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MEDCAC Meeting 12/8/1999 - Autologous Stem Cell Transplantation (AuSCT) for Multiple Myeloma & Human Tumor Assay Systems (Executive Committee)

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Autologous Stem Cell Transplantation (AuSCT) for Multiple Myeloma

AuSCT is a process used to treat various malignancies in which stem cells are harvested from a patient's bone marrow or peripheral blood, stored, and then given back to the patient following severely myelotoxic doses of chemotherapy and/or radiotherapy. Section 35-30.1 of the Coverage Issues Manual (CIM) states that AuSCT is a non-covered condition in the treatment for multiple myeloma (MM). This decision was based on the insufficiency of data to establish efficacy. The Health Care Financing Administration (HCFA) must evaluate whether new scientific data on AuSCT supports reconsideration for national coverage in the MM population.

Human Tumor Assay Systems

Human Tumor Assay Systems are tests that detect resistance and/or sensitivity to chemotherapeutic agents. The Coverage Issues Appendix, §50-41 now reads: "Human tumor drug sensitivity assays are considered experimental, and therefore, not covered under Medicare at this time." HCFA must evaluate whether current literature supports the accuracy of available chemosensitivity testing; and, whether the assays are "reasonable and necessary" oncology treatment.

Federal Register Notice

Agenda for December 8, 1999 Meeting

Panel Chairperson: Harold C. Sox, M.D.
Executive Secretary: Sharon Lappalainen

8:00 – 8:05 a.m.

Opening Remarks – Introduction

8:05 – 8:30 a.m.

Panel Business
  1. Review of Tentative Meeting Dates & Agenda Items
  2. Types of issues, items & services to be brought to panel
The Panel will be asked to consider the levels of evidence, types of information needed, and the nature of issues that would be considered by the MCAC.

8:30 – 9:00 a.m.

HCFA Presentation – Levels of Evidence
Ron Milhorn,
Health Insurance Specialist

9:00 – 10:00 a.m.

Scheduled Commentaries and Open Public Comments

Public attendees who have contacted the executive secretary prior to the meeting, will address the panel and present information relevant to the agenda. Speakers are asked to state whether or not they have any financial involvement with manufacturers of any products being discussed or with their competitors.

10:00 – 10:30 a.m.

Open Committee Deliberation – Levels of Evidence

This Portion of the Meeting Is Open to Public Observers. Public Observers May Not Participate Except at the Specific Request of the Chairperson.

10:30 – 10:45 a.m.

BREAK

10:45 – 11:45 a.m.

Open Committee Deliberation, continued

This Portion of the Meeting Is Open to Public Observers. Public Observers May Not Participate Except at the Specific Request of the Chairperson.

11:45 - 12:00

Open Public Comment

12:00 – 1:00 p.m.

LUNCH

1:00 – 1:30 p.m.

Committee Conclusions - Levels of Evidence

1:30 – 2:15 p.m.

Review of Medical Specialty Panel Recommendation

The committee will review the recommendations of the Laboratory and Diagnostic Services Panel made at the November 15-16, 1999 panel meeting regarding human tumor assay systems.

2:15 – 2:30 p.m.

BREAK

2:30 – 3:15 p.m.

Review of Medical Specialty Panel Recommendation

The committee will review the recommendations of the Drug, Biologics, and Therapeutics Panel made at the September 15-16, 1999 panel meeting regarding the combination of stem cell transplantation and high dose chemotherapy for the treatment of multiple myeloma.

3:15 – 3:30 p.m.

Open Public Comments

Public attendees who have contacted the executive secretary prior to the meeting, will address the panel and present information relevant to the agenda. Speakers are asked to state whether or not they have any financial involvement with manufacturers of any products being discussed or with their competitors.

3:30 – 4:00 p.m.

Panel Recommendations & Vote

ADJOURN

Minutes of December 8, 1999 Meeting

Attendees

Harold C. Sox, M.D.
Chairperson

Robert H. Brook, MD
Vice-Chairperson

Sharon Lappalainen
Executive Secretary

Voting Members
Thomas V. Holohan, MA, MD, FACP
Leslie P. Francis, JD, PhD
John H. Ferguson, MD
Robert L. Murray, PhD
Alan M. Garber, MD, PhD
Michael D. Maves, MD, MBA
David M. Eddy, MD, PhD
Frank J. Papatheofanis, MD, PhD
Ronald M. Davis, MD
Daisy Alford-Smith, PhD
Joe W. Johnson, DC

Consumer Representative
Linda Bergthold, PhD

Industry Representative
Randel E. Richner, MPH

HCFA Representatives
Hugh F. Hill III, MD, JD
Ron Milhorn
John Whyte, MD
Harry Burke, MD, PhD.

Open Public Session
Greg Raab, PhD
Bradley Thompson, JD
Larry M. Wiesenthal, MD, PhD
Robert Nagourney, MD
Frank Kiesner
Elizabeth Panke, MD, PhD

Wednesday, December 8, 1999, 8:00 a.m.

The Executive Committee met and heard reports from recent meetings of the Medicare Coverage Advisory Committee (MCAC) medical specialty panels. The committee also considered how to provide guidance to and substantive coordination among MCAC panels. For example, the Committee considered the levels of evidence, types of information needed, and the nature of issues that would be considered by the medical specialty panels at future meetings. This was the first meeting of the Executive Committee of the MCAC and it began with the introduction of the panelists, a reading of the conflict of interest statement, and the call to order.

Opening Remarks. Dr. Hill made opening remarks and reviewed the charge of the Executive Committee. He referred to the new coverage process that outlined when coverage decisions may be referred to the MCAC. He stated in general, coverage issues might be referred: 1) if it is the subject of significant scientific or medical controversy, 2) if there is a major split of opinion among researchers and clinicians regarding the medical effectiveness of the service, 3) if there is a question regarding the appropriateness of staff or setting, 4) if there is the potential to have a major impact on the Medicare program, and 5) if it is subject to broad public controversy.

HCFA Presentation. Ron Milhorn, provided a review of the Coverage Group’s use of medical evidence and the development of an evidenced-based decision making approach. He stated that Medicare has increasingly stressed the need for published scientific studies in order to develop coverage policies. He outlined the "Procedures for Making National Coverage Decisions" that were published in the Federal Register. He pointed out that HCFA was currently working on a proposed regulation that would outline criteria to be used in making coverage decisions, which would provide a foundation for the development of sector specific guidance documents. He stated the importance of items proposed for coverage demonstrates safety, clinical effectiveness, and comparative benefit. He then outlined the types of evidence that might be needed, stressing that the amount and kind of evidence required will vary according to the nature of the service or item requested for coverage. He concluded by indicating that assessing medical evidence was very important in making Medicare coverage decisions.

Dr. Harry Burke, MD, PhD, a consultant for HCFA, told the committee that much of what is considered for Medicare coverage has not undergone the FDA’s formal pre-market review process and stressed the importance of reviewing the adequacy of the medical evidence. His discussion centered on the demonstration of comparative benefit and the presentation of evidence. He indicated that new tests, treatments, or devices could be compared against existing technologies in terms of safety, efficacy and clinical benefit. He felt that individual patients should be allowed to decide if the clinical benefit of the intervention is commensurate with the risk given the severity of the disease. Dr. Burke then discussed different types of supportive medical evidence, such as prospective randomized clinical trials (RTC) and retrospective studies. He proposed rating the evidence as strong, moderate, or weak. Large, randomized clinical trials and large retrospective clinical studies that have been replicated could be rated as strong evidence. He thought that small RTCs, small retrospective, or non-replicated retrospective studies could be rated as weak evidence. For certain items, such as medical equipment, only functional and pricing equivalence need be demonstrated. Lastly, he felt that the presentation of evidence to HCFA should be scientifically improved.

Open Public Comments and Scheduled Commentaries. During the morning session panelists heard from 3 scheduled speakers.

Greg Raab, PhD and Brad Thompson, JD, from the Health Industry Manufacturers Association (HIMA) shared their views on the Medicare coverage criteria. HIMA applauded HCFA for publishing "Procedures for Making National Coverage Decisions" and for establishing the MCAC. Dr. Raab stressed the importance of coverage criteria because of its direct influence on the capacity of many medical device companies to undertake and develop new products. The HIMA representative indicated that the proper forum for developing coverage criteria for the Medicare program is the Federal rulemaking process and not the deliberation of the MCAC. He reminded the panel that its charter states that the MCAC was established as a technical committee, not to recommend policy for the Agency. Dr. Raab then highlighted key principles that HIMA believes should be included in the Medicare coverage criteria regulation: 1) the patient should come first and economic factors should play no role, 2) coverage decisions should be guided by clinical evidence that is reasonable, clinically relevant, and collaboratively developed, 3) Medicare should amend its current policy on investigational devices, 4) HCFA should not make national non-coverage decisions unless the product or service is not effective or that it causes patient harm, and lastly 5) HIMA believes that coverage restrictions, through appropriateness reviews, should be grounded in clinical evidence and frequently upgraded.

Larry M. Weisenthal, MD, PhD of Weisenthal Cancer Group gave his perspective as a laboratory-based private practitioner and as a medical oncologist. He addressed 4 specific issues as they related to his experience: 1) comparative evidence, 2) the importance defining the relevance of evidence to be considered, 3) consider conflicts of interest of those presenting evidence, and 4) the need for the proposed service and to consider the risk of not providing that service. He then illustrated each of his points by providing examples. He stressed the importance of matching the therapy to the patient, so that the patient receives the best treatment and indicated that definitive studies are needed.

Open Committee Discussion – Levels of Evidence. Several questions and concerns were raised by panelists that were directed towards the various presenters. Many issues were related to the inclusion of cost as a factor and to the extent of the MCAC’s authority to discuss levels of evidence. Dr. Hugh Hill was asked to clarify the role of the Executive Committee in helping panels to consider the evidence.

Dr. Alan Garber presented a document that he authored called "Standards of Clinical Evidence and their Application." He described what others have done in this area and mentioned options for the EC’s consideration. He also cited a chapter from an Institute of Medicine publication "Methods of Technology Assessment." He urged the adoption of a 2-step process: 1) rating the quality of the medical evidence, and 2) question improvement/advantages to health outcomes.

Panelists agreed that the issues presented to them were difficult and acknowledged the need for a structured background paper for rating of the evidence and for deciding if the evidence was adequate. Other panelists expressed similar concerns: how much evidence was enough, how to identify the right evidence, and how to rate it? One panelist suggested the formation of a workgroup that would provide a consistent approach to the medical evidence that is presented before MCAC panels. Other panelists supported the idea and felt the approach should be put together in the form of a document that would be available to the public. One panelist felt that no medical specialty panel should be conducted until such information had been put together. In addition, the panelist felt that the framing and ordering of questions posed to the committee had a profound effect on the thinking of the panel. He then recommended the development of a structured sequence to questions. Lastly, it was proposed to operationalize the process of reviewing and rating of the medical evidence with the goal of achieving consistency, uniformity and correctness of MCAC decisions. Many panelists queried HCFA as to what extent cost might or might not be taken into consideration. Some felt that cost was very important, others felt that is was not part of what the MCAC could consider. The panelists agreed that on the issue of cost, they would need clarification.

HCFA Presentation. John Whyte, MD, spoke about the evaluation of new technologies. He provided an overview of the process by which coverage decisions are made and urged the panel to engage in a dialogue about how HCFA should use medical evidence to make coverage decisions. He stated that the challenge for the Agency was to determine when there is sufficient evidence to cover a new technology. He stated that HCFA wants to be assured that the new technology is safe, effective, benefits outweigh risks, there is evidence of improved outcomes, and has added value. Regarding the issue of costs, he indicated that there are many aspects to costs, both opportunity and additive costs. He concluded by stating that Medicare covers those items that are reasonable and necessary for the improvement of the lives of the beneficiaries and he encouraged the committee to engage in a dialogue on these issues.

Motions, Discussions and Recommendations –Levels of Evidence. The committee voted regarding the following motions as they related to the discussion of levels of medical evidence. A quorum of 12 voting members was present, no member was recused from participation due to conflicts of interest:

On the first motion, HCFA should develop a tutorial in order to educate MCAC members on how to evaluate medical evidence, this motion was tabled by a vote of 9 in favor and 3 opposed. The motion was tabled so that the second motion may be considered.

On the second motion, the EC should offer advice to HCFA on a structured approach used to assemble medical evidence on which the MCAC medical specialty panels would make their deliberations, the motion carried by a unanimous vote, all were in favor.

On the third motion, the EC should authorize the Chair to appoint a subcommittee to work on the structured approach stated above, the motion carried by a unanimous vote, all were in favor.

Each panelist was invited to voice their comments on what they’d heard. Panelists agreed that they should advise HCFA to develop a training package for panel members that would cover the principles of medical evidence so that MCAC members would be prepared to engage in this process. Panelists also indicated that the result of the subcommittee’s work should be brought back to the EC for full discussion and an opportunity for public participation at the next meeting.

Report of Medical Specialty Panel Recommendations. Drs. Ferguson and Murray, Chair and Vice-Chair of the Laboratory and Diagnostic Services Panel reported that panel’s recommendation on Human Tumor Assay Systems (HTAS). They stated that the panel was presented with many different tests from several companies involving many cancers and many drugs. Both felt that because of the variety of technologies and the number of speakers, it was difficult to have adequate discussion time devoted to each type. Dr. Ferguson also indicated that some of the presentations were repetitive and others were not contributory. Overall, he felt the agenda was too full and that the questions were difficult to pose in the form of motions for voting. He was unsure about whether the coverage proponents had received all of the critique information in advance so that they might be prepared to respond. He also indicated the paucity of RTCs for laboratory tests. Both indicated that the medical literature on the use of HTAS in chronic lymphocytic leukemia was reasonable, but for other cancer indications, it was suggestive but not as persuasive. Both had suggestions for better organizing the panel package and for revising/restating the questions posed.

Open Panel Discussion. Panelists agreed that the amount of information presented on HTAS issue was daunting. One panelist indicated that the evaluation of laboratory tests is fundamentally different and more difficult than the evaluation of treatments. Other panelists stated that the literature supporting laboratory tests usually does not provide receiver-operating characteristic (ROC) curve analysis, which is a measure of the sensitivity and specificity of the test. Without having this information, it is difficult to examine the performance of different studies or different tests. Other panelists had a number of similar comments regarding how should the literature be evaluated, the availability of survival data, and the content and format of the panel’s report.

Report of Medical Specialty Panel Recommendation. Drs. Holohan and Leslie Francis, the Chair and Vice-Chair of the Drugs, Biologics and Therapeutics (DBT) Panel gave a report of that panel’s recommendation on the combination of autologous stem cell transplantation and high dose chemotherapy in the treatment of multiple myeloma. Dr. Holohan pointed out that he held a dissenting opinion on the recommendation from that of the DBT panel. He felt that the panel’s conclusions were ill advised in that they were not based upon the evidence that was provided. He stated that the background materials consisted of literature reprints. Dr. Holohan felt that the questions posed to the panel were vague and the time allowed for consideration was limited. He agreed with the previous report in that presentations were not always direct or to the point, and there were a number of inconsistencies in the information presented. Overall, he had serious reservations about the final conclusions of the panel. Dr. Francis concurred.

Open Committee Discussion. One panelist asked if they were in direct opposition to what their panels had recommended? They also questioned the role of the Chair as a guide to their panel, because it appeared to be unclear. Dr. Holohan indicated that he dissented with his panel’s recommendation. Dr. Francis indicated that she voted in favor the panel’s recommendations but with a great deal of reluctance. Other EC members questioned the current practice of oncology with respect to stem cell transplantation’s use in multiple myeloma patients receiving high dose chemotherapy. Some panelists had questions relating to cost and cost analysis. Others questioned the data analysis and raised issues about process.

Open Public Session. During the afternoon session, panelists heard from the public, 4 of the 5 scheduled speakers were present.

Dr. Robert Nagourney, founder of Rational Therapeutics, a hematologist and oncologist provided his testimony on the subject HTAS. He indicated that he is an investigator of a HTAS technology that is based on cell-death events or apoptosis. He asserted that apoptosis is the proper endpoint of study for HTAS. He believed that the reason the panel could not come to a conclusion was because too many technologies, endpoints, measures and results were presented. He stated only studies using cell death endpoints correlated strongly with survival outcomes. He strongly felt that the results of HTAS that used cell proliferation endpoints should not have been combined with cell-death endpoints. He recommended that the conclusions of the panel should not be ratified because it would put an end to investigational work in this area.

Dr. Larry Weisenthal of Weisenthal Cancer Group, recommended that the EC ratify the panel’s recommendation and read from the transcript of the November meeting. He cited many sections of the transcript where panelists had stated that HTAS show promise for clinical utility. He asserted that HTAS should be covered and that the data presented was supportive. He urged the EC to consider this and focus on what was in the transcript of the meeting.

Mr. Frank Kiesner, president of Oncotech Inc., stated two points. First, he asked that the panel not accept Dr. Nagourney’s position. Second, he stated that although it was very important to focus on the process, the judgement of the LDS panel was sound and should be upheld. He felt that the EC should exercise caution about the message that would be sent out in the event of non-ratification.

Dr. Elizabeth Panke, Director of Genetica Laboratories related her experiences with HTAS both professionally as a practicing pathologist and personally as an ovarian cancer patient. She told of her diagnosis and of her decision to use HTAS to help in her treatment decisions. She stated that samples of her malignant cells were sent to two different laboratories that offered HTAS testing. Each lab used a different endpoint. When the results came back, one lab report indicated that her cancer was not resistant to the drugs tested, the other lab report indicated that her cancer was resistant to the drugs tested except for the combination of cisplatin and gemcitabine. After receiving this combination as treatment, she has improved. She concluded that because of the disparities between lab reports, more studies are needed before broad-based coverage of HTAS should be recommended.

Motions, Discussions and Recommendations – Reports of Medical Specialty Panel Recommendation. The committee voted regarding the following motions as they related to the reports of the medical specialty panel recommendations. A quorum of 12 voting members was present no member was recused from participation due to conflicts of interest:

For the report of the Laboratory and Diagnostic Services Panel, the motion: 1) the EC should take no action, 2) thank the panel for its conscientious work, 3) ask the panel to reconsider these matters after the EC and HCFA have established a consistent process for panel review and assessment of the evidence, and 4) each of the various HTAS should be reviewed on an item-by-item basis. The motion carried with 8 in favor and 4 opposed. Those opposed did not agree that the panel should revisit the issue again and preferred to see ratification.

For the report of the Drugs, Biologics and Therapeutics Panel, the motion: 1) the EC take no action, 2) thank the panel for its conscientious work, and 3) ask the panels to reconsider these matters after the EC and HCFA have established a consistent process for panel review and assessment of the evidence. The motion carried with 9 in favor and 3 opposed. Those opposed did not agree that the panel should not revisit the issue again and preferred to see ratification.

Adjournment, Wednesday, December 8, 1999, 4:07 p.m. The meeting adjourned at 4:07 p.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.

_________________________________
Sharon K. Lappalainen,
Executive Secretary, HCFA

I approve the minutes of this meeting
as recorded in this summary.

______________________________
Harold C. Sox, M.D.
Chairperson

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