TTFT Response to Comments - JA DME

1. Commenter noted that the FDA approved the device on the basis of results from a multi-center randomized controlled phase III clinical trial. The FDA PMA approval followed a positive vote from the FDA's independent Medical Device Advisory Committee's Neurological Devices Panel with a majority in favor of both device efficacy and safety; therefore, it should be covered by Medicare.

Response:  The Medical Directors disagree.  While the FDA did give final approval of the PMA application through a "positive vote", the FDA's Medical Device Advisory Committee's Neurological Devices Panel decision was split (six "yes" and six "no") on the question of efficacy ("Is there a reasonable assurance that the NovoTTF-100A is effective for use in patients who meet the criteria specified in the proposed indication?").  The deciding tie-breaker vote was cast by the panel chairperson. A review of the FDA panel's meeting transcript details numerous examples of doubt expressed by panel members over the effectiveness of this therapy for recurrent GBM.

2. Several commenters emphasized that the NovoTTF-100A should be covered because it was "standard of care" as evidenced by the National Comprehensive Cancer Network's (NCCN^®) designation of a 2B level of evidence.

Response: The Medical Directors disagree. As a reminder, the NCCN^® Categories of Evidence and Consensus are:

• Category 1: Based upon high-level evidence, there is uniform NCCN^® consensus that the intervention is appropriate.
• Category 2A: Based upon lower-level evidence, there is uniform NCCN^® consensus that the intervention is appropriate.
• Category 2B: Based upon lower-level evidence, there is NCCN^® consensus that the intervention is appropriate.
• Category 3: Based upon any level of evidence, there is major NCCN^® disagreement that the intervention is appropriate.

Although Centers for Medicare & Medicaid Services (CMS) does not address NCCN^® guidelines specifically as it relates to medical devices used to treat cancer, it does provides guidance to contractors in the acceptance of evidence from NCCN^® for off-label use of drugs and biologicals in an anti-chemotherapeutic regimen. Found in the Medicare Benefit Policy Manual (Internet-Only Manual 100-02, Chapter 15, Section 50.4.5, the interpretive manual guidance states:

The listed compendia employ various rating and recommendation systems that may not be readily cross-walked from compendium to compendium. In general, a use is identified by a compendium as medically accepted if the:

1. Indication is a Category 1 or 2A in NCCN, or Class 1, Class IIa, or  Class IIb in DrugDex; or,
2. Narrative text in AHFS-DI or Clinical Pharmacology is supportive.

A use is not medically accepted by a compendium if the:

1. Indication is a Category 3 in NCCN or a Class III in DrugDex; or,
2. Narrative text in AHFS or Clinical Pharmacology is "not supportive."

The complete absence of narrative text on a use is considered neither supportive nor non-supportive.

The DME MAC medical directors note the absence of explicit instructions for a "2B" recommendation; however, it is clear that CMS intends that the contractors use the highest level of evidence possible in making coverage determinations. The NovoTTF-100A, with a 2B rating by NCCN^®, clear does not fall within the "generally medically accepted" category as envisioned by CMS.

3. A commenter was critical of several references cited in the draft LCD bibliography, noting that they were published either prior to the pivotal trial, referenced coverage policies from other countries or failed to cite a single publication that calls into question the quality of the EF-11 (pivotal trial) trial design or results.

Response: The Medical Directors partially agree. The bibliography for an LCD is not intended to be a complete compendium of all studies reviewed during the development of the policy but rather key articles and information that reflects a more global understanding of a technology or service. During the comment period, the manufacturer provided the medical directors with additional information and clinical literature. This updated information was reviewed; however, it was not persuasive in changing the final policy position.

With respect to the commenter's last point about published studies that "call into question the quality of the EF-11 trial design or results", articles are rarely published that specifically attack the quality or results of a clinical trial except when appearing in publications widely read by the entire medical community or the results impact a significant portion of the population in general. The pivotal trial results were published in the European Journal of Oncology about a treatment modality that, by the manufacturer's data, impacts fewer than 7,000 patients world-wide. This is not meant as a criticism of the quality of the journal or the subscribers; it simply makes the point that there is not likely to be peer-reviewed publications critical of this specific study.

Although not published in any medical journal, the FDA's Medical Device Advisory Committee's Neurological Devices Panel public meeting was quite critical of the trial design and conclusions reached in the pivotal trial submitted as evidence for the Pre-Market Approval (PMA) application. As noted above, the panel expressed serious doubts about the efficacy of the NovoTTF-100A device and was only able to reach a positive "reasonable assurance" vote on effectiveness through the chairperson's tiebreaker.