BLOGSCAN - Media Hype of the Vagus Nerve Stimulator for Depression

A post on the Schwitzer Health News blog contrasted how Medicare decided that Cyberonics' vagus nerve stimulator did not have sufficient evidence supporting its use for depression versus how much hype the device has recently received from the news media.

Post Title → BLOGSCAN - Media Hype of the Vagus Nerve Stimulator for Depression

Money and Medical Journals

The past month has seen exposés of authors who failed to disclose financial interests in JAMA and in Neuropsychopharmacology, the official journal of the American College of Neuropsychopharmacology (ACNP). As noted today by Catherine DeAngelis, editor of JAMA, the press gave wide exposure to these incidents. The specifics of the ACNP incident went well beyond a procedural failure to disclose. The publication in question was a major review of a new treatment for refractory depression, known as vagus nerve stimulation (VNS). Evidence for the efficacy of this treatment is modest at best: when the FDA approved it recently for the depression indication, the decision was made over the strenuous objections of FDA staffers, and it triggered an inquiry by Sen. Charles Grassley in the Senate Finance Committee, which issued a scathing report on the process.

The review article, published in the July 2006 issue of Neuropsychopharmacology, dealt with the purported mechanism of action of VNS in depression. The substantive ethical concerns with this publication are as follows. First, all 8 academic authors are members of the Mechanism of Action Advisory Board of the corporation that markets VNS. These affiliations were not revealed. In addition, some authors are recipients of research grants from the corporation, which also was not disclosed. Second, the article acknowledged "editorial support" from a professional writer, who acknowledged to the Wall Street Journal that she was employed by the corporation for the task of writing a first draft. Although the authors claimed they provided substantive input after the first draft, it is ethically dubious to use a hired writer for a first draft. As Drummond Rennie, past editor of BMJ, commented in Science this week, "It is very bad scientific and ethical practice to have a nonauthor write the first draft." When senior academics behave in this way, it sets a poor example for junior faculty and trainees.

Third, the review went beyond a discussion of the putative mechanism of action of VNS by summarizing the regulatory status and evidence of efficacy of this treatment. In presenting this summary, the review carefully followed the corporation's marketing message and branding language. There is no discernible difference between the corporation's press releases and the text of the review article on these topics. The review did not address the controversy surrounding the FDA approval process. In these respects, the review has the hallmarks of a ghostwritten article. As described by Leemon McHenry, who has written on conflict of interest issues in medicine, "I have ... seen contracts between the pharmaceutical companies and the ghostwriting companies with the plan of production and the budget. What is particularly interesting about these is the fact that it is clear that the company owns the manuscript until it is released to the "authors." The company's legal department reviews the manuscript and releases it at the end of the process. The first draft isn't even reviewed by the "authors." This is all internal until the second draft." It appears very likely that the VNS review was carefully screened by the corporation to ensure that the first draft was "on message" before being released to the "authors" for them to strengthen the hard science surrounding the stealth infomercial.

Fourth, the review acknowledged an "unrestricted educational grant" from the corporation. As the professional writer was already being paid by the corporation, the question arises, who was the grantee and where did the money end up? Does not this euphemism, now so common, hijack the original meaning of the term, to serve as a cover for a corporate payment to the authors?

Fifth, the lead author of the review, Charles Nemeroff, is chair of the Advisory Board for the corporation. This circumstance was not disclosed.

Sixth, the same individual is also editor-in-chief of the journal in which the review appeared, an arrangement that a recent New York Times editorial called "incestuous."

Seventh, the corporation issued a coordinated press release in early July 2006, calling attention to the newly published, favorable review article. This press release featured Charles Nemeroff shilling for the corporation's product, but it did not disclose the consultant status of Dr. Nemeroff and the other authors.

Overall, the appearance here is of a slick, coordinated, public relations-disinformation campaign in which ACNP and its journal were exploited by paid consultants of the corporation. The double non-disclosure is especially revealing. Oh, and by the way, should there be any lingering doubt about the careful planning of this incident, we should note that the corporation ordered 10,000 reprints of the article. So much for this being an independent review, conceived and executed by dispassionate and disinterested senior academic authors.

Lessons to Learn

In light of these events, here are some lessons for all concerned with quality in medical journals. First, find an editor possessed of trustworthy ethical instincts, who will respect the boundary between personal agendas and institutional priorities.

Second, create a firewall against corporate marketing tactics designed to buy influence. Chief among these is acknowledgement of an “unrestricted educational grant” from a corporation. Everybody knows this is code for a payoff to the authors. Another tactic is designation of the group as some b.s. term like “International Consensus Group for Anxiety and Depression.” It is not hard to find examples of such "key opinion leader" fictions, funded by Pharma to meet at junkets in congenial resorts with the support of “unrestricted educational grants.” Legitimate journals like Neuropsychopharmacology should not allow themselves to be co-opted by these deceptive marketing tactics.

Likewise, acknowledgement of “editorial support” should trigger some inquiry as to the exact arrangements, including who paid for it. Whenever an “unrestricted educational grant” is acknowledged, an honest broker needs to verify the money trail and auditing process. Who paid what to whom and where did the money end up? Members of ACNP would do well to insist that articles featuring these marketing tactics should be routinely rejected by Neuropsychopharmacology. Let the marketeers go to some other journal. It is a sad sign of the corruption of standards nowadays that one even needs to make these points.

Post Title → Money and Medical Journals

Won't Get Fooled Again, Again, Again

In mid-July, there were three well-publicized cases in which authors of scholarly articles in prominent medical journals failed to disclose important financial arrangements that may have affected what they wrote. In fact, each case was so well-publicized that I thought it did not need additional comment from Health Care Renewal.

The cases were:

• An article published in JAMA in February found that withdrawing anti-depressants from pregnant women was associated with relapse of depression [Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295:499-507.]. A letter published in JAMA in July revealed that "all 9 0f the physician coauthors have been paid by antidepressant manufacturers, while only 2 reported disclosures." (See coverage from the Wall Street Journal, available through the Pittsburgh Post-Gazette here.)
• An article was published in Neuropyschopharmacology in July about vagus nerve stimulation as a treatment for depression [Nemeroff CB, Mayberg HS, Krahl SE. VNS therapy in treatment-resistant depression: clinical evidence and neurobiological mechanisms. Neuropsychopharmacology 2006; 31, 1345–1355.] The Wall Street Journal discovered that eight of the article's nine authors had financial ties to Cyberonics Inc, the manufacturer of the device. The ninth author is an employee of the company, which was disclosed." (See previous post on Cyberonics here.)
• An article published in JAMA in July found an association between migraine headaches and the risk of cardiovascular disease and stroke for women [Kurth T, Gaziano JM, Cook NR et al. Migraine and the risk of cardiovascular disease in women. JAMA 2006; 296: 283-291]. The editor of JAMA then discovered that all six authors of the study had financial ties to makers of treatments for migraines or heart-related problems, but did not disclose these relationships, (see the JAMA corrections here, AP here, and PharmaGossip here.)

What has been remarkable is the editorial response to these cases in two of the US most widely-read newspapers.
By Jennifer Washburn in the Los Angeles Times,

Most of us place enormous faith in our universities. We trust that they are autonomous, independent institutions committed to education, scholarship, academic freedom and the production of knowledge free from the influence of special interest groups. Right?

Wrong. In the last 25 years, the United States has given birth to a market-model university, one where professors increasingly work 'for hire.'

Each university is afraid to tighten its rules for fear that this might drive talented faculty (and industry dollars) to other schools with more lax policies. But until the top U.S. research universities collectively adopt one rigorous, uniform policy, their autonomy will continue to erode.

By an anonymous editorial writer in the New York Times, (via the Houston Chronicle),

Leading medical journals seem to be having a difficult time disentangling themselves from the pharmaceutical and medical device industries. If they cannot stop printing articles by scientists with close ties to these businesses, they should at least force the authors to disclose their conflicts of interest publicly so that doctors and patients are forewarned that the interpretations may be biased.
It seems imperative that more muscle be put into forcing disclosure and publication of conflicts of interest. If all leading journals agreed to punish authors who fail to reveal their conflicts by refusing to accept further manuscripts from them, a lot more authors would be inclined to fess up. Better yet, journals should try much harder to find authors free of conflicts. That is the best hope for retaining credibility with doctors and the public.

And by Benedict Carey in the New York Times,

Companies don’t just hire doctors to do research — a practice that in theory ought to help keep businesses scientifically honest — they also trade on the researchers’ names. Like producers shopping a new a movie, they go for star power, an A-list cast with names that themselves sell a product, and pull other doctors along, even when the evidence for a treatment is not strong.

One of the supposed strengths of American science is that it is decentralized and diverse: there are dozens of top researchers who are competitive and critical, enforcing a high standard. But when many or most of the leading figures are playing for the same team — an all-star team — that lineup itself may carry the day, regardless of the science.

With this topic finally getting widespread notice in medical journals and in the main-stream media, I hope it is not hopelessly naive to expect some action. At the very least, we need much more rigorous disclosure requirements for authors of articles in medical journals, and generally for people who bill themselves as academics writing or speaking about medical and health care issues in any venue. In addition, we need broadly based rules about conflict of interest that apply to all people who make decisions in health care.

[For the theme music, go here.]

Post Title → Won't Get Fooled Again, Again, Again

Now Cyberonic's Executives' Stock Options Questioned

Last year, we posted about the curious goings-on during the US Food and Drug Administration (FDA) evaluation of a device made by Cyberonics touted as a treatment for severe, refractory depression. The implanted electrical vagus nerve stimulator is invasive end expensive. A single, unpublished randomized controlled trial failed to show that it had statistically significant benefit, that is, that any apparent differences in improvement rates in treated and untreated patients were not do to chance alone. Were the benefits real, they would only affect a small number of patients. Nonetheless, the FDA advisory panel seemed more swayed by patient's testimonial evidence.

We then posted about an ongoing investigation by the US Senate Finance Committee that showed how an FDA official approved the device against the advice of staff scientists, who emphasized the device's known adverse effects versus uncertainty about any benefits.

Now, Cyberonics is back in the news again. Yesterday, the Associated Press, and today, the New York Times reported questions about Cyberonics awarded stock options to its top executives. According to the Times,

[Stock analyst Amit] Hazan, who said he was surveying all the companies he follows for potential backdating issues, focused on Cyberonics options that were granted at a special board meeting on the evening of June 15, 2004. That was only hours after a Food and Drug Administration advisory panel recommended that the agency approve Cyberonics's request to market its implantable nerve stimulator as a treatment for severe chronic depression.

Mr. Cummins received options on 150,000 shares at an exercise price of $19.58, the closing price the day before the F.D.A. panel's recommendation. The chief medical officer, Dr. Richard L. Rudolph, and the vice president for regulatory affairs, Alan D. Totah, who played pivotal roles in winning the panel's backing, each received options on 10,000 shares at that price.

The shares soared when trading resumed the next day, June 16, closing at $34.81, as investors bet that Cyberonics might soon be selling a new approach to treating the most severe forms of depression, a condition that affects millions of Americans annually.

'The board acted on an event before investors were able to do so,' Mr. Hazan said yesterday in an interview. 'It's a perfect example of an abusive option. Options are supposed to be an incentive to align executives' interests with shareholders. This was just a reward.'

Mr. Hazan said that because the options were priced below what would become the market value the instant that trading resumed, they should have been accounted for as compensation in that quarter. Because the company did not do so, it might have to restate its earnings for that fiscal year, he said.

Today, Reuters reported that "the chief financial officer of Cyberonics ... denied allegations that certain stock options were timed to create a windfall for executives.... CFO Pam Westbrook said the allegations were 'inaccurate and without merit' and that the company fully followed securities laws in granting the options."

Now that we have been publishing Health Care Renewal for a while, it's fascinating to see how organizations that appear on the blog for one particular management problem often show up again, and sometimes again and again for other management problems. So now, not only should physicians be skeptical about the evidence on which proponents of Cyberonics' vagus nerve stimulator base their advocacy, but also stock holders should be skeptical about the priorities of the company's top leaders.

ADDENDUM (June 12, 2006): The US Securities and Exchange Commission (SEC) is now investigating Cyberonics' stock option grants to executives (see Reuters).

Post Title → Now Cyberonic's Executives' Stock Options Questioned

Why Did the FDA Approve the Vagus Nerve Stimulator for Depression?

The New York Times revealed a report by the Senate Finance Committee, chaired by Sen. Charles Grassley (R-Iowa), on the US Food and Drug Administration's (FDAs) approval of a vagus nerve stimulation device to treat chronic depression.
We had previously posted about how an advisory committee to the FDA made the device "approvable" even though the the only relevant randomized controlled trial (RCT) found no significant improvement in patients in whom the device was implanted and turned on compared to patients in whom it was implanted but not turned on. The panel did hear some emotional testimonials on behalf of the device. Dissenters on the advisory committee at the time thought the decision was "nuts."
The Senate Committee found that Dr Daniel G Schultz, director of the FDA Center for Devices and Radiological Health, approved the device despite objections from staff scientists. The Times reported the devices' adverse effects include "voice alteration, increased cough, shortness of breath, neck pain and difficulty swallowing. The device has also been linked to rare reports of death, heart problems and vocal cord paralysis."
Emails from FDA internal reviewers of the device stated, "In my opinion, they do not have adequate data, and I don't understand how this can move forward," and "As an MD interested in science, it seems to me that such an approval would be akin to approving an experimental product."
The device is made by Cyberonics Inc. It's CEO, Robert P Cummins, said it is "the only safe and effective treatment opiton ever specifically developed, studied, F.D.A.-approved and fully informatively labeled for the treatment of chronic or recurrent treatment-resistant depression." It is not clear how he justified his statement that the device is "effective," given the results of the RCT.
Cyberonics, based in Houston, appears to have unique political connections. It includes among its directors former Congressman Tony Coehlo, who a Washington Times editorial recently charged was responsible for setting up the system that allowed the Abramoff scandal to occur.
The device reportedly costs $15,000.
It is not clear whose priorities were served by its approval, nor whether science was trumped by emotion, or something else in this case.

Post Title → Why Did the FDA Approve the Vagus Nerve Stimulator for Depression?

Questionable Deliberations on the Vagus Nerve Stimulator to Treat Severe Depression

The NY Times reports on the curious deliberations by a US Food and Drug Administration (FDA) expert advisory panel on the approval of an implanted vagus nerve stimulator as a treatment for severe depression. The committee was informed about the results of a randomized controlled trial which, as far as I can tell after several PubMed searches, has not yet been published.
The Times reports the trial showed that 17/111 patients who had the stimulator implanted and turned on had improvements in "standard measures of disease severity," while 11/110 who had it implanted, but not turned on also improved. This small increase in the likelihood of improvement was not statistically significant, i.e., could have been due to chance alone, rather than be an effect of the device. Furthermore, the absolute benefit increase implied by these data is at most 4.3%. That is, were 100 people to get the device, this data implies only 4 of them might improve because of it, while the rest would either not improve, or would have improved even without it.
Nonetheless, after hearing some emotional testimonials by patients who claimed that the device helped them, the advisory committee voted to make the device "approvable." The panel's chair, Dr. Kyra Becker, said "the feeling was that anything that gives these people hope is potentially worthwhile." However, one dissenter, Dr. Richard Malone, was bewildered by the panel's decision, "I walked out of there thinking I was nuts. It was stunning, but then I find much of life stunning."
The FDA does not have as rigorous standards to approve devices as those to approve drugs. However, when a device costs $15,000, is invasive, cannot be easily removed, and at best seems as if it may help only a small minority of patients, as is the case for the vagus nerve stimulator, the wisdom of these relatively lax standards comes into question.
Another question is why a scientific advisory committee, staffed ostensibly by medical experts, seemed more attentive to testimonials than to the results of a randomized controlled trial. Perhaps we will get some answers from an investigation by the Senate Finance Committee, which apparently is ongoing.

Post Title → Questionable Deliberations on the Vagus Nerve Stimulator to Treat Severe Depression