FOOD ADVISORY COMMITTEE AND DIETARY
THE ROLE OF GLUCOSOSAMINE AND CHONDROITIN
SULFATE IN OSTEOARTHRITIS
FURAN CONTAMINANTS IN FOODS
Tuesday, June 8, 2004
5150 Pooks Hill Road
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.
Dr. Craig Rowlands
C O N T E N T S
Call to Order
Sanford A. Miller, Ph.D., Chair 4
Review of Issues
Dr. Craig Rowlands 6
Committee Discussion 8
Concluding Comments 103
1 P R O C E E D I N G S
2 Call to Order
3 DR. MILLER: Good morning. We are going
4 to begin the second day of the meetings of the Food
5 Advisory Committee. This morning and the first
6 part of this afternoon will be spent with the
7 committee deliberating the information that we have
8 received so far and try to develop a consensus
9 response to the three questions that were presented
10 to us by the FDA for us to respond to.
11 Before we begin our work for today, there
12 is a couple of issues I need to make and Linda also
13 has some administrative things that need to be
14 brought to your attention.
15 First, two of the members of the
16 committee, Dr. David Felson and Dr. Annette
17 Dickinson will not be with us today. They were
18 unable to stay for the two days of the meeting, and
19 I think we will miss them. But, for the record,
20 they won't be with us.
21 Secondly, it is really important that we
22 stick to the time frame as closely as possible. We
1 have another subject to discuss, the Food Advisory
2 Committee has another subject to discuss, and that
3 is the contamination of foods with furans, and we
4 have to be out of this room, I have been informed,
5 by 6 o'clock at the very latest, otherwise, we will
6 find ourselves in the middle of a wedding, that
7 that is not going to help our deliberations to any
8 great extent.
9 So, we will do that. At 1:45, this
10 section of the meeting will adjourn and the
11 temporary voting members and the members of the
12 Supplements Subcommittee that have joined us will
13 be excused, with our thanks, of course, and we will
14 continue on with the furan part of the meeting with
15 a new group of temporary voting members, and so on,
16 and so forth.
18 MS. REED: Good morning, everyone. I just
19 have a couple of administrative announcements,
20 information I want to give you. If anyone needs
21 transportation back to their respective airports,
22 please see Sharon Barcelos [ph], who is sitting out
1 front at the registration desk, and she will get
2 that arranged for you.
3 Also, just as a reminder, I believe
4 checkout is at noon for anybody who needs to check
5 out. Also, if you would like to have your briefing
6 materials Fed Ex'd back to your business or
7 residence, we have Fed Ex boxes and labels outside
8 also where Sharon is sitting, if anybody wants to
9 take advantage of doing that versus carrying it
10 back with them, so please see Sharon for those
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
2 Review of Issues
3 DR. ROWLANDS: Good morning. I am going
4 to read the questions as I read them yesterday,
5 which is I am going to combine Questions 1, the A
6 and B, and then Questions 2, the A and B, and then
7 Question 3, I will read as written.
8 Question 1 is: Is 1(a), joint
9 degeneration, and Question 1(b), cartilage
10 deterioration, a state of health leading to
11 disease, which is a modifiable risk factor
12 surrogate endpoint for OA risk reduction?
13 Then, we would like to know what are the
14 strengths and limitations of the scientific
15 evidence on this issue.
16 Question 2 is: If we assume that for
17 2(a), joint degeneration, and for Question 2(b),
18 cartilage deteriorating, is a modifiable risk
19 factor surrogate endpoint for OA risk reduction,
20 and we assume that research demonstrates that a
21 dietary substance treats, mitigates, or slows joint
22 degeneration or cartilage deterioration in patients
1 diagnosed with osteoarthritis, is it scientifically
2 valid to use such research to suggest a reduced
3 risk of OA in the general healthy population, that
4 is, individuals without osteoarthritis, from
5 consumption of the dietary substance?
6 Question 3 is: If human data are absent,
7 can the results from animal and in vitro models of
8 OA demonstrate risk reduction of OA in humans?
9 3(a) To the extent that animal or in
10 vitro models of OA may be useful, what animal
11 models or in vitro models, types of evidence and
12 endpoints should be used to assess risk reduction
13 of OA in humans?
14 3(b) If limited human data are available,
15 what data should be based on human studies and what
16 data could be based on animal and in vitro studies
17 to determine whether the overall data are useful in
18 assessing a reduced risk of OA in humans?
19 If there is any clarification needed or
20 anything on those questions, you can ask me or
21 actually you could ask any of the FDA staff for any
22 clarifications if you like.
1 DR. MILLER: Any comments? Dr. Cush.
2 DR. CUSH: Well, actually, I would like to
3 provide a clarification, I think to Question 1(a).
4 I would like joint degeneration to be considered
5 separately from cartilage deterioration.
6 Joint degeneration, I think would
7 basically be an analogous definition of
8 osteoarthritis. I don't believe that it is a state
9 that leads to, I mean it is a net result that is
10 osteoarthritis. It is a poor choice of words, and
11 should not be any kind of labeling, and should be
12 rejected outright.
13 I think to move on to cartilage
14 deterioration, which is sort of the target of the
15 initial damage of the disorder, something that we
16 measure. Joint degeneration is too global, too
17 vague, but it nonetheless does imply the net result
18 of osteoarthritis.
19 So, that term I believe is faulty and
20 should be eliminated.
21 DR. ROWLANDS: Okay. Of course, the
22 questions are written separately as 1(a) and then
2 Committee Discussion
3 DR. MILLER: Any comments or response to
4 that? Yes.
5 DR. BLONZ: Edward Blonz. Now, the
6 question I would pose to that is, does the joint
7 degeneration process begin and then lead to
8 osteoporosis, or as soon as joint degeneration has
9 begun, you are already there? Osteoarthritis,
10 forgive me.
11 DR. CUSH: Again, this goes back to
12 yesterday's definition of the transition from
13 healthy to disease state, which is an impossibility
14 to define I think in this instance, and I don't
15 believe that joint degeneration implies a lesser,
16 more minor, or protein state of the net result,
17 which is osteoarthritis.
18 I think it embodies what we see in
19 osteoarthritis, which is again the whole joint
20 being affected by more primordial events that begin
21 with cartilage pathology.
22 DR. MILLER: It seems to me, as I said
1 yesterday, it seems to me that there is a
2 fundamental issue that somehow or other we need to
3 comment on, and that is the question on which much
4 of the discussion is based, and that is, there is
5 at some point when osteoarthritis or any of the
6 pre-quals [ph] of osteoarthritis that we are
7 discussing to see whether they have any ultimate
8 impact does or does not exist.
9 I mean, to exaggerate, if you listen to
10 the conversation about the continuum, and you can
11 argue the continuum begins at conception and ends
12 at death, and those kind of continuums are not
13 unknown in biology, and it just seems to me that we
14 need to address that question, if the basic issue
15 that the FDA is trying to deal with is going to be
16 responded to.
17 Yes, David.
18 DR. ABRAMSON: I think, Dr. Miller, that
19 is the nub that we are struggling with, and I think
20 one of the issues that is important to review from
21 yesterday's discussion is that our clinical ability
22 to detect osteoarthritis is very crude at the
1 earliest stages and particularly the imaging
2 technology is very crude, and we rely on that.
3 So, histologically, we all would be able
4 to sit around a table with a pathologist and
5 differentiate normal cartilage from early
6 degenerative changes of cartilage, and that is how,
7 in fact, when you do studies of OA, you define it
8 pathologically, not by imaging.
9 Imaging is useful for clinical trials, as
10 Dr. Simon said, and also for clinical care of
11 patients, but the disease, as is atherosclerosis
12 present for years perhaps before the patient is
13 symptomatic, but a pathologist can see
14 atherosclerosis and a pathologist can see
15 osteoarthritis, and that doesn't happen necessarily
16 when you are 15 or 17, it happens in the later
18 The other related dilemma is the disease
19 osteoarthritis pathologically can be detected early
20 with fibrillations and fissuring, but then in only
21 some people does it advance at a rate that they get
22 it at age 55 or 75, or perhaps 100, but there is a
1 continuum where I think we would call this
2 cartilage abnormality osteoarthritis.
3 So, I think the limitations of our
4 diagnostic tools are part of the problem here, but
5 the disease can be detected if one looks carefully
6 enough at many of these earlier points.
7 DR. MILLER: Well, it is impossible--I
8 will just lay this on the table--to say that you
9 can't distinguish a period in which osteoarthritis
10 or the phenomenon that lead to full-blown
11 osteoarthritis can't be determined.
12 DR. LANE: I think that that is true. I
13 mean what Dr. Abramson says is we neither have the
14 imaging techniques, nor do we have a measurement in
15 the blood or serum that you could at which point
16 say this, like cholesterol, we don't have a
17 cholesterol, we don't have a level of a marker of
18 bone or cartilage turnover that we could say this
19 person is at so high a risk of getting OA that we
20 should do something about it.
21 We neither have an imaging tool nor a
22 serum marker in this continuum, and until the
1 person comes to medical care with pain in their
2 joint, it is unclear. Even if they have a x-ray
3 and it's abnormal, it is unclear they are going to
4 get a clinical disease.
5 As Dr. Felson said yesterday, only 30
6 percent of people who have significant radiographic
7 changes ever have clinical painful disease.
8 DR. MILLER: I understand that. What I am
9 just trying to say is that if that be the case, and
10 there is a consensus that that is the case, then,
11 that is what we ought to say. That is all I am
12 trying to say.
13 DR. LANE: Okay.
14 DR. MILLER: Dr. Cush.
15 DR. CUSH: I would like to reiterate a
16 point that was brought up by David Felson
17 yesterday, and that was in spite of what appears to
18 be a struggle as to what we know and what we don't
19 know, no rheumatologist has difficulty making a
20 diagnosis of osteoarthritis. It is a very certain
21 disease, it is easy to diagnose.
22 What we are talking about here, in this
1 continuum that may begin with genetic factors, and
2 then biochemical factors, then immunologic events,
3 then physiochemical events, and then sometime
4 shortly thereafter, symptoms might ensue, and then
5 are followed by damage and the functional
6 consequences of disease.
7 All along the way, imaging, depending on
8 how good or sensitive it is or is not, or a
9 biomarker, how sensitive it is, it may be present
10 or it may be absent, but they don't factor as much
11 into this as the symptoms do, so it is when
12 symptoms begin that we recognize this constellation
13 of findings and we make this diagnosis.
14 What is not known is what is pre-OA, we
15 don't have a diagnosis of pre-osteoarthritis. In
16 fact, we don't have great risk factors. We know
17 risk factors, we know there are some genetic risk
18 factors, which is for a minority of individuals.
19 We know that obesity and we know that
20 certain lifestyles or occupations are risk factors
21 for osteoarthritis, and those are modifiable, but
22 by the way, none of those subsets have these
1 nutritional supplements been applied to and shown
2 to have protective benefit.
3 So, you know, we are being asked to
4 address whether or not some intervention might be
5 applied to a healthy population to protect us
6 against the disease.
7 Again, I have a problem with connecting
8 the dots. We saw some good research and good
9 results applied to people with disease, but
10 applying them to the general population who may or
11 may not have this is, I think a gigantic leap of
12 faith that is going to be difficult to make.
13 DR. MILLER: Dr. Zeisel.
14 DR. ZEISEL: I would like to suggest that
15 we approach this bit by bit, and not jump to the
16 treatment of OA or prevention of OA at this moment,
17 but rather the question before us is, is cartilage
18 degeneration a predecessor of OA in the individuals
19 who develop OA.
20 Now, that doesn't mean that everybody who
21 has cartilage degeneration is going to go on to
22 develop OA, but in the individuals who develop OA,
1 is cartilage degeneration a predecessor, and from
2 what I have heard, I would argue that it is, that
3 people who go on to develop OA start with cartilage
5 Again, we might parse that very finely,
6 but, in general, you have some cartilage
7 degeneration that gets worse and worse until some
8 point when you develop frank symptomatology that is
9 picked up.
10 So, if we can agree on that, we can agree
11 on a Question 1(b) that it's a deterioration of
12 state of health leading to a disease. Now, it
13 doesn't always lead to the disease, but it is clear
14 that sometimes it does.
15 Is that a reasonable statement?
16 DR. LANE: Well, I have a little trouble
17 with it, because you are saying that the cartilage
18 degeneration is starting out leading to something,
19 and I think, as was brought up yesterday, the joint
20 is a structure, and what leads to the painful
21 disease OA is cartilage and bone changes.
22 So, I ask Dr. Abramson should we separate
1 out the cartilage, I am not so sure.
2 DR. ABRAMSON: Well, I guess the semantic
3 issue here is I would argue that cartilage
4 degeneration is the earliest phase of
5 osteoarthritis, therefore, it is not a normal
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
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
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
22 So, the notion that it is a normal process
1 with time, I think, you know, it depends at what
2 point in time, and it is not necessarily therefore
3 everyone is going to get OA and at the earliest
4 sign. So, you can have normal cartilage, and I
5 would suggest that the degenerative changes that
6 the pathologist can see is osteoarthritis.
7 DR. ZEISEL: But we have also heard, I
8 believe, that you can have abnormal cartilage, and
9 not have osteoarthritis, that, by definition, there
10 are some people going around with abnormal
11 cartilage and they do not have osteoarthritis by
12 the clinician's recognition of that disease.
13 So, having abnormal cartilage cannot be
14 the sine qua non of having osteoarthritis. What I
15 am trying to say is that it can precede it, and
16 therefore, there must be people who will develop
17 osteoarthritis who have the start of cartilage
18 degeneration, and the question at hand is, is that
19 a marker that is worthwhile following as something
20 that you could intervene in. I mean I think that
21 is what Question 1(b) is.
22 DR. MILLER: Well, couldn't that be a rate
1 function? In other words, a rate of degeneration
2 that could take place, and if you don't live long
3 enough for it to express itself, so to speak.
4 I mean the problem, let me see if I can
5 focus this discussion a little bit, a little more,
6 the problem that the FDA faces is being able to
7 determine whether or not the results you are
8 looking at is mitigation of existing disease or is
9 it risk reduction--I have to be careful what words
10 I use--whether it is a risk reduction function.
11 That is the problem that they face, and
12 there are many ways to deal with this. One is to
13 get a consensus for an arbitrary distinction at
14 what point one process begins and the other ends,
15 recognizing that you are trying to deal with a
16 point on a continuum.
17 I am not sure we could do that here, but
18 if there is some agreement, we can recognize that.
19 DR. LANE: I think, Dr. Miller, that is a
20 very important point, because research that Dr.
21 Felson and our group do has shown us surprisingly
22 that the risk factors for getting the disease at
1 this point, with the research done, are different
2 than what causes it to get worse.
3 So, armed with that data and the
4 literature for both hip and knee OA, we may have to
5 make a bit of a distinction even though
6 theoretically, we think the continuum should, we
7 really don't have the data to support that today.
8 DR. MILLER: Basically, you have got to
9 draw that bright line somewhere.
10 DR. LANE: That's right, we have to put a
11 dotted line, that is exactly right.
12 DR. MILLER: Recognizing that there is a
13 big variation.
14 DR. LANE: That's right.
15 DR. MILLER: We have a number of people
16 that have been trying to get some questions in
17 here, and to be fair, I have got to give them a
19 Dr. Espinoza.
20 DR. ESPINOZA: I don't have any problems
21 with the question posed by FDA regarding joint
22 deterioration and cartilage degeneration.
1 Cartilage degeneration might be the hallmark of the
2 disease that we call osteoarthritis, but
3 osteoarthritis is much more than that.
4 I definitely feel that joint deterioration
5 should be considered at least a relevant question
6 for us to discuss here.
7 DR. MILLER: Dr. Nelson.
8 DR. NELSON: Following up on the questions
9 about the continuum, we are interested in risk
10 factors for this particular discussion, correct?
11 DR. MILLER: Right.
12 DR. NELSON: As I understood it, there
13 could be 75-year-olds that have no anatomical
14 changes, and clearly they have no risk of
15 developing osteoarthritis, but then there are
16 others that do, in fact, have these changes, but
17 have no symptomatology, so they have risk factors,
18 but it hasn't led to the problem.
19 As I understood it, the disease was, as I
20 think Dr. Zeisel allude to it, the disease is
21 really considered a disease once the patient
22 presents symptoms.
1 In that situation, would not, in fact,
2 cartilage deterioration be a risk factor that may
3 or may not be modifiable, but before the disease
5 DR. ABRAMSON: The difficulty for me here
6 is that we define osteoarthritis as when the
7 symptoms begin at one level, but we can all look at
8 an x-ray and say this asymptomatic patient has
9 osteoarthritis of the knee or back, so there is
10 three levels by which we make this diagnosis.
11 We make a clinical diagnosis, we make a
12 radiographic diagnosis, and we make a histological
13 diagnosis, and depending on which part of the
14 elephant you are looking at, the elephant still has
15 osteoarthritis, the disease of tissue degeneration.
16 So, I think the analogy to other diseases
17 then becomes important, and it depends what the FDA
18 wants to call the onset of the disease. If it
19 limits itself to symptoms, that is one way of
20 looking at it, but is hypertension a disease if the
21 person doesn't have a stroke until it had 20 years
22 of hypertension, is a plaque in the coronary artery
1 atherosclerosis if the patient hasn't had angina.
2 So, I would suggest that the disease is a
3 set of pathogenic events in tissue and tissue
4 injury that we don't have either the imaging
5 technology or the patient may be asymptomatic up to
6 a point, but eventually that patient who has that
7 disease will most commonly get some kind of
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
18 DR. MILLER: Dr. Kale.
19 DR. KALE: It seems clear that the
20 degeneration of cartilage is necessary, but not
21 sufficient to create the syndrome of
22 osteoarthritis, but if we are forced to acknowledge
1 that every human being will develop this condition
2 of cartilage degeneration, but may or may not
3 develop the syndrome of osteoarthritis, then, we
4 have embraced a very large definition, which is
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
10 The notion that you could prevent the
11 syndrome from developing by using a product like
12 chondroitin sulfate or glucosamine, with the
13 possibility of reducing a universe of patients from
14 having the symptoms, and given again that we are
15 all going to develop some evidence of cartilage
16 degeneration, seems like a very worthy idea, and
17 the fact that we can't define a modifiable risk
18 factor for our satisfaction seems an unfair burden
19 to place on the petitioners.
20 My basic point is that in a certain sense,
21 walnuts are to LDL as chondroitin sulfate or
22 glucosamine is to reduction of cartilage
1 degeneration, and in that sense, the modifiable
2 risk factor would be, for the purpose of this
3 hearing, would be modifying the risk factor of
4 degenerating cartilage.
5 You could reduce the degeneration of
6 cartilage and, in some patients, some fortunate few
7 or some fortunate many, they would not go ahead and
8 develop osteoarthritis and perhaps the rest would.
9 That is no better than we can say for
10 Lipitor or any other drug or any other drug as we
11 are trying to treat diseases relevant to, say,
12 cardiovascular disease.
13 DR. MILLER: Dr. Cush.
14 DR. CUSH: I think that it is clear we
15 can't make any 100 percent certain statements about
16 relatedness and/or discrete time variables where
17 events, pathologic or otherwise, lead to actual
19 I think what we can say is, you know, use
20 the term "reasonable certainty," and I think that
21 is much more operationally important here.
22 I would use the analogy that is a
1 catastrophic motor vehicle accident or skiing
2 accident a risk factor for developing
3 osteoarthritis? Yes, it is. I mean such an
4 individual is more likely than not to have his or
5 her cartilage damaged to the point that it will
6 lead to a secondary osteoarthritic joint.
7 Similarly, although that is much more of a
8 macroscopic insult, here, we are talking about
9 microscopic insults, hence, I would say that
10 cartilage degeneration or deterioration is also a
11 risk factor for the development of osteoarthritis,
12 and a statement using sort of a reasonably certain
14 I think most of us, I wasn't happy with
15 it, but I think that we know that, in fact, that
16 that is not a good thing, and there is a reasonable
17 risk for development of osteoarthritis.
18 DR. MILLER: Dr. Dwyer.
19 DR. DWYER: I think where I am confused
20 is, is it a risk factor or is it a sign that the
21 disease is already present. To me, it seems like
22 it is a sign, from what some of you experts say, it
1 is a sign that the disease is already there. So,
2 it is not a risk factor, it is a sign of the
3 disease, which is different, at least in my head it
4 is different.
5 DR. CUSH: For the person who gets the
6 disease, yes, it is, but as we have said, there are
7 people who have cartilage abnormalities who will
8 never have symptoms.
9 DR. DWYER: But that doesn't bother me
10 because all of these diseases are multifactorial,
11 so there are a lot of people who have a whole bunch
12 of different characteristics, but they don't get
13 the disease.
14 DR. CUSH: I don't understand. I mean you
15 are going to discard those people who have, and not
16 consider them, is that what you are saying, people
17 who have cartilage abnormalities, because again, if
18 we are going to accept that they are not important,
19 then, we may be overtreating or subjecting a large
20 segment of the population to products that they may
21 not need. I think we have to consider them.
22 DR. MILLER: Dr. Zeisel.
1 DR. ZEISEL: Let's retreat to some ground
2 that has already been covered, I believe, by the
3 FDA. Individuals, treatments that can lower
4 cholesterol are allowed to say that they are
5 beneficial in the prevention of atherosclerosis and
6 cardiovascular disease.
7 We all know that everybody 17 years and up
8 has atherosclerosis already to some extent, that
9 none of them, if taken apart by a pathologist,
10 won't show atherosclerosis, and yet we don't say
11 they have the disease, and we are willing to say
12 that in even a 30-year-old or 40-year-old or
13 50-year-old, lowering cholesterol is reducing a
14 risk factor for cardiovascular disease even though
15 they have it by any definition, that we all have
16 some cardiovascular disease right now.
17 So, I think drawing on that analogy,
18 saying that reducing cartilage degeneration is a
19 reduction in risk for developing osteoarthritis
20 seems to be a fair parallel, and just as everybody
21 with high cholesterol doesn't go on to develop an
22 MI or need a bypass, everybody who has abnormal
1 cartilage doesn't go on to need a knee replacement
2 or whatever.
3 So, I think we have a fair analogy to a
4 situation that is already in place, and that if we
5 start from there, we can move on to ask some of the
6 more difficult questions about whether changes in
7 evidence of this risk factor have anything to
8 do--in diseased patients have anything to do with
9 changes in patients who you would not have
10 clinically said had the disease osteoarthritis.
11 DR. MILLER: Dr. Blonz.
12 DR. BLONZ: So, we keep coming back to the
13 same point. Are we dealing with, as soon as it's
14 here, you have got the disease, or is it a process
15 which can be thought of as a risk factor that
16 basically puts you in queue to the point that all
17 we are doing is waiting for you to report the
18 symptoms and then get the radiographic
19 confirmation, and then you are officially labeled,
20 and the disease is put on your chart?
21 So, we are dealing with terminology and
22 subjectivity, not having the objective factors like
1 we might have with coronary artery disease where we
2 can measure this biomarker of cholesterol in the
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
2 Dr. Lane.
3 DR. LANE: I would like to comment on
4 that, two points. One is I think there is a
5 continuum that keep being jumped to, and I am
6 concerned about it. One is we know that if you
7 have heart disease and your cholesterol is high,
8 and you take the statin and you lower the
9 cholesterol, and the disease slows down its
10 progression, and that data led us then to looking
11 at lowering cholesterol in people who didn't have
12 clinical disease, and then found that, gee, it did
13 prevent the onset of the clinical disease.
14 But even though we know cardiovascular
15 disease is a continuum, we have strong evidence to
16 support now that lowering your cholesterol prevents
17 an event of the clinical disease, and I feel
18 strongly that we need to show that all we know, I
19 know so far with the medications on the table, if
20 you have disease, they do something, but we don't
21 have anything on the preventive side, and your
22 point is well taken that until we know what those
1 markers or surrogates are to tell us disease is
2 coming, we are just jumping into an unknown area.
3 That is why I am a little concerned about
4 making parallels.
5 DR. ZEISEL: There are lots of people with
6 high cholesterol that don't get heart disease,
7 there are lots of people with low cholesterol that
8 go on and have MIs, it is just as uncertain, but
9 somehow people have said they are willing to say
10 that there is enough of a relationship that they
11 are willing to use this imperfect biomarker, and I
12 think cartilage degeneration is that similar thing.
13 There are some things that don't exactly
14 fit, that don't always follow, but, in general, you
15 feel that a person is at higher risk if you come in
16 and their cartilage is degenerating, of coming down
17 with a clinical syndrome, and I think the same
18 thing is true with cholesterol.
19 Many people have very low cholesterol and
20 go on to have heart attacks. They have heart
21 attacks for other reasons than cholesterol, and
22 that may be true with OA.
1 DR. MILLER: Dr. Waslien.
2 DR. WASLIEN: I think we need to look at
3 the history of the development of these two
4 indicators to call an analogy with cardiovascular
5 disease when it took us 20, 30 years to do the
6 clinical lipid trials to prove that indeed lowering
7 cholesterol would have an effect.
8 I think we are at the stage of saying
9 maybe reduction in cartilage will have an effect,
10 but we don't have data to prove it. So, to jump to
11 the conclusion of saying, well, we will use this as
12 a marker when we don't have the kind of many years,
13 I mean the cholesterol history is 40, 50 years old,
14 of knowing that people had elevated cholesterols,
15 but not knowing if it made any difference.
16 So, I think we are in that stage of saying
17 yes, people have degenerated cartilage, but will
18 changing that degeneration have any effect on
19 osteoarthritis, I think those trials are needed
20 before we can say anything.
21 DR. MILLER: Well, it is possible for us
22 to say that there is a relationship, we don't
1 understand it yet, and that once we get the data,
2 it can be used, and to indicate we don't have the
3 data yet. I mean there are a lot of possibilities.
4 The DRI Committee at the Institute of
5 Medicine ran into this with the relationship
6 between saturated fat and cholesterol. The
7 American Heart Association published a chart that
8 showed the relationship between saturated fat in
9 the diet and cholesterol, serum cholesterol, went
10 to zero, in other words, you had some increase in
11 cholesterol even at very low levels of saturated
12 fat intake.
13 They came to the conclusion that they had
14 to make an arbitrary distinction, is it possible
15 not to have saturated fat in the diet.
16 Dr. Cush.
17 DR. CUSH: I would like to first caution
18 everybody to stop talking about diseases which you
19 know too much about, meaning like, you know,
20 hyperlipidemia and stroke, because we have great
21 models and, as was stated, many years of history,
22 and we don't know that the analogy to
1 osteoarthritis is going to be as clear.
2 It seems logical, but it may, in fact, not
3 be, and osteoarthritis may not be one disease, but
4 may be several. I mean, for instance, in lupus, a
5 disease that we know a lot about, that we see a lot
6 of it, but all of those patients have some degree
7 of renal damage that one would pick up on biopsy,
8 but yet there is only a small proportion of them
9 with certain types of damage that will go to
10 develop renal failure and outcomes there.
11 Again, we have to be careful about
12 extrapolation from other human models, and even
13 animal models, that there is a gigantic leap of
14 faith which makes us all the more uncertain.
15 I think that cartilage and cartilage
16 deterioration could be a surrogate marker for the
17 disease, but the problem is that that is not
18 something that is measure in daily routine
19 practice. We don't measure that, we don't examine
20 that, I don't image that. As we heard, there are
21 lots of problems with quantifying and assessing
22 cartilage damage even in well constructed trials.
1 But I think we have to move on, because I
2 think we have said this over and over that as Dr.
3 Blonz said, if you have cartilage deterioration,
4 you are in queue. It is a risk factor for the
5 development of disease. I think that that is
6 something that has been said over and over. I
7 don't know there is much disagreement with that at
8 this point.
9 So, I mean I think that question has been
10 answered and we can move on.
11 DR. MILLER: Dr. Russell.
12 DR. RUSSELL: This is a question for the
13 rheumatologists. Is there some point along the
14 continuum of joint deterioration where it becomes
15 really much more likely that a person will develop
17 I mean I realize you can have significant
18 deterioration without developing the clinical
19 syndrome, but is there some point along the
20 continuum to say, well, this person is really
21 likely to?
22 DR. CUSH: No. You are asking for more
1 certainty that has already been expressed, so no.
2 DR. LANE: Not only no, but what is
3 surprising is if you take all the data we have, an
4 x-ray, and everything else, and the people that you
5 think should have it don't, and the people that
6 have sometimes a more normal x-ray, when they go to
7 surgery, et cetera, do.
8 DR. RUSSELL: Thank you.
9 DR. MILLER: Dr. McBride.
10 DR. McBRIDE: I have a little trouble with
11 the analogy with the cholesterol, because, as a
12 neurologist, if you have a stroke, it's a big deal,
13 and it is not the same kind of a continuum as
15 We are a little bit bogged own here with
16 semantics, but if you look at the FDA definition of
17 a modifiable risk factor, which is what we are
18 being asked, it is a measurement of a variable
19 related to a disease that may serve as an indicator
20 or predictor of that disease.
21 If we all agree that by the time you have
22 pain and dysfunction that you have the disease, it
1 is hard not to call cartilage deterioration a risk
2 factor. Certainly, it would not be ignored in any
3 kind of early studies looking at prevention. I
4 mean there is a whole other question of whether or
5 not modifying it during the disease means that you
6 can modify the risk. We have to take that up.
7 DR. MILLER: Dr. Krinsky.
8 DR. KRINSKY: I agree with Dr. McBride,
9 with her comments, but the thing that concerns me
10 about the cholesterol/cardiovascular disease
11 analogy is that I don't see where we have a
12 cholesterol, and lacking a cholesterol, the analogy
13 fails, so that unless there is an appropriate
14 biomarker for determining the moment or, at some
15 time, the extent of your cartilage deterioration,
16 how does one evaluate this short of having a
17 patient wait a week, a month, a year before they
18 report pain. I don't see whether you can evaluate
20 DR. MILLER: Well, just a matter of
21 clarification, it would seem to me that there is no
22 reference to a time scale here, in other words, how
1 long after you have identified joint degeneration
2 do you have to develop full-blown osteoarthritis
3 for that to be a reasonable relationship. I don't
4 see that. All you have to do is be able to
5 ultimately show that there is some relationship no
6 matter how slow the rate may be.
7 Dr. Harris.
8 DR. HARRIS: I would like to return to Dr.
9 Miller's point regarding the possibility that we
10 may be diagnosing something that is not related to
11 arthritis or may not have the same outcome.
12 In preparing for this meeting, I did do
13 some reviewing of the literature that basically the
14 question of could there be other factors involved,
15 and one thing that struck me very unusually was a
16 condition called Wilson's disease in which there is
17 actually an accumulation of copper in the joints
18 that leads to swelling, and so forth.
19 I was hoping to find papers that would
20 suggest that Wilson's disease is indeed a very good
21 predictor or people who suffer that disease are
22 going to be perhaps coming down early with
1 arthritis. I could not find that evidence, but it
2 does indicate that there could be other mitigating
3 factors here other than just one case we are
4 dealing with two different diseases and mixing the
5 two of them together may be the wrong thing to look
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
14 DR. HARRIS: Yes, I think that was the
15 point I was trying to make, that there could be
16 other factors. Perhaps this is addressing the
17 question of the etiology, but it is also addressing
18 the question of a misdiagnosis.
19 DR. MILLER: Dr. Kale.
20 DR. KALE: Yes, I am one of the proponents
21 of the LDL/osteoarthritis analogy, and I still
22 think that it holds, and I think it holds to a
1 reasonable degree of medical certainty, because the
2 final common pathway, again necessary but not
3 sufficient, in the development of osteoarthritis
4 has to be some degeneration of cartilage whether
5 the degeneration is primary or secondary as in the
6 case hemochromatosis or Wilson's disease or trauma
7 or infection or rheumatoid disease, whatever it
8 happens to be.
9 if there is a reasonable likelihood that a
10 product, call it glucosamine or chondroitin
11 sulfate, can preserve the cartilage and reduce its
12 likelihood to a reasonable degree from degenerating
13 and becoming a sufficient, unfortunately, as well
14 as necessary, cause of the syndrome of
15 osteoarthritis, if you can prevent that, then, it
16 strikes me it has the same status, without meaning
17 to demean it, as walnuts. It is a modifiable risk.
18 You modify the risk of osteoarthritis by
19 providing a dietary product that seems to work
20 beneficially on cartilage to preserve it. In that
21 sense, once again, I would retreat back to the
22 analogy as being reasonable. Walnuts is to LDL as
1 chondroitin or glucosamine is to cartilage.
2 DR. CUSH: That latter point, I mean you
3 now have ventured into the proof of intervention
4 having an effect on the biomarker and outcome.
5 DR. KALE: What I am trying to do is say
6 that there is a modifiable risk factor, and that is
7 cartilage, probably, and I agree with what you said
8 earlier, that if you can make a reasonable
9 assumption, I think this is still reasonable, based
10 on clinical data, I mean obviously we haven't got
11 the sort of data you have for--there is not a
12 generation of data as there is for cholesterol.
13 So, the best one can do under the circumstances.
14 The other point I would make, by the way,
15 it seems to me, because I am old enough to remember
16 this, that coumadin and linoxin, these are drugs
17 that were never tested, we simply believe they
18 worked in the patient populations for whom we used
19 them, and we continue to do so, and that is a
20 reasonable presumption, and it seems to be a
21 reasonable presumption.
22 I am making a similar reasonable
1 presumption about this particular product.
2 DR. MILLER: Well, we have to be careful
3 using drug examples. The standard for evaluating
4 drugs is different than the standard for evaluating
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
16 It seems like to me it would be hard to
17 say that it is not.
18 DR. MILLER: Dr. Archer.
19 DR. ARCHER: I just need some
20 clarification on a point. I thought I heard Dr.
21 Cush say that in the diagnosis, he didn't diagnose
22 it radiologically, in which case, I am now talking
1 about deterioration of cartilage.
2 If that is the case, are we talking about
3 joint space reduction, which is kind of one step
4 back, so we are looking at a predictor of another
5 predictor? So, I am getting a bit confused as to
6 what it is we are actually talking about here.
7 If cartilage deterioration is something
8 that you really don't know about until the patient
9 presents with symptoms in most cases, is that a
10 predictor, or is it a reasonable predictor?
11 DR. MILLER: Dr. Abramson.
12 DR. ABRAMSON: I guess that comes back to
13 our fundamental discussion, is Alzheimer's disease
14 a disease before a person is overtly demented, or
15 is it a pathological event that happens over time,
16 the signal for which symptomatologywise, we see
17 towards the end stage of that process.
18 Again, I think, and we have different
19 views, I think the LDL may not be a good analogy
20 because it is truly a surrogate marker of a process
21 that leads to damaged tissue, and one of the
22 reasons that there is discrepancies as to whether
1 lowering or not is helpful, is it may be not even a
2 true marker of the disease, but a surrogate for
3 something else that a statin is doing, for example,
4 whereas, fibrillated cartilage arguably is the
5 earliest phase of the disease that we call
6 osteoarthritis, like the first plaque in the brain
7 of someone who is going to get Alzheimer's disease.
8 I would be certainly willing to say it is
9 a necessary event along the pathway that ultimately
10 leads to clinical symptoms, but kind of the
11 medieval discussion we are having now is, is this
12 the disease or is it a marker of the disease.
13 Perhaps that has some legal ramifications with
14 regard to the charge to the committee because I
15 would argue that it is not normal joint, it's the
16 first event in a very protracted process, and that
17 process where we are struggling in the field is to
18 figure out, even if we jump beyond the histology
19 and we jump to the imaging and biomarkers, trying
20 to predict who is going to get the disease, knowing
21 the earliest markers, has led to a lot of
22 surprises. Things that we think are going to
1 predict bad outcome tend not necessarily to be the
3 So, I think, you know, just to come back,
4 I think it is how we define earliest phase of
5 disease versus a marker of that disease when we are
6 in the tissue itself that we are kind of having a
7 debate over.
8 DR. MILLER: Dr. Dwyer.
9 DR. DWYER: I just wanted to make sure I
10 had understood what particularly the
11 rheumatologists had said.
12 Are you saying that cartilage
13 deterioration and joint degeneration are risk
14 factors of disease, the first step in a protracted
15 process that may or may not be modifiable? In
16 other words, is the argument really over whether
17 there is modification, everybody agrees that there
18 is a risk factor?
19 DR. ABRAMSON: I guess what I am saying is
20 that the earliest phase of a disease--the disease
21 has a set of histological changes that a
22 pathologist will differentiate, hemochromatosis,
1 you know, OA from RA, from earliest phases of these
2 diseases, you can determine by pathological
4 Just having that earliest phase of
5 fibrillation or fissuring, which is what they early
6 see, the deterioration, it doesn't predict that
7 that patient is going to develop clinical symptoms,
8 and people follow different courses. Understanding
9 why some people follow different courses, I think
10 is the challenge in this particular field, but the
11 disease arguably starts with these earliest
12 classical changes of osteoarthritis.
13 DR. DWYER: So, it goes back that it is
14 necessary, but not sufficient.
15 DR. MILLER: Dr. Blonz.
16 DR. BLONZ: So, I am looking at the
17 semantics of the Question No. 1. If this were
18 worded is a degenerated joint a state of health,
19 that is very different than joint degeneration.
20 Similarly, is a deteriorated cartilage,
21 then it is a fait accompli, so we know there is a
22 homeostasis going on within the joint milieu where
1 you end up getting synthesis and degradation
2 hopefully in balance, but as soon as that turns
3 into a negative where you have more degeneration
4 than resynthesis, you have the process of
5 degeneration or deterioration in the joint and in
6 the cartilage.
7 When this progresses to the point where
8 you have a change that could be identified
9 histologically or symptomatically, then, you would
10 end up getting this diagnosis.
11 So, if we can look at the process and then
12 take the step forward, is this a process that once
13 it begins, once you have got that negative going
14 on, can this be modified prior to the diagnosis of
15 osteoarthritis, then, we may be able to step
16 forward and to answering 1(a) and 1(b).
17 DR. MILLER: Dr. McBride.
18 DR. McBRIDE: I again just keep coming
19 back to the issue, the semantics of the earliest
20 joint degeneration or cartilage deterioration,
21 whether or not that is a disease, I don't think we
22 are going to be able to answer, but the question is
1 can you imagine that if you have 100 people
2 with--and you name the measurement, however it can
3 be measured--that show cartilage degeneration and
4 100 who do not, is it too big a leap in faith to
5 say that the 100 who have it are at higher risk for
6 osteoarthritis? That is what a risk factor is.
7 DR. MILLER: Dr. Nelson.
8 DR. NELSON: A question for the
9 rheumatologists. Is an individual with clear
10 anatomic signs of deterioration and change, but
11 expresses no pain or says he or she has no pain, is
12 that person in a healthy state?
13 DR. CUSH: Go ahead.
14 DR. ABRAMSON: Well, yes, they can
15 certainly be in a healthy, functional,
16 non-disease--that is a difficult issue. That
17 depends on how you define health. That is why I
18 would argue that joint degeneration is not normal
19 age matched, in other words, you may have the
20 disease, but not have symptoms of the disease. It
21 is not a normal state for your cartilage.
22 Now, whether you are a normal person, to
1 the extent that most of us may have some OA and
2 like to think ourselves as normal healthy
3 individuals, I mean is another kind of discussion.
4 DR. CUSH: So, to answer your question, in
5 Dr. Abramson's lab, he can have a age matched
6 individual who has no symptoms, but may have some
7 joint degeneration or may have none at all.
8 But you can also have someone who has
9 joint degeneration, whatever that may be, and no
10 symptoms, and that person can have what we call a
11 neuropathic joint or Charcot joint due to syphilis.
12 Obviously, that is not a good state of health.
13 I strongly dislike the term joint
14 degeneration because of the vagueness of it and the
15 multitude of inputs that may lead to it, you know,
16 land mine gout, rheumatoid arthritis, syphilis,
17 whatever, all lead to joint degeneration. I would
18 not want the FDA to be joined to that term for
19 these proceedings, but that is my impression. I
20 would ask the chairman to address these points
21 maybe directly at each of the rheumatologists, and
22 then see if we can move on or not.
1 DR. ESPINOZA: Just to confuse you some
2 more, you know, we made the diagnosis routinely of
3 osteoarthritis in individuals, they are totally
4 asymptomatic now. That is routinely.
5 DR. MILLER: Dr. Cush, would you argue
6 that cartilage deterioration has the same problem?
7 DR. CUSH: No, because as Dr. Abramson
8 pointed out, cartilage deterioration is the
9 pathognomonic finding, maybe the earliest finding
10 that sets off the cascade that leads to
11 osteoarthritis. I think it has a specificity
12 attached to it that is appropriate to these
14 DR. MILLER: So, for Question 1, would you
15 agree--I will just lay this on the table--that
16 there is a consensus that joint degeneration is not
17 a state of health leading to the disease,
18 modifiable risk factors, and cartilage
19 deterioration is?
20 DR. CUSH: That is how I would
21 characterize it. As I stated earlier, I think that
22 if one has evidence of cartilage deterioration, as
1 Dr. Blonz said, you are in queue and you are at
2 risk although it is not certain that you will get
3 there, at least you are at risk.
4 It appears that it may be modifiable, yes.
5 DR. MILLER: I am just probing the depths
6 of your belief.
7 Ms. Halloran.
8 MS. HALLORAN: It sounds like--so we do
9 have consensus that joint degeneration is not a
10 state of health, et cetera, and that cartilage
11 deterioration is, and we can perhaps go on to what
12 are the strengths and limitations of the evidence.
13 We, I think have consensus that cartilage
14 is necessary, but not sufficient, that there may be
15 other factors, precipitating factors that lead to
16 disease, which are as yet unidentified and that the
17 entire population actually falls over a certain
18 age, falls into the people, the group at risk, so
19 that identifying this risk pool, there may be
20 limitations on its usefulness. At least that is
21 what I would say.
22 DR. MILLER: Dr. Lane.
1 DR. LANE: I just wanted to clarify
2 something for the record. I actually think, you
3 know, I agree with cartilage deterioration, that is
4 probably the best we can do, but we have to be very
5 careful because you would think that we would have
6 clear evidence that slow cartilage degeneration
7 would modify the disease and both, for the most
8 part, in clinical trials and otherwise, we don't
9 have that, but I believe that I have faith in
10 that, but that is what it is, it's faith because
11 our multiple examples came up yesterday, and will
12 continue to, that by slowing it, we haven't changed
14 DR. MILLER: Dr. Mehendale.
15 DR. MEHENDALE: I wanted to reinforce the
16 same concept that Dr. Lane just said, and that is
17 the implication of disease if we accept that
18 cartilage deterioration is pathognomonic. What I
19 heard was to about a third of the patients.
20 We could also say it is not pathognomonic
21 for two-thirds of the people. So, we are still
22 trying to protect the one third where it could be
1 pathognomonic. The other side of this is we make
2 an assumption that there is something we could
3 overcome by supplementing with these substances in
4 the third where it is pathognomonic. I think the
5 concept that Dr. Lane just said. I just wanted to
7 DR. MILLER: Dr. Abramson/
8 DR. ABRAMSON: We are making some
9 progress, but I would like Dr. Rowlands now,
10 because we are not coming down to the language, I
11 am not fully sure I understand.
12 How do we define, what is meant by
13 cartilage deterioration and what is the distinction
14 between that and cartilage degeneration?
15 DR. ROWLANDS: These were specifically
16 worded by the petitioners. That is how we chose
17 these terms. FDA did not come up with these terms,
18 but they have been used in the literature, and this
19 is the language that they wanted in the claims, so
20 that is why they were actually worded this way.
21 DR. ABRAMSON: I hate to beat a dead horse
22 here, but I don't understand--maybe Dr. Cush who
1 did make a differentiation--I am not sure that I
2 understand if we agree to one and not the other,
3 what is the distinction that we are being asked to
4 make by the petitioner.
5 DR. ROWLANDS: These are specifically
6 written as separate questions, so that if you can
7 agree to one and not the other, that is fine. You
8 don't have to link them together. They are written
9 specifically to be separate, so that you can
10 actually conceptually deal with them separately if
11 you wish, that's fine.
12 DR. CUSH: I would respond by saying that
13 it was written, in 1(a), the more pedestrian sort
14 of terminology that, you know, something may be
15 good for joint health and protecting its joint
16 degeneration, and whatever, and that is again a
17 very lay person's view of what is obviously a much
18 more complex issue, as I indicated with may
19 analogies and why I wouldn't want that.
20 I think that nonetheless, the lay public
21 has some knowledge of cartilage as being involved
22 here, and that may be the target of therapies and
1 interventions, so to use that also.
2 I think it would obviously be much more
3 advantageous to any product out in the public
4 domain to have the more generally accepted, more
5 widely recognized terminology albeit misleading.
6 DR. MILLER: Does that clarify the
7 situation for you as much as it is going to?
8 Dr. Blonz.
9 DR. BLONZ: Let me pose the question then.
10 If you have cartilage deterioration, do you not
11 also have degeneration of the joint?
12 DR. CUSH: Yes, and the converse, no.
13 So, my statements go to is it a modifiable
14 risk factor or surrogate endpoint of OA risk
16 What we learned yesterday and what we know
17 from the literature is that weight reduction is a
18 modifiable risk factor for osteoarthritis, certain
19 occupational adjustments are modifiable risk
20 factors. What wasn't stated, but probably is true
21 from other lines of evidence, is that control of
22 inflammation would be a modifiable risk factor for
1 OA progression.
2 What we don't know is changes in this
3 parameter as modifiable risk factor for OA
5 DR. MILLER: Dr. Lane.
6 DR. LANE: I want to just make a point for
7 the record. A modifiable risk factor is actually
8 one that you have tested and the evidence is
9 strong, evidence meaning a randomized controlled
10 trial or a couple population studies.
11 Weight loss has never--there is one
12 epidemiologic study in OA from Framingham that
13 shows that people who lost 12 pounds over five
14 years had less knee pain. There has never been a
15 randomized controlled trial showing that weight
16 reduction change joint degeneration, i.e.,
17 cartilage narrowing or pain.
18 So, we use modified risk factor, that
19 would assume that there is some very strong
20 evidence behind it. We all believe that weight
21 loss is going to help, but it has never been shown,
22 so careful, careful.
1 DR. MILLER: I think if you read the
2 question, there is a way of dealing with that.
3 There is really two questions that are being asked.
4 One, are they modifiable risk factors, and, two,
5 what is the evidence to support it.
6 I think it is perfectly possible to say
7 that yes, it's a modifiable risk factor, but the
8 evidence isn't strong or whatever.
9 DR. LANE: I agree.
10 DR. MILLER: Dr. Zeisel.
11 DR. ZEISEL: Why don't we just try to move
12 forward and say that we have some consensus that
13 cartilage deterioration is a modifiable risk
14 factor, but the evidence for it is not particular
16 DR. MILLER: We are coming to that. I
17 just want to make sure that everybody feels that
18 they have had a chance to express their views.
19 Dr. McBride.
20 DR. McBRIDE: It sounds like part of the
21 difficulty we are having is with the word
22 "modifiable." Actually, in the definition of risk
1 factor or at least in the first part of that
2 definition, that word "modifiable" doesn't appear.
3 I am sure we are probably not allowed to
4 change the question, but if we put the word
5 "potentially," would that help?
6 DR. LANE: I would say yes because, you
7 see, where we are at here is pathologically, and I
8 don't even know if Steve and I know the answer to
9 this, if you have a little bit of cartilage
10 narrowing, that may mean already that your
11 cartilage is going, and even though you might lose
12 50 pounds, your cartilage is still going to go.
13 So, it is potential.
14 DR. MILLER: I think one point that would
15 be worthwhile re-emphasizing again is that this,
16 like most biological processes, are multifactorial,
17 there are a number of factors that are certainly
18 going to affect the outcome.
19 From what I understand, and naively
20 listening to the discussion over the last two days,
21 that there isn't enough data to be able to really
22 define what these multiple factors, how they
1 interact, et cetera.
2 I think as far as being able to say
3 potentially, we could say whatever we want. We
4 don't have to modify the questions. We just have
5 to say yes, cartilage deterioration is a state of
6 health leading to disease or is a potential
7 modifiable risk factor, so we can just lay that out
8 any way we see fit.
9 Dr. Zeisel.
10 DR. ZEISEL: So, the argument is not that
11 it's modifiable, we clearly saw evidence that you
12 can modify cartilage deterioration, make it go up
13 or down, what the argument is, is whether that
14 modification has anything to do with delay of the
15 onset of OA.
16 DR. MILLER: Right.
17 DR. ZEISEL: So, it is a modifiable risk
18 factor, and the strength of evidence that it
19 modifies OA is weak, but there is no question that
20 you could modify cartilage because we have seen
21 that you can have more or less. It may not be
22 perfect cartilage, but that is for an argument. It
1 certainly is a modifiable factor just like taking
2 cholesterol down or up can be done, or taking
3 atheromas up or down can occur.
4 So, I think it has to be a modifiable risk
5 factor, it just may not modify the risk for
6 osteoarthritis, which is a different question,
7 which is where the scientific evidence comes in.
8 DR. MILLER: Right.
9 Dr. McBride.
10 DR. McBRIDE: Well, I don't think we heard
11 very much evidence that it is modifiable in the
12 pre-disease state with disease defined as symptoms.
13 DR. MILLER: Again, I think the issue is
14 we can agree that cartilage deterioration is a
15 modifiable risk factor or potentially a modifiable
16 risk factor, modifiable potential risk factor, but
17 we don't necessarily have to say that there is any
18 evidence that there is anything that does that.
19 That is a different question.
20 So, can we agree that a distinction can be
21 made between joint degeneration and cartilage
22 deterioration in the context of this question, and
1 that we can argue that joint degeneration is not a
2 modifiable risk factor, and cartilage deterioration
3 is a modifiable risk factor?
4 DR. CUSH: Only in terms of OA risk
5 reduction, because again, joint deterioration is a
6 modifiable risk factor for a lot of different
7 things, and this is what my career is based on.
8 You know, I am trying to modify joint deterioration
9 through things that we do to treat, but I treat
10 over 100 different types of arthritis, so here
11 today we are talking about osteoarthritis.
12 DR. MILLER: Okay. By the way, just to
13 make sure everybody understands, these discussions
14 will be reflected in the report, in the transcript
15 of the report.
16 DR. CUSH: Oops.
18 DR. MILLER: Just trying to help you out.
19 I think we have discussed the strengths
20 and limitations of the scientific evidence on this
21 issue to some extent. Does anybody want to add any
22 comment to that?
1 So, we have a consensus on Question 1?
3 Question 2. I have to admit that I have
4 trouble trying to make a distinction between
5 Question 1 and Question 2 here.
6 DR. CUSH: Mr. Chairman, I would like to
7 suggest that Dr. Zeisel's sort of summary comment
8 is probably the most accurate.
9 DR. MILLER: Fine.
10 DR. CUSH: That again, that it is a
11 potentially modifiable risk factor, but that the
12 association with--that it may alter OA risk
13 reduction is questionable.
14 DR. MILLER: We will take your comment
15 from the transcript, and we will take it verbatim.
16 DR. ROWLANDS: Take away my translation,
17 so now you only have the question.
18 DR. MILLER: This again comes to the
19 question of how to define a generally healthy
20 population. I think we have discussed that at
21 great length.
22 Do anybody else have any further comments
1 to make on this issue?
2 DR. ZEISEL: So, here, the only issue that
3 came up yesterday is are there normal joints in
4 patients with OA, that the study of which would
5 give you data that has to do with deterioration in
6 "normal" individuals, or is having OA in one joint
7 enough to indicate that all the other joints are OA
8 joints, because I think we all agree that studies
9 in an OA patient do not accurately predict in their
10 OA knee, for instance, that a treatment that might
11 mitigate the already osteoarthritic knee's
12 progression might have nothing to do with the
13 incipient disease's progression earlier.
14 But the question is are in their otherwise
15 not diagnosed joints, do they have OA or are they
16 incipient OA, and therefore, you could use data in
17 a study that used OA patients, but you could not
18 use the OA knee, but rather the control knee.
19 DR. MILLER: Dr. Lane.
20 DR. LANE: Unfortunately, the studies that
21 are there, and one of them was actually just
22 NIH-funded and completed rather recently, the data,
1 the answer is we don't have that data, and probably
2 that data will take another five to seven years at
3 best to accumulate.
4 A very large study was done, I mentioned
5 yesterday, where people who seemingly had a normal
6 knee were treated with an agent that was to prevent
7 OA, but they didn't get OA, the controls didn't get
8 OA, so we don't have that data, unless you guys
9 know that.
10 DR. MILLER: Dr. Cush.
11 DR. CUSH: No, I think that again we are
12 talking about the development of OA in the
13 contralateral meaning of the person who has an
14 index OA, let's say, on the right side, but not on
15 the left, and then would some intervention prevent
16 the normal knee from developing disease, and that
17 is the kind of research we need to look at, and
18 that is very important research.
19 I think getting to this question, the
20 language of a dietary substance treating,
21 mitigating, or slowing joint degeneration again
22 does sound like that used for a drug, and not for a
1 dietary supplement, but nonetheless, the question
2 is, is it valid to use such research to suggest a
3 risk of OA in the general population being reduced
4 if that dietary substance is applied, I think only
5 if there is research to that effect, because we
6 learned yesterday that, you know, that the
7 chondrocyte is different at different stage of the
8 disease, and how it functions, and most of these
9 trials about changing joint deterioration of
10 cartilage deterioration thus far have been focused
11 not on people at risk, or on normal people, but
12 instead, have been focused on people who have the
13 disease, well-established disease.
14 And to say that the cartilage would behave
15 the same in a normal person, or a person who has
16 risk factors, whether that be a genetic risk
17 factor, or a traumatic risk factor, or a copper
18 deposition risk factor is really unknown, and I
19 think that is again a gigantic leap of faith for
20 which I can't connect the dots.
21 DR. MILLER: Dr. Blonz.
22 DR. BLONZ: So, you if we read Question 2,
1 there is an assumption that that data is in hand.
2 If we assume that research demonstrates that this
3 has this effect, granted we don't have that data
4 right now, but if that research existed, would show
5 that the substances at question could produce this
6 desired effect, would we run with it, and that is
7 really what we are being asked to by this question.
8 DR. CUSH: The question states, Dr. Blonz,
9 in OA patients, if it produced that desired effect
10 in OA patients, would it then be reasonable to
11 extrapolate that to a normal healthy population.
12 DR. MILLER: If we could define what that
13 normal healthy population is.
14 DR. CUSH: All of us, for instance.
15 DR. MILLER: That's pushing it.
16 Dr. Abramson.
17 DR. ABRAMSON: I think just to pick up on
18 those two points, I mean we do have data that was
19 presented by the applicants yesterday that in real
20 disease, in OA, there may be some slowing of
21 progression using these compounds, but I think that
22 is based on data and the notion of what is going on
1 in the diseased tissue, that, as Dr. Cush says,
2 might not be applicable to very different
3 circumstances in normal tissue.
4 I think that we have some little evidence,
5 and Dr. Lane referred to one of the NIH studies was
6 a study looking at doxycycline where it was looking
7 for the development of OA in the contralateral
8 knee, beginning with an index knee which was
9 diseased, in patients who were likely to progress,
10 and the unexpected outcome was that the
11 doxycycline, which its mechanism of action is based
12 on many of these events that we were talking about
13 yesterday, protected the knees from progressing
14 where those events were occurring in the signal
15 knee, but the primary outcome was that it might
16 also prevent progression in the high-risk,
17 relatively normal knee on the opposite side, and it
18 had no effect on the osteoarthritis in the
19 contralateral knee.
20 If the data are correct, it tells us that
21 interfering with processes in the disease doesn't
22 affect normal chondrocytes from developing
1 osteoarthritis, and I think that is a very
2 important study in that regard.
3 DR. MILLER: That is an important study.
4 Dr. Nelson.
5 DR. NELSON: Dr. Abramson basically
6 addressed my question, which was about the
7 contralateral knee that didn't show any anatomical
8 indication, or even if it did show anatomical
9 indication, would these agents slow or retard the
11 In the study you cited, did the
12 contralateral knee have anatomical indication, or
13 were they clean knees, so to speak?
14 DR. ABRAMSON: It's a good question. With
15 doxycycline, as I recall the study, it had either
16 no evidence or early evidence. They were not
17 clearly clean knees, though, but they were
18 significantly better and sometimes had minimal
19 signs of osteoarthritis.
20 DR. MILLER: Dr. Downer.
21 DR. DOWNER: I would like to go back. We
22 are being asked to use the data, use it as
1 implications for the general healthy population,
2 and I guess we really still do need to define what
3 that is.
4 You say that it is probably all of us
5 perhaps, and the question really is at what point
6 or how do we actually diagnose or say this is a
7 healthy population, is it a population of
8 absolutely free from OA, from the signs of it, from
9 the precursors of it, at what age or to what stage
10 do we really define that, since the implications
11 here are for the healthy population in fact?
12 DR. MILLER: Jean.
13 MS. HALLORAN: To respond to that point,
14 it seems like we are talking about healthy
15 population could refer to two kinds of healthy
16 population, the younger one that has no signs of
17 cartilage deterioration, or the older ones that
18 have signs, but yet no pain or symptoms of disease,
19 but it seems pretty clear from our experts that you
20 can't extrapolate to either of these healthy
21 populations from the population with disease. So,
22 it sounds like the answer to this question is no.
1 DR. MILLER: Dr. Russell.
2 DR. RUSSELL: Going back to the question
3 about whether a normal population would respond the
4 same way in a disease population, there was a
5 misstatement yesterday actually by one of the
6 presenters on the finger joint osteoarthritis
7 issue, because I looked at that trial last night.
8 It was a double-blind, placebo-controlled trial
9 using chondroitin sulfate, looking at the
10 progression of finger joint arthritis, as well as
11 new joints that would be involved.
12 When compared with the placebo controls,
13 none of the chondroitin sulfates prevented OA from
14 occurring in previously normal finger joints, that
15 is, they progressed in other finger joints whether
16 or not the person was on placebo or not.
17 However, the classic OA associated
18 anatomical lesions, when they were considered, OA
19 was less progressive in the treatment group, so
20 there was a response, in other words, or a
21 treatment effect in the people who had established
22 OA, but not in formerly normal joints, there
2 DR. LANE: Thank you for that
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
15 DR. MILLER: Dr. Zeisel.
16 DR. ZEISEL: So, let's be careful. We are
17 not being asked here to decide whether glucosamine
18 or chondroitin sulfate has anything to do with
19 this. We are just being asked can you design a
20 study in patients who have osteoarthritis, that
21 could shed light on the question about joint
22 development in normal people.
1 We heard really two types of answers, Dr.
2 Cush saying no, they are never normal, and right
3 after that, Dr. Abramson saying, well, in the
4 doxycycline study it didn't work, showing that
5 normal joints or relatively normal joints don't
6 respond the same as diseased joints, and in that
7 case, I would interpret that as saying that you can
8 use the contralateral knee or another joint in that
9 person to draw some inference about what would
10 happen in the less developed or relatively normal
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
20 It seems to me we are hearing several
21 answers, and we should resolve that.
22 DR. MILLER: That is a very important
1 point. We are not evaluating the petitions or any
2 other data that suggested any one particular
3 compound, whether it is the two that happened to be
4 the focus of the petitions here, or any other that
5 might come up in the future.
6 We are just trying to give the agency some
7 advice, so they can develop standards that could be
8 used for any material for which such claims are
9 going to be made. Good point.
10 Dr. Kale.
11 DR. KALE: No.
12 DR. MILLER: Dr. Lane.
13 DR. LANE: Yes. I think in the spirit of
14 giving advice, where I feel that we have come to a
15 stop sign or a stoplight, and we haven't gotten the
16 green light yet, and that is, that the reason that
17 I have a level of discomfort saying if you have OA
18 in one knee, if the other knee is normal, follow
19 that for the development of disease is because
20 probably the other knee isn't normal, but that is
21 because when I take an x-ray, it looks normal, but
22 when I use a better technology, which the field as
1 you heard yesterday is starting to embrace, and
2 that is MRI, and some fancy aspects of the MRI
3 where you can use gadolinium and sodium, and get
4 information about the chondrocyte metabolism and
5 the inflammation, and how much proteoglycan there
6 is, when we start to use those imaging modalities,
7 we will probably be better able to say what is
8 normal and what is a little diseased or a lot
9 diseased, but we can't do that with x-rays.
10 Does that make some sense to everybody
11 right now? So, the state of the art running a
12 clinical trial doesn't give us the information we
13 need to say what is normal or abnormal. Hopefully,
14 in terms of advice to the agency, that these
15 initiatives, that they are really driving it, using
16 MRI to try to distinguish what is disease and what
17 isn't disease, we will be able hopefully to do
19 That's my comment.
20 DR. MILLER: Is it fair to say--I am just
21 trying to clarify this in my own mind--is it fair
22 to say that in studies that looked at purportedly
1 normal tissue and diseased tissue, that the
2 response to the test materials was different?
3 DR. LANE: Yes, with the caveat that using
4 an x-ray outcome, that's right, using the x-ray
6 DR. MILLER: Using the tools that we have
8 DR. LANE: That's right.
9 DR. MILLER: Because that is a distinction
10 because we could say, for example, and I don't know
11 if we would get a consensus on this, that the
12 answer to this question is no, that based on
13 currently available data, there is no evidence to
14 suggest that one could be used to extrapolate to
15 the other.
16 DR. LANE: Yes, I agree.
17 DR. MILLER: I am just laying this out for
18 everybody, because consensus means everybody.
19 Dr. McBride.
20 DR. McBRIDE: Yes, I would agree with
21 that. I mean we are being asked is it
22 scientifically valid to use the results of
1 treatment trials to suggest that you can prevent,
2 even in some earlier stage of the illness, and no
3 matter how you define that, and I think that is
5 DR. MILLER: Dr. Abramson.
6 DR. ABRAMSON: Just one or two points.
7 Dr. Cush has the data on the doxycycline, and just
8 to be more specific, the diseased knees were
9 protected by 33 percent and progression in
10 doxycycline, but the primary endpoint was to look
11 at the opposite knee, which had zero or 1-plus
12 calgrin [ph], so maybe not normal, as Nancy says,
13 but certainly a different stage of the disease, and
14 there was no effect.
15 So, at least that informs us that at
16 different stages of the disease, a cartilage may be
17 more or less sensitive to an intervention. Most of
18 the studies that we have seen from the sponsor, and
19 we all engage in, is in the more advanced disease
20 where there IL-1 being added to the cartilage, so
21 it more mimics the responsive side.
22 I just wanted to go back to Dr. Zeisel's
1 comment, though, because I read this as a negative
2 answer, because it says that the data in the
3 diseased cartilage allows us to suggest a reduced
4 risk of OA in the generally healthy population.
5 It basically allows us, in my view, to ask
6 the question in a healthy population, but not to
7 make any statements about healthy population.
8 DR. MILLER: Dr. Zeisel.
9 DR. ZEISEL: Again, what this question to
10 me is trying to get at is how would you design the
11 experiment to do the experiment right. One way
12 would be to take randomly selected people with no
13 disease, follow them for 50 years, and ask do they
14 develop osteoarthritis. That is an impractical
15 experiment to do.
16 So, the question is, is it ever acceptable
17 to take individuals who have a joint involved with
18 osteoarthritis and follow their other joints, and
19 argue that that is a surrogate for the longer study
20 because these people are at higher risk for
21 developing other joint disease for whatever reason,
22 and that they have properties that are similar
1 enough to the general population that you could
2 then extrapolate the data from that population to
3 make conclusions about the general.
4 What I am hearing is that in a way they
5 behave differently in their non-involved joints,
6 that that behavior is what you, as experts, would
7 predict for the normal population to some extent
8 behaving differently than the actively involved
9 inflamed joint, and that it is a reasonable
10 surrogate, although not perfect surrogate, but in
11 any experiment, we can't be perfect unless we are
12 willing to wait several generations to figure this
14 Am I right that use of another knee could
15 be designed in a study, not that it hasn't been
16 done well by the people presenting to us today on
17 these treatments, but that could you design a study
18 in which you used other joints to draw data that we
19 would then feel was reasonable to extrapolate with
20 reasonable certainty, although not absolute
21 certainty, and I think that is the question.
22 DR. MILLER: That is part of the question.
1 I think the other part of the question is, is there
2 data available today that will allow extrapolation
3 from experiments with OA patients to patients who
4 are reportedly without OA.
5 DR. ZEISEL: I think that doesn't ever say
6 anything that there is data already. It just says
7 is it scientifically valid to design an experiment
8 that would use that.
9 DR. MILLER: To use such research. I mean
10 the question the agency faces is how to deal with
11 claims that say that there is a risk reduction for
12 the use of any material for OA.
13 DR. ZEISEL: So, I think what we can reach
14 consensus, it is not valid to use data in the
15 involved joint because we have said that that can
16 be very different, and I think we can all agree
17 with that.
18 So, now we are getting to the second
19 point, is there any data from an OA patient that
20 you could use in a study, so could you go back and
21 re-analyze if those normal joint x-rays were
22 available and come back to this FDA with a
1 presentation saying that we saw something and we
2 met some criteria, and now--
3 DR. MILLER: I think you can say both.
4 There are two separate issues.
5 DR. ZEISEL: Yes.
6 DR. MILLER: Dr. Dwyer.
7 DR. DWYER: So, is it the opinion of the
8 rest of the group that very high risk people may
9 be, in their non-involved joints, may or may not be
10 reasonable surrogates, and we really don't know.
11 It seems to me that it is a good bet, but we really
12 don't know.
13 DR. LANE: That's right. That's the
14 biggest issue, why we are doing the osteoarthritis
15 initiative, because we don't yet know in those
16 high-risk individuals exactly what is going to
17 trigger the onset of the disease, and to say we
18 know otherwise is really a bit unfounded at this
20 DR. MILLER: Dr. Kale.
21 DR. KALE: I have two questions. First of
22 all, in the case of the doxycycline study, how long
1 was that study conducted for before it was
2 determined that the--just 30 months.
3 And the second issue is looking back at
4 the target tissue here, which is cartilage, I think
5 I am embarrassingly confused about the answer to
6 this question, which is that if you give
7 chondroitin or glucosamine to a diseased
8 chondrocyte, say, one involved in the process of
9 demonstrating osteoarthritis, does it, in fact,
10 make different endproducts than normal cartilage
11 does when you give chondroitin sulfate or
12 glucosamine to that cartilage.
13 DR. ABRAMSON: My understanding of the
14 data is that glucosamine and chondroitin
15 beneficially influence the cytokines, the abnormal
16 metabolism of chondrocytes, particularly if you add
17 IL-1, so it is very good for reasons that were well
18 demonstrated yesterday in blocking these
19 inflammatory processes and the metalloproteinase
21 What I heard yesterday is that since those
22 features are not typical of normal chondrocytes,
1 and NF-kappa B is not activated, you know, IL-1 is
2 not being produced, nitric oxide is not being
3 produced, that therefore when you give glucosamine
4 or chondroitin sulfate to a normal chondrocyte, not
5 making those things and it works, let's say, by
6 inhibiting NF kappa B, it has no significant effect
7 on the normal chondrocyte with regard to these
8 catabolic events.
9 Therefore, while I think the data is
10 increasingly very interesting, that it does have
11 beneficial effects on this inflamed catabolic
12 chondrocyte, it is not clear to anyone I think what
13 effect it has on a normal cartilage and whether it
14 will prevent anything.
15 I think that is why when I read this
16 statement, it says to me based on those studies of
17 deteriorative cartilage and some interesting
18 studies from Ajinsta and Pervelka [ph] in patients,
19 that we can use to extrapolate what looks to be
20 increasingly interesting evidence that the drug
21 does work in the degenerated state, that we can
22 then use it to say that it is going to help healthy
1 people, and that is the dilemma.
2 DR. KALE: That's my understanding, too.
3 So, the question I had is sort of more Walt
4 Disneyfied, which is what if the chondroitin
5 sulfate or the glucosamine is present, because you
6 have taken it prophylactically, in the case of
7 somebody who would, because they are alive,
8 ultimately develop osteoarthritis, what effect does
9 that have on the final common pathway of IL-1, and
10 so on, might it not modify the outcome?
11 DR. ABRAMSON: We don't know until the
12 studies are done, and the tetracycline, doxycycline
13 study is very preliminary, so one doesn't want to
14 overstate its validity, but the tetracycline seems
15 to work on these IL-1 mediated processes. It
16 inhibits nitric oxide and some other things, and
17 what Ken Brandt is beginning to think, that maybe
18 those processes are more important in the late
19 stage of disease, and therefore, we can't be sure
20 that blocking those same processes in early disease
21 will block those events in early disease that may
22 be mediated by different growth factors that set
1 the thing forward. That is the dilemma.
2 DR. LANE: I want to reiterate that,
3 because that is the experiment that was done. You
4 took a relatively normal cartilage, gave it
5 something, if it started to degenerate, you would
6 prevent. It didn't, so that is the beginnings of--
7 DR. KALE: But it didn't in 30 months.
8 The question is what is the proper geologic time
9 frame. Thirty months can't be. I mean this a
10 glacial disease, it may be a glacial disease.
11 DR. CUSH: Those people are also selected
12 to be at higher risk because they were obese, so
13 they had other risk factors to possibly progress.
14 DR. MILLER: Dr. Nelson.
15 DR. NELSON: Also, isn't doxycycline just
16 one agent? I mean we aren't generalizing the issue
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.
22 DR. MILLER: It is much more fun to argue
1 without data.
2 DR. LANE: We said that here is a set of
3 chondrocytes that were all prepped, so that when
4 they started to make a bad enzyme, if they started
5 to make it, you were going to inhibit it. You
6 know, this was the perfect situation.
7 DR. NELSON: My other question again was
8 to I guess the rheumatologists in this, is we have
9 abnormal chondrocytes, we have evidence, but no
10 symptomatology no pain, are those people still part
11 of the general healthy population that we could use
12 data from the contralateral knee or the
13 contralateral hip to provide for the general
14 healthy population whether they had--well, you
15 would have to qualify that, I guess, whether they
16 had some symptoms, some existence of a risk factor
17 or not.
18 DR. ABRAMSON: Even if they are generally
19 healthy and have subclinical or pre-disease, the
20 argument could still be made that modifying end
21 disease processes is not going to affect their
22 progression into disease. That is the unknown,
1 because they are different processes that happen
2 early on OA.
3 DR. LANE: And these natural history
4 studies that are just starting up now, when we have
5 some of that data, we will be able to comfortably
6 begin to answer that question.
7 DR. MILLER: Dr. Blonz.
8 DR. BLONZ: So, what I am hearing is that
9 the contralateral knee data is informative, but not
10 sufficient to serve as a surrogate, and that seeing
11 as we don't have information at present that can
12 segregate those individuals in queue for imminent
13 osteoarthritis, that to talk about the general
14 population and applying the data we learned about,
15 treating people with the active disease does not
16 seem to be a connect for us at present.
17 DR. MILLER: I think that is a good sum.
18 Dr. Zeisel.
19 DR. ZEISEL: Again, I think it would be
20 much more constructive for us not to get into the
21 specific data like we have been doing. I don't
22 agree with Steve that we are being asked to say
1 from this that there is an effect of chondroitin or
3 All we are being asked here is, is it
4 possible to design an experiment that would
5 convince this panel that any agent can reduce the
6 risk of osteoarthritis, and using osteoarthritic
7 patients, and if the answer is no, then, we have to
8 say no.
9 If the answer is it is informative and we
10 would like to see that data, but it would not be
11 sufficient to convince us, that is what we should
12 say, but I don't think we need to get into the
13 specifics of whether doxycycline or chondroitin or
14 anything else made any difference, because it's
15 immaterial. We are talking about agent X and agent
16 Y for this type of question.
17 DR. MILLER: I agree, but actually, they
18 are really two questions. One is there is no data
19 to suggest that current available data can be used
20 for this purpose, and that second, it simply says
21 that it may be possible to design an experiment,
22 but we don't know yet how to do that.
1 Dr. Krinsky.
2 DR. KRINSKY: To me, the operative terms
3 in this question is scientifically valid, and it
4 seems to me that what I have heard from the
5 rheumatologists, and scientifically valid to use
6 such research, so to me, we are not talking about
7 the future, we are talking about the past and the
8 present, and it would seem to me that based on what
9 we have heard of research in the past and the
10 present research that we do not have scientifically
11 valid evidence for proposing that this be used for
12 a general healthy population.
13 We may in the future and that would be
14 wonderful, but we can't deal with maybes, we have
15 to deal with science. This is why we are here, we
16 are looking at scientifically based evidence, and
17 not hopeful evidence.
18 DR. MILLER: I agree, in fact, I think
19 there is a consensus to that fact, but what I am
20 saying is that it may be useful to indicate that we
21 haven't closed the door implying that there is no
22 way of doing it.
1 I think that part of the problem is the
2 lack of data in what I hear in the field.
3 DR. LANE: Yes, lack of data and not
4 really having really utilized the technologies
5 available, you know, they are in development that
6 we could actually--
7 DR. MILLER: We don't have to say anything
8 more than as I indicated, that it may be possible
9 sometime in the future to do this, and close that
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.
19 MS. HALLORAN: I think we seemed to agree
20 that the next step would be looking at what the
21 normal joint would do under treatment, but that I
22 at least would want to then see maybe a five-year
1 study of people over 50 or something like that to
2 see how it would affect a somewhat at risk, but
3 still asymptomatic population, that that would be
4 data that would also be desirable.
5 DR. MILLER: We can get into a long
6 discussion about what such experiments ought to
7 contain, and I think my own feeling is that we can
8 make some comment, but I am not sure that really
9 that helps to answer the questions that we are
10 being asked to deal with.
11 I would love to be able to get into a
12 discussion about how to design experiments like
13 this, particularly as a non-expert.
14 Well, I guess we have reached a consensus
15 on this one, as well. Again, the nature of the
16 discussion will be reflected in the report, and, of
17 course, we will have a complete transcript of the
19 We will use certain summary statements
20 that some of you have made in the report verbatim
21 from the record.
22 It is now about 10 minutes of 10:00. I
1 propose we take a break now before we come back to
2 look at Question 3. Come back in 15 minutes,
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
16 Does anybody have any views on that
17 subject? Johanna.
18 DR. DWYER: Could we hear from the
19 rheumatologists on their views?
20 DR. MILLER: That is what I am waiting
21 for, to see someone raise their hand.
22 DR. LANE: We were electing Dr. Abramson
1 who has still I think some non-human models in his
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