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“Obama Promises $156 Million to Alzheimer’s…But where will the money come from?” That’s easy: the NCCAM!

The quoted language above is part of the headline of this story in today’s The Scientist:

Citing the rising tide of Americans with Alzheimer’s—projections suggest 10 million people will be afflicted by 2050—the Obama administration and top National Institutes of Health officials are taking action. On February 7, they announced that they will add an additional $80 million to the 2013 NIH budget for the Alzheimer’s research program.

The problem is that there ain’t no such thing as a free lunch:

However, Richard Hodes, director of the NIH’s National Institute on Aging, told Nature that the 2013 dollars still have to be approved by Congress in the next budget and, if not, existing programs may need to be cut. And this year’s $50 million is likely to bump other projects, perhaps at NIH’s National Human Genome Research Institute. “If there’s a finite budget anywhere, once there’s more of something, there is less of something else,” he said.

Often such budget compromises are difficult, because there is no ready way to choose between two or more competing recipients of taxpayers’ money, each of which might be comparably worthy. Thus it is with a great sense of relief that in this case, we in the biomedical community can assure President Obama that no such dilemma exists. This is one of those occasional decisions that requires no hair-pulling whatsoever. The obvious solution is to defund the National Center for Complementary and Alternative Medicine (NCCAM), which, at about $130 million/yr, would solve the problem of funding Alzheimer’s research and take the heat off other worthy programs such as those mentioned by Richard Hodes.

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Posted in: History, Medical Academia, Medical Ethics, Politics and Regulation, Science and Medicine

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Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 2

NB: If you haven’t yet read Part 1 of this blog, please do so now; Part 2 will not summarize it.

At the end of Part 1, I wrote:

We do not need formal statistics or a new, randomized trial with a larger sample size to justify dismissing the Gonzalez regimen.

In his editorial for the JCO, Mark Levine made a different argument:

Can it be concluded that [the] study proves that enzyme therapy is markedly inferior? On the basis of the study design, my answer is no. It is not possible to make a silk purse out of a sow’s ear.

That conclusion may be correct in the EBM sense, but it misses the crucial point of why the trial was (ostensibly) done: to determine, once and for all, whether there was anything to the near-miraculous claims that proponents had made for a highly implausible “detoxification” regimen for cancer of the pancreas. Gonzalez himself had admitted at the trial’s inception that nothing short of an outcome matching the hype would do:

DR. GONZALEZ: It’s set up as a survival study. We’re looking at survival.

SPEAKER: Do you have an idea of what you’re looking for?

DR. GONZALEZ: Well, Jeff [Jeffrey White, the director of the Office of Cancer Complementary and Alternative Medicine at the NCI—KA] and I were just talking a couple weeks ago. You know, to get any kind of data that would be beyond criticism is—-always be criticism, but at least three times.

You would want in the successful group to be three times — the median to be three times out from the lesser successful groups.

So, for example, if the average survival with chemo, which we suspect will be 5 months, you would want my therapy to be at least — the median survival to be at least 15, 16, 17 months, as it was in the pilot study.

We’re looking for a median survival three times out from the chemo group to be significant.

Recall that the median survival in the Gonzalez arm eventually turned out to be 4.3 months.

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Posted in: Cancer, Clinical Trials, Health Fraud, Medical Academia, Medical Ethics, Politics and Regulation, Science and Medicine

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Evidence-Based Medicine, Human Studies Ethics, and the ‘Gonzalez Regimen’: a Disappointing Editorial in the Journal of Clinical Oncology Part 1

Background: the distinction between EBM and SBM

An important theme on the Science-Based Medicine blog, and the very reason for its name, has been its emphasis on examining all the evidence—not merely the results of clinical trials—for various claims, particularly for those that are implausible. We’ve discussed the distinction between Science-Based Medicine (SBM) and the more limited Evidence-Based Medicine (EBM) several times, for example here (I began my own discussion here and added a bit of formality here, here, and here). Let me summarize by quoting John Ioannidis:

…the probability that a research finding is indeed true depends on the prior probability of it being true (before doing the study), the statistical power of the study, and the level of statistical significance.

EBM, in a nutshell, ignores prior probability† (unless there is no other available evidence) and falls for the “p-value fallacy”; SBM does not. Please don’t bicker about this if you haven’t read the links above and some of their own references, particularly the EBM Levels of Evidence scheme and two articles by Steven Goodman (here and here). Also, note that it is not necessary to agree with Ioannidis that “most published research findings are false” to agree with his assertion, quoted above, about what determines the probability that a research finding is true.

The distinction between SBM and EBM has important implications for medical practice ethics, research ethics, human subject protections, allocation of scarce resources, epistemology in health care, public perceptions of medical knowledge and of the health professions, and more. EBM, as practiced in the 20 years of its formal existence, is poorly equipped to evaluate implausible claims because it fails to acknowledge that even if scientific plausibility is not sufficient to establish the validity of a new treatment, it is necessary for doing so.

Thus, in their recent foray into applying the tools of EBM to implausible health claims, government and academic investigators have made at least two, serious mistakes: first, they have subjected unwary subjects to dangerous but unnecessary trials in a quest for “evidence,” failing to realize that definitive evidence already exists; second, they have been largely incapable of pronouncing ineffective methods ineffective. At best, even after conducting predictably disconfirming trials of vanishingly unlikely claims, they have declared such methods merely “unproven,” almost always urging “further research.” That may be the proper EBM response, but it is a far cry from the reality. As I opined a couple of years ago, the founders of the EBM movement apparently “never saw ‘CAM’ coming.”

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Posted in: Cancer, Clinical Trials, Medical Academia, Medical Ethics, Politics and Regulation, Science and Medicine

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My NCCAM Wish List

For a number of reasons, well-argued many times here on SBM, it would be beneficial to American citizens if the National Center for Complementary and Alternative Medicine (NCCAM) were abolished. This does not seem to be in the cards anytime soon. Here, then, are my suggestions for making the Center less dangerous and less of a marketing tool for pseudomedicine than it has been since its inception. Some suggestions might even make the Center somewhat useful. They are listed in order of priority. The Center should:

1. Abandon all unethical trials, beginning with the Trial to Assess Chelation Therapy (TACT, which is under the joint auspices of the NHLBI). This should be done in a very public manner. The reasons for abandoning the TACT, in summary, are as follows.

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Posted in: Medical Ethics, Politics and Regulation, Science and Medicine

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“Gonzalez Regimen” for Cancer of the Pancreas: Even Worse than We Thought (Part II: Loose Ends)

Last week I discussed the dismal results of the “Gonzalez Trial” for cancer of the pancreas,* as reported in an article recently posted on the website of the Journal of Clinical Oncology. I promised that this week I’d discuss “troubling information, both stated and unstated [in the report],” and also some ethical issues. More has come to light in the past few days, including Nicholas Gonzalez’s own voluminous, angry response to the JCO article. I’ll comment upon that below, but first a brief review.

The trial was begun in 1999 under the auspices of Columbia University, after Rep. Dan Burton had pressured NCI Director Richard Klausner to fund it. It was originally conceived as a randomized, controlled trial comparing the “Gonzalez Regimen” to standard chemotherapy for cancer of the pancreas. In the first year, however, only 2 subjects had been accrued, purportedly because those seeking Gonzalez’s treatment were not willing to risk random assignment to the chemotherapy arm. In 2000, the protocol was changed to a “prospective, cohort study” to allow potential subjects to choose which treatment they would follow. Gonzalez himself was to provide the ‘enzyme’ treatments.

After that there was little public information about the trial for several years, other than a few determination letters from the Office of Human Research Protections and a frightening account of the experience of one subject treated by Gonzalez. By 2006 or so, those of us who pay attention to creeping pseudomedicine in the academy were wondering what had become of it. About a year ago we found out: the trial had been quietly “terminated” in 2005 after it met “pre-determined stopping criteria.” As explained here, that meant that the Gonzalez group had not fared well.

Four years after the trial’s ‘termination,’ the report was finally published: The Gonzalez cohort had not only fared much worse than the cohort that received chemotherapy, but it had fared worse than a comparable group of historical controls. Here, again, is the survival graph from the JCO paper:

Snapshot 2009-09-11 16-16-15

The Gonzalez group had also fared much worse in ‘quality of life’ scores, which included a measure of pain.

Now let’s read between the lines. Forgive me for taking shortcuts; I’m a little pressed for time. (more…)

Posted in: Clinical Trials, Health Fraud, Herbs & Supplements, Medical Academia, Medical Ethics, Science and Medicine, Science and the Media

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“Gonzalez Regimen” for Cancer of the Pancreas: Even Worse than We Thought (Part I: Results)

ResearchBlogging.org

Review

One of the more bizarre and unpleasant “CAM” claims, but one taken very seriously at the NIH, at Columbia University, and on Capitol Hill, is the cancer “detoxification” regimen advocated by Dr. Nicholas Gonzalez:

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.

Veteran SBM readers will recall that in the spring of 2008 I posted a series of essays* about this regimen and about the trial that compared it to standard treatment for subjects with cancer of the pancreas. The NIH had funded the trial, to be conducted under the auspices of Columbia, after arm-twisting by Rep. Dan Burton [R-IN], a powerful champion of quackery, and much to the delight of the “Harkinites.”

In the fall of 2008 I posted an addendum based on a little-known determination letter that the Office for Human Research Protections (OHRP) had sent to Columbia during the previous June. The letter revealed that the trial had been terminated in October, 2005, due to “pre-determined stopping criteria.” This demonstrated that Gonzalez’s regimen must have been found to be substantially worse than the current standard of care for cancer of the pancreas, as ineffective as that standard may be. I urge readers who require a review or an introduction to the topic to read that posting, which also considered why no formal report of the trial had yet been made available.

Now, finally, the formal report has been published online by the Journal of Clinical Oncology (JCO):

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Posted in: Cancer, Clinical Trials, Health Fraud, Herbs & Supplements, Medical Academia, Medical Ethics, Politics and Regulation, Science and Medicine

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The “Gonzalez Trial” for Pancreatic Cancer: Outcome Revealed

A Review

Dr. Lipson’s “detoxification” post on Thanksgiving Day and Dr. Gorski’s recent post about “Gerson Therapy” were timely, because last weekend I noticed something that I should have noticed months ago. Before delivering the punch line, let me remind you, Dear Reader, of the nature of the topic. 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 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 supposedly provided the justification for the trial, had failed to support any real promise (the case series had previously been considered by reader Dr. Peter Moran, who also found them wanting).

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 were major problems with the Gonzalez trial from the outset, and that for at least one subject the regimen was 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.

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Posted in: Cancer, Clinical Trials, Medical Academia, Medical Ethics, Politics and Regulation

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“Patient-Centered Care” and the Society for Integrative Oncology

Should Medical Journals Inform Readers if a Book Reviewer can’t be Objective?

At the end of last week’s post I suggested that book reviewer Donald Abrams and the New England Journal of Medicine had withheld information useful for evaluating Abrams’ review: that he is the Secretary/Treasurer of the Society for Integrative Oncology (SIO), the organization of which Lorenzo Cohen, the first editor of the book that Abrams reviewed,* is President. I also promised to look at material from the book and from the Society’s website in order to discover “data that will allow even the most conventional oncologists to appreciate [the value of 'integrative' methods].”

There is little question that Abrams and Cohen know each other, or at least that Abrams couldn’t have been expected to write an entirely objective review of Cohen’s book. Abrams is the Program Chair for the Society’s upcoming 5th International Conference, sponsored by the American Cancer Society. He and Cohen will be sharing the stage for the “Intro/Welcome.” Does it matter that most NEJM readers wouldn’t have learned of this association by reading the review? Probably not, in the case of readers who are well-versed in the misleading language of “CAM.”

I believe that most readers of medical journals are not so sophisticated. Otherwise, how could it have been so easy for “CAM” literature to seep through the usual evaluative filters, not only in medical schools and government but in the editorial boardrooms of prestigious journals? For anyone from the Journal who might be following this thread, Dr. Sampson’s satirical but deadly serious account of “how we did it” is obligatory reading.

Do “Integrative Oncology” Methods have Value?

Now let’s take a look at what Dr. Cohen’s book and the SIO are up to. The book’s introduction and table of contents are available on Amazon.com. The introduction contains the usual, misleading assertions and falsehoods that are ubiquitous in “CAM” promotions. I’ve added a few hyperlinks:

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Posted in: Book & movie reviews, Cancer, Energy Medicine, Medical Ethics

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The Ethics of “CAM” Trials: Gonzo (Part VI)

Part V of this Blog argued that the NCCAM-sponsored trial of the “Gonzalez regimen” for cancer of the pancreas is unethical by numerous criteria.† To provide an illustration, it quoted a case history of one of the trial’s subjects, who had died in 2002.¹ It had been written by the subject’s friend, mathematician Susan Gurney. A similar story was told on ABC 20/20 in 2000, albeit not about a trial subject. Each of these cases demonstrates the wide breadth of Gonzalez’s quackery, as did his brush with the New York medical board during the 1990s.

This entry addresses some aspects of how those in charge of the trial failed in their duty to protect human subjects. By implication, it suggests what is necessary to prevent similar travesties in the future. It also addresses, to the small extent that the information exists, what appear to be the final ethical violations: first, that the trial will never be completed, thus having “expose[d] subjects to risks or inconvenience to no purpose.” Second, that Columbia University and the responsible investigators have no intention of explaining why.

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Posted in: Cancer, Clinical Trials, Medical Academia, Medical Ethics, Science and Medicine

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The Ethics of “CAM” Trials: Gonzo (Part V)

Part IV of this blog ended by observing that the NIH-funded trial of the “Gonzalez regimen” for cancer of the pancreas,† to have begun in March, 1999, was in trouble almost as soon as it started. As originally designed, it was to have been a randomized, controlled trial comparing gemcitabine, the standard chemotherapy, to the “Gonzalez regimen” of pancreatic enzymes, “supplements,” twice-daily coffee enemas, and other purported methods of “detoxification.” By June, 1999, according to Dr. John Chabot, the Columbia University surgeon acting as Principal Investigator (PI) of the trial, only 3 of the first 50 potential subjects had agreed to be randomized, and none of the three met the eligibility criteria. By January, 2000 it had become clear that the trial would not accrue a sufficient number of subjects if it remained randomized, because almost all of the potential subjects were intent on being in the “nutritional,” ie, the Gonzalez arm.

Trouble with Randomizing

The investigators at Columbia therefore decided to change the protocol to a “single-armed, non-randomized case-cohort study where patients will only be enrolled in what was the nutritional arm.” Paradoxically, PI John Chabot had recently explained, at the 1999 Comprehensive Cancer Care Conference of James Gordon’s Center for Mind-Body Medicine, why this would not be a scientifically sound design:

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