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.