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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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The mammography wars heat up again

PRELUDE: THE PROBLEM WITH SCREENING

If there’s one aspect of science-based medicine (SBM) that makes it hard, particularly for practitioners, it’s SBM’s continual requirement that we adjust what we do based on new information from science and clinical trials. It’s not easy for patients, either. To lay people, SBM’s greatest strength, its continual improvement and evolution as new evidence becomes available, can appear to be inconsistency, and that seeming inconsistency is all too often an opening for quackery. Even when there isn’t an opening for quackery, it can cause a lot of confusion; some physicians are often resistant to changing their practice. It’s not for nothing that there’s an old joke in medical circles that no outdated medical practice completely dies until a new generation of physicians comes up through the ranks and the older physicians who believe in the practice either retire or die. There’s some truth in that. As I’ve said before, SBM is messy. In particular, the process of applying new science as the data become available to a problem that’s already as complicated as screening asymptomatic people for a disease in order to intervene earlier and, hopefully, save lives can be fraught with confusion and difficulties.

Certainly one of the most contentious issues in medicine over the last few years has been the issue of screening for various cancers. The main cancers that we most commonly subject populations to routine mass screening for include prostate, colon, cervical, and breast cancer. Because I’m a breast cancer surgeon, I most frequently have to deal with breast cancer screening, which means, in essence, screening with mammography. The reason is that mammography is inexpensive, well-tested, and, in general, very effective.

Or so we thought. Last week, yet another piece of evidence to muddle the picture was published in the New England Journal of Medicine (NEJM) and hit the news media in outlets such as the New York Times (Mammograms’ Value in Cancer Fight at Issue).
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Posted in: Cancer, Clinical Trials, Diagnostic tests & procedures, Politics and Regulation

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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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Using attacks on science by the anti-vaccine movement as a “teachable moment”

Last week, I wrote one of my usual ridiculously detailed posts analyzing a recent study (Price et al) that, if science and reason ruled, would be the last nail in the coffin of the hypothesis connecting autism with the mercury-containing preservative, thimerosal, which used to be in many childhood vaccines but was phased out beginning in 1999 and disappearing in infant vaccines except for the flu vaccine by early 2002. Of course, for at least the last five years, the thimerosal-autism hypothesis has been a notion whose coffin already had so many nails pounded into it that Price et al probably had a hard time finding even a tiny area of virgin wood into which to pound even a tiny nail of a study published in an impact factor one journal, much less the spike that their study in Pediatrics represented.

Unfortunately, as we know, in the anti-vaccine movement unreason rules, and, not unexpectedly, as a result this study has changed little in the debate, the fortuitously ironic happenstance of its being released the day before Mark Blaxill and Dan Olmsted’s anti-mercury screed Age of Autism not withstanding. To physicians and scientists, it is another strong piece of data being added to the confluence of evidence that has shown no link between mercury in vaccines and autism (or vaccines themselves and autism, for that matter). It is yet another confirmation that vaccines are safe. In contrast, to the anti-vaccine movement, it is simply yet another confirmation that the CDC is hopelessly biased, that scientists are in on a conspiracy to suppress The Truth, and that they are the poor persecuted minority, the only ones who know What Is Really Going On.

When I wrote my post last week, I didn’t know whether or not it would be worth my while to comment on the response of anti-vaccine activists to the study. The reason is that, as fun as it is to reveal their responses to be as vacuous as they are, I wasn’t sure that it would be educational. Granted, sometimes educational value takes a back seat to criticism, but sometimes it’s just too easy. In any case, by mid-week, there had been virtually no criticism of the study yet from the usual sources; so I figured it to be a moot point whether or not I would end up writing about this study one last time. Then, on Thursday morning I noted an e-mail in my in box. In order to keep my finger on the pulse of various pseudoscience movements, I subscribe to e-mail lists of various crank organizations, one of which is Generation Rescue and another of which is SafeMinds. SafeMinds, as you may recall, is the organization headed up by Sallie Bernard. As you may also recall, Bernard was originally on the external consulting committee that participated in the design of Price et al, and, before it, Thompson et al, the two of which ultimately made up a one-two punch against the mercury-autism hypothesis. When she saw that the results of Thompson et al were going against her idea and that no link between thimerosal-containing vaccines and neurodevelopmental disorders was showing up in the preliminary analyses, she resigned from the committee and started attacking Thompson et al. What surprised me was that she wasn’t ready with a criticism of Price et al when it was released.
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Posted in: Clinical Trials, Vaccines

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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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Brain Balance

A member of Quackwatch’s Healthfraud discussion list recently reported from a health fair:

One booth was a bit of a mystery for me: Brain Balance. “Is your child struggling with ADHD, dyslexia, autism, Asperger’s, Tourette’s, or other related disorders?” A quick glance at their website makes it seem that they may be legitimate.

No, a quick glance at their website makes it seem that they are not legitimate, and a more detailed examination confirms that initial impression. (more…)

Posted in: Clinical Trials, Neuroscience/Mental Health

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“Complex, multi-component therapy” can be studied well

This August was a tough month for SBM bloggers reading The New England Journal of Medicine (NEJM). Just one week after a review of acupuncture for back pain—in which the authors recommended referring patients to traditionally trained acupuncturists despite data showing that traditional needling does not outperform a blinded sham control (click here here here for the trifecta takedown)— NEJM featured an original article about a study of Tai Chi for fibromyalgia. As critiqued by Dr. Gorski, the control intervention for the Tai Chi study was arguably inappropriate: the test and control groups experienced different intensities of exercise, for different durations of time, led by different instructors with different levels of enthusiasm. The special pleading and the weak design were not of themselves surprising, only their presence in such an august journal.

A group of editorial authors in that same NEJM issue preemptively address the SBM critics by describing Tai Chi as a “complex, multi-component therapy” and thereby implying that an appropriate sham cannot easily be designed. I agree that studying Tai Chi must be trickier than matching drugs to sugar pills. But “complex, multi-component” interventions can indeed be studied in a way that leads to convincing conclusions, as illustrated in the August 25, 2010 issue of The Journal of the American Medical Association (JAMA). A team of Boston psychologists studied a complex, multi-component intervention for attention deficit-hyperactivity disorder (ADHD) and reported their findings in “Cognitive Behavioral Therapy vs Relaxation With Educational Support for Medication-Treated Adults With ADHD and Persistent Symptoms: A Randomized Controlled Trial.” The abstract: (more…)

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Avastin and metastatic breast cancer: When science-based medicine collides with FDA regulation

One of the most frustrating aspects of taking care of cancer patients is that in general, with only a few specific exceptions, we do not have good curative therapies for patients with stage IV cancer, particularly solid tumors. Consequently, patients with stage IV disease are viewed as “incurable” because, the vast majority of the time, they are incurable. Over the years, we have thrown everything but the kitchen sink at patients with stage IV disease, largely with dissapointing results. That’s not to say that the few specific exceptions to which I alluded are not a reason for hope. After all, patients with colorectal cancer and liver metastases used to have a median survival of around 6 months, but these days, with newer chemotherapeutic regimens like FOLFOX plus Avastin, median survival has more than tripled. While expecting to live less than two years is cold comfort to cancer patients with this particular clinical situation, the prognosis is far better than it was.

Of course, I specifically mentioned Avastin because it’s been in the news a lot recently with respect to my area of clinical specialty, breast cancer. Specifically, beginning in July there started appearing a spate of stories about the FDA considering revoking the approval of Avastin for advanced breast cancer based on recent studies that demonstrate that it does not prolong survival in these patients. Many lay people and patients find this reconsideration of Avastin to be quite puzzling, given that the drug was granted accelerated approval in 2008 and has since gone on to be used fairly widely. Given that the case of Avastin in breast cancer is rapidly becoming a classic case study of how messy science-based medicine can be when practiced in the public eye and debated among pharmaceutical companies, the government, and patient advocacy groups.
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Posted in: Cancer, Clinical Trials, Pharmaceuticals, Politics and Regulation

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Tai chi and fibromyalgia in the New England Journal of Medicine: An “alternative” frame succeeds

It never seems to fail. I go away for a few days, in this case to combine fun with pleasure and pleasure with fun by giving a talk to the Chicago Skeptics and at the same time meeting my brand new (well, by this time three weeks old) nephew for the first time, and something always happens. Before I get to what happened, I just want to point out that the talk actually went pretty darned well. I was utterly shocked that it was pretty much standing room only, with perhaps 50 people there to hear me. Honestly, don’t you people have anything better to do on a beautiful Saturday afternoon in August? But, seriously, the whole thing was a blast, and the assembled skeptics there didn’t even let me off the hook, as at least a couple of them asked some fairly challenging questions, one of which, I must admit, I wasn’t prepared for. In any case, my thanks go out to Dr. Jennifer Newport, skeptical Chicago pediatrician extraordinaire and organizer of my talk and the party at her apartment afterward. Between the two events she raised hundreds of dollars for the vaccination drive going on at DragonCon this weekend, Chicago Skeptics, the Women Thinking Free Foundation, and CFI-Chicago for inviting me and being such fantastic hosts.

Back to business. Science-based medicine (SBM) business, that is.

What happened while I was away could almost be characterized by the New England Journal of Medicine (NEJM) singing “Oops, I did it again.” Three weeks ago, the hallowed pages of the NEJM hosted a truly execrably credulous review article about acupuncture. So bad was the article that it “merited” the incredibly rare triple beat-down from this very blog, with posts by Steve Novella, the ever-irascible Mark Crislip, and myself in rapid succession applying the clue-by-four. As I was preparing to leave for Chicago on Thursday, I happened to look at the very latest issue of the NEJM hot off the presses, and what to my wondering (and watering–it is ragweed season) eyes should appear but an article reporting a study on the use of tai chi in treating fibromyalgia. Entitled A Randomized Trial of Tai Chi for Fibromyalgia, the study comes out of the Tufts University School of Medicine and the Newton-Wellesley Hospital in Boston and was carried out by a team led by Chenchen Wang, MD, MPH. Not surprisingly, the study has gotten a lot of play in the media, for example, in this story in the L.A. Times, which is at least reasonably restrained, probably because it an AP wire story by Marilynn Marchione, who has written some excellent articles about “alternative” medicine before. Even the usually reliable GoozNews seems smitten with this study beyond what it rates, characterizing it as “rare victory for the National Institute of Health’s National Center for Complementary and Alternative Medicine and Sen. Tom Harkin (D-IA), who routinely comes under fire for pushing funding for these types of studies.”

I’m less impressed. You’ll see what I mean in a few minutes, I hope. First, however, let’s look at the study itself.
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Posted in: Clinical Trials, Medical Academia, Science and the Media

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