Medical Device Daily Associate Managing Editor

A top federal medical official overruled the unanimous opinion of his scientific staff when he decided last year to approve a pacemaker-like device to treat persistent depression, a Senate committee report charged last week.

The report charged that the device, the surgically implanted Vagus Nerve Stimulation (VNS) system made by Cyberonics (Houston), had not proved effective against depression in its only clinical trial for treatment of that illness. As a result, scientists at the FDA repeatedly and unanimously recommended rejecting the application of the company to sell it as such a treatment, said the report, written by the staff of the Senate Finance Committee.

The agency's stated reasons for rejecting the approval included worsening depression, potential biases stemming from a non-randomized control and an inability to distinguish one-year VNS effects from placebo and concomitant treatment effects. That rejection marked the first time the agency had rejected an expedited review premarket approval supplement after a panel recommendation to approve such a device.

But Dr. Daniel Schultz, director of the Center for Devices and Radiological Health (CDRH) at the FDA, kept moving the application along and eventually decided to approve it, the report said.

The report said Schultz approved the Cyberonics application over objections from more than 20 agency scientists, medical officers and management staff. FDA reviewers saw Cyberonics' data as “weak,“ the report said.

Schultz's approval followed the backing of the FDA's Neurological Devices Panel, which voted its recommendation to approve the depression indication 5-2 back in 2004 (Medical Device Daily, June 17, 2004). Still, the Senate committee, which for two years has been investigating the decision-making processes at the FDA, could find no previous instance in which the director of the CDRH had approved a device in the face of unanimous opposition from staff scientists and administrators beneath him, the report said.

The VNS system is surgically implanted in the upper chest, and its wires are threaded into the neck. Batteries in the device stimulate a nerve leading to the brain.

The device has been approved since 1997 for the treatment of epilepsy in some patients. Common side effects include voice alteration, increased cough, shortness of breath, neck pain and difficulty swallowing. The device also has been linked to rare reports of death, heart problems and vocal cord paralysis.

“Instead of relying on the comprehensive scientific evaluation of its scientists and medical officers, it appears that the FDA lowered its threshold for evidence of effectiveness,“ the report said.

Sen. Charles Grassley (R-Iowa), the Senate Finance Committee chairman and an outspoken critic of the FDA, questioned the product's approval Thursday during a speech on the Senate floor.

“I am greatly concerned the FDA standard for approval may not have been met here, and if that's the case it raises further difficult questions about whether Medicare or Medicaid dollars should be used to pay for this device now,“ he said.

Grassley, whose committee oversees the Medicaid and Medicare healthcare programs, said he worried the device may not meet the usual FDA criteria for safety and effectiveness. He also said that the agency should have made the internal dissent public.

“The FDA has limited the kind and quality of information publicly available to patients and their doctors and deprived them of information that may be relevant to their own risk-benefit analysis,“ the report said.

In its conclusion, the report also said that the level of scientific dissent within the FDA regarding the effectiveness of the VNS therapy system raises concerns about the use of taxpayer dollars to pay for a $25,000 device.

“Whether or not a device is effective is not only a major public safety concern, but also a very important financial concern,“ the report said.

Susan Bro, an FDA spokeswoman, told The New York Times that the device had been approved because many people with persistent depression “are otherwise on their way to institutionalization, because of the seriousness of their illness.“

Bro said top officials did “occasionally overrule staff recommendations after assessing all data, expert opinion and medical need.“

In a scathing 1,900-word written response, Skip Cummins, Cyberonics' chairman and CEO, said the investigators who wrote the report had failed to interview many experts on serious depression.

Cummins said his company's device was “the only safe and effective treatment option ever specifically developed, studied, FDA-approved and fully informatively labeled for the treatment of chronic or recurrent treatment-resistant depression.“

“[That report] basically just documents in gory detail that those with the least experience and least knowledge and those who are least willing to apply the appropriate laws, regulations and precedents unanimously agreed that VNS shouldn't be approved,“ Cummins told Medical Device Daily.

As for Schultz, Cummins commended him for doing his job. “[Schultz] advised us on what our options were, we pursued the options, we submitted the additional information, he subjected that additional information – in the form of a PMA supplement amendment – to a very rigorous review and he listened to experts in the field.“

He said he would not apologize that the studies that led to VNS approval for treatment-resistant depression (TRD) were “specifically different than your typical eight- to 10-week, placebo-controlled acute drug studies, where you're just challenging a drug to beat placebo in non-resistant patients. That is not science as defined by the need of Americans with TRD.“

As a condition of its approval, the FDA is requiring Cyberonics to conduct a 450-patient, postmarket dosing study and a 1,000-patient, five-year outcome registry, standards that antidepressant drugs are not held to, Cummins noted.

He also indicated that this latest report was just one in a long list of problems for the company stemming from the public's misunderstanding of what just exactly TRD is.

“One of the many challenges that Cyberonics has continuously faced during its eight-year research program to develop the first safe and effective treatment option for Americans with chronic or recurrent treatment-resistant depression is that very few Americans understand TRD and can distinguish it from depression,“ Cummins said.

“Psychiatrists who specialize in TRD and the treatments commonly used to treat patients with TRD, such as ECT, know it and the patients whose lives have been ruined by TRD and their families know it. Most others, including many FDA drug and device regulators, politicians, third-party payers and the general public, know little about TRD and cannot distinguish TRD as an illness from depression.“

Cummins said he believes that ultimately the company will get a positive national coverage policy decision from the Centers for Medicare & Medicaid Services (Baltimore) national coverage policy decision for use of the VNS therapy in TRD patients.

“What's going to carry that day and argument is not a Senate Finance Committee report, not statements by Sen. Grassley – not statements by inexperienced, underqualified FDA junior bureaucrats. What's going to carry the day is the data and the opinions of experts.“

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