FDA Panel Narrowly Backs NovoTTF Brain Tumor Device

Janis C. Kelly

March 18, 2011

March 18, 2010 — Yesterday, a US Food and Drug Administration (FDA) advisory panel voted narrowly to recommend approval of a novel treatment for recurrent glioblastoma multiforme (GBM), despite the fact that the device, the NovoTTF-100A, failed to meet the primary efficacy end point (overall survival) in the pivotal trial meant to establish superiority over best recurrent GBM salvage chemotherapy.

The Neurological Devices Panel of the Medical Devices Advisory Committee action was motivated by the relative safety of NovoTTF, compared with the devastating adverse effects of GBM chemotherapy, and by the possibility that the device might offer a dramatically better quality of life (compared with chemotherapy) for patients with recurrent GBM, whose life expectancy is measured in months rather than years.

New Approach to Brain Tumor Control

NovoTTF device

NovoTTF is a completely new approach to brain tumor control. The portable battery-powered home use device sets up a grid of low-intensity alternating electric fields that scramble the microtubules of any brain cell undergoing mitosis. The result is that as tumor cells begin to divide, they are destroyed. Most brain cells are nondividing and so are not destroyed by the NovoTTF.

NovoTTF consists of a thin helmet-like array of electrodes fixed to the scalp with tape and connected to a 6-pound battery-powered signal generator that the patient carries around in a tote bag. NovoTTF is meant to be used nearly continuously (for at least 18 hours per day) to bathe the tumor in a mild 200 mHz electric field. The most common adverse effect in clinical trials was a mild scalp rash that responded to cortisone cream. Notably, NovoTTF produces no heating of the tissues.

To use the device, the patient shaves his or her scalp, attaches the electrodes, and turns on the laptop-like generator. NovoTTF can be easily removed for bathing, swimming, or sports activity, and the rechargeable batteries have to be changed about every 4 hours.

At the FDA hearing, Eilon Kirson, MD, PhD, head of research and development at the closely held Israeli company NovoCure, said that the majority of patients in the trial actually used the device for about 20 hours per day. According to Dr. Kirson, at least 4 months of use is required before the therapeutic effect begins, and ongoing use is required to sustain the effect.

NovoCure was asking for NovoTTF approval "as monotherapy, after surgical and radiation options have been exhausted, in place of standard medical therapy" for the treatment of histologically or radiologically confirmed GBM after recurrence in the supratentorial region of the brain. In support of that application, NovoCure submitted data from a pivotal phase 3 trial — an open-label randomized controlled study that compared NovoTTF with "best standard care," defined in the protocol as including temozolomide (Temodar), nitrosoureas, procarbazine, PCV (procarbazine, lomustine, and vincristine), and platinum-based regimens. Later, bevacizumab (Avastin), irinotecan (Camptosar), and etoposide (VP-16, Vepesid) were added to the best standard care list.

Based on a 10-patient pilot study of NovoTTF that reported a median survival of more than 14 months (nearly twice what would be expected with effective chemotherapy), the company designed the pivotal phase 3 trial, which involved 237 patients, to show that NovoTTF produced superior overall survival, compared with best standard care.

Results from this pivotal trial have already been reported at medical meetings, most recently in December 2010 at the Society for Neuro-Oncology annual meeting in Montreal, Quebec, where experts reacted to the findings both with enthusiasm and antagonism, as reported at the time by Medscape Medical News.

No Difference in Overall Survival

The results from the trial show no significant difference in overall survival, which was 6.3 months with NovoTTF and 6.4 months with best standard care.

The NovoCure presenters argued that this made NovoTTF and best standard salvage chemotherapy at least equivalent in efficacy, but FDA statistician JianXiou "Chorge" Chu, PhD, shot that down. Dr. Chu pointed out that the study was designed as a superiority trial, and that lack of superiority cannot be interpreted as equivalence, which would have required more patients and a different trial design.

In support of the late decision to aim for a noninferiority claim, the sponsor presented several post hoc analyses in addition to the standard intention-to-treat analysis. FDA analysts and several of the panel members were critical of this strategy. It rested in part on a per-protocol analysis that required at least 4 weeks of NovoTTF use for a patient to be included in the treatment group, but only a single chemotherapy dose for inclusion in the best standard care group, potentially biasing the data.

On the question of whether the data showed NovoTTF to be effective for the treatment of recurrent GBM, the panel split 6 to 6. The tie was resolved by chair Robert W. Hurst, MD, from Pennsylvania University Hospital, in Philadelphia, who voted "yes".

Safety Issues Straightforward

The safety issues were more straightforward. The panel voted unanimously that the data showed NovoTTF to be safe for use in this patient population. However, psychiatry expert Sarah H. Lisanby, MD, from Duke University, in Durham, North Carolina, expressed concern about the adverse-effect data showing more central nervous system, seizure, and neuropsychiatric disorders in the NovoTTF group, although the difference was not statistically significant.

Company researchers described the NovoTTF electrical field as having no stimulatory effects on nerve or muscle tissue, but Dr. Lisanby noted that an electrical stimulus too weak to trigger neural activity might still have an adverse effect on seizure occurrence and/or resolution. Dr. Lisanby was also concerned that no formal neurocognitive assessments were done. Quality-of-life conclusions were based on a questionnaire developed by the European Organisation for Research and Treatment of Cancer (EORTC), which has not been validated in this population.

The panel asked for a rewrite of the proposed labeling, noting that the current proposal is that NovoTTF would be approved for the monotherapy of recurrent GBM once surgery and radiation had been exhausted, but does not specify that patients with recurrent GBM would still be candidates for chemotherapy.

The panel voted 7 to 3 (with 2 abstentions) that overall, the benefits of NovoTTF outweigh the risks in recurrent GBM.

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