00197

4 VOLUME II

5 (Afternoon Session - November 15, 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

00198

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.

00199

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

00200

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

00201

1 PANEL PROCEEDINGS

2 (The meeting was called to order at

3 1:16 p.m., Monday, November 15, 1999.

4 DR. FERGUSON: Dr. Sausville?

5 DR. SAUSVILLE: Good afternoon, all.

6 And if I could have the first overhead, this says

7 who I am, and the general topic that I hope

8 you're interested in hearing about this

9 afternoon. Anyway, my task this afternoon is to

10 provide an overview, at least from the

11 perspective of the preclinical therapeutics

12 development program of NCI of antitumor drug

13 sensitivity testing. And I will approach this,

14 therefore, from the standpoint of one who uses

15 tests like this, and indeed, in some cases

16 actually tests that have been used for this

17 purpose for the preclinical selection of drugs

18 for more detailed evaluation, as well as from the

19 perspective of an oncologist who has occasionally

20 thought about using these tests in the treatment

21 of patients. Next.

22 So the basis for this issue in cancer

23 derives directly from the infectious diseases

24 experience, wherein a number of different disease

25 categories, such as tuberculosis, where it's well

00202

1 established that one has to establish that a

2 particular patient's infected bacillus is

3 sensitive to the agents, and a number of

4 non-tuberculosis indications, which would

5 include, for example, pyelonephritis or

6 endocarditis, where it is well established from

7 the standpoint of standard medical practice that

8 such sensitivity tests are that valuable. Next.

9 The assays as applied to cancer ideally

10 would have 95 percent sensitivity and

11 specificity, and short of that goal, would

12 hopefully be better in predicting outcome than

13 the empirical choice of the physician. And the

14 essence of the question from an oncological

15 standpoint, therefore, is whether a particular

16 test conveys information over and above what is

17 implicit in the histologic diagnosis of a

18 patient's tumor. Ideally the test would be

19 biased in favor of detecting sensitivity rather

20 than resisting, for this reason, and ultimately,

21 these tests should be able to demonstrate an

22 impact on ultimate outcome, as opposed to simply

23 response, since in oncology, good outcome begins

24 with the response, it does not end with a

25 response. One ultimately has to have evidence of

00203

1 tangible clinical benefit that changes outcome.

2 Next.

3 So among the specific assays that

4 through the years have been utilized include the

5 by now classical Hamburger Salmon clonogenic

6 assay, wherein tumors that were biopsied for

7 example, were disaggregated, plated in agarose or

8 other solid media after relatively brief

9 exposures to drug, and ultimately colonies

10 counted in 14 days. There have been

11 modifications to this, most notably the capillary

12 tube modification used by Von Hoff and

13 colleagues, and it seems to increase the number

14 of patients for which valuable data are

15 obtained. Modifications of this also include

16 radionuclide based assays, in which radioactive

17 thymidine is added after three days and thus,

18 although it is a soft agar base, one can obtain

19 information after shorter periods of time. And

20 there are also non-agar based assays assessing

21 radionuclide uptake in mass culture. Next.

22 Technical problems with clonogenic

23 assays include a number of artifacts intrinsic to

24 the practice of the assay, including clumping of

25 tumor cells, the potential of growth perturbation

00204

1 from manipulation of potential clonogenic cells,

2 reduced nutrient uptake from nonclonogenic cells,

3 with increase in the size of colonies that grow

4 out in the treated cells. Counting evaluations

5 with a potential large coefficient of variation,

6 and poor cloning efficiencies. And a major

7 limitation in the widespread use of this

8 technique relates to the fact that in many

9 instances, the majority of the specimens are not

10 actually valuable, and there is the inability of

11 this type of assay to score small numbers of

12 resistant cells, which in a clinical scenario are

13 thought to translate new ultimately resistance to

14 therapy, of the sort that is manifest by the

15 subsequent relapse of a patient with drug

16 resistant tumor. Next.

17 In various reviews, actually extending

18 from the initial use of this technique into the

19 early '80s, the cumulative experience is that a

20 relatively small fraction of patients actually

21 have colony growth. And the data that is

22 tabulated here is contained in the references

23 that were indicated. But also, there is the

24 finding that the tests are clearly better at

25 predicting negative or resistant assays, than

00205

1 sensitive assays, such that for example, if one

2 looks at those specimens that were sensitive in

3 vitro as opposed to sensitive in vivo, we have a

4 60 percent true positive, with a range of 47 to

5 71 percent. In contrast to those specimens that

6 were resistant in vitro and resistant in vivo,

7 where there was, as you can see, a 97 percent

8 true negative information. Next.

9 This led to a so-called perspective

10 evaluation of chemotherapy selection utilizing a

11 clonogenic assay, as opposed to the choice of a

12 clinician. And again, this was published by von

13 Hoff and colleagues in 1990 in the Journal of the

14 National Cancer Institute. And in the 133

15 patients randomized in a single agent therapy, of

16 those where the therapy was assigned by a

17 clinician, one had one partial response, and in

18 19 of 68 that were possible to have an assay

19 directed assignment, there were four partial

20 responses. Certainly there was no evidence that

21 this was statistically different and one

22 concluded, or this article concluded, that what

23 one might conceive of potentially a somewhat

24 improved response rate, did not translate into

25 any noticeable effect on survival. And again,

00206

1 approximately a third of the tests could not be

2 evaluated, and there were clearly no evidence of

3 survival in patients either treated according to

4 that which was recommended by the physician, or

5 all patients that were compared versus the test

6 population. Next.

7 Other specific assays which have come

8 to the fore in an effort to meet some of the

9 clear difficulties in the widespread use of the

10 clonogenic assay include the so-called

11 differential standing cytoxicity assay, or DiSC

12 assay, pioneered by Weisenthal and colleagues.

13 And here, one is essentially assessing the effect

14 on whether or not cells remain alive after short

15 periods of culture after exposure to a drug.

16 Thus, either marrow, buffy coat or a tumor

17 suspension after disaggregation, can be treated

18 with drug for anywhere from one hour to four

19 days. Interestingly, the quantification was

20 aided by the addition of so-called duck red blood

21 cells, which are easily distinguishable

22 microscopically, a dye added, and then after a

23 cytospin, one can either assess the dead cells

24 per duck red blood cells, or live cells per duck

25 red blood cells, based on the differential

00207

1 staining of live and dead cells with either

2 fast-green, which stains dead cells, or HD, which

3 stains live cells.

4 Over variants of this approach include

5 the so-called MTT assay, which is a dye that

6 depends for its coloration properties as to

7 whether or not it is reduced by living

8 mitochondria, or a fluorescein assay, where live

9 cells take up a dye, hydrolyze to it in a point

10 that is detected by a change in fluorescence.

11 But all of these techniques, again, don't then

12 depend on the growth out of clonogenic cells, but

13 rather allow a relatively short term exposure to

14 the drug to define whether there is an effect on

15 the viability of the cells. Next.

16 When this assay was, and again, this is

17 in reference to the DiSC assay, was applied

18 initially to hematologic neoplasms, there was

19 clear evidence that there was increased cell

20 survival, that is to say resistance in patients

21 who ultimately were not responsive to

22 chemotherapy that was assigned on the basis of a

23 knowledge of the tests. So in that respect, the

24 assay was certainly suggestive that it might

25 eventually correlate with clinical outcome. And

00208

1 in addition, there was a fairly good

2 correspondence, again, with delineation of true

3 positives and true negatives by this assay.

4 Next.

5 When this assay was applied to the

6 somewhat more difficult clinical category of

7 patients with lung cancer, here in an initial

8 study with non-small cell assay, the DiSC assay

9 was performed assessing sensitivity to ten drugs,

10 treating with a regimen that ultimately

11 incorporated the three most sensitive agents. In

12 this series of 25 patients, there was a 36

13 percent partial response rate with a median

14 duration of 6.5 months and with the, if you want

15 to read, it looks to be responders and a median,

16 or I should say a median survival of about seven

17 months, with an overall of about 12 months.

18 There was clearly a threefold lower assay

19 survival. That is to say, people with greater

20 cell kill in responders versus non-responders.

21 However, these authors concluded that outcome as

22 measured by response rate and survival is within

23 the range reported by the literature, that is to

24 say, even though you can detect this difference,

25 the issue of whether or not it ultimately caused

00209

1 a different outcome that might be afforded by

2 treating with drugs that would be available from

3 the literature and without knowing the patient's

4 histologic diagnosis was not apparent. In

5 addition, some drugs clearly had a much greater

6 discordance in the predictive value of the test.

7 Thus for example, 5 fluorouracil did

8 not seem to have any ultimate value in its

9 performance, and on the other hand, etoposide,

10 behavior to etoposide, was essentially predictive

11 of the behavior of all of the of the drugs. And

12 actually from a scientific perspective, we now

13 recognize that since many of these agents act by

14 inducing apoptosis, this actual result

15 retrospectively, is not that surprising.

16 Interestingly, this paper also

17 introduced the concept of so-called extreme drug

18 resistance. That is to say, you can define

19 patients who had greater than one or more

20 standard deviations resistance than the median in

21 the population, and these patients essentially

22 had zero percent response to any of the agents.

23 Next.

24 This assay was also applied in a study

25 that was recently published from the NIH, and

00210

1 attempted to individualize chemotherapy for

2 patients with non-small cell lung cancer. And

3 from a population of 165 study patients, 21

4 received DiSC based regimens, and these had a 9

5 percent partial response rate. Whereas, 69

6 patients received empiric treatment with

7 etoposide and cisplatin; these had a 14 percent

8 partial response rate. And ultimately, the

9 survival of in vitro best regimen was comparable

10 to what one would have expected from the

11 empirically chosen chemotherapy.

12 Interestingly, this study also revealed

13 an issue that also has to come up in any test in

14 which there is a second or subsequent procedure

15 to obtain tissue, in that the survival of

16 patients who had any in vitro test was actually

17 worse than those without, and this implies

18 potentially that those people that had a

19 sufficient volume of tumor to have the tests had

20 an intrinsically less survival than those that

21 did not. Next.

22 And the last clinical study that I'll

23 touch on also emanated from the NCI and was

24 published in 1997. This attempted to use the

25 DiSC assay in limited stage small cell, and here

00211

1 we turn the somewhat, and consider the use of the

2 test in what may be considered in its most

3 favorable scenario, because this disease which is

4 traditionally, and now actually standardly

5 treated with the combination of radiation therapy

6 and chemotherapy, would potentially treat

7 empirically with a regimen known to produce a

8 high level of response, and then come back after

9 finishing consolidation with radiation

10 sensitivity with either a chosen regimen based on

11 the in vitro sensitivity or a standard approach

12 using an additional three drugs that the patient

13 had not seen previously that would be regarded as

14 standard or part of the standard care of patients

15 with small cell lung cancer.

16 And in this study, there was actually a

17 trend towards somewhat improved survival in

18 patients who could actually receive the in vitro

19 best regimen, but it certainly was just a trend.

20 And most interestingly, of the 54 patients that

21 were entered, the minority of the patients could

22 actually be successfully biopsied in this very,

23 shall we say well coordinated, well resourced

24 clinical trials scenario. Next.

25 So in terms of summarizing what I list

00212

1 here as my own disinterested perspective on

2 whether or not chemosensitivity testing is what

3 one would might consider to be ready to prime

4 time in widespread use, I would offer that from

5 my perspective, no method has emerged as a

6 quote-unquote gold standard, owing to

7 methodologic variation and the definition of what

8 constitutes resistance or sensitive tests. The

9 unfortunate fact that one cannot get reliable

10 data from most if not many patients. And in the

11 few completed prospective or randomized trials,

12 there is little assurance that ultimately there

13 is a difference effected by the test.

14 What we ultimately need if tests of

15 this nature are to be potentially useful, is

16 probably better drugs, because in point of fact,

17 since most of the drugs are unfortunately

18 inactive in many of the diseases in which these

19 tests would be used, knowing that they won't work

20 is not actually terribly valuable.

21 We need a method that is applicable to

22 all specimens obtained in real time with the

23 diagnostic specimen; that is to say, to require a

24 second test, or second procedure, in order to

25 obtain the specimen, inevitably indicating or

00213

1 introduces potential biases in studies related to

2 those patients who could withstand or undergo

3 these procedures, as well as of course, making

4 the test, the performance of the test more costly

5 than one might potentially desire.

6 But on the other hand, I think the

7 future holds potentially with newer approaches,

8 including gene expression arrays, serial analysis

9 of gene expression, there may be better, and

10 hopefully more useful techniques to assess this

11 in the future. But whatever the test, be it some

12 permutation of a currently available test, or one

13 of the newer methodologies here, its ultimate

14 value should be established in prospective

15 randomized trials where one uses the

16 diagnostically guided as opposed to the empirical

17 treatment before assessing whether or not it is

18 openly valuable.

19 And I thank you for your attention.

20 DR. FERGUSON: Thank you, Dr.

21 Sausville. I think you've gone in shorter time

22 than even I asked for, and so I'll open for a

23 question or comment. Yes, Dr. Hoffman?

24 DR. HOFFMAN: Yes. I would like to ask

25 Dr. Sausville his opinion about the assays that

00214

1 were discussed this morning, based on three

2 dimensional culture and other new third

3 generation techniques that address these problems

4 and have shown to be able to assess greater than

5 95 percent of the patients' specimens, have shown

6 survival benefit, have shown very high

7 correlation to response. I would like Dr.

8 Sausville's comments on this morning's talks.

9 DR. SAUSVILLE: Again, I wasn't here

10 this morning, and indeed, my brief was not to

11 comment on specific assays from this morning's

12 activities, but to offer an overview of problems

13 in the field in general. And I would certainly

14 say that if the tests that were proposed this

15 morning seem of interest, the real question is

16 have they been evaluated in prospective

17 randomized studies. Because unless they have

18 not, or I should say until they have, one, and

19 since as far as I'm aware, they have not, it

20 would be, I think premature to conclude that they

21 are, therefore, of widespread general use.

22 DR. FERGUSON: Dr. Weisenthal?

23 DR. WEISENTHAL: Now would be as good a

24 time as any to address the issue of the

25 requirement of prospective randomized trials for

00215

1 acceptance of this technology. I think it's a

2 very important issue, several speakers have

3 raised it, and the issue is this: Should these

4 tests be used in clinical medicine until it has

5 been established in prospective randomized trials

6 that patients treated on the basis of assay

7 result have a superior therapeutic outcome to

8 patients treated without the assay result? The

9 cop-out way to answer this, which I'm not, this

10 is not my answer to it, but what I could say if I

11 wanted to cop out, and it's perfectly valid, is

12 that never has the bar been raised so high for

13 any diagnostic test in history.

14 Dr. Sausville began his talk by

15 pointing out bacterial cultures done in

16 sensitivity testing, including one of his

17 examples was serum bactericidal testing. Serum

18 bactericidal testing, for those of you who may

19 know it, is something that Medicare does

20 reimburse for. It's very controversial, it's

21 much more controversial actually than cell

22 culture drug resistance testing. The performance

23 characteristics are certainly inferior based on

24 sensitivity and specificity. And furthermore,

25 there has certainly never been a prospective

00216

1 randomized trial showing survival advantage or

2 therapeutic outcome, you know, higher cure rate

3 or anything, whether you use serum bactericidal

4 testing or not, or any other form of antibiotic

5 sensitivity test.

6 We're talking about laboratory tests,

7 not a therapeutic agent, and I think that one

8 would be advised, at least first of all, to judge

9 them on the basis of the way that other

10 laboratory tests have been judged, and that is,

11 do they have acceptable accuracy, sensitivity and

12 specificity?

13 However, moving on to the question of

14 the prospective randomized trial, all of us, no

15 one more than those of us who have been working

16 in this field for 20 years, would love to see

17 prospective randomized trials, physician's choice

18 therapy versus assay directed therapy. This has

19 been the Holy Grail. I hope before I d