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Of the Trial to Assess Chelation Therapy, Bayes, the NIH, and Human Studies Ethics

An experiment is ethical or not at its inception; it does not become ethical post hoc—ends do not justify means.
~ Henry K. Beecher

tact

A couple of weeks ago, Dr. Josephine Briggs, the Director of the National Center for Complementary and Alternative Medicine (NCCAM), posted a short essay on the NCCAM Research Blog touting the results of the Trial to Assess Chelation Therapy (TACT) (italics added):

The authors found that those receiving the active treatment clearly fared better than those receiving placebo. The accompanying editorial in the AHJ reminds readers about the value of equipoise and the need to “test our beliefs against evidence.”

Most physicians did not expect benefit from chelation treatment for cardiovascular disease. I readily admit, initially, I also did not expect we would find evidence that these treatments reduce heart attack, strokes, or death. So, the evidence of benefit coming from analyses of the TACT trial has been a surprise to many of us. The subgroup analyses are suggesting sizable benefit for diabetic patients—and also, importantly, no benefit for the non-diabetic patient. Clearly subgroup analyses, even if prespecified, do not give us the final answer. But it is also clear that more research is needed to test these important findings.

And TACT findings are indeed a reminder of the importance of retaining equipoise [sic], seeking further research aimed at replicating the findings, and neither accepting nor rejecting findings based on personal biases. The scientific process is designed to weed out our preconceived notions and replace them with evidence.

Dr. Briggs concluded:

So, TACT is a reminder—an open mind is at the center of the scientific method.

Dr. Briggs’s title was “Bayes’ Rule and Being Ready To Change Our Minds”, a reference to a recent editorial that had accompanied one of the TACT papers. That editorial, by Dr. Sanjay Kaul, a physician and statistician from UCLA, begins with this quotation:

Preconceived notions are the locks on the door to wisdom.
~ Merry Browne

Here is the relevant passage from Dr. Kaul’s editorial (italics added):

Sixth, it has been argued that the trial was unethical because there was no compelling clinical or preclinical evidence that chelation therapy has significant efficacy against atherosclerotic cardiovascular disease, and given that chelation therapy can cause harm, the risk was not minimal. A Bayesian analysis would not look kindly on the results because of the low prior probability of treatment effect (the so-called implausibility argument).6 This is an uncharitable (and unwarranted) interpretation of the data because previous systematic reviews concluded, “insufficient evidence to decide on the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes among people with atherosclerotic cardiovascular disease.” It is axiomatic that absence of evidence of efficacy is not the same as evidence of the absence of efficacy.

From a Bayesian perspective, the strength of evidence is often summarized using a Bayes factor, which is a measure of how well 2 competing hypotheses (the null and the alternate) predict the data. The Bayes factor and the corresponding strength of evidence for the primary end point result in TACT overall, and diabetic cohorts are shown in Table 1. The p-value of 0.035 for TACT overall cohort translates into a Bayes factor of 0.108, which means the evidence supports the null hypothesis ≈1/9th as strongly as it does the alternative. This reduces the null probability from 50% pretrial (justified by suspension of one’s belief in treatment effect) to 10% post-trial. Although this does not represent strong evidence against the null, it does reduce the level of skepticism surrounding chelation therapy. In the diabetic cohort, the nominal p-value of 0.0002 translates into a Bayes factor of 0.002 (1/500), which reduces the extremely skeptical prior null probability of 95% to 4% post- trial, indicating very strong evidence against the null.

In concluding, Dr. Kaul states:

Finally, TACT highlights the double standard when it comes to accepting inconvenient results not aligned with our preconceived notions on so-called dubious quack cures such as chelation…

Closed minds?

Dr. Kaul’s reference “6” above is to a lengthy article that we published in 2008 titled “Why the NIH Trial to Assess Chelation Therapy Should Be Abandoned”. So, it seems, both Drs. Briggs and Kaul were chastising us for our biased, preconceived beliefs about so-called dubious quack cures. Our minds were, apparently, not open. Let’s examine this contention. (more…)

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

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More evidence that routine multivitamin use should be avoided

If scientific evidence guides our health decisions, we will look back at the vitamin craze of the last few decades with disbelief. Indiscriminate use is, in most cases, probably useless and potentially harmful. We are collectively throwing away billions of dollars into supplements, chasing the idea of benefits that have never materialized. Multivitamins are marketed with a veneer of science but that image is a mirage – rigorous testing doesn’t support the health claims. But I don’t think the routine use of vitamins will disappear anytime soon. It’s a skillfully-marketed panacea that about half of us buy into.

Not all vitamin and mineral supplementation is useless. They can be used appropriately, when our decisions are informed by scientific evidence: Folic acid prevents neural tube defects in the developing fetus. Vitamin B12 can reverse anemia. Vitamin D is recommended for breastfeeding babies to prevent deficiency. Vitamin K injections in newborns prevent potentially catastrophic bleeding events. But the most common reason for taking vitamins isn’t a clear need, but rather our desire to “improve overall health”. It’s deemed “primary prevention” – the belief that we’re just filling in the gaps in our diet. Others may believe that if vitamins are good, then more vitamins must be better. And there is no debate that we need dietary vitamins to live. The case for indiscriminate supplementation, however, has never been established. We’ve been led to believe, through very effective marketing, that taking vitamins is beneficial to our overall health – even if our health status is reasonably good. So if supplements truly provide real benefits, then we should be able to verify this claim by studying health effects in populations of people that consume vitamins for years at a time. Those studies have been done. Different endpoints, different study populations, and different combinations of vitamins. The evidence is clear. Routine multivitamin supplementation doesn’t offer any meaningful health benefits. The parrot is dead. (more…)

Posted in: Herbs & Supplements, Science and Medicine

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The result of the Trial to Assess Chelation Therapy (TACT): As underwhelming as expected

Chelation therapy.

It’s one of the most common quackeries out there, used by a wide variety of practitioners for a wide variety of ailments blamed on “heavy metal toxicity.” Chelation therapy, which involves using chemicals that can bind to the metal ions and allow them to be excreted by the kidneys, is actually standard therapy for certain types of acute heavy metal poisoning, such as iron overload due to transfusion, aluminum overload due to hemodialysis, copper toxicity due to Wilson’s disease, acute heavy metal toxicity, and a handful of other indications.

My personal interest in chelation therapy developed out of its use by unscrupulous practitioners who blamed autism on the mercury-containing thimerosal preservative that used to be in many childhood vaccines until 2001 but has since all but disappeared from such vaccines except for one vaccine (the flu vaccine, for which a thimerosal-free alternative is available) and in trace amounts in some other vaccines. Mercury became a convenient bogeyman to add to the list of “toxins” antivaccinationists hype in vaccines. In fact, my very first post after I introduced myself on this very blog discussed the idea that mercury in vaccines was a significant cause of autism and autism spectrum disorders, and I’ve periodically written about such things ever since, in particular the bad science of Mark and David Geier, whose idea that chemical castration of children with Lupron “works” against “mercury-induced” autism is based on a chemically ridiculous idea that somehow testosterone binds mercury and makes it harder to chelate. Unfortunately, this particular autism quackery has real consequences and has been responsible for the death of a child.

Chelation isn’t just for autism, however. Despite many practitioners advertising it for autism, cancer (often with dubious studies that I might have to take a look at), Alzheimer’s disease (which Hugh Fudenberg has blamed on the flu vaccine, a claim parroted by Bill Maher, of course!), and just about every ailment under the sun, it’s easy to forget that the original use for chelation therapy promoted by “alternative medicine” practitioners was for cardiovascular disease. When it is used for coronary artery disease or autism, on a strictly stoichiometric and pharmacological basis, it is extremely implausible. Moreover, it is not without potential complications, including renal damage and cardiac arrhythmias due to sudden drops in calcium levels. Such arrhythmias can and have led to death in children, and in adults complications such as renal failure and death.
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Of SBM and EBM Redux. Part III: Parapsychology is the Role Model for “CAM” Research

This is the third post in this series*; please see Part II for a review. Part II offered several arguments against the assertion that it is a good idea to perform efficacy trials of medical claims that have been refuted by basic science or by other, pre-trial evidence. This post will add to those arguments, continuing to identify the inadequacies of the tools of Evidence-Based Medicine (EBM) as applied to such claims.

Prof. Simon Replies

Prior to the posting of Part II, statistician Steve Simon, whose views had been the impetus for this series, posted another article on his blog, responding to Part I of this series. He agreed with some of what both Dr. Gorski and I had written:

The blog post by Dr. Atwood points out a critical distinction between “biologically implausible” and “no known mechanism of action” and I must concede this point. There are certain therapies in CAM that take the claim of biological plausibility to an extreme. It’s not as if those therapies are just implausible. It is that those therapies must posit a mechanism that “would necessarily violate scientific principles that rest on far more solid ground than any number of equivocal, bias-and-error-prone clinical trials could hope to overturn.” Examples of such therapies are homeopathy, energy medicine, chiropractic subluxations, craniosacral rhythms, and coffee enemas.

The Science Based Medicine site would argue that randomized trials for these therapies are never justified. And it bothers Dr. Atwood when a systematic review from the Cochrane Collaboration states that no conclusions can be drawn about homeopathy as a treatment for asthma because of a lack of evidence from well conducted clinical trials. There’s plenty of evidence from basic physics and chemistry that can allow you to draw strong conclusions about whether homeopathy is an effective treatment for asthma. So the Cochrane Collaboration is ignoring this evidence, and worse still, is implicitly (and sometimes explicitly) calling for more research in this area.

On the other hand:

There are a host of issues worth discussing here, but let me limit myself for now to one very basic issue. Is any research justified for a therapy like homeopathy when basic physics and chemistry will provide more than enough evidence by itself to suggest that such research is futile(?) Worse still, the randomized trial is subject to numerous biases that can lead to erroneous conclusions.

I disagree for a variety of reasons.

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Posted in: Acupuncture, Clinical Trials, Energy Medicine, Faith Healing & Spirituality, Herbs & Supplements, Homeopathy, Medical Academia, Medical Ethics, Science and Medicine

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Of SBM and EBM Redux. Part II: Is it a Good Idea to test Highly Implausible Health Claims?

Review

This is the second post in a series* prompted by an essay by statistician Stephen Simon, who argued that Evidence-Based Medicine (EBM) is not lacking in the ways that we at Science-Based Medicine have argued. David Gorski responded here, and Prof. Simon responded to Dr. Gorski here. Between that response and the comments following Dr. Gorski’s post it became clear to me that a new round of discussion would be worth the effort.

Part I of this series provided ample evidence for EBM’s “scientific blind spot”: the EBM Levels of Evidence scheme and EBM’s most conspicuous exponents consistently fail to consider all of the evidence relevant to efficacy claims, choosing instead to rely almost exclusively on randomized, controlled trials (RCTs). The several quoted Cochrane abstracts, regarding homeopathy and Laetrile, suggest that in the EBM lexicon, “evidence” and “RCTs” are almost synonymous. Yet basic science or preliminary clinical studies provide evidence sufficient to refute some health claims (e.g., homeopathy and Laetrile), particularly those emanating from the social movement known by the euphemism “CAM.”

It’s remarkable to consider just how unremarkable that last sentence ought to be. EBM’s founders understood the proper role of the rigorous clinical trial: to be the final arbiter of any claim that had already demonstrated promise by all other criteria—basic science, animal studies, legitimate case series, small controlled trials, “expert opinion,” whatever (but not inexpert opinion). EBM’s founders knew that such pieces of evidence, promising though they may be, are insufficient because they “routinely lead to false positive conclusions about efficacy.” They must have assumed, even if they felt no need to articulate it, that claims lacking such promise were not part of the discussion. Nevertheless, the obvious point was somehow lost in the subsequent formalization of EBM methods, and seems to have been entirely forgotten just when it ought to have resurfaced: during the conception of the Center for Evidence-Based Medicine’s Introduction to Evidence-Based Complementary Medicine.

Thus, in 2000, the American Heart Journal (AHJ) could publish an unchallenged editorial arguing that Na2EDTA chelation “therapy” could not be ruled out as efficacious for atherosclerotic cardiovascular disease because it hadn’t yet been subjected to any large RCTs—never mind that there had been several small ones, and abundant additional evidence from basic science, case studies, and legal documents, all demonstrating that the treatment is both useless and dangerous. The well-powered RCT had somehow been transformed, for practical purposes, from the final arbiter of efficacy to the only arbiter. If preliminary evidence was no longer to have practical consequences, why bother with it at all? This was surely an example of what Prof. Simon calls “Poorly Implemented Evidence Based Medicine,” but one that was also implemented by the very EBM experts who ought to have recognized the fallacy.

There will be more evidence for these assertions as we proceed, but the main thrust of Part II is to begin to respond to this statement from Prof. Simon: “There is some societal value in testing therapies that are in wide use, even though there is no scientifically valid reason to believe that those therapies work.”

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Posted in: Chiropractic, Clinical Trials, Energy Medicine, Health Fraud, History, Homeopathy, Medical Academia, Medical Ethics, Naturopathy, Politics and Regulation, Science and Medicine

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2009′s Top 5 Threats To Science In Medicine

As 2009 comes to an end, it seems that everyone is creating year-in-review lists. I thought I’d jump on the list band wagon and offer my purely subjective top 5 threats to rational thought in healthcare and medicine.

Of course, it strikes me as rather ironic that we’re having this discussion – who knew that medicine could be divorced from science in the first place? I thought the two went hand-in-hand, like a nice antigen and its receptor… and yet, here we are, on the verge of tremendous technological breakthroughs (thanks to advances in our understanding of molecular genetics, immunology, and biochemistry, etc.), faced with a growing number of people who prefer to resort to placebo-based remedies (such as heavy-metal laced herbs or vigorously shaken water) and Christian Science Prayer.

And so, without further ado, here’s my list of the top 5 threats to science in medicine for 2009 and beyond:
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NIH Awards $30 Million Research Dollars To Convicted Felons: Cliff’s Notes Version

In case you’re coming late to this discussion (or have ADD), I’ve summarized Dr. Kimball Atwood’s terrific analysis of the ongoing clinical trial (TACT trial) in which convicted felons were awarded $30 million by the NIH.

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In one of the most unethical clinical trial debacles of our time, the NIH approved a research study (called the TACT Trial – Trial to Assess Chelation Therapy – a supposed treatment for arteriosclerosis) in which the treatment had no evidence for potential benefit, and clear evidence of potential harm – and even the risk of death. Amazingly, the researchers neglected to mention this risk in their informed consent document. The NIH awarded $30 million of our tax dollars to ~100 researchers to enroll 2000 patients in this risky study (ongoing from 2003-present). Even more astounding is the fact that several of the researchers have been disciplined for substandard practices by state medical boards; several have been involved in insurance fraud; at least 3 are convicted felons.

But wait, there’s more.

The treatment under investigation, IV injection of Na2EDTA, is specifically contraindicated for “generalized arteriosclerosis” by the FDA. There have been over 30 reported cases of accidental death caused by the administration of this drug – and prior to the TACT, 4 RCTs and several substudies of chelation for either CAD or PVD, involving 285 subjects, had been reported. None found chelation superior to placebo.

So, Why Was This Study Approved?

The NIH and the TACT principal investigator (PI) argued that there was a substantial demand for chelation, creating a “public health imperative” to perform a large trial as soon as possible. In reality, the number of people using the therapy was only a small fraction of what the PI reported.

It’s hard to know exactly what happened “behind the scenes” to pressure NIH to go forward with the study – however a few things are clear: 1) the National Heart, Lung, and Blood Institute (NHLBI) initially declined to approve the study based on lack of scientific merit 2) congressman Dan Burton and at least one of his staffers (Beth Clay) and a lobbyist (Bill Chatfield) worked tirelessly to get the study approved through a different institute – NCCAM 3) some of the evidence used to support the trial was falsified (The RFA cited several articles by Edward McDonagh, the chelationist who had previously admitted in a court of law to having falsified his data.) 4) The NIH Special Emphasis Panel that approved the TACT protocol included L. Terry Chappell, whom the protocol had named as a participant in the TACT.

All evidence seems to suggest that political meddling managed to trump science in this case – putting the lives of 2000 study subjects at risk, without any likely benefit to them or medicine.

A formal analysis of the sordid history and ethical violations of the TACT trial was published by the Medscape Journal of Medicine on May 13, 2008. Atwood et al. provide a rigorous, 9-part commentary with 326 references in review of the case. Congressman Burton’s staffer, Beth Clay, published what is essentially a character assassination of Dr. Atwood in response.

The NIH Writes TACT Investigators a Strongly Worded Letter

On May 27, 2009 the Office for Human Research Protections Committee sent a letter to the investigators of TACT, stating that they found, “multiple instances of substandard practices, insurance fraud, and felony activity on the part of the investigators.” The letter describes a list of irregularities and recommends various changes to the research protocol.

It is almost unheard of for a letter from the NIH to state that research study investigators are guilty of fraud and felony activity – but what I don’t understand is why they haven’t shut down the study. Perhaps this is their first step towards that goal? Let’s hope so.

Conclusion

The TACT trial has subjected 2000 unwary subjects and $30 million of public money to an unethical trial of a dubious treatment that, had it been accurately represented and judged by the usual criteria, would certainly have been disqualified. Political meddling in health and medical affairs is dangerous business, and must be opposed as strongly as possible. Congressmen like Tom Harkin and Dan Burton should not be allowed to push their political agendas and requests for publicly funded pseudoscience on the NIH. I can only hope that the new NIH director will have the courage to fend off demands for unethical trials from political appointees.

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

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Tactless About TACT: Critiques Without Substance Should Be Abandoned

In May 2008, the article “Why the NIH Trial to Assess Chelation Therapy (TACT) Should Be Abandoned” was published online in the Medscape Journal of Medicine. The authors included two of our own SBM bloggers, Kimball Atwood and Wallace Sampson, along with Elizabeth Woeckner and Robert Baratz. It showed that the existing evidence on treating heart disease with IV chelation did not justify further study, and that the TACT trial was questionable on several ethical points. Their ethical concerns were taken seriously enough that enrollment in the trial was put on hold pending an investigation. It has now been re-opened after a few band-aids were applied to the ethical concerns. The scientific concerns were never addressed.

I have seen many critiques of the Atwood study, and not a single one has offered any cogent criticism of its factual content or reasoning. Most of them could have been written by someone who had not bothered to read beyond the title. Their arguments can be boiled down to a few puerile points that can be further simplified to:

(1) I believe the testimonial evidence that chelation works.
(2) Atwood and his co-authors are bad guys.

Now Beth Clay has chimed in with an article entitled “Study of Chelation Therapy Should Not Be Abandoned.” I found it truly painful to read, but even the worst has some value as a bad example. Clay’s article could be used for a game of “Count the Errors.” I will point out some of them below. (more…)

Posted in: Clinical Trials, Politics and Regulation, Science and Medicine

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