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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…)

Posted in: Clinical Trials

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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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Risibility. The Superior Therapeutic Intervention?

Dad always thought laughter was the best medicine, which I guess is why several of us died of tuberculosis.

~Jack Handey, “Deep Thoughts

We have a saying in medicine that you can’t kill a jerk.  Not that we try to kill anyone, but that particularly unpleasant individuals, rife with psychopathology, survive whatever illness comes their way.  The corollary is that particularly nice people are prone to having horrible diseases with unpleasant outcomes.  We all know intellectually that it is not true, but there is an ongoing feeling in health care providers that somehow patient personality determines the consequences of their diseases.  As an aside, I am often  left with the explanation for patients that the reason for their odd infection comes down to bad luck.  Everyone responds something to the effect that “Typical. I get all the bad luck.”  I have never had a patient say, “That’s odd, I am usually so lucky.”

On the question of nurture versus nature, raising two children has convinced me of the relative lack of importance of nurture in the personalities of my children.  While abusive/pathologic environments will certainly lead to pathologic personalities,  for the average child raised in middle class America I can’t help but think that, to quote Popeye, “I yam what I yam and that’s all what I yam.”  I expect to be schooled in the comments on that subject.  Yes, I read the Blank Slate and have some understanding of the literature.  And yet.  My kids, my friends kids.  I watch them grow in what is (and isn’t) a similar environment and end up with diverse personalities that often appear present before they can speak.  I am well aware of the multiple logical fallacies that lead to that conclusion.  Parenthood and medical practice (where people seem to do the same damn stupid things over and over) have lead me to the conclusion that free will is mostly a myth and we are mostly programmed to behave the way we do. Discuss.  It is not the main point of the post, but my bias.

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Posted in: Clinical Trials, Faith Healing & Spirituality, Humor, Science and Medicine

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Glucosamine: The Unsinkable Rubber Duck

Glucosamine is widely used for osteoarthritis pain. It is not as impossible as homeopathy, but its rationale is improbable. As I explained in a previous post,

Wallace Sampson, one of the other authors of this blog, has pointed out that the amount of glucosamine in the typical supplement dose is on the order of 1/1000th to 1/10,000th of the available glucosamine in the body, most of which is produced by the body itself. He says, “Glucosamine is not an essential nutrient like a vitamin or an essential amino acid, for which small amounts make a large difference. How much difference could that small additional amount make? If glucosamine or chondroitin worked, this would be a medical first and worthy of a Nobel. It probably cannot work.”

Nevertheless, glucosamine (alone or with chondroitin) is widely used, and there are some supporting studies. But they are trumped by a number of well-designed studies that show it works no better than placebo, as well as a study showing that patients who had allegedly responded to glucosamine couldn’t tell the difference when their pills were replaced with placebos. The GAIT trial was a large, well-designed, multicenter study published in The New England Journal of Medicine that showed no effect in knee osteoarthritis. A subsequent study of hip osteoarthritis also showed it worked no better than placebo.

A new study shows that glucosamine works no better than placebo for osteoarthritis pain in the low back. It was published in the JAMA: Effect of Glucosamine on Pain-Related Disability in Patients with Chronic Low Back Pain and Degenerative Lumbar Osteoarthritis: A Randomized Controlled Trial, by Wilkens et al. (more…)

Posted in: Clinical Trials, Herbs & Supplements

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Homeopathy in the ICU?

ResearchBlogging.orgEditor’s note: It’s still a holiday weekend in the United States. I had considered simply taking the day off altogether, particularly since I’m busily working on my talk for TAM8–which (holy crap!) is in a mere three days–but then I figured today’s a good time to resurrect a “classic” (if you will) post that I wrote a few years ago, dust it off, and post it. I decided to do this mainly because I had been planning on bringing this post to SBM at some point right from the very beginning of SBM.

Regular readers of this blog are probably familiar with a certain homeopath named Dana Ullman. So persistent is he in his pseudoscientific arguments for the magic that is homeopathy that fellow SBM blogger Kimball Atwood once postulated a humorous law he dubbed the Dull-Man Law:

In any discussion involving science or medicine, being Dana Ullman loses you the argument immediately…and gets you laughed out of the room.

Kimball then pointed to a number of studies that Ullman likes to cite ad nauseam that supposedly “prove” the efficacy of homeopathy. One study Kimball didn’t mention, however, is a favorite of Ullman’s, one he likes to trot out time and time again. Specifically, it’s a study of homeopathy in the ICU that was published, in all places, in Chest, a respectable journal that, as you might expect, is dedicated to research on diseases of the chest, such as chronic obstructive pulmonary disease (COPD), cardiac disease, and basically any disease that manifests its pathology in the chest, although it primarily deals with critical care. I first learned of this study way back in 2007 from Dr. R. W., who at the time commented quite aptly that the article impressed him with just how far into the medical mainstream woo has penetrated, while retired doc also expressed his dismay.

Although I do feel a bit guilty not providing you with more original peerless prose pontificating on medical pseudoscience that you know and (hopefully) love, this article is constantly trotted out by homeopaths, even five years later, and that makes it worth updating an older post from another source. So here’s the abstract:
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Posted in: Clinical Trials, Homeopathy

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The latest chapter in the seemingly never-ending saga of dichloroacetate as a cancer treatment

The road from an idea to a useful drug is a long one, and in cancer it is often particularly long. One reason is that to be able to tell whether a given treatment is effective against cancer often takes several years at a minimum, in order to determine if patients receiving the new treatment are surviving their disease longer than those who are not. Surrogate endpoints are usually not enough. Tumor shrinkage in response to a drug often does not correlate with prolongation of survival, although the converse (i.e., lack of tumor shrinkage in response to a new drug) does strongly correlate with failure of a treatment to prolong survival. In other words, effects observed on surrogate endpoints are not enough to judge whether a cancer therapy is working or not.

Three years ago, predating the existence of this blog by nearly a year, I became aware of a story that involved many of the issues in bringing a compound from the laboratory to the clinic. The case was unusual in that is is very rare to see the scientific process by which new drugs progress through the stages of cancer research, from concept to testing in cell culture to testing in animals to testing in humans challenged so strongly by patients themselves. The reason that this normally doesn’t occur is that new cancer treatments are almost always the product of either university-conducted research, pharmaceutical company-conducted research, or partnerships between the two. This case was markedly different in that it involved a chemical that was not only easy to synthesize, but cheap and long out of patent. Even more intriguing, it targeted a metabolic abnormality found in many cancer cells, an abnormality first described nearly 80 years before by Otto Warburg in 1928. This latter aspect of the drug gave it every appearance of a “rediscovery” of old wisdom that big pharma had ignored for 80 years, and that only added to its mystique.

The chemical was dichloroacetate (DCA), and three years ago it created a world-wide sensation. Last week, it created a sensation again, as breathless news reports once again overhyped its promise. Since I’ve been following the story since early 2007, I appear to be in as good a position as anyone to tell the story thus far and put the new findings into context. To begin that process, let’s head back to January 2007.
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Posted in: Cancer, Clinical Trials, Health Fraud

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A homeopathy supporter notices our visit with the director of NCCAM

On April 2, Steve Novella, Kimball Atwood, and I visited the National Center for Complementary and Alternative Medicine (NCCAM) to meet with its director, Dr. Josephine Briggs. I’m not going to rehash what was said because we agreed that Steve would handle that task, and he did so admirably last week. I agree with Steve that it was encouraging that Dr. Briggs apparently reads this blog and shares many of our concerns about NCCAM, the poor science that it has funded, and its use by promoters of unscientific medicine to promote their quackery. Most heartening of all was that she appeared to recognize how much CAM is infused with anti-vaccine beliefs and, worse, the promotion of these beliefs to the detriment of public health.

Those positive reactions to what was a friendly but frank exchange of views notwithstanding, as we were sitting in a conference room next to Dr. Briggs’ office, I couldn’t help but wonder what the reaction of CAM promoters would be when they found out about this meeting. Now I know. John Weeks over at The Integrator Blog is not happy:

Novella’s posting reads like a Fox News interview: 95% his team’s point, then a brief NCCAM response. That Briggs asked for the meeting likely grew out of an early March conference at Yale at which Novella and she both participated. For this, she deserves the Barack Obama Big Tent award for her proven interest in sitting down with everyone, no matter which party affiliation or belief. (Some have said this was proven in early 2008 when Briggs met with me.) Arguably, Briggs takes her openness to dialogue further than the President. While Obama has kept arms length from leaders who call for the demise of the United States, Briggs has now met with those who have been lobbing bombs at her professional home for years, calling steadily for NCCAM’s destruction.

Because our previous calls for the closing of a relatively small government institute because we view it as a poor use of taxpayer money is just like calling for the downfall of the United States government. Weeks clearly likes ridiculously overblown hyperbole. Interestingly enough, what appeared to upset Mr. Weeks the most was our discussion of homeopathy with Dr. Briggs. As Steve put it:
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Posted in: Clinical Trials, Homeopathy, Medical Academia

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