Department of Health and Human Services
DEPARTMENTAL APPEALS BOARD
Civil Remedies Division
In re LCD Complaint:
Tumor Treatment Field Therapy
LCD ID Number: L34823
Contractor: Noridian Healthcare Solutions, LLC
Docket No. C-19-1011
Decision No. CR5915
Local Coverage Determination (LCD) L34823 permits Medicare coverage for Tumor Treatment Field Therapy (TTFT) (E0766) to treat newly diagnosed glioblastoma multiforme (GBM) when a Medicare beneficiary meets a variety of criteria listed in the LCD. However, L34823 prohibits coverage of TTFT to treat GBM when it recurs following initial treatment (e.g., surgery, radiotherapy, and chemotherapy). Primarily based on the Food and Drug Administration’s (FDA) approval of TTFT and arguments that the medical community generally accepts TTFT as an effective treatment for recurrent GBM, the Aggrieved Party (AP) challenges L34823’s prohibition on coverage.1 Noridian Healthcare Solutions, LLC (Noridian), one of the Medicare contractors that drafted L34823 and the party defending its validity, asserts that the prohibition on
coverage for TTFT to treat recurrent GBM is reasonable because the only clinical trial showing TTFT’s effectiveness for recurrent GBM (i.e., the EF-11 Study) suffered from many problems and protocol violations, the FDA panel of experts was split as to whether TTFT is effective for recurrent GBM, and the medical community is not united in its support for TTFT to treat recurrent GBM.
Based on the record as a whole, the effectiveness of TTFT to treat recurrent GBM, unlike TTFT to treat newly diagnosed GBM, is still an issue of debate in the medical community. It was reasonable for Noridian to consider that the EF-11 Study was not definitive and included aspects that are questionable, that the experts empaneled by the FDA split on the question as to TTFT’s effectiveness regarding recurrent GBM, and that National Comprehensive Cancer Network (NCCN) Guidelines provide the lowest level recommendation for TTFT as a treatment option for recurrent GBM and note that there is disagreement among its panel of experts as to TTFT’s effectiveness. While many in the medical community prescribe TTFT for patients with recurrent GBM and the AP’s expert witnesses testified that they believe it to be effective, there is sufficient support for me to conclude that Noridian’s prohibition on Medicare coverage is reasonable. Therefore, I conclude that the challenged provision in this case is valid under the reasonableness standard in the Social Security Act. 42 C.F.R. § 426.450(a)(2).
I. Local Coverage Determinations
The Medicare program is a public insurance program primarily for individuals 65-years-old and above that pays most of the costs associated with hospital, post-hospital, home health, and hospice services, as well as physician and other health care practitioner services, tests, and treatments. See 42 U.S.C. §§ 1395c, 1395j, 1395k. However, the Medicare program only covers the cost of health care items and services that are reasonable and necessary. 42 U.S.C. § 1395y(a)(1)(A).
An LCD is “a determination by a fiscal intermediary or a carrier under part A or part B [of the Medicare program], as applicable, respecting whether or not a particular item or service is covered on an intermediary- or carrier-wide basis under such parts, in accordance with [42 U.S.C. § 1395y(a)(1)(A)].” 42 U.S.C. § 1395ff(f)(2)(B). Fiscal intermediaries and carriers are collectively known as contractors. See 42 C.F.R. § 426.110 (definition of Contractor).
Contractors must, at least 45 days before an LCD becomes effective, make the following information available on its internet website and on the Medicare website: the entire LCD; where and when the proposed LCD was first made public; hyperlinks to the proposed determination and a response to comments submitted to the contractor concerning the proposed determination; a summary of the evidence that was considered by the contractor during the development of the LCD and a list of the sources of such evidence; and an explanation of the rationale that supports the LCD. 42 U.S.C.
§ 1395y(l)(5)(D). The Secretary of Health and Human Services (Secretary) coordinates the LCDs issued by the various contractors and determines when to adopt LCDs nationally. 42 U.S.C. § 1395y(l)(5)(A)-(C).
When a contractor relies on an LCD to deny a claim, the contractor must disclose such reliance in the determination. 42 U.S.C. § 1395ff(a)(4)(A)(i). Although contractors follow their own LCDs, LCDs “shall not be binding on the qualified independent contractor in making a decision with respect to a reconsideration” but “the qualified independent contractor shall consider the local coverage determination in making such decision.” 42 U.S.C. § 1395ff(c)(3)(B)(ii)(II). At the next two stages of the Medicare claims review process, adjudicators “are not bound by LCDs . . . but will give substantial deference to these policies if they are applicable to a particular case.” 42 C.F.R. § 405.1062(a).
If an LCD prohibits Medicare coverage for a health care item or service that a beneficiary needs, the beneficiary may file a complaint to challenge the LCD or a provision in the LCD. In a proceeding that is distinct from a Medicare claims appeal, an administrative law judge evaluates the reasonableness of the challenged LCD or provision of the LCD based on the LCD record and evidence submitted during the proceeding. In doing so, the administrative law judge will “defer only to the reasonable findings of fact, reasonable interpretations of law, and reasonable applications of fact to law by the Secretary.” 42 U.S.C. § 1395ff(f)(2)(A)(i)(III). When challenging an LCD or a provision of an LCD, the beneficiary has the burden of proving the allegations in his or her complaint by a preponderance of the evidence. 42 C.F.R. § 426.330.
A party may appeal the administrative law judge’s decision to the Departmental Appeals Board (DAB), and the DAB’s decision is subject to judicial review. 42 U.S.C. § 1395ff(f)(2), (5); 42 C.F.R. §§ 426.465, 426.490.
II. Procedural History
On August 6, 2019, the AP filed a complaint (Complaint) challenging the validity of the provision in L34823 that categorically prohibited Medicare coverage for TTFT as not reasonable and necessary. Complaint ¶¶ 3, 21, 47. The AP had recurrent GBM and his physician prescribed TTFT. Complaint ¶¶ 8, 32-33. Initially, the AP’s private insurance covered TTFT. Complaint ¶¶ 9, 34. However, in July 2018, the AP became eligible for Medicare and Noridian denied coverage for TTFT.2 Complaint ¶¶ 10, 34.
On August 22, 2019, I issued an Acknowledgment of Receipt of Acceptable Complaint; Order to File LCD Record; and Briefing Schedule. See 42 C.F.R. §§ 426.410(d)(3), 426.425(a)-(b). On September 25, 2019, the AP moved for an order compelling Noridian to submit additional documentation as part of the record, which Noridian opposed in an October 30, 2019 filing. On November 21, 2019, I granted the AP’s motion in part and denied it in part, and I ordered Noridian to refile all of its exhibits in a manner that comported with my August 22, 2019 Order.
Noridian complied with my November 21, 2019 Order and filed 50 exhibits as the record in L34823 (CMS Exs. 1-50). Subsequently, the AP filed his statement as to why the LCD record was not complete or adequate to support the validity of the challenged provision, along with nearly 400 exhibits (A. Exs. 1-392).
On February 5, 2020, Noridian moved for dismissal of the AP’s complaint because Noridian reevaluated the AP’s denied claims for TTFT to treat his recurrent GBM and decided that the AP should receive Medicare coverage despite the LCD’s prohibition on coverage. In essence, Noridian argued that the AP no longer had standing to maintain this action.
The AP opposed dismissal, asserting that his claims had not been allowed as alleged by Noridian. In support of the opposition, the AP submitted A. Exhibits 393 and 394. On March 3, 2020, I ordered Noridian to submit copies of the revised determinations proving that the AP’s TTFT claims had been allowed. Noridian responded to the March 3, 2020 Order. On March 27, 2020, I denied Noridian’s motion to dismiss because several claims that Noridian denied were pending review by adjudicators at other levels of the Medicare claims appeal process. Therefore, I concluded that the AP still had standing to maintain the Complaint in the present matter. See 42 U.S.C. § 1395ff(f)(5); 42 C.F.R. § 426.110 (definition of Aggrieved party).
On April 16, 2020, Noridian filed its defense of the validity of L34823.
On June 8, 2020, the AP provided notice that Noridian had denied another claim for TTFT. On June 10, 2020, Noridian filed notice that it revised the determination to allow the claim.
On June 17, 2020, I issued an Order in which I concluded that L34823’s record, as submitted by Noridian, was insufficient to support the validity of the challenged provision’s total prohibition of Medicare coverage for TTFT to treat recurrent GBM. Tumor Treatment Field Therapy LCD ID No. L34823, ALJ Ruling No. 2020-12 (HHS
CRD June 17, 2020). I did so because: 1) Noridian had not submitted all of the documents in the record for L34823, as required under the regulations; 2) Noridian primarily relied on documents dating from 2013 or earlier, and the AP had submitted more recent ones showing greater acceptance of TTFT in the medical community to treat recurrent GBM; 3) Noridian had submitted additional documents that had not been in L34823’s record, thus indicating that the LCD record was potentially deficient; 4) Noridian decided that the AP should receive Medicare coverage for TTFT, indicating that a categorical prohibition on coverage might not be sufficiently supported; and 5) the AP submitted numerous statements and documents from physicians concerning the efficacy of TTFT to treat recurrent GBM. Tumor Treatment Field Therapy, ALJ Ruling No. 2020-12 at 7-8.
Having concluded that a full evaluation of evidence was necessary to determine the validity of the challenged provision, I established in the June 17, 2020 Order a schedule for the parties to engage in discovery and indicated that the parties would be able to submit additional evidence when discovery was completed. Tumor Treatment Field Therapy, ALJ Ruling No. 2020-12 at 8; see 42 U.S.C. § 1395ff(f)(2)(A)(i)(I); 42 C.F.R. § 426.425(c)(1), (3).
On July 1, 2020, the AP gave notice that he was seeking discovery, i.e., submitting document requests and interrogatories to Noridian. On that same date, Noridian gave notice that it would not seek discovery from the AP. On July 22, 2020, Noridian submitted the missing documents from the LCD record for L34823, which Noridian marked as CMS Exhibits 51-73.
On August 11, 2020, I issued an order noting that discovery was completed and setting dates for the submission of additional exhibits, including written direct testimony from expert witnesses. In response, Noridian submitted CMS Exhibits 74 through 77, none of which were written direct testimony from expert witnesses. The AP submitted A. Exhibits 395 through 403, which included the written direct testimony for six expert witnesses (A. Exs. 398-403).
Noridian did not object to any of the AP’s proposed exhibits but requested to cross-examine the AP’s expert witnesses. The AP objected to CMS Exhibit 74 because it was duplicative of A. Exhibit 13.
Following coordination with the parties and witnesses, on October 20, 2020, I issued a Notice of Joint Telephonic Hearing and Ruling on Evidentiary Objections (Notice) for the present LCD challenge case and the LCD challenge case docketed under C-20-331. I did this for the following reasons: the APs in the respective cases were represented by the same representative; Noridian was represented by the same representatives in both cases; both cases involve challenges to provisions in L34823; and the purpose of both hearings was for Noridian to cross-examine the same six expert witnesses. The Notice
stated that I would hold the hearing on two days (i.e., November 19, 2020, and December 11, 2020) based on the availability of the witnesses and the previously stated schedules of the parties’ representatives. Further, in the Notice, I sustained the AP’s objection to CMS Exhibit 74 filed in this case as duplicative. In addition, I addressed Noridian’s objection to the November 19, 2020 hearing date because one of Noridian’s representatives had developed a conflict. I concluded that Noridian had three other representatives who were all legally trained who could appear at the hearing. Finally, in the Notice, I stated procedures for the hearing, which included the requirement that questions on cross-examination would be calculated to assist the party in supporting its case or to call into question the written direct testimony of the witness. I prohibited questioning of the type used in depositions. The Notice made clear that the parties must file any final motions before the start of the hearing and that I would not entertain motions at the hearing that could have been made before the hearing.
On October 27, 2020, Noridian withdrew its objection to the November 19, 2020 hearing date, indicating that its representative with a conflict had been able to resolve the conflict.
Based on information from the parties, on November 6, 2020, I gave notice of adjustments to the times at which the experts would appear on the days set for the hearing.
On November 19, 2020, I held a telephonic hearing at which Noridian cross-examined the following expert witnesses for the AP: Scott Turner, M.D. (A. Ex. 400; Hearing Transcript (Tr.) at 16-75); Louis Nabors, M.D. (A. Ex. 401; Tr. at 81-129); and Anand Shivnani, M.D. (A. Ex. 402; Tr. at 131-172). Tr. at 1-184. At the hearing, I admitted all of the AP’s proposed exhibits that appear on the AP’s September 11, 2020 amended exhibit list and all of Noridian’s proposed exhibits, except CMS Ex. 74, that appear on Noridian’s September 11, 2020 amended exhibit list. Tr. at 10-11.
On December 11, 2020, I held a telephonic hearing at which Noridian cross-examined the following expert witnesses for the AP: Eric T. Wong, M.D. (A. Ex. 399; Tr. 193-267); and Steven Toms, M.D. (A. Ex. 398; Tr. 280-335). Dr. George Ansstas was to appear but did not without explanation. Therefore, I excluded his written direct testimony from the record (A. Ex. 403). Tr. at 270, 277-78; see 42 C.F.R. § 426.440(e).
At and in between both days of the hearing, the AP’s representative objected to the appearance of Noridian’s lead representative at the hearing because he is not a licensed attorney. Although a CMS official ratified the lead representative’s appointment in writing, the AP’s representative argued that the appointment caused confusion as to whether Noridian or CMS was the party defending the LCD in this case. I denied the objection to the appearance of Noridian’s lead representative at the hearing and
concluded that Noridian was the party defending the LCD. Tr. at 4-9, 180-81, 188-91, 194, 196, 272-75.3
On January 25, 2021, the AP provided notice of an order from an administrative law judge at the Office of Medicare Hearings and Appeals returning the AP’s 2019 Medicare claims for TTFT to the Medicare Appeals Council. I admit that order (i.e., A. Exhibit 404) into the record because the AP submitted it as required by 42 C.F.R. § 426.310(b).
On March 12, 2021, the AP filed a post-hearing brief (A. Br.) and proposed A. Exhibit 405, which is a transcript from the March 6, 2019 Contractor Advisory Committee (CAC) meeting related to the reconsideration/revisions of L34823. The AP claims it should be part of the revised record for L34823. Noridian did not object. This document should have been submitted as part of the LCD record. See 42 C.F.R. § 426.418(a)(2)(iv). Therefore, I admit it into the record of this case.
On April 9, 2021, Noridian moved for the dismissal of the AP’s Complaint, alleging that the Complaint was untimely. Noridian submitted proposed CMS Exhibit 78. I stayed the briefing schedule and the AP responded to the motion and submitted A. Exhibits 406 and 407 to show the timeliness of the Complaint. On April 16, 2021, I denied Noridian’s motion to dismiss, finding that the AP’s Complaint was timely filed under the reasoning in Pneumatic Compression Devices, DAB No. 2082 (2007). Further, I excluded proposed CMS Exhibit 78 because it was not properly marked and paginated as required by the regulations and my orders in this case. However, I admitted A. Exhibits 406 and 407 into the record because they were properly marked.
On April 21, 2021, Noridian filed its post-hearing brief (N. Br.) along with six proposed exhibits (CMS Exs. 78-83). I exclude these documents because they are not substantive documents that are part of the LCD record and were not timely filed in accordance with my previous orders. See 42 C.F.R. § 426.405(c)(7).
On May 5, 2021, the AP filed a reply brief (A. Reply).
The sole issue that I decide in this case is:
Whether L34823’s denial of Medicare coverage for TTFT to treat recurrent GBM is valid under the reasonableness standard.
In post-hearing briefing, the AP extensively argued that Noridian failed to properly publish L34823 in conformance with the requirements in 42 U.S.C. §§ 1395y(l)(5)(D) and 1395hh. See A. Br. at 2-3, 18-23; A. Reply at 13-14. Noridian responded to those arguments. N. Br. at 24-34.
I do not have jurisdiction to consider this new issue because the AP did not raise it in the Complaint. 42 C.F.R. § 426.431(a)(1). Further, the statute under which I am conducting the present review limits an administrative law judge to evaluating the factual record to determine if the substantive provisions of the LCD are reasonable and not whether the LCD was properly published. 42 U.S.C. § 1395ff(f)(2)(A)(i)(I).
IV. Findings of Fact, Conclusions of Law, and Analysis
1. GBM is the most common and aggressive type of malignant brain tumor in humans, with most patients dying within two years of diagnosis and only five to ten percent alive five years after a GBM diagnosis. Following initial treatment, GBM generally recurs within nine months, at which point there is no clear standard of care. Chemotherapy is the primary treatment option at recurrence.
Although GBM is a rare form of malignant tumor generally, “[GBM] is the most common and aggressive primary brain tumor with an annual incidence of 3.19 per 100000. The disease course is typically rapid, with only approximately 1 in 4 patients alive 2 years after diagnosis, and only 5% to 10% of patients alive at 5 years.” A. Ex. 70 at 2. “The overall prognosis is poor with the best standard care.” A. Ex. 73 at 1. Further, “GBM is characterized by infiltrative growth and invariably recurs even with aggressive initial therapy.” A. Ex. 73 at 1.
Generally, the “[s]tandard treatment consists of maximal safe surgical resection or a diagnostic biopsy, followed by radiotherapy (60 Gy) with concomitant daily temozolomide chemotherapy, and then maintenance treatment with temozolomide for 6 to 12 months.” A. Ex. 71 at 3. Despite treatment, “most patients will die within 1 to 2 years . . . During the last decade [before 2015], all attempts to improve the outcome for patients with glioblastoma have failed when evaluated in large randomized trials.” A. Ex. 71 at 3.
After initial treatment for newly diagnosed GBM, most tumors recur within nine months. CMS Ex. 8 at 2. After recurrence, only about 20% of patients may be candidates for repeat surgery and re-irradiation occurs rarely; therefore, chemotherapy is the primary treatment option. CMS Ex. 8 at 2. “For patients with recurrent GBM, treatment options are limited, and there is no clear standard of care. . . . Hence, there is a critical need for additional treatments for patients with recurrent GBM.” A. Ex. 73 at 1-2.
2. TTFT is a treatment for GBM that uses electric fields to slow the progression of GBM.
TTFT is “an antimitotic treatment that selectively affects dividing glioblastoma cells by delivering low-intensity, intermediate-frequency (200 kHz) alternating electric fields via transducer arrays applied to the scalp. [TTFT] cause[s] mitotic arrest and apoptosis of rapidly dividing cells.” CMS Ex. 62 at 2; see A. Ex. 73 at 2. “TTFields are generated between opposing ceramic transducers strategically placed directly on the skin on opposing sides to create alternating electric fields through targeted tumor regions.” A. Ex. 76 at 2. In short, TTFT uses electric current to interfere with cell division and slow down the progression of GBM. That electric current is delivered by a device named Optune™ (developed by Novocure Ltd.), previously called NovoTTF-100A, consisting of “[four] transducer arrays placed on the shaved scalp and connected to a portable device set to generate 200-kHz electric fields within the brain.” A. Ex. 71 at 3; see CMS Ex. 8 at 2-3. A TTFT device is “a wearable, portable medical device that are [sic] administered by the patient at home.” A. Ex. 76 at 3.
3. The only Phase 3 clinical trial to test TTFT as a treatment for recurrent GBM, the EF-11 Study, failed in its designed purpose to show that TTFT, as a monotherapy for recurrent GBM, was superior to chemotherapy. An analysis by the physicians who conducted the EF-11 Study posited that the study showed TTFT to be at least equivalent to chemotherapy.
Based on a promising single arm pilot trial using TTFT, the Phase 3 EF-11 Study was conducted to compare TTFT, as a monotherapy, with chemotherapy to treat recurrent GBM. CMS Ex. 8 at 3. The EF-11 Study was conducted from September 2006 until May 2009, and included 237 patients from 28 institutions in seven countries. CMS Ex. 8 at 4. Novocure sponsored the EF-11 Study. Tr. at 38-39.
The EF-11 Study was composed of patients 18 years of age and older, who had radiologically confirmed progression of GBM, and a Karnofsky performance status (KPS) score of greater than or equal to 70, who had previously had therapy that included radiotherapy with or without concomitant and/or adjuvant temozolomide. CMS Ex. 8 at 3. Participation in the EF-11 Study was not restricted to patients who were on their first recurrence of GBM but included individuals with more than one recurrence. CMS Ex. 8 at 3.
The EF-11 Study randomized patients at a 1:1 ratio to receive either TTFT monotherapy (i.e., 120 patients) or the best available chemotherapy according to the local physician’s choice for each patient (i.e., 117 patients). For the group receiving TTFT, the patients had transducer arrays placed on their scalps so that they would receive continuous treatment even while at home. Patients could take two one-hour breaks each day to take
care of personal needs and two to three days off each time they completed four weeks of treatment. CMS Ex. 8 at 3-4; A. Ex. 73 at 2.
Of the 120 patients who were to receive TTFT, only 116 patients actually started treatment and 93 patients completed four weeks of therapy. CMS Ex. 8 at 4. In the control group, 112 patients completed one full treatment course of chemotherapy. CMS Ex. 8 at 5. By 39 months, 220 patients had died; however, the median survival for the TTFT group was marginally higher when compared to the control group (i.e., 6.6 months versus 6.0 months). CMS Ex. 8 at 5. While both groups showed 20% survival at one-year, the two-year survival rate was 8% for the TTFT group versus 5% for the control group, and the three-year survival rate was 4% for the TTFT group versus 1% for the control group. CMS Ex. 8 at 5.
The results of the EF-11 Study did not meet expectations. The EF-11 Study had been designed to show the superiority of TTFT over chemotherapy to treat recurrent GBM. The study did not show that. The published analysis of the EF-11 Study posited the possibility that TTFT was shown to be equivalent in efficacy to chemotherapy. It stated:
The trial had been designed for superiority. Since the control group in the trial is an active chemotherapy control which showed similar efficacy to that seen in previous trials and the device was used as monotherapy it is reasonable to analyse [sic] the results also in the context of a non-inferiority analysis. The HR [hazard ratio] for death in the TTF group compared to the active control chemotherapy group was below 1.0 (0.86; 95% CI 0.66–1.12), indicating that TTF may be at least equivalent to active chemotherapy.
CMS Ex. 8 at 5-6. The analysis also indicated that TTFT favorably compared with chemotherapy regarding toxicity and quality of life. CMS Ex. 8 at 1, 7.
One subgroup analysis of data from the EF-11 Study indicated that a full cycle of TTFT (i.e., four weeks) was needed to produce positive results “because the anti-tumor effect from alternating electric fields requires continuous treatment and disappears when stopped, while the biological effects of chemotherapy may persist for 4 to 6 weeks after dosing.” A. Ex. 73 at 6. The analysis also identified factors that appear to be indicators that TTFT would have a better effect on recurrent GBM than chemotherapy. A. Ex. 73 at 3-5. Another subgroup analysis of data from the EF-11 Study indicated that the group receiving TTFT had more patients respond to treatment than the group receiving chemotherapy; however, the chemotherapy group responded more quickly to treatment at 5.8 months versus 8.4 months for TTFT. A. Ex. 74 at 2. An article discussing the results of the EF-11 Study indicated that among the patients receiving TTFT, the main predictor
of improved length of survival was using TTFT for more than 18 hours a day. A. Ex. 79 at 4.
One article reviewing the EF-11 Study raised some concerns that the study lacked homogeneity because it had a heterogenous patient population and patients in the control group received different chemotherapy treatments based on the best available treatment under the current local practice where they were located. Further, the article noted that a number of patients were discontinued from TTFT less than a month after starting it. A. Ex. 78 at 4.
4. The FDA approved TTFT as a monotherapy treatment for recurrent GBM. The Chair of the FDA Neurological Devices Panel (FDA Panel) had to cast the deciding vote because the FDA Panel evenly split on whether there was a reasonable assurance that TTFT was effective.
Following the EF-11 Study, Novocure applied for FDA approval to market its TTFT device.
On March 17, 2011, the FDA Panel, consisting of a chair, three voting members, and nine temporary voting members, held a meeting and open public hearing related to the premarket approval application for Novocure’s Optune TTFT device (called NovoTTF-100A at the time of the FDA Panel hearing) to treat recurrent GBM. CMS Ex. 1 at 1, 6, 125.
At the meeting, Novocure’s Chief Medical Officer summarized that the “NovoTTF system was well tolerated by patients with brain and lung tumors, and our pilot clinical studies have consistently demonstrated better efficacy than historical control data, together with a lower toxicity than the existing treatments for both GBM and non-small cell lung cancer patients.” CMS Ex. 1 at 26. Novocure’s second witness summarized the results of the EF-11 Study as: “Time to progression was longer in NovoTTF. There’s almost doubling of the response rate seen on an MRI scan in patients with NovoTTF, and comparable and perhaps somewhat better 1-year survival rates in the NovoTTF patients.” CMS Ex. 1 at 35. Novocure’s Chief Medical Officer also discussed the EF-11 Study, acknowledging that the EF-11 was a “failed superiority study” and it is difficult to convert that into a “non-inferiority analysis,” but explained why the data was useful. CMS Ex. 1 at 36-39. The Chief Medical Officer concluded that “we can say that the NovoTTF is as effective as active best standard of care chemotherapy.” CMS Ex. 1 at 39. Novocure’s third witness summarized his findings as “NovoTTF is safe and significantly less toxic than existing treatment options for recurring [GBM].” CMS Ex. 1 at 46.
FDA personnel involved in reviewing Novocure’s premarket application also spoke during the hearing and relayed to the FDA Panel a variety of concerns. FDA staff also
thought it significant that Novocure intended TTFT as a monotherapy, in place of standard FDA-approved chemotherapy regimens. CMS Ex. 1 at 79.
FDA staff made it clear that the EF-11 Study was not designed to demonstrate non-inferiority and that it failed in its designed purpose to show superiority of TTFT to chemotherapy. CMS Ex. 1 at 76, 82, 88. FDA staff also noted that the EF-11 Study indicated that use of Novocure’s TTFT device brought a higher incidence of central nervous system and neuropsychiatric adverse events when compared to the control group. CMS Ex. 1 at 81.
FDA staff noted several irregularities with the EF-11 Study. FDA staff stated that “additional agents [were] used during the study that were not in conformance with the protocol-specified list of chemotherapeutic agents and should therefore be considered protocol violations.” CMS Ex. 1 at 78. Specifically, FDA staff had significant concerns that the EF-11 Study included subjects who had received Avastin, even though that was not part of the protocol and was not yet approved by the FDA for the treatment of GBM. CMS Ex. 1 at 84-86.
FDA staff also raised the point that the EF-11 Study compared patients receiving continuous TTFT with patients who only received one dose of chemotherapy rather than the medical practice of multiple cycles of chemotherapy. CMS Ex. 1 at 82.
Further, FDA staff did not think that patients who died or showed tumor progression during the required four-week period of TTFT treatment should have been excluded from the EF-11 protocol analysis. CMS Ex. 1 at 91.
Overall, FDA staff thought the “failure of the study to detect a statistically significant difference between the two groups [i.e., the TTFT arm and the chemotherapy arm] does not lead to the establishment of a statistical non-inferiority of NovoTTF as compare[d] [to chemotherapy.] Finally, it is very difficult to draw a sound statistical conclusion regarding the applicant’s non-inferiority claim.” CMS Ex. 1 at 93.
During panel deliberations on specific questions posed by the FDA, the FDA Panel members also spoke. One member stated that:
I do have questions about the safety regarding the [central nervous system] and neuropsychiatric adverse events that were reported. One of my concerns is that there was not a systematic assessment of neuropsychological or neurocognitive or psychiatric side effects in the studies that were presented, and without a systematic assessment, we can't know what the risks are. But again, even in the absence of that, I still have a question about how we weigh those risks
versus the benefits and what would reach the level of a concern from the FDA perspective.
CMS Ex. 1 at 159. Another member said:
I not only think it was inappropriate to include the chemotherapy patients who had only 1 dose in the analysis, I think it's completely inappropriate to drop out the patients who had less than 4 weeks of the NovoCure device. That's sort of saying, well, we're going to throw out all of the patients who failed and only analyze the ones in whom it worked. I think all of the patients -- you've got to go one way or the other, either all out on both sides or they're all in on both sides, and I prefer all in on both sides.
CMS Ex. 1 at 165-66. A different panel member agreed: “[N]one of our neuro-oncologists would accept a single dose of chemotherapy as meeting any criterion of enough therapy to potentially have an important effect. So I think this is a huge problem in understanding the data.” CMS Ex. 1 at 166. In regard to the use of Avastin, a panel member stated the following: “You know, the model gets worse. Not only is Avastin not treated in a consistent way through the trial, one of the explanations for early dropouts early in the trial is that Avastin was available to them outside of the trial but not in it. So an Avastin bias gets in early and then we include them later as a not prespecified acceptable chemotherapy regimen and then we have evidence that that inclusion does clearly introduce a bias into the outcome results. So this just isn’t going to fly.” CMS Ex. 1 at 176.
As to converting superiority trial results into a non-inferiority analysis, a panel member stated: “[A] nonsignificant superiority result does not imply non-inferiority or no difference or equivalence, and so we have to be careful about that.” CMS Ex. 1 at 178. Another panel member stated: “The main issue with the inferiority . . . is just it’s how much gray area are we willing to accept in this overlap between the control and the best medical and the TTF and is it, you know, that we could be approving a device that’s half as effective as best medical therapy . . . .” CMS Ex. 1 at 194.
Another panel member was concerned at approving TTFT as a monotherapy for recurrent GBM. Doing so, the member reasoned, would result in discarding other efficacious treatments for patients and relying only on TTFT. CMS Ex. 1 at 197-98.
The FDA Panel voted on the questions posed by the FDA. The FDA Panel unanimously voted that there was a reasonable assurance that TTFT was safe for patients who met certain requirements. On the second question, as to whether there is a reasonable assurance that TTFT is effective for use in patients who meet certain criteria, the panel
split evenly with six “yes” votes and six “no” votes - the deadlock broken by the Chair of the FDA Panel in favor of effectiveness. The third question was whether the benefits of TTFT outweigh its risks, to which seven voted “yes,” three “no,” and two abstained. CMS Ex. 1 at 221-22. Therefore, the FDA Panel voted in favor of FDA approval for Novocure’s TTFT device to treat recurrent GBM. CMS Ex. 6 at 1, 37-38.
In an April 8, 2011 letter, the FDA approved the use of Novocure’s TTFT device for the treatment of recurrent GBM. A. Ex. 5. The FDA provided the following indications for the use of TTFT:
This device is indicated for treatment of adult patients (22 years of age or older) with histologically-confirmed [GBM], following histologically- or radiologically – confirmed recurrence in the supratentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.
A. Ex. 5 at 1.
5. Subsequent to the EF-11 Study, another Phase 3 clinical trial was conducted in order to test the effectiveness of TTFT, in conjunction with chemotherapy, to treat newly diagnosed GBM. This study, the EF-14 Study, was highly successful. The EF-14 Study did not directly involve the treatment of recurrent GBM; however, it accumulated data from a portion of the study’s patients who continued to receive TTFT and chemotherapy to treat their later recurring GBM. While the data collected indicated that TTFT and chemotherapy were more effective than chemotherapy alone to treat recurrent GBM, this evidence did not support TTFT’s efficacy as a monotherapy to treat recurrent GBM. Further, this data was collected from a patient population that was heterogenous, thus reducing the conclusions that could be drawn from the data. Finally, the data regarding the patients with recurrent GBM was not gathered as part of a clinical trial but as a post hoc adjunct to the EF-14 Study, further limiting the conclusions that could be made from it.
From July 2009 to November 2014, the EF-14 Phase 3 trial was conducted at 83 centers in the United States, Canada, Europe, Israel, and South Korea, with the objective to evaluate the efficacy and safety of TTFT used on patients with GBM in combination with maintenance temozolomide (chemotherapy) after initial treatment with temozolomide and radiotherapy. CMS Ex. 71 at 2-3. Unlike the EF-11 Study, the EF-14 Study involved only patients who were newly diagnosed with GBM rather than with recurrent GBM, and
TTFT was provided along with chemotherapy rather than as a monotherapy. See CMS Ex. 71 at 6.
The 2015 interim analysis of the EF-14 Study indicated that TTFT with temozolomide “significantly prolonged progression-free and overall survival.” CMS Ex. 61 at 2. The final analysis of the EF-14 Study in 2017 was that TTFT with temozolomide versus temozolomide alone “resulted in statistically significant improvement in progression-free survival and overall survival.” CMS Ex. 62 at 1.
More specifically, the final assessment of the EF-14 Study showed that the median progression-free survival was 6.7 months for patients who received TTFT plus temozolomide compared with 4.0 months for temozolomide-only patients. Median overall survival was 20.9 months for the group with TTFT plus temozolomide and 16 months with temozolomide alone. Two years following enrollment in the study, 43% of patients receiving TTFT and temozolomide were still alive and 31% of temozolomide-only patients were alive. After three years, 26% of patients were alive who received TTFT and temozolomide as compared to 16% who only received temozolomide. Finally, after five years, 13% of the patients were alive when receiving TTFT and temozolomide as compared to 5% of patients who received only temozolomide. CMS Ex. 62 at 6.
The final assessment noted that “[p]atients 65 years or older had shorter survival than patients younger than 65 years. In both age groups, TTF[T] plus temozolomide was associated with significantly increased survival compared with temozolomide alone for older . . . and younger patients.” CMS Ex. 62 at 7.
The EF-14 Study permitted patients who had a recurrence of GBM, whether in the TTFT and temozolomide group or the temozolomide-only group, to receive TTFT and temozolomide. A total of 144 patients participated and received both TTFT and temozolomide and 60 patients opted to receive chemotherapy alone. A. Ex. 146 at 1, 3. At 12.6 months of treatment, median survival for those who received TTFT and chemotherapy after first recurrence was 11.8 months as compared to 9.2 months for the chemotherapy alone group. A. Ex. 146 at 4. A post hoc analysis of this data derived from EF-14 Study participants “demonstrated that TTFields significantly improves [survivability] when combined with second-line treatment after first disease recurrence. . . . However, it should be acknowledged that this study provides no information on the possible benefit of continuation of TTFields alone in this patient population.” A. Ex. 146 at 5 (emphasis added). The analysis indicated that there was support for “continued use of TTFields plus chemotherapy after first recurrence.” A. Ex. 146 at 5-6. However, the authors of the post hoc analysis indicated that there were limitations to their conclusions because it was a post hoc analysis and the individuals in the group were heterogenous (i.e., there were some who had started TTFT when diagnosed and others who started after a first recurrence). A. Ex. 146 at 6-7.
6. Based on the EF-14 Study, the FDA approved TTFT in conjunction with chemotherapy as a treatment for newly diagnosed GBM. The FDA approval did not include treatment of recurrent GBM with TTFT and chemotherapy.
Following the EF-14 Study, in an October 5, 2015 letter, the FDA approved the use of Novocure’s Optune TTFT device in conjunction with chemotherapy for the treatment of newly diagnosed GBM. A. Ex. 6.4 The FDA stated the following indications for the TTFT device’s use and the restrictions the FDA placed on the TTFT device:
This device is indicated as a treatment for adult patients (22 years of age or older) with histologically-confirmed glioblastoma multiforme (GBM). Optune™ with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery and completion of radiation therapy together with concomitant standard of care chemotherapy.
A. Ex. 6 at 1. Therefore, the FDA separately approved TTFT to treat newly diagnosed GBM based on a completely new clinical trial that paired TTFT with chemotherapy. The FDA did not extend approval of TTFT with temozolomide for recurrent GBM.
7. From 2011 to 2013, a Patient Registry Dataset (PRiDe) tracked the length of survival of patients who received TTFT to treat recurrent GBM. Despite positive results, the PRiDe did not track how many of the patients used TTFT in conjunction with other treatments, such as chemotherapy; therefore, it cannot clearly support TTFT as a monotherapy treatment for GBM. Further, the possibility of patients on the PRiDe exhibiting pseudoprogression after receiving chemotherapy could not be ruled out and may have affected the results.
The Patient Registry Dataset (PRiDe) was created and composed of all individuals with recurrent GBM who received TTFT from 2011 to 2013. A. Ex. 80 at 1. The baseline characteristics of the individuals were based on patient chart review and the length of survival was determined by Social Security Death Date Registry records and obituaries. A. Ex. 80 at 3. Four hundred fifty-seven patients with recurrent GBM were treated with TTFT between October 2011 and November 2013. A. Ex. 80 at 3.
An analysis of the data indicated that individuals in the PRiDe appeared to have markedly longer survival than those in the EF-11 Study (i.e., 9.6 months versus 6.6 months). A. Ex. 80 at 4. The analysis indicated that a higher degree of compliance with TTFT
treatment may be a significant prognostic factor for the increased survival rate. A. Ex. 80 at 4-5. Further, a greater proportion of PRiDe individuals started TTFT after the first recurrence, rather than after having experienced second or subsequent recurrences, as compared with the participants in the EF-11 Study. A. Ex. 80 at 6. In addition, KPS score may have been a factor in TTFT being more effective, as the PRiDe individuals who had a higher average KPS score may have been more capable of maintaining compliance with TTFT. A. Ex. 80 at 7. The analysis also concluded that individuals in the PRiDe might have received TTFT at the same time that they were receiving other treatments:
Finally, the PRiDe dataset did not capture patients on combination treatments in which additional biologic therapy or chemotherapy were added to NovoTTF Therapy. It is possible that the longer survival seen in clinical practice with NovoTTF Therapy compared to NovoTTF monotherapy in the EF-11 trial is a reflection of combination use of NovoTTF Therapy with biological agents or cytotoxic chemotherapy. In fact, preclinical data have suggested that TTFields are additive or even synergistic with chemotherapies in cell culture. Therefore, the potential benefits of combining NovoTTF Therapy with other systemic therapies warrant further investigation.
A. Ex. 80 at 8; see A. Ex. 141 at 5; cf. A. Ex. 18 ¶ 8 (declaration of practicing oncologist who prescribes TTFT “for patients who have recurrent [GBM] in combination with chemotherapy in patients with good bone marrow function.”).
Another analysis questioned the information gathered from the PRiDe, as follows:
In the PriDE dataset reflecting routine clinical use of the device, patients who received TTFields at first recurrence were treated for a median of 6.2 months and had a median survival of 20 months, comparing favorably with recent trial results investigating other novel agents. However, a strong selection bias and inclusion of patients with pseudoprogression after initial TMZ [temozolomide] chemoradiotherapy cannot be ruled out in this uncontrolled routine practice patient population. The best results with this novel treatment modality have been achieved when TTFields were administered early in the disease course in combination with standard maintenance TMZ therapy, similar to that shown 10 years ago when TMZ was added to standard radiotherapy.
A. Ex. 78 at 7.
8. The NCCN Guidelines provide a Level 2B recommendation for the use of TTFT to treat recurrent GBM. A Level 2B recommendation is one that lacks uniform consensus among the NCCN panel of experts and is based on “lower-level evidence.” NCCN first gave a Level 2B recommendation in 2013 but rescinded that recommendation in 2014. However, NCCN subsequently reinstated the Level 2B recommendation. The chair of the NCCN panel that approved this recommendation testified that the EF-11 Study was the basis for the recommendation but thought that panel members were influenced by the success of the EF-14 Study in reinstating the Level 2B recommendation. The 2019 NCCN Guidelines added the following disclaimer: “Due to lack of clear efficacy data for alternating electric field therapy in EF-11, the panel is divided about recommending it for the treatment of recurrent [GBM].”
“The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.” CMS Ex. 49 at 5; A. Ex. 12 at 3. The NCCN committee is composed of over 30 physicians from institutions across the United States, including renowned cancer hospitals such as: the Mayo Clinic Cancer Center; Yale Cancer Center; the Cancer Center at Johns Hopkins; Memorial Sloan Kettering Cancer Center; St. Jude Children’s Research Hospital; and the Duke Cancer Institute. CMS Ex. 49 at 2; A. Ex. 12 at 2.
NCCN ranks the evaluation of evidence and consensus concerning treatments into four categories. These are:
- Category or Level 1: Based on high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
- Category or Level 2A: Based on lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
- Category or Level 2B: Based on lower-level evidence, there is NCCN consensus that the intervention is appropriate.
- Category or Level 3: Based on any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
CMS Ex. 44 at 1; CMS Ex. 45 at 3.
In 2013, NCCN gave a Level 2B recommendation, i.e., the lowest recommendation available that was based on a “consensus” rather than the higher levels with “uniform consensus,” for treating recurrent GBM with TTFT. CMS Ex. 44 at 7. After this, NCCN
reversed itself, opting not to recommend the use of TTFT, then reversed itself again and provided a Level 2B recommendation. See Tr. at 101. In 2018 and 2019, NCCN continued to give a Level 2B recommendation for TTFT to treat recurrent GBM. CMS Ex. 49 at 20; A. Ex. 12 at 16. In 2018, NCCN noted that “[d]ue to the lack of efficacy, not all panelists recommended” TTFT to treat recurrent GBM. CMS Ex. 49 at 84. In 2019, NCCN provided the following lengthier warning of the disagreement among panelists concerning the use of TTFT for recurrent GBM:
Alternating electric field therapy is also FDA approved for treating recurrent glioblastoma based on the safety results of this medical device from the EF-11 clinical trial. This phase III study randomized 237 patients with recurrent glioblastoma to alternating electric field therapy or the treating oncologist’s choice of chemotherapy. The study did not meet its primary endpoint of demonstrating an improvement in survival in the cohort of patients treated with alternating electric field therapy. Although median OS [overall survival] was similar in both of the treatment arms [(]6.6 vs. 6 months), the study had not been powered for non-inferiority determination. Due to lack of clear efficacy data for alternating electric field therapy in EF-11, the panel is divided about recommending it for the treatment of recurrent glioblastoma.
A. Ex. 12 at 94 (emphasis added) (footnote omitted).
Dr. Nabors, one of the expert witnesses who testified in this proceeding, has been, for the past ten years, the chair of the NCCN committee that creates the guidelines for Central Nervous System Cancers, such as GBM. Tr. at 85; CMS Ex. 44 at 2; CMS Ex. 49 at 2; A. Ex. 12 at 2; see CMS Ex. 45 at 2. Dr. Nabors testified that “[t]he NCCN guidelines translate clinical trial data and publications into practice guidelines, i.e., the NCCN guidelines translate medical discoveries into clinical care recommendations.” A. Ex. 401 ¶ 18.
Dr. Nabors testified that “[t]he NCCN guidelines are evidence-based, consensus-driven management decisions and interventions to ensure that patients receive the best treatments and supportive services that are most likely to lead to an optimal outcome for each individual patient.” A. Ex. 401 ¶ 13. Dr. Nabors explained how his committee decides what it will recommend, the evidence they use, and the importance of these recommendations in the medical community:
The NCCN guidelines are developed and updated by over 1500 clinicians and oncology researchers from the 30 NCCN
member institutions. To ensure the guidelines reflect the consensus of each disease subspecialist, each guideline is circulated among the multidisciplinary faculty at each NCCN member institution for comment.
The NCCN guidelines are based on the best evidence available when they are derived and are updated continuously as new data and clinical information become available.
Because the NCCN guidelines are drafted by experts in the management of the relevant cancer and their expert interpretation on the appropriate translation of clinical trials and publications into practice guidelines, the NCCN guidelines are recognized as the standard for clinical decision-making and policy and are used not only in the United States, but around the world.
A. Ex. 401 ¶¶ 14-16 (emphasis added).
Dr. Nabors also testified that the NCCN Guidelines constitute a compilation and evaluation of evidence related to treatments. “I understand that Noridian has asserted that the NCCN guidelines are simply an opinion of some clinicians. However, the NCCN guidelines are evidence-based and consensus-driven by those who have expertise in treating the condition and are familiar with the full body of peer-reviewed literature and patient care considerations.” A. Ex. 401 ¶ 17.
Regarding recurrent GBM, Dr. Nabors testified that NCCN gave TTFT a Level 2B recommendation, which meant there was consensus that it should be considered an option based on evidence that is lower than that which is needed for a Level 1 recommendation. A. Ex. 401 ¶ 26. Dr. Nabors testified that a Level 2B recommendation requires more than 50% of the panel members to vote to recommend the treatment. Tr. at 103-04. Based on this recommendation, Dr. Nabors testified that TTFT should be among the treatment options for recurrent GBM, especially because many patients with recurrent GBM are too weak to receive chemotherapy again and TTFT is the only option. A. Ex. 401 ¶¶ 32-33, 35-36.
On cross-examination, Dr. Nabors testified that the EF-11 study was the primary support for the Level 2B recommendation in the 2013 NCCN Guidelines for TTFT to treat recurrent GBM. Tr. at 96. Dr. Nabors also confirmed that NCCN had provided a Level 2B recommendation, then changed it to Level 3 (i.e., not recommended), and then changed it back again to a Level 2B recommendation; however, he was uncertain of the dates when that occurred. See Tr. at 101. Dr. Nabors also stated that the change back to
a Level 2B recommendation was based on the EF-11 Study and not additional evidence. Tr. at 102. However, Dr. Nabors also thought that the successful EF-14 Study probably influenced some panel members as to TTFT’s efficacy for recurrent GBM. Tr. at 118-19. Dr. Nabors agreed that even by 2018, not all of the panel members agreed that TTFT should be recommended to treat recurrent GBM. Tr. at 106. “I believe the panel remained very consistent between these time intervals [2018 to 2019]. And that members of the panel questioned and had concerns about this form of therapy in recurrent disease.” Tr. at 109.
I credit Dr. Nabor’s testimony. He has a high level of expertise related to the treatment of GBM as well as his academic qualifications. After graduating from medical school, Dr. Nabors completed a residency in neurology and a fellowship in neuro-oncology, and became board certified by the American Board of Psychiatry and Neurology. A. Ex. 401 ¶ 4. At the University of Alabama at Birmingham, Dr. Nabors is: the Director of the Center for Clinical Translational Science’s Clinical Research Unit; on the medical staff at its hospital; is an associate scientist in the Neuro-oncology Program; and holds additional appointments in the Department of Biomedical Engineering and the Department of Cell Biology. A. Ex. 401 ¶¶ 6-7.
In addition, Dr. Nabors has served as the Chair of the NCCN CNS [Central Nervous System] Tumor Guidelines Committee from 2011 to present, which is “the committee that sets the guidelines for brain tumor care in the United States.” A. Ex. 401 ¶ 8. Dr. Nabors testified that his expertise includes clinical evaluation of novel cancer therapies, and Dr. Nabors has been the principal investigator for a significant number of clinical trials focusing on tumors of the CNS. A. Ex. 401 ¶¶ 10-11; see A. Ex. 401 at 25-27. In the field of oncology, Dr. Nabors has published numerous peer-reviewed articles and multi-book chapters and has served as editor and reviewer for peer-reviewed journals. A. Ex. 401 ¶ 12; A. Ex. 401 at 14-22, 24-25. Although Dr. Nabors participated in one of Novocure’s clinical trials, he testified that neither he nor the division at the University of Alabama that he is in charge of received compensation from Novocure. Tr. at 84. Finally, Noridian quotes Dr. Nabors in its brief without challenging his testimony. N. Br. at 22.
Although I credit Dr. Nabors’ testimony and opinion, I note that his testimony in support of TTFT for the treatment of recurrent GBM was not detailed or extensive. Dr. Nabors primarily testified that it should be considered as an option because that is what NCCN recommended. However, Dr. Nabors’ testimony regarding the divisions on his NCCN panel also speaks to the limited acceptance that TTFT has for treating recurrent GBM.
9. In 2015, CMS contractors Noridian and CGS Administrators, Inc. (CGS) published LCD L34823 categorically denying Medicare coverage for TTFT. In 2019, based on a reconsideration request and following a lengthy process that included a meeting of a CAC, public meetings, and the submission of
public comments, Noridian and CGS permitted Medicare coverage for TTFT to treat newly diagnosed GBM if beneficiaries met certain criteria. Noridian and CGS did not reconsider the prohibition on coverage for TTFT to treat recurrent GBM, and the revised LCD categorically prohibited coverage to treat recurrent GBM.
Medicare contractor NHIC Corp. (NHIC) proposed publishing LCD L34730, which would prohibit coverage for TTFT as not reasonable and necessary. NHIC indicated that a public comment period would begin on December 27, 2013. CMS Ex. 27. Notice of a public meeting in January 2014 was also provided. CMS Ex. 75.
In June 2014, NHIC published L34730, which included the following provision: “[TTFT] will be denied as not reasonable and necessary.” The LCD became effective on August 1, 2014. CMS Ex. 29.
NHIC also issued in June 2014 a “Response to Comment Summary” concerning L34730. CMS Ex. 28. One of the comments urged Medicare coverage for TTFT because, based on a phase 3 clinical trial (i.e., the EF-11 Study), the FDA had approved Novocure’s TTFT device. CMS Ex. 28 at 1. NHIC responded that the FDA Panel had split on the question of TTFT’s efficacy with six votes in favor and six opposed. NHIC said that, although the panel chairperson voted in favor, the panel meeting transcript detailed numerous examples of doubt expressed by panel members concerning the effectiveness of TTFT for the treatment of recurrent GBM. CMS Ex. 28 at 1.
Several other commentors urged Medicare coverage for Novocure’s TTFT device based on NCCN’s Category 2B recommendation for the use of TTFT. NHIC responded that a Category 2B recommendation is based on lower-level evidence. NHIC thought this insufficient because CMS expects Medicare contractors to use the highest level of evidence possible when making coverage determinations. CMS Ex. 28.
LCD L34730 was retired on September 30, 2015. CMS Ex. 29 at 2.
Effective October 1, 2015, Noridian and CGS published LCD L34823, which continued to categorically prohibit Medicare coverage for TTFT. See A. Ex. 1 at 2, 16; CMS Ex. 36 at 2, 16. However, in a June 20, 2018 letter, Novocure requested that CGS reconsider L34823’s prohibition on coverage for TTFT. CMS Ex. 35. Novocure posited that CGS should permit coverage for the use of TTFT for patients who either have newly diagnosed GBM or recurrent GBM. CMS Ex. 35 at 1. Novocure based its request on the two randomized controlled trials it conducted (i.e., the EF-11 Study and EF-14 Study) and FDA approval for the use of the Optune TTFT device to treat newly diagnosed and recurrent GBM. CMS Ex. 35 at 1-2. Novocure also cited four peer-reviewed published articles based on the information derived from the randomized controlled clinical trials,
as well as the 2018 NCCN Guidelines, as showing the general acceptance of TTFT by the medical community. CMS Ex. 35 at 3.
In an August 7, 2018 letter, CGS responded to Novocure that it would reconsider coverage for TTFT to treat newly diagnosed GBM. CMS Ex. 74. However, it deemed Novocure’s request for reconsideration of coverage for TTFT to treat recurrent GBM to be invalid because Novocure only submitted evidence of TTFT’s efficacy that had already been considered. CMS Ex. 74 at 2; see A. Ex. 1 at 9; CMS Ex. 36 at 9; CMS Ex. 38 at 5.
Noridian participated with CGS in conducting the reconsideration of the prohibition on coverage for TTFT, which included empaneling a 13-member CAC in March 2019, holding a public meeting, and receiving and responding to public comments. A. Ex. 1 at 6-9; CMS Ex. 36 at 6-9; CMS Ex. 38 at 3-9.
In 2019, 80 practitioners or researchers submitted comments during the LCD reconsideration process. CMS Ex. 38 at 3. Of these, the record includes comments from 30 oncologists who expressly supported the extension of Medicare coverage to TTFT to treat recurrent GBM. A. Exs. 46, 48-50, 52-55, 57, 59-65, 68, 369, 372-74, 376-78, 380, 382-83, 385-87, 392.
Noridian and CGS published a final revised version of L34823 that provided Medicare coverage for TTFT to treat beneficiaries who had newly diagnosed GBM and met certain criteria. A. Ex. 1 at 4, 9; CMS Ex. 36 at 4, 9. However, L34823 included the following provision: “[TTFT] will be denied as not reasonable and necessary for the treatment of recurrent GBM.” A. Ex. 1 at 5; CMS Ex. 36 at 5. L34823 included the following information concerning coverage for recurrent GBM:
In April 2011 the [FDA] approved the marketing of the NovoTTF-100A (later rebranded Optune®) for the treatment of recurrent GBM. The original LCD for TTFT was effective in August 2014, following an Open Meeting and solicitation of public comments. The DME MACs determined that, based on the strength and quality of the evidence available at that time, TTFT was not reasonable and necessary for the treatment of GBM.
In 2018 the DME MACs received a request to reconsider the decision on recurrent GBM. The requestor, Novocure, did not submit new evidence in support of revised coverage for recurrent disease. Consequently, pursuant to Chapter 13 of the CMS Program Integrity Manual (CMS Pub. 100-08), the DME MACs determined that the request was invalid.
A. Ex. 1 at 9; CMS Ex. 36 at 9. Similar information was provided in Local Coverage Article A56688 (with an effective date of July 18, 2019) published contemporaneously with the revised LCD. CMS Ex. 38 at 4-5.
10. The AP’s expert witnesses all testified in support of the use of TTFT as a treatment for recurrent GBM. However, most of the expert witnesses acknowledged weaknesses in the EF-11 Study and/or divisions in the medical community as to TTFT’s effectiveness with regard to recurrent GBM.
The AP provided five expert witnesses to testify in this case. I have discussed one of those experts, Dr. Nabors, in conjunction with the NCCN Guidelines above due to his direct connection to those Guidelines. Here, I discuss the other witnesses and note that they testified consistently with Dr. Nabors as to their belief that TTFT should be an option to treat recurrent GBM. They also mostly testified consistently with Dr. Nabors as to the medical community’s divisions or concerns about TTFT as such an option.
Eric T. Wong, M.D.
Dr. Wong, a physician and professor of neurology at Harvard Medical School, is a leading expert in neuro-oncology and TTFT. Dr. Wong’s experience and training in the field of neuro-oncology is impressive, including fellowships following medical school at both Memorial Sloan-Kettering Cancer Center and MD Anderson Cancer Center. A. Ex. 399 ¶ 3. In addition to being a Harvard Medical School associate professor, he is also a Neuro-Oncology Protocol Review Committee member at the Dana Farber/Harvard Cancer Center, and Director of the Brain Tumor Program and Neuro-oncology fellowship training program at the Beth Israel Deaconess Medical Center. A. Ex. 399 ¶ 4. Dr. Wong has authored 72 peer-reviewed articles as well as chapters in books, primarily on oncology-related subjects, including GBM and TTFT. A. Ex. 399 at 32-38.
Dr. Wong has served or is serving as principal or co-investigator in many clinical trials and translational research projects involving GBM, including as an investigator on clinical trials involving various chemotherapy agents and TTFT. A. Ex. 399 ¶ 9. Dr. Wong testified that he participated as an investigator with the EF-11 Study. Tr. at 204.
In regard to evidence supporting the effectiveness of TTFT for recurrent GBM, Dr. Wong testified that “[t]he published TTFT registry results showed that those with recurrent GBM who had TTFT had improved outcomes relative to those who did not, i.e., the ‘real world experience’ shows improved outcomes for those who use TTFT.” A. Ex. 399 ¶ 32. Dr. Wong testified that he has treated over 100 patients with GBM and has been prescribing TTFT since 2011. Dr. Wong opined that “TTFT is clinically useful and
effective and medically necessary for patients who have GBM, including those who have recurrent GBM.” A. Ex. 399 ¶¶ 33-34.
On cross-examination, Dr. Wong testified that the EF-11 Study was designed as a trial to test the superiority of TTFT to chemotherapy, but the EF-11 Study found TTFT was not superior to chemotherapy. Tr. at 220-21. Dr. Wong stated that the EF-11 Study “was not powered . . . as a non-inferiority or equivalency trial.” Tr. at 221. Dr. Wong testified that a 2004 study with ten patients showed that TTFT had a significant survival advantage compared to chemotherapy but that the EF-11 Study had “no survival advantage” compared to the “control group” and “wasn’t sufficiently powered.” Tr. at 246-47.
However, despite the EF-11’s limited results, Dr. Wong testified that a protocol analysis was presented to the FDA in support of TTFT. Tr. at 221; see Tr. at 243 (“However, the pre-protocol population did show a benefit and because of that, I believe that [TTFT] offer[s] a survival advantage to recurrent [GBM], the recurrent [GBM] population.”). Regarding treatment for recurrent GBM, Dr. Wong thought that TTFT “may not be for everyone,” so he obtained the primary data from Novocure and conducted an independent analysis to identify factors that can potentially help in identifying the patients who may benefit from TTFT. Tr. at 243-44. Dr. Wong testified that he agreed there were limitations to the results from the EF-11 Study; however, “as a clinician interpreting this study, I do not just interpret the study at face value . . . there were sub-analyses that were done that led me to believe that there is some efficacy against recurrent [GBM].” Tr. at 223 (emphasis added).
Dr. Wong testified that an analysis of the data from the EF-11 Study indicated that the patients in the TTFT group all had secondary glioblastomas and a marker called IDH1 mutation. Tr. at 247-48. Dr. Wong stated that another important finding was that the patients in the TTFT group did not use dexamethasone or used it only in very low doses. Tr. at 248. Ultimately, when all the patients in the study were analyzed regarding the effects of dexamethasone, dexamethasone was found to be a “confounding” factor in the trial. Tr. at 248.
Dr. Wong further testified that studies regarding treatments for recurrent GBM now only admit patients who have had a single recurrence; however, the EF-11 Study allowed patients who had a third, fourth, fifth, and even sixth recurrence of GBM. Tr. at 248-49. In doing so, the study included patients for whom no treatment would have worked. Tr. at 250-51. Dr. Wong testified that this heterogeneity of patients was a weakness in the EF-11 Study. Tr. at 264; see Tr. at 251. In addition, he agreed there was heterogeneity in the EF-11 Study because the chemotherapy control arm of the study permitted the physician’s choice of individualized chemotherapy, rather than having a single chemotherapy approach for all patients in the control arm. Tr. at 264, 266.
On cross-examination, Dr. Wong acknowledged that the NCCN Guidelines from 2013 gave a Level 2B recommendation for the use of TTFT to treat recurrent GBM, and that NCCN Guidelines lowered that to Level 3 (representing major NCCN disagreement that intervention is appropriate) in 2014. Tr. at 224-25; CMS Exs. 44-45. Dr. Wong testified that he was aware that the 2018 NCCN Guidelines indicated that not all panelists recommended TTFT for recurrent GBM and acknowledged a difference in opinion among neuro-oncologists about TTFT. Tr. at 234-38; CMS Ex. 49 at 20. Dr. Wong also acknowledged that the 2019 NCCN Guidelines provided a category 2B recommendation for the treatment of recurrent GBM with TTFT. Tr. at 239; A. Ex. 12 at 94.
Noridian levels a charge of financial bias against Dr. Wong, asserting that Dr. Wong has received significant compensation from Novocure. N. Br. at 23. However, Noridian fails to mention that Dr. Wong testified that this “compensation” is primarily grant money provided to the institution he works for to pay for the costs related to the clinical trial. Tr. at 240. Dr. Wong testified: “I don't personally benefit from running the clinical trials or doing any scientific research at my institution.” Tr. at 266.
Since 2007, Dr. Wong has received three grants (i.e. funding) from Novocure that went to the institution where he works (2007 or 2008, 2010 or 2011, and 2015) for translational research in the laboratory to investigate the basic mechanism of action of TTFT. Tr. at 197, 199. He received a grant of approximately $100,000 for the EF-11 TTFT study and less than $100,000 for the 2015 study. Tr. at 198-200. In 2018, based on another trial opening, he received $30,000 in grant money and, based on future work, the amount might reach approximately $150,000. Tr. at 200-01. Dr. Wong also testified about another grant from 2010 to the present that is about $250,000 in direct costs with additional indirect costs charged by Dr. Wong’s institution. Tr. at 202. Dr. Wong also estimated that he personally received less than $20,000 from Novocure for work done on Novocure advisory boards, and about $2,000 for giving lectures on behalf of Novocure. Tr. 202-04, 207.
I credit Dr. Wong’s testimony. Dr. Wong’s resume shows that his medical career since his graduation from medical school in 1989 has been devoted to neurology and oncology. A Ex. 399 at 5-7, 19-30, 44-54. Dr. Wong has published extensively in those fields, serving as an editorial member with the Journal of Clinical Oncology, Central Nervous System Tumors, as well as being an ad hoc reviewer for many neurology and oncology publications. A. Ex. 399 at 7-8. As mentioned above, Dr. Wong has published 72 peer-reviewed articles on or related to oncology and neurology, some of which involve GBM and TTFT specifically. A. Ex. 399 at 32-38. He also has authored chapters in ten books on the same subjects, including two on TTFT. A. Ex. 399 at 42-43.
While Noridian wants me to disregard Dr. Wong’s testimony because his institution has received grant money to conduct clinical trials, I believe that Dr. Wong’s lengthy and deep experience using TTFT as a treatment for GBM makes him one of the best persons
to provide an opinion in this case. He does not work for Novocure but for Harvard Medical School. He is an expert in clinical trials and participated as an investigator in the EF-11 Study. I have no reason to question the integrity of Dr. Wong based on the limited personal compensation he has received from Novocure. Further, Dr. Wong’s testimony is consistent with that of Dr. Nabors, an expert witness in this proceeding who took no money from Novocure.
Although a distraction from the substance of this case, I must digress to address Noridian’s complaint that it did not have the opportunity to conduct discovery before the hearing related to the AP’s witnesses. N. Br. at 21-22, 23 n.15 (“Due to Noridian’s inability to conduct discovery on these apparent conflicts [of interest] before the hearing, Noridian’s opportunity to question the witnesses about these reported payments at the hearing was limited.”). Noridian also claims the following:
Noridian’s representative probed the AP’s experts’ opinions and apparent conflicts of interest for the first time during the hearing, see, e.g., Dkt 103a at 198:4–207:17. Despite the Tribunal’s possible suggestion otherwise, Dkt 103 at 31:21–32:12, Noridian did not have an opportunity to engage in earlier discovery of the experts because expert lists were not due until September 11, 2020, when the AP’s counsel submitted her list, see Order (Dkt 69) at 2 (Aug. 11, 2020), and discovery had closed more than a month prior to that date, see Order (Dkt 60) at 7 (June 17, 2020) (ending discovery on July 31, 2020). Noridian’s questioning at the hearing was therefore necessarily limited both in scope and by witness time allocations, as Noridian effectively was required to conduct both discovery and cross examination simultaneously at the hearing.
N. Br. at 23 n.14.
Noridian’s claims are misleading.
I provided both parties with an opportunity to serve discovery demands on the other party and informed the parties that the rules governing discovery were located at 42 C.F.R. § 426.432. Tumor Treatment Field Therapy, ALJ Ruling No. 2020-12 at 8. That regulation states that discovery in LCD challenge cases consists of requests for production of documents and/or up to ten written interrogatory questions. 42 C.F.R. § 426.432(c).
While Noridian may posit that it was unable to engage in discovery because the AP’s prehearing exchange, which included the full written direct testimony for each expert
witness, was not submitted until after discovery closed, this simple chronology fails to account for the fact that Noridian should have served interrogatories on the AP requesting the names and a summary of expected testimony for any and all witnesses that the AP intended to present in the case. Noridian should have also asked about the expected witnesses’ financial conflicts of interests. Further, Noridian should have requested document production regarding the AP’s expected witnesses. Instead, Noridian filed on July 1, 2020, a document entitled Notice of Contractor Not Seeking Discovery. DAB E-File Document No. 64.
Having failed to make use of its right to discovery, Noridian could still have requested that I permit additional discovery after receiving the AP’s subsequent prehearing submission with the written direct testimony of the expert witnesses. However, Noridian opted to wait until the telephonic hearing to question the expert witnesses about documents not in the record that they could not see. Tr. at 19-20, 262, 287-89; see N. Br. at 23 n.15. It is Noridian’s fault if its questioning could not have been as fulsome had it utilized its right to discovery.
I make one further note regarding Noridian’s allegations. At the hearing, I gave Noridian’s representative leeway to question the witnesses concerning their potential financial conflicts of interest. Tr. at 18-25, 83-84, 134, 197-208, 282-93. Further, although Noridian appears to complain that it was limited due to the time slots scheduled for each witness, one of Noridian’s representatives stated in an October 19, 2020 email that “Noridian expects to spend less than 30 minutes with each witness, however depending on the responses, it is possible that some witnesses may take longer.” DAB E-File Document No. 84. I allocated two hours each for four witnesses and one and one-half hours each for two witnesses. DAB E-File Document No. 90.
I give significant weight to Dr. Wong’s expert testimony, due to his background, training, and scholarly achievements in the field of neuro-oncology, as well as his detailed knowledge of TTFT as a treatment for GBM. However, despite his view that TTFT should be a treatment for recurrent GBM, his testimony provides much reason to doubt the efficacy of the EF-11 Study. As summarized above, Dr. Wong acknowledges the shortcomings of the EF-11 Study, both in design and results. Dr. Wong also conducted his own independent analysis on the premise that TTFT for recurrent GBM may work well with some people but not others. Finally, in acknowledging that NCCN Guidelines have not uniformly recommended TTFT to treat recurrent GBM, Dr. Wong indicated that there is disagreement in the oncology community.
Steven A. Toms, M.D.
Dr. Toms, a physician and professor at Brown University’s Medical School, is another significant expert in neuro-oncology who testified in this proceeding. Dr. Toms completed a residency in neurological surgery at the Cleveland Clinic Foundation and a fellowship in neurosurgical oncology at MD Anderson Cancer Center. He is board-certified by the American Board of Neurological Surgeons and a Fellow of the American Association of Neurological Surgeons. Dr. Toms is a professor in the Departments of Neurosurgery, Medicine, and Health Policy at Brown University’s Medical School. He is the Vice-Chairman of the Department of Neurosurgery and Director of the Brain Tumor Program at Lifespan Health System. He has been the principal investigator for a number of clinical research studies, including studies on the development of therapeutic approaches for primary brain tumors and cancer metastasis to the brain. He also served as an investigator on studies related to TTFT to treat GBM. Dr. Toms has published over ninety peer-reviewed articles and various chapters in books, including articles concerning GBM and TTFT. A. Ex. 398 ¶¶ 2-9; A. Ex. 398 at 6-8, 11-19.
Dr. Toms testified that he strongly disagreed that there is no evidence of the effectiveness of TTFT for recurrent GBM and that TTFT “is clinically useful and effective and medically necessary for patients . . . who have recurrent GBM.” A. Ex. 398 ¶¶ 40, 45. Dr. Toms also testified that Medicare’s restriction on coverage for TTFT to treat recurrent GBM is not consistent with the standard of care. A. Ex. 398 ¶ 47.
Dr. Toms’ opinion was based, in part, on his experience treating over a hundred patients who had GBM, both newly diagnosed and recurrent, with TTFT. A. Ex. 398 ¶ 44. Dr. Toms also cited a subset analysis from the EF-14 Study of patients who continued in the clinical trial after recurrence, which showed increased overall survival and progression-free survival. A. Ex. 398 ¶¶ 41-42. Dr. Toms explained that the sub-analysis “suggested -- although [the EF-14 Study] was neither designed nor powered for that, it did reach statistical significance and strongly suggested that [TTFT] [was] effective, you know, when delivered even at a later period in time.” Tr. at 326-27; see Tr. at 329-30. On cross-examination Dr. Toms testified that the EF-14 Study was designed for individuals with newly diagnosed GBM, not recurrent, although there was some opportunity for individuals in the “nontreatment arm” of the study to cross-over and obtain TTFT when they experienced a first recurrence. Tr. at 309-10.
When asked about NCCN’s past history of recommending TTFT for the treatment of recurrent GBM in 2013 at Level 2B and then changing the recommendation to Level 3 in 2014, Dr. Toms could not recall those specific matters, but stated that “the way [TTFT] had been approved for recurrent [GBM] . . . was quite controversial at the time.” Tr. at 313, 316-17. Dr. Toms also stated, in regard to the 2018 NCCN recommendation, he was aware of the controversy around recommending TTFT to treat recurrent GBM. Tr. at 320.
On cross-examination, Dr. Toms stated that some of his patients were in the EF-11 Study, but Dr. Toms also stated that he was not involved in the design of the EF-11 Study and not an expert in study size statistical analysis. Tr. at 304-05. As a result, Dr. Toms did not think he was qualified to answer questions as to the EF-11 Study’s design, in terms of giving his views on it being a superiority study versus an equivalency study. Tr. at 305-06.
Noridian only attempts to discredit Dr. Toms through alleged financial conflicts of interest with Novocure. However, on cross-examination, Dr. Toms testified that Novocure did not provide funding to him personally for any of his research. Tr. at 282. He confirmed that Novocure was providing funding to Lifespan, the medical facility that Dr. Toms is affiliated with, for a trial on which Dr. Toms would participate as an investigator. Tr. at 282. “The hospital is getting research funding. I am not receiving anything for my lab nor is it a grant that I’ve applied for and received funding for.” Tr. at 283. When asked further questions, Dr. Toms replied: “I personally have received no dollars for research directly from them. The hospitals at which I have worked have received whatever administrative charges they charge back to the company for running these trials.” Tr. at 285. Dr. Toms had attempted to determine some of the amounts paid by Novocure for trials it had requested, in part because a report indicated Dr. Toms had received $420,000; however, Dr. Toms denied receiving any of that money. Tr. at 285-86, 289-90 (“I still cannot even fathom where that money came from or went.”).
In terms of other payments unrelated to trials which he received from Novocure, Dr. Toms testified that he received personal compensation of about $2,000-$3,000 from Novocure for providing international lectures and about $1,500 to $2,000 for serving on a strategic advisory board. Tr. at 287. Dr. Toms estimated that the compensation he personally received represented less than one-half of one percent of his overall income. Tr. at 325.
Dr. Toms is an expert in oncology and has significant and lengthy experience with TTFT, including serving as an investigator in the EF-14 Study. He contributed to the published interim and final analyses of the EF-14 Study (CMS Exs. 61-62). While he has taken modest amounts of money from Novocure, I cannot disregard, as Noridian would have me do, his opinions related to this case. Further, Dr. Toms testified consistently with the other experts in this case. Therefore, I fully credit his testimony.
I note that, like Dr. Wong, despite supporting TTFT for the treatment of recurrent GBM, Dr. Toms acknowledges the controversy at NCCN regarding the Level 2B recommendation. Further, Dr. Toms’ knowledge of the EF-11 Study was too limited for him to discuss its design, but as an expert on the EF-14 Study, Dr. Toms stated that he based his views of TTFT for recurrent GBM on the EF-14 Study. Therefore, Dr. Toms thought the data collected incidental from the EF-14 Study was significant in his view of
the efficacy of TTFT’s use in recurrent GBM. Therefore, while acknowledging Dr. Toms’ experience with TTFT as support for TTFT’s use in treating recurrent GBM, I find that Dr. Toms’ primary expertise is with the EF-14 Study and this limits the weight I afford his views concerning TTFT to treat recurrent GBM.
Scott Turner, M.D.
Dr. Turner, a physician and a professor of Neurology at the University of Missouri-Kansas City, is another expert in neuro-oncology who testified in this proceeding. After receiving his medical degree, Dr. Turner completed a residency in neurology and a fellowship in neuro-oncology at the State University of New York at Stony Brook and Duke University, respectively. A. Ex. 400 ¶ 2. He is board-certified by the American Board of Psychiatry and Neurology and has exclusively practiced neuro-oncology. A. Ex. 400 ¶¶ 4-5. Dr. Turner was the Director of Neuro-Oncology at St. Luke’s Marion Bloch Neuroscience Institute and Assistant Professor of Neurology at the University of Missouri-Kansas City School of Medicine from 2018 to 2020, but was in the process of moving to a position at the University of California at Irvine. A. Ex. 400 ¶ 3. His expertise includes clinical therapeutic treatments of primary brain tumors. A. Ex. 400 ¶ 6. Dr. Turner has authored a number of articles on oncological subjects. A. Ex. 400 at 7-8.
Dr. Turner participated as an investigator in the EF-11 Study and the EF-14 Study. A. Ex. 400 ¶ 9. He testified that the EF-11 Study was aimed at determining “whether or not TTFT alone was superior to chemotherapy in treating patients who have recurrent GBM. The trial design hypothesized that TTFT would be 30% more effective than chemotherapy in controlling the progression of recurrent GBM.” A. Ex. 400 ¶ 10. The EF-11 Study included patients with multiple recurrences of GBM. A. Ex. 400 ¶ 11. Dr. Turner testified that: “The EF-11 clinical trial did not show TTFT alone was 30% more effective than chemotherapy in treating recurrent GBM. Although it was not designed as an equivalency trial, the results do show that TTFT is as effective as chemotherapy in treating GBM.” A. Ex. 400 ¶ 12; see Tr. at 66. Dr. Turner further testified that, because TTFT is as effective as chemotherapy, NCCN Guidelines included it with a Level 2 recommendation, meaning that TTFT is an option to consider. A. Ex. 400 ¶ 13. Dr. Turner pointed out that NCCN Guidelines are evidence-based and reflect the consensus of oncologists who treat a specific type of tumor, and what published peer-reviewed literature supports. A. Ex. 400 ¶¶ 16-17.
On cross-examination, Dr. Turner agreed that it is very difficult to convert a failed superiority clinical trial into a non-inferiority analysis. Tr. at 50. Dr. Turner also agreed that “underpowered studies” frequently mistakenly conclude that the tested treatment is as effective as other treatments. Tr. at 50.
Noridian did not specifically argue that I should not credit Dr. Turner’s testimony but did allege that all of the expert witnesses had potential conflicts of interest. N. Br. at 23. I find no evidence of this regarding Dr. Turner. Dr. Turner testified that he has not received money from Novocure but has been occasionally taken to dinner by a Novocure representative. Tr. at 18. Noridian mentions this in its brief without attributing it to Dr. Turner. N. Br. at 29-30. Dr. Turner also served on an advisory board for Novocure, which Dr. Turner thought was limited to reimbursement of travel costs involved with that work. Tr. at 20, 24. Finally, Dr. Turner participated in the EF-14 Study, but did not receive compensation for that. Tr. at 26.
I credit Dr. Turner’s expert testimony. It is consistent with the testimony of the other experts. Dr. Turner participated in the EF-14 Study with no compensation and on an advisory board with no cash remuneration. I will not disregard the testimony of a physician who has direct and detailed knowledge of both GBM and TTFT because he received a few dinners in the past from Novocure. Serving on an advisory board for TTFT shows that Dr. Turner is sufficiently knowledgeable such that Novocure wanted his input. Dr. Turner’s involvement in helping to test a treatment for a disease like GBM shows his interest in ensuring proper care for his patients.
However, as indicated above, Dr. Turner’s support for TTFT to treat recurrent GBM must be tempered by the fact that he agreed that it is very difficult to convert a superiority study (such as the EF-11) to an equivalency study. Further, Dr. Turner reflects what appears to be the status of the medical community, i.e., a recognition that the evidence of efficacy is questionable but an opinion either for or against the use of TTFT to treat recurrent GBM should be based on an individual physician assessment.
Anand Shivnani, MD
Dr. Shivnani is a board-certified radiation oncologist and has been a radiation oncologist since 2006, following completion of his residency in the Radiation Oncology Department at Northwestern University Medical School. Dr. Shivnani authored nine published articles that primarily deal with radiation and chemotherapy in the treatment of cancer. A. Ex. 402 ¶¶ 2-5; A. Ex. 402 at 4, 5. Dr. Shivnani has also made presentations on that subject, or related ones, and received a 2018 award as an investigator in the US Oncology Radiation Research Program. A. Ex. 402 at 5-6.
Dr. Shivnani testified that “I have treated many patients who have a GBM.” A. Ex. 402 ¶ 10; see Tr. at 139. Further, he served as “an investigator in many clinical trials, including clinical trials involving GBM,” as well as one involving “TTFT and lung cancer.” A. Ex. 402 ¶¶ 7-8.
Dr. Shivnani testified that he believes “that TTFT is clinically useful, effective and medically necessary for patients who have a GBM, including those who have recurrent
GBM.” A. Ex. 402 ¶ 28. He stated that the EF-11 Study results “did not show TTFT was 30% superior to chemotherapy” (as was the premise for the study); the study showed “TTFT was equivalent to chemotherapy.” A. Ex. 402 ¶ 23. Further, Dr. Shivnani’s opinion was based in part on the EF-14 Study, which, while having the goal of studying the effectiveness of TTFT in the treatment of newly diagnosed GBM, resulted in “an incidental finding . . . that those whose GBM recurred, also did better on TTFT than those who did not have TTFT after recurrence.” A. Ex. 402 ¶ 22; see Tr. at 143; see also Tr. 165, 167. Finally, Dr. Shivnani testified that published peer-reviewed literature shows that individuals using TTFT to treat recurrent GBM had improved outcomes relative to those who did not. A. Ex. 402 ¶ 21. Dr. Shivnani thought the importance of TTFT is that it provides the only option for patients who are too weak to resume chemotherapy following recurrence. A. Ex. 402 ¶¶ 20-27.
When asked, on cross-examination, if the practice in the EF-11 Study, to exclude from the study a patient who died or had progression of GBM in the first four weeks of receiving TTFT therapy could make the survival rate for patients receiving TTFT appear better than if all the patients in the Study were included in the results, Dr. Shivnani answered that it was possibly the case. Tr at 157-58.
Noridian did not specifically argue that I should not credit Dr. Shivnani’s testimony but did allege that all of the expert witnesses had potential conflicts of interest. N. Br. at 23. Dr. Shivnani testified that he received approximately $5,000 from Novocure. Tr. at 134. But he clarified that this money was paid to U.S. Oncology Research and Dr. Shivnani did not receive it personally or directly. Tr. at 168. Dr. Shivnani previously participated in one Novocure clinical study and is going to participate in a second. Tr. at 134.
I credit Dr. Shivnani’s testimony. There is insufficient evidence of a financial conflict of interest. However, as with the other experts, Dr. Shivnani’s testimony showed a support for using TTFT to treat recurrent GBM, but Dr. Shivnani also conceded that the EF-11 Study did not achieve its goal and that the exclusion of certain information could have made the survival rate appear better than it actually was. Further, Dr. Shivnani’s testimony was based on the EF-14 Study, which did not did not specifically seek to test the efficacy of TTFT for recurrent GBM.
11. Noridian could reasonably conclude that TTFT, as approved by the FDA to treat recurrent GBM (i.e., as a monotherapy), lacks sufficient evidence of efficacy for Medicare coverage. Noridian reasonably considered the flaws with the EF-11 Study and its analysis, the fact that the FDA Panel split on the issue of whether TTFT was effective to treat recurrent GBM, and the NCCN Guidelines’ lowest level recommendation for its use with a disclaimer that the NCCN panel is divided on the issue of efficacy.
Congress set the parameters for the review of an LCD as follows:
The administrative law judge.—
(I) shall review the record and shall permit discovery and the taking of evidence to evaluate the reasonableness of the determination, if the administrative law judge determines that the record is incomplete or lacks adequate information to support the validity of the determination;
(II) may, as appropriate, consult with appropriate scientific and clinical experts; and
(III) shall defer only to the reasonable findings of fact, reasonable interpretations of law, and reasonable applications of fact to law by the Secretary.
42 U.S.C. § 1395ff(f)(2)(A)(i).
Based on this statute, the Secretary’s regulations define the “reasonableness standard” that I am to apply as the following:
In determining whether LCDs . . . are valid, the adjudicator must uphold a challenged policy (or a provision or provisions of a challenged policy) if the findings of fact, interpretations of law, and applications of fact to law by the contractor or CMS are reasonable based on the LCD . . . record and the relevant record developed before the ALJ or the Board.
42 C.F.R. § 426.110; see 42 C.F.R. § 426.405(b) (“An [administrative law judge] defers only to reasonable findings of fact, reasonable interpretations of law, and reasonable applications of fact to law by the Secretary.”).
The AP provides significant evidence in favor of the efficacy of TTFT to treat recurrent GBM, including expert witnesses of the highest knowledge and experience. However, while there is no doubt that the EF-14 Study showed that TTFT with chemotherapy was significantly more effective than chemotherapy alone when treating newly diagnosed GBM, the EF-11 Study failed to show that TTFT as a monotherapy for recurrent GBM was more effective than chemotherapy. TTFT’s success at treating newly diagnosed GBM in conjunction with chemotherapy should not be mistaken as evidence that TTFT, as a monotherapy for recurrent GBM, is clearly effective.5 The AP at times conflates the
success of the EF-14 Study with the limited performance of the EF-11 Study, and claims that the EF-14 Study included patients with recurrent GBM, when the EF-14 Study did not directly do so as part of that study, but just as an option for patients to continue to receive TTFT and chemotherapy once recurrence occurred. Despite this, the AP’s case is strong. However, given the deferential standard that I must apply in this case, I cannot conclude that L34823’s prohibition on coverage for TTFT to treat recurrent GBM is not reasonable.
In favor of coverage, the AP points out that the FDA approved TTFT for the treatment of recurrent GBM and that, based on a comment in the Federal Register, believes CMS is to accept the FDA’s determination as to effectiveness. A. Br. at 7. Again, regarding the NCCN Guidelines, the AP acknowledges that NCCN provided the lowest level recommendation but makes the point that it nonetheless is recommended as an option for recurrent GBM. A. Br. at 8-9.
The AP also argues that Noridian failed to consider other evidence, such as the views of experts in the field, and asserts that the challenged LCD provision cannot be cured by its litigation position in this case.6 A. Br. at 10. The AP references the expert witnesses he provided in this case as evidence that TTFT to treat recurrent GBM is effective. A. Br. at 13.
The AP also relies on the incidental data and post hoc analysis related to the EF-14 Study, which allowed study participants to continue with TTFT treatment after GBM recurred (i.e., after the patients had concluded their official role in the EF-14 Study). The AP, however, concedes that the EF-14 Study was not designed to evaluate TTFT’s effectiveness in treating recurrent GBM. A. Br. at 14 n.23. Similarly, the AP argues that the PRiDe showed that patients who had recurrent GBM and received TTFT lived significantly longer than those who did not. A. Br. at 15.
Finally, the AP challenges why Noridian covers additional surgery, radiation, and chemotherapy for recurrent GBM when there is no evidence that they are more effective than TTFT. A. Br. at 11.
In response, Noridian argues that its determination to prohibit Medicare coverage for TTFT to treat recurrent GBM is reasonable. Noridian asserts that there is only one clinical trial, the EF-11 Study, on which to base the efficacy of TTFT for recurrent GBM. N. Br. at 2. Noridian then raises its concerns that the EF-11 Study arguably suffered from methodological defects. N. Br. at 2. Further, Noridian distinguishes the EF-11 Study from the very successful EF-14 Study, which provided evidence for the efficacy of TTFT and chemotherapy for patients with newly diagnosed GBM and not recurrent GBM. N. Br. at 2-4, 8-9.
Noridian also claims that it followed a hierarchy of evidence as stated in the Medicare Program Integrity Manual (MPIM), which requires scientific studies to be given preference above other evidence, such as clinical evidence. N. Br. at 3. Therefore, Noridian focused its attack on the EF-11 Study as follows:
Although the EF-11 trial was a randomized clinical trial, Noridian rationally ascribed it less weight due to deficiencies in trial design and significant deviations from standard clinical trial methodologies, as explained below. Even with those deviations, the EF-11 trial still failed to demonstrate that TTFT was superior to chemotherapy and, moreover, was neither designed nor powered to conclude that TTFT was non-inferior to chemotherapy. In other words, TTFT failed to achieve the goal of the EF-11 trial: the trial was designed to study TTFT superiority, not equivalence, and any attempt to read equivalence into the results is nothing but a post-hoc misuse of the study.
N. Br. at 3 (footnote omitted); see N. Br at 5.
Noridian noted that six members of the 13 person FDA Panel did not believe there was a reasonable assurance that the NovoTTF-100A is effective for treating recurrent GBM, and it provided eight specific concerns with the EF-11 Study, which arose during the FDA Panel meeting in 2013:
- The EF-11 Study failed to achieve its main goal of demonstrating that TTFT was superior to chemotherapy for treating recurrent GBM;
- The EF-11 Study was not designed to prove that TTFT was equivalent to chemotherapy for treating recurrent GBM and had not enrolled enough patients to properly conclude that TTFT was not inferior to chemotherapy;
- The EF-11 Study enrolled heterogeneous patients in the two arms of the study (A. Ex. 75 at 9) in that patients in the TTFT arm had received different chemotherapy agents and had different disease progression rates when compared to patients in the non-TTFT arm, which meant that there were “differences in patient characteristics at the beginning of the trial (baseline)”;
- The EF-11 Study removed healthier patients from the control (non-TTFT) arm and removed more severally ill patients from the TTFT arm, and did not explain why;
- The EF-11 Study had a protocol violation because it introduced additional chemotherapy agents and provided those agents to certain patients in the non-TTFT arm of the study, making it difficult to determine whether the reported results were due to TTFT or the chemotherapy agent (CMS Ex. 1 at 78);
- The EF-11 Study excluded from its analysis patients who did not receive at least four weeks of TTFT, which was a deviation of protocol and “could only make the TTFT arm appear to have better results”;
- The EF-11 Study was to compare TTFT to the best standard chemotherapy; however, some patients only received one dose of chemotherapy, which is not the standard of care, and yet those patients were not removed from the study’s analysis.
- The data analysis stage of the EF-11 Study deviated from study protocol and excluded patients who died or showed tumor progression within the required minimum four weeks of TTFT treatment, thus making the TTFT arm appear to have better results.
N. Br. at 11-12.
Noridian also argues that the 2018 NCCN Guidelines provided its lowest recommendation, a Category 2B, for the use of TTFT to treat recurrent GBM. This recommendation means that NCCN’s panel had not achieved uniform consensus. N. Br. at 13. Noridian points out that in 2013, NCCN gave TTFT a Category 2B recommendation but, in 2014, NCCN did not recommend TTFT. From 2015 to the present, NCCN once again recommends TTFT to treat recurrent GBM with a Category 2B recommendation. N. Br. at 14-15.
Noridian further argues that the AP’s expert witness testimony is insufficient to carry the AP’s burden of proof in this case because the witnesses only cited the EF-11 Study (and sometimes the EF-14 Study), and their testimony does not necessarily reflect that of the entire medical community. Noridian cites as an example the testimony of Dr. Nabors, who testified to disagreement among the NCCN panel concerning the efficacy of TTFT for recurrent GBM. N. Br. at 21-22.
Noridian asserts that the AP relies on two publications (A. Exs. 73-74) that are “merely sub-analyses and treatment-based analyses of the EF-11 trial data and carry the same flaws as the original EF-11 trial, since they are derived from the same primary data.” N. Br. at 9.
Noridian asserts that, despite a number of articles that the AP submitted into the record in this case and statements from physicians, a rational person could still have reached the conclusion that Noridian did, which was to prohibit coverage for TTFT for recurrent GBM. N. Br. at 7-8.
The AP replied to Noridian as follows:
At base, the ALJ need only decide whether the decision to exclude recurrent patients from TTFT coverage was reasonable when:
1) Treating such patients with TTFT is the standard of care;
2) TTFT is approved by the FDA as safe and effective for recurrent patients;
3) A clinical trial (the EF-14 trial) conclusively proved that the treatment was safe and effective for recurrent patients;
4) Multiple publications in peer-reviewed journals concluded that TTFT was safe and effective for recurrent patients;
5) All of the witnesses, articles, etc. offered evidence in support of coverage without the exclusion and none offered evidence in support of the exclusion;
6) It would be unethical to even attempt to conduct a study withholding TTFT from recurrent patients and that fact has been recognized by the EF-14 data and safety monitoring committee, the FDA, and the CAC members; and
7) The exclusion is founded, according to Noridian’s own statement, on simple denialism of the EF-14 trial and the publications related thereto.
A. Reply at 1.
In the reply, the AP relied heavily on the EF-14 Study as support for the effectiveness of TTFT to treat GBM and, for the first time, asserts that NCCN gave a Level 1 recommendation for combined TTFT and chemotherapy to treat recurrent GBM:
Relevant to this case are two [NCCN] Guideline provisions. The first tracks the EF-11 trial and allows for chemotherapy or TTFT for recurrent patients. See A. Ex. 12 at 16. This has a level 2B recommendation. The second tracks the EF-14 trial and allows for chemotherapy and TTFT for GBM patients, regardless of whether they are newly diagnosed or recurrent. See A. Ex. 12 at 14. This has a level 1 recommendation.
Because the LCD in this case requires chemotherapy plus TTFT, the AP believes that the level 1 recommendation is most applicable. This is fully consistent with the EF-14 trial including recurrent patients and the Kesari article analyzing the benefits specifically to recurrent patients in the trial. Nevertheless, even if the 2B recommendation was applied, again, the NCCN Guidelines recommend TTFT for recurrent patients and there is no support for the exclusion.
AP Reply at 10.
While, as mentioned above, the AP provides much evidence in support of his position, an evaluation of the entire record in conjunction with Noridian’s concerns related to the EF-11 Study forces me to conclude that Noridian’s prohibition of Medicare coverage for TTFT to treat recurrent GBM is reasonable.
The EF-11 Study has many flaws that gave members of the medical community concern. And the record reveals that most of the articles discussing the efficacy of TTFT to treat recurrent GBM point to the EF-11 Study and the FDA approval. Therefore, if Noridian remains reasonably unconvinced of the EF-11 Study, which was not properly powered to determine TTFT’s equivalence to chemotherapy, then Noridian would properly have concerns in determining whether Medicare should cover TTFT to treat recurrent GBM.
Further, FDA approval does not mandate Medicare coverage. See Int’l Rehab. Scis., Inc. v. Sebelius, 688 F.3d 994, 1002 (9th Cir. 2012). In the case of the approval of TTFT to treat recurrent GBM, the FDA Panel was heavily divided as to the efficacy of TTFT. Therefore, while approved by the FDA, its efficacy could still be reasonably questioned.
In fact, the NCCN panel did just that when, in 2013, it first provided a Level 2B recommendation for TTFT to treat recurrent GBM, then reversed itself and did not
recommend it, and then finally recommended it again at Level 2B. The expert witnesses in this proceeding testified to the controversy and division in the medical profession that TTFT has engendered, as reflected by the NCCN panel. While NCCN recommends TTFT to treat recurrent GBM, it did so with a bare majority of the panel, an acknowledgment that the recommendation is based on lower-level evidence, and a warning as to concerns that panel members have over the efficacy of TTFT to treat recurrent GBM. A. Ex. 12 at 16, 94.
It is significant that NCCN indicates in its recommendation for the treatment of recurrent GBM that “[t]he efficacy of standard-of-care treatment for recurrent [GBM] is suboptimal, so for eligible patients consideration of clinical trials is highly encouraged.” A. Ex. 12 at 16. Therefore, while NCCN provides a weak recommendation for TTFT to treat recurrent GBM, it essentially undercuts that recommendation by recommending that patients enter clinical trials for as yet untested treatments rather than submit to standard treatment. This speaks to the terrible survival prospects that patients have when attempting to ward off an intractable disease like GBM.
The AP, perhaps realizing that the EF-11 Study, a divided FDA panel vote for approval, and an uncertain recommendation from NCCN might mean his position would not prevail, decided in his reply brief to rely heavily on the EF-14 Study as evidence of the efficacy of TTFT with chemotherapy to treat recurrent GBM. As mentioned already, the AP goes so far as to allege that NCCN has given a Level 1 recommendation for combined TTFT and chemotherapy to treat recurrent GBM.
However, as discussed above, the EF-14 Study did not include testing related to recurrent GBM. A. Ex. 70 at 2 (The EF-14 Study “was designed to test the efficacy and safety of [TTFT] in combination with best standard of care in the treatment of newly diagnosed [GBM].”). Neither the interim nor final analysis of the EF-14 Study discusses recurrent GBM, except in relation to the EF-11 Study. See A. Exs. 70-71. The data that the AP wants to pull from the EF-14 Study was merely derivative information that has limited scientific value. A. Ex. 146 at 6-7. Further, there is no evidence to conclude that NCCN gave a Level 1 recommendation for TTFT with chemotherapy to treat recurrent GBM. In the Guidelines, the NCCN recommendation appears on pages with pathways delineated with arrows for different recommended treatment options. The Level 1 recommendation related to TTFT for newly diagnosed GBM ends with a final arrow to the words: “See Recurrence GLIO-5.” A. Ex. 12 at 14-15; see A. Ex. 401 ¶ 25. “GLIO-5” is the page of the NCCN Guidelines with the pathways that include the Level 2B recommendation for TTFT as a monotherapy treatment for recurrent GBM. A. Ex. 12 at 16. Such an interpretation is clearly supported by Dr. Nabors’ testimony. A. Ex. 401 ¶ 26.
Finally, I note that, as discussed in detail above, I have considered the testimony of the expert witnesses in this case. I respect their opinions and believe that, like the NCCN, they realize that treatment options for recurrent GBM are limited and having more
treatment options is better than fewer. However, their clinical experience regarding the use of TTFT to treat recurrent GBM as a monotherapy is insufficient to overcome the legitimate concerns that Noridian has raised.
The Secretary provided guidance as to when the fact-finding in an LCD was reasonable.
So long as the outcome is one that could be reached by a rational person, based on the evidence in the record as a whole (including logical inferences drawn from that evidence), the determination must be upheld. This is not simply based on the quantity of the evidence submitted, but also includes an evaluation of the persuasiveness of the material. If the contractor or CMS has a logical reason as to why some evidence is given more weight than other evidence, the [administrative law judge] and the Board may not overturn the determination simply because they would have accorded more weight to the evidence in support of coverage.
68 Fed. Reg. 63,692, 63,703 (Nov. 7, 2003).
Under the reasonableness standard, as interpreted above, I conclude that Noridian’s bases for preclusion of Medicare coverage for TTFT to treat recurrent GBM is reasonable, and I am not free to overturn that determination.
The prohibition on Medicare coverage for the use of TTFT to treat recurrent GBM is reasonable and valid.
Scott Anderson Administrative Law Judge
1. An AP is a Medicare beneficiary, or his or her estate, who challenges a provision of an LCD that directs the denial of Medicare coverage for a needed health care item or service. 42 U.S.C. § 1395ff(f)(2)(A)(i), (5); 42 C.F.R. §§ 426.110 (definitions of Aggrieved party and Party), 426.320(a). On March 5, 2021, the AP’s representative filed notice that the AP passed away and that the AP’s estate authorized the present challenge to the LCD to continue. Therefore, the AP’s estate is substituted as a party in this case. 68 Fed. Reg. 63,692, 63,696 (Nov. 7, 2003) (“We have revised the final rule to permit the estate of a beneficiary, as a successor in interest, to continue a challenge in those cases where the aggrieved party received the service and filed a timely complaint prior to death.”). For privacy, this decision does not identify the AP.
- back to note 1 2. At the time the AP filed the Complaint, L34823 categorically prohibited coverage for TTFT. However, shortly before the filing of the Complaint, revisions to L34823 were published to allow coverage for TTFT when used to treat newly diagnosed GBM. The revisions did not become effective until after the AP filed the Complaint. Because coverage to treat recurrent GBM is still prohibited, the AP’s Complaint remained valid for adjudication. 42 C.F.R. § 426.420(e)(2); see Tumor Treatment Field Therapy LCD ID No. L34823, ALJ Ruling No. 2020-12 at 5 (HHS CRD June 17, 2020).
- back to note 2 3. During the hearing, I indicated that I would address these matters more fully in my decision. I did so in the decision for the case docketed under C-20-331. See Tumor Treatment Field Therapy LCD ID No. L34823, DAB CR5902 at 6-13 (2021). I incorporate that discussion into this decision.
- back to note 3 4. A. Ex. 6 is incorrectly marked as A. Ex. 34.
- back to note 4 5. The AP’s Complaint expressly references the FDA approval for TTFT to treat GBM in 2011 and 2015. As discussed earlier in this decision, in 2011 the FDA approved TTFT as a monotherapy for treating recurrent GBM. A. Ex. 5 at 1. In 2015, the FDA approved TTFT with chemotherapy as a treatment for newly diagnosed GBM. A. Ex. 6 at 1. Although the AP references a medical article indicating life expectancy for patients who received TTFT plus chemotherapy after a first recurrence (A. Br. at 1 n.5), TTFT under those circumstances is not approved by the FDA.
- back to note 5 6. Noridian has taken the position that CMS guidance provides a hierarchy of evidence that either precludes or limits the importance of clinical evidence. N. Br. at 3. In C-20-331, I ruled that the Secretary expressly rejected the concept of a hierarchy of evidence when promulgating the regulations for the review of LCDs and that scientific and clinical evidence both needed to be considered on their merits. See Tumor Treatment Field Therapy, DAB CR5902 at 44-50. I adopt that interpretation for this case as well and have considered both scientific and clinical evidence in this case. Regardless as to what Noridian considered when establishing the challenged provision in L34823, my review includes all evidence admitted to the record in this proceeding, in addition to the LCD record. 42 C.F.R. § 426.458(a).
- back to note 6