             I have asked them to put the questions up



             20   on the screen and leave them up there, so that they


             21   will be in front of us during our discussions


             22   today.











              1             Craig.


              2                         Review of Issues


              3             DR. ROWLANDS:  Good morning.  I am going


              4   to read the questions as I read them yesterday,



              5   which is I am going to combine Questions 1, the A


              6   and B, and then Questions 2, the A and B, and then


              7   Question 3, I will read as written.


              8             Question 1 is:  Is 1(a), joint


              9   degeneration, and Question 1(b), cartilage



             10   deterioration, a state of health leading to


             11   disease, which is a modifiable risk factor


             12   surrogate endpoint for OA risk reduction?


             13             Then, we would like to know what are the


             14   strengths and limitations of the scientific



             15   evidence on this issue.


             16             Question 2 is:  If we assume that for


             17   2(a), joint degeneration, and for Question 2(b),


             18   cartilage deteriorating, is a modifiable risk


             19   factor surrogate endpoint for OA risk reduction,



             20   and we assume that research demonstrates that a


             21   dietary substance treats, mitigates, or slows joint


             22   degeneration or cartilage deterioration in patients











              1   diagnosed with osteoarthritis, is it scientifically


              2   valid to use such research to suggest a reduced


              3   risk of OA in the general healthy population, that


              4   is, individuals without osteoarthritis, from



              5   consumption of the dietary substance?


              6             Question 3 is:  If human data are absent,


              7   can the results from animal and in vitro models of


              8   OA demonstrate risk reduction of OA in humans?


              9             3(a)  To the extent that animal or in



             10   vitro models of OA may be useful, what animal


             11   models or in vitro models, types of evidence and


             12   endpoints should be used to assess risk reduction


             13   of OA in humans?


             14             3(b)  If limited human data are available,



             15   what data should be based on human studies and what


             16   data could be based on animal and in vitro studies


             17   to determine whether the overall data are useful in


             18   assessing a reduced risk of OA in humans?


             19             If there is any clarification needed or



             20   anything on those questions, you can ask me or


             21   actually you could ask any of the FDA staff for any


             22   clarifications if you like.











              1             DR. MILLER:  Any comments?  Dr. Cush.


              2             DR. CUSH:  Well, actually, I would like to


              3   provide a clarification, I think to Question 1(a).


              4   I would like joint degeneration to be considered



              5   separately from cartilage deterioration.


              6             Joint degeneration, I think would


              7   basically be an analogous definition of


              8   osteoarthritis.  I don't believe that it is a state


              9   that leads to, I mean it is a net result that is



             10   osteoarthritis.  It is a poor choice of words, and


             11   should not be any kind of labeling, and should be


             12   rejected outright.


             13             I think to move on to cartilage


             14   deterioration, which is sort of the target of the



             15   initial damage of the disorder, something that we


             16   measure.  Joint degeneration is too global, too


             17   vague, but it nonetheless does imply the net result


             18   of osteoarthritis.


             19             So, that term I believe is faulty and



             20   should be eliminated.


             21             DR. ROWLANDS:  Okay.  Of course, the


             22   questions are written separately as 1(a) and then











              1   1(b).


              2                       Committee Discussion


              3             DR. MILLER:  Any comments or response to


              4   that?  Yes.



              5             DR. BLONZ:  Edward Blonz.  Now, the


              6   question I would pose to that is, does the joint


              7   degeneration process begin and then lead to


              8   osteoporosis, or as soon as joint degeneration has


              9   begun, you are already there?  Osteoarthritis,



             10   forgive me.


             11             DR. CUSH:  Again, this goes back to


             12   yesterday's definition of the transition from


             13   healthy to disease state, which is an impossibility


             14   to define I think in this instance, and I don't



             15   believe that joint degeneration implies a lesser,


             16   more minor, or protein state of the net result,


             17   which is osteoarthritis.


             18             I think it embodies what we see in


             19   osteoarthritis, which is again the whole joint



             20   being affected by more primordial events that begin


             21   with cartilage pathology.


             22             DR. MILLER:  It seems to me, as I said











              1   yesterday, it seems to me that there is a


              2   fundamental issue that somehow or other we need to


              3   comment on, and that is the question on which much


              4   of the discussion is based, and that is, there is



              5   at some point when osteoarthritis or any of the


              6   pre-quals [ph] of osteoarthritis that we are


              7   discussing to see whether they have any ultimate


              8   impact does or does not exist.


              9             I mean, to exaggerate, if you listen to



             10   the conversation about the continuum, and you can


             11   argue the continuum begins at conception and ends


             12   at death, and those kind of continuums are not


             13   unknown in biology, and it just seems to me that we


             14   need to address that question, if the basic issue



             15   that the FDA is trying to deal with is going to be


             16   responded to.


             17             Yes, David.


             18             DR. ABRAMSON:  I think, Dr. Miller, that


             19   is the nub that we are struggling with, and I think



             20   one of the issues that is important to review from


             21   yesterday's discussion is that our clinical ability


             22   to detect osteoarthritis is very crude at the











              1   earliest stages and particularly the imaging


              2   technology is very crude, and we rely on that.


              3             So, histologically, we all would be able


              4   to sit around a table with a pathologist and



              5   differentiate normal cartilage from early


              6   degenerative changes of cartilage, and that is how,


              7   in fact, when you do studies of OA, you define it


              8   pathologically, not by imaging.


              9             Imaging is useful for clinical trials, as



             10   Dr. Simon said, and also for clinical care of


             11   patients, but the disease, as is atherosclerosis


             12   present for years perhaps before the patient is


             13   symptomatic, but a pathologist can see


             14   atherosclerosis and a pathologist can see



             15   osteoarthritis, and that doesn't happen necessarily


             16   when you are 15 or 17, it happens in the later


             17   decades.


             18             The other related dilemma is the disease


             19   osteoarthritis pathologically can be detected early



             20   with fibrillations and fissuring, but then in only


             21   some people does it advance at a rate that they get


             22   it at age 55 or 75, or perhaps 100, but there is a











              1   continuum where I think we would call this


              2   cartilage abnormality osteoarthritis.


              3             So, I think the limitations of our


              4   diagnostic tools are part of the problem here, but



              5   the disease can be detected if one looks carefully


              6   enough at many of these earlier points.


              7             DR. MILLER:  Well, it is impossible--I


              8   will just lay this on the table--to say that you


              9   can't distinguish a period in which osteoarthritis



             10   or the phenomenon that lead to full-blown


             11   osteoarthritis can't be determined.


             12             DR. LANE:  I think that that is true.  I


             13   mean what Dr. Abramson says is we neither have the


             14   imaging techniques, nor do we have a measurement in



             15   the blood or serum that you could at which point


             16   say this, like cholesterol, we don't have a


             17   cholesterol, we don't have a level of a marker of


             18   bone or cartilage turnover that we could say this


             19   person is at so high a risk of getting OA that we



             20   should do something about it.


             21             We neither have an imaging tool nor a


             22   serum marker in this continuum, and until the











              1   person comes to medical care with pain in their


              2   joint, it is unclear.  Even if they have a x-ray


              3   and it's abnormal, it is unclear they are going to


              4   get a clinical disease.



              5             As Dr. Felson said yesterday, only 30


              6   percent of people who have significant radiographic


              7   changes ever have clinical painful disease.


              8             DR. MILLER:  I understand that.  What I am


              9   just trying to say is that if that be the case, and



             10   there is a consensus that that is the case, then,


             11   that is what we ought to say.  That is all I am


             12   trying to say.


             13             DR. LANE:  Okay.


             14             DR. MILLER:  Dr. Cush.



             15             DR. CUSH:  I would like to reiterate a


             16   point that was brought up by David Felson


             17   yesterday, and that was in spite of what appears to


             18   be a struggle as to what we know and what we don't


             19   know, no rheumatologist has difficulty making a



             20   diagnosis of osteoarthritis.  It is a very certain


             21   disease, it is easy to diagnose.


             22             What we are talking about here, in this











              1   continuum that may begin with genetic factors, and


              2   then biochemical factors, then immunologic events,


              3   then physiochemical events, and then sometime


              4   shortly thereafter, symptoms might ensue, and then



              5   are followed by damage and the functional


              6   consequences of disease.


              7             All along the way, imaging, depending on


              8   how good or sensitive it is or is not, or a


              9   biomarker, how sensitive it is, it may be present



             10   or it may be absent, but they don't factor as much


             11   into this as the symptoms do, so it is when


             12   symptoms begin that we recognize this constellation


             13   of findings and we make this diagnosis.


             14             What is not known is what is pre-OA, we



             15   don't have a diagnosis of pre-osteoarthritis.  In


             16   fact, we don't have great risk factors.  We know


             17   risk factors, we know there are some genetic risk


             18   factors, which is for a minority of individuals.


             19             We know that obesity and we know that



             20   certain lifestyles or occupations are risk factors


             21   for osteoarthritis, and those are modifiable, but


             22   by the way, none of those subsets have these











              1   nutritional supplements been applied to and shown


              2   to have protective benefit.


              3             So, you know, we are being asked to


              4   address whether or not some intervention might be



              5   applied to a healthy population to protect us


              6   against the disease.


              7             Again, I have a problem with connecting


              8   the dots.  We saw some good research and good


              9   results applied to people with disease, but



             10   applying them to the general population who may or


             11   may not have this is, I think a gigantic leap of


             12   faith that is going to be difficult to make.


             13             DR. MILLER:  Dr. Zeisel.


             14             DR. ZEISEL:  I would like to suggest that



             15   we approach this bit by bit, and not jump to the


             16   treatment of OA or prevention of OA at this moment,


             17   but rather the question before us is, is cartilage


             18   degeneration a predecessor of OA in the individuals


             19   who develop OA.



             20             Now, that doesn't mean that everybody who


             21   has cartilage degeneration is going to go on to


             22   develop OA, but in the individuals who develop OA,











              1   is cartilage degeneration a predecessor, and from


              2   what I have heard, I would argue that it is, that


              3   people who go on to develop OA start with cartilage


              4   degeneration.



              5             Again, we might parse that very finely,


              6   but, in general, you have some cartilage


              7   degeneration that gets worse and worse until some


              8   point when you develop frank symptomatology that is


              9   picked up.



             10             So, if we can agree on that, we can agree


             11   on a Question 1(b) that it's a deterioration of


             12   state of health leading to a disease.  Now, it


             13   doesn't always lead to the disease, but it is clear


             14   that sometimes it does.



             15             Is that a reasonable statement?


             16             DR. LANE:  Well, I have a little trouble


             17   with it, because you are saying that the cartilage


             18   degeneration is starting out leading to something,


             19   and I think, as was brought up yesterday, the joint



             20   is a structure, and what leads to the painful


             21   disease OA is cartilage and bone changes.


             22             So, I ask Dr. Abramson should we separate











              1   out the cartilage, I am not so sure.


              2             DR. ABRAMSON:  Well, I guess the semantic


              3   issue here is I would argue that cartilage


              4   degeneration is the earliest phase of



              5   osteoarthritis, therefore, it is not a normal


              6   state.


              7             DR. ZEISEL:  Well, again, I think that we


              8   cannot come to any resolution here as a committee


              9   if we--you know, it's like arguing when birth



             10   starts.  We can get down and keep going back and


             11   back.


             12             I think that our problem here is that we


             13   all realize that realistically, there is a stage at


             14   which cartilage falls slightly behind in its repair



             15   versus synthesis rate, and that that is a minuscule


             16   change that is only detectable by the finest cell


             17   biology, but eventually, it goes on and it can't be


             18   the disease at the first mistake. Otherwise, then,


             19   there is nothing you could ever prevent, because



             20   you have the disease the first time the first


             21   cartilage cell doesn't make the right amount of


             22   cartilage.











              1             So, I think realistically, it is hard to


              2   accept that you define the disease as when the


              3   first cartilage cell doesn't make the right amount


              4   of cartilage.



              5             DR. ABRAMSON:  That does become a


              6   theological discussion, but the point that I would


              7   make is how do we define cartilage degeneration


              8   even for this discussion, and I would suggest that


              9   although we talked about OA as being an inevitably



             10   disease-related disease, in point of fact, it is


             11   not--when you are 75 years old, maybe only 30


             12   percent of people have it.


             13             I can tell you in our laboratory, we rely


             14   on getting normal tissue age matched before we do



             15   studies by the pathologist, and you can find lots


             16   of people who come to surgery for fractures or


             17   other reason who have absolutely normal cartilage


             18   at age 70, that you then have to say, okay, I am


             19   going to do my study, and that is a normal person



             20   age 70, and this is a person who has


             21   osteoarthritis.


             22             So, the notion that it is a normal process











              1   with time, I think, you know, it depends at what


              2   point in time, and it is not necessarily therefore


              3   everyone is going to get OA and at the earliest


              4   sign.  So, you can have normal cartilage, and I



              5   would suggest that the degenerative changes that


              6   the pathologist can see is osteoarthritis.


              7             DR. ZEISEL:  But we have also heard, I


              8   believe, that you can have abnormal cartilage, and


              9   not have osteoarthritis, that, by definition, there



             10   are some people going around with abnormal


             11   cartilage and they do not have osteoarthritis by


             12   the clinician's recognition of that disease.


             13             So, having abnormal cartilage cannot be


             14   the sine qua non of having osteoarthritis.  What I



             15   am trying to say is that it can precede it, and


             16   therefore, there must be people who will develop


             17   osteoarthritis who have the start of cartilage


             18   degeneration, and the question at hand is, is that


             19   a marker that is worthwhile following as something



             20   that you could intervene in.  I mean I think that


             21   is what Question 1(b) is.


             22             DR. MILLER:  Well, couldn't that be a rate











              1   function?  In other words, a rate of degeneration


              2   that could take place, and if you don't live long


              3   enough for it to express itself, so to speak.


              4             I mean the problem, let me see if I can



              5   focus this discussion a little bit, a little more,


              6   the problem that the FDA faces is being able to


              7   determine whether or not the results you are


              8   looking at is mitigation of existing disease or is


              9   it risk reduction--I have to be careful what words



             10   I use--whether it is a risk reduction function.


             11             That is the problem that they face, and


             12   there are many ways to deal with this.  One is to


             13   get a consensus for an arbitrary distinction at


             14   what point one process begins and the other ends,



             15   recognizing that you are trying to deal with a


             16   point on a continuum.


             17             I am not sure we could do that here, but


             18   if there is some agreement, we can recognize that.


             19             DR. LANE:  I think, Dr. Miller, that is a



             20   very important point, because research that Dr.


             21   Felson and our group do has shown us surprisingly


             22   that the risk factors for getting the disease at











              1   this point, with the research done, are different


              2   than what causes it to get worse.


              3             So, armed with that data and the


              4   literature for both hip and knee OA, we may have to



              5   make a bit of a distinction even though


              6   theoretically, we think the continuum should, we


              7   really don't have the data to support that today.


              8             DR. MILLER:  Basically, you have got to


              9   draw that bright line somewhere.



             10             DR. LANE:  That's right, we have to put a


             11   dotted line, that is exactly right.


             12             DR. MILLER:  Recognizing that there is a


             13   big variation.


             14             DR. LANE:  That's right.



             15             DR. MILLER:  We have a number of people


             16   that have been trying to get some questions in


             17   here, and to be fair, I have got to give them a


             18   chance.


             19             Dr. Espinoza.



             20             DR. ESPINOZA:  I don't have any problems


             21   with the question posed by FDA regarding joint


             22   deterioration and cartilage degeneration.











              1   Cartilage degeneration might be the hallmark of the


              2   disease that we call osteoarthritis, but


              3   osteoarthritis is much more than that.


              4             I definitely feel that joint deterioration



              5   should be considered at least a relevant question


              6   for us to discuss here.


              7             DR. MILLER:  Dr. Nelson.


              8             DR. NELSON:  Following up on the questions


              9   about the continuum, we are interested in risk



             10   factors for this particular discussion, correct?


             11             DR. MILLER:  Right.


             12             DR. NELSON:  As I understood it, there


             13   could be 75-year-olds that have no anatomical


             14   changes, and clearly they have no risk of



             15   developing osteoarthritis, but then there are


             16   others that do, in fact, have these changes, but


             17   have no symptomatology, so they have risk factors,


             18   but it hasn't led to the problem.


             19             As I understood it, the disease was, as I



             20   think Dr. Zeisel allude to it, the disease is


             21   really considered a disease once the patient


             22   presents symptoms.











              1             In that situation, would not, in fact,


              2   cartilage deterioration be a risk factor that may


              3   or may not be modifiable, but before the disease


              4   appears?



              5             DR. ABRAMSON:  The difficulty for me here


              6   is that we define osteoarthritis as when the


              7   symptoms begin at one level, but we can all look at


              8   an x-ray and say this asymptomatic patient has


              9   osteoarthritis of the knee or back, so there is



             10   three levels by which we make this diagnosis.


             11             We make a clinical diagnosis, we make a


             12   radiographic diagnosis, and we make a histological


             13   diagnosis, and depending on which part of the


             14   elephant you are looking at, the elephant still has



             15   osteoarthritis, the disease of tissue degeneration.


             16             So, I think the analogy to other diseases


             17   then becomes important, and it depends what the FDA


             18   wants to call the onset of the disease.  If it


             19   limits itself to symptoms, that is one way of



             20   looking at it, but is hypertension a disease if the


             21   person doesn't have a stroke until it had 20 years


             22   of hypertension, is a plaque in the coronary artery











              1   atherosclerosis if the patient hasn't had angina.


              2             So, I would suggest that the disease is a


              3   set of pathogenic events in tissue and tissue


              4   injury that we don't have either the imaging



              5   technology or the patient may be asymptomatic up to


              6   a point, but eventually that patient who has that


              7   disease will most commonly get some kind of


              8   symptom.


              9             The symptoms of osteoarthritis don't come



             10   from where a lot of the pathogenic changes are


             11   happening because there is no nerves there, but


             12   eventually, the organ fails, eventually symptoms


             13   will occur, so I think this is a definitional


             14   problem.  I think the disease can be all of those



             15   different things, and this discussion I think has


             16   to decide which of those things we want to call


             17   osteoarthritis.


             18             DR. MILLER:  Dr. Kale.


             19             DR. KALE:  It seems clear that the



             20   degeneration of cartilage is necessary, but not


             21   sufficient to create the syndrome of


             22   osteoarthritis, but if we are forced to acknowledge











              1   that every human being will develop this condition


              2   of cartilage degeneration, but may or may not


              3   develop the syndrome of osteoarthritis, then, we


              4   have embraced a very large definition, which is



              5   fine.


              6             I feel uncomfortable holding the


              7   petitioners responsible for changing that or


              8   clarifying the universe for us when we can't do it


              9   ourselves.



             10             The notion that you could prevent the


             11   syndrome from developing by using a product like


             12   chondroitin sulfate or glucosamine, with the


             13   possibility of reducing a universe of patients from


             14   having the symptoms, and given again that we are



             15   all going to develop some evidence of cartilage


             16   degeneration, seems like a very worthy idea, and


             17   the fact that we can't define a modifiable risk


             18   factor for our satisfaction seems an unfair burden


             19   to place on the petitioners.



             20             My basic point is that in a certain sense,


             21   walnuts are to LDL as chondroitin sulfate or


             22   glucosamine is to reduction of cartilage











              1   degeneration, and in that sense, the modifiable


              2   risk factor would be, for the purpose of this


              3   hearing, would be modifying the risk factor of


              4   degenerating cartilage.



              5             You could reduce the degeneration of


              6   cartilage and, in some patients, some fortunate few


              7   or some fortunate many, they would not go ahead and


              8   develop osteoarthritis and perhaps the rest would.


              9             That is no better than we can say for



             10   Lipitor or any other drug or any other drug as we


             11   are trying to treat diseases relevant to, say,


             12   cardiovascular disease.


             13             DR. MILLER:  Dr. Cush.


             14             DR. CUSH:  I think that it is clear we



             15   can't make any 100 percent certain statements about


             16   relatedness and/or discrete time variables where


             17   events, pathologic or otherwise, lead to actual


             18   disease.


             19             I think what we can say is, you know, use



             20   the term "reasonable certainty," and I think that


             21   is much more operationally important here.


             22             I would use the analogy that is a











              1   catastrophic motor vehicle accident or skiing


              2   accident a risk factor for developing


              3   osteoarthritis?  Yes, it is.  I mean such an


              4   individual is more likely than not to have his or



              5   her cartilage damaged to the point that it will


              6   lead to a secondary osteoarthritic joint.


              7             Similarly, although that is much more of a


              8   macroscopic insult, here, we are talking about


              9   microscopic insults, hence, I would say that



             10   cartilage degeneration or deterioration is also a


             11   risk factor for the development of osteoarthritis,


             12   and a statement using sort of a reasonably certain


             13   terminology.


             14             I think most of us, I wasn't happy with



             15   it, but I think that we know that, in fact, that


             16   that is not a good thing, and there is a reasonable


             17   risk for development of osteoarthritis.


             18             DR. MILLER:  Dr. Dwyer.


             19             DR. DWYER:  I think where I am confused



             20   is, is it a risk factor or is it a sign that the


             21   disease is already present.  To me, it seems like


             22   it is a sign, from what some of you experts say, it











              1   is a sign that the disease is already there.  So,


              2   it is not a risk factor, it is a sign of the


              3   disease, which is different, at least in my head it


              4   is different.



              5             DR. CUSH:  For the person who gets the


              6   disease, yes, it is, but as we have said, there are


              7   people who have cartilage abnormalities who will


              8   never have symptoms.


              9             DR. DWYER:  But that doesn't bother me



             10   because all of these diseases are multifactorial,


             11   so there are a lot of people who have a whole bunch


             12   of different characteristics, but they don't get


             13   the disease.


             14             DR. CUSH:  I don't understand.  I mean you



             15   are going to discard those people who have, and not


             16   consider them, is that what you are saying, people


             17   who have cartilage abnormalities, because again, if


             18   we are going to accept that they are not important,


             19   then, we may be overtreating or subjecting a large



             20   segment of the population to products that they may


             21   not need.  I think we have to consider them.


             22             DR. MILLER:  Dr. Zeisel.











              1             DR. ZEISEL:  Let's retreat to some ground


              2   that has already been covered, I believe, by the


              3   FDA.  Individuals, treatments that can lower


              4   cholesterol are allowed to say that they are



              5   beneficial in the prevention of atherosclerosis and


              6   cardiovascular disease.


              7             We all know that everybody 17 years and up


              8   has atherosclerosis already to some extent, that


              9   none of them, if taken apart by a pathologist,



             10   won't show atherosclerosis, and yet we don't say


             11   they have the disease, and we are willing to say


             12   that in even a 30-year-old or 40-year-old or


             13   50-year-old, lowering cholesterol is reducing a


             14   risk factor for cardiovascular disease even though



             15   they have it by any definition, that we all have


             16   some cardiovascular disease right now.


             17             So, I think drawing on that analogy,


             18   saying that reducing cartilage degeneration is a


             19   reduction in risk for developing osteoarthritis



             20   seems to be a fair parallel, and just as everybody


             21   with high cholesterol doesn't go on to develop an


             22   MI or need a bypass, everybody who has abnormal











              1   cartilage doesn't go on to need a knee replacement


              2   or whatever.


              3             So, I think we have a fair analogy to a


              4   situation that is already in place, and that if we



              5   start from there, we can move on to ask some of the


              6   more difficult questions about whether changes in


              7   evidence of this risk factor have anything to


              8   do--in diseased patients have anything to do with


              9   changes in patients who you would not have



             10   clinically said had the disease osteoarthritis.


             11             DR. MILLER:  Dr. Blonz.


             12             DR. BLONZ:  So, we keep coming back to the


             13   same point.  Are we dealing with, as soon as it's


             14   here, you have got the disease, or is it a process



             15   which can be thought of as a risk factor that


             16   basically puts you in queue to the point that all


             17   we are doing is waiting for you to report the


             18   symptoms and then get the radiographic


             19   confirmation, and then you are officially labeled,



             20   and the disease is put on your chart?


             21             So, we are dealing with terminology and


             22   subjectivity, not having the objective factors like











              1   we might have with coronary artery disease where we


              2   can measure this biomarker of cholesterol in the


              3   bloodstream.


              4             So, we are actually dealing with the



              5   second half of the question, the strength and


              6   weaknesses before we deal with the first half of


              7   the question.


              8             So, I will pose it, of course, to the


              9   experts in the field.  If we had a measure of joint



             10   deterioration prior to the reporting of


             11   symptomatology by the patient, if we had this


             12   marker, would this be something, if we could modify


             13   it, we could reduce the risk?


             14             DR. MILLER:  Isn't that one of the reasons



             15   the NIH study is being one?


             16             DR. LANE:  Yes.


             17             DR. MILLER:  Now, again, just throwing an


             18   idea on the table, it is perfectly possible for us


             19   to say that if the data was available, it is almost



             20   an arbitrary distinction, because we can't get away


             21   from the concept of a continuum, and if this is


             22   going to be useful, then, we may just have to say











              1   that.


              2             Dr. Lane.


              3             DR. LANE:  I would like to comment on


              4   that, two points.  One is I think there is a



              5   continuum that keep being jumped to, and I am


              6   concerned about it.  One is we know that if you


              7   have heart disease and your cholesterol is high,


              8   and you take the statin and you lower the


              9   cholesterol, and the disease slows down its



             10   progression, and that data led us then to looking


             11   at lowering cholesterol in people who didn't have


             12   clinical disease, and then found that, gee, it did


             13   prevent the onset of the clinical disease.


             14             But even though we know cardiovascular



             15   disease is a continuum, we have strong evidence to


             16   support now that lowering your cholesterol prevents


             17   an event of the clinical disease, and I feel


             18   strongly that we need to show that all we know, I


             19   know so far with the medications on the table, if



             20   you have disease, they do something, but we don't


             21   have anything on the preventive side, and your


             22   point is well taken that until we know what those











              1   markers or surrogates are to tell us disease is


              2   coming, we are just jumping into an unknown area.


              3             That is why I am a little concerned about


              4   making parallels.



              5             DR. ZEISEL:  There are lots of people with


              6   high cholesterol that don't get heart disease,


              7   there are lots of people with low cholesterol that


              8   go on and have MIs, it is just as uncertain, but


              9   somehow people have said they are willing to say



             10   that there is enough of a relationship that they


             11   are willing to use this imperfect biomarker, and I


             12   think cartilage degeneration is that similar thing.


             13             There are some things that don't exactly


             14   fit, that don't always follow, but, in general, you



             15   feel that a person is at higher risk if you come in


             16   and their cartilage is degenerating, of coming down


             17   with a clinical syndrome, and I think the same


             18   thing is true with cholesterol.


             19             Many people have very low cholesterol and



             20   go on to have heart attacks.  They have heart


             21   attacks for other reasons than cholesterol, and


             22   that may be true with OA.











              1             DR. MILLER:  Dr. Waslien.


              2             DR. WASLIEN:  I think we need to look at


              3   the history of the development of these two


              4   indicators to call an analogy with cardiovascular



              5   disease when it took us 20, 30 years to do the


              6   clinical lipid trials to prove that indeed lowering


              7   cholesterol would have an effect.


              8             I think we are at the stage of saying


              9   maybe reduction in cartilage will have an effect,



             10   but we don't have data to prove it.  So, to jump to


             11   the conclusion of saying, well, we will use this as


             12   a marker when we don't have the kind of many years,


             13   I mean the cholesterol history is 40, 50 years old,


             14   of knowing that people had elevated cholesterols,



             15   but not knowing if it made any difference.


             16             So, I think we are in that stage of saying


             17   yes, people have degenerated cartilage, but will


             18   changing that degeneration have any effect on


             19   osteoarthritis, I think those trials are needed



             20   before we can say anything.


             21             DR. MILLER:  Well, it is possible for us


             22   to say that there is a relationship, we don't











              1   understand it yet, and that once we get the data,


              2   it can be used, and to indicate we don't have the


              3   data yet.  I mean there are a lot of possibilities.


              4             The DRI Committee at the Institute of



              5   Medicine ran into this with the relationship


              6   between saturated fat and cholesterol.  The


              7   American Heart Association published a chart that


              8   showed the relationship between saturated fat in


              9   the diet and cholesterol, serum cholesterol, went



             10   to zero, in other words, you had some increase in


             11   cholesterol even at very low levels of saturated


             12   fat intake.


             13             They came to the conclusion that they had


             14   to make an arbitrary distinction, is it possible



             15   not to have saturated fat in the diet.


             16             Dr. Cush.


             17             DR. CUSH:  I would like to first caution


             18   everybody to stop talking about diseases which you


             19   know too much about, meaning like, you know,



             20   hyperlipidemia and stroke, because we have great


             21   models and, as was stated, many years of history,


             22   and we don't know that the analogy to











              1   osteoarthritis is going to be as clear.


              2             It seems logical, but it may, in fact, not


              3   be, and osteoarthritis may not be one disease, but


              4   may be several.  I mean, for instance, in lupus, a



              5   disease that we know a lot about, that we see a lot


              6   of it, but all of those patients have some degree


              7   of renal damage that one would pick up on biopsy,


              8   but yet there is only a small proportion of them


              9   with certain types of damage that will go to



             10   develop renal failure and outcomes there.


             11             Again, we have to be careful about


             12   extrapolation from other human models, and even


             13   animal models, that there is a gigantic leap of


             14   faith which makes us all the more uncertain.



             15             I think that cartilage and cartilage


             16   deterioration could be a surrogate marker for the


             17   disease, but the problem is that that is not


             18   something that is measure in daily routine


             19   practice.  We don't measure that, we don't examine



             20   that, I don't image that.  As we heard, there are


             21   lots of problems with quantifying and assessing


             22   cartilage damage even in well constructed trials.











              1             But I think we have to move on, because I


              2   think we have said this over and over that as Dr.


              3   Blonz said, if you have cartilage deterioration,


              4   you are in queue.  It is a risk factor for the



              5   development of disease.  I think that that is


              6   something that has been said over and over.  I


              7   don't know there is much disagreement with that at


              8   this point.


              9             So, I mean I think that question has been



             10   answered and we can move on.


             11             DR. MILLER:  Dr. Russell.


             12             DR. RUSSELL:  This is a question for the


             13   rheumatologists.  Is there some point along the


             14   continuum of joint deterioration where it becomes



             15   really much more likely that a person will develop


             16   osteoarthritis?


             17             I mean I realize you can have significant


             18   deterioration without developing the clinical


             19   syndrome, but is there some point along the



             20   continuum to say, well, this person is really


             21   likely to?


             22             DR. CUSH:  No.  You are asking for more











              1   certainty that has already been expressed, so no.


              2             DR. LANE:  Not only no, but what is


              3   surprising is if you take all the data we have, an


              4   x-ray, and everything else, and the people that you



              5   think should have it don't, and the people that


              6   have sometimes a more normal x-ray, when they go to


              7   surgery, et cetera, do.


              8             DR. RUSSELL:  Thank you.


              9             DR. MILLER:  Dr. McBride.



             10             DR. McBRIDE:  I have a little trouble with


             11   the analogy with the cholesterol, because, as a


             12   neurologist, if you have a stroke, it's a big deal,


             13   and it is not the same kind of a continuum as


             14   osteoarthritis.



             15             We are a little bit bogged own here with


             16   semantics, but if you look at the FDA definition of


             17   a modifiable risk factor, which is what we are


             18   being asked, it is a measurement of a variable


             19   related to a disease that may serve as an indicator



             20   or predictor of that disease.


             21             If we all agree that by the time you have


             22   pain and dysfunction that you have the disease, it











              1   is hard not to call cartilage deterioration a risk


              2   factor.  Certainly, it would not be ignored in any


              3   kind of early studies looking at prevention.  I


              4   mean there is a whole other question of whether or



              5   not modifying it during the disease means that you


              6   can modify the risk.  We have to take that up.


              7             DR. MILLER:  Dr. Krinsky.


              8             DR. KRINSKY:  I agree with Dr. McBride,


              9   with her comments, but the thing that concerns me



             10   about the cholesterol/cardiovascular disease


             11   analogy is that I don't see where we have a


             12   cholesterol, and lacking a cholesterol, the analogy


             13   fails, so that unless there is an appropriate


             14   biomarker for determining the moment or, at some



             15   time, the extent of your cartilage deterioration,


             16   how does one evaluate this short of having a


             17   patient wait a week, a month, a year before they


             18   report pain.  I don't see whether you can evaluate


             19   that.



             20             DR. MILLER:  Well, just a matter of


             21   clarification, it would seem to me that there is no


             22   reference to a time scale here, in other words, how











              1   long after you have identified joint degeneration


              2   do you have to develop full-blown osteoarthritis


              3   for that to be a reasonable relationship.  I don't


              4   see that.  All you have to do is be able to



              5   ultimately show that there is some relationship no


              6   matter how slow the rate may be.


              7             Dr. Harris.


              8             DR. HARRIS:  I would like to return to Dr.


              9   Miller's point regarding the possibility that we



             10   may be diagnosing something that is not related to


             11   arthritis or may not have the same outcome.


             12             In preparing for this meeting, I did do


             13   some reviewing of the literature that basically the


             14   question of could there be other factors involved,



             15   and one thing that struck me very unusually was a


             16   condition called Wilson's disease in which there is


             17   actually an accumulation of copper in the joints


             18   that leads to swelling, and so forth.


             19             I was hoping to find papers that would



             20   suggest that Wilson's disease is indeed a very good


             21   predictor or people who suffer that disease are


             22   going to be perhaps coming down early with











              1   arthritis.  I could not find that evidence, but it


              2   does indicate that there could be other mitigating


              3   factors here other than just one case we are


              4   dealing with two different diseases and mixing the



              5   two of them together may be the wrong thing to look


              6   at.


              7             DR. CUSH:  Wilson's disease is just like a


              8   car accident or whatever provokes the cartilage


              9   insult.  The deposition of copper in the cartilage,



             10   it is the first event that leads to its


             11   deterioration.  It is the same as other deposition


             12   diseases or other forms of secondary


             13   osteoarthritis.


             14             DR. HARRIS:  Yes, I think that was the



             15   point I was trying to make, that there could be


             16   other factors.  Perhaps this is addressing the


             17   question of the etiology, but it is also addressing


             18   the question of a misdiagnosis.


             19             DR. MILLER:  Dr. Kale.



             20             DR. KALE:  Yes, I am one of the proponents


             21   of the LDL/osteoarthritis analogy, and I still


             22   think that it holds, and I think it holds to a











              1   reasonable degree of medical certainty, because the


              2   final common pathway, again necessary but not


              3   sufficient, in the development of osteoarthritis


              4   has to be some degeneration of cartilage whether



              5   the degeneration is primary or secondary as in the


              6   case hemochromatosis or Wilson's disease or trauma


              7   or infection or rheumatoid disease, whatever it


              8   happens to be.


              9             if there is a reasonable likelihood that a



             10   product, call it glucosamine or chondroitin


             11   sulfate, can preserve the cartilage and reduce its


             12   likelihood to a reasonable degree from degenerating


             13   and becoming a sufficient, unfortunately, as well


             14   as necessary, cause of the syndrome of



             15   osteoarthritis, if you can prevent that, then, it


             16   strikes me it has the same status, without meaning


             17   to demean it, as walnuts.  It is a modifiable risk.


             18             You modify the risk of osteoarthritis by


             19   providing a dietary product that seems to work



             20   beneficially on cartilage to preserve it.  In that


             21   sense, once again, I would retreat back to the


             22   analogy as being reasonable.  Walnuts is to LDL as











              1   chondroitin or glucosamine is to cartilage.


              2             DR. CUSH:  That latter point, I mean you


              3   now have ventured into the proof of intervention


              4   having an effect on the biomarker and outcome.



              5             DR. KALE:  What I am trying to do is say


              6   that there is a modifiable risk factor, and that is


              7   cartilage, probably, and I agree with what you said


              8   earlier, that if you can make a reasonable


              9   assumption, I think this is still reasonable, based



             10   on clinical data, I mean obviously we haven't got


             11   the sort of data you have for--there is not a


             12   generation of data as there is for cholesterol.


             13   So, the best one can do under the circumstances.


             14             The other point I would make, by the way,



             15   it seems to me, because I am old enough to remember


             16   this, that coumadin and linoxin, these are drugs


             17   that were never tested, we simply believe they


             18   worked in the patient populations for whom we used


             19   them, and we continue to do so, and that is a



             20   reasonable presumption, and it seems to be a


             21   reasonable presumption.


             22             I am making a similar reasonable











              1   presumption about this particular product.


              2             DR. MILLER:  Well, we have to be careful


              3   using drug examples.  The standard for evaluating


              4   drugs is different than the standard for evaluating



              5   foods.


              6             DR. KALE:  Okay.  Vitamin D to rickets.


              7             DR. MILLER:  All right.  I will buy that.


              8             Dr. McBride.


              9             DR. McBRIDE:  I was just going to, in



             10   answer, say that we are not trying to say that this


             11   is the only risk factor, but it is a risk factor.


             12   The question is, is it a risk factor.  We are not


             13   even asked to say is it modifiable, that is a whole


             14   other question, but we are being asked is it a risk



             15   factor.


             16             It seems like to me it would be hard to


             17   say that it is not.


             18             DR. MILLER:  Dr. Archer.


             19             DR. ARCHER:  I just need some



             20   clarification on a point.  I thought I heard Dr.


             21   Cush say that in the diagnosis, he didn't diagnose


             22   it radiologically, in which case, I am now talking











              1   about deterioration of cartilage.


              2             If that is the case, are we talking about


              3   joint space reduction, which is kind of one step


              4   back, so we are looking at a predictor of another



              5   predictor?  So, I am getting a bit confused as to


              6   what it is we are actually talking about here.


              7             If cartilage deterioration is something


              8   that you really don't know about until the patient


              9   presents with symptoms in most cases, is that a



             10   predictor, or is it a reasonable predictor?


             11             DR. MILLER:  Dr. Abramson.


             12             DR. ABRAMSON:  I guess that comes back to


             13   our fundamental discussion, is Alzheimer's disease


             14   a disease before a person is overtly demented, or



             15   is it a pathological event that happens over time,


             16   the signal for which symptomatologywise, we see


             17   towards the end stage of that process.


             18             Again, I think, and we have different


             19   views, I think the LDL may not be a good analogy



             20   because it is truly a surrogate marker of a process


             21   that leads to damaged tissue, and one of the


             22   reasons that there is discrepancies as to whether











              1   lowering or not is helpful, is it may be not even a


              2   true marker of the disease, but a surrogate for


              3   something else that a statin is doing, for example,


              4   whereas, fibrillated cartilage arguably is the



              5   earliest phase of the disease that we call


              6   osteoarthritis, like the first plaque in the brain


              7   of someone who is going to get Alzheimer's disease.


              8             I would be certainly willing to say it is


              9   a necessary event along the pathway that ultimately



             10   leads to clinical symptoms, but kind of the


             11   medieval discussion we are having now is, is this


             12   the disease or is it a marker of the disease.


             13   Perhaps that has some legal ramifications with


             14   regard to the charge to the committee because I



             15   would argue that it is not normal joint, it's the


             16   first event in a very protracted process, and that


             17   process where we are struggling in the field is to


             18   figure out, even if we jump beyond the histology


             19   and we jump to the imaging and biomarkers, trying



             20   to predict who is going to get the disease, knowing


             21   the earliest markers, has led to a lot of


             22   surprises.  Things that we think are going to











              1   predict bad outcome tend not necessarily to be the


              2   case.


              3             So, I think, you know, just to come back,


              4   I think it is how we define earliest phase of



              5   disease versus a marker of that disease when we are


              6   in the tissue itself that we are kind of having a


              7   debate over.


              8             DR. MILLER:  Dr. Dwyer.


              9             DR. DWYER:  I just wanted to make sure I



             10   had understood what particularly the


             11   rheumatologists had said.


             12             Are you saying that cartilage


             13   deterioration and joint degeneration are risk


             14   factors of disease, the first step in a protracted



             15   process that may or may not be modifiable?  In


             16   other words, is the argument really over whether


             17   there is modification, everybody agrees that there


             18   is a risk factor?


             19             DR. ABRAMSON:  I guess what I am saying is



             20   that the earliest phase of a disease--the disease


             21   has a set of histological changes that a


             22   pathologist will differentiate, hemochromatosis,











              1   you know, OA from RA, from earliest phases of these


              2   diseases, you can determine by pathological


              3   criteria.


              4             Just having that earliest phase of



              5   fibrillation or fissuring, which is what they early


              6   see, the deterioration, it doesn't predict that


              7   that patient is going to develop clinical symptoms,


              8   and people follow different courses. Understanding


              9   why some people follow different courses, I think



             10   is the challenge in this particular field, but the


             11   disease arguably starts with these earliest


             12   classical changes of osteoarthritis.


             13             DR. DWYER:  So, it goes back that it is


             14   necessary, but not sufficient.



             15             DR. MILLER:  Dr. Blonz.


             16             DR. BLONZ:  So, I am looking at the


             17   semantics of the Question No. 1.  If this were


             18   worded is a degenerated joint a state of health,


             19   that is very different than joint degeneration.



             20             Similarly, is a deteriorated cartilage,


             21   then it is a fait accompli, so we know there is a


             22   homeostasis going on within the joint milieu where











              1   you end up getting synthesis and degradation


              2   hopefully in balance, but as soon as that turns


              3   into a negative where you have more degeneration


              4   than resynthesis, you have the process of



              5   degeneration or deterioration in the joint and in


              6   the cartilage.


              7             When this progresses to the point where


              8   you have a change that could be identified


              9   histologically or symptomatically, then, you would



             10   end up getting this diagnosis.


             11             So, if we can look at the process and then


             12   take the step forward, is this a process that once


             13   it begins, once you have got that negative going


             14   on, can this be modified prior to the diagnosis of



             15   osteoarthritis, then, we may be able to step


             16   forward and to answering 1(a) and 1(b).


             17             DR. MILLER:  Dr. McBride.


             18             DR. McBRIDE:  I again just keep coming


             19   back to the issue, the semantics of the earliest



             20   joint degeneration or cartilage deterioration,


             21   whether or not that is a disease, I don't think we


             22   are going to be able to answer, but the question is











              1   can you imagine that if you have 100 people


              2   with--and you name the measurement, however it can


              3   be measured--that show cartilage degeneration and


              4   100 who do not, is it too big a leap in faith to



              5   say that the 100 who have it are at higher risk for


              6   osteoarthritis?  That is what a risk factor is.


              7             DR. MILLER:  Dr. Nelson.


              8             DR. NELSON:  A question for the


              9   rheumatologists.  Is an individual with clear



             10   anatomic signs of deterioration and change, but


             11   expresses no pain or says he or she has no pain, is


             12   that person in a healthy state?


             13             DR. CUSH:  Go ahead.


             14             DR. ABRAMSON:  Well, yes, they can



             15   certainly be in a healthy, functional,


             16   non-disease--that is a difficult issue.  That


             17   depends on how you define health.  That is why I


             18   would argue that joint degeneration is not normal


             19   age matched, in other words, you may have the



             20   disease, but not have symptoms of the disease.  It


             21   is not a normal state for your cartilage.


             22             Now, whether you are a normal person, to











              1   the extent that most of us may have some OA and


              2   like to think ourselves as normal healthy


              3   individuals, I mean is another kind of discussion.


              4             DR. CUSH:  So, to answer your question, in



              5   Dr. Abramson's lab, he can have a age matched


              6   individual who has no symptoms, but may have some


              7   joint degeneration or may have none at all.


              8             But you can also have someone who has


              9   joint degeneration, whatever that may be, and no



             10   symptoms, and that person can have what we call a


             11   neuropathic joint or Charcot joint due to syphilis.


             12   Obviously, that is not a good state of health.


             13             I strongly dislike the term joint


             14   degeneration because of the vagueness of it and the



             15   multitude of inputs that may lead to it, you know,


             16   land mine gout, rheumatoid arthritis, syphilis,


             17   whatever, all lead to joint degeneration.  I would


             18   not want the FDA to be joined to that term for


             19   these proceedings, but that is my impression.  I



             20   would ask the chairman to address these points


             21   maybe directly at each of the rheumatologists, and


             22   then see if we can move on or not.











              1             DR. ESPINOZA:  Just to confuse you some


              2   more, you know, we made the diagnosis routinely of


              3   osteoarthritis in individuals, they are totally


              4   asymptomatic now.  That is routinely.



              5             DR. MILLER:  Dr. Cush, would you argue


              6   that cartilage deterioration has the same problem?


              7             DR. CUSH:  No, because as Dr. Abramson


              8   pointed out, cartilage deterioration is the


              9   pathognomonic finding, maybe the earliest finding



             10   that sets off the cascade that leads to


             11   osteoarthritis.  I think it has a specificity


             12   attached to it that is appropriate to these


             13   proceedings.


             14             DR. MILLER:  So, for Question 1, would you



             15   agree--I will just lay this on the table--that


             16   there is a consensus that joint degeneration is not


             17   a state of health leading to the disease,


             18   modifiable risk factors, and cartilage


             19   deterioration is?



             20             DR. CUSH:  That is how I would


             21   characterize it.  As I stated earlier, I think that


             22   if one has evidence of cartilage deterioration, as











              1   Dr. Blonz said, you are in queue and you are at


              2   risk although it is not certain that you will get


              3   there, at least you are at risk.


              4             It appears that it may be modifiable, yes.



              5             DR. MILLER:  I am just probing the depths


              6   of your belief.


              7             Ms. Halloran.


              8             MS. HALLORAN:  It sounds like--so we do


              9   have consensus that joint degeneration is not a



             10   state of health, et cetera, and that cartilage


             11   deterioration is, and we can perhaps go on to what


             12   are the strengths and limitations of the evidence.


             13             We, I think have consensus that cartilage


             14   is necessary, but not sufficient, that there may be



             15   other factors, precipitating factors that lead to


             16   disease, which are as yet unidentified and that the


             17   entire population actually falls over a certain


             18   age, falls into the people, the group at risk, so


             19   that identifying this risk pool, there may be



             20   limitations on its usefulness.  At least that is


             21   what I would say.


             22             DR. MILLER:  Dr. Lane.











              1             DR. LANE:  I just wanted to clarify


              2   something for the record.  I actually think, you


              3   know, I agree with cartilage deterioration, that is


              4   probably the best we can do, but we have to be very



              5   careful because you would think that we would have


              6   clear evidence that slow cartilage degeneration


              7   would modify the disease and both, for the most


              8   part, in clinical trials and otherwise, we don't


              9   have that, but  I believe that I have faith in



             10   that, but that is what it is, it's faith because


             11   our multiple examples came up yesterday, and will


             12   continue to, that by slowing it, we haven't changed


             13   things.


             14             DR. MILLER:  Dr. Mehendale.



             15             DR. MEHENDALE:  I wanted to reinforce the


             16   same concept that Dr. Lane just said, and that is


             17   the implication of disease if we accept that


             18   cartilage deterioration is pathognomonic.  What I


             19   heard was to about a third of the patients.



             20             We could also say it is not pathognomonic


             21   for two-thirds of the people.  So, we are still


             22   trying to protect the one third where it could be











              1   pathognomonic.  The other side of this is we make


              2   an assumption that there is something we could


              3   overcome by supplementing with these substances in


              4   the third where it is pathognomonic.  I think the



              5   concept that Dr. Lane just said.  I just wanted to


              6   reinforce.


              7             DR. MILLER:  Dr. Abramson/


              8             DR. ABRAMSON:  We are making some


              9   progress, but I would like Dr. Rowlands now,



             10   because we are not coming down to the language, I


             11   am not fully sure I understand.


             12             How do we define, what is meant by


             13   cartilage deterioration and what is the distinction


             14   between that and cartilage degeneration?



             15             DR. ROWLANDS:  These were specifically


             16   worded by the petitioners.  That is how we chose


             17   these terms.  FDA did not come up with these terms,


             18   but they have been used in the literature, and this


             19   is the language that they wanted in the claims, so



             20   that is why they were actually worded this way.


             21             DR. ABRAMSON:  I hate to beat a dead horse


             22   here, but I don't understand--maybe Dr. Cush who











              1   did make a differentiation--I am not sure that I


              2   understand if we agree to one and not the other,


              3   what is the distinction that we are being asked to


              4   make by the petitioner.



              5             DR. ROWLANDS:  These are specifically


              6   written as separate questions, so that if you can


              7   agree to one and not the other, that is fine.  You


              8   don't have to link them together.  They are written


              9   specifically to be separate, so that you can



             10   actually conceptually deal with them separately if


             11   you wish, that's fine.


             12             DR. CUSH:  I would respond by saying that


             13   it was written, in 1(a), the more pedestrian sort


             14   of terminology that, you know, something may be



             15   good for joint health and protecting its joint


             16   degeneration, and whatever, and that is again a


             17   very lay person's view of what is obviously a much


             18   more complex issue, as I indicated with may


             19   analogies and why I wouldn't want that.



             20             I think that nonetheless, the lay public


             21   has some knowledge of cartilage as being involved


             22   here, and that may be the target of therapies and











              1   interventions, so to use that also.


              2             I think it would obviously be much more


              3   advantageous to any product out in the public


              4   domain to have the more generally accepted, more



              5   widely recognized terminology albeit misleading.


              6             DR. MILLER:  Does that clarify the


              7   situation for you as much as it is going to?


              8             Dr. Blonz.


              9             DR. BLONZ:  Let me pose the question then.



             10   If you have cartilage deterioration, do you not


             11   also have degeneration of the joint?


             12             DR. CUSH:  Yes, and the converse, no.


             13             So, my statements go to is it a modifiable


             14   risk factor or surrogate endpoint of OA risk



             15   reduction.


             16             What we learned yesterday and what we know


             17   from the literature is that weight reduction is a


             18   modifiable risk factor for osteoarthritis, certain


             19   occupational adjustments are modifiable risk



             20   factors.  What wasn't stated, but probably is true


             21   from other lines of evidence, is that control of


             22   inflammation would be a modifiable risk factor for











              1   OA progression.


              2             What we don't know is changes in this


              3   parameter as modifiable risk factor for OA


              4   reduction.



              5             DR. MILLER:  Dr. Lane.


              6             DR. LANE:  I want to just make a point for


              7   the record.  A modifiable risk factor is actually


              8   one that you have tested and the evidence is


              9   strong, evidence meaning a randomized controlled



             10   trial or a couple population studies.


             11             Weight loss has never--there is one


             12   epidemiologic study in OA from Framingham that


             13   shows that people who lost 12 pounds over five


             14   years had less knee pain.  There has never been a



             15   randomized controlled trial showing that weight


             16   reduction change joint degeneration, i.e.,


             17   cartilage narrowing or pain.


             18             So, we use modified risk factor, that


             19   would assume that there is some very strong



             20   evidence behind it.  We all believe that weight


             21   loss is going to help, but it has never been shown,


             22   so careful, careful.











              1             DR. MILLER:  I think if you read the


              2   question, there is a way of dealing with that.


              3   There is really two questions that are being asked.


              4   One, are they modifiable risk factors, and, two,



              5   what is the evidence to support it.


              6             I think it is perfectly possible to say


              7   that yes, it's a modifiable risk factor, but the


              8   evidence isn't strong or whatever.


              9             DR. LANE:  I agree.



             10             DR. MILLER:  Dr. Zeisel.


             11             DR. ZEISEL:  Why don't we just try to move


             12   forward and say that we have some consensus that


             13   cartilage deterioration is a modifiable risk


             14   factor, but the evidence for it is not particular



             15   strong.


             16             DR. MILLER:  We are coming to that.  I


             17   just want to make sure that everybody feels that


             18   they have had a chance to express their views.


             19             Dr. McBride.



             20             DR. McBRIDE:  It sounds like part of the


             21   difficulty we are having is with the word


             22   "modifiable."  Actually, in the definition of risk











              1   factor or at least in the first part of that


              2   definition, that word "modifiable" doesn't appear.


              3             I am sure we are probably not allowed to


              4   change the question, but if we put the word



              5   "potentially," would that help?


              6             DR. LANE:  I would say yes because, you


              7   see, where we are at here is pathologically, and I


              8   don't even know if Steve and I know the answer to


              9   this, if you have a little bit of cartilage



             10   narrowing, that may mean already that your


             11   cartilage is going, and even though you might lose


             12   50 pounds, your cartilage is still going to go.


             13             So, it is potential.


             14             DR. MILLER:  I think one point that would



             15   be worthwhile re-emphasizing again is that this,


             16   like most biological processes, are multifactorial,


             17   there are a number of factors that are certainly


             18   going to affect the outcome.


             19             From what I understand, and naively



             20   listening to the discussion over the last two days,


             21   that there isn't enough data to be able to really


             22   define what these multiple factors, how they











              1   interact, et cetera.


              2             I think as far as being able to say


              3   potentially, we could say whatever we want.  We


              4   don't have to modify the questions.  We just have



              5   to say yes, cartilage deterioration is a state of


              6   health leading to disease or is a potential


              7   modifiable risk factor, so we can just lay that out


              8   any way we see fit.


              9             Dr. Zeisel.



             10             DR. ZEISEL:  So, the argument is not that


             11   it's modifiable, we clearly saw evidence that you


             12   can modify cartilage deterioration, make it go up


             13   or down, what the argument is, is whether that


             14   modification has anything to do with delay of the



             15   onset of OA.


             16             DR. MILLER:  Right.


             17             DR. ZEISEL:  So, it is a modifiable risk


             18   factor, and the strength of evidence that it


             19   modifies OA is weak, but there is no question that



             20   you could modify cartilage because we have seen


             21   that you can have more or less.  It may not be


             22   perfect cartilage, but that is for an argument.  It











              1   certainly is a modifiable factor just like taking


              2   cholesterol down or up can be done, or taking


              3   atheromas up or down can occur.


              4             So, I think it has to be a modifiable risk



              5   factor, it just may not modify the risk for


              6   osteoarthritis, which is a different question,


              7   which is where the scientific evidence comes in.


              8             DR. MILLER:  Right.


              9             Dr. McBride.



             10             DR. McBRIDE:  Well, I don't think we heard


             11   very much evidence that it is modifiable in the


             12   pre-disease state with disease defined as symptoms.


             13             DR. MILLER:  Again, I think the issue is


             14   we can agree that cartilage deterioration is a



             15   modifiable risk factor or potentially a modifiable


             16   risk factor, modifiable potential risk factor, but


             17   we don't necessarily have to say that there is any


             18   evidence that there is anything that does that.


             19   That is a different question.



             20             So, can we agree that a distinction can be


             21   made between joint degeneration and cartilage


             22   deterioration in the context of this question, and











              1   that we can argue that joint degeneration is not a


              2   modifiable risk factor, and cartilage deterioration


              3   is a modifiable risk factor?


              4             DR. CUSH:  Only in terms of OA risk



              5   reduction, because again, joint deterioration is a


              6   modifiable risk factor for a lot of different


              7   things, and this is what my career is based on.


              8   You know, I am trying to modify joint deterioration


              9   through things that we do to treat, but I treat



             10   over 100 different types of arthritis, so here


             11   today we are talking about osteoarthritis.


             12             DR. MILLER:  Okay.  By the way, just to


             13   make sure everybody understands, these discussions


             14   will be reflected in the report, in the transcript



             15   of the report.


             16             DR. CUSH:  Oops.


             17             [Laughter.]


             18             DR. MILLER:  Just trying to help you out.


             19             I think we have discussed the strengths



             20   and limitations of the scientific evidence on this


             21   issue to some extent.  Does anybody want to add any


             22   comment to that?











              1             So, we have a consensus on Question 1?


              2   Okay.


              3             Question 2.  I have to admit that I have


              4   trouble trying to make a distinction between



              5   Question 1 and Question 2 here.


              6             DR. CUSH:  Mr. Chairman, I would like to


              7   suggest that Dr. Zeisel's sort of summary comment


              8   is probably the most accurate.


              9             DR. MILLER:  Fine.



             10             DR. CUSH:  That again, that it is a


             11   potentially modifiable risk factor, but that the


             12   association with--that it may alter OA risk


             13   reduction is questionable.


             14             DR. MILLER:  We will take your comment



             15   from the transcript, and we will take it verbatim.


             16             DR. ROWLANDS:  Take away my translation,


             17   so now you only have the question.


             18             DR. MILLER:  This again comes to the


             19   question of how to define a generally healthy



             20   population.  I think we have discussed that at


             21   great length.


             22             Do anybody else have any further comments











              1   to make on this issue?


              2             DR. ZEISEL:  So, here, the only issue that


              3   came up yesterday is are there normal joints in


              4   patients with OA, that the study of which would



              5   give you data that has to do with deterioration in


              6   "normal" individuals, or is having OA in one joint


              7   enough to indicate that all the other joints are OA


              8   joints, because I think we all agree that studies


              9   in an OA patient do not accurately predict in their



             10   OA knee, for instance, that a treatment that might


             11   mitigate the already osteoarthritic knee's


             12   progression might have nothing to do with the


             13   incipient disease's progression earlier.


             14             But the question is are in their otherwise



             15   not diagnosed joints, do they have OA or are they


             16   incipient OA, and therefore, you could use data in


             17   a study that used OA patients, but you could not


             18   use the OA knee, but rather the control knee.


             19             DR. MILLER:  Dr. Lane.



             20             DR. LANE:  Unfortunately, the studies that


             21   are there, and one of them was actually just


             22   NIH-funded and completed rather recently, the data,











              1   the answer is we don't have that data, and probably


              2   that data will take another five to seven years at


              3   best to accumulate.


              4             A very large study was done, I mentioned



              5   yesterday, where people who seemingly had a normal


              6   knee were treated with an agent that was to prevent


              7   OA, but they didn't get OA, the controls didn't get


              8   OA, so we don't have that data, unless you guys


              9   know that.



             10             DR. MILLER:  Dr. Cush.


             11             DR. CUSH:  No, I think that again we are


             12   talking about the development of OA in the


             13   contralateral meaning of the person who has an


             14   index OA, let's say, on the right side, but not on



             15   the left, and then would some intervention prevent


             16   the normal knee from developing disease, and that


             17   is the kind of research we need to look at, and


             18   that is very important research.


             19             I think getting to this question, the



             20   language of a dietary substance treating,


             21   mitigating, or slowing joint degeneration again


             22   does sound like that used for a drug, and not for a











              1   dietary supplement, but nonetheless, the question


              2   is, is it valid to use such research to suggest a


              3   risk of OA in the general population being reduced


              4   if that dietary substance is applied, I think only



              5   if there is research to that effect, because we


              6   learned yesterday that, you know, that the


              7   chondrocyte is different at different stage of the


              8   disease, and how it functions, and most of these


              9   trials about changing joint deterioration of



             10   cartilage deterioration thus far have been focused


             11   not on people at risk, or on normal people, but


             12   instead, have been focused on people who have the


             13   disease, well-established disease.


             14             And to say that the cartilage would behave



             15   the same in a normal person, or a person who has


             16   risk factors, whether that be a genetic risk


             17   factor, or a traumatic risk factor, or a copper


             18   deposition risk factor is really unknown, and I


             19   think that is again a gigantic leap of faith for



             20   which I can't connect the dots.


             21             DR. MILLER:  Dr. Blonz.


             22             DR. BLONZ:  So, you if we read Question 2,











              1   there is an assumption that that data is in hand.


              2   If we assume that research demonstrates that this


              3   has this effect, granted we don't have that data


              4   right now, but if that research existed, would show



              5   that the substances at question could produce this


              6   desired effect, would we run with it, and that is


              7   really what we are being asked to by this question.


              8             DR. CUSH:  The question states, Dr. Blonz,


              9   in OA patients, if it produced that desired effect



             10   in OA patients, would it then be reasonable to


             11   extrapolate that to a normal healthy population.


             12             DR. MILLER:  If we could define what that


             13   normal healthy population is.


             14             DR. CUSH:  All of us, for instance.



             15             DR. MILLER:  That's pushing it.


             16             Dr. Abramson.


             17             DR. ABRAMSON:  I think just to pick up on


             18   those two points, I mean we do have data that was


             19   presented by the applicants yesterday that in real



             20   disease, in OA, there may be some slowing of


             21   progression using these compounds, but I think that


             22   is based on data and the notion of what is going on











              1   in the diseased tissue, that, as Dr. Cush says,


              2   might not be applicable to very different


              3   circumstances in normal tissue.


              4             I think that we have some little evidence,



              5   and Dr. Lane referred to one of the NIH studies was


              6   a study looking at doxycycline where it was looking


              7   for the development of OA in the contralateral


              8   knee, beginning with an index knee which was


              9   diseased, in patients who were likely to progress,



             10   and the unexpected outcome was that the


             11   doxycycline, which its mechanism of action is based


             12   on many of these events that we were talking about


             13   yesterday, protected the knees from progressing


             14   where those events were occurring in the signal



             15   knee, but the primary outcome was that it might


             16   also prevent progression in the high-risk,


             17   relatively normal knee on the opposite side, and it


             18   had no effect on the osteoarthritis in the


             19   contralateral knee.



             20             If the data are correct, it tells us that


             21   interfering with processes in the disease doesn't


             22   affect normal chondrocytes from developing











              1   osteoarthritis, and I think that is a very


              2   important study in that regard.


              3             DR. MILLER:  That is an important study.


              4             Dr. Nelson.



              5             DR. NELSON:  Dr. Abramson basically


              6   addressed my question, which was about the


              7   contralateral knee that didn't show any anatomical


              8   indication, or even if it did show anatomical


              9   indication, would these agents slow or retard the



             10   issue.


             11             In the study you cited, did the


             12   contralateral knee have anatomical indication, or


             13   were they clean knees, so to speak?


             14             DR. ABRAMSON:  It's a good question.  With



             15   doxycycline, as I recall the study, it had either


             16   no evidence or early evidence.  They were not


             17   clearly clean knees, though, but they were


             18   significantly better and sometimes had minimal


             19   signs of osteoarthritis.



             20             DR. MILLER:  Dr. Downer.


             21             DR. DOWNER:  I would like to go back.  We


             22   are being asked to use the data, use it as











              1   implications for the general healthy population,


              2   and I guess we really still do need to define what


              3   that is.


              4             You say that it is probably all of us



              5   perhaps, and the question really is at what point


              6   or how do we actually diagnose or say this is a


              7   healthy population, is it a population of


              8   absolutely free from OA, from the signs of it, from


              9   the precursors of it, at what age or to what stage



             10   do we really define that, since the implications


             11   here are for the healthy population in fact?


             12             DR. MILLER:  Jean.


             13             MS. HALLORAN:  To respond to that point,


             14   it seems like we are talking about healthy



             15   population could refer to two kinds of healthy


             16   population, the younger one that has no signs of


             17   cartilage deterioration, or the older ones that


             18   have signs, but yet no pain or symptoms of disease,


             19   but it seems pretty clear from our experts that you



             20   can't extrapolate to either of these healthy


             21   populations from the population with disease.  So,


             22   it sounds like the answer to this question is no.











              1             DR. MILLER:  Dr. Russell.


              2             DR. RUSSELL:  Going back to the question


              3   about whether a normal population would respond the


              4   same way in a disease population, there was a



              5   misstatement yesterday actually by one of the


              6   presenters on the finger joint osteoarthritis


              7   issue, because I looked at that trial last night.


              8   It was a double-blind, placebo-controlled trial


              9   using chondroitin sulfate, looking at the



             10   progression of finger joint arthritis, as well as


             11   new joints that would be involved.


             12             When compared with the placebo controls,


             13   none of the chondroitin sulfates prevented OA from


             14   occurring in previously normal finger joints, that



             15   is, they progressed in other finger joints whether


             16   or not the person was on placebo or not.


             17             However, the classic OA associated


             18   anatomical lesions, when they were considered, OA


             19   was less progressive in the treatment group, so



             20   there was a response, in other words, or a


             21   treatment effect in the people who had established


             22   OA, but not in formerly normal joints, there











              1   weren't.


              2             DR. LANE:  Thank you for that


              3   clarification.


              4             DR. MILLER:  Dr. McBride.



              5             DR. McBRIDE:  I was just going to say that


              6   I think the issue of semantics of when the disease


              7   starts is less important here, partially for the


              8   reasons that you stated, but we are asked to


              9   assume, in a sense, this question creates the



             10   assumption that we are talking about


             11   pre-symptomatic joint, but that already have


             12   cartilage degeneration, and the issue is we haven't


             13   heard any evidence that that is modifiable by these


             14   substances.



             15             DR. MILLER:  Dr. Zeisel.


             16             DR. ZEISEL:  So, let's be careful.  We are


             17   not being asked here to decide whether glucosamine


             18   or chondroitin sulfate has anything to do with


             19   this.  We are just being asked can you design a



             20   study in patients who have osteoarthritis, that


             21   could shed light on the question about joint


             22   development in normal people.











              1             We heard really two types of answers, Dr.


              2   Cush saying no, they are never normal, and right


              3   after that, Dr. Abramson saying, well, in the


              4   doxycycline study it didn't work, showing that



              5   normal joints or relatively normal joints don't


              6   respond the same as diseased joints, and in that


              7   case, I would interpret that as saying that you can


              8   use the contralateral knee or another joint in that


              9   person to draw some inference about what would



             10   happen in the less developed or relatively normal


             11   joint.


             12             I think we can't have it both ways, and we


             13   don't have to get into whether anybody presented us


             14   any data that has to do with chondroitin or



             15   glucosamine in normal joints or in osteoarthritic


             16   contralateral knees.  We just have to ask


             17   ourselves, for any treatment whatsoever, would we


             18   use other joints in people who have a single joint


             19   involved.



             20             It seems to me we are hearing several


             21   answers, and we should resolve that.


             22             DR. MILLER:  That is a very important











              1   point.  We are not evaluating the petitions or any


              2   other data that suggested any one particular


              3   compound, whether it is the two that happened to be


              4   the focus of the petitions here, or any other that



              5   might come up in the future.


              6             We are just trying to give the agency some


              7   advice, so they can develop standards that could be


              8   used for any material for which such claims are


              9   going to be made.  Good point.



             10             Dr. Kale.


             11             DR. KALE:  No.


             12             DR. MILLER:  Dr. Lane.


             13             DR. LANE:  Yes.  I think in the spirit of


             14   giving advice, where I feel that we have come to a



             15   stop sign or a stoplight, and we haven't gotten the


             16   green light yet, and that is, that the reason that


             17   I have a level of discomfort saying if you have OA


             18   in one knee, if the other knee is normal, follow


             19   that for the development of disease is because



             20   probably the other knee isn't normal, but that is


             21   because when I take an x-ray, it looks normal, but


             22   when I use a better technology, which the field as











              1   you heard yesterday is starting to embrace, and


              2   that is MRI, and some fancy aspects of the MRI


              3   where you can use gadolinium and sodium, and get


              4   information about the chondrocyte metabolism and



              5   the inflammation, and how much proteoglycan there


              6   is, when we start to use those imaging modalities,


              7   we will probably be better able to say what is


              8   normal and what is a little diseased or a lot


              9   diseased, but we can't do that with x-rays.



             10             Does that make some sense to everybody


             11   right now?  So, the state of the art running a


             12   clinical trial doesn't give us the information we


             13   need to say what is normal or abnormal.  Hopefully,


             14   in terms of advice to the agency, that these



             15   initiatives, that they are really driving it, using


             16   MRI to try to distinguish what is disease and what


             17   isn't disease, we will be able hopefully to do


             18   that.


             19             That's my comment.



             20             DR. MILLER:  Is it fair to say--I am just


             21   trying to clarify this in my own mind--is it fair


             22   to say that in studies that looked at purportedly











              1   normal tissue and diseased tissue, that the


              2   response to the test materials was different?


              3             DR. LANE:  Yes, with the caveat that using


              4   an x-ray outcome, that's right, using the x-ray



              5   outcome.


              6             DR. MILLER:  Using the tools that we have


              7   available.


              8             DR. LANE:  That's right.


              9             DR. MILLER:  Because that is a distinction



             10   because we could say, for example, and I don't know


             11   if we would get a consensus on this, that the


             12   answer to this question is no, that based on


             13   currently available data, there is no evidence to


             14   suggest that one could be used to extrapolate to



             15   the other.


             16             DR. LANE:  Yes, I agree.


             17             DR. MILLER:  I am just laying this out for


             18   everybody, because consensus means everybody.


             19             Dr. McBride.



             20             DR. McBRIDE:  Yes, I would agree with


             21   that.  I mean we are being asked is it


             22   scientifically valid to use the results of











              1   treatment trials to suggest that you can prevent,


              2   even in some earlier stage of the illness, and no


              3   matter how you define that, and I think that is


              4   invalid.



              5             DR. MILLER:  Dr. Abramson.


              6             DR. ABRAMSON:  Just one or two points.


              7   Dr. Cush has the data on the doxycycline, and just


              8   to be more specific, the diseased knees were


              9   protected by 33 percent and progression in



             10   doxycycline, but the primary endpoint was to look


             11   at the opposite knee, which had zero or 1-plus


             12   calgrin [ph], so maybe not normal, as Nancy says,


             13   but certainly a different stage of the disease, and


             14   there was no effect.



             15             So, at least that informs us that at


             16   different stages of the disease, a cartilage may be


             17   more or less sensitive to an intervention.  Most of


             18   the studies that we have seen from the sponsor, and


             19   we all engage in, is in the more advanced disease



             20   where there IL-1 being added to the cartilage, so


             21   it more mimics the responsive side.


             22             I just wanted to go back to Dr. Zeisel's











              1   comment, though, because I read this as a negative


              2   answer, because it says that the data in the


              3   diseased cartilage allows us to suggest a reduced


              4   risk of OA in the generally healthy population.



              5             It basically allows us, in my view, to ask


              6   the question in a healthy population, but not to


              7   make any statements about healthy population.


              8             DR. MILLER:  Dr. Zeisel.


              9             DR. ZEISEL:  Again, what this question to



             10   me is trying to get at is how would you design the


             11   experiment to do the experiment right.  One way


             12   would be to take randomly selected people with no


             13   disease, follow them for 50 years, and ask do they


             14   develop osteoarthritis.  That is an impractical



             15   experiment to do.


             16             So, the question is, is it ever acceptable


             17   to take individuals who have a joint involved with


             18   osteoarthritis and follow their other joints, and


             19   argue that that is a surrogate for the longer study



             20   because these people are at higher risk for


             21   developing other joint disease for whatever reason,


             22   and that they have properties that are similar











              1   enough to the general population that you could


              2   then extrapolate the data from that population to


              3   make conclusions about the general.


              4             What I am hearing is that in a way they



              5   behave differently in their non-involved joints,


              6   that that behavior is what you, as experts, would


              7   predict for the normal population to some extent


              8   behaving differently than the actively involved


              9   inflamed joint, and that it is a reasonable



             10   surrogate, although not perfect surrogate, but in


             11   any experiment, we can't be perfect unless we are


             12   willing to wait several generations to figure this


             13   out.


             14             Am I right that use of another knee could



             15   be designed in a study, not that it hasn't been


             16   done well by the people presenting to us today on


             17   these treatments, but that could you design a study


             18   in which you used other joints to draw data that we


             19   would then feel was reasonable to extrapolate with



             20   reasonable certainty, although not absolute


             21   certainty, and I think that is the question.


             22             DR. MILLER:  That is part of the question.











              1   I think the other part of the question is, is there


              2   data available today that will allow extrapolation


              3   from experiments with OA patients to patients who


              4   are reportedly without OA.



              5             DR. ZEISEL:  I think that doesn't ever say


              6   anything that there is data already.  It just says


              7   is it scientifically valid to design an experiment


              8   that would use that.


              9             DR. MILLER:  To use such research.  I mean



             10   the question the agency faces is how to deal with


             11   claims that say that there is a risk reduction for


             12   the use of any material for OA.


             13             DR. ZEISEL:  So, I think what we can reach


             14   consensus, it is not valid to use data in the



             15   involved joint because we have said that that can


             16   be very different, and I think we can all agree


             17   with that.


             18             So, now we are getting to the second


             19   point, is there any data from an OA patient that



             20   you could use in a study, so could you go back and


             21   re-analyze if those normal joint x-rays were


             22   available and come back to this FDA with a











              1   presentation saying that we saw something and we


              2   met some criteria, and now--


              3             DR. MILLER:  I think you can say both.


              4   There are two separate issues.



              5             DR. ZEISEL:  Yes.


              6             DR. MILLER:  Dr. Dwyer.


              7             DR. DWYER:  So, is it the opinion of the


              8   rest of the group that very high risk people may


              9   be, in their non-involved joints, may or may not be



             10   reasonable surrogates, and we really don't know.


             11   It seems to me that it is a good bet, but we really


             12   don't know.


             13             DR. LANE:  That's right.  That's the


             14   biggest issue, why we are doing the osteoarthritis



             15   initiative, because we don't yet know in those


             16   high-risk individuals exactly what is going to


             17   trigger the onset of the disease, and to say we


             18   know otherwise is really a bit unfounded at this


             19   time.



             20             DR. MILLER:  Dr. Kale.


             21             DR. KALE:  I have two questions.  First of


             22   all, in the case of the doxycycline study, how long











              1   was that study conducted for before it was


              2   determined that the--just 30 months.


              3             And the second issue is looking back at


              4   the target tissue here, which is cartilage, I think



              5   I am embarrassingly confused about the answer to


              6   this question, which is that if you give


              7   chondroitin or glucosamine to a diseased


              8   chondrocyte, say, one involved in the process of


              9   demonstrating osteoarthritis, does it, in fact,



             10   make different endproducts than normal cartilage


             11   does when you give chondroitin sulfate or


             12   glucosamine to that cartilage.


             13             DR. ABRAMSON:  My understanding of the


             14   data is that glucosamine and chondroitin



             15   beneficially influence the cytokines, the abnormal


             16   metabolism of chondrocytes, particularly if you add


             17   IL-1, so it is very good for reasons that were well


             18   demonstrated yesterday in blocking these


             19   inflammatory processes and the metalloproteinase



             20   production.


             21             What I heard yesterday is that since those


             22   features are not typical of normal chondrocytes,











              1   and NF-kappa B is not activated, you know, IL-1 is


              2   not being produced, nitric oxide is not being


              3   produced, that therefore when you give glucosamine


              4   or chondroitin sulfate to a normal chondrocyte, not



              5   making those things and it works, let's say, by


              6   inhibiting NF kappa B, it has no significant effect


              7   on the normal chondrocyte with regard to these


              8   catabolic events.


              9             Therefore, while I think the data is



             10   increasingly very interesting, that it does have


             11   beneficial effects on this inflamed catabolic


             12   chondrocyte, it is not clear to anyone I think what


             13   effect it has on a normal cartilage and whether it


             14   will prevent anything.



             15             I think that is why when I read this


             16   statement, it says to me based on those studies of


             17   deteriorative cartilage and some interesting


             18   studies from Ajinsta and Pervelka [ph] in patients,


             19   that we can use to extrapolate what looks to be



             20   increasingly interesting evidence that the drug


             21   does work in the degenerated state, that we can


             22   then use it to say that it is going to help healthy











              1   people, and that is the dilemma.


              2             DR. KALE:  That's my understanding, too.


              3   So, the question I had is sort of more Walt


              4   Disneyfied, which is what if the chondroitin



              5   sulfate or the glucosamine is present, because you


              6   have taken it prophylactically, in the case of


              7   somebody who would, because they are alive,


              8   ultimately develop osteoarthritis, what effect does


              9   that have on the final common pathway of IL-1, and



             10   so on, might it not modify the outcome?


             11             DR. ABRAMSON:  We don't know until the


             12   studies are done, and the tetracycline, doxycycline


             13   study is very preliminary, so one doesn't want to


             14   overstate its validity, but the tetracycline seems



             15   to work on these IL-1 mediated processes.  It


             16   inhibits nitric oxide and some other things, and


             17   what Ken Brandt is beginning to think, that maybe


             18   those processes are more important in the late


             19   stage of disease, and therefore, we can't be sure



             20   that blocking those same processes in early disease


             21   will block those events in early disease that may


             22   be mediated by different growth factors that set











              1   the thing forward.  That is the dilemma.


              2             DR. LANE:  I want to reiterate that,


              3   because that is the experiment that was done.  You


              4   took a relatively normal cartilage, gave it



              5   something, if it started to degenerate, you would


              6   prevent.  It didn't, so that is the beginnings of--


              7             DR. KALE:  But it didn't in 30 months.


              8   The question is what is the proper geologic time


              9   frame.  Thirty months can't be. I mean this a



             10   glacial disease, it may be a glacial disease.


             11             DR. CUSH:  Those people are also selected


             12   to be at higher risk because they were obese, so


             13   they had other risk factors to possibly progress.


             14             DR. MILLER:  Dr. Nelson.



             15             DR. NELSON:  Also, isn't doxycycline just


             16   one agent?  I mean we aren't generalizing the issue


             17   to--


             18             DR. LANE:  No, no, we are not


             19   generalizing, but I mean, come on, this is a field



             20   without data, let's at least enjoy this data.


             21             [Laughter.]


             22             DR. MILLER:  It is much more fun to argue











              1   without data.


              2             DR. LANE:  We said that here is a set of


              3   chondrocytes that were all prepped, so that when


              4   they started to make a bad enzyme, if they started



              5   to make it, you were going to inhibit it.  You


              6   know, this was the perfect situation.


              7             DR. NELSON:  My other question again was


              8   to I guess the rheumatologists in this, is we have


              9   abnormal chondrocytes, we have evidence, but no



             10   symptomatology no pain, are those people still part


             11   of the general healthy population that we could use


             12   data from the contralateral knee or the


             13   contralateral hip to provide for the general


             14   healthy population whether they had--well, you



             15   would have to qualify that, I guess, whether they


             16   had some symptoms, some existence of a risk factor


             17   or not.


             18             DR. ABRAMSON:  Even if they are generally


             19   healthy and have subclinical or pre-disease, the



             20   argument could still be made that modifying end


             21   disease processes is not going to affect their


             22   progression into disease.  That is the unknown,











              1   because they are different processes that happen


              2   early on OA.


              3             DR. LANE:  And these natural history


              4   studies that are just starting up now, when we have



              5   some of that data, we will be able to comfortably


              6   begin to answer that question.


              7             DR. MILLER:  Dr. Blonz.


              8             DR. BLONZ:  So, what I am hearing is that


              9   the contralateral knee data is informative, but not



             10   sufficient to serve as a surrogate, and that seeing


             11   as we don't have information at present that can


             12   segregate those individuals in queue for imminent


             13   osteoarthritis, that to talk about the general


             14   population and applying the data we learned about,



             15   treating people with the active disease does not


             16   seem to be a connect for us at present.


             17             DR. MILLER:  I think that is a good sum.


             18             Dr. Zeisel.


             19             DR. ZEISEL:  Again, I think it would be



             20   much more constructive for us not to get into the


             21   specific data like we have been doing.  I don't


             22   agree with Steve that we are being asked to say











              1   from this that there is an effect of chondroitin or


              2   anything.


              3             All we are being asked here is, is it


              4   possible to design an experiment that would



              5   convince this panel that any agent can reduce the


              6   risk of osteoarthritis, and using osteoarthritic


              7   patients, and if the answer is no, then, we have to


              8   say no.


              9             If the answer is it is informative and we



             10   would like to see that data, but it would not be


             11   sufficient to convince us, that is what we should


             12   say, but I don't think we need to get into the


             13   specifics of whether doxycycline or chondroitin or


             14   anything else made any difference, because it's



             15   immaterial.  We are talking about agent X and agent


             16   Y for this type of question.


             17             DR. MILLER:  I agree, but actually, they


             18   are really two questions.  One is there is no data


             19   to suggest that current available data can be used



             20   for this purpose, and that second, it simply says


             21   that it may be possible to design an experiment,


             22   but we don't know yet how to do that.











              1             Dr. Krinsky.


              2             DR. KRINSKY:  To me, the operative terms


              3   in this question is scientifically valid, and it


              4   seems to me that what I have heard from the



              5   rheumatologists, and scientifically valid to use


              6   such research, so to me, we are not talking about


              7   the future, we are talking about the past and the


              8   present, and it would seem to me that based on what


              9   we have heard of research in the past and the



             10   present research that we do not have scientifically


             11   valid evidence for proposing that this be used for


             12   a general healthy population.


             13             We may in the future and that would be


             14   wonderful, but we can't deal with maybes, we have



             15   to deal with science. This is why we are here, we


             16   are looking at scientifically based evidence, and


             17   not hopeful evidence.


             18             DR. MILLER:  I agree, in fact, I think


             19   there is a consensus to that fact, but what I am



             20   saying is that it may be useful to indicate that we


             21   haven't closed the door implying that there is no


             22   way of doing it.











              1             I think that part of the problem is the


              2   lack of data in what I hear in the field.


              3             DR. LANE:  Yes, lack of data and not


              4   really having really utilized the technologies



              5   available, you know, they are in development that


              6   we could actually--


              7             DR. MILLER:  We don't have to say anything


              8   more than as I indicated, that it may be possible


              9   sometime in the future to do this, and close that



             10   door.


             11             DR. ZEISEL:  I think we have agreed that


             12   any data generated in the osteoarthritic knee


             13   itself, or joint itself, we would find difficult to


             14   accept even in the future no matter how the



             15   experiment is done as indicative of what a normal


             16   joint might do.


             17             DR. MILLER:  Right.


             18             Jean.


             19             MS. HALLORAN:  I think we seemed to agree



             20   that the next step would be looking at what the


             21   normal joint would do under treatment, but that I


             22   at least would want to then see maybe a five-year











              1   study of people over 50 or something like that to


              2   see how it would affect a somewhat at risk, but


              3   still asymptomatic population, that that would be


              4   data that would also be desirable.



              5             DR. MILLER:  We can get into a long


              6   discussion about what such experiments ought to


              7   contain, and I think my own feeling is that we can


              8   make some comment, but I am not sure that really


              9   that helps to answer the questions that we are



             10   being asked to deal with.


             11             I would love to be able to get into a


             12   discussion about how to design experiments like


             13   this, particularly as a non-expert.


             14             Well, I guess we have reached a consensus



             15   on this one, as well.  Again, the nature of the


             16   discussion will be reflected in the report, and, of


             17   course, we will have a complete transcript of the


             18   discussion.


             19             We will use certain summary statements



             20   that some of you have made in the report verbatim


             21   from the record.


             22             It is now about 10 minutes of 10:00.  I











              1   propose we take a break now before we come back to


              2   look at Question 3. Come back in 15 minutes,


              3   please.


              4             [Break.]



              5             DR. MILLER:  Can we reconvene.


              6             We have discussed the first two questions.


              7   We have come to the third question, which has to do


              8   with the issue of whether animal studies can be


              9   used in place of human information in order to deal



             10   with the issue of risk reduction of OA in humans.


             11             The first question to be addressed is to


             12   what extent animal or in vitro models of OA may be


             13   useful, what animal models or types of endpoints


             14   should be used to assess risk reduction of OA in



             15   humans.


             16             Does anybody have any views on that


             17   subject?  Johanna.


             18             DR. DWYER:  Could we hear from the


             19   rheumatologists on their views?



             20             DR. MILLER:  That is what I am waiting


             21   for, to see someone raise their hand.


             22             DR. LANE:  We were electing Dr. Abramson











              1   who has still I think some non-human models in his


              2   laboratory.


              3             DR. ABRAMSON:  Do you want the long answer


              4   or the short answer?



              5             DR. MILLER:  Let's take something medium


              6   size and we will decide.


              7             DR. ABRAMSON:  This is a very difficult


              8   field because there is not a great consensus on


              9   what a good animal model is for OA, and usually, if



             10   you are developing drugs, you need to have a couple


             11   of different kinds.


             12             There are genetic guinea pig models, there


             13   are anterior cruciate models that Dr. Altman


             14   referred to, and they become pieces of the puzzle



             15   as you are trying to think about intervention, you


             16   know, proof of concept, they are useful in that


             17   regard, but I think the general consensus in the


             18   community is that they provide you some information