August 23, 2006
Lurie, P and Stine, N: “Responding to three articles regarding vagus nerve stimulation (VNS) for Depression,” Biological Psychiatry, December 15, 2006; 60:12, 1382.
To the Editor:
Three studies published in the September 1 issue represent the primary data that formed the basis for the FDA’s approval of Cyberonics’ vagus nerve stimulation (VNS) device for treatment-resistant depression. Together, they demonstrate the low threshold for approval employed by the agency.
The authors of the first study (Rush et al 2005a), the most rigorously designed and the only randomized controlled trial of the three, conclude that their study “did not yield definitive evidence of short-term efficacy.” A more accurate statement would be that it “failed to provide any evidence of efficacy by the usual yardsticks” (p < .05 for the primary outcome). Even though there was no significant difference between active VNS and a group with VNS implanted but not turned on for the primary outcome and in nine of ten secondary analyses, the authors selected only the one statistically significant finding to appear alongside the primary outcome in their figure. In the second study (Rush et al 2005b), a 12-month, open-label, uncontrolled follow-up to the first study, all patients received stimulation. The authors appropriately conclude that comparative long-term data are needed.
The third study (George et al 2005) simply added a nonrandomized control group after the first two studies were inconclusive; the authors note that it was only conducted after the first study was negative and the second unconvincing, and admit that the comparison arm “had not originally been intended to serve as the [control]; it was intended to describe health care costs.” Nonetheless, this study was evidently the principal basis for the FDA’s approval. However, the lack of randomization and unblinded nature of the comparison group, combined with the questionable use of the only positive (secondary) outcome measure from the first trial as the primary outcome variable in the third trial, make this comparison less than rigorous. The subjective nature of the outcome variables, the tendency of patients with relapsing conditions to improve after they enter studies because they enroll at their worst, and the placebo effect all heighten the need for a randomized control.
Further, the authors make the claim that the effects of there being different study sites for the VNS and control arms and concomitant antidepressant treatment changes (not permitted in the randomized trial, but permitted in the third study) were negligible. However, they fail to mention that an analysis mandated by the FDA looked at both of these factors together and found that in data censored for medication changes and restricted to overlapping sites VNS had no statistically significant impact upon primary or secondary endpoints. The FDA’s statistical review repeatedly deemed aspects of this non-randomized comparison “questionable,” and concluded that “it is unclear whether the effectiveness claim … has been demonstrated” (Food and Drug Administration 2004).
On August 12, 2004, scientists at the FDA overruled a 5-2 Advisory Committee vote and declared VNS “not approvable” (Cyberonics 2004). In a surprising move, after apparently receiving more data from the nonrandomized third study, the FDA mysteriously reversed itself on February 2, 2005 and declared the device approvable (Cyberonics 2005). An investigation by the Senate Finance Committee found that all of the more than 20 FDA officials contacted by the Committee opposed the approval of VNS for depression. The director of the device bureau overrode them all (United States Senate Committee on Finance 2006).
It is disturbing that the FDA considers these data adequate grounds for approving a new device, particularly when it would never approve a drug for depression on these grounds. We recommend that physicians take the gross inadequacy of these data into account before prescribing VNS to their patients.
Public Citizen’s Health Research Group
Public Citizen’s Health Research Group
Cyberonics, Inc. (2004): FDA ignores panel recommendation and determines cyberonics’ expedited review depression PMA-supplement not approvable. Press Release, August 12, 2004. Available at: http://www.cyberonics.com/PressRelease_detail.asp?ID=DAE078D5-911D-47C7
-991F-7B38DB094DCC. Accessed September 20, 2005.
Cyberonics, Inc. (2005): FDA deems cyberonics’ VNS therapy system approvable for chronic or recurrent treatment-resistant depression (TRD). Press Release, February 2, 2005. Available at http://www.cyberonics.com/PressRelease_detail.asp?ID=E7C61130-4364-4372
-9B66-C6B7E33CC895. Accessed April 1, 2005.
Food and Drug Administration (2004): Final Statistical Summary Review for PMA P970003/S50 (Original and Various Amendments), Vagus Nerve Stimulator (VNS) Therapy System for Depression, Cyberonics, Inc. Available at http://www.fda.gov/ohrms/dockets/ac/04/briefing/4047b1.htm. Accessed September 20, 2005.
George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, et al (2005): A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry 58:364–373.
Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan SK, Davis SM, et al (2005a): Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry 58:347–354.
Rush AJ, Sackeim HA, Marangell LB, George MS, Brannan SK, Davis SM, et al (2005b): Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry 58:355–363.
United States Senate Committee on Finance (2006): Review of the FDA’s approval process for the vagus nerve stimulation therapy system for treatment-resistant depression. February 2006. Available at https://www.citizen.org/sites/default/files/02_2006_report.pdf.