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4 VOLUME III

5 (Morning Session - November 16, 1999)

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10 HUMAN TUMOR ASSAY SYSTEMS

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12 HEALTH CARE FINANCING ADMINISTRATION

13 Medicare Coverage Advisory Committee

14 Laboratory & Diagnostic Services Panel

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20 November 15 and 16, 1999

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22 Sheraton Inner Harbor Hotel

23 Baltimore, Maryland

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1 Panelists

2 Chairperson

John H. Ferguson, M.D.

3

Vice-Chairperson

4 Robert L. Murray, M.D.

5 Voting Members

David N. Sundwall, M.D.

6 George G. Klee, M.D., Ph.D.

Paul D. Mintz, M.D.

7 Richard J. Hausner, M.D.

Mary E. Kass, M.D.

8 Cheryl J. Kraft, M.S.

Neysa R. Simmers, M.B.A.

9 John J.S. Brooks, M.D.

Paul M. Fischer, M.D.

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Temporary Voting Member

11 Kathy Helzlsouer, M.D.

12 Consumer Representative

Kathryn A. Snow, M.H.A.

13

Industry Representative

14 James (Rod) Barnes, M.B.A.

15 Carrier Medical Director

Bryan Loy, M.D., M.B.A.

16

Director of Coverage, HCFA

17 Grant Bagley, M.D.

18 Executive Secretary

Katherine Tillman, R.N., M.S.

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1 TABLE OF CONTENTS

Page

2 Welcome and Conflict of Interest Statement

Katherine Tillman, R.N., M.A. 5

3

Opening Remarks & Overview

4 Grant Bagley, M.D. 10

5 Chairman's Remarks

John H. Ferguson, M.D. 28

6

Brian E. Harvey, M.D., Ph.D. 30

7

Open Public Comments & Scheduled Commentaries

8 Frank J. Kiesner, J.D. 48

Larry Weisenthal, M.D. 57

9 Randy Stein 92

Richard H. Nalick, M.D. 99

10 William R. Grace, M.D. 108

John P. Fruehauf, M.D., Ph.D. 110

11 James Orr, M.D. 127

Robert M. Hoffman, Ph.D. 131

12 Andrew G. Bosanquet, Ph.D. 136

David Alberts, M.D. 142

13 Robert Nagourney, M.D. 147

David Kern, M.D. 159

14 Daniel F. Hayes, M.D. 168

Bryan Loy, M.D. 178

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LUNCH 196

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VOLUME II

17

Open Public Comments & Scheduled Commentaries

18 Edward Sausville, M.D. 201

Harry Handelsman, D.O. 227

19 Harry Burke, M.D., Ph.D. 234

Mitchell I. Burken, M.D. 262

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Open Committee Discussion 304

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Day One Adjournment 330

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1 TABLE OF CONTENTS (Continued)

2 VOLUME III

3 Opening Remarks - Introduction 336

4 Open Committee Discussion 337

5 Motions, Discussions and

Recommendations 425

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Adjournment 487

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1 PANEL PROCEEDINGS

2 (The meeting was called to order at

3 8:05 a.m., Monday, November 15, 1999.)

4 DR. FERGUSON: Miss Tillman, our right

5 hand, is here, and has some announcements and

6 pronouncements.

7 MS. TILLMAN: Good morning, and welcome

8 again. First of all, I am going to read the

9 conflict of interest statement again. Conflict

10 of interest for the Laboratory and Diagnostic

11 Services Panel meeting November 15th and 16th,

12 1999. The following announcement addresses

13 conflict of interest issues associated with this

14 meeting, and is made part of the record to

15 preclude even the appearance of an impropriety.

16 To determine if any conflict existed, the Agency

17 reviewed the submitted agenda and all financial

18 interests reported by the committee participants.

19 The conflict of interest statute prohibits

20 special government employees from participating

21 in matters that could affect their or their

22 employer's financial interests. The Agency has

23 determined that all members and consultants may

24 participate in the matters before the committee

25 today.

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1 With respect to all other participants,

2 we ask that in the interest of fairness, that all

3 persons making statements or presentations

4 disclose any current or previous financial

5 involvement with any firm whose products or

6 services they may wish to comment on.

7 In addition to that, we request that

8 anyone with a cell phone please turn it off, so

9 it doesn't disrupt the discussion this morning.

10 Also, as the speakers either come to

11 the microphone or the panel members begin to

12 speak, if you could identify yourself for the

13 record, since we have a court reporter here, and

14 it would make it easier for him to identify who's

15 speaking.

16 And also, anyone who would like a

17 transcript of the meeting can contact Mr. Paul

18 Gasparotti, with Salomon Reporting Services, and

19 he can make a transcript available for you.

20 Dr. Ferguson?

21 Opening Remarks - Introduction

22 DR. FERGUSON: Thank you. This

23 morning, we'll be primarily discussing among the

24 panel members, and then voting on the questions,

25 or the questions proposed as points to vote on.

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1 I would like to remind those in the

2 audience that we would like to keep this

3 restricted to the panel's discussion, except on

4 points of reference where we may need some points

5 clarified from members who presented yesterday,

6 until the 11 to 11:30 session, which we can open

7 up to four or five minute remarks by some who

8 presented their work yesterday.

9 Open Committee Discussion

10 DR. FERGUSON: Now I would like to

11 start this morning and kind of go around among

12 the panel members to get their ideas and their

13 comments and critiques and concerns, and

14 questions on what we've heard, and anything they

15 think that is important that we should know

16 about. Maybe I could start over there on the far

17 right.

18 DR. MINTZ: My concern here is trying

19 to hone in on -- these tests are reasonable, and

20 it's reasonable in a setting of a malignancy to

21 do this. The question I think with which I'm

22 wrestling is when are they necessary. And it's

23 hard to hone in on the data that we have seen on

24 specific situations where we find them

25 necessary. I look forward to further comments

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1 this morning on can we identify situations and

2 disease states where we feel collectively that

3 this test is necessary.

4 I am just beginning to read the

5 articles by Dr. Bosanquet here in CLL, but I do

6 find them interesting, and I'm ready to be

7 persuaded, but I would like a little time to look

8 through them. But as we address these questions

9 this morning, I am interested in hearing further

10 from the participants yesterday as to where we

11 can find specific situations where we might deem

12 this a necessary test. And I look forward to my

13 colleagues trying to identify that situation. I

14 at present have not identified such a situation,

15 but I am open to being persuaded.

16 DR. FERGUSON: Very good. Kathy?

17 DR. HELZLSOUER: Yeah. I agree that

18 intuitively these make sense to be used, and I am

19 wrestling with the same things. I think cancer

20 is too large of a disease entity, and it seems

21 that there probably are settings, and maybe CLL

22 is one of them, where these tests are

23 appropriately used. There is the issue of

24 metastatic versus primary settings, or adjuvant

25 setting, or trying to sort out once they've been

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1 previously treated.

2 And I'm not convinced, although we

3 heard a lot about quality of life, and I believe

4 that's a very good clinical indication for this,

5 that if you can avoid unnecessary chemotherapy,

6 that's extremely relevant and important, but I'm

7 not convinced yet, given the specificity of the

8 overall test results, that we have 80 percent,

9 plus the 10 to 20 percent problem with

10 acquisition of tissues appropriate processing,

11 how many will be spared. And my readings of some

12 of the graphs yesterday and some of the articles

13 here, that if you still have 20 percent that,

14 that's the specificity in the combined group,

15 would you feel comfortable eliminating that for

16 an individual, because there is still a chance 20

17 percent of the time they would still be sensitive

18 in vivo, they will still respond. And when you

19 get down to a metastatic setting when people will

20 choose something for even a 1 percent benefit,

21 it's hard for me to see that you will be

22 eliminating a lot of chemotherapy. So that's one

23 thing that I would like more clarification on.

24 I think that the problem is that there

25 isn't much information on the clinical outcome,

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1 although there's a correlation with survivors,

2 it's the problem we always have with reviewing

3 issues, that responders always do better than

4 non-responders, and it's probably a good marker

5 for responders. But I think we have to see how

6 we can clinically use that in either choosing

7 chemotherapy, and I think the compelling argument

8 is the issue of avoiding unnecessary

9 chemotherapy, but I'm not sure I have the

10 evidence to say that would actually be done in

11 practice.

12 DR. FERGUSON: Thank you. Miss Kraft,

13 do you have some?

14 MS. KRAFT: Cheryl Kraft responding.

15 First of all, what was pointed out yesterday was

16 two different percentages of how many people

17 don't respond to any type of chemotherapy or

18 cancer treatment, one being 70 percent and the

19 other being 76.3 percent. So it's clear that we

20 don't know how to manage cancer patients so that

21 they can survive. So the question to ask is,

22 will the tests that are available to us, these

23 human tissue assay systems, help us in prolonging

24 or help the physician in treating the patient?

25 From what I can tell in the studies

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1 that I've read, that the use of these tests and

2 the way the doctors use these tests in treating

3 patients, that there were no negative effects to

4 the patient or consequence to the patients, with

5 the exception of one trial that was outlined in

6 one of the studies. So that being, do these

7 tests then have, test for drug resistance at a

8 sensitivity that is great enough so that the

9 physicians can interpret the benefit to the

10 patient? Well due to the fact that drug

11 resistance is growing and is definitely

12 multifactorial, as one of the articles said, and

13 the heterogeneity in cancer tumors is great, then

14 are we not, and myself, trying to make sense out

15 of all the articles I have read, and in which

16 cancers and which drugs should be treated for

17 which specific cancers, are we not maybe trying

18 to fit a heterogenetic tumor into a box? I think

19 analytical people try to fit everything into a

20 box.

21 And so what I would like to put forth

22 to the panel is that maybe we should step out of

23 the box and we need to look at, since again, all

24 these tumors are heterogenetic, should we look at

25 just continuing to do what has been done, that

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1 being continuing to test all types of these

2 cancer tumors against all the drugs available to

3 us and see, and continue to treat patients

4 accordingly? Now none of the patients in none of

5 the articles were denied treatment of drugs that

6 they were considered to be resistant to, so

7 taking that into consideration, maybe the studies

8 should continue to be done.

9 However, during that time, this panel

10 needs to think of should the patients, even

11 though this may not be definitively designed for

12 a specific tumor and a specific drug, should the

13 patients really be denied a test? And this is a

14 laboratory test we are talking about. Should

15 they be denied a laboratory test that could

16 possibly benefit them?

17 I think, again, this laboratory test is

18 a tool for a physician. The physician should

19 take advantage of all the tools available to him

20 to treat a patient. And since studies show that

21 only 25 to 30 percent, again, of patients do

22 respond to the test and/or the drugs and/or the

23 correlation of the drugs and the chemotherapy

24 that we have available to them, should we not

25 consider, due consideration to looking at the

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1 advantage of these human tissue assay tests and

2 the resistance that has been found to

3 chemotherapy drugs?

4 DR. FERGUSON: Okay. Thank you.

5 Dr. Hausner?

6 DR. HAUSNER: Dr. Richard Hausner. For

7 me, I would like to take the approach to try and

8 put my comments in the context of my own clinical

9 experience, my own day-to-day, I'm a working

10 pathologist, although I am on the active clinical

11 faculty of Baylor College of Medicine and the

12 University of Texas Health Science Center in

13 Houston. I practice in a community hospital, but

14 I have very long reach in terms of my clinical

15 experience. I have a big practice. And I can

16 tell you that in Houston, Texas, where there is

17 quite a bit of health care going on on a daily

18 basis, not once ever in my life, with all of the

19 cancer patients that I've seen, have I once been

20 asked to harvest tissue for this procedure. Not

21 ever. And I can tell you that if any of the

22 patients in my practice had had this testing,

23 that we would have been involved in the

24 harvesting by definition, because the surgeons

25 would have surely asked. So I know that it

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1 hasn't happened.

2 Nevertheless -- and I came in here

3 reading the source material with that bias,

4 because I had that bias from the very beginning.

5 But nevertheless, somewhere around the middle of

6 yesterday afternoon, my thoughts began to

7 crystallize, and they crystallized during the

8 time that, in the afternoon session when the data

9 was put up to a tremendous amount of scrutiny and

10 a very sophisticated critique, and I thought that

11 it held up pretty darned well. And I have come

12 to the conclusion that while over the past 20

13 years of the research that has developed for this

14 technique, it clearly was a research tool and not

15 ready for prime time, that the decision was

16 correct not to allow this into Medicare's realm

17 and therefore, give it the validity to go

18 forward.

19 Because what is someone's exciting

20 front line technique comes very close to someone

21 else's quackery, and at some point it would have

22 been premature to allow this. But I believe now

23 that the third generation technologies clearly

24 take this beyond a research tool and that from

25 this point forward, I would hope that the

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1 clinical studies will be conducted to refine

2 where this could be best used.

3 Another analogy would be that a, that

4 if this technique is not permitted in its current

5 state, then the panel ought to reconvene and

6 consider removing microbiologic sensitivity

7 testing from the armamentarium of physicians, if

8 this is not approved. The truth, I believe, lies

9 somewhere in the middle, therefore, and just like

10 so many other things we do in medicine, that this

11 is a useful tool, imperfect as it is, and the

12 ground rules may have to be carefully defined,

13 but to turn the test away in its entirety, I

14 believe would be inappropriate.

15 And in closing, I would point to the

16 final paragraph of Dr. Weisenthal's paper in

17 which he talked about whether we use the civil or

18 criminal criteria of preponderance of evidence

19 versus beyond a reasonable doubt. Beyond a

20 reasonable doubt, we don't have. Preponderance

21 of evidence, I believe we do. And therefore, my

22 conclusion is, as a rough sketch, is that

23 something ought to be done towards bringing this

24 test into, as another tool for physicians to

25 use.

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1 DR. FERGUSON: Thank you. Dr. Kass.

2 DR. KASS: Thank you. Mary Kass.

3 First of all, I think my first question

4 was about the testing methodology, but I think

5 that there is overwhelming evidence to show that

6 these tests meet all the normal QC, all of the

7 normal standards that all other laboratory tests

8 have to meet. I think that they're valid, I

9 think that they are reproducible, so the third

10 generation of tests for me is no longer a concern

11 in that respect.

12 The question has been raised about

13 necessary versus clinical utility. I don't know

14 how to define a necessary laboratory test; I

15 think that's really in the mind of the user.

16 When I was in training, which wasn't all that

17 long ago, the emergency room of a downtown urban

18 hospital in Washington, D.C. didn't even have a

19 laboratory open from midnight until eight a.m.

20 because there were no laboratory tests that were

21 necessary to make clinical diagnoses. But we've

22 come a long way since then, and I think medicine

23 has grown and realized that there are many things

24 that can help physicians do a better job in

25 taking care of their patients. So the clinical

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1 utility of this test, I think has been

2 demonstrated, to certainly my satisfaction.

3 The fact that the test is difficult to

4 do because you have to acquire fresh tissue, it

5 has to be shipped in a certain way quickly to a

6 laboratory, that doesn't bother me either. That

7 doesn't change its utility. I remember when we

8 first started doing flow cytometry, the transport

9 of specimens to do flow cytometry on was a big

10 challenge to us. Now we do it routinely and we

11 don't lose specimens in the transport process.

12 It is very intriguing to me that this

13 particular methodology may be very helpful in

14 evaluating new drugs, the number of new

15 chemotherapeutic agents that are rapidly being

16 introduced to try to help us have a greater

17 impact to the treatment of cancer. I think that

18 anything that we could use to help define which

19 modalities have a greater possibility of working

20 and which don't, would be very helpful. I think

21 it also allows the earlier consideration of other

22 treatment modalities for patients, rather than

23 going through a whole course of chemotherapy and

24 waiting for the end point of no response.

25 Earlier in the course of that, a clinician may

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1 have an opportunity to switch a chemotherapeutic

2 drug, or remove one which has a very toxic side

3 effect from the treatment regimen.

4 I guess in summation, I think that we

5 haven't done a terrific job in treating most of

6 the solid tumors. I think everyone is very

7 disappointed in the fact that we haven't been

8 able to have greater success than we have. I

9 think that this is another tool, one of many,

10 that could be available to clinicians that might

11 help, certainly in terms of the quality of life,

12 if we could remove drugs from the treatment

13 regimen that were not effective, and perhaps in a

14 better outcome.

15 I think the patient that testified

16 yesterday, that's one case, it's anecdotal.

17 However, I've practiced pathology for 32 years; I

18 have never seen a patient with widely

19 disseminated pancreatic carcinoma that survived.

20 You have to take notice of that. I think that's

21 worth listening to.

22 So, I think that's the summation of my

23 comments.

24 DR. FERGUSON: Thank you. Miss Snow?

25 MS. SNOW: I'm Kate Snow. I'm the

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1 consumer voice for this panel. I listened very

2 intently to all of yesterday's testimony and I

3 agree that Mr. Stein was very compelling, and I

4 too have never seen a pancreatic cancer

5 survivor. However, I did not know how old this

6 gentleman was, or if he had other comorbidities.

7 I believe that if I were a cancer victim, I would

8 want this study available for my use. I would

9 feel it was reasonable and I would also very much

10 feel it was necessary.

11 Listening to the quality of life and

12 the cost of life that could be gained, and to

13 decrease the burdens for individuals was also

14 very compelling. If it takes the guess out of

15 the therapy that's used, I think it's a very good

16 tool to have available to us.

17 I struggle with whether or not this

18 test will be available in a way where those of us

19 in northern rural Michigan will have access to

20 this kind of tool or not, and what that might

21 look like in the future.

22 I do feel there is a possibility for a

23 cost effectiveness. It may need some more

24 research and looking into exactly how cost

25 effective this could be, both for the medical

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1 community as well as the beneficiary.

2 And I think that's all I have to say

3 for now.

4 DR. FERGUSON: Thank you very much.

5 Dr. Loy?

6 DR. LOY: I'm Dr. Bryan Loy, and I

7 listened also very intently yesterday to the

8 presentations being made. I have a couple of

9 comments, first of all regarding the

10 presentations. I noticed a number of cancers

11 were being elaborated on. I am still not clear

12 at what point in the clinical progression of the

13 disease, or how often the testing should take

14 place.

15 However, having said that, this does

16 sound like this is a tool that be could be very

17 useful. But having listened to the presentations

18 yesterday, again, we were focusing on specific

19 cancers, and to try to take that tool and apply

20 it to all cancers at this point in all clinical

21 scenarios, doesn't seem to be quite reasonab