The Neurological Devices Panel (the Panel) met on Friday, January 26, 2007 to review the information in a premarket notification (510(k)) submission for the Neuronetics, Inc., NeuroStar™ System, K061053. The proposed indication for use for the NeuroStar System, a repetitive transcranial magnetic stimulation device, is for the treatment of major depressive disorder (MDD). The Panel was asked to determine if the risk to benefit profile of the NeuroStar™ System was comparable to the risk to benefit profile of predicate electroconvulsive therapy (ECT) devices. The Panel was not asked for a recommendation regarding the regulatory determination of substantial equivalence for this 510(k) submission.
The safety and effectiveness of the NeuroStar™ System was evaluated in a clinical trial consisting of three phases identified as Study 01, Study 02 and Study 03. Study 01 was designed as a multi-center, randomized, parallel-group, sham-controlled clinical trial to demonstrate the safety and effectiveness of the device for subjects diagnosed with DSM-IV defined major depression, which did not benefit from prior adequate treatment with oral antidepressants during their current major depressive episode. Study 02 was an open-label clinical phase for subjects who had received either active treatment or sham treatment in Study 01. Subjects in Study 02 were considered non-responders based on pre-defined criteria for response to treatment in Study 01. Study 03 was an open-label, uncontrolled clinical trial to demonstrate the durability of rTMS treatments. Subjects from Study 01 and/or Study 02, who were considered responders, based on pre-defined success criteria, were followed for six months while receiving oral antidepressant monotherapy.
The sponsor presented their results of the three study groups to the Panel. Then FDA presented their analysis of the data. The Panel had a general discussion of the information they had reviewed prior to the meeting and of the presentations they had heard. They then responded to FDA’s questions. The following summarizes the Panel’s responses to FDA’s questions:
1. Please discuss the results for the primary effectiveness endpoint (MADRS at Week 4), including the statistical and clinical significance of:a. The results from the pre-specified per-protocol analysis; and
The Panel’s consensus was that the efficacy was not established; some stated that the device’s effectiveness was “small,” “borderline,” “marginal” and “of questionable clinical significance.” The Study 01 endpoint with a p value of 0.057 per se was not considered a fatal flaw in the study analysis. The Panel did not believe that clinical significance was demonstrated with these results.
b. The sponsor’s post-hoc adjustment and the results obtained.
Considering that the magnitude of the effect size, the Panel thought that post-hoc analysis was problematic.
2. The results for multiple secondary outcome measures were provided in the marketing submission. These included various analyses for several different clinician-rated and patient-rated severity scales. Please discuss:a. The scientific validity of analyzing secondary outcomes as a measure of device effectiveness given that the per-protocol primary effectiveness endpoint did not achieve statistical significance and how the need to correct for multiplicity testing should be addressed;
The Panel agreed that when a p-value is of borderline significance, it may be appropriate to look at secondary endpoints. However, there was no prespecified multiplicity adjustment, and various post-hoc statistical methods to examine multiplicity effects gave varying results of limited clinical relevance. Examination of 13 of 26 endpoints in the multiplicity analysis when the p-value for the primary endpoint is known is problematic.
b. The clinical significance and consistency among the secondary effectiveness endpoints at Week 4; and
The Panel repeated their responses for question 2a. Even without multiplicity adjustment, the variation in results made interpretation of the secondary endpoints difficult and problematic for the panel. In general, the panel believed that the analyses of the secondary effectiveness endpoints did not contribute significant information to help establish the effectiveness of the device.
c. The relative importance of clinician-rated versus patient-rated scales when assessing depression symptoms and responses to therapy.
The Panel stated that clinician-rated were more appropriate than patient-related scales in depression studies. They stated that patient-rated scales were important, but they often lagged behind clinician-rated scales.
3. Given that more than half of the evaluable population (N=156) exited Study 01 between Weeks 4 and 6, please discuss the effectiveness results from Week 6 and how, if at all, they contribute to the interpretation of the Week 4 data for the NeuroStar™ System.
The Panel stated that there were too many non-random dropouts to reliably interpret these results. The Panel’s consensus was that the Week 6 data was of limited value and did not provide supportive data for establishing effectiveness.
4. The sponsor conducted several analyses to assess difference in application site pain among treatment groups and the integrity of the study blind. Considering the information provided, please discuss the issue of blinding and any potential impact on the clinical data and results.
The Panel stated the clinical trial was well designed. The Panel agreed that unblinding was greater in the active group, and considering the magnitude of the effect size, it may have influenced the study results.
5. Given that both Study 02 and Study 03 were open label and had missing data, please discuss any conclusions that can be drawn from these studies.
The Panel indicated that the Study 02 and Study 03 results did not provide significant information in support of device effectiveness but that they did provide additional safety information.
6. Please discuss the safety results reported in the clinical trial and whether they raise any concerns.
In general, the Panel thought the device was reasonably safe.
7. Based on the trial design treatment with this device would require that subjects be withdrawn from antidepressant medications prior to treatment with the device. Please comment on whether removing medication therapy while instituting device therapy poses any clinical safety concerns.
The Panel did not reach a consensus on the safety of the NeuroStar™ System treatment when used with concomitant antidepressant therapy. Some panel members expressed concern with antidepressant medication withdrawal during treatment with this device.
8. The mean number of ATHF level 3 exposures for subjects enrolled into Study 01 was 1.6. Over 50 % of the subjects met the criteria for ATHF group1, i.e., had failed only one antidepressant medication during the current episode. Please discuss your interpretation of the severity of the depressive episode of subjects enrolled in Study 01.
The Panel stated that when considering an individual patient, the severity of an episode of depression and the degree of treatment resistance are not the same. The Panel believed the study was not designed to stratify the results by such categories. They stated that although the studied patient population may be less severely depressed than ECT candidates, in general there were no major differences.
9. The sponsor has submitted the following Indications for Use (IFU) statement:“The treatment of Major Depressive Disorder (MDD).”
Considering that the IFU should reflect the population that was studied, please discuss whether the sponsor’s clinical trial supports this general IFU. If not, please comment on the population which might be best considered for treatment with this device, based on the specific population enrolled and evaluated in the clinical trial.
The Panel thought that if the device was to be marketed, the population should be limited to the patient population that was studied, i.e., patients who had not received benefit from at least one medication in the current episode. In addition, it should not be indicated for subjects with psychoses.
10. Taking into account your day’s deliberations and your responses to the prior FDA questions please discuss your interpretation of the overall risk-to-benefit profile for the NeuroStar™ System for the proposed indication for use as well as how that profile compares to that of ECT devices.
The Panel believed that the study data for the NeuroStar™ System did not establish a risk to benefit profile that was comparable to the risk to benefit profile of the predicate device, ECT, because effectiveness had not been demonstrated. The Panel agreed that the safety profile of the device was better than of ECT devices. The Panel believed an additional study would be necessary to establish effectiveness. Some Panel members believed that the device showed a signal of effectiveness and that it would be worth pursuing another study to demonstrate effectiveness.
The Panel also heard and discussed Conditions of Approval Study Reports for two recently approved neurological device premarket approval (PMA) applications: Confluent Surgical, Inc.’s Dural Sealant System, for use as an adjunct to sutured dural repair during cranial surgery to provide watertight closure, and Cyberonics, Inc.’s VNS Therapy System, for treatment-resistant chronic or recurrent depression. The sponsors of these two devices presented progress reports on their studies followed by FDA presentations. The Panel then commented on these presentations. They asked for clarification on study issues, and expressed some concerns about publicly disseminating the early (partial) results of the studies.
The Panel membership for this meeting consisted of three neurologists, an interventional neuroradiologist, a statistician, four psychiatrists, a statistician, a consumer representative, and an industry representative.
Contact: Janet L. Scudiero, Executive Secretary, at 240-276-3737 or Janet.Scudiero@fda.hhs.gov.
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