Cyberonics stunned by not approvable letter

Cyberonics, from Houston, TX, has been stunned by a not-approvable letter from the FDA. The FDA wrote that 'notwithstanding their (the Neurological Devices Panel's) recommendation, we regret to inform you that (your) PMA-Supplement, absent additional information, must be considered not approvable.'

FDA's stated reasons included worsening depression, potential biases stemming from a non-randomised control and an inability to distinguish one-year VNS effects from placebo and concomitant treatment effects.

'We are shocked and bewildered by FDA's inexplicable decision to ignore its expert Advisory Panel's recommendation,' thundered Robert Cummins, Cyberonics' chairman of the board and chief executive officer.

'FDA's Center for Neurological and Restorative Devices had no prior depression experience before the VNS submission and as a result, FDA deputised four of the seven voting members of its expert Advisory Panel. All four of these deputised members were psychiatrists, including three who also serve on the antidepressant drug Advisory Panel. All of the reasons cited in yesterday's not-approvable letter were addressed at the Panel meeting on June 15 prior to the Panel's vote recommending approval.

FDA has now chosen inexplicably to ignore not only the recommendation of its panel of experts, but also the strong recommendations of numerous psychiatric thought leaders and the compelling testimony and needs of people with treatment-resistant depression who today have no long-term treatment for their lifelong and life-threatening illness.'

'Depression is the leading cause of disability for women in the US and every month an estimated 2,500 Americans with treatment-resistant depression commit suicide, not attempt, actually commit suicide.' continued Mr Cummins. 'The VNS studies targeted patients with extreme treatment-resistant depression that are excluded from other antidepressant studies, including studies of electro-convulsive therapy (ECT). Despite the extreme treatment resistance of the VNS patients, after one year of treatment, one out of six were depression free and 56% had realised a meaningful benefit. Most importantly, approximately 70% of the VNS responders sustained their response out to two years.

By comparison, an active control group of similarly resistant patients treated for one year with currently available treatments (no VNS) predictably showed minimal response and no sustained response. Once again, FDA's specially chosen Advisory Panel of experts considered this one-year data to be compelling and sufficient to recommend approval.'

'This is the first Expedited Review PMA-Supplement in history with a favorable Panel recommendation that has been determined by FDA to be not approvable,' concluded Mr. Cummins. 'In its letter, FDA seems to be rationalising its unprecedented decision based on FDA's seemingly arbitrary preference for a randomised controlled study that is neither required by the regulations nor the norm in the majority of device approval precedents reported by FDA in a recent CDRH Staff College Report.

Apparently, FDA believes that the absence of a randomised control is adequate justification to leave 4.4m Americans at significant suicide risk without a treatment option. FDA's expert Advisory Panel, people living with treatment-resistant depression, psychiatric thought leaders, payers and all of us at Cyberonics strongly disagree.'

'We are in the process of arranging a meeting with senior FDA management to discuss their letter,' commented David Wise, Cyberonics' vice president and general counsel. 'We are actively considering all regulatory and legal options, including those successfully employed by other device companies to reverse inexplicable decisions and obtain PMA approvals.'

VNS therapy and Cyberonics

Cyberonics designs, develops and markets medical devices for the long-term treatment of epilepsy and other chronic neurological disorders using a unique therapy, vagus nerve stimulation (VNS). Stimulation is delivered by the VNS Therapy System, an implantable generator similar to a cardiac pacemaker. The VNS Therapy System delivers preprogrammed intermittent mild electrical pulses to the vagus nerve 24 hours a day. The Company's initial market is epilepsy, which is characterised by recurrent seizures. Epilepsy is the second most prevalent neurological disorder. The Cyberonics VNS Therapy System was approved by the FDA on July 16, 1997 for use as an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications. The VNS Therapy System is also approved for sale as a treatment for epilepsy in all the member countries of the European Economic Area, Canada, Australia and other markets. To date, more than 27,000 epilepsy patients in 24 countries have accumulated over 79,000 patient years of experience using VNS Therapy. The VNS Therapy System is approved for sale in the European Economic Area and in Canada as a treatment for depression in patients with treatment-resistant or treatment-intolerant major depressive episodes including unipolar depression and bipolar disorder (manic depression). VNS Therapy is at various levels of investigational clinical study as a potential treatment for depression, anxiety disorders, Alzheimer's disease, and chronic headache/migraine.