Minutes of November 15-16, 1999 Meeting
OPEN SESSION
Sheraton Inner Harbor Hotel
300 South Charles Street
Baltimore, MD 21201
Attendees
John H. Ferguson, M.D.
Chairperson
Robert L. Murray, Ph.D.
Vice-Chairperson
Katherine Tillman, R.N., M.A.
Executive Secretary
Voting Members
David N. Sundwall, M.D.
George G. Klee, M.D., Ph.D.
Paul D. Mintz, M.D.
Richard J. Hausner, M.D.
Mary E. Kass, M.D.
Cheryl J. Kraft, M.S.
Neysa R. Simmers, M.B.A.
John J.S. Brooks, M.D.
Paul M. Fischer, M.D.
Temporary Voting Member
Kathy Helzlsouer, M.D.
Consumer Representative
Kathryn A. Snow, M.H.A.
Industry Representative
James (Rod) Barnes, M.B.A.
Carrier Medical Director
Bryan Loy, M.D., M.B.A.
HCFA Representative
Grant Bagley, M.D.
Monday, November 15, 1999, 8:00 a.m.
The Laboratory and Diagnostics Services Advisory Panel met on November 15-16, 1999, to discuss human tumor assay systems. This was the first meeting for this medical specialty panel of the Medicare Coverage Advisory Committee (MCAC). The meeting began with the introduction of the panelists, a reading of the conflict of interest statement, and the call to order.
HCFA Presentation. HCFA provided an introduction and overview of the Medicare statute under the Social Security Act and the new Medicare coverage process. The statute states that Medicare may pay for those services that are reasonable and necessary for the diagnosis or treatment of an illness or injury.
The HCFA representative then discussed the agenda topic and gave a brief history of the issues surrounding sensitivity and resistance tests using in vitro human drug assay systems. He concluded his presentation by asking the panelists to consider the following questions during their deliberations:
1) The scientific evidence amassed thus far on Human Tumor Assay Systems (HTAS) seems to more frequently measure outcomes by clinical response rather than survival rates. Is this appropriate? What outcome measures should we rely upon to best assess clinical utility?
2) The assay techniques described in the literature test responses to single drugs. What is the evidence supporting these tests in combination therapies?
3) Does the scientific evidence demonstrate a clinical benefit to using HTASs to direct or exclude treatment for hematological cancers, solid tumors, both, or neither?
4) If the test results indicate that a neoplasm is resistant to a particular drug, should that preclude use of that drug during the course of treatment for that neoplasm?
5) Is there sufficient scientific evidence that demonstrates the clinical utility of HTASs in selecting appropriate cancer chemotherapy?
6) What additional concerns, questions, or issues would the committee like addressed?
Chairperson’s Opening Remarks. The Chairperson informed the panel of its charge to review the evidence and evaluate its quality, to arrive at some conclusions regarding the appropriateness of the in vitro assay tests in treating cancer patients, and to answer the questions presented by HCFA.
FDA Presentation. A representative from the Food and Drug Administration, Center for Devices and Office of Device Evaluation presented an overview of the processes by which a medical device can gain FDA approval. He also presented information on the current status of FDA policy, that being that the drugs being used in the in vitro assays falls outside the scope of the analyte specific reagent rule. He encouraged the panelists to first see if the FDA threshold has been met, and then look at the evidence from there.
Open Public Comments and Scheduled Commentaries. During the morning session the panelists heard from 13 scheduled speakers, 10 of whom are involved with research in the field of HTAS and supported Medicare coverage for the procedures, one of whom is a patient who had his pancreatic cancer successfully treated following assay-directed chemotherapy, one of whom represented the American Society of Clinical Oncology (ASCO) and presented the Society’s position, and one who is a carrier medical director.
The first speaker was Mr. Frank Kiesner, President and CEO of Oncotech, who presented an overview of the industry, and commented on payment decisions that have been made by various carriers, stating that in most instances they have been approved after dealing with the question of medical necessity versus investigational, but that basically all Medicare claims have been denied on a local coverage basis, as investigational technology. He concluded by encouraging the panel to focus on this question: Can you take malignant cells from a patient into an in vitro environment, test them in a controlled laboratory assay, identify either resistance or sensitivity, and then translate that into usable information for the clinician.
Dr. Larry Weisenthal presented the panel with an overview of his 20 years of full-time research. He emphasized to the panel that they are considering a laboratory test, not a treatment. He addressed the use of three-dimensional cell death assays, focusing on DiSc and MTT assays and their ability to demonstrate sensitivity or resistance to different chemotherapeutic agents, and summarized the results of his studies. He contended that three studies conducted by the National Cancer Institute (NCI) were all flawed, pointing out his reasons for that contention. He addressed the issue of drug synergy and encouraged testing in combination when synergy is present.
Mr. Randy Stein, a patient who had been diagnosed with Stage IV pancreatic cancer in January 1997, told the panel about his treatment and results. He was informed that in his assays, although Gemzar and Cisplatin had scored poorly individually, that when combined, reacted favorably to his tumor and displayed a tremendous synergy. After chemotherapy utilizing Gemzar and Cisplatin through July of 1999, his PET scan revealed no cancer anywhere in his body, and he is begging for approval of coverage.
Dr. Richard Nalick, a gynecologic oncologist, informed the panel of his clinical experience with clonogenic assays, stated that he had initially used the assay only in patients who had failed treatment, but because of results, started using assays up front, and that has proven very effective in his practice. He stressed the value of testing in combination. He then presented one specific case study where after a bone marrow transplant after diagnosis of ovarian cancer, and his patient accruing a bill of over $200,000, assays indicated a sensitivity to Gemcitabine and platinum in combination, and after treatment with this combination, she is now cancer-free.
Dr. William Grace, a medical oncologist, stated that he is a believer in the assays, and is currently doing some exciting work with pancreatic cancer.
Dr. John Fruehauf, M.D., Ph.D., medical director for Oncotech, presented results of studies showing how assays can predict response and how they relate to patient survival, concluding that in vitro assays specificity and sensitivity response is comparable to other clinical tests, and that assay-directed therapy has improved outcomes.
Dr. Jimmy Orr, a gynecologic oncologist, cited a peer-reviewed article from Cancer Journal addressing cost effectiveness of treatment of women with advanced ovarian cancer by cytoreductive surgery and assay-directed chemotherapy, which concluded the assay-directed therapy appeared very favorably.
Dr. Robert Hoffman, president of AntiCancer, Inc., presented a summary of his work with the histoculture drug response assay (HDRA), concluding that HDRA-directed therapy can increase survival.
Dr. Andrew Bosanquet presented a summary of his work with DiSC assay on patients with chronic lymphocytic leukemia (CLL).
Dr. David Alberts summarized the presentations of the first eight speakers, concluding that in vitro drug response assays have matured with third generation technologies, and that their accuracy, sensitivity and specificity are excellent, and comparable to conventional testing.
Dr. Robert Nagourney presented his studies focusing on cell proliferation end points versus cell death or apoptotic end points. He pointed to studies that had been done on bladder, non-small cell lung, breast and ovarian cancers. He urged the panel to view this ongoing research as a work in progress, with a lot of encouraging observations.
Dr. David Kern, a paid consultant for ImPath, summarized his studies focusing on the resistance side of assays, in an effort to rule out agents that would not work clinically. He encouraged the standard to be applied to laboratory tests be the levels of evidence proposed by the Center for Disease Control (CDC), rather than the NCI standards. He asserted that Medicare would see an immediate cost benefit if the assays prevented the use of drugs that are clinically worthless.
Dr. Daniel Hayes, a medical oncologist, presented ASCO’s position. ASCO is interested in establishing guidelines for the members of the Society. The ASCO view currently is that in vitro assays are promising; however, the current data are insufficient to withhold potentially effective drugs, and prospective clinical trials are needed to address the issue.
Dr. Bryan Loy, Carrier Medical Director for the State of Kentucky, presented the panel with his views from the CMD perspective. He pointed out that this is the appropriate forum to be discussing HTASs, as opposed to the local carrier level. He urged the panel, and HCFA, to include well-defined parameters in any policy that is adopted, as any unaddressed issues are left for local carrier evaluation, which can lead to disparate coverage. He commented that he had surveyed CMDs throughout the United States and only two states had received requests for coverage for HSATs. He opined that although some evidence points to the use of HSAT for specific clinical indications, evidence supporting broad national coverage is insufficient.
Recess. Following Dr. Loy’s testimony, the meeting recessed for lunch from 12:03 until 1:00 p.m.
Scheduled Commentaries. Following lunch, the panel heard from three scheduled commentators.
Dr. Edward Sausville, Associate Director, Developmental Program, NCI, presented an overview of HSAT from the perspective of the preclinical therapeutics development program of NCI. He stated that the assays ideally would have 95 percent sensitivity and specificity and, short of that goal, would be better in predicting outcome than empirical choice. His conclusion is that no method has emerged as a gold standard and that in the few completed prospective or randomized trials, there is little assurance that there is a difference in outcome effected by the test.
Dr. Harry Handelsman, of the Center for Practice and Technology Assessment, presented a critique of the 1990 Kern and Weisenthal article on suprapharmacologic drug exposures, commenting that studies comparing tumor responses to chemotherapy selected by in vitro testing with empirical chemotherapy have produced conflicting results, and that the clinical utility of the assay has not been established.
Dr. Harry Burke discussed levels of evidence, test accuracy, and also commented on the Kern and Weisenthal article.
Dr. Mitchell Burken, from HCFA, summarized the presentations from the other presenters and found after his systematic review there is not strong medical evidence supporting the overall clinical utility of HTAS. He further noted that there was rare use of blinding, but there were a higher number of clinical correlations for DiSC and MTT formats and, as a result, HTAS may have a greater potential clinical utility for hematologic neoplasms.
Open Committee Discussion. Several questions or concerns were raised by panelists and addressed by the speakers: Feasibility of going back over test data to do a disease- specific analysis. Apparent bias when, if sensitivity to a drug were shown, a patient would be treated by that drug, whereas if resistance was shown, there was still physician’s choice in the chemotherapy. Clarification on whether combinations had been routinely tested. Reproducibility of the tests. Accessibility to the tests if there are only a few labs performing them. Comparability of the different assay procedures. When is optimal time to biopsy, pretreatment or posttreatment?
Recess. The meeting recessed at 4:33 p.m., November 15, 1999, to reconvene at 8:00 a.m., November 16, 1999.
Tuesday, November 16, 1999, 8:00 a.m.
The Laboratory and Diagnostic Services Panel meeting reconvened for the second day on November 16, 1999. The meeting began with a reading of the conflict of interest statement.
Chairperson’s Opening Remarks. The chairperson announced that this session would be primarily restricted to panel discussion until the open public session, which would then be followed by voting of the panel.
Open Committee Discussion. Each panelist was invited to voice their comments, critiques, concerns or questions on what they’ve heard. Many panelists commented that while they believed the tests were reasonable, they were unsure of exactly when the tests should be used. Several panelists commented that they felt there was stronger evidence for the use of the assays on hematologic disease, specifically CLL, than with solid tumors and other cancer forms. Two panelists voiced their concern that if approved for coverage, the test might not be made available universally, particularly in rural areas. Other panelists voiced their concern of where these tests would fit clinically. There were concerns voiced about possible bias in the research; the studies were small; question whether first and second stage tumors had been studied; when is the test most useful. There was a general feeling among the panelists that the tests seemed to be cost effective, and that they should be added to the tools that a physician has available.
The HCFA representative explained to the panel the effect of an approved national coverage, and encouraged specificity in any conclusions reached by the panel; he further asked that the panel try to stay within the framework of the questions proposed. He also explained to the panel the role of administrative law judges in appeals of coverage rulings. He informed the panel that if coverage is approved, HCFA would be limited in its power to collect data, and could not direct NCI or anyone else to actually perform clinical trials.
Motions, Discussions and Recommendations. The Chairperson announced that the panel would allow discussion and public comment on each motion as it was offered.
On the first question, the panel voted unanimously in favor of the motion that the advisory committee recommend that the clinical response as well as survival rates be accepted as appropriate measures of clinical utility.
On the second question, the panel voted unanimously in favor of the motion that evidence was presented to this panel supporting these tests with combinations of drugs.
On the third question, the panel voted unanimously in favor of the motion that HTASs demonstrate a clinical utility for directing treatment of CLL, and promise for other solid and hematologic tumors.
On the fourth question, the panel voted unanimously in favor of the motion that if a human tumor assay test result indicates that a neoplasm is resistant to a particular drug, that that may not preclude the use of that drug during the course of that treatment for that neoplasm.
On the fifth question, there were two separate motions made and withdrawn before the one acted on, where the panel voted unanimously in favor of the motion that question number five be removed from the panel’s considerations.
On the sixth question, rather than vote on specific motions, the panel stated concerns in the record for HCFA to consider when drafting policy.
A point of order was raised concerning one of the withdrawn motions respecting the fifth question, which had been withdrawn by its presenter after a vote had been called for. To insure clarity, the chairperson called for a vote. The panel voted one for, eight voted against, and two abstained on the motion that there is not sufficient scientific evidence to demonstrate the clinical utility in selecting appropriate therapy.
Adjournment. The meeting adjourned at 11:55 a.m.
I certify that I attended the meeting
of the Laboratory and Diagnostic Services Panel
on November 15 and 16, 1999, and that
these minutes accurately reflect what
transpired.
_________________________________
Katherine Tillman, R.N., M.A.
Executive Secretary, HCFA
I approve the minutes of this meeting
as recorded in this summary.
______________________________
John H. Ferguson, M.D.
Chairperson
