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

A Review; then Back to the Gonzalez Regimen†

Part I of this blog introduced the topic of the “Gonzalez regimen” for treating cancer: “Intensive Pancreatic Proteolytic Enzyme Therapy With Ancillary Nutritional Support” and “detoxification” with twice daily coffee enemas, daily “skin brushing,” “a complete liver flush and a clean sweep and purge on a rotating basis each month,” and more. The topic was occasioned by the federal Office for Human Research Protections having recently cited Columbia University, for the second time, for violations of human subject protections in its NIH-funded trial of Gonzalez’s method as a treatment for cancer of the pancreas.

Part I discussed the implausible and bizarre regimen and cited Gonzalez’s troubles with malpractice suits and with the New York medical board during the 1990s. It ended by wondering what could have induced the NIH to give a $1.5 million grant to Columbia University to study the method.

Parts II and III began to answer that question, tracing some of the key events and individuals from the Laetrile wars in the 1970s to the NCI-funded trial of Laetrile reported in 1982, to the ”immuno-augmentative therapy” (IAT) battles of the mid-’80s, to the Report on “Unconventional Cancer Treatments” by the Congressional Office of Technology Assessment (OTA) in 1990, which in turn led to the NCI adopting its “Best Case Series Program” in 1991.

The end of Part III hinted that the conspiracy mongering that had greeted every attempt by the government to explain its positions on implausible cancer treatments, from Laetrile to the OTA report, ultimately led to the creation of the Office of Alternative Medicine (OAM) at the NIH, also in 1991. There is plenty of evidence for that, both from the conspiracy mongers themselves and from more level-headed observers. Each time the government acted—to fund a trial of Laetrile, to solicit the OTA report and propose a study of IAT, to establish the NCI “Best Case Series” program, and to establish the OAM—it was not because of scientific or medical considerations, but because of political pressure. More on that from time to time, but now back to Dr. Gonzalez.

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Posted in: Cancer, Clinical Trials, Health Fraud, Medical Academia, Medical Ethics

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Borderlines in research

This is a slight departure from the usual fare of pseudoscience, but a matter that should concern us because of the vulnerability this matter confers on medicine – the borderline practices of major medical centers. The article can be viewed here.

Several days ago the San Francisco Chronicle printed a second article about the plight of a 37 year old woman (EP) with an inflammatory breast cancer who was denied insurance coverage for an expensive treatment, high-dose chemotherapy with autologous bone marrow (or stem cell) transplant or infusion (HDCT/BMT or SDI.) The institution is the MD Anderson Cancer Center in Houston. The problem is that although the treatment is effective, it is no moreso than moderate dose HDCT without the marrow or stem cell infusion, and also is more expensive and has significant morbidity.

Inflammatory breast cancer is a highly aggressive form that is usually regarded as “advanced” when diagnosed, that is, spread beyond the breast and regional lymph nodes. One cannot tell from the article whether EP’s cancer spread is documented or implied. But because of the poor prognosis and presumed incurability in either case, options are limited. In the 1980s -90s, HDCT/BMT was thought to be a promising method on the basis of studies that showed a prolonged disease-free and overall survival compared to results of prior studies using more conservative treatment. The problem then was that the studies were uncontrolled.

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Posted in: Cancer, Clinical Trials, Medical Ethics

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Studying Placebo Effects

ResearchBlogging.orgMeasuring placebo effects (often misleadingly referred to as the placebo effect – singular) is a part of standard clinical trial design, because they need to be distinguished from the physiological effects of the treatment under study. Rarely, however, are placebo effects the actual target being measured, but such is the case with a new study published in the most recent edition of the British Medical Journal (BMJ) – Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. (Here is a summary if you cannot access the article directly.)

Dr. Ted Kaptchuk et.al. studied the response to various placebo treatments in 262 adults with irritable bowel syndrome (IBS). The three groups were designed to address three major categories of placebo effects: 1) response to the process of being assessed and observed, 2) response to being given a placebo treatment, and 3) response to the patient-practitioner relationship. These types of placebo effects were represented by three treatment arms: 1) observation alone, 2) placebo acupuncture, 3) placebo acupuncture plus an “augmented” practitioner-patient relationship – with added “warmth, attention, and confidence.”

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Posted in: Clinical Trials, Science and Medicine

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

Laetrile and the Politics of NIH-Sponsored trials of “Alternative Cancer Treatments”

Part I of this blog ended by asking how, in light of the implausible and arduous nature of the “Gonzalez regimen” for cancer of the pancreas, and the unconvincing “best case series,” the NIH could ever have decided to fund a trial of it.† This entry will begin to answer that question. In so doing it may seem to veer from the original subject, but hold on to your seats: what you’ll find here is a piece of the treasure map that leads to the Mother Lode of Fool’s Gold that is government-sponsored “CAM” research.

All historical accounts of the encroachment of implausible claims into the research agenda of the NIH must begin with Laetrile. By that is meant all implausible claims, not merely those having to do with cancer. Elsewhere we have traced the history of “chelation therapy” for coronary artery disease, and have shown that its origins as a political movement, eventually leading to an unethical, $30 million, 2000 subject NIH trial, were intimately associated with people and organizations advocating Laetrile—the most lucrative health fraud ever perpetrated in the United States. In that essay we offer evidence that the creation of the NCCAM itself was at least partly attributable to the history of Laetrile and its advocates. Several good histories or partial histories of the Laetrile debacle are available online, including here, here, here, here, here, and here. The best,¹ but one that does not seem to be available online, is by the recently deceased dean of historians of American quackery, James Harvey Young. (more…)

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

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

Blogger’s note: This blog, which is rough going in places, will be presented in either 2 or 3 parts (I won’t know which until next week). I’ll post a part each week until it is complete, but due to overwhelming popular demand I promise to maintain the every-other-week posting of the far more amusing Weekly Waluation of the Weasel Words of Woo/2.

Introduction

On Feb. 25, 2008, the federal Office for Human Research Protections (OHRP) cited Columbia University Medical Center (CUMC) for violating Title 45, Part 46 of the Code of Federal Regulations: Protection of Human Subjects (45CFR§46). The violations involved Columbia’s administration of the NIH-sponsored trial of the bizarre “Gonzalez Regimen” for treating cancer of the pancreas.† The OHRP’s determination letter to Steven Shea, MD, the Director of the Division of General Medicine and Senior Vice-Dean at CUMC, cited ethical problems of a serious kind:

We determine that the informed consent for the 40 of 62 subjects referenced by CUMC was not documented prior to the start of research activities, nor was the requirement for documentation waived by the CUMC IRB for subjects in this study.

It was the second time that the OHRP had cited Columbia for its dubious management of the “Gonzalez” trial. The first occurred in Dec. 2002, after investigators had determined that the trial’s consent form “did not list the risk of death from coffee enemas.” The OHRP listed several other violations at that time, but “redacted” them from the letter that it made available to the public. (more…)

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

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When impressive science fails to impress patients

One of the greatest challenges in medicine can sometimes be to convince patients that the results of scientific and medical research apply to them, or, at the very least, to explain how such results apply. One of the reasons that medicine based not on science or evidence fluorishes is because it can be so hard to explain to patients why a particular intervention is viewed as effective. My co-blogger Steve Novella wrote about some of the fallibilities of human perception that lead to perceiving correlations and treatment effectiveness where there are none. R. Robert Bausell wrote about the same thing in his recent book Snake Oil Science. While it is undoubtedly true that people tend to pay more attention to anecdotes than to studies and statistics, there is also another reason why doctors often have problems convincing patients of the value of health interventions, and that’s the difference in perception and how we value different kinds of evidence.

A couple of years ago, I came across an article that explains this gulf between how those of us trying to practice science- and evidence-based medicine perceive the world and how most human beings not trained in medicine or science perceive it. The article, which was published in 2006 in the New York Times and written by Dr. Abigail Zuker, proposed one reason why this might be, beginning with a discussion with her mother in which she tries to convince her of the benefit of exercise, even in the elderly, a concept that her mother would have none of and dismissed contemptuously:

“Studies,” she says, dripping scorn. “Don’t give me studies. Look at Tee. Look at all the exercise she did. She never stopped exercising. Look what happened to her.”

End of discussion. Tee, her old friend and contemporary, took physical fitness seriously, and wound up bedbound in a nursing home, felled by osteoporosis and strokes, while my mother, who has not broken a sweat in the last 60 years, still totters around on ever-thinning pins. So much for exercise. So much for studies. So much for modern clinical medicine, based on the randomized allocation of treatment and placebo. All that beautiful science, stymied by the single, incontrovertible, inescapable image of Tee, the one who exercised but grew hunched and crippled anyway.

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Posted in: Clinical Trials, Public Health, Science and Medicine

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Do Antidepressants Work? The Effect of Publication Bias

A recent meta-analysis of the most commonly prescribed antidepressant drugs raises some very important questions for science-based medicine. The study: Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration, was conducted by Irving Kirsch and colleagues, who reviewed clinical trials of six antidepressants (fluoxetine, venlafaxine, nefazodone, paroxetine, sertraline, and citalopram). They looked at all studies submitted to the FDA prior to approval, whether published or unpublished. They found:

Drug–placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

The press has largely reported this study as showing that “antidepressants don’t work” but the full story is more complex. This analysis certainly has important implications for how we should view the body of evidence for these antidepressants. It also illuminates the possible role of publication bias in the body of scientific literature – something that has far ranging implications for science-based medicine.

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Posted in: Clinical Trials, Neuroscience/Mental Health, Pharmaceuticals, Science and Medicine

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RCT Plausibility Scale

RCT Plausibility Scale

After a few intro paragraphs, I want to present a scale of probability to estimate a value of a “prior” to plug into the formula for obtaining a Bayes Factor. The scale can help to estimate a value, but will still rely on an estimate, the non-quantitative element in Bayesian simulations. However, the checklist may at least provide some objective bases on which to hang a value, and that value would actually make a semi-quantitative statement of its own. Although that value would retain some subjective quality, it would at least be backed by known quantities and laws of nature.

Begging your patience again, I became aware of this problem in 1999 when asked to moderate an online (BioMednet.com) debate on “CAM” among 4 physicians. My role soon morphed into participant-debater when I could not get all to agree on what I thought was obvious common ground to proceed with the discussion – that 1) concepts that violate scientific laws do not have to be subjected to clinical trial (RCT) and that trial results had to be interpreted in light of previous knowledge; and 2) clinical trials could not constitute adequate evidence in the absence of plausibility because their results were too varied and inconsistent. The matter was p-recipitated by systematic reviews (SRs) showing efficacy of acupuncture in back pain. I was truly surprised when one of the participants (Dr. Edzard Ernst) assured me that indeed, RCTs were now the gold standard for efficacy. The debate went downhill from there.

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Posted in: Clinical Trials, Science and Medicine

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Bad scientific arguments in the service of animal rights activism

One of the greatest threats to the preclinical research necessary for science-based medicine today is animal rights activism. The magnitude of the problem came to the forefront again last week with the news that animal rights terrorists tried to enter the home of a researcher at the University of California Santa Cruz (UCSC) whose research uses mice to study breast cancer and neurologic disease while she and her husband were having a birthday party for one of their children and assaulted her husband, who had gone to the front of the house to confront them. Fortunately, the license plate number of the car fleeing the scene was reported to police, leading to a raid on a house by police and the confiscation of computers and other materials. This attack appeared to be the latest crescendo in an increasing campaign of harrassment and intimidation by animal rights “activists” that has also been observed in nearby Berkeley.

This sort of threat to researchers is not a problem just in Santa Cruz and the Bay area, but in particular has been a problem in southern California as well. Just earlier this week, the University of California Los Angeles announced that it was suing several animal rights groups and individuals suspected of attacks on researchers who use animals, including UCLA Primate Freedom Project, the Animal Liberation Front (ALF), and the Animal Liberation Brigade (ALB), as well as several individuals believed to affiliate with these groups. The inciting event for this action was the second attack on the home of Edythe London, Professor of Psychiatry and Bio-behavioral Sciences and of Molecular and Medical Pharmacology at the David Geffen School of Medicine at UCLA, in early February. Her research involves the use of primate models to study nicotine addiction. In this most recent attack, an attempt was made to set her house on fire. This came on the heels of a previous attack in October, in which animal rights activists flooded her house. Prior to that, animal rights terrorists had indeed succeeded in their aim of intimidating a scientist sufficiently that he gave up animal research after a fellow researcher was targeted with a Molotov cocktail meant for her home that was mistakenly placed on the porch of an elderly neighbor. Also, we in the U.S. often forget how much more radical animal rights extremists are in the U.K., where the campaign of intimidation takes the form of death threats, intimidation of personnel of companies that supply researchers, and even in one case digging up the grave of Gladys Hammond, whose family ran a farm that raised Guinea pigs for use in medical research, and stealing her remains.

Readers may make the argument that my introduction to this discussion is unfairly inflammatory, but I have my reasons for starting this way, and I think they are good ones. First, make no mistake, the aim of the most radical of these activists is nothing short of the cessation of the use of all animals in biomedical research. Second, sooner or later, someone will be hurt or killed. As a researcher who on occasion uses mouse models of cancer myself, I state up front that I could be on the firing line just as much as the UCSC researcher or others and am justifiably disturbed when I hear spokesperson for the ALF Dr. Jerry Vlasak, for example, repeatedly advocate violence against researchers who use animals. In this article, I am not going to discuss the moral issues involved in animal research. What I am going to discuss is the seemingly scientific arguments that some opponents of animal research and animal rights activists like to invoke, arguments increasingly used in addition to the moral arguments that extremists use to justify their actions. If the arguments of opponents of animal rights research were indeed good science, then their appropriation by extremists would not allow me to do much other than bemoan the misuse of valid science as a justification for extremism. Unfortunately, such is not the case, and the bad scientific arguments used by opponents of animal research are often piled onto the extreme moral arguments that fuel actions such as those earlier this week at UCSC. Consequently, given the events of the last month or so, I thought I would take this opportunity to look at some of the common scientific indictments of animal research by its opponents.
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Posted in: Basic Science, Clinical Trials, Politics and Regulation, Science and Medicine

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Glucosamine Update: A New Study and a New Product

ResearchBlogging.orgWhen I recently wrote about glucosamine, I discussed the evidence up through the New England Journal of Medicine study of 2006, which I thought was a pretty definitive study showing that neither glucosamine, chondroitin or a combination of the two was more effective than placebo.  Subsequent studies have continued to fuel the controversy. One 2007 study showed that glucosamine sulfate was better than placebo for knee osteoarthritis.  Another 2007 study showed that glucosamine HCl and chondroitin, with or without exercise, were no better than placebo for knee osteoarthritis. Sources like the Natural Medicines Comprehensive Database believe the evidence favors glucosamine sulfate but not glucosamine hydrochloride.

A new study was published 19 February 2008 in the prestigious Annals of Internal Medicine.  It is arguably the best study to date, and may shed some light on the controversy. Carried out in the Netherlands in a primary care setting, it studied 222 patients with hip osteoarthritis over a 2 year period. Half the patients took glucosamine sulfate 1500 mg a day; half took a placebo. They concluded that glucosamine sulfate was no better than placebo in reducing symptoms and progression of hip osteoarthritis. (more…)

Posted in: Clinical Trials, Herbs & Supplements

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