00331

4 VOLUME III

5 (Morning Session - November 16, 1999)

10 HUMAN TUMOR ASSAY SYSTEMS

12 HEALTH CARE FINANCING ADMINISTRATION

13 Medicare Coverage Advisory Committee

14 Laboratory & Diagnostic Services Panel

20 November 15 and 16, 1999

22 Sheraton Inner Harbor Hotel

23 Baltimore, Maryland

00332

1 Panelists

2 Chairperson

John H. Ferguson, M.D.

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.

Temporary Voting Member

11 Kathy Helzlsouer, M.D.

12 Consumer Representative

Kathryn A. Snow, M.H.A.

Industry Representative

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

15 Carrier Medical Director

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

Director of Coverage, HCFA

17 Grant Bagley, M.D.

18 Executive Secretary

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

00333

1 TABLE OF CONTENTS

Page

2 Welcome and Conflict of Interest Statement

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

Opening Remarks & Overview

4 Grant Bagley, M.D. 10

5 Chairman's Remarks

John H. Ferguson, M.D. 28

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

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

LUNCH 196

VOLUME II

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

Open Committee Discussion 304

Day One Adjournment 330

00334

1 TABLE OF CONTENTS (Continued)

2 VOLUME III

3 Opening Remarks - Introduction 336

4 Open Committee Discussion 337

5 Motions, Discussions and

Recommendations 425

Adjournment 487

00335

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.

00336

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.

00337

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

00338

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

00339

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,

00340

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

00341

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

00342

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

00343

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

00344

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

00345

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.

00346

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

00347

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

00348

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

00349

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

00350

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 reasonable at

22 this point. We really didn't talk a lot about

23 the sarcomas, or trying to talk about such broad

24 fields as hematopoietic neoplasms. I think at

25 least in my mind, I would need some more

00351

1 convincing evidence to try to apply this

2 technology wide spread, and I think that this is

3 certainly germane to a policy type discussion.

4 The other piece that's still lacking in

5 my mind is where this really fits clinically.

6 Because some cancers are clearly curable with

7 chemotherapy, or they're curable with radiation

8 therapy in combination with chemotherapy, or

9 they're curable with surgical resection, or any

10 of those combinations. And trying to really fit

11 this into that niche is going to be quite

12 difficult to do from a policy perspective.

13 Having said that, I think that there

14 certainly is some promise. I think there is some

15 utility that has been potentially demonstrated

16 here, but I am not clear on where this fits yet.

17 DR. FERGUSON: Thank you. Dr. Murray?

18 DR. MURRAY: Thank you. I am Robert

19 Murray, and I've kind of grouped my comments into

20 four areas. The first point is that I believe

21 what we are supposed to be doing is looking at

22 the questions that were presented, the six

23 specific questions that we would like to come to

24 grips with and arrive at answers to. I sense

25 that we have been taking the view from 35,000

00352

1 feet and not from the detail level that we need

2 to or that we were asked to. I am concerned

3 about that, and I really think that we have

4 looked mostly at number 5, which asks, is there

5 evidence to support clinical utility? I sense

6 that from the speakers who have voiced their

7 opinions and also reflecting my own that the

8 answer is yes, there is evidence for utility in

9 certain cases.

10 The second point is, we're stumbling

11 over reasonable and necessary versus clinical

12 utility. Reasonable and necessary is in the

13 statute, and Dr. Bagley gave us a couple examples

14 of how you can assess reasonable and necessary.

15 I view it as a term of art. I don't think we

16 look first at reasonable in isolation, and then

17 we look at necessary in isolation. We'll

18 certainly get thoroughly enmeshed in what kind of

19 necessity. As was already mentioned, no

20 laboratory test may be necessary, mathematically

21 necessary. You can certainly find alternatives.

22 But nonetheless, utility is perhaps an equivalent

23 term that we have in fact focused on. But again,

24 we are looking at a very high level.

25 And Dr. Loy's comments yesterday, and

00353

1 his comments just a moment ago, I think remind us

2 that we need to come to conclusions that are

3 going to allow a very high legal of specificity.

4 We can't just say, I don't think we should say,

5 at the end of this session, yes, there are some

6 situations when some testing might be

7 appropriate. That is simply not the level of

8 guidance that we need. Some of us went through

9 negotiated rule making over the past year and we

10 realize how difficult it is to draft a national

11 coverage decision with the uniformity and

12 specificity. So I am concerned about the fact

13 that we are, we seem to agree that there are some

14 situations in which there is utility, but we're

15 far from reaching the level of specificity that

16 we ultimately will need.

17 The third point is just my own

18 reaction. Spending my life generally in the

19 laboratory, I tend to analogize all of the

20 situations, the questions, to existing laboratory

21 tests. There is no question that many laboratory

22 tests which are routinely approved currently have

23 nowhere near the evidence, nowhere near the

24 accuracy and predictive value that the tests that

25 we're considering today, that we heard about

00354

1 yesterday, have already demonstrated. Yes, we do

2 have to look at outcomes. We have to look at

3 outcomes measured in different ways. We have to

4 look at evidence. But the evidence, even if the

5 bar is raised higher, the evidence that we have

6 heard certainly exceeds the evidence that we have

7 for many, many tests currently in use.

8 My fourth and last point is actually

9 two very minor specific objective questions, and

10 perhaps Dr. Bagley can respond to one or both of

11 them. In Dr. Weisenthal's paper that he included

12 in the packet, there is a reference to a Medicare

13 hearing in April of 1998 which seemed to indicate

14 that it was a decision of what I would assume was

15 an administrative law judge, ruled that these

16 tests would be covered. And my question is,

17 which I'm not asking for an answer now, but

18 sometime before noon, does that decision affect

19 our decision here? If a judge has already ruled

20 that they are coverable, then what are we

21 debating?

22 And the last and very minor point, a

23 question that perhaps one or perhaps several of

24 yesterday's speakers could answer, are any of the

25 tests that have been suggested, the tests

00355

1 performed that are being currently offered on the

2 market, are any of them covered by patent

3 protection? Are we doing anything, are we making

4 a decision on issues that would force or

5 encourage or would support limitation in the

6 availability of the test? And again, I am not

7 asking for an answer now, but if sometimes

8 perhaps during the open discussion, I am curious

9 what level of patent protection there is

10 currently, could these tests be offered by any

11 laboratory if they were approved? That's all of

12 my comments.

13 DR. FERGUSON: Thank you.

14 I had a number of things, mostly in the

15 form of questions myself. But I guess some can

16 be considered comments. First, there are several

17 different tests done by several different groups

18 that we were exposed to. Not all seemed to be

19 equal or equivalent to each other, they were used

20 in many different kinds of cancers. This leaves

21 a large number of combinations and permutations

22 for us to grapple with. And it's hard to put

23 them, as a matter of fact, I would say it's

24 impossible to put them all in one basket and say,

25 you know, treat them all together. At least I

00356

1 would find it difficult, given the amounts of

2 data and studies that we saw, all for different

3 tests and so on, so this in my view makes it a

4 difficult job.

5 A second, that many of the studies that

6 we saw were on the small side, small numbers of

7 patients.

8 Number three, it wasn't always clear to

9 me how the patients were chosen for these studies

10 or from what populations they were chosen. In

11 other words, what the denominator was, how did

12 these patients get into the study. Sometimes it

13 was. I'm giving sort of an overall, at least

14 what my concerns were. It's clear that these

15 patients had to be self selected in a way that

16 there was an accessible tumor to be biopsied or

17 surgically removed, that some patients who

18 perhaps had recurrences weren't available, once

19 they had tumors that recurred, because they were

20 deep or in bone, or inaccessible in some other

21 way, or weren't willing to put up with biopsies

22 and so on. So that there were patients that

23 might possibly benefit but couldn't because they

24 didn't have tumor available. Whereas the tumors,

25 the easily accessible, perhaps is in leukemia

00357

1 patients and lymphomas, where tissue is

2 reasonably easily available, and maybe that's a

3 different group. I mean obviously, maybe they're

4 self selected in that way to be better and more

5 responsive. But any way, it is a bit of an

6 issue, I think. It's hard to treat them all

7 equal when you need tissue in order to do this

8 test.

9 The fifth point, it seemed like to me

10 on most of the studies we were dealing with

11 advanced tumors, mostly recurrent after stage 2.

12 I wondered how many actually stage one and stage

13 two type patients had been studied.

14 Number six, that in -- it seems to be a

15 number of papers alluded to the fact, or studied

16 the fact that even cancer cells from the same

17 patient were different, in other words, that the

18 primary site tested different than the metastatic

19 site. Which brought up the notion, and this was

20 again stated and makes it somewhat difficult,

21 that patients had been treated, their cancers now

22 become more resistant and test differently with

23 these tests. So this is just another factor

24 which makes the testing, you know, when you test,

25 after treatment, before treatment, and whether

00358

1 you test a metastatic site, the primary site, do

2 you still have that and so on. This all adds

3 other things and as Dr. Loy mentioned, when is

4 this test most useful? And so this just raises

5 to me another set of questions.

6 Then I think what was mentioned by

7 Dr. Barnes yesterday, in a number of areas there

8 are several histologic types of cancers, so we

9 weren't always given that kind of information,

10 and whether they all test the same or might test

11 the same. Ovarian cancer is a multidimensional

12 animal, as I understand it.

13 So, those were my concerns. Having

14 said that, I also felt that in some of the

15 studies that were presented, I was impressed with

16 some of the leukemic studies and some others that

17 there is some usefulness and that it needs to be

18 mined, but mined carefully and under the right

19 conditions.

20 Just another comment about randomized

21 trials. Where I sat at the NIH as chair of the

22 technology assessment committee for the American

23 Academy of Neurology for a number of years, the

24 number of randomized trials with outcome

25 measurements for diagnostic tests, I don't

00359

1 believe I could have counted on one hand. I

2 would have to look very hard to find those

3 tests. I remember seeing reference to one or

4 two, but -- and there may be more, but I think

5 there is no question that for diagnostic tests,

6 randomized trials with good clinical outcomes are

7 extremely rare and I believe that, however, they

8 should be done. We need better standards.

9 Dr. Bagley?

10 DR. BAGLEY: I would like to bring up a

11 couple of other, or reiterate a couple of other

12 notions which I just want to sort of bring to the

13 forefront for us to keep in mind as we consider

14 these.

15 Dr. Loy brought up a very important

16 point, I think, yesterday. And it's one that's

17 easy to lose sight of when, as Dr. Murray said,

18 looking from 35,000 feet. And that is that any

19 recommendations that you make, that are then

20 placed or implemented in the policy, need to be

21 done with some specificity. We normally don't

22 write policies that simply say, pay for test

23 whenever a patient's physician thinks it's

24 necessary. Now that might be a reasonable

25 policy, but Medicare isn't designed to work that

00360

1 way. And in fact, we've learned from long

2 experience that if we do things that way, that

3 while it works 99 percent of the time, the 1

4 percent of the time that it doesn't work, it is a

5 disaster, because there are, there is fraud and

6 abuse in Medicare. It is a very very small

7 proportion of what goes on, but it accounts for a

8 large portion of the dollars, and they're the

9 dollars that belong to the beneficiaries of the

10 program, and they need to be protected.

11 And perhaps that's the reason that

12 Congress gave us the admonition that we shouldn't

13 just pay for medical service, we shouldn't pay

14 for medical service that a patient or a physician

15 thought was reasonable and necessary, but

16 actually the prescription that's written in the

17 law is written in the negative. It says, Health

18 Care Financing Administration will make no

19 payment for a service unless it is reasonable and

20 necessary. That means there has to be some

21 policy determination and there has to be some

22 review, some process by which we determine the

23 things that are reasonable and necessary.

24 Now with diagnostic tests, it's perhaps

25 a little more difficult than it is for therapies.

00361

1 When we're talking about treatments, we're

2 talking about options that a patient can take,

3 and in fact, they can select from one of the

4 options, and as long as there is evidence that

5 they are reasonable choices, it then becomes a

6 little easier to come to the notion that it's

7 reasonable and necessary. But diagnostic tests

8 become a little bit more difficult, because

9 diagnostic tests, after all, give us information.

10 Patients want information, physicians want

11 information, and we're all taught that the more

12 information we have, the better off we are, more

13 information gives us better results. But that's

14 not always the case.

15 First of all, that, when Medicare views

16 a service or a test or a drug, or anything else,

17 as a covered service, therefore, it will be paid

18 for by Medicare, it's easy to lose sight of the

19 fact that that doesn't -- it's paid for by

20 Medicare. It means it's paid for by the

21 beneficiaries in the Medicare program. Medicare

22 is after all a program which is funded by the

23 beneficiaries, and the future beneficiaries,

24 which is all of us. And in fact, the payment

25 comes from that source, and in fact it doesn't

00362

1 come entirely from that source. Some of it comes

2 directly from the pockets of the patients who are

3 receiving the service.

4 And what we're talking about here is a

5 combination service. Some of what we're talking

6 about may ultimately come under the heading of

7 laboratory testing, but a great deal of what

8 we're talking about is not laboratory testing,

9 but it's physician service. It's interpretation,

10 physician interpretation, and it really comes

11 under the heading of consultation, it's a

12 physician consultation. And when it is paid for

13 by Medicare, so called, it means that 80 percent

14 of it comes from the premiums which are paid by

15 the Medicare beneficiaries, premiums that are

16 paid for the part B Medicare service, which is

17 optional, although most beneficiaries do opt for

18 that. But they pay a premium every month and

19 that premium pays the service. That premium is

20 determined in some part by the amount of payment

21 in the program. It's a health insurance premium.

22 And the remaining 20 percent comes from the

23 beneficiary. So these tests are not tree.

24 Now, it doesn't matter if they're free

25 or not. If someone has a fatal disease and they

00363

1 offer hope and they offer an improved way to

2 treat it, then we don't really put a price on

3 that, nor do the patients. But we need to

4 remember that there was that last notion that I

5 put up yesterday when we talked about what was

6 reasonable and necessary. And that was, once

7 something's safe and effective and once something

8 has demonstrated utility, and the risks outweigh

9 the benefits, then perhaps we should also look at

10 the issue of whether or not it adds value.

11 Now value is not a new concept, it's

12 not a new concept in considering medical

13 treatment. We've always done that. We've always

14 done that with diagnostic tests. As long ago as

15 when I went to medical school, the notion was

16 given to us very early that tests are not

17 something to be used indiscriminately. When you

18 order a test you should consider, is the

19 information needed, is it going to make a

20 difference and therefore, am I properly using

21 this resource? So the notion of does it add

22 value to the patient's treatment is very

23 important, and I think that needs to be kept in

24 mind.

25 And then the next point, which follows

00364

1 on what Dr. Mintz said, is it reasonable, is it

2 necessary? I think it is an important concept,

3 because for it to be reasonable and necessary

4 both, it needs to offer not only information, not

5 only information which may be correct, but

6 information which is likely to influence the

7 course of treatment. Is it information the

8 patient and the physician need? If it's going to

9 guide therapy, then it should give us a decision

10 in which we should do this. Now there is an

11 interesting, there's an interesting interplay

12 between what's reasonable and necessary.

13 We have recently been looking at the

14 same thing in terms of what's reasonable and

15 necessary in terms of a test with regard to using

16 PET scans for many diagnostic uses. And in many

17 ways it's the same kind of a process we're going

18 through here; we're saying when is it reasonable

19 and necessary, and for what conditions, because

20 it's used for many many things, and the evidence

21 is stronger for some uses than others. And as we

22 approach that we say, well, if it's reasonable

23 and necessary, then it's diagnostic information

24 which is useful. Now we had just such a

25 situation when we considered the use of a PET

00365

1 scan for evaluation of a single pulmonary

2 nodule. The argument was that a single pulmonary

3 nodule evaluated with a PET scan in which the

4 nodule turns out to be not metabolically active

5 or occult would eliminate the need for a biopsy

6 and in fact, we can do a PET scan, if we get a

7 negative result, we don't needed to a biopsy.

8 But that's certainly a powerful argument, and for

9 a patient making a decision about whether or not

10 to have an invasive biopsy, it certainly is a

11 reasonable option.

12 But we then looked at it and said, well

13 then, if we use PET scans to eliminate the need

14 for an open biopsy, how would we view an open

15 biopsy that was performed after a negative PET

16 scan for a single pulmonary nodule? Then we

17 would be left with the dilemma of saying if the

18 PET scan was reasonable and necessary because it

19 could prevent an open biopsy, then was the biopsy

20 after the negative PET scan reasonable and

21 necessary? It's hard to say they were both. And

22 we are faced with the same dilemma here. We have

23 a test, which we are told is useful to patients,

24 because it will allow us to more accurately

25 select their chemotherapeutic agents. We can

00366

1 avoid toxic agents which won't be effective, or

2 we can select new expensive agents which are only

3 used when they are effective. Now that's a

4 persuasive argument.

5 But then we had the organization which

6 represents most of the oncologists in the country

7 stand up and say they are neutral on this

8 procedure, but the one thing they're sure of is

9 if we allow this procedure, we shouldn't pay

10 attention to the results. That's what they

11 said. It should not be used to withhold

12 therapy. Which means, if a drug is shown to be

13 resistant we shouldn't withhold the drug, based

14 on the test, or if a drug is shown to be not

15 sensitive and it's an expensive drug, we should

16 use it anyway. That seems to me to be hard to

17 understand. That you can take a neutral position

18 about a test and say it looks okay, we think it's

19 reasonable to do it, as long as we aren't asked

20 to pay attention to the results.

21 And that gets back to the final point I

22 made yesterday, is that in terms of looking at

23 the evidence and one of the things is to look at

24 the evidence and say, where does it take us

25 clinically? And not just say, it's good enough

00367

1 to pay for but not good enough to pay attention

2 to. We should say, it's not only good enough to

3 pay for, but the evidence is so strong in a given

4 area and perhaps it's a given tumor, perhaps it's

5 a given kind of patient, perhaps it's for given

6 drugs, but if the evidence is strong enough that

7 we should pay, we should not only pay, we should

8 promote and at some point we should insist,

9 because after all, if it was reasonable and

10 necessary to do the test, if we then ignored the

11 test in future therapy, would in fact that

12 therapy be reasonable and necessary?

13 So, I am simply putting those problems

14 that we deal with in writing policy into context

15 for you, because I think you need to keep those

16 in mind as we answer these questions. Because as

17 Dr. Loy said yesterday, we need to have

18 specificity because reasonable and necessary as a

19 test means it might be reasonable and necessary

20 to pay attention to the results when that

21 happens.

22 And then just finally Dr. Murray's

23 question about what happened in terms of the fact

24 that an administrative law judge overturned a

25 claim denial. We are talking about policy here,

00368

1 policy which says, this is how it's going to

2 apply to the entire Medicare population. And

3 when we write policy, it applies to everyone.

4 When we write a policy that says we will pay for

5 PET scans for single pulmonary nodules, it means

6 we pay for single pulmonary nodules for

7 everyone. And we don't pay for another use that

8 we haven't dealt with. Now that means that we've

9 written a national policy and it applies to

10 everyone, every carrier, every beneficiary, and

11 every administrative law judge in the appeals

12 process. It is binding on everyone. That's why

13 we make national policy on bright line issues,

14 when we know which side of the line the coverage

15 policy ought to be.

16 The opposite is true when we don't have

17 a bright line. We leave it to the carriers to

18 make policy based on input from the carrier

19 advisory committee and also to review claims on a

20 claim by claim basis if necessary. And when

21 carriers review claims on a claim by claim basis

22 and make a denial of a specific claim for a

23 specific individual, that individual by right can

24 appeal that claim, and that appeal process if

25 carried to its conclusion has a hearing before an

00369

1 administrative law judge. That administrative

2 law judge hears the facts and can overturn the

3 carrier's decision to deny that claim, but can

4 only overturn that decision if there is no

5 national coverage decision in place which can

6 influence that.

7 So what we're talking about here is a

8 binding national process, not an administrative

9 law judge. When the administrative law judge,

10 and administrative law judges are with the Social

11 Security Administration, they are not medically

12 trained, and an administrative law judge hears an

13 appeal, overturns it, it applies to that

14 beneficiary and that claim only. It is not

15 precedent, it does not apply to other

16 beneficiaries, other claims, other carriers, or

17 Medicare as a whole.

18 DR. FERGUSON: So, you remind me, your

19 slide yesterday said that these procedures are

20 not, there is a national coverage policy; isn't

21 that correct? So the administrative law judge

22 couldn't have overturned the noncoverage.

23 DR. BAGLEY: The administrative law

24 judges are bound by national coverage decisions.

25 In areas where we have a national noncoverage

00370

1 decision and an appeal for an individual claim

2 goes to administrative law judge, the

3 administrative law judge is bound by the national

4 noncoverage decision. There have been cases

5 where administrative law judges have overturned

6 claims denials which were ultimately in conflict

7 with national coverage decisions, and your

8 question is, how can that happen? Well, it

9 happens, and the solution to that is that there

10 needs to be an overturning of the administrative

11 law judge's position, the denial of the claim.

12 That at times doesn't happen and the claim is

13 paid, and if it's not appealed by the government,

14 the claim is paid, so that process can lead to

15 claims payment. But in general, the policy we're

16 writing, the fact remains that the policy that

17 we're writing is binding, it is national, and if

18 all of the appeals don't go both ways, that can

19 happen.

20 DR. FERGUSON: Thank you. Mr. Barnes?

21 MR. BARNES: Well, as you know, I'm the

22 industry rep on the panel and as such, I have

23 tried to be a liaison with the proponents of

24 reimbursement, which I understood was my job.

25 And to some extent I sort of feel like I'm

00371

1 sitting at the wrong table at this particular

2 moment, and you'll understand. But let me offer

3 just a couple very quick thoughts.

4 The process, a couple comments on

5 process, I guess. One is that the industry

6 representatives here yesterday heard some

7 criticisms of studies, and in fact a lot of

8 attention yesterday afternoon was paid to quality

9 of studies and science, and it, while I'm not an

10 advocate for the industry, it does make sense to

11 see if they might have any particular thoughts to

12 share with this panel today, and I would

13 encourage the chair to allow that opportunity.

14 There was a lot of interaction with

15 regard to Dr. Burke's presentation, but I think

16 Dr. Burken's review of a great number of studies,

17 and in particular the statement that a couple of

18 things were reversed on some of his slides which

19 panel members had been looking at overnight might

20 prompt the industry to want to clarify a couple

21 of points. So I guess I would encourage that to

22 be allowed.

23 A couple of panelists so far have

24 encouraged the panel to pay attention to much

25 greater detail, to really define what cancers,

00372

1 what drugs, what tests, and I think that might

2 have been a general sense of the panel

3 yesterday. And so, my second comment on process

4 is that the way that we have conducted this

5 session over the last one plus days really isn't

6 very conducive to all of the details that you

7 three gentlemen have said you'd like to hear

8 about. And I don't have a solution for that, but

9 I think basically, I just don't see how that

10 could have worked very well, given all the

11 different variables that you'd like to hear more

12 details on, so it makes it kind of difficult.

13 The comments yesterday on the quality

14 of the research did not, I agree with several

15 panelists, did not seem to outweigh the general

16 notion that there clearly is benefit to patients

17 from this test, and that from time to time I

18 guess kind of made me a little bit frustrated. I

19 was sitting here thinking that there are a number

20 of small companies or even very small labs who

21 can't quite present the randomized clinical trial

22 that many of us would like to see, the conclusive

23 once and all for cause and effect, RCT. But they

24 do seem to present a good mass of evidence

25 suggesting patient benefit, as has been

00373

1 mentioned, and I certainly, if I personally or

2 someone in my family was involved, I would like

3 them to have access to this test.

4 Speaking about access to the test, I

5 think it was Mr. Kiesner in his early comments

6 yesterday who pointed to the numbers of hospitals

7 that send specimens in the volume of testing that

8 they do. I have spoken a little bit to these

9 folks, and it would appear that a number of

10 people in U.S. managed care organizations have

11 gone through an assessment of this testing

12 technology and have indeed decided that it is

13 something that is of value and something that

14 they are willing to submit information, rather

15 tissue for. So I guess I would be interested in

16 hearing more about who some of those plans are

17 and what kinds of evaluations have happened

18 previously.

19 The negotiated rule making came up, and

20 I understand there in fact was a consensus

21 document that was put together, and I'm sorry, I

22 am not familiar with what happened during

23 negotiated rule making, but my understanding is

24 that there was a movement in the direction of

25 recommending reimbursement for this testing, and

00374

1 also that the ASCO signed on to, I'm not sure

2 what the term would be, but did indeed agree,

3 unlike yesterday's discussion where we heard they

4 were neutral, and I think I would like to hear

5 some more about that. I think there were a

6 couple panelists involved, and it would be

7 interesting to know some more about that.

8 Evidently, the gentleman from ASCO was not aware

9 of that.

10 In my real life, a health economist, I

11 appreciate Dr. Bagley's information and

12 perspective on valued added. That was the last

13 step in the stair case of defining reasonable and

14 necessary. I would be interested in hearing some

15 more from Dr. Bosanquet, if that's possible. I

16 understood he had quality adjusted life year

17 information suggesting utility, and I believe a

18 study that has been published that hasn't really

19 been made available to the panel, it's in the

20 Technology Assessment Journal, which most of the

21 panelists probably don't see. But I think that

22 kind of information has in fact been

23 accumulated. So perhaps he will have a chance to

24 share that with us later. Thank you.

25 DR. BROOKS: My comments are a little

00375

1 bit along the lines of a number of the others,

2 and I just want to start out by saying --

3 DR. FERGUSON: Do you want to say your

4 name for the record?

5 DR. BROOKS: Yeah. John Brooks. As a

6 pathologist, I certainly came to this without

7 much knowledge or interest, in a sense of one who

8 would give chemotherapeutic drugs, and kind of

9 evaluated it in the same way as I would evaluate

10 any new upcoming test that we have actually to

11 evaluate, almost every week I would say, in the

12 clinical laboratories. As a pathologist,

13 generally, my thought would be that we like to

14 see more tests done and certainly, useful tests

15 are very helpful to people. So you know, in

16 evaluating the information that I got beforehand

17 and that we heard here, I was certainly impressed

18 with how much had been done. I was actually a

19 little bit surprised at how much had not been

20 done, however. I mean, in some settings, it

21 certainly seems to me like the data is there for

22 utility. I am not doubting that the test, I mean

23 it's been mentioned before by a number of people

24 that, you know, I actually believe that the test

25 does test resistance and so forth, and that we

00376

1 may have to decide which of the tests might be

2 recommended, or maybe two tests, A and B,

3 whatever, but histology specific type of data

4 wasn't necessarily there, except in certain

5 situations.

6 You know, the hematopoietic

7 malignancies certainly seemed to have really

8 pretty good hard data. For example, one question

9 that kept occurring to me is how often in an

10 individual tumor type, not a site, not just

11 ovary, but a specific type in that ovary, because

12 that's what the clinician diagnosis is. And that

13 kind of information, for example, is available in

14 CLL. And the articles provided to us this

15 morning tell me that you know, for example, 12

16 percent of patients with CLL, which I view as a

17 pretty high number for a very uniform type of

18 disease, you know, where the markers, et cetera,

19 are quite similar case to case, showed a

20 difference. Whereas, if I had had such data in

21 small cell, et cetera, I certainly would be much

22 more persuaded that the test is useful to

23 people.

24 In other words, if we're trying to

25 define a policy, and suppose we had a tumor whose

00377

1 data showed it never, it always had the same

2 resistance pattern, then you wouldn't want to

3 necessarily, although I may be foolish, to order

4 over and over again to get the same result.

5 All that said though, you know, I do

6 view that there is data there that shows some

7 clinical utility. The question in my mind then

8 becomes, how would you write a policy,

9 et cetera. What I would like to see, just

10 apropos, forget chemotherapy is something that

11 says, you know, people who have diabetes ought to

12 get a glucose test, and we'll pay for that every

13 time. Okay.

14 So then I come to the issue of denial,

15 because as it was brought up before, we had ASCO

16 there saying that, you know, sure, go ahead and

17 do the test, be we might not pay any attention to

18 it, and we sure want to give the drug that's

19 resistant. I mean, that's kind of what I heard.

20 I was thinking about that overnight and I was

21 wondering, well, okay, can I think of something

22 to explain that position? And even though I'm a

23 pathologist, I actually talk to people a lot.

24 We're actually not in the closet, and we're out

25 in the public, and I love patients, and in fact,

00378

1 patients call me all the time. Okay.

2 So let's take diabetes. So suppose we

3 have a diabetic test, suppose we don't have a

4 glucose test, and the new proposal is, I've got a

5 better glucose test to tell if somebody has

6 diabetes. And if they have a sensitivity

7 specificity of 80ish percent, or maybe even 90

8 percent. So okay, now I have a patient and I am

9 a clinician treating this patient. The patient

10 has a negative new glucose test, and it's

11 negative. Should I be denied giving insulin to

12 this patient? It sounds pretty reasonable. But

13 maybe, you know, the test is imperfect, and maybe

14 by looking in the eyes and by looking at the

15 weight and by looking at this and that, I could

16 figure out a way as a clinician in an imperfect

17 world, and certainly not with our glucose tests

18 that we have now, that you could in fact see

19 people should have insulin because of a, not gut

20 feeling, but as a group of symptoms and signs

21 that I see in the patient, that I should be able

22 to give insulin to that patient.

23 So with that said, I'm a little bit

24 torn in fact, as to the issue of if a test is

25 really good and it shows a negative result,

00379

1 should you deny the drug being given. And I

2 guess that's kind of where I am. And in a sense,

3 you could look at things that happened in other

4 arenas. I'm aware that when they were doing the

5 surgical treatment, you know, surgery versus

6 medical treatment for coronary artery disease,

7 and the surgeons said that, you know, the

8 cabbage, or bypass was better, it took us ten

9 years to figure out what that was all about,

10 mainly because there was no clinical trial.

11 So another question that occurs to me,

12 and I don't have the answer, and I want to hear

13 what happens the rest of this morning, is if this

14 is approved, do we want just America to use it

15 willy-nilly? That is, this person uses it over

16 here to treat this person, et cetera, and nobody

17 gathers any data. And I don't mean gathering

18 data by the companies, I mean publicly gathered

19 data. So another question therefore that occurs

20 to me is that if we approve it for specific

21 histologies or, you know, certain restricted

22 diseases or otherwise, should the -- should this

23 be for a period of time and should the data be

24 gathered by an independent source? Now that's

25 not to say a clinical trial. A clinical trial,

00380

1 you know, you have mentioned is very difficult to

2 start, especially if it is only directed at the

3 DiSC assay or whatever. But for example, you

4 could just have the results go into a central

5 repository, and the physician who used the test

6 would be required to say exactly how he treated

7 that patient, for how long, and was it on

8 protocol or off protocol.

9 My final question is, what does this do

10 to clinical trials? And we have large public

11 groups, cancer, breast cancer groups, prostate

12 cancer groups, et cetera, working very hard to

13 define what are the best therapies for each of

14 these cancers. Now those cancers at least are

15 more defined amongst themselves. If we bring in

16 such a test as this, do we undercut what's being

17 done in those trials, because, in other words, I

18 want to dovetail them, but I need to know how. I

19 don't want to see suddenly everything being done

20 willy-nilly based on a test that after all, only

21 seems to have an 80 percent or so sensitivity.

22 In other words, there are patients who are

23 resistant who may respond. I think that's the

24 question.

25 So with, those are the questions I have

00381

1 in my mind, and I would like to listen to more.

2 DR. FERGUSON: Paul Fischer.

3 DR. FISCHER: In preparation for this

4 meeting I called a couple of the thoughtful

5 oncologists in the Augusta area and asked them

6 about their knowledge and experience with this

7 test. They were uniform that in their opinion

8 that it was not something that was useful because

9 people did not behave the way the test would

10 predict when they were given chemotherapy. And

11 what I realized after listening to the folks

12 yesterday was that there are really two cultural

13 views here. The one cultural view is histology

14 driven. We look under the microscope, we see a

15 particular histology, and we therefore know what

16 drugs to give. The other world view is the test

17 tube driven world view. And when they were

18 showing slides yesterday, one of the speakers

19 said, well, I know what to give because I see all

20 these cells got killed. So it's a really

21 different way of believing what is going on in

22 the world.

23 And then the question for me becomes,

24 do the champions of the technology who spoke

25 yesterday, do they represent pioneers or nuts?

00382

1 And I think that's what HCFA has to decide,

2 because does HCFA advance the standard of care

3 where the average oncologist says we don't

4 believe in this, but HCFA is going to pay for

5 this so let's try it, or do they support the

6 current standard of care, which is to let the

7 histology world decide what to do.

8 The problem I have as a family doctor

9 is that in my total practice experience I believe

10 that probably my patients have been hurt as much

11 by chemotherapy as they've been helped. And

12 that's even given some of the wonderful drugs

13 that do respond beautifully to chemotherapy. But

14 I regularly protect my patients from oncologists

15 who have this histology world view. If there is

16 a tumor, it needs chemotherapy. And if you

17 didn't respond to the first one, you get the next

18 one. So eventually you're given drugs that are

19 more and more toxic, less likely to benefit the

20 patient, but because you've still got tumor, you

21 need another course of chemotherapy.

22 Now my way of dealing with this in

23 practice is to be very selective of who I send my

24 patients to, and some oncologists are

25 conservative and some are not, and I avoid the

00383

1 latter. But I, you know, on a weekly basis sit

2 down and talk with a husband and wife and talk to

3 them because they had some advice from an

4 oncologist that they should go through this

5 chemotherapy and to be quite frank about it, it's

6 not always a very balanced view of whether the

7 patient is going to benefit from it. So I really

8 believe we need to move beyond the current

9 situation and put some brakes on this histology

10 driven world view which encourages more and more

11 chemotherapy given with less and less benefits.

12 And I'm not sure we need to say that we

13 have proven that this technology is useful for

14 every tumor and every drug. You know, obviously

15 they haven't. But clearly they have in CLL. You

16 know, I'd like the people who give chemotherapy

17 to stop for a second and say well, gee, maybe

18 there are some other ways to think about who

19 needs what, and this seems as good as any

20 approach currently available, and I would

21 therefore, I will vote to support some sort of

22 funding for this when we get to the end of the

23 morning.

24 DR. FERGUSON: Dr. Klee.

25 DR. KLEE: Hello. My name is George

00384

1 Klee, and I guess as I looked at the data that we

2 had sent to us early on, it looks like you have a

3 valid laboratory test. But where the issue sort

4 of comes is where does this fit into the practice

5 of medicine and how does it improve patient care

6 in the longer run? You know, if we were to look

7 it in sort of a protocol design, a selection of

8 which drug should be used in which diseases, that

9 seems to be a legitimate application that could

10 go forward. Looking at it on individual patients

11 is where the issue seems to come into play, and

12 if so, which patients and for what decision

13 purpose are we looking at it?

14 The data that was sent with the packet

15 seemed to indicate that the best utility for the

16 test was in the negative predictive value. That

17 is, in response to determine which patients are

18 not likely to respond to chemotherapy. And I was

19 pretty well convinced of that until yesterday's

20 presentation by Dr. Burken. And going through

21 the numbers that were in those slides, and I

22 tried to tally them up last night, there are very

23 few that are up in that 99 percent negative

24 predictive value. You know, there was a few of

25 them that had numbers less than 20 that had 100

00385

1 percent negative predicted value, but there was a

2 lot of cases that were, a lot of publications

3 that were referenced there that had negative

4 predictive values in the 20 to 60 percent range,

5 which doesn't really make too much sense if you

6 have an a priori odds of 70 percent, that

7 apparently these are not prevalence adjusted.

8 And although the presentations went

9 through a lot of explanation of the Bayesian

10 theory, it would be nice to have these numbers

11 prevalence adjusted. But even so, if you start

12 with this at a 50-50 with those lower odds, it's

13 getting up to a point where it's not looking like

14 this test would really be that useful. You know,

15 if you had something that's, you know, you have a

16 priori odds of 70 percent, and you can only get

17 it up to 80 percent chance that this drug is not

18 going to respond, that's not very much of an

19 improvement over the prior. You know, if you're

20 taking it up so you've got a chance of one in a

21 hundred that this drug is not going to respond,

22 then I think we've got something we can use in a

23 clinical decision. So I guess I would like to

24 see some of that information further clarified

25 and presented in the form that, you know, several

00386

1 presenters have indicated that the Bayesian

2 theory is needed, and it's the post odds that

3 we're looking at in terms of the negative

4 predictive value on these tests.

5 I guess I'd like to expand on several

6 of the issues that were raised by other members

7 of the panel here in terms of, we've got a

8 multitude of diseases, and where does this fit

9 in? You know, we've got a multitude of drugs,

10 we've got a multitude of subclasses of these

11 diseases in terms of whether it be histology or

12 whether it be in terms of just other clinical

13 classifications as to the stage of the disease

14 and things like that. It looked like it's too

15 big of a matrix that we're trying to deal in

16 here, and it didn't look like one size fits all

17 for the answer to that.

18 And I agree with the general assessment

19 that the leukemias, CLL in particular, seemed to

20 be one where the focus looked a little more

21 channeled in an area where we can say that there

22 is a definite improvement based on at least a few

23 trials that have been out there. But at the same

24 time, when we look to see, there was a question I

25 was asking there yesterday, has it really been

00387

1 compared to using this test versus not using the

2 test. That seems like where you would find out

3 whether or not there is a benefit for the test.

4 And those studies have not been done.

5 And I would like to maybe inquire a

6 little bit more of Dr. Bagley, that at our

7 orientation session, you had mentioned that there

8 is some new activities going on with HCFA where

9 tests can be prospectively monitored in terms of

10 utility, and perhaps introducing this in a

11 disease management strategy with controlled

12 output, you know, similar to what Dr. Brooks was

13 alluding to, but is that something that through

14 the funding mechanisms of HCFA, that this could

15 be carried out, since NCI doesn't look like they

16 have carried this out recently. They looked at

17 it many years ago. And if this is not part of

18 the clinical trial approach, we need an alternate

19 way to do this. It doesn't seem like it's

20 something that's a yes no answer, perhaps a

21 controlled introduction in a very focused disease

22 with the output monitoring required as to what

23 happened to these patients, was there benefit in

24 terms of quality of life years or in terms of

25 survival, or in terms of any other parameters you

00388

1 might put up. But it looks like if we're going

2 to take the practice of medicine to this higher

3 plane that has been alluded to several times, we

4 are going to need to do it in a controlled

5 manner. Somebody's going to have to pay for it.

6 It's not reasonable, I think, to have the burden

7 of this put back into the people that may be

8 making the test, but it needs to be looked at in

9 terms of those that would be benefitting from it

10 and as it is part of health care policy, then it

11 looks like it should be, you know, integrated

12 through, whether it may be a joint venture

13 between NCI and HCFA, to say how do we carry this

14 out in a manner that we can say, give this a

15 controlled trial over X number of years, see

16 what's going to happen, only apply it in a very

17 limited focused area, for example CLL, and then

18 try to see, did it make an impact, did it change

19 the way that we're caring for these patients?

20 Did it change the benefit in terms of life

21 expectancy or quality of life years for the

22 patients.

23 DR. BAGLEY: Let me answer that real

24 quickly, and I'll try to make it a quick answer,

25 because that's a long complicated issue. And it

00389

1 has to do with when should Medicare become

2 involved in issues that are not quite settled,

3 how should we continue to look at things, and

4 what can do? I'll give you some examples and

5 tell you where we do do it then, and then tell

6 you how limited that option is.

7 In two areas of diagnostic testing, we

8 have recently written cautious coverage policies,

9 not that different from what we're dealing with

10 here today, new technologies have a lot of

11 promise, clinical community doesn't know quite

12 how to use it, they are not so sure they're going

13 to use it to replace something else, we're not so

14 sure it's going to improve care, but we

15 cautiously advance coverage, and say we'll not

16 only pay for it, but in paying for it we will

17 collect some information. Now we can't collect

18 very much information. By law, we can only

19 collect the information necessary to process the

20 claims. But we can interpret that to the point

21 of saying we can get a certain amount of clinical

22 information because that's what we process claims

23 in.

24 Those two example list are magnetic

25 resonance angiography of the head and neck, which

00390

1 is new and controversial. We added some coverage

2 for MRA for head and neck vessels, and at the

3 same time we cover it, we gather some information

4 on what the indications were and how it's used,

5 so that we can continue to evaluate it and say is

6 it making a difference.

7 We're doing the same thing with the

8 other example I mentioned, PET scans. PET scans

9 for single pulmonary nodules which, you know, the

10 promise was, it's a better less invasive way to

11 monitor these patients. We're collecting the

12 information from the claims in such a way that we

13 will have an idea of what the experience was, and

14 are these patients avoiding biopsy, or are they

15 getting some other ones. That's one place to do

16 it.

17 But remember that in a very limited way

18 we have gone forward and said that we are very

19 cautious. And we have to be very clear that

20 we're not doing research, because research is not

21 only not Medicare's job, it's prohibited. So we

22 are not doing research, but we are at least

23 monitoring early diffusion of technology.

24 The third place we have done that is in

25 another area called lung volume reduction

00391

1 surgery, which is a new surgical procedure. It

2 has the promise of helping patients with

3 emphysema. It was early touted as a miracle

4 cure, some people still believe it is, and we are

5 promoting it very heavily. And we looked at it

6 early on, and realized that this would be another

7 issue such as is turning out to be, bone marrow

8 transplant for breast cancer, something that

9 after ten years not only was never proven to be

10 beneficial, in fact it turns out it may be

11 harmful. And so, lung volume reduction surgery,

12 we're gathering information at the same time

13 we're paying for it in limited clinical trial.

14 But in general, it is very difficult

15 and may not even be possible, although it's

16 tempting at times for an issue like this, to say

17 gee, it's early, let's pay for it and keep an eye

18 on it, and then we will sort of stimulate the

19 research.

20 In the previous panel we had a multiple

21 myeloma, which is at the current time

22 investigational, and the question was, is it

23 ready to move to prime time? We made it clear to

24 that panel and I think it ought to be clear to

25 this panel and future panels, that when Medicare

00392

1 covers in an area that -- the day of the clinical

2 trial is gone. We can accumulate information

3 from case series, we can watch patients, but the

4 day of the clinical trial is over when Medicare

5 starts to cover it. There will be no

6 randomization for that procedure ever again,

7 because we have made the decision by coverage of

8 saying randomization is no longer necessary, we

9 have the answer.

10 DR. FERGUSON: Dr. Sundwall?

11 DR. SUNDWALL: Thank you. I feel

12 fortunate going at the end of this discussion, so

13 I get the benefit of all these experts, and I

14 don't mean to be flip about that. I really

15 appreciate the expertise of the panel, more

16 analytical than those of you who carefully

17 reviewed the studies. My perspective is that of

18 a family physician like Paul, who is taking care

19 of patients, diagnosed cancer, followed them

20 through chemotherapy, and seen sometimes the

21 benefits, more often the heartache and morbidity

22 that's associated with that. That doesn't mean

23 I'm not a believer, it's just that I think we

24 need to have a very healthy skepticism about

25 current cancer treatments.

00393

1 I am also coming at it from the

2 perspective of someone who's spent most of my

3 adult life in health policy here in Washington in

4 different capacities, and I'm very familiar with

5 the tension between those advocating something

6 new and wonderful, and the payers who in their

7 responsibility to monitor how we spend our funds,

8 make sure they are done appropriately.

9 However, I must admit that through the

10 course of the discussion yesterday, I was

11 reminded of a quip I once heard about economists,

12 which was intended to be funny, but the

13 economists were described as people who, when

14 something is proven to work in practice they want

15 to find out if it works in theory. And it seemed

16 to me the preponderance of evidence was that this

17 is in fact a useful tool, it's information, I

18 think in some respects it has been oversold in

19 what it promises, but I look at it more simply as

20 Grant described, it's information. And it

21 clearly would be useful to me and my patients in

22 making decisions about chemotherapy.

23 I think to put it in context of

24 reasonable and necessary is wise. It is

25 reasonable. Whether it is necessary, I think

00394

1 must be left to the discretion of those experts

2 who are going to be using it.

3 And Grant, I just have a quick question

4 for you, because I'm not clear in my mind, maybe

5 I should be at this stage of our panel's life,

6 but I'm not. Let's assume for the sake of

7 discussion that this panel has consensus that it

8 is reasonable to pay for. However, to determine

9 what's necessary is going to, because I know

10 about this having participated in the negotiated

11 rule making, that won't be done willy-nilly as

12 you were talking to Dr. Brooks, that won't

13 happen, because Medicare doesn't willy-nilly pay

14 for anything. It will either be then subject to

15 development of a national coverage policy, or

16 left for medical review. And how do you envision

17 the next step? Will it be an LLMP or will it be,

18 will you ask us, not us, but will you convene

19 another panel or will you ask us to reconvene and

20 develop what we in negotiated rule making did?

21 For those of you who don't know what that was, we

22 did wrestle over several months and developed

23 coverage policies, was it 23 tests or 24?

24 DR. BAGLEY: It seemed like 124, David.

25 DR. SUNDWALL: For those of us who

00395

1 participated, it was a 13 month process in total,

2 and it felt like going to the dentist for three

3 days at a time, but we did it, and it was a

4 useful thing. So do you think this kind of

5 testing would be subject to a national medical

6 review policy or would you leave it at the

7 discretion of the carriers?

8 DR. BAGLEY: Well, given the fact that

9 the whole negotiated rule making process was

10 driven by mandate from Congress, and the goal was

11 that there be national policies for laboratory

12 tests, and even when they weren't national

13 policies they should be uniform across all the

14 regions, I think it would be our goal to in one

15 fashion or another to try to make the policies as

16 nationally uniform as possible. That means

17 making them as specific and data driven as

18 possible, and that means being as specific as

19 possible in what we're dealing with. And most

20 likely, it's going to require something beyond

21 what this panel will do in terms of mining

22 through the literature. So should this panel

23 make a recommendation that we be, that we go down

24 a path of looking for specific kinds of

25 indications, of drug tumor combinations in which

00396

1 the evidence is somewhat better, then I think we

2 would undertake the task of trying to mine the

3 literature for that purpose. But I don't see

4 reconvening this panel. But I also think our job

5 would be to try to find a consistent policy which

6 could be applied nationally, whether it be

7 regionally uniform or national, I think we would

8 try to have some uniformity.

9 DR. SUNDWALL: Because I think that

10 would calm a lot of the concerns that I have

11 heard about today, the idea that if some of us

12 say that it's okay, then it's just universally

13 available. I think there needs to be guidance

14 and expertise on how it's appropriately applied.

15 The last comment I would just make is,

16 I think from a health policy standpoint, we keep

17 talking about quality access and costs, and

18 access I think is important, and this is a useful

19 technology and ought to be accessible to Medicare

20 beneficiaries appropriately applied. I do think

21 the cost issue is promising. I was disturbed by

22 the testimony of the American Cancer Society

23 clinical oncologist yesterday. It seemed very

24 self serving. We're neutral, but by the way,

25 cover chemotherapy, and don't you dare tell us

00397

1 what we can't use. And I really thought that was

2 not constructive, and I think it's troublesome.

3 And I mean, you must hear this all the

4 time. A typical provider tells HCFA, I don't

5 want much, I just want more. But I thought the

6 oncologists were not constructive, and I'm

7 perplexed why they were not more supportive of

8 this when in fact they were during negotiated

9 rule making, and I assume this young man was

10 speaking on behalf of the society. But I do

11 think in the event this is approved, I think one

12 of the questions you posed before us merits

13 discussion and hopefully we'll have it through

14 all of the tests we talked about that, and that

15 is, no, I don't think HCFA should pay for things

16 that don't work.

17 DR. FERGUSON: Okay. Miss Simmers?

18 MS. SIMMERS: I think this fits into

19 the category of the tools that a physician should

20 use in order to dose, or what course of treatment

21 to endeavor and to go in that dialogue between

22 the patient and the physician and the family.

23 I think the one presenter and one panel

24 member pointed out something that I think about

25 all the time, at least in one region, and I think

00398

1 it unfair to have Medicare beneficiaries pay

2 their insurance premium and not get access to

3 that test. So I'm very much the 35,000 foot view

4 of the Medicare beneficiaries' needs and how well

5 what we decide to recommend would serve those

6 beneficiaries. And I think Dr. Bagley's point

7 about they help pay for it is very valid. They

8 do help pay for it, and as insurance carriers are

9 paid, I think the same level of access should be

10 available to Medicare beneficiaries that there

11 are provided for those who have private

12 insurance.

13 I have some concerns, however.

14 Certainly the accessibility of the test, although

15 I am convinced there are ways to address that, I

16 think there would be a duty to promote this as,

17 promote its accessibility not only in very small

18 regional areas, but nationwide, should we decide

19 to cover it. I think there are some valid

20 research and scientific questions to be

21 answered. I do believe that this is a diagnostic

22 test and should be held to that criteria, and not

23 to that of therapy. I think that was clear, and

24 although I think the science could be better,

25 it's not a perfect world, and what we see is at

00399

1 least compelling evidence to continue.

2 The policy specific issues, certainly I

3 am not the expert in that area, but is does seem

4 to be available to us to look at those cancers

5 and what circumstances with what drugs are best

6 pursued under this coverage recommendation,

7 should we make it. It seems to me the processes

8 are in place to do that, so I don't fear that it

9 can't be done. And certainly, the devil will be

10 in the details of that kind of process.

11 But after everyone has said their

12 piece, I guess if any of us in this room were to

13 face the terrible news from our clinician

14 tomorrow that we had cancer, who among us would

15 say no, this assay is not for me. And I believe

16 if it's for us, it is for Medicare beneficiaries

17 as well. So that's my comment.

18 DR. FERGUSON: Thank you. Before

19 asking some more of the panel, I have one

20 clarification, Grant, or anybody else. As I

21 understand it, our job is really to answer these

22 questions, which can be posed in the form of

23 motions. For us to add some more questions like

24 should Medicare cover this, yes or no, for our

25 panel, or under what circumstances for our panel,

00400

1 I did not think was our job. Has that been

2 changed?

3 DR. BAGLEY: No. We spent a long time

4 with these questions as staff. We spent a great

5 deal of time toiling over them. And the reason

6 is that the answers to these questions we think

7 are particularly relevant in giving us some

8 guidance in developing a policy. So I think we

9 are particularly interested, and the number one

10 goal should be, you know, to go through those

11 questions and give us not only answers, and they

12 aren't really yes or no questions necessarily,

13 but to give us some discussion and to give us

14 some rationale. And that's one of the biggest

15 reasons for having this transcribed word for

16 word, so that discussion around those questions

17 can, we can use as guidance in trying to develop

18 some policy.

19 So I think once these questions have

20 been dealt with, and we can have the discussion

21 and the committee's thinking around these

22 questions, the reason for number six is that the

23 committee can then entertain some other issues,

24 and I think we can hear the other concerns from

25 the committee or from individual committee

00401

1 members. But I think at this point, it is

2 particularly important and relevant to deal with

3 the questions presented, because we felt those

4 were necessary for us to have the direction for

5 policy.

6 DR. FERGUSON: I was going to ask that

7 we handle question five last and put six before

8 it, because it seemed that the fifth question was

9 sort of the bottom line question. Is that --

10 DR. BAGLEY: That's not inappropriate,

11 as long as, before lunch time, we deal with

12 question five.

13 MR. MINTZ: I have a question. Grant's

14 comments just prompted a question. I had the

15 privilege of serving on the myeloma panel, and we

16 went beyond the questions certainly to the very

17 direct question of coverage, you know, by virtue

18 of motions that were made during the course of

19 discussion. I'm interested in your comments

20 about that, and whether you felt the panel sort

21 of exceeded its charge in that regard, or whether

22 that was just something that happened in due

23 course and was appropriate.

24 DR. BAGLEY: Our lesson learned from

25 the myeloma panel and again, the reason for

00402

1 toiling over those questions as we did, our

2 lesson learned was, number one, the committee

3 discussion was far too short. We had lots of

4 presentations from the outside, the committee

5 didn't have much discussion, so when we took it

6 all home to try to make sense of it, we thought,

7 I wonder what this committee member was thinking,

8 I wonder what they were thinking. So that was

9 number one lesson; we wanted to know why the

10 committee is making the decisions they are, not

11 just do this, do that.

12 Lesson number two is, it's very easy

13 for the committed to sit here and say, and we've

14 heard a sense of that this morning, you know,

15 this sounds pretty reasonable and I think I would

16 want it, so other people ought to have it

17 available. On the other hand, it needs to be

18 fit, we need to look at the science, the policy

19 has to be restricted and figure out where it

20 fits, and maybe gather some data, so we think

21 HCFA ought to pay for it, but only when

22 reasonable and necessary, and they ought to

23 gather some data. We knew that coming in, so our

24 sense is that that's the policy direction we need

25 to go, and we need to hear from the committee.

00403

1 Not that the committee can say, cover it for this

2 ICD-9 code and this one, but we need some policy

3 directions on what we need to look for.

4 So, the lesson learned from myeloma is

5 -- and that's why we fashioned the questions, so

6 I don't think it's totally inappropriate for the

7 committee to make some expressions, but the

8 myeloma panel left us to cover this, but I really

9 think it's necessary, and we did have good

10 people, and the right kind of people and figured

11 it out. That's not being that critical, but you

12 know what I mean.

13 DR. MINTZ: But it did direct, it did

14 have a specific vote on coverage. It went

15 through cytogenetics and it went through each of

16 the clinical conditions and voted 11 times, I

17 think, to cover under a variety of circumstances.

18 DR. BAGLEY: That's very true, and

19 we're cognizant of that. But I think our goal in

20 fashioning these questions, at least as far as

21 threshold issues, were to give us the information

22 that we need for policy.

23 DR. MINTZ: So it is a different

24 direction in that sense?

25 DR. BAGLEY: Yeah, I think it is. And

00404

1 I think it also makes it clear that HCFA, after

2 all, cannot abrogate the coverage decision making

3 to the panel. The panel is advisory and the

4 panel needs to give us advice so that we can make

5 the coverage decisions, and simply having

6 battling coverage decisions doesn't help the

7 information we need to make the decisions.

8 MR. MINTZ: Just for this panel's

9 information, the myeloma panel voted to cover

10 everything but refractory relapse, and went

11 through a whole series of votes to do that. So

12 it is very different from what we experienced.

13 DR. BROOKS: Dr. Bagley, I guess your

14 response to one of the other questions and

15 whether or not, you know, clinical trials are

16 over when Medicare decides to make a decision is

17 like very very crucial to me, because we have

18 data on certain areas that I think we all agree

19 at least has clinical utility. But what we

20 actually don't have in each individual, patient

21 by patient, whether they got the sensitive drugs

22 or not in all those studies. And so, I still do

23 look upon it as a potential willy-nilly thing

24 unless we collect data as we go, and maybe

25 reevaluate in a few years as to what -- because

00405

1 you know, we have that 20 percent problem there,

2 and that was brought up in the negative

3 predictive value.

4 So, I would really like to know whether

5 or not in a coverage decision, you can mandate a

6 trial that is, you know, it may not be the usual

7 clinical trial that everyone thinks about, but at

8 least, that you can say, I'm going to have the

9 NCI or the CDC or somebody, collect data as we go

10 here, that if people are not using the test to

11 give the sensitive drugs after a few years, then

12 what's the sense of having the test? Or if

13 everybody's just ignoring the results and so

14 forth, or in fact, if when they get a negative

15 result and people went ahead to treat with the

16 negative drugs and they responded 25 or 30

17 percent of the time, which is about the 30

18 percent of the time they respond to almost

19 anything, so I would like to really know that.

20 And so, what's your answer to that question as to

21 whether you can require in a coverage decision

22 that at least ongoing, much more than your

23 claim? I mean, I don't believe you can evaluate

24 this by your claim data, you know, who got what.

25 DR. BAGLEY: Well, it's -- it would be

00406

1 long and time consuming for us to try to tie a

2 coverage decision to what NCI was doing, and it

3 would probably, we would be here years from now

4 talking about the same issue. That's one

5 possibility. But the other one is that normally

6 if it requires a clinical trial, we don't cover

7 it, and if it's gone beyond that and then

8 diffuses, we do cover it. Now as I mentioned,

9 there are ways in which we can cover things and

10 we can gather information, and by law we can only

11 gather what's necessary to process the claims.

12 But it's surprising, the amount of clinical

13 information that that makes available to us. It

14 is a fairly rich data resource.

15 And I mentioned, for example, PET scans

16 for single pulmonary nodules. Now what that

17 policy says is that, it says that the purpose of

18 this is as an alternative to open biopsy, and

19 that we would not expect to see open biopsies

20 after single pulmonary nodules. That's what it

21 says in the narrative of the policy. Does that

22 mean that we would never pay for an open biopsy

23 after a negative PET scan for a single pulmonary

24 nodule? No, of course not, because there are

25 going to be clinical circumstances in which it's

00407

1 necessary. But it does say, and it's an

2 expression, and what we did, the way we described

3 it is that we said, you know, when you approach a

4 PET scan for a single pulmonary nodule, you have

5 reached a fork in the road.

6 And we would look at sensitive testing,

7 or resistance testing, as a fork in the road. We

8 have a test. We're going to do a test, and that

9 test is a fork in the road for us, and depending

10 on the result, we're going to go down path A or

11 path B. Now, I think that a physician and a

12 patient should have a full discussion of that

13 fork in the road before they go down a path. And

14 to do the test and say, well, this test was a

15 fork in the road but don't like the answer, let's

16 go the other direction, makes you wonder whether

17 the test was necessary or whether the direction

18 is necessary.

19 And so what we would do, hypothetically

20 for example, is that the policy would say that we

21 would ordinarily consider it not medically

22 necessary, or not reasonable and necessary to use

23 chemotherapeutic agents shown to be resistant or

24 not sensitive by this testing system. That means

25 that an oncologist ordering the test, and then

00408

1 embarking on a course of therapy which was not

2 shown to be beneficial by the testing would be

3 very likely to having a carrier medical director

4 say, I think these claims are not reasonable and

5 necessary, I'm going to deny them. And then they

6 could go practice their medicine in front of an

7 administrative law judge.

8 And I think that would not be an

9 unreasonable kind of policy. That would allow us

10 to gather some kinds of information, and we would

11 see where it goes. But to say we are going to

12 put a clinical trial together as part of our

13 coverage, I mean when we start paying for it, the

14 ability to collect information, and the impetus

15 out there, and the stimulus for people to do

16 clinical trials goes away. And we've seen it

17 time and time again. And bone marrow transplant

18 for bone cancer, I think is a perfect example.

19 When payments started, the clinical trials

20 stopped. And it was only after many many years

21 of accumulated data that we then found out that

22 this was not a wise course.

23 DR. FERGUSON: Dr. Hausner?

24 DR. HAUSNER: This is a question for

25 Dr. Bagley, so that I can understand the

00409

1 process. The test itself would be relatively

2 expensive, say compared to a CBC, in other words,

3 whatever the price is, and I know we're not

4 talking about price, but let's establish that. A

5 concern that I have, and this is, I practice

6 pathology in a world probably quite similar to

7 the world that Dr. Fischer practices his family

8 practice, and the question of proper utilization

9 is very much on my mind. Would the decision to

10 pay for the test eventually reflect itself in a

11 hospital DRG? In other words, would the test be

12 so expensive that the DRG for say CLL have to be

13 modified in order to incorporate the test?

14 The second question that I have, and

15 it's a concern particularly for CLL, which is a

16 malignancy that sometimes isn't even really

17 treated in an older patient necessarily, would be

18 how to avoid this becoming a standard beginning

19 of disease test that might or might not be used?

20 Is there any way to monitor, and I know you can't

21 say, well, by God, if you do this test, you'd

22 better get some chemotherapy. I am not quite

23 advocating that. But you know, do you understand

24 the flavor of what I'm asking? Because from my

25 point of view, I want to do the right thing for

00410

1 the patients, but at the same time, I don't want

2 to inadvertently give a group the key to the

3 treasury.

4 DR. BAGLEY: Well, nothing in Medicare

5 is simple. Let me start out by saying that.

6 It's always complicated. And the one, well, one

7 of my adages in Medicare is that however

8 complicated it seems to be, it will be more

9 complicated by the time you get to the end. So

10 how this would be paid for and in what fashion

11 is, I think is something for the future to

12 decide. Obviously a patient in the hospital who

13 undergoes surgery or biopsy and the tissue is

14 harvested in the hospital, then the test itself

15 is going to become part of the DRG. Now if that

16 means that the cost of many malignancies is going

17 to go up, there is a way, and the mechanism is

18 that the DRG over time can reflect increased

19 costs. But it's not rapid, it's a slow process.

20 Would all of the costs of this be part of the

21 DRG? No, it wouldn't be, because some things are

22 not included in the DRG. You know, physician

23 services are not included in the DRG. So to the

24 extent that some of these are physician services,

25 pathology services, consultation service, you

00411

1 know, and a certain portion of these tests are

2 evaluation and billed as consultation services,

3 not as laboratory services, then they wouldn't be

4 in the DRG, but they would be in the part B

5 physician fee schedule payable out of part B, and

6 they would become simply payments from that

7 mechanism. So you know, it's going to be fairly

8 complicated, but I think it's -- you bring up the

9 point that the inpatient part of this is going to

10 be in the DRG, and it's going to impact on how

11 hospitals choose to have oncology patients taken

12 care of and their admission status.

13 DR. FERGUSON: Kathy, and then Dr.

14 Fischer.

15 DR. HELZLSOUER: This is Kathy

16 Helzlsouer. I just want to raise for discussion

17 among the panel how we are going to define

18 clinical utility, because I think that's the crux

19 of it and really the first question brings this

20 out. If utility is going to define as, is this a

21 marker of response rates, I think that's what the

22 literature has been designed to show. I think

23 the appeal that Dr. Fischer did, that gee, if I

24 could get oncologists to stop treating when it's

25 appropriate and not have all the side effects,

00412

1 that's great, but we don't have any evidence that

2 this would change clinical practice, that those

3 oncologists that you don't refer to because they

4 say never never never quit, they are probably

5 still going to say never never never quit, they

6 may not even do the tests and if they do it, they

7 probably won't always use the results. And we

8 don't have any evidence that it's -- would it

9 change practice or should it, because of this

10 issue of false positives, false negatives. And

11 negative predictive values, we learned yesterday,

12 is highly dependent on the prevalence of the

13 population under study. So we have to be careful

14 of the literature that we're looking at in using

15 negative predictive value or positive predictive

16 value to guide us.

17 So I think, like I said, it seems

18 reasonable to me, it gives them added

19 information. If that's the criteria, then that's

20 fine. But if we really want more than that, and

21 we expect this to change practice, I guess I'm

22 not convinced that it would or should. And we

23 don't have -- the issue of the added value, I

24 think comes up, because in the literature that we

25 have here, with the exception of the CLL study,

00413

1 which I am just looking through this morning, is

2 what is the added benefit beyond what we already

3 know, which is what Dr. Brooks is raising. Do we

4 have all the other markers that are now being

5 used and accepted, not just histology, but other

6 prognostic markers really define who's going to

7 ultimately respond and not respond. Does this

8 add something to that information or doesn't it?

9 We don't have from the studies that have been

10 done to date anything to say what the added

11 benefit of this test truly is, with the exception

12 of perhaps CLL.

13 So I agree with you. I think that as I

14 said, a huge benefit would be if you could

15 eliminate toxicity from agents that would not be

16 used, and that may be the case, at least the

17 first line. But you're talking about a specific

18 situation too, which is the other overriding

19 issue. You're talking about metastatic end stage

20 disease when you were jumping to chemotherapy.

21 So that's what I'm struggling with. I think if

22 the diagnostic tests say it's not in the patient,

23 there's obviously no harm. The only harm would

24 be, though, it it's used to guide therapy and

25 there's a significant rate of people that would

00414

1 not get therapy that would be potentially

2 beneficial, with 20 percent response rates in the

3 face of a test that says resistant. So if the

4 policy is tied to eliminating most chemotherapy,

5 I think there is the potential for harm here in

6 how the tests would be used.

7 DR. FERGUSON: Dr. Fischer?

8 DR. FISCHER: Yeah. We talked

9 yesterday about where the bar should be set for

10 the level of evidence. I would hope that the bar

11 wouldn't be set at the level where the people who

12 were coming up with this test have to demonstrate

13 that somehow oncologist's behavior has changed

14 for the better. That's much higher than we need.

15 DR. HELZLSOUER: That's your argument

16 for using the test, though.

17 DR. FISCHER: But to borrow Greenspan's

18 term, I'm not worried about irrational exuberance

19 with this test. I mean, the fact is, most people

20 don't believe it, and I think that it's a much

21 smaller job for the champions of this technology

22 to convince us than it is to convince all the

23 oncologists of the world. And I think that, you

24 know, that will happen. The evidence that we saw

25 from '99 that has been published is a lot better

00415

1 than was published in 97, and it looks like we

2 are on to some good things here.

3 This is very different than

4 orthopedists and MRIs, you know, where you have

5 an orthopedist and an MRI, you've got somebody

6 getting a test. This is not something that's

7 going to overwhelm the oncology community

8 overnight because most people don't believe it.

9 And I think the champions are going to be

10 expected to publish data that will be disease and

11 drug specific, and to the extent that evidence is

12 persuasive, people will change their behaviors.

13 So I don't want Medicare doing any studies, to be

14 quite honest with you, and I wouldn't trust them

15 to do it. I think that the scientific community

16 is going to answer these questions over time.

17 The question is whether Medicare should pay for

18 it given what we know about it at this point in

19 time and you know, I think the date is pretty

20 persuasive. I am hopeful that that will change

21 the practice of oncology, because I see a very

22 different part of that practice than what the

23 average oncologist does. And they're the

24 patients and their family who have failed

25 chemotherapy with very terrible results.

00416

1 And I just want to repeat this one more

2 time. In the total practice, in my total

3 practice, there has been as much harm as benefit

4 from oncology.

5 DR. FERGUSON: Yes?

6 DR. BROOKS: Well, I don't personally

7 believe that, because over the course of 25

8 years, as has been published in a number of

9 publications, the survival rate for cancer is

10 going up, precisely because of all the clinical

11 trials and so forth, so I just do not believe the

12 American public is being harmed by oncology.

13 DR. FISCHER: I didn't mean oncology, I

14 meant chemotherapy, excuse me. Oncology is

15 different.

16 DR. BROOKS: But it is chemotherapy.

17 DR. FISCHER: No, no. It's a lot of

18 things, including detection of cancers earlier.

19 But in terms of somebody now has to get

20 chemotherapy and you're looking at their benefits

21 versus the cost, it's on balance a very hard call

22 to me, to say that my patient practice has

23 benefitted more than they have been harmed by

24 chemotherapy.

25 DR. FERGUSON: All right. Miss Kraft,

00417

1 and then we're going to have a break.

2 MS. KRAFT: I'd just like to echo

3 Dr. Fischer's comments. I mean, the statistics

4 prove that only one in every four patients

5 actually respond from treatment of cancer. And

6 I'd also like to comment on Dr. Bagley's comment

7 that bone marrow treatment for breast cancer

8 patients, deciding to pay for that was a bad

9 decision. Well, I don't necessarily look at it

10 that way. I mean, it was determined that it

11 would be funded, and did not the testing and all

12 that was done following the approval of that show

13 the American public that yes, bone marrow

14 transplants shouldn't be used in breast cancer?

15 And then to comment with Dr. Brooks's

16 comment about if this is approved, will clinical

17 trials stop and no testing will be done, again, I

18 echo Dr. Fischer's comment with the fact that I

19 don't think there is any laboratory test out

20 there that has been approved and been funded by

21 Medicare where as soon as it's approved and

22 funded that the testing in that laboratory, test

23 in any trial has stopped in modern medicine, for

24 the last 20 years. I think after a test is

25 funded by Medicare, that the trials and -- not

00418

1 necessarily the trials, shall we say, but the

2 testing done on patients increases 10 to

3 100-fold. So I think after approval the test

4 will probably find out a lot more information

5 than we have so far here today.

6 DR. FERGUSON: Thank you. We will

7 convene back here at 10:15.

8 (Recess taken from 10:00 a.m. until

9 10:20 a.m.)

10 DR. FERGUSON: Can we come to order?

11 Dr. Bagley has one point of order. Dr. Bagley?

12 DR. BAGLEY: Now we're getting to the

13 end of this, and I've given you an explanation of

14 why we presented the questions. And we need to

15 go through these questions, and Dr. Ferguson is

16 going to go through them in an orderly process

17 and we're going to get through them by noon.

18 People have travel plans and we are going to be

19 out of here at noon. So we have to keep to a

20 schedule.

21 Before we start voting on these

22 questions, I want to clarify one issue, or at

23 least one thing that might be a misperception.

24 The new process, and this is only the second time

25 we have done an advisory committee, but the new

00419

1 process which we put together, which I think is a

2 real step forward, is a process in which we do

3 these things in the open, we do them in a way

4 that we get input from all parties, and that's

5 why the committee is supposed to represent all

6 parties, and that's why we've got the opportunity

7 for public dialogue here. But it is a new

8 process, and I think we are feeling our way

9 along, and it's one in which I think the medical

10 profession itself is trying to find their proper

11 role in where they ought to be here, and what

12 they ought to be saying.

13 And this advisory committee process is

14 not for every issue. I mean, if we had every

15 issue before a committee like this, we would only

16 handle 10, 11 or 12 issues a year, and we would

17 not adopt many new things for Medicare. So it's

18 only for selected issues. Now, how do we select

19 them? Well, we've announced our reasoning is if

20 it has a high impact for the Medicare program, an

21 important advance, something that affects lots of

22 Medicare beneficiaries, something that is very

23 important for Medicare and its beneficiaries. If

24 it's something that is controversial in the

25 scientific community. If it is something in

00420

1 which there is a varying coverage, which appears

2 to be quite disparate without good explanation

3 across the country. Well, I think you've heard

4 in a day and a half that this issue clearly meets

5 all three of those criteria. We though it did,

6 and that's why we presented it to this

7 committee.

8 But think on those for a minute.

9 Significant controversy within the scientific

10 community. We heard that and we've tried to

11 bring that to the fore and present it. And I --

12 the reason for this is I want to explain the fact

13 that I don't think you should read anything into

14 the fact that we made a staff presentation on

15 this issue, in which we pointed out what we

16 thought were many problems with the literature

17 and many gaps. That shouldn't be looked at as

18 prejudicial. That shouldn't be looked at as the

19 fact that we have a position or we have anything

20 else. It was in terms of balance, because as

21 you've noted, there are many proponents of this

22 procedure who are pointing out the favorable

23 aspects of the literature and the promise of this

24 procedure, and we are relying on them to make

25 that presentation. But we think in terms of

00421

1 balance, we wouldn't have brought it here if it

2 was one sided, if it was easy. And we want the

3 committee to hear both sides. And if we have

4 presented, at least been the devil's advocate in

5 saying there are some problems in this

6 literature, this is an early technology, this is

7 controversy in the medical community, and if we

8 as a staff, or if I have as the HCFA member here,

9 appeared to point out problems, if that appeared

10 to be negative, I want to correct that

11 misperception.

12 If we had our mind made up, we wouldn't

13 need to come to this panel. If we knew the

14 answers, we wouldn't need to come to this panel.

15 If they were easy questions, we wouldn't need to

16 come to this panel. So when it's been necessary,

17 we have been the devil's advocate and brought up

18 the contrary arguments, because there has been

19 adequate representation of the pros, we've tried

20 to bring up the cons, only for the purpose of

21 presenting this to the panel and having presented

22 it to the panel and having made it clear that we

23 don't have our minds made up, that we are after

24 all neutral, and waiting the panel's

25 deliberations also. So having made that

00422

1 hopefully clear, that there should be no bias at

2 this point, let the deliberations begin.

3 DR. FERGUSON: Thank you. Before we

4 start, are there any other points that the panel

5 would like to make before we start on these?

6 DR. LOY: I would just like to point

7 out that this discussion has been compared to

8 many other diagnostic tests and I really don't,

9 at least in my mind, I don't see this as a

10 diagnostic test. The diagnosis has already been

11 made. Clinically probably has already been

12 confirmed via other laboratory tests or other

13 modalities. I see this as a test which gives

14 probability into the likely outcome in terms of

15 response from a specific therapeutic modality, so

16 I think it's a little different from a diagnostic

17 test, and I don't think it should be compared to

18 other diagnostic tests.

19 DR. FERGUSON: Thank you. Yes,

20 Dr. Brooks?

21 DR. BROOKS: Yes. I guess I want to

22 ask my former question a different way of

23 Dr. Bagley, which is to say that, can Medicare in

24 its rule making or whatever coverage decision

25 it's called, put a requirement not to things in

00423

1 general, but if there are to be new clinical

2 trials of new agents, new agents now, or a new

3 agent combined with various other old agents on

4 various clinical arms by the government supported

5 NCI system with the C Comps, everything else,

6 that those new trials employ this new technology,

7 so that data at least may be gathered by that

8 process?

9 DR. BAGLEY: Well, real quickly, no, we

10 can't tell NCI what to do, we can't tell oncology

11 groups what to do, and we can't dictate clinical

12 trials.

13 On the other hand, oncology is a unique

14 area in which most of oncology is a clinical

15 trial. Most of the drugs we pay for are

16 investigational. In fact, if it becomes too

17 settled, then the next generation is

18 investigational, and that becomes standard

19 practice in oncology. So oncology is a little

20 unique that way. So much of what we do pay for

21 in standard daily practice is in fact a Phase III

22 clinical trial, a protocol, or even a Phase II

23 clinical trial in some cases. So, there will

24 likely be in the future, you know, should the

25 promise of this technology hold true, there will

00424

1 likely be in the future an approach by Medicare

2 for some hypothetical new chemotherapy agent

3 which is very expensive, very controversial, and

4 can be shown to be associated with a high

5 predictive value. There is hypothetically a

6 Medicare coverage policy in the wings which will

7 say we are not going to pay for this until it's

8 shown to be effective. Maybe this isn't the test

9 that's going to do it, but I think the day will

10 be there when we will select chemotherapy in a

11 more rational way and that will happen. So yes,

12 I mean, that approach can be put into policy, but

13 not directly in the way of we're directing

14 clinical trials, but when we are paying for the

15 drug, we can say this is how we'll pay for it.

16 DR. FERGUSON: All right. Yes,

17 Dr. Loy?

18 DR. LOY: I'd like to make one other

19 comment and that is, in answering these questions

20 that we have been presented with, I would hope

21 again that the panel would try to be very

22 specific about these. I feel like we're, again,

23 flying around 35,000 feet, and I think there is a

24 real need for trying to hone in on which specific

25 clinical indications, when, why and how often

00425

1 these tests should be performed, and that should

2 be part of these answers to these questions, in

3 my opinion.

4 DR. FERGUSON: Well, I'm not sure we

5 can do that, but I don't say that it's not

6 important. That may be the crux. However, we

7 will do what the possible is, and see. Now what

8 we're going to do is the following: I have asked

9 several members of the committee to propose a

10 motion, these questions, individual questions as

11 a form of a motion, and then we will have

12 somebody second that, whoever chooses, and then

13 we will discuss these individual things for about

14 eight minutes or so, and then we will have a vote

15 on that motion. And it will be a simultaneous

16 vote of this panel, not a sequential vote.

17 And the voting members, you may have on

18 your list, but the chair is not a voting member

19 unless there is a tie. Interestingly, we have 11

20 voting members, so I'll see. Supreme Court.

21 Now, Dr. Murray has volunteered to make

22 a motion for the first question.

23 Motions, Discussions and Recommendations

24 DR. MURRAY: I guess that's my reward

25 for saying that we have to get to the questions

00426

1 in my comments earlier. So with regard to the

2 first question, the issue of scientific evidence,

3 it's my belief that scientific knowledge is best

4 advanced in a free and open arena, not one that

5 comes with administrative preconditions, and

6 accordingly:

7 I move that the advisory committee

8 recommend that the clinical response as well as

9 survival rates be accepted as appropriate

10 measures of clinical utility.

11 Just repeating that, I move that the

12 advisory committee recommend in favor of clinical

13 response, not to rule out, but that clinical

14 response not further defined be acceptable as an

15 appropriate measure of clinical utility.

16 DR. MINTZ: I'll second that.

17 DR. FERGUSON: Moved and seconded.

18 Now, is there some discussion on this point? Dr.

19 Klee.

20 DR. KLEE: Does the term clinical

21 response include quality of life, or is that

22 inferred or explicitly --

23 DR. HELZLSOUER: May I make a comment?

24 This is Kathy Helzlsouer. I don't think it

25 should include quality of life, because we have

00427

1 absolutely no data to judge quality of life

2 issues here. So I think it's clinical response

3 is defined responders, non-responders, as we have

4 in the data. That would be my opinion.

5 DR. MURRAY: I did not intend to

6 include quality of life as a clinical response.

7 However, it goes without saying that many

8 measurable clinical criteria affect quality of

9 life. So I think it's a bit semantic, but to

10 answer your question, no, quality of life as a

11 specific criterion is not intended to be

12 included.

13 DR. FERGUSON: Is there further

14 discussion on this?

15 DR. BROOKS: So Dr. Murray, I would

16 gather then that your motion would be to say both

17 to the second part of that, what outcome measures

18 should we rely on to best assess clinical

19 utility, both clinical response and survival

20 rates?

21 DR. MURRAY: That's correct. That

22 would be an equivalent way of stating the

23 motion.

24 DR. BAGLEY: What we're talking about

25 is trying to be very procedural, and as we go

00428

1 through each one of these questions, I think some

2 of them will be quicker, some will take a little

3 longer. We want to afford an opportunity if

4 there's a relevant public comment somebody needs

5 to make, whether we should do all the questions

6 first or go each question, and I think what we're

7 going to do, if they can be very brief, but

8 again, if they're relevant, take a public comment

9 before we vote on each question, if it's

10 necessary.

11 DR. FERGUSON: Is there further

12 discussion from the panel regarding this motion?

13 All right. Is there a comment or some point from

14 the floor regarding this motion?

15 We have our protocol lady again coming

16 to tell us. My script is missing.

17 Would anybody like to make any lasting

18 remarks? This is for posterity. Speak now or

19 forever hold your piece. Okay.

20 Can I have the recorder read the

21 question, or read the motion back?

22 THE REPORTER: It will take me a second

23 to find it, but yes.

24 DR. FERGUSON: I thought I was trying

25 to be very precise about this. If it's going to

00429

1 take a while, maybe you could just read it again.

2 DR. MURRAY: The motion is that the

3 advisory committee recommend that clinical

4 response as well as survival rates be accepted as

5 appropriate measures of clinical utility.

6 DR. FERGUSON: Okay. All in favor,

7 raise your right hand. Okay.

8 All opposed?

9 For the record, it was unanimous.

10 Do I have to read their names? Okay.

11 So, unanimously approved by Robert Murray, David

12 Sundwall, George Klee, Paul Mintz, Richard

13 Hausner, Mary Kass, Cheryl Kraft, Neysa Simmers,

14 John Brooks, Paul Fischer, and Kathy Helzlsouer.

15 Now, we will move on to question number

16 two. I have asked Dr. Kass to make a motion

17 regarding question number two.

18 DR. KASS: I'm not certain how to put

19 this in the form of a motion. But I would submit

20 that evidence was presented yesterday showing

21 that tests have been done with combinations of

22 drugs, and continues to be done, so I think that

23 evidence was presented supporting this. I'm not

24 quite sure how to state that in the form of a

25 motion.

00430

1 I suppose I could move that that has

2 been presented to this panel.

3 DR. LOY: Second.

4 DR. FERGUSON: So it has been moved and

5 seconded, that evidence was presented to the

6 panel supporting these tests with combinations of

7 drugs. Is that it?

8 DR. KASS: Yes, sir.

9 DR. FERGUSON: Is there discussion on

10 this point?

11 DR. BROOKS: Yeah, I think it depends

12 what we're talking about, because the question

13 reads: The assay described in the literature

14 test responses to single drugs. What is the

15 evidence reporting test results in combination

16 chemotherapies? Combination chemotherapies were

17 tested in the tests, but I think the question

18 gets at whether there were responses to

19 combinations. Is that correct, or maybe I am

20 misreading that, because certainly I agree, there

21 were.

22 DR. KASS: I was reading that as test

23 responses.

24 DR. FERGUSON: Dr. Sundwall?

25 DR. SUNDWALL: Just a comment. I'm not

00431

1 sure it's useful for us to revisit this, but I

2 did hear yesterday that these tests are

3 customarily done on single agents, and that

4 provides the utility to the oncologist for the

5 decision making. However, it is possible to do

6 the combination treatments and they are sometimes

7 done but were not considered that useful. And

8 I'm not sure how -- it's not for me to decide, or

9 possibly this panel, but I think we ought to be

10 clear if we make this a consensus of the

11 committee that in fact it's customarily done on a

12 single chemotherapeutic agent, and if any of our

13 experts want to clarify that, they can.

14 DR. FERGUSON: Well, I asked this

15 question specifically yesterday, because it

16 seemed to me that most of the stuff we were

17 presented was with single agent testing. And I

18 was told by a number of the presenters that in

19 fact routinely they do test two agents together

20 on a single test, and that that is, although I

21 don't know how much of the publications indicated

22 that, but apparently some did.

23 So, is there further discussion about

24 this?

25 Is there a public comment on it?

00432

1 Okay. Dr. Weisenthal, and Dr. Nagourney too.

2 Briefly.

3 DR. WEISENTHAL: Yes. This is Larry

4 Weisenthal. The data that you heard yesterday,

5 there were three separate types of data which

6 dealt with that issue.

7 Firstly, the majority of the

8 correlations published in the literature of the

9 2,000 some correlation targets, actually if you

10 take all technologies, 4,000 some, 2,000 cell

11 death and 2,000 cell proliferation, of all those

12 reported in the literature, the majority of those

13 patients in fact were treated with combination

14 chemotherapy.

15 DR. FERGUSON: We are talking about --

16 this is referring to testing the drugs.

17 DR. WEISENTHAL: Yes, in 60 seconds.

18 The majority of those patients were treated with

19 combination chemotherapy. In some of the

20 studies, the activity of the best single agent

21 was used to predict for the activity of the

22 combination, and that works very well, and the

23 biologic explanation for that is that most

24 chemotherapy is additive and not synergistic, so

25 normally and frequently, it's the activity of the

00433

1 most active agent that determines how the

2 combination is going to do.

3 Many of the published correlations,

4 however, were actually combinations were tested,

5 and patient response to combination therapy was

6 compared with the testing in combination.

7 Thirdly, it's very important in only a

8 few situations, but in some situations it's very

9 important to test the drugs in combination. A

10 good example is Mr. Stein, who testified so

11 eloquently. His tests showed resistance to all

12 of the single agents but a unique synergy in that

13 one combination. And also the patient that Dr.

14 Nalick presented with the failure of the bone

15 marrow transplant, she was resistant to all

16 single agents, but to one unique combination.

17 So in special unique cases where we

18 actually get synergy, it makes sense to do that

19 and it is done.

20 DR. FERGUSON: Thank you. Dr.

21 Nagourney?

22 DR. NAGOURNEY: Basically my comment is

23 just to second that very issue, that there are

24 profound synergies in some combinations, some of

25 which can actually rescue patients from failure

00434

1 of both single agents. I think that biological

2 validity is forthcoming in publication. So I

3 think that combination sometimes can be uniquely

4 interactive and do have biologic validity in the

5 test tube that directly applies to clinical

6 outcomes.

7 DR. FERGUSON: Thank you. Mitch, did

8 you want to say something?

9 DR. BURKEN: Yes. Dr. Mitch Burken.

10 I'd just like to clarify a couple of things from

11 my presentation yesterday that relates to this

12 question. The issue that I think was intended by

13 this wording was what is available in the

14 literature to show the applicability of single

15 agent testing to combination regimens, as opposed

16 to what may be going on in the lab under special

17 cases. So I think this relates specifically to

18 the articles in the bibliography and those

19 presented to the panel about making inferences

20 from single drug to combination therapy, making

21 that jump.

22 DR. FERGUSON: Other comments from the

23 audience? From the panel? Do you want to read

24 this?

25 (Portion of record read.)

00435

1 DR. FERGUSON: Okay. Call for the

2 vote. All in favor of this motion? Okay. It

3 looks again unanimous, and this vote was

4 supported by -- do I read these names again? I

5 don't have to? I only have to read them once; if

6 it's unanimous, I only read them once. Sorry.

7 I'm on a learning curve here too.

8 Now, we move on to question number

9 three, and I've asked Dr. Fischer to make a

10 motion regarding this question.

11 DR. FISCHER: This gets to the issue of

12 the 64 bins that we talked about yesterday. In

13 particular, which tumors have been shown to be

14 useful to test, and I'd like to change the

15 question to the following position, that I move

16 that the panel accept:

17 In considering the presented evidence,

18 the advisory panel believes that HTASs

19 demonstrate a clear clinical benefit for

20 directing treatment of CLL, and promise for other

21 solid and hematologic tumors.

22 DR. FERGUSON: Okay. Is there a

23 second?

24 DR. SUNDWALL: Second.

25 DR. FERGUSON: Dr. Sundwall seconds.

00436

1 Is there some discussion? You're saying --

2 DR. MINTZ: I would be more comfortable

3 with the motion if the word clear was removed,

4 and simply said demonstrate clinical benefit,

5 only because of the uncertainties.

6 DR. FISCHER: I'd accept that.

7 DR. MINTZ: So would you amend the

8 motion to remove clear?

9 DR. FISCHER: Yes.

10 DR. FERGUSON: Okay. Kathy?

11 DR. HELZLSOUER: I guess I'm -- this is

12 Kathy Helzlsouer -- concerned a little bit about

13 actually the term clinical benefit, how we define

14 that. I'm very comfortable with these that are

15 markers of response, and can be used clinically,

16 but I think even in this trial, I haven't had

17 time to look at the one article that we gave

18 thoroughly, but to state that this has clear

19 clinical benefit is a pretty strong statement. I

20 think it shows clear benefit in directing some

21 therapy there, I might be much more comfortable

22 with that as amended as such.

23 DR. SUNDWALL: Suggestion. For

24 consistency's sake, I wonder if we should

25 substitute clinical utility as used above, with

00437

1 that definition.

2 DR. HELZLSOUER: I like that, and would

3 be much more comfortable.

4 DR. FISCHER: I'd accept that.

5 DR. FERGUSON: Okay so instead of clear

6 clinical benefit, clinical utility. Take off

7 clear. Okay? Dr. Fischer, can you restate that

8 please?

9 DR. FISCHER: Yes. In considering the

10 presented evidence, the advisory panel believes

11 that HTASs demonstrate clinical utility for

12 directing treatment of CLL, and promise for other

13 solid and hematologic tumors.

14 DR. HELZLSOUER: I second that motion.

15 DR. FERGUSON: Okay. Now, is there

16 further discussion on this amended motion? Yes,

17 Dr. Loy?

18 DR. LOY: I would only bring up the

19 point that has been brought up before, and that

20 is that I don't know that we really defined in

21 the course of disease where that clinical utility

22 might be. There are certainly CLLs that are

23 treated differently and diagnoses that are

24 treated, as compared to the way they are treated

25 at end stage disease or Richter's syndrome.

00438

1 DR. FERGUSON: Are there discussions

2 around that point, or others?

3 DR. BROOKS: I just guess, just that

4 there is nothing in the questions that, in other

5 words, the way it's written, and I very much

6 prefer to the way it is on paper, there is

7 nothing about stage of disease, which diseases,

8 et cetera, so I think we just have to consider it

9 as a whole.

10 DR. FERGUSON: I don't want to upstage

11 HCFA, but I think that to ask the questions in a

12 way that would prescribe specific therapies too

13 tightly would not be what HCFA would want. I

14 mean, in other words, to write a prescription for

15 the practice of medicine is not what we're trying

16 to do. Am I right?

17 DR. BAGLEY: Well, we get accused of it

18 all the time, but no, I think as I said, while

19 the questions in some ways are specific and some

20 ways are general, we worked pretty hard on it to

21 give us some direction.

22 DR. KLEE: It's my sense that you're

23 not going to be able to use tissue type to

24 determine which patient you're going to pay for,

25 given what we know at this point in time, and

00439

1 that's why this is a little more vague.

2 DR. MINTZ: Yes, but I think, Grant,

3 you did ask for direction, and I feel that though

4 we have modified the language to say clinical

5 utility, I feel strongly that this motion should

6 be supported. Dr. Bosanquet's article in the

7 British Journal of Hematology, I think speaks to

8 my sense that HCFA should cover this test for

9 CLL, and since you want a sense of the committee,

10 I think that's it.

11 DR. FISCHER: But not exclude it for

12 other things.

13 DR. MINTZ: Agreed, yes.

14 DR. FERGUSON: Is there some -- yes,

15 Dr. Bosanquet, or others from the audience?

16 DR. BOSANQUET: Some of the panel

17 members have said some nice things about the work

18 that comes out of my laboratory, which is perhaps

19 the smallest laboratory represented here. The

20 motion, and I'm sorry, I am going to inject an

21 added level of slight problem here, but you're

22 talking as a committee about the test, or the

23 methodology, and what I want to bring out is that

24 for hematologics, the extreme drug resistance

25 assays are not the -- some of the incorporation

00440

1 assays are not relevant for hematologics, it is

2 not anything used to test the hematologic

3 neoplasms. The DiSC assay and the MTT assay are

4 very similar procedures, and are relevant to the

5 hematologics. So I would caution you to say that

6 hematologics, or CLL in particular, can be tested

7 by this procedure, because there are actually two

8 different procedures. One is the drug resistance

9 assay, much of which has been presented to you.

10 The other is a drug sensitivity assay. Because

11 hematologics have a higher probability response

12 and you can't do a sensitivity assay there, I

13 think the added value of a drug sensitivity assay

14 is also higher, because you are no longer only

15 excluding the bad drugs, you're proposing good

16 drugs. Randy Stein, I would put to you, wouldn't

17 have been here on a drug resistance assay.

18 DR. FERGUSON: Thank you. I think my

19 previous comment might hold, that we're not going

20 to get that specific. Okay, Dr. Fruehauf.

21 DR. FRUEHAUF: Just trying to

22 understand the motion, in terms of how narrow or

23 broad it tends to be, but I wanted to emphasize

24 from my own experience in the field that

25 resistance is important, and that's not to

00441

1 minimize the value of sensitivity, but if

2 sensitivity is the only word used in the motion,

3 I think that detracts from where actually half of

4 the data are in the field.

5 DR. FISCHER: Yeah, but there is

6 nothing in the motion about either of those. I

7 mean, the term that I thought I had used was

8 HTAs, assuming that that incorporated all the

9 assays. Is that not true?

10 DR. FRUEHAUF: Well, yes. Okay. So

11 when you say directing therapy, because of my

12 long-standing experience in the field, you think

13 of that as meaning the selection of drugs rather

14 than the deselection of drugs, and so I'm just

15 asking for a clarification, that what you're

16 saying is these assays are applicable to solid

17 tumors and hematologics.

18 DR. FISCHER: Yes.

19 DR. FRUEHAUF: And you wanted to

20 emphasize that --

21 DR. FISCHER: The evidence is very good

22 for CLL.

23 DR. FRUEHAUF: The evidence is very

24 good for CLL.

25 DR. FISCHER: That's precisely my

00442

1 point.

2 DR. FRUEHAUF: Resistance, solid

3 tumors; I just wanted to ask for clarification.

4 DR. FERGUSON: I think the language can

5 stand where it does.

6 DR. BAGLEY: The fact that we are

7 considering these methodologies together, and

8 while there may be differences between them,

9 there may be different approaches, we chose to

10 put them together, because we didn't want to use

11 this panel process for single products. And I'm

12 also mindful of the fact that previously extreme

13 drug resistance testing was considered at the

14 negotiated rule making for laboratories and Dr.

15 Weisenthal showed up and said, wait a minute.

16 Extreme drug resistance testing and drug

17 sensitivity testing are really variants of the

18 same technology. There are some differences,

19 there are some nuances, but we are testing

20 susceptibility of tumor cells to drugs, and

21 whether we approach it from the right side or the

22 left, it's the same technology. And we took that

23 to heart and we're looking at all these

24 technologies together.

25 DR. FERGUSON: Thank you. Okay. I

00443

1 guess I will call for a vote. All in favor of

2 this motion, raise your right hand. And again,

3 we have a unanimous vote, and I have learned I

4 don't have to repeat people's names.

5 Now, question number four. I asked

6 Dr. Mintz to makes a motion.

7 DR. MINTZ: I move that if a human

8 tumor assay result indicates that a neoplasm is

9 resistant to a particular drug, that that should

10 not preclude the use of that drug during the

11 course of treatment for that neoplasm.

12 DR. HELZLSOUER: Second the motion.

13 DR. FERGUSON: Is there some discussion

14 on that point?

15 DR. BAGLEY: Well, I would start

16 simply by saying that I see this as a guidance,

17 and as a tool, that whether we consider it a

18 diagnostic test or a prognostic test, you know,

19 nothing comes to mind that has 100 percent

20 positive or negative predictive value, and I

21 think this is providing a piece of information to

22 the clinician.

23 DR. FERGUSON: I think that my sense, I

24 am not supposed to vote and I won't, but that a

25 laboratory test is, I think the clinician's view

00444

1 of that patient considering all things that they

2 have in their hands has to take precedence over a

3 single test. We've come across that in

4 neurology, on whether to turn off the respirator

5 if somebody's somatosensory evoke responses are

6 negative. They get measured, you know, and

7 people say, well, they're negative, so we can

8 unplug this patient. I believe that's not the

9 way to practice good medicine. At any rate, is

10 there further discussion about this point?

11 DR. BAGLEY: I don't like to ask the

12 question, because I would like to get some

13 discussion from the panel about where we are

14 headed in this thing, and to say, gee, a test

15 which shows the drug is resistant shouldn't

16 preclude using that drug, and I'm curious as to

17 why people think that the test would have

18 utility, which we voted that it did, if you

19 wouldn't use the result to guide therapy, if you

20 said well, it's just prognostic. And I would

21 think that prognosis ought to guide therapy. And

22 so, I mean I realize that physicians are uniquely

23 able to ignore information they don't like. I

24 mean, that's why the aircraft accident rate among

25 physician pilots is like six times the normal.

00445

1 DR. FERGUSON: Grant's a pilot, I might

2 add.

3 DR. BAGLEY: Because they use weather

4 reports the way they use laboratory tests.

5 DR. HAUSNER: Let me try to take a

6 crack at it. Use the analogy of a patient with a

7 urinary tract infection, that we start an

8 antibody, say Keflex, and we do our sensitivity

9 testing on the organism. Then we find out a day

10 and a half later that the drug, that the organism

11 on the plate is resistant to Keflex. Go back to

12 the patient, back pain has gone away, urine has

13 cleared up, fever is gone, and no one, any

14 insurance company said well, you need to stop

15 that Keflex immediately, because it was

16 resistant. And it's an easy question in the

17 context of say a urinary tract infection, because

18 we're dealing with shorter time frames, less is

19 at stake, less money, and it's something that we

20 don't even think about. I don't think anyone

21 here would vote to stop the use of an antibiotic

22 if it's resistant on the plate and the patient is

23 doing better.

24 In clinical oncology, which I don't

25 practice, we're dealing with a little different

00446

1 time frame and more is at stake, so I could

2 envision a situation, though maybe I'm stupid,

3 someone could correct me, in which a patient

4 comes in say, with a big meaty Steinal mass, has

5 some form of lymphatic lymphoma, their trachea is

6 being compressed, they've got to get on some

7 chemo. Meaty stenoscopy is done. Tissue is

8 harvested, chemotherapy is started. And then two

9 weeks later, ta da, the organism, the tumor is

10 not apparently, not sensitive to the

11 chemotherapy. Patient course is breathing better

12 and doing well. What do you do then?

13 So I think that as illogical as it may

14 seem to people who aren't in the field, there is

15 really no other way to answer that question at

16 the current time than the way the motion has been

17 stated. There just isn't any way that I could

18 walk out of here and do it any other way, as

19 illogical as it seems to appear.

20 DR. BAGLEY: Well, let me follow up on

21 your example, because it's a good one. You make

22 a good point about clinical response as opposed

23 to the testing. But let's take your urinary

24 infection patient and you put him on Keflex, or

25 let's say you put him on Bacterin, you do a

00447

1 culture and sensitivity, and the culture comes

2 back three or four days later and it says this is

3 resistant to Bacterin, and they're doing better,

4 and they're clinically better. I don't think

5 most even managed care plans would ask for the

6 money back for the Bacterin. But on the other

7 hand, say they didn't respond, and they weren't

8 doing better on Bacterin, and you looked at the

9 culture and sensitive, and it said this is

10 sensitive to ampicillin and resistant to Keflex.

11 Now I don't know many managed care plans that

12 would say sure, go ahead and give him Keflex.

13 It's more expensive and it's resistant to it, but

14 go ahead and give it to him anyway. I think

15 that's the flavor of the question, is if we don't

16 have clinical response but we've got a prognostic

17 test, should the test guide therapy to the extent

18 of saying we should or shouldn't treat it?

19 That's the direction the question is going.

20 DR. FERGUSON: Yes, Dr. Mintz?

21 DR. MINTZ: I will take it from a

22 different angle briefly. Yes, it should guide

23 therapy. But if I had CLL and I were resistant

24 to fludaribine, don't start me on that. But if

25 it becomes fulminant, and if the other therapy

00448

1 has not worked, by all means, try it. You know,

2 I think it's a guideline, I think it's a tool,

3 but I don't think that because it can't be

4 expected to have a hundred percent positive or

5 negative predictive value, that it should

6 preclude the use of an agent when other

7 apparently beneficial agents aren't working.

8 DR. FERGUSON: Dr. Brooks?

9 DR. BROOKS: Yeah. I think I would

10 follow up on both of them and agree with them.

11 And I think the rational answer to your question

12 is it's not a perfect test. If it was a perfect

13 test, then I would agree, we should preclude

14 whatever it is, insulin in the example I gave,

15 but since it's not a perfect test, then you

16 shouldn't. And secondly, along the line of

17 Dr. Mintz talking, this may be the last drug in

18 the series. I mean, people have cancer, and they

19 may have seen four or five or six drugs, and now

20 you have a result that says it's resistant to

21 Taxol and yet, as we know, there might be a 20

22 percent chance this patient may respond to

23 Taxol. I'm going to have trouble as a clinician

24 explaining to that patient that, you know, I

25 can't give that because that result's resistant.

00449

1 I know there is a 20 percent chance, but I'm not

2 going to give that to you. So, I think for the

3 combination of those two reasons.

4 DR. BAGLEY: But even to the point of

5 -- I mean, you said it shouldn't preclude

6 therapy, but then you said well, gee, if I had

7 CLL and fludaribine showed resistant, I wouldn't

8 give it but I'd give it eventually if nothing

9 else worked. I mean, in a way, there you're

10 saying that we wouldn't give it as primary

11 therapy, but we might reserve it, and that

12 becomes a qualified answer, and I think that's an

13 important nuance.

14 DR. BROOKS: Well, that's because it's

15 a qualified test. It's not a perfect test.

16 DR. BAGLEY: But you're saying that if

17 it showed if it was resistant, you wouldn't use

18 that drug, until you had exhausted the ones that

19 didn't show the same thing. I think that's an

20 important distinction.

21 DR. FERGUSON: Two more points down at

22 the end, and then we're going to call for a vote.

23 MS. SIMMERS: I think to clarify it a

24 little bit, what you're trying to do is find the

25 drug that has the most probability of working and

00450

1 using it first, and then move down the line.

2 When you get to 20 percent, you're pretty

3 desperate, but should you exclude it from the

4 possible clinical modalities to take care of this

5 patient, and I think the answer is clearly no.

6 DR. FERGUSON: Dr. Sundwall?

7 DR. SUNDWALL: It's clear to me that

8 this issue is huge, and what we're talking about

9 is futile care, we're talking about explicit

10 rationing, and I really sympathize with HCFA

11 because I understand that with all our best

12 efforts to rationalize payment, everyone wants

13 that caveat, but yeah, in my case, in case I'm

14 dying, pull out all the stops. And as long as we

15 understand that, as much as we'd might like to,

16 Grant, we are not going to resolve these issues,

17 because it would be tantamount to explicit

18 rationing, and I don't think we are prepared to

19 do that.

20 DR. FERGUSON: Dr. Helzlsouer?

21 DR. HELZLSOUER: Yeah. I think it

22 should guide but not dictate care. I don't think

23 we can use the test to dictate care, and there

24 would be lots of reasons in addition to the fact

25 that you might have a situation, since 20 percent

00451

1 would respond even if they were resistant on this

2 assay, according to the literature we have, and

3 that's based on sensitivity response. You could

4 have a situation where somebody, you still have a

5 20 percent chance, and in combination you might

6 choose a less toxic drug rather than a more toxic

7 to which they are sensitive, because you're using

8 it in combination. There are a variety of

9 scenarios you can come up with that this test

10 alone should not be your sole, to dictate therapy

11 alone, and there has to be a combination of other

12 factors along with this test result.

13 DR. FERGUSON: Dr. Murray?

14 DR. MURRAY: I'm a little uncomfortable

15 with the motion as stated, because it seems to

16 undermine the value of these tests, that -- I

17 agree with what has been said, that there are

18 extraordinary circumstances, there are primary

19 failures, when it is appropriate to overrule as

20 it were, the results of the laboratory tests.

21 But the motion as stated seemed to indicate that

22 the test need not be given any weight, and yet

23 what I hear various panelists stating, yes, it

24 guides therapy, yes, you use it for your first

25 line choice, and I would like to see the motion

00452

1 amended to reflect that, perhaps with a clause,

2 in the absence of extraordinary circumstances, or

3 unless primary modalities have failed.

4 DR. HELZLSOUER: Well, I guess my

5 concern with your point is that if we had had the

6 evidence to say there was clinical benefit, which

7 is what we took out of the other one, we would

8 probably be having a little different view, and

9 be more willing to be restrictive perhaps, but we

10 don't have that evidence. We just have evidence

11 that this can mark response to certain therapies

12 and even at that, it's not a perfect test. So in

13 the absence of knowing that it really has a

14 benefit in terms of clinical outcomes, and we

15 don't have the evidence for that, I don't see how

16 we can be more restrictive.

17 DR. BROOKS: And we had the situation

18 earlier, and yesterday, as to how high to raise

19 the clinical bar to approve a test. Now if we

20 raised it to perfection, then I think there is

21 something to be said for that, but we didn't.

22 And in fact in the prior questions, we don't

23 expect anywhere near perfection. And we have the

24 20 percent issue for example. So I think as long

25 as that's the bar, that's the results of these

00453

1 tests, then it's going to be hard to tie

2 somebody's hands. And all it means, I know from

3 Medicare's point of view is one thing, tying the

4 doctor's hands, but what you're doing is tying

5 the patient's choices.

6 DR. MINTZ: I concur with those

7 comments, and not to repeat them, the motion was

8 really intended to be neutral in that regard.

9 The motion was intended simply to say that it

10 doesn't preclude payment for the use of that

11 test. And I saw it as not a heavy handed motion,

12 but rather as a very lightweight motion, in that

13 it really puts this in the hands of the

14 clinician, and that was the intent of the motion.

15 DR. FERGUSON: Okay. Can you read that

16 back?

17 DR. MINTZ: I can do it.

18 If a human tumor assay test result

19 indicates that a neoplasm is resistant to a

20 particular drug, that that does not preclude the

21 use of that drug during the course of that

22 treatment for that neoplasm.

23 DR. SUNDWALL: Before we vote, can we

24 modify that to say may not? That's a little

25 softer, because it would leave an open window,

00454

1 but give a little more weight to the test.

2 DR. MINTZ: I accept that. Of course I

3 didn't say shall not.

4 DR. FERGUSON: So you said -- read it

5 again now.

6 DR. MINTZ: Okay. I hope I'm reading

7 the same thing. If a human tumor assay test

8 result indicates that a neoplasm is resistant to

9 a particular drug, that this may not preclude the

10 use of that drug during the course of treatment

11 for that neoplasm.

12 DR. FERGUSON: Okay.

13 DR. BAGLEY: You know, the questions as

14 they are presented, I think the discussion we

15 had, the discussion I tried to provoke, and I

16 think successfully did, about what does it mean,

17 doesn't preclude is useful. And that's one of

18 the lessons we learned in the multiple myeloma

19 panel. We have to have a rich enough discussion

20 around the questions so -- we aren't bound by any

21 recommendation that, exactly the way it is

22 worded, but the discussion around it, which we

23 will have record of, as we try to interpret what

24 the sense of the committee was, I think is

25 fleshed out. So, by trying to provoke that

00455

1 little bit of a question about what does it mean

2 to use something resistant, I wanted to stimulate

3 that discussion so we would have that kind of a

4 rich record so that we could interpret what this

5 vote means, and I think we have done that

6 successfully.

7 DR. FERGUSON: Looks like you did. It

8 seems to me the easiest question took the

9 longest. I call for the vote. All in favor of

10 this motion?

11 Oh, I'm sorry; what? Public comment?

12 Thanks. Does the public have a brief comment?

13 Three milliseconds?

14 UNIDENTIFIED SPEAKER: One brief

15 comment. I'm a gynecological oncologist. Out of

16 about 500 patients that I have taken care of

17 using assays over a period of about 15 and about

18 -- over -- using about 300 patients with these

19 third generation assays, I can say that I've seen

20 two that I recalled, and possibly three patients

21 who have responded to a drug that was read as EDR

22 on the assay, three out of maybe 300 something.

23 DR. FERGUSON: Thank you. All right.

24 So that was again a unanimous vote, unfortunately

25 taken before the public comment. I guess the

00456

1 woodshed isn't too far away.

2 Now, I have asked Dr. Klee to formulate

3 question number five in the form of a motion.

4 DR. KLEE: Number five. I guess I will

5 just have to take it the way it's written here

6 and make a motion, in that:

7 I move that the advisory committee

8 recommend that there is not sufficient scientific

9 evidence to demonstrate the clinical utility of

10 HTASs in selecting appropriate cancer

11 chemotherapy.

12 DR. FERGUSON: Okay. Is there a second

13 to that?

14 DR. MURRAY: Second.

15 DR. FERGUSON: All right. It has been

16 moved and seconded that there is not sufficient

17 evidence for these tests. Is there some

18 discussion on that point?

19 DR. SUNDWALL: I'm surprised. I

20 thought that the discussion so far would indicate

21 there is sufficient scientific evidence to

22 demonstrate clinical utility in the selection of

23 an appropriate chemotherapeutic agent, and

24 inserting not in there surprises me.

25 DR. KLEE: The reason I was putting it

00457

1 that way is that this is a very comprehensive

2 statement and if we look at it in all disease

3 states, we haven't seen data, so there isn't

4 sufficient information in that. If we target it

5 to one specific one, we have already said that up

6 in the earlier ones, where we looked at CLL. So

7 I think as it's stated, I don't think there is

8 sufficient scientific evidence to recommend this

9 across the board.

10 DR. FERGUSON: So you're in effect

11 saying it's a bit too broad. Yes, Dr. Kass?

12 DR. KASS: My problem with the motion

13 as stated is that if I'm being confused by it

14 after sitting here for a day and a half and

15 listening to all the discussions, I'm afraid that

16 when the Medicare coverage policy is written that

17 it's going to be confusing to the people in HCFA

18 as to what our intention was. I would like to

19 see a motion that clarified exactly the point

20 that you're trying to make.

21 DR. HAUSNER: I would like to have a

22 crack at just that. To, if you would consider

23 this as I don't know, an amendment or a revision,

24 adding something to the effect that there is

25 sufficient scientific evidence, et cetera, in

00458

1 certain cases, and you can add in that in other

2 cases, there have not been. And we can use the

3 example of CLL if you want as the poster

4 malignancy for which perhaps there is, or just

5 leave that out. But rather than -- because

6 what's implicit in your motion is, and I

7 understand what you're saying, you're saying that

8 if we said it just, there is sufficient

9 scientific evidence that demonstrates the

10 clinical utility, et cetera, that that's far too

11 broad. Right?

12 DR. KLEE: Yes.

13 DR. HAUSNER: And so what I'm saying

14 is, your motion is far too broad the other way,

15 it's too much the other way.

16 DR. KLEE: Right.

17 DR. HAUSNER: But what you really meant

18 and what you were trying to reflect, which I

19 agree with, is that it is not yet a closed book.

20 But in order to be consistent with everything

21 else that we said, I propose that you revise your

22 motion something along the lines that I said

23 about saying that there is for certain

24 malignancies scientific evidence that

25 demonstrates the clinical utility of HTASs,

00459

1 something along those lines.

2 DR. FERGUSON: Kathy, and then Dr.

3 Kass.

4 DR. HELZLSOUER: This is Kathy

5 Helzlsouer. I think the confusion is that in

6 number three we changed clinical benefit to

7 clinical utility, and so we all think we voted on

8 five, which says clinical utility, which says

9 clinical utility. Since we weren't comfortable

10 with the term clinical benefit, and amended that

11 motions, so it's almost now, five is similar to

12 what we did in three, and maybe we need some

13 clarification from Grant as to if you want

14 something else addressed in this.

15 DR. FERGUSON: Dr. Kass?

16 DR. KASS: I agree absolutely with

17 that, and perhaps if someone could read to us

18 what we voted on specifically in number three, I

19 think it would become apparent that it was very

20 clearly stated in that what you're trying to get

21 at.

22 DR. BROOKS: I think it stated promise,

23 so that if we change five to include promise, I

24 think it would be equivalent to three.

25 DR. FERGUSON: We said clinical utility

00460

1 for hematologic cancers and promise for solid

2 tumors; is that correct?

3 DR. HELZLSOUER: CLL specifically.

4 DR. FERGUSON: Did we say CLL

5 specifically? Dr. Fischer?

6 DR. FISCHER: Yeah. I don't think

7 we're going to add much by doing anything with

8 five. I think we should just drop it. The

9 sentiment in the discussion around this issue was

10 done under three, and I think the semantics are

11 just going to confuse everyone, so I move that we

12 drop five.

13 DR. FERGUSON: Just a minute. We have

14 a motion on the table, that's been moved and

15 seconded and you know, we have to -- Roger's

16 rules, is it? No, Robert's.

17 DR. SUNDWALL: The motion wasn't

18 seconded.

19 DR. FERGUSON: It was seconded. It's

20 been moved and seconded.

21 DR. HAUSNER: Call the question. And

22 my point would be that if it's defeated. Then we

23 have a clean slate. I think quite honestly that

24 Dr. Fischer's idea about quashing it -- I just

25 want to ask Dr. Bagley, is this written in stone

00461

1 that we have to do anything with these

2 questions? The answer is no?

3 DR. BAGLEY: No, they are written in

4 stone, and -- well, soft stone. But I mean, the

5 purpose of these questions was to generate the

6 discussion and to get the sense of the committee

7 around these issues. And I think again, the way

8 three was modified, addresses much of the issue,

9 I think the discussion around it discusses much

10 of the issue, and I sense a reluctance in the

11 committee to take a definitive vote on question

12 number five in a definitely broad or definitely

13 proscriptive form, and if the committee decides

14 to not deal with that issue and not take a vote

15 on that, that is an acceptable alternative.

16 DR. HAUSNER: I'd like to call the

17 question on the motion.

18 DR. KLEE: Or can I withdraw my

19 motion?

20 DR. BAGLEY: I mean there's no reason,

21 because of it having been made, there is no

22 reason that it has to be put to a definitive vote

23 at this time and put people in an uncomfortable

24 position of voting on something they didn't mean

25 to vote on.

00462

1 DR. FERGUSON: Just a minute now. The

2 question has been called.

3 DR. HAUSNER: Well, unless he

4 withdraws.

5 DR. KLEE: I was just withdrawing the

6 motion.

7 DR. FERGUSON: Okay. I guess we can do

8 that.

9 DR. MURRAY: I withdraw my second.

10 DR. FERGUSON: Okay. The question has

11 been withdrawn. Not even tabled, I guess.

12 Withdrawn.

13 DR. HAUSNER: To nail it down, may I

14 make a motion that the committee not consider

15 question number five, just to nail it down?

16 DR. FERGUSON: You can make that

17 motion.

18 DR. HAUSNER: I make a motion that

19 question number five not be considered by the

20 committee at this time.

21 DR. HELZLSOUER: Well, we already did

22 consider it actually. We considered it in number

23 three,.

24 DR. FERGUSON: Well, I mean, do I --

25 has it been seconded? Is there a second to not

00463

1 considering question number five? It's been

2 moved that we not consider question number five.

3 Is there a second?

4 DR. KLEE: I second it.

5 DR. FERGUSON: Okay. There's a

6 second. Now, is there discussion?

7 DR. MURRAY: I'm a little puzzled by

8 the problem, because we have come very close to

9 number five. I have a question for Dr. Klee. In

10 your original now withdrawn motion, when you said

11 selecting as it's written here, in selecting an

12 appropriate cancer therapy, what exactly did you

13 mean by selecting? Did it specifically include

14 selecting and excluding? Because I do have a

15 problem with -- I supported your motion to find

16 that there is not sufficient scientific evidence

17 for selection, but there is sufficient scientific

18 evidence for excluding, so what exactly did you

19 mean by selecting?

20 DR. KLEE: I was just reading it

21 literally, so selecting was rule in, was

22 predominantly, but I also had concerns about the

23 rule out. I don't think there was sufficient

24 scientific evidence for many of the disease

25 entities or subgroups thereof to make a statement

00464

1 like that, so it was across the board that I had

2 concerns. But I think it has been addressed as

3 it has already been discussed in issue number

4 three where we said there is promise, and we have

5 one case where it looks like there is some

6 clinical utility. So I, that was the basis of

7 withdrawing this motion, is because it looks like

8 we can't go further than what we have already

9 said with issue number three.

10 DR. FERGUSON: All right. It's been

11 moved and -- yes, go ahead.

12 DR. BROOKS: It almost gets to whether

13 we want to say any negative. In other words, if

14 we want to use five, not as being very similar to

15 three, but whether we want to change it in such a

16 way as to state that we don't think these have

17 proven value in every cancer, because --

18 DR. KLEE: Is that not captured in the

19 discussion?

20 DR. FERGUSON: Okay. Is there any

21 further discussion about removing number five?

22 All right. It has been moved and seconded.

23 Is there any discussion from the group,

24 the audience, presenters about removing question

25 number five?

00465

1 DR. NAGOURNEY: Robert Nagourney. And

2 I think both three and five speak to an issue

3 that Dr. Bosanquet raised, and which confronts me

4 directly. We have in one course of discussion

5 looked over different technologies, different end

6 points, different utilities for end points. What

7 I'm concerned by is that my work, which is

8 specifically designated on the basis of what I

9 believe to be a better scientific understanding

10 of tumor biology, the concept of cell death, the

11 measurement of cell death as being a robust

12 predictor of response, my concern here is that

13 HCFA will make a decision that these assays are

14 all the same, and that the measurement of tumor

15 biology can all pretty well be determined.

16 And to use Dr. Weisenthal's analogy

17 where one finds the person on the roadside and in

18 determining whether they're alive or dead, they

19 can do a core temperature, EEG or EKG, or check

20 for pulse or check or response to stimulus, one

21 does not do a sperm count. You are not looking

22 for proliferative capacity to assess viability.

23 The assay end points that we have sort of skirted

24 over are distinct. Some measure cell viability,

25 and those have been extremely compellingly argued

00466

1 in favor of by much of the data, if you really

2 dissect the data. Most of what you heard, which

3 convinced you to these remarkable unanimous

4 decisions has been Randy Stein, who was not

5 determined to have been improved in his outcome

6 by eliminating every other possible combination

7 of drug resistant phenomenon, but in fact by

8 identifying an active treatment.

9 Or Dr. Nalick, who eloquently argued in

10 favor of how well the cells can pick treatments.

11 Pick treatments. And what I'm afraid of here as

12 a clinician who comes under HCFA guidelines, and

13 who practices medicine, whose father has cancer,

14 you could make a decision that you will approve

15 all these tests and they're all really great, and

16 although I know you are not here to determine

17 reimbursement issues, I will find myself

18 constrained with a difficult and arduous assay

19 which requires larger numbers of drugs under

20 different conditions for prolonged periods of

21 time with subjective and labor intensive tests,

22 to make meaningful selections of cancer

23 treatments. And I will be reimbursed by HCFA, or

24 my patients will be covered by HCFA at a level

25 that covers the lowest common denominator,

00467

1 eliminate a drug that has a five or ten percent

2 chance. And I will be effectively unable to

3 provide the best test to my patients. And HCFA

4 stipulations say that you either accept HCFA,

5 Medicare reimbursements for an approved test in

6 every situation, or sign off HCFA for two years.

7 What this effectively means is that you reimburse

8 these all the same, and the cheapest assay

9 becomes the assay that's reimbursed, then I write

10 a prescription for my father if I don't get this

11 test approved in a way that I can afford to do

12 it.

13 So I think that number three and number

14 five speak to issues that there are different

15 tests here, and when you send your message to the

16 next committee, there is going to have to be some

17 distinction between the fact that some tests are

18 difficult and give information to select

19 treatments, and some tests are easier and give

20 more limited amounts of information. And that's

21 sort of be skirted over, and it concerns me

22 gravely.

23 DR. FERGUSON: Thank you. Is there

24 further discussion or comment on this removing

25 this question.

00468

1 MR. STRINGER: I'm Jerry Stringer.

2 I'm a consultant, although I am here on my own

3 today. Just in terms of the committee guiding

4 the development of the coverage policy, I

5 actually think it would be important to make a

6 statement -- you made a statement that it's --

7 basically that it's reasonable and necessary for

8 this test on some occasions. I think as the

9 experts, it would be nice to know whether you

10 felt that question five, I think says, are there

11 occasions where use of this test would change

12 which chemotherapy agent a patient would get. So

13 I think that's basically all it says; if you do

14 the test, is there a chance that the treatment

15 would change.

16 Another level of it, does this test

17 have the possibility, or is there scientific

18 evidence that improves patient outcomes in terms

19 of quality of life, and then ultimately the

20 question is, does this test improve patient

21 longevity? Is there scientific evidence on each

22 of those three steps? And I think those

23 questions being answered by the experts will help

24 the coverage policy makers in formulating when

25 the test should be covered, and under what

00469

1 circumstances.

2 DR. FERGUSON: Dr. Hausner?

3 DR. HAUSNER: I guess I didn't really

4 reveal my full plan. If question number five is

5 deleted at this time, my plan was to add number

6 five as question number six, what additional

7 concerns, questions or would the committee like

8 addressed and basically in a rather clumsy way

9 be, table it in that fashion. That was what I

10 was going to do if it were still an open motion,

11 if it were to be defeated.

12 The other comment that I've just got to

13 say, talking about the Randy Stein case somehow

14 or another influencing my opinion, that is a

15 remarkable story, just that. I don't know what

16 happened there. That could be explained by

17 somebody trying for sainthood. I mean, Mother

18 Theresa might have had some effect on that case

19 as much as anything that we were told about. So

20 that had no influence, although it's a very

21 gratifying story.

22 DR. FERGUSON: Dr. Fischer?

23 DR. FISCHER: You know, I feel like I'm

24 dealing with my kids here. I think, you know, I

25 think the committee went as far as it could,

00470

1 given the science that it was presented, and I

2 feel we are getting beat up on right now, and I'd

3 give you the same recommendation I'd give my

4 kids, settle down and wait a while.

5 DR. FERGUSON: Mr. Kiesner?

6 MR. KIESNER: Yes. I think when I look

7 at this question, it is very broad, and I think

8 that the general tenor of what I have heard here

9 today is that there has been a wealth of

10 scientific evidence which compares very favorably

11 to other diagnostic tests, and the panel believes

12 that there is appropriate clinical application of

13 this, but we have not given you, nor have you had

14 the time nor maybe is it appropriate for you to

15 try to comprehend all of the clinical settings in

16 which these types of tests can be used. I think

17 that it is appropriate for this committee to say

18 that there is sufficient scientific evidence for

19 human tumor assay systems to be used in relation

20 to selecting or deselecting a given drug. And

21 then I think it has to go one step further in

22 terms of the policy at some further point in

23 time, and by an entity other than this panel in

24 order to define that specificity. And I would

25 feel that an answer to number five in that sense,

00471

1 holds that there has been scientific evidence,

2 that there has been clinical utility, which would

3 parallel the answer to question number three, and

4 that, some indication that this should be used by

5 HCFA as the sentiment of the committee, to look

6 in more depth at the clinical setting, and I

7 think that would be the most appropriate way to

8 handle this.

9 DR. FERGUSON: Thank you. We're going

10 to call this -- go ahead. One more.

11 DR. BROOKS: Yeah. Just a quick

12 comment. I mean, I kind of agree with Dr.

13 Fischer. You know, we are kind of being boxed

14 around the corner here a little bit, because on

15 the one hand you would like it to say that is of

16 utility in selecting and deselecting the

17 chemotherapy. And I believe that, you know, with

18 my father being a lawyer, if we say that sort of

19 stuff, then we just voted on we wouldn't preclude

20 therapy based on the assay. So I think it's gets

21 too multiple on their questions. And if you're

22 saying that you think there is clinical benefit

23 as opposed to utility, then we come back to the

24 other thing, and we certainly could, and I am not

25 proposing any motion, but you know, then we could

00472

1 have a motion based on benefit, so I think, you

2 know, there is various issues in this question.

3 DR. FERGUSON: I am going to call this

4 question. All in favor of this removing number

5 five? I believe that it's unanimous. Okay.

6 Now, does somebody want to -- I mean,

7 there are what additional concerns, questions or

8 issues? I haven't asked for a motion on that,

9 but yes?

10 DR. HAUSNER: My motion is, I would

11 like to make a motion that number five be

12 incorporated as an additional concern for future

13 consideration. I am a little -- when it says

14 would the committee like addressed by who, I

15 assume it's not by us, but I think that number

16 five is still an open issue for the future as

17 this story continues to develop. So assuming

18 that it's not us, I make the motion that the

19 committee recognize that the question number

20 five, is there sufficient scientific evidence,

21 et cetera, be addressed at a later date.

22 DR. FERGUSON: Is there a second? Dr.

23 Sundwall?

24 DR. SUNDWALL: Could I amend that

25 before I second it?

00473

1 DR. FERGUSON: Sure.

2 DR. SUNDWALL: The discussion to me is

3 either or, which I don't quite understand. I

4 think the problem word is sufficient, and I would

5 support your issue to be on the table for further

6 consideration if it read something like there is

7 scientific evidence demonstrating the clinical

8 utility of ST assays; however, more research

9 needs to be done to document their utility,

10 particularly in solid tumors.

11 DR. HAUSNER: I accept that, and maybe

12 you made the motion and I'll second it; okay?

13 DR. FERGUSON: It's been moved and

14 seconded, I guess. Dr. Sundwall, do you want to

15 read it?

16 DR. SUNDWALL: There is scientific

17 evidence to demonstrate the clinical utility of

18 STASs; however, more research needs to be done,

19 particularly in documenting their utility in

20 solid tumors.

21 DR. FERGUSON: Okay. And it has been

22 seconded. Now, is there some discussion on that

23 motion? Yes, Dr. Fischer.

24 DR. FISCHER: You know, it sounds like

25 the answer is in on hematologic tumors, which it

00474

1 certainly isn't. You know, I think lots of

2 questions come from this, particular tumors,

3 particular assays, particular drugs, when does it

4 and when doesn't it work. We don't know. I

5 think we have really been pushed as far as the

6 committee is going to, and so, I feel quite at

7 piece about where we are at.

8 DR. FERGUSON: Yes?

9 MS. SIMMERS: It seems to me that for

10 question six, what really needed is sort of a

11 laundry list of those concerns and questions that

12 we have remaining, but we're not going to come to

13 a conclusion about making a motion about them,

14 but that we want HCFA to know that they are

15 concerns of ours. And I think this whole issue

16 of clinical trials and their continuation or

17 further research, whichever you way you want to

18 state that, is one of the concerns that has been

19 expressed several times. And I think if it makes

20 the list, there is not really a need for a more

21 specific motion, but just the sense of that, to

22 be registered with HCFA.

23 DR. FERGUSON: Okay. Dr. Brooks?

24 DR. BROOKS: Yeah. I just wanted to

25 say that I would agree with the previous speaker

00475

1 that, you know, rather than have another motion,

2 although we certainly could have that one motion,

3 but I would not want that one motion to preclude

4 giving the additional concerns or whatever that

5 we may have, that we may want to voice.

6 DR. FERGUSON: Okay. Kathy?

7 DR. HELZLSOUER: Yeah. I guess the

8 issue for me, that motion, sounds similar to what

9 we already voted on, so I don't see, I guess the

10 utility, if you will, of rephrasing what we

11 already voted on. Think the issue that should be

12 reflected is where we changed that was the

13 clinical benefit. I agree with Dr. Fischer, that

14 we've gone as far as we can with the evidence

15 provided, and my concern is that we don't have

16 the evidence of clinical benefit and that's what

17 still needs to be shown, in whatever ways, and

18 whatever trials, so that's where I have the

19 concern.

20 DR. FERGUSON: Okay. Do you want to --

21 DR. SUNDWALL: Yeah, I would like to

22 withdraw. I have to look at our FDA and see. If

23 I can withdraw my motion, I think that we

24 probably all listed some things we think are

25 issues, and I wonder if maybe the committee needs

00476

1 to discuss that, or because we are duly appointed

2 committee members, we couldn't in fact provide

3 for you those issues.

4 DR. FERGUSON: Right. There is a sense

5 of, maybe somebody could itemize these things.

6 There is a sense of the committee that there are

7 some issues that require addressing for which

8 patients is this, are these the best tests, when,

9 when should they be given, what tests, when along

10 their treatment protocols. I mean, all kind of

11 things of that nature and others, I'm sure.

12 Yes?

13 MS. KRAFT: I think that's what

14 Dr. Nagourney was getting at is he wants us to

15 define some of our concerns, because all of us

16 that have dealt with Medicare and Medicare

17 reimbursements are concerned with defining what

18 will we be reimbursed for when we order HTA assay

19 tests, and then, will Medicare take the flying

20 leap forward and then define, unbeknownst to us,

21 maybe what tests they will pay for and what they

22 won't. So one concern of mine is that they, in

23 defining what they're going to reimburse, that

24 they contact some of the scientists and

25 physicians in the audience that are doing this

00477

1 research, that they find out what is the cost of

2 producing the test and get some real life cost

3 data, so when they set what they are going to pay

4 the physicians for doing these tests, that they

5 have realistic up to date direct costs.

6 DR. FERGUSON: Maybe we could just,

7 since we're doing pretty well on time, we have 15

8 more minutes, just put some of our concerns on

9 the table for HCFA's consideration, as sort of

10 our final. Yes, please?

11 MS. SIMMERS: I have three on my list

12 and I'm sure there are going to be many others I

13 agree with. One, I think this whole issue of

14 continued research, and I believe the stimulus is

15 there to do it, because as Dr. Bagley pointed

16 out, oncology is much different, and I believe in

17 order to convince those that are the gatekeepers

18 of ordering these tests so that it opens up to

19 Medicare beneficiaries, the research will have to

20 support the use of that technology, so it should

21 happen, but it is a continued concern that we get

22 better evidence of the utility and benefit of

23 these tests.

24 I continue to be concerned that the

25 industry work on and continually be cognizant of

00478

1 accessibility of all Medicare beneficiaries who

2 are facing a cancer diagnosis, and just not be

3 some limited accessibility wise, and they look at

4 ways to address that.

5 And certainly the policy development,

6 for those of us who have dealt with carriers on a

7 daily basis, and for their side of the equation,

8 the policy does need to be more specific. I

9 don't think this is the forum where that happens,

10 because there are processes in place that HCFA

11 has used before to develop those kinds of

12 policies, and I certainly want to see that kind

13 of process go on, so that reasonable and specific

14 policies are set forth.

15 Those were the tree three that I was

16 concerned about.

17 DR. FERGUSON: Dr. Sunderwall, did you

18 have some?

19 DR. SUNDERWALL: My only contribution

20 at this time is that I think this particular

21 group of tests under this rubric, whatever STAs,

22 lends itself very well to a national coverage

23 policy. We have experience from negotiated rule

24 making where in fact this would be, could be done

25 with the right expertise, and I would strongly

00479

1 recommend that be the next step from HCFA. I

2 think it would address most of the concerns

3 people have about appropriate application and

4 whether it should be paid for.

5 And I would just second what Cheryl

6 just said about appropriate reimbursement,

7 because I do think that it would be a shame to

8 give a green light to add this to the

9 armamentarium of oncologists and physicians, and

10 then find out that it's so underpaid that it's

11 not being used.

12 DR. FERGUSON: Okay, thank you.

13 Dr. Klee?

14 DR. KLEE: I had three different things

15 that I'd like to see brought up. One is this

16 question of monitoring the effectiveness of this

17 program if it's put in place, and perhaps even

18 having a sunset clause and review after a certain

19 period of time, to say, did it really meet the

20 expectations that we had hoped for for this

21 length of time?

22 The second would be to further

23 delineate this question of which tests are

24 appropriate for which type of tumors. You know,

25 which ones are proliferative, which ones do we

00480

1 want to have apoptosis markers and such in

2 there.

3 The other is a further delineation in

4 terms of which types of patients are appropriate

5 for testing. There are certain tumors that are

6 going to have universally good response, or

7 fairly good response, and it doesn't seem like

8 this would be appropriate for that group of

9 patients. And on the other end of the

10 distribution, you've got some that there is no

11 appropriate therapy, or responsive therapy that's

12 going to be coming in, and therefore, treating

13 may not be dependent upon this testing also. So

14 I think it's along the line of the presentation

15 we had yesterday, that we are looking in the

16 middle part of the distribution rather than the

17 extremes. We need to define what those extremes

18 are, or what the middle is in terms of disease

19 therapy indications for this particular

20 technology.

21 DR. FERGUSON: Dr. Fischer?

22 DR. FISCHER: No.

23 DR. FERGUSON: Dr. Brooks?

24 DR. BROOKS: Yeah, a few things. One,

25 I would go back to ASCO's position and so HCFA

00481

1 may, I wouldn't require it, but they may wish to

2 have further clarification on how ASCO views

3 these tests, just as additional information for

4 the record, I suppose.

5 What I would like to say and make

6 almost a recommendation for is that just as with

7 certain testing that's done in clinical labs all

8 the time, whether it be for HIV, hepatitis C, et

9 cetera, you know, there is a requirement that we

10 keep certain data, that if approved for coverage

11 and payment, that there be a requirement of those

12 who were ordering or doing the tests, that they

13 keep certain data available, and that data be

14 open and available to external groups, as our

15 data is now.

16 And finally, I think coverage, as

17 mentioned by Miss Kraft a little earlier, or

18 perhaps yesterday, I kind of agree with her, that

19 coverage may actually unable further research to

20 go forward. There will be some type of payment,

21 no matter on what level, and that may shake out

22 which test is better. It may actually foster

23 further research to enhance the test and allow

24 these tests to be used in clinical trials by the

25 oncology groups, so I think that may well be the

00482

1 case.

2 DR. BAGLEY: I think I gave my concerns

3 in the beginning.

4 MR. BARNES: Just very quickly, I would

5 like to encourage in conjunction with the comment

6 about looking at the true cost of the test, that

7 the work at HCFA go further to look at the net

8 cost to Medicare, that the economic analysis and

9 quality of life analysis, which you heard a

10 little bit about, be taken into consideration.

11 DR. FERGUSON: Okay. My concerns are

12 mostly which tests for which patients, and when

13 in the course of the disease, which I think need

14 to be still looked into.

15 DR. MURRAY: I think that my comment

16 perhaps duplicates Dr. Brooks, but I know that

17 it's common practice in many, perhaps all

18 genetics laboratories, cytogenetic laboratories

19 that do prenatal testing, it's common practice

20 for them to follow up with outcomes and to

21 correlate their test result with the fetal

22 outcome. And I would encourage the laboratories

23 that do this type of testing to make that

24 effort. Of course you can't demand it as a

25 condition of testing, but our experience in

00483

1 genetic testing is that obstetricians are very

2 cooperative and I would expect that the

3 oncologists would be equally cooperative. While

4 that doesn't constitute research and perhaps may

5 not be publishable to the extent possible, that

6 should be available for review.

7 DR. FERGUSON: Dr. Loy?

8 DR. LOY: Based on Dr. Nagourney's

9 comments, I hope some attention is give to

10 elaborating on the differences between different

11 testing modalities and when there may be

12 appropriate use of each one of those modalities.

13 Then I also have an interest in

14 addressing the appropriate frequency of testing,

15 how many times you're going to allow this as

16 reasonable and necessary, over the course of

17 treating patients. And then finally, some

18 attention to who is responsible for choosing the

19 drug of choice for testing. If there was never

20 the intent to use a specific chemotherapeutic

21 agent in the regimen to begin with, then it would

22 seem inappropriate to me that the oncologist

23 should have, the treating oncologist should have

24 some say so about that to begin with.

25 And then finally, I hope that there is

00484

1 some consideration given to, from a carrier

2 standpoint, of the documentation requirement.

3 DR. FERGUSON: Miss Snow?

4 MS. SNOW: My only concern is that we

5 keep in mind the assessability and affordability

6 for the beneficiaries.

7 DR. FERGUSON: Thank you. Dr. Kass,

8 no? Dr. Hausner, no. No?

9 DR. MINTZ: My concerns have been

10 already stated by others, but I want to use this

11 opportunity to state that I think the sense of

12 the committee was best expressed in motion number

13 three, and that these tests show promise for

14 clinical utility, and that motion deliberately

15 did not state, distinguish between sensitivity

16 and resistance testing, so I think the sense of

17 the committee reflects that it is supportive of

18 both sets of testing.

19 And I would only add that I also hope

20 the coverage is adequate to permit this

21 technology to be used.

22 DR. FERGUSON: Dr. Bagley.

23 DR. BAGLEY: I want to do one little

24 bit of parliamentary cleanup work, since in the

25 frenzy of doing the right thing, we may have

00485

1 gotten ourselves cross wise with Ferguson's, or

2 Robert's Rules of Order. We had a motion on

3 number five, which was seconded. I believe

4 someone reminded me that the questions was

5 called. We can go back and look at the record,

6 but I believe the question was called, and then

7 there was this withdrawal. And actually I'm

8 unclear as to whether that's allowable, but I

9 think we could get ourselves, have a clean record

10 if we consider the fact that motion number five

11 was, the original motion which was, there is not

12 scientific evidence was made, seconded, question

13 called. If we vote on that and it's voted down,

14 and the committee already then went on to vote,

15 saying their sense on number five was that it was

16 dealt with in number six, I think the record will

17 clearly reflect it, but I think perhaps it would

18 be worthwhile to clean up that issue and vote on

19 that original at motion number five,.

20 DR. FERGUSON: He withdrew the motion.

21 DR. BAGLEY: Well, there's a question

22 as to whether that's an allowable procedure after

23 the question's been called, so I think if we

24 voted on it, the committee voted on it, if they

25 vote it down, they could then make a motion and

00486

1 say see question three in the discussion, that's

2 our sense.

3 DR. FERGUSON: Okay. I guess we should

4 vote on Dr. Klee's original motion. Restate the

5 motion.

6 DR. BAGLEY: That there is not

7 scientific, that there is not sufficient

8 scientific evidence to demonstrate the clinical

9 utility in selecting appropriate therapy.

10 DR. FERGUSON: All right. So I am

11 going to call for the vote on that. All in favor

12 of that? One vote in favor. I guess I have to

13 read. That was Dr. Klee that voted in favor.

14 Do I have to read the -- no. All

15 against? And I guess there is an abstainer or

16 two. Wait a second. So everybody else voted

17 against, is that correct? All against, please

18 raise your hands. Dr. Mintz, you're not raising

19 your hand; does that mean you're abstaining?

20 DR. MINTZ: Yes.

21 DR. BROOKS: And so am I.

22 DR. FERGUSON: So we have two

23 abstainers, and I need to read who abstained?

24 Boy, you guys really -- let's see. Dr. Mintz

25 abstained, Dr. Brooks abstained. Did anybody

00487

1 else abstain? And all the rest voted against.

2 You want me to restate that?

3 One voted for this motion, two

4 abstained, and the rest voted against it. Okay.

5 All we all right with Roger's, Robert's? Do I

6 get by my badge for going to Congress.

7 DR. SUNDWALL: Before people leave,

8 could I call to the attention something that

9 people may or may not be aware of, that Dr.

10 Bagley won't be with us anymore in this capacity.

11 Dr. Bagley is leaving government, and all of us

12 who've worked with him I think owe him a debt of

13 gratitude for his fairness, his intellect and his

14 perseverance.

15 DR. FERGUSON: The meeting is

16 adjourned.

17 (The meeting adjourned at 11:55 a.m.,

18 November 16, 1999.)