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The Guatemala syphilis experiment and medical ethics in science-based medicine

Several of the bloggers here at SBM have repeatedly criticized various clinical trials for so-called “complementary and alternative medicine” interventions for various conditions and diseases (or should I say dis-eases?) for being completely unethical. Examples include the misbegotten clinical trial for the Gonzalez protocol for pancreatic cancer, which — surprise, surprise! — ended up showing that patients undergoing Dr. Gonzalez’s combination of 150 supplements a day, dietary manipulations, and coffee enemas, actually did much worse than those undergoing standard of care, despite how depressingly poor the results of standard of care are; clinical trials of homeopathy in Honduras and other Third World countries, which both Wally Sampson and I lambasted; and ongoing clinical trial of chelation therapy for cardiovascular disease. I’ve also criticized the “autism biomed” movement, that amalgamation of parents who believe that vaccines cause autism and yet are willing to subject their children to all sorts of quackery to “cure” the “vaccine injury” of uncontrolled and unethical experimentation on autistic children. As valid as all these criticisms are, it is important to recognize that science-based medicine is not free of its own abuse of ethics.

A couple of weeks ago, I wrote about the concept of clinical equipoise. Clinical equipoise is a critical concept in any clinical trial. Basically, a state of clinical equipoise exists when there is genuine scientific uncertainty over which of the options being tested in/on living, breathing human beings is better, and any clinical trial in which a state of clinical equipoise does not exist is at the very least ethically dodgy and probably downright unethical. For example, when the occasional anti-vaccine activist argues for a randomized controlled clinical trial comparing vaccinated children and unvaccinated children, it’s easy to shoot that idea down as unethical because there is no clinical equipoise. The children receiving placebo vaccines would be put at a much higher risk of suffering harm compared to the vaccinated children because they would be left unprotected against life-threatening diseases. In the realm of conventional medicine, the reason that few cancer clinical trials involve a placebo control group anymore but instead test a new therapy either against the standard of care or with the standard of care is because in many, if not nearly all, cases placebo use in a cancer patient is unethical when there exists effective therapy, even if the therapy is not all that effective. What all this boils down to is that science is only part of the basis of science-based medicine. Medical ethics must take precedence. After all, arguably the most efficacious way to test a new antibiotic would be to infect people with the bacteria the antibiotic treats and then divide these people up into a placebo control group and a group receiving the antibiotics to see how each group does. After all, this is the sort of thing that the Nazis and Japanese did during World War II, and the same sort of dehumanization and abuse of research subjects that every ethical precept regarding human subjects research that has been developed since then, such as the Helsinki Declaration of 1964, has been designed to prevent.

Unfortunately, medical scientists in the U.S. have not always lived up to these precepts. The most famous example is arguably the Tuskegee syphilis experiment, in which poor black men with syphilis were studied and the control group denied effective therapy for syphilis even after it was known that penicillin was an effective treatment for syphilis. This study spanned 40 years, from 1932 to 1972, and is justifiably held up as one of the worst examples of research misconduct in American history, if not the history of the world. The shock the revelation of this study to the American public in 1972, when it learned of men dying of syphilis, women contracting syphilis, and babies being born with congenital syphilis, all unnecessarily, led to Belmont Report and the establishment of the Office for Human Research Protections (OHRP).

It turns out that there was an even worse atrocity against medical science perpetrated by U.S. investigators in Guatemala over 60 years ago that only now has come to light in stories in the New York Times, MSNBC, and elsewhere. So bad was the offense that Secretary of State Hillary Clinton and Secretary of Health and Human Services Kathleen Sebelius have issued a formal apology to the Guatemalan government for the experiments in which Guatemalan prisoners were intentionally infected with syphilis and then treated with antibiotics, an apology that President Obama reiterated in a personal telephone call to Guatemalan President Alvaro Colom on Friday.
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Posted in: Clinical Trials, Medical Ethics

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Chelation: Compounding Pharmacy’s Problems

Chelation is the provision of a substance to increase the body’s excretion of heavy metals. In poisoning situations (lead, aluminum, iron, etc.), chelation is medically necessary, objectively effective, and approved for use. But the same term has a completely different meaning in the alternative medicine universe, where proponents often believe heavy metal toxicity is the “one true cause” of disease, and chelation can undo microvascular inflammation, atherosclerosis, and even aging itself. From early days as an unproven treatment of coronary artery disease, its use has expanded to include autism, Alzheimer’s disease, cancer, and dozens of other diseases. Today, chelation is widely available. Regrettably, my own profession, pharmacy,  facilitates this pseudoscience by manufacturing and selling chelation products.

Provoked urine tests are a common entry point to chelation therapy. Patients are given a product to provoke heavy metal excretion. The urine is tested and the patient is informed that they’re “toxic” and require chelation. Unfortunately, these results are meaningless and provide no evidence that chelation is medically necessary. But that’s the justification used for advocating a treatment regimen that will be useless at best and fatal at worst. A recent Medical Letter review concluded:

Medical Letter consultants believe that the use of chelation therapy in non-standard protocols for unsubstantiated indications should be discouraged. The results of provoked urine testing are not an acceptable basis for such treatment.

Providing chelation to patients isn’t a straightforward matter. It’s typically an intravenous infusion (though there are some oral products). Unless you’re part of the dubious TACT trial, which has administration centres across the United States and Canada, there are few products commercially available. For example, edetate calcium disodium (EDTA) is approved for sale in the United States but not Canada. Edetate disodium (also called EDTA) is not approved for sale in either country. But these products are widely available: they’re manufactured by pharmacists in pharmacies.
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Posted in: Health Fraud, Medical Ethics, Pharmaceuticals

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Clinical equipoise versus scientific rigor in cancer clinical trials

A critical aspect of both evidence-based medicine (EBM) and science-based medicine (SBM) is the randomized clinical trial. Ideally, particularly for conditions with a large subjective component in symptomatology, the trial should be randomized, double-blind, and placebo-controlled. As Kimball Atwood pointed out just last week, in EBM, scientific prior probability tends to be discounted while in SBM it is not, particularly for therapies that are wildly improbable strictly on the basis of basic science, but for both the randomized clinical trial remains, in essence, where the “rubber hits the road,” so to speak. Indeed, when the prior probability of a therapy working based on preclinical basic science investigations appears high, EBM and SBM should be (and are, for the most part) more or less indistinguishable.

The ethics of clinical trials, however, demand a characteristic known as clinical equipoise. Stated briefly, for purposes of clinical trials, clinical equipoise demands that at the time a clinical trial is being carried out there be a state of genuine scientific uncertainty in the medical community over which of the drugs or treatments being tested is more efficacious and safer. One reason (among many) why the Gonzalez trial was completely unethical was a lack of clinical equipose. (Lack of adequate informed consent was another.) Lack of clinical equipoise is also the reason why a prospective randomized, double-blind, placebo-controlled clinical trial testing an unvaccinated group versus a vaccinated control group to determine whether vaccines cause autism would be completely unethical. Such a trial would egregiously violate the principle of clinical equipoise because the unvaccinated group would be left unprotected against potentially life-threatening vaccine-preventable diseases, and that is completely unacceptable from an ethical perspective. Consequently, we have had to rely on on the accumulation of data from less rigorous trial designs to demonstrate that there is no correlation between vaccines and autism. Even so, the accumulated weight of such evidence is enough, and for some questions that is the best we can do because scientific rigor sometimes conflicts with human subjects research ethics. This is an extreme example of lack of clinical equipoise, but it illustrates the point. If we know (or have good scientific reason to suspect) that one treatment is better than another, it is unethical to randomize patients to the arm that receives what is, based on what is known at the time of the trial, likely to be an inferior treatment.

Sometimes, however, the question of whether clinical equipoise exists in a clinical trial is not so obvious as it is for trials proposed by cranks. This situation sometimes crops up in clinical trials for cancer. I was reminded of this issue by a front page story in the New York Times yesterday, New Drugs Stir Debate on Basic Rules of Clinical Trials. In it, reporter Amy Harmon uses a classic human interest story to highlight the issue of clinical equipoise in a clinical trial for a new drug for melanoma that shows great promise. In brief, it is the story of two cousins, one of whom is receiving the new “wonder drug” (whether it is truly a wonder drug or not remains to be seen) in a clinical trial and one of whom is receiving the current standard of care for stage IV melanoma, which, to put it bluntly, sucks in that it has very little effect in prolonging life:
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Posted in: Cancer, Clinical Trials, Medical Ethics

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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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Ghostwriting As Marketing Tool

An article in the latest issue of PLOS Medicine, The Haunting of Medical Journals: How Ghostwriting Sold “HRT”, details the use of ghostwriting as a marketing tool for pharmaceutical companies. It is a chilling discussion of how at least one pharmaceutical company, Wyeth, used the peer-reviewed literature as a method of distributing marketing messages to physicians.

The author, Adriane J. Fugh-Berman, details a practice that cuts at the heart of science-based medicine – the exploitation and distortion of the literature. The medical profession needs to jealously guard the legitimacy and purity of the peer-review process and the medical scientific literature. I am never one to gratuitously bash “Big Pharma” – this is often used as a method of casually dismissing inconvenient scientific evidence. But at the same time, pharmaceutical companies are in the business of making money. While they are a carefully regulated industry, some in the industry seek ways to skirt around regulations that limit their ability to market their products.

While most physicians consider themselves savvy with respect to pharmaceutical marketing, the story told by Fugh-Berman is one of profound naivete. I guess it should not be a surprise that some academics were bamboozled by expert salespersons who spent a lot of time and effort, apparently, figuring out ways to deceive and manipulate them. But now that the story is out, naivete is no longer an excuse. Here is what happened:

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

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A pox on your bank account: failure to vaccinate and its legal consequences

Here’s a question anti-vaxers may want to consider:

Can the parents of an unvaccinated child be held liable if their child becomes infected with a vaccine-preventable disease which then spreads from their child to another child or children?

Yes, they can.

In fact, for over 125 years, courts in this country have recognized a cause of action for negligent transmission of an infectious disease. In the first reported case (New York, 1884) the defendant infected the plaintiff with whooping cough. Cases since then have run the gamut: smallpox, tuberculosis, unspecified “venereal disease,” typhoid fever, scarlet fever, diphtheria, hepatitis, herpes, gonorrhea, HIV. If your favorite infectious disease is not on this list, don’t worry. The disease may vary, but the legal principles remain the same.
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Posted in: Legal, Medical Ethics, Public Health, Vaccines

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Open Letter to Dr. Josephine Briggs

Josephine P. Briggs, M.D.

Director, National Center for Complementary and Alternative Medicine

Dear Dr. Briggs,

As you know, we’ve met twice. The first time was at the Yale “Integrative Medicine” Symposium in March. The second was in April, when Drs. Novella, Gorski and I met with you for an hour at the NCCAM in Bethesda. At the time I concluded that you favor science-based medicine, although you are in the awkward position of having to appear ‘open-minded’ about nonsense.

More about that below, but first let me address the principal reason for this letter: it is disturbing that you will shortly appear at the 25th Anniversary Convention of the American Association of Naturopathic Physicians (AANP). It is disturbing for two reasons: first, it suggests that you know little about the tenets and methods of the group that you’ll be addressing; second, your presence will be interpreted as an endorsement of those methods and of that group—whether or not that is your intention. If you read nothing more of this letter or its links, please read the following articles (they’re “part of your education,” as my 91 y.o. mother used to say to me):

Naturopathy: A Critical Appraisal

Naturopathy, Pseudoscience, and Medicine: Myths and Fallacies vs Truth

The first article is an introduction to the group to which you will be speaking; the second is my response to complaints, from that group and a few of its apologists, about the first article. It was a surprise to me that the editor, George Lundberg, preferred that I make my response a comprehensive one.

Thus the second article inevitably became the crash course—call it CAM for Smarties—that your predecessors never offered you, replete with examples of useless and dangerous pseudoscientific methods, real science being brought to bear in evaluating such methods, proponents’ inaccurate or cherry-picked citations of biomedical literature, bits of pertinent but little-known history, the standard logical fallacies, embarrassing socio-political machinations, wasteful and dangerous ‘research’ (funded—unwittingly, I’m sure—by the NCCAM), bait-and-switch labeling of rational methods as “CAM,” vacuous assertions about ‘toxins’ and ”curing the underlying cause, not just suppressing the symptoms,” anti-vaccination hysteria, misleading language, the obligatory recycling of psychokinesis claims, and more.

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Posted in: Homeopathy, Medical Ethics, Naturopathy, Politics and Regulation, Science and Medicine, Science and the Media, Vaccines

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New CMS Chief Donald Berwick: a Trojan Horse for Quackery?

NB: I posted this on Health Care Renewal a couple of days ago, figuring that Dr. Gorski’s post would suffice for the SBM readership (he and I had discussed the topic while at TAM8 last week). But Managing Editor Gorski has asked me to repost it here, which I’m happy to do. I am especially pleased to demonstrate that I am capable of writing a shorter post than is Dr. Gorski. ;-)

On July 7, President Obama appointed Dr. Donald Berwick as Administrator of the Centers for Medicare and Medicaid Services (CMS). Dr. Berwick, a pediatrician, is well known as the CEO of the non-profit Institute for Healthcare Improvement (IHI), which “exists to close the enormous gap between the health care we have and the health care we should have — a gap so large in the US that the Institute of Medicine (IOM) in 2001 called it a ‘quality chasm’.” Dr. Berwick was one of the authors of that IOM report. His IHI has been a major player in the patient safety movement, most notably with its “100,000 Lives Campaign” and, more recently, its “5 Million Lives Campaign.”

Berwick’s CMS gig is a “recess appointment”: it was made during the Senate’s July 4th recess period, without a formal confirmation hearing—although such a hearing must take place before the end of this Senate term, if he is to remain in the position. A recent story suggested that Obama had made the recess appointment in order to avoid a reprise of “last year’s divisive health care debate.” The president had originally nominated Berwick for the position in April, and Republicans have opposed “Berwick’s views on rationing of care,” claiming that he “would deny needed care based on cost.”

A “Patient-Centered Extremist”

If there is a problem with the appointment, it is likely to be roughly the opposite of what Republicans might suppose: Dr. Berwick is a self-described “Patient-Centered Extremist.” He favors letting patients have the last word in decisions about their care even if that means, for example, choosing to have unnecessary and expensive hi-tech studies. In an article for Health Affairs published about a year ago, he explicitly argued against the “professionally dominant view of quality of health care”:

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Posted in: Health Fraud, Homeopathy, Medical Ethics, Politics and Regulation, Science and Medicine, Science and the Media

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Professional Integrity for Sale? “Sure,” Says Medscape!

Some chiropractors also practice homeopathy. According to Frank King, D.C., many more should be doing just that:

Homeopathy is an energetic form of natural medicine that corrects nerve interferences, absent nerve reflexes, and pathological nerve response patterns that the chiropractic adjustment alone does not correct. The appropriate homeopathic remedies will eliminate aberrant nerve reflexes and pathological nerve responses which cause recurrent subluxation complexes.

Not only does homeopathy correct nerve interferences, it empowers the doctor of chiropractic to reach the entire nervous system. What this means is that we can now better affect the whole person, and all of the maladies that affect us. Homeopathy’s energetic approach reaches deep within the nervous system, correcting nerve interferences where the hands of chiropractic alone cannot reach. Homeopathy is the missing link that enables the chiropractor to truly affect the whole nervous system!

But that’s not all:

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

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