1

 

                              FOOD ADVISORY COMMITTEE AND DIETARY

 

                                    SUPPLEMENTS SUBCOMMITTEE

 

 

 

 

 

 

 

 

 

 

                           THE ROLE OF GLUCOSOSAMINE AND CHONDROITIN

 

                                   SULFATE IN OSTEOARTHRITIS

 

                                              AND

 

                                  FURAN CONTAMINANTS IN FOODS

 

 

 

 

 

 

 

 

 

 

 

 

                                     Tuesday, June 8, 2004

 

                                           8:00 a.m.

 

 

 

 

 

 

 

 

                                       Bethesda Marriott

                                         Grand Ballroom

                                      5150 Pooks Hill Road

                                       Bethesda, Maryland


 

 

 

 

 

 

 

 

                                                                             2

 

                                          PARTICIPANTS

 

                  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.

 

                  FDA

 

                  Jeanne Latham

                  Dr. Craig Rowlands


 

 

 

 

 

 

 

 

                                                                             3

 

                                        C O N T E N T S

 

                                                                          Page

 

                  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


 

 

 

 

 

 

 

 

                                                                             4

 

              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


 

 

 

 

 

 

 

 

                                                                             5

 

              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


 

 

 

 

 

 

 

 

                                                                             6

 

              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.


 

 

 

 

 

 

 

 

                                                                             7

 

              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


 

 

 

 

 

 

 

 

                                                                             8

 

              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.


 

 

 

 

 

 

 

 

                                                                             9

 

              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


 

 

 

 

 

 

 

 

                                                                            10

 

              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


 

 

 

 

 

 

 

 

                                                                            11

 

              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


 

 

 

 

 

 

 

 

                                                                            12

 

              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


 

 

 

 

 

 

 

 

                                                                            13

 

              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


 

 

 

 

 

 

 

 

                                                                            14

 

              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


 

 

 

 

 

 

 

 

                                                                            15

 

              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


 

 

 

 

 

 

 

 

                                                                            16

 

              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,


 

 

 

 

 

 

 

 

                                                                            17

 

              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


 

 

 

 

 

 

 

 

                                                                            18

 

              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.


 

 

 

 

 

 

 

 

                                                                            19

 

              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


 

 

 

 

 

 

 

 

                                                                            20

 

              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


 

 

 

 

 

 

 

 

                                                                            21

 

              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


 

 

 

 

 

 

 

 

                                                                            22

 

              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.


 

 

 

 

 

 

 

 

                                                                            23

 

              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.


 

 

 

 

 

 

 

 

                                                                            24

 

              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


 

 

 

 

 

 

 

 

                                                                            25

 

              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


 

 

 

 

 

 

 

 

                                                                            26

 

              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


 

 

 

 

 

 

 

 

                                                                            27

 

              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


 

 

 

 

 

 

 

 

                                                                            28

 

              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


 

 

 

 

 

 

 

 

                                                                            29

 

              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.


 

 

 

 

 

 

 

 

                                                                            30

 

              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


 

 

 

 

 

 

 

 

                                                                            31

 

              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


 

 

 

 

 

 

 

 

                                                                            32

 

              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


 

 

 

 

 

 

 

 

                                                                            33

 

              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


 

 

 

 

 

 

 

 

                                                                            34

 

              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.


 

 

 

 

 

 

 

 

                                                                            35

 

              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


 

 

 

 

 

 

 

 

                                                                            36

 

              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


 

 

 

 

 

 

 

 

                                                                            37

 

              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.


 

 

 

 

 

 

 

 

                                                                            38

 

              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


 

 

 

 

 

 

 

 

                                                                            39

 

              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


 

 

 

 

 

 

 

 

                                                                            40

 

              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


 

 

 

 

 

 

 

 

                                                                            41

 

              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


 

 

 

 

 

 

 

 

                                                                            42

 

              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


 

 

 

 

 

 

 

 

                                                                            43

 

              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


 

 

 

 

 

 

 

 

                                                                            44

 

              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


 

 

 

 

 

 

 

 

                                                                            45

 

              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


 

 

 

 

 

 

 

 

                                                                            46

 

              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


 

 

 

 

 

 

 

 

                                                                            47

 

              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


 

 

 

 

 

 

 

 

                                                                            48

 

              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,


 

 

 

 

 

 

 

 

                                                                            49

 

              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


 

 

 

 

 

 

 

 

                                                                            50

 

              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


 

 

 

 

 

 

 

 

                                                                            51

 

              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


 

 

 

 

 

 

 

 

                                                                            52

 

              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.


 

 

 

 

 

 

 

 

                                                                            53

 

              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


 

 

 

 

 

 

 

 

                                                                            54

 

              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.


 

 

 

 

 

 

 

 

                                                                            55

 

              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


 

 

 

 

 

 

 

 

                                                                            56

 

              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


 

 

 

 

 

 

 

 

                                                                            57

 

              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


 

 

 

 

 

 

 

 

                                                                            58

 

              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


 

 

 

 

 

 

 

 

                                                                            59

 

              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.


 

 

 

 

 

 

 

 

                                                                            60

 

              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


 

 

 

 

 

 

 

 

                                                                            61

 

              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


 

 

 

 

 

 

 

 

                                                                            62

 

              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


 

 

 

 

 

 

 

 

                                                                            63

 

              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


 

 

 

 

 

 

 

 

                                                                            64

 

              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?


 

 

 

 

 

 

 

 

                                                                            65

 

              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


 

 

 

 

 

 

 

 

                                                                            66

 

              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,


 

 

 

 

 

 

 

 

                                                                            67

 

              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


 

 

 

 

 

 

 

 

                                                                            68

 

              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,


 

 

 

 

 

 

 

 

                                                                            69

 

              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


 

 

 

 

 

 

 

 

                                                                            70

 

              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


 

 

 

 

 

 

 

 

                                                                            71

 

              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


 

 

 

 

 

 

 

 

                                                                            72

 

              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.


 

 

 

 

 

 

 

 

                                                                            73

 

              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


 

 

 

 

 

 

 

 

                                                                            74

 

              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.


 

 

 

 

 

 

 

 

                                                                            75

 

              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


 

 

 

 

 

 

 

 

                                                                            76

 

              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


 

 

 

 

 

 

 

 

                                                                            77

 

              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


 

 

 

 

 

 

 

 

                                                                            78

 

              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


 

 

 

 

 

 

 

 

                                                                            79

 

              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


 

 

 

 

 

 

 

 

                                                                            80

 

              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


 

 

 

 

 

 

 

 

                                                                            81

 

              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.


 

 

 

 

 

 

 

 

                                                                            82

 

              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


 

 

 

 

 

 

 

 

                                                                            83

 

              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


 

 

 

 

 

 

 

 

                                                                            84

 

              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,


 

 

 

 

 

 

 

 

                                                                            85

 

              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


 

 

 

 

 

 

 

 

                                                                            86

 

              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


 

 

 

 

 

 

 

 

                                                                            87

 

              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


 

 

 

 

 

 

 

 

                                                                            88

 

              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,


 

 

 

 

 

 

 

 

                                                                            89

 

              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


 

 

 

 

 

 

 

 

                                                                            90

 

              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.


 

 

 

 

 

 

 

 

                                                                            91

 

              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.


 

 

 

 

 

 

 

 

                                                                            92

 

              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


 

 

 

 

 

 

 

 

                                                                            93

 

              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


 

 

 

 

 

 

 

 

                                                                            94

 

              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


 

 

 

 

 

 

 

 

                                                                            95

 

              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