A Professor and an Anti-Aging Tonic

Last week, the Wall Street Journal reported on another variation on the theme of medical school faculty members with ties to industry:

A prominent anti-aging researcher quit the scientific advisory board of a dietary-supplement maker after spending six months helping to promote a syrup that hints at extending life.

Since August, David Sinclair, a professor at Harvard Medical School, lent his support to a Shaklee Corp. drink called the Vivix Cellular Anti-Aging Tonic, touted as 'the world's best anti-aging supplement.'

Following questions by The Wall Street Journal about his seeming endorsement of the product, Dr. Sinclair resigned from the board last week and now says his name has been misused in connection with Vivix, which contains the antioxidant resveratrol. Shaklee, based in Pleasanton, Calif., disputes this and says he approved all uses of his name in its advertising material.

In obtaining the backing of Dr. Sinclair this summer, Shaklee scored a coup. Dr. Sinclair knows resveratrol; in 2006, he led a study showing the molecule could counteract the ill effects of overfeeding laboratory mice. One notable benefit: resveratrol let overweight mice live about 114 weeks on average, compared with 102 weeks without the chemical.

In August, Dr. Sinclair joined Shaklee's Scientific Advisory Board, a paid position, and enthusiastically introduced Vivix to the company's sales force in New Orleans. He joined Shaklee's chief doctor in a joint radio appearance, and his picture and name are often used on Vivix sales sites run by Shaklee's salespeople.

Shaklee declined to say how much it paid Dr. Sinclair to be on the advisory board.

Dr. Sinclair -- who has a Ph.D. in biochemistry and molecular genetics but isn't a medical doctor -- now says he was misinterpreted. 'I have submitted my resignation to Shaklee and exercised my right to terminate my agreement,' he wrote in an e-mailed response to questions. 'This decision was prompted in significant part by my recent realization as to how my association with Shaklee and my research have been used contrary to the intents and purposes of my agreement.'

'To my dismay I have found numerous uses of my name and reputation on the Web and in other media that implies endorsement by me of Shaklee's Vivix product,' he wrote.

In a statement, Shaklee said that 'every implied product endorsement was in Dr. Sinclair's own words and every Shaklee use of his name -- whether in print or video -- was pre-approved by him in keeping with our agreement.'

It is not clear from this story whether [Associate] Professor Sinclair initially signed off on specific uses of his name and reputation to promote the Shaklee product. But it does seem clear that with his approval or not, his name, and his academic reputation, including his position at Harvard, were used to hawk a product for its supposed anti-aging effects. This continues the sorry story of medical academics' reputations being used to market health care products.

But watch the video of Sinclair speaking to a large, cheering, whistling audience of Shaklee sales representatives, on a huge stage, with his name in huge letters behind him, and after a brassy musical introduction. (The video is embedded in the WSJ article, or can be found here.) As the WSJ reported, he said, apparently enthusiastically,

Together, as part of the Shaklee family...we can take this technology right now, to our friends, to our family, and really have the benefits of this new technology right now, within our lifetimes, and you'll learn more about the Vivix product later

So whether there were some promotions that used Sinclair's name or words without his authorization, in this obviously commercial, and Hollywood-style setting, Sinclair appeared not as a sober scientist, but as a rousing pitchman. Watch the video and it is hard to disbelieve that he willingly, enthusiastically was using his academic status and authority to promote Shaklee's commercial interests.

Academics have long been trusted to seek and disseminate the truth in a spirit of free enquiry. Academics who use their reputations to sell products, and take advantage of their reputation thus to enrich themselves, violate this trust. When the academics who do so are medical academics (even if they are not physicians), they also violate the trust of patients.

Those of us who care about the future of academic medicine need to see that medical faculty and academic medical institutions disentangle themselves from those who sell health care products or services.

The “Gonzalez Trial” for Pancreatic Cancer: Outcome Revealed

The regimen advocated by Nicholas Gonzalez is a variation of a “detoxification” treatment for cancer that has been around, in one form or another, for more than 50 years ("Gerson Therapy” is another example). Here is the National Cancer Institute’s (NCI) description:

Patients receive pancreatic enzymes orally every 4 hours and at meals daily on days 1-16, followed by 5 days of rest. Patients receive magnesium citrate and Papaya Plus with the pancreatic enzymes. Additionally, patients receive nutritional supplementation with vitamins, minerals, trace elements, and animal glandular products 4 times per day on days 1-16, followed by 5 days of rest. Courses repeat every 21 days until death despite relapse. Patients consume a moderate vegetarian metabolizer diet during the course of therapy, which excludes red meat, poultry, and white sugar. Coffee enemas are performed twice a day, along with skin brushing daily, skin cleansing once a week with castor oil during the first 6 months of therapy, and a salt and soda bath each week. Patients also undergo a complete liver flush and a clean sweep and purge on a rotating basis each month during the 5 days of rest.

As unlikely as it may seem, in 1999 American taxpayers began paying for people with cancer of the pancreas to be subjected to that regimen, in a trial sponsored by the National Center for Complementary and Alternative Medicine (NCCAM) and the NCI, conducted under the auspices of Columbia University. Gonzalez provided the treatments. A few months ago, on Science-Based Medicine, I presented a multi-part treatise on the “Gonzalez regimen” and the trial. It demonstrated that all evidence, from basic science to clinical, including the case series that had supposedly provided the justification for the trial, failed to support any real promise for the treatment.

It showed that the impetus for the trial, as has been true for other regrettable trials of implausible health claims, can be traced not to science but to the reactionary politics of anti-intellectual populism: initially to Laetrile and to the “Harkinites,” and more recently to the Honorable Dan Burton (R-IN). It reported that there had been major problems with the Gonzalez trial from the outset, and that for at least one subject the regimen had been more torture than therapy. It reported that for unclear reasons the trial had come to a halt a couple of years ago, and that it appeared that there would never be a report of its findings.

That series of posts also argued what was later summarized here: that, for good reasons, the New York State Board for Professional Medical Conduct had nearly revoked Dr. Gonzalez’s medical license during the 1990s—only to retreat from that position after two misguided academics had testified that his regimen might benefit cancer patients.

The apparent non-outcome of the Gonzalez trial would be the final insult among its numerous, serious ethical violations. These were discussed, at some length, here and here; they include the fallacy of 'popularity,' which has been the NCCAM's primary rationale for human trials of implausible health claims. On June 2, 2008, one month after the last posting of the series, new information about the Gonzalez trial became available in the form of a determination letter from the federal Office of Human Research Protections (OHRP). In part, it stated:

The complainant alleged that a minimum of 72 subjects were to be enrolled under the IRB-approved protocol, but that the study was terminated with only 62 enrolled subjects, in violation of HHS regulations… CUMC [Columbia University Medical Center] reported that the Data Safety and Monitoring Committee (DSMC) for this protocol recommended that the study be terminated before it reached its full enrollment of 72 subjects. At its September 30, 2005 meeting, the DSMC recommended that the study be terminated due to predetermined stopping criteria. This information was submitted to the CUMC IRB on October 17, 2005, and the study termination was approved by the IRB.

What this means, in summary, is that the trial must have found the Gonzalez regimen to be either much better or much worse than standard treatment for cancer of the pancreas. It is certain that it was much worse, of course, because otherwise we would have heard about it years ago. I have offered additional evidence for that conclusion, and an explanation for why this information has not been reported by the responsible investigators, in a longer version of this posting.

Another Misuse of EBM

We agree with Roy Poses' comment on the recent JAMA article about EBM, particularly regarding some of its unfortunate "misuses." In the article that stands as the defining credo of Health Care Renewal, Roy wrote:

Most physicians believe that medicine should be based on science. Evidence based medicine, (EBM) ‘‘the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients’’ [74], is a refinement of this view. Meanwhile, the scientific basis of medicine is under increasingly severe attack.

We'd like to take this opportunity to identify a misuse of EBM that, ironically, contributes to the attack on the scientific basis of medicine, and that authors Montori and Guyatt didn't consider--probably because they are unaware of it. We explain it in the following letter, submitted to JAMA in response to their article. We discuss it at more length on the other blog to which we contribute, Science-Based Medicine, referenced from the letter:

To the editor:

In their recent article, “Progress in Evidence-Based Medicine,” Drs. Montori and Guyatt include important caveats about misuses of EBM. They mention trials funded by industry. They list several, documented problems with such trials, and correctly warn that these can result in erroneous interpretations by “unsophisticated users of the medical literature.” They correctly worry about “abandoning appropriate skepticism.”

There is a related misuse of EBM that leads to erroneous interpretations even by sophisticated authors, and that calls attention to systematic problems in EBM: trials of highly implausible hypotheses. Thus, regarding the homeopathic preparation Oscillococcinum, the Cochrane Collaboration writes:

Though promising, the data were not strong enough to make a general recommendation to use Oscillococcinum for first-line treatment of influenza and influenza-like syndromes. Further research is warranted…[1]

The data, however, are not promising, and further research is not warranted. The reason is that for highly implausible treatments, existing knowledge easily trumps modestly “positive” trial data. In the case of homeopathy, each of its tenets has been more than adequately disproved, and its claim that the potency of a “remedy” increases with each dilution of the original substance, continuing well past the point at which not a molecule of that substance remains in the preparation, contradicts physical reality.[2]

Such considerations reveal at least two, related problems with the evidence of EBM as it pertains to clinical trials. The first is explicit: by relegating “physiology, bench research or ‘first principles’” to Level 5 of its “Levels of Evidence” hierarchy, EBM fails to acknowledge that consistency with firmly established knowledge is a necessary, even if insufficient, basis for accepting a hypothetical treatment as effective.[2]

The second problem is part of the culture, if not the letter of EBM: by eschewing Bayesian in favor of “frequentist” statistics, its practitioners can excuse themselves from justifying estimates of prior probability, and erroneously conclude that trial data tell us more about reality than they do.[3-5]

In January, 2008, several colleagues began the blog Science-Based Medicine, referenced below.* The name, which could just as well have been “knowledge-based medicine,” is a frank recognition of the EBM weaknesses described above. Because of our interests, Science-Based Medicine’s content is predominantly, though not entirely, concerned with implausible health claims. Its larger message, however, is that these claims call attention to fundamental ways in which EBM can be improved, such as to justify its own claim to being an arbiter of real evidence.

Kimball C. Atwood, IV

Wallace I. Sampson

10/19/2008

* Steven Novella, David Gorski, Harriet Hall, Wallace Sampson, Kimball Atwood

[1] Vickers A, Smith C. Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001957. DOI: 10.1002/14651858.CD001957.pub3.

[2] Atwood K. Homeopathy and Evidence-Based Medicine: Back to the Future Part V. Science-Based Medicine 2008 (Feb. 8). http://www.sciencebasedmedicine.org/?p=42. Accessed October 19, 2008

[3] Atwood K. Prior Probability: the Dirty Little Secret of “Evidence-Based Alternative Medicine.” Science-Based Medicine 2008 (Feb. 15). http://www.sciencebasedmedicine.org/?p=48. Accessed October 19, 2008

[4] Goodman SN. Toward evidence-based medical statistics. 1: The P value fallacy. Ann Intern Med. 1999;130:995-1004.

[5] Goodman SN. Toward evidence-based medical statistics. 2: The Bayes factor. Ann Intern Med. 1999;130:1005-13.

Update on the NIH “Trial to Assess Chelation Therapy”

(Some of the following is identical to a post on Science-Based Medicine dated 9/26/08.)

A few days ago, while gathering information for a post on Science-Based Medicine about intravenous hydrogen peroxide, I noticed this:

ACAM Supports NIH Decision to Suspend TACT Trial

September 3, 2008, Laguna Hills, Calif. — The American College for Advancement in Medicine, ACAM today announced its support for the National Institute for Health’s (NIH) decision to suspend patient accrual of the Trial to Assess Chelation Therapy (TACT) Trial until allegations of impropriety can be proven false. ACAM believes that the TACT trial represents a important milestone in assessing the role of chelation therapy in modern healthcare and respects the decision of the NIH.

ACAM continue to work with Dr Tony Lamas to answer the unfounded allegations of impropriety.

“We believe that the Office of Human Research Protection (OHRP) will find that the allegations are of a political nature. To serve the best interests of participants enrolled in the TACT trial and all patients and their physicians who seek answers about chelation therapy, we call for a swift end to the moratorium and resumption of the trial,” said Jeanne Drisko, MD, President of ACAM.

I alerted a few others, including Stephen Barrett of Quackwatch, who queried the news room of the National Heart, Lung and Blood Institute (NHLBI: the joint sponsor, along with the NCCAM, of the trial) and got this reply:

The investigators and institutions performing the Trial to Assess Chelation Therapy (TACT), in conjunction with their Institutional Review Boards, have temporarily and voluntarily suspended enrollment of new participants in the study. NIH has not issued any announcement or press release about this action. To contact the Office for Human Research Protections’ (OHRP) press office, call Pat El-Hinnawy, (202) 253-0458.

The “allegations of impropriety” mentioned in the ACAM press release had been made by my co-authors and me in a comprehensive article previously introduced on Health Care Renewal here. The article is available in its entirety here. In June, we made a formal complaint to the federal Office of Human Research Protections (OHRP), citing that article and additional information posted on Science-Based Medicine here. That our complaint was the instigating factor for the recent “decision to suspend patient accrual” is suggested by an email that I received last week:

I would like to know who is paying you guys off. Finally we have a chance to assess Chelation therapy and put the issue to rest and to find out whether or not it really works and you bozos screw it all up. I know that the trial was stopped and it is your fault. What are you afraid of? Why are you not decrying all of the injuries caused by medications and unnecessary surgeries? Why are we the citizens of the US deprived of a trial of EDTA so that we can judge for ourselves?

Anyone who is a thinking man, can only be disappointed in you. [sic]

Binyamin Rothstein, D.O.

Rothstein, unlike many of his fellow ACAM members, does not appear to be a TACT investigator. Like them, however, he touts chelation, intravenous hydrogen peroxide, and other baseless and dangerous treatments. He has harmed patients, his protestations nothwithstanding. His medical license was revoked in 2005, but that hasn’t hindered him from using smoke and mirrors in his relentless pursuit of profit from nonsense. He’s even managed to promote himself to the public without revealing key items from his resumé—one of the many reasons that even the most diligent regulation can’t always protect the public from scoundrels.

At least two reporters have recently covered the story (here and here). They mostly get it right. The AP report, however, states that chelation "is mainly used to treat lead poisoning." That is not technically false, but is misleading because disodium EDTA (Na2EDTA), the drug used in the TACT, has never been approved for lead poisoning and is considerably more dangerous than calcium EDTA, the drug that is so approved. Ironically, one of our objections to the TACT is that its literature---including protocols, consent forms, and subject recruitment pitches---conflates the two drugs so as to make the study drug appear safer than it is.

Indeed, the FDA has recently withdrawn its approval of Na2EDTA, citing "important safety information" and the possibility that it may be confused with the less dangerous CaEDTA:

As noted in the January 16, 2008, Public Health Advisory, there have been cases where children and adults have died when they were mistakenly given edetate disodium instead of edetate calcium disodium (calcium disodium versenate) or when edetate disodium was used for indications other than those approved by FDA.

Readers might remember that we at HCR have previously discussed the important distinction between the two EDTA salts, after a 5-year old boy was killed in Pennsylvania when a quack administered Na2EDTA to him as a treatment for autism. At the time a CDC expert was so surprised that anyone would infuse Na2EDTA that she concluded, erroneously, that it must have been a drug error: "a case of look-alike/sound-alike medications." The PA medical board's investigation subsequently confirmed that the practitioner had intended to give Na2EDTA, exactly as we had predicted.

The TACT should now be stopped altogether. Contrary to the ACAM press release, our objections to the TACT are scrupulously documented and not “of a political nature.” They are of a scientific and ethical nature. They will not be proven false, because the evidence for them is overwhelming.

The NIH Trial to Assess Chelation Therapy (TACT): an unethical study sponsored by taxpayers

Two occasional HCR bloggers are co-authors of an article published this week:

Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned

Kimball C. Atwood IV, MD; Elizabeth Woeckner, AB, MA; Robert S. Baratz, MD, DDS, PhD; Wallace I. Sampson, MD

Medscape J Med. 2008;10(5):115. ©2008 Medscape
Posted 05/13/2008

Abstract:

The National Institutes of Health (NIH) Trial to Assess Chelation Therapy (TACT) was begun in 2003 and is expected to be completed in 2009. It is a trial of office-based, intravenous disodium ethylene-diamine-tetra-acetic acid (Na2EDTA) as a treatment for coronary artery disease (CAD). A few case series in the 1950s and early 1960s had found Na2EDTA to be ineffective for CAD or peripheral vascular disease (PVD). Nevertheless, a
few hundred physicians, almost all of whom advocate other dubious treatments, continued to peddle chelation as an office treatment. They claim that chelation dramatically improves symptoms and prolongs life in 80% to 90% of patients. In
response, academics performed 4 controlled trials during the 1990s. None favored chelation, but chelationists repudiated those findings.

We have investigated the method and the trial. We present our findings in 4 parts: history, origin and nature of the TACT, state of the evidence, and risks. We present evidence that chelationists and their organization, the American College for Advancement in Medicine, used political connections to pressure the NIH to fund the TACT. The TACT protocols justified the trial by misrepresenting case series and by ignoring evidence of risks. The trial employs nearly 100 unfit co-investigators. It conflates disodium EDTA and another, somewhat safer drug. It lacks precautions necessary to minimize risks. The consent form reflects those shortcomings and fails to disclose apparent proprietary interests. The trial's outcome will be unreliable and almost certainly equivocal, thus defeating its stated purpose.

We conclude that the TACT is unethical, dangerous, pointless, and wasteful. It should be abandoned.

The entire article is available at: http://journal.medscape.com/viewarticle/570625_print

You may be asked to "register"; don't worry, it's free. The article is very long, but the Introduction, Executive Summary, Discussion, and Conclusion are reasonably succinct and make the important points. Readers who want to learn more details, who want to see more evidence for our assertions, or who are compelled by an odd fascination with crackpotism (my own weakness) will want to read more.

I've posted a similar announcement on Science-Based Medicine.