Project coordinator slams VNS study - Part 1
Vagus nerve stimulation, or VNS, is marketed as a treatment for severe depression.Flickr.com/fakeelvis
February 27, 2012
The device manufacturer swears it’s effective. The FDA approved it. But is there any evidence for vagus nerve stimulation (VNS) for treatment-resistant depression?
Susan Ricketts contacted me after reading “Vagus nerve stimulation (VNS) for depression: Does it work?” on this site. Now, in an exclusive interview, Ricketts describes her experience as Project Coordinator on the D-02 clinical trial of VNS for depression. It was the single randomized, controlled trial submitted to the FDA, but one Ricketts says was so poorly managed she ended up walking away from the job, minus a paycheck, but with integrity intact.
Excerpts from the interview begin in Part 2 of this article; first, some background information:
What is vagus nerve stimulation?
In VNS, a device is surgically implanted in the patient’s neck and connected to the vagus nerve. When switched on, the device shoots electrical impulses through that nerve and into the brain.
VNS has been shown to be effective in controlling seizures in severe cases of epilepsy, but there has never been solid evidence it works on depression.
Even so, it was approved by the FDA for treatment-resistant depression in 2005, over loud objections from FDA staff and the consumer group Public Citizen, among others. The approval process raised so many red flags it was the subject of a U.S. Senate investigation.
Many people think VNS is a radical but effective last-ditch treatment for depression that responds to nothing else. That belief is due largely to long-term and continuing marketing efforts by Cyberonics, Inc., the device manufacturer.
Cyberonics has managed to get its own press releases and a few vaguely scientific studies onto high-profile health websites. Unfortunately, that’s where many people go for health information, not realizing these sites are often used as free advertising space by pharmaceutical and device manufacturers with a serious financial stake in moving product off the shelves.
Understanding scientific studies
To understand why the evidence falls short, it’s important to know a few buzzwords.
In a randomized, controlled clinical trial, scientists compare the effects of a treatment on two randomly populated groups of patients, one group receiving the treatment being tested and the other group, called a control group, not getting the treatment. The control group receives a placebo or “sugar pill” (in the case of VNS, an inactive device), because patients who know whether they are being treated or not might be subject to the “placebo effect” and show improvement (or not) due to their own expectations.
Researchers try to eliminate every possible variable that could influence the results other than the treatment itself.
To envision this, imagine you are trying to find out if orange popsicles melt faster than green popsicles. You lay the popsicles out in two groups and observe them, and note that the orange popsicles do, in fact, melt much faster than green ones. Then you realize the group of orange popsicles was in direct sunlight. Oops! That’s an example of a variable affecting your results. Good thing you didn’t rush an article to the scientific journals.
Most VNS trials for depression were decidedly of the hot-popsicle type. In one study, for instance, subjects were allowed to use treatments other than VNS during the study, and to switch between the additional treatments. Even if the results of such a trial showed depression was relieved, it would be impossible to tell whether it was due to VNS, the add-on treatment, the combination – or pure chance.
Behind the scenes
Four years after VNS’s approval for depression, a report to Oregon Health & Science University’s Center for Evidence Based Policy found only one randomized, controlled study in the literature, and that study showed no benefit for VNS.
As it happens, that single trial, the D-02 study, was the one Susan Ricketts worked on. What she saw shocked her.
Project coordinator slams VNS study – Part 2
Depression affects approximately 121 million people worldwide, according to the World Health Organization.Flickr.com/sacks08
February 27, 2012
When the FDA evaluated clinical trials on vagus nerve stimulation (VNS) for depression, they were presented with written reports. Susan Ricketts, on the other hand, was behind the scenes. She was Project Coordinator on the D-02 clinical trial, the only study rated above “poor” in a report prepared for Oregon Health & Science University.
Ricketts had worked on numerous studies previously, and she was unprepared for Cyberonics’ lack of professionalism.
Susan Ricketts: “When I started on the D-02 VNS trial, I’d had long-term research jobs, including eght years at Dartmouth and two and a half years at Regents Hospital. But I lasted six months [on the VNS trial], because it was the most poorly run trial I’ve ever seen.
“I was the Project Coordinator. The patients had already been recruited, and randomly assigned to receive the VNS implant. The implants were either turned on or turned off during the course of the trial, and we followed their progress and symptoms throughout. I was the unblinded person on the trial, which means I was the one who knew whether a person's device was turned on or turned off. I actually manipulated the software to turn it on or off.
“One of the first things that happened was when I went in, in my estimation the records that patients had filed were very disorganized, in disarray. So one of my first goals was to get the records in order.
"In a clinical trial – let’s say someone’s having a symptom, even a cold or flu symptom – you have to follow those symptoms very carefully, and track pain, severity, how long it lasted – because that’s how you track side effects, or adverse effects.
“It casts doubt on all clinical trials, all drug trials, all device trials.” – Project Coordinator Susan Ricketts
“Because they’d already been through three project coordinators, the tracking of patients’ histories throughout the trial was really atrocious. I called up patients to verify information; I went back with patients through their charts to make sure all the information was complete.
“The principal investigator should be on top of these things, and certainly the people from [device manufacturer] Cyberonics, who come through and review the records – they should have been on top of this. It never should have been as bad as what I saw.
“Another thing, during a study when the language in a consent form changes, you have to make sure that every person in the study reads that new consent form and signs off on it. That was not being done consistently.
“Cyberonics should have been there on a regular basis, making sure those records were clean and complete, and making sure those consent forms were signed.”
Q. Because ideally, they want an absolutely flawless study ?
“Exactly! They’re having to report to the FDA. And my feeling was, if the FDA had come in and done an audit, they would have failed it."
Q. Reading about the FDA approval, there were reports that Cyberonics people were bullying the FDA. Did you see any of that behavior?
“That’s actually what brought me to your article. And those later reports – it just brought back that feeling, that this was a company that was literally shoving its way through approval. Cyberonics was a bully; the people that worked for them were bullies.”
Q. What were your concerns regarding the integrity of results?
“Before I left, when I made the decision to leave, I just kind of looked at the records and reviewed people’s scores.
“To make [people with depression] think VNS is scientifically proven to help them? It’s an atrocity.” – Project Coordinator Susan Ricketts
“I could see, even without a statistical analysis – and by the way, I do have training in statistical analysis – you could tell that, during the 12-week trial, there wasn’t any difference in depression scores between people who had the device turned on, or not. The 12-week efficacy study was just not going to show any results.” (Ricketts was right.)
“I was trained in research, worked in research all my life, and I have great respect for the way people conduct research. And to see Cyberonics get away with this – it just casts doubt on all clinical trials, all drug trials, all device trials – everything’s suspect when something like this goes through with very little scientific evidence."
Q. Cyberonics continues even now to say their device has been proven to be a success.
“I think there’s a great bias against psychiatry and mental health. We wouldn’t be pushing a chemotherapy drug that didn’t work; we wouldn’t be pushing a heart stent that didn’t work.
“We’re talking about people who have treatment-resistant depression. They’ve failed at least two other methods, they've tried drugs, psychotherapy, even ECT.
"These are people for whom we should have tremendous compassion. And to make them think that this device is going to help them? And that it’s scientifically proven to help them? It’s an atrocity."