Archive for Clinical Trials

The perils and pitfalls of “patient-driven” clinical research

Dying of cancer can be a horrible way to go, but as a cancer specialist I sometimes forget that there are diseases that are equally, if not more, horrible. One that always comes to mind is amyotropic lateral sclerosis (ALS), more commonly known as Lou Gehrig’s disease. It is a motor neuron disease whose clinical course is characterized by progressive weakness, muscle atrophy and spasticity, with ultimate progression to respiratory muscles leading to difficulty breathing and speaking (dysarthria) and to the muscles controlling swallowing. The rate of clinical course is variable, often beginning with muscle twitching in an arm or a leg or slurring of speech. Ultimately, however, ALS progresses to the loss of ability to move, speak, eat, or breathe. The most common cause of death is from respiratory failure, usually within three to five years after diagnosis, although there is the occasional outlier with a less malignant form of the disease with a slower course of progression who can live a long time, such as Steven Hawking.

In other words, ALS is a lot like cancer in some ways. It is a progressive, fatal disease that usually kills within a few years at most. On the other hand, it is different from cancer in that, at least for many cancers we actually do have effective treatments that prolong life, in some cases indefinitely. In contrast the most effective treatment we currently have for ALS is a drug (riluzole) that is not particularly effective—it prolongs life by months—and can be best described as better than nothing, but not by a whole lot. So it is not surprising that ALS patients, like cancer patients, become desperate and willing to try anything. This is completely understandable, but sometimes this desperation leads to activities that are far more likely to do harm than good. I was reminded of this when I came across a post in the antivaccine propaganda blog, Age of Autism, referring to an article in The Scientist entitled Medical Mavericks. The fortuitous posting of this story, which was apparently designed to try to show that it’s not as crazy as critics have said to be treating autistic children with “Miracle Mineral Solution” (MMS) (which is a bleach) given that the introduction explicitly mentioned Kerri Rivera and the patient described in the article used sodium chlorite to treat his ALS, provided me the opening to discuss a group whose existence and advocacy brings up a complex tangle of issues that boil down to questions of how far patient autonomy should be allowed to go. I’m referring to a company, PatientsLikeMe, which describes itself thusly:

Posted in: Cancer, Clinical Trials, Neuroscience/Mental Health

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Journal Club

There is a tradition in medical training called Journal Club. The first rule of Journal Club is you do not talk about Journal Club. In Journal Club, at least in the iterations in which I have participated, one article is selected by an attending, everyone reads it, then the strengths, weakness and applicability are discussed by the group. Usually a top notch, ground breaking article was the focus, one that had high potential clinical impact. But since they were good articles in good journals, there was not a lot to learn about in reguards to critical thinking. While the attending would put the article in context and maybe discuss some rudimentary statistics, there was little that was discussed about the quality of the study. The main take home from every study was to question the applicability of the results to populations that were not old, white males, since it seemed all the ground breaking studies back in the day were a VA Cooperative study of one sort or another.

As I remember it, there was not really a conceptual frame work with which to evaluate studies. Bayes theorem, and its application to clinical medicine was never explicitly discussed outside of testing, where you have to consider the prior plausibility of the patient having a disease before you can decide if the test results is a true positive or not. In Portland, Oregon, the chance that a Lyme serology is a false positive is much greater than a test done in Portland, Maine. Generally speaking in the information overload state that is the practice of medicine, clinical trials are generally taken at face value and tests are considered infallible. Which is a shame, as I wonder how much suboptimal medicine is inflicted on patients by not considering prior plausibility and how accurate a given test is in either ruling in or out a disease. There seems to be a whole industry built around treating patients with no risks for Lyme but have positive tests of doubtful provenance. We never discussed the prior plausibility and its effect on the outcomes of a studied treatment. (more…)

Posted in: Clinical Trials, Science and Medicine

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Meet the new drugs, same as the old drugs?

“Targeted therapy.” It’s the holy grail of cancer research these days. If you listen to its most vocal proponents, it’s the path towards “personalized medicine” that improves survival with much lower toxicity. With the advent of the revolution in genomics that has transformed cancer research over the last decade, including the petabytes of sequence and gene expression data that pour out of universities and research institutes, the promise of one day being able to a patient’s tumor, determining the specific derangements in genome and gene expression that drive its uncontrolled proliferation, and finding drugs to target these abnormalities seems more tantalizingly close than ever. Indeed, it seems so close that even dubious practitioners, such as Stanislaw Burzynski, have jumped on the bandwagon, co-opting the terms used by real oncologists and real cancer researchers to sell “personalized gene-targeted cancer therapy,” which in their hands are really no more than a parody of efforts to synthesize the enormous quantity of genomic data each patient’s tumor possesses and figure out how best to take advantage of it, a “personalized genomic therapy for dummies,” if you will.

That’s not to say that there aren’t roadblocks to realizing this vision. The problems to be overcome are substantial, and I’ve discussed them multiple times before. For example, just a couple of weeks ago I discussed an example of just what it takes to apply these new genomic techniques to an individual patient. The resources required are staggering, and, more problematic, there often aren’t any single “magic bullet” molecular pathways identified that can be targeted with existing drugs. The case I discussed was a fortunate man indeed in that such a pathway was identified, but most tumors are driven by many derangements in growth control, metabolism, migration, and the other hallmarks of malignancy described by Robert Weinberg. Worse, in many cases we don’t even have drugs that can attack many of the abnormalities that drive cancer progression. Then there’s the issue of tumor heterogeneity, which comes about because cancer is as good example of a disease as I can think of in which evolution due to natural selection results in incredible differences in the cancer cells in one part of the tumor compared to other parts of the tumor or in the tumor metastases. A “targeted” therapy that targets the genetic abnormalities in one part of the cancer might well fail to target the genetic abnormalities driving another part of the tumor.

These, and many other reasons, are why we haven’t “cured cancer” yet.

Posted in: Cancer, Clinical Trials

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The Plausibility Problem

From the very outset, the founders of Science Based Medicine have have emphasized the importance of plausibility in the critical evaluation of scientific claims in medicine. What exactly does “plausibility” mean, and how should we apply it in science? My simple definition of plausibility would be “the likelihood that a premise is true.” The application in science is a little more complicated.

Consciously or unconsciously, we all consider plausibility in interpreting events in our lives. For example, if one of your coworkers showed up late for work and grumbled about a traffic jam, you would likely accept his story without question. If, instead, the same coworker attributed his tardiness to an alien abduction, you would not be so charitable. In each case, he has provided the same level of evidence: his anecdotal account. You are likely to accept one story and reject the other because of a perceived difference in the plausibility. The skeptic’s mantra “Extraordinary Claims Require Extraordinary Evidence” expresses this concept in a qualitative way.

Evidence-based medicine has traditionally ignored plausibility when interpreting the evidence for a medical intervention. Science-based medicine, as envisioned by the creators of this blog, includes plausibility when making these judgements.

Since experiment research employs rigorous controls, and statistical criteria, you might assume that plausibility is not an issue, however, this is not entirely true. An article written by John Ioannidis entitled “Why Most Published Research Findings Are False” is cited frequently as a reference for the impact of plausibility on the interpretation of research results. This article enumerates numerous factor leading to erroneous research conclusions. Most of them have been dealt with on this blog at one time or another. To me, the most eye-opening aspect of the paper was a quantitive approach to the influence of plausibility in interpreting positive research findings. I was never taught this approach in medical school, or in any other venue. When it comes to implausible hypotheses, the traditional P-value can be very misleading.

As good as Ioannidis’ article is, it is not easy reading for the statistically or mathematically challenged. What I attempt to do in this post is to demonstrate the importance of plausibility in graphic format, without a lot of complex math. If you can grasp the concepts in this post, you will have an understanding that many researchers, and consumers of research, lack.

Posted in: Basic Science, Clinical Trials

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Why Do They Do Studies Like This?

A recently published study claims to have shown that a proprietary mixture of velvet bean and Chlorophytum borivilianum improves sleep quality. The journal, Integrative Medicine Insights, is online, peer-reviewed, PubMed indexed, open-access, and it charges authors $1848.00 to publish their article. It advertises editorial decisions in 3 weeks and publication in 2 weeks after acceptance. I can see two reasons why authors might be willing to pay that much for publication: to speed the process of getting important research results out to the public, or because their research is poor quality and they know it would be rejected by other journals.

The quality of this study is unfortunately typical of much of the research on alternative medicine.

Description of Study

The full text is available for download here.  The title is “A Dietary Supplement Containing Chlorophytum Borivilianum and Velvet Bean Improves Sleep Quality in Men and Women.” They gave a proprietary supplement mixture to 18 young healthy subjects with self-reported impairment of sleep quality (defined as routine difficulty falling asleep, waking more than twice during the night, and awaking in the morning feeling tired) and had them fill out a questionnaire about sleep quality before and after the trial. They also measured heart rate, blood pressure, CBC, metabolic panel, and lipid panels.

Posted in: Clinical Trials, Herbs & Supplements

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The future of cancer therapy?

I was contemplating writing a post along the same lines as Harriet’s post about evolutionary medicine last week, but then on Sunday morning I saw an article that piqued my interest. Sorry, Harriet, my response, if I get to it, might have to wait until next week, although we could always discuss the usefulness (versus the lack thereof) of evolutionary medicine over a beer or two at The Amazing Meeting in a few days. In the meantime, this week’s topic will revisit a topic near and dear to my heart, a topic that I tend to view (sort of) in a similar way as Harriet views evolutionary medicine, namely personalized medicine or the “individualization” of treatments. It’s a topic I’ve written about at least twice before and that Brennen McKenzie wrote about just last week. In essence, we both pointed out that when it comes to “complementary and alternative medicine” (CAM) or “integrative medicine” treatments for various conditions and diseases, what CAM practitioners claim to be able to do with respect to “individualized care” is nonsense based on fantasy. Science-based medicine already provides individualized care, but it’s individualized care based on science and clinical trials, not tooth fairy science.

Serendipitously, this point was driven home over the weekend in an article by Gina Kolata in the New York Times entitled In Treatment for Leukemia, Glimpses of the Future. While the story is basically one long anecdote that shows what can be done when new genomic technologies are applied to cancer, it also shows why we are a very long way from the true “individualization” of cancer care. It also turns out that I’ve discussed the same basic story before, but here I’ll try to discuss it in a bit more detail.

Posted in: Cancer, Clinical Trials, Medical Ethics

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NCCAM on “integrative medicine”: What’s in a word?

I don’t know how I’ve missed this, given that it’s been in existence now for a month and a half, but I have. Regular readers (and even fairly recent readers, given that I write about this topic relatively frequently) know that I’m not a big fan of the National Center for Complementary and Alternative Medicine (NCCAM). (Come to think of it, neither is anyone else writing for this blog.) Just search this blog for “NCCAM” if you don’t believe me. I’ve explained the reasons many times, but the CliffsNotes version is that NCCAM is an enormous waste of taxpayer money, dedicated as it is to the study of modalities that are at best highly implausible and at worst break well-established laws of physics (i.e., “energy healing”). I do concede that, since the latest NCCAM director (Dr. Josephine Briggs) took over, there has been a noticeable attempt to bring more scientific rigor to NCCAM, and to some extent Dr. Briggs has succeeded. At the very least she is a legitimate scientist with an impressive pre-NCCAM track record, and I do fear who will succeed her when she moves on or retires given that there is enormous pressure from the CAM community to appoint one of their own as director.

Unfortunately, as rigorous a scientist as Dr. Briggs was in her former life, since coming to NCCAM she has gradually been assimilated into the culture of the place. Indeed, although it is good that NCCAM has backed away from studying woo like homeopathy and distance healing, the co-optation of science-based modalities such as exercise, diet, and natural products pharmacology has continued apace. Worse, the recently released five year strategic plan for NCCAM admitted that the science funded by NCCAM in the past was crap and, in essence, promised to do some real science for a change. That’s why on occasion I’ve jokingly said that we should take off and nuke NCCAM from orbit. It’s the only way to be sure. On the other hand, no doubt someone would think I seriously mean that we should nuke NCCAM. Of course, I’d never advocate that! NCCAM is located right smack dab in the middle of the NIH campus. The collateral damage would be unacceptable.

I keed. I keed. I’m not kidding, though, when I echo the questioning of why NCCAM still exists.

Posted in: Clinical Trials, Medical Academia, Politics and Regulation

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POM: Not So Wonderful

“POM Wonderful” is a brand of pomegranate juice. It is manufactured by a company owned by Linda and Stewart Resnick, California billionaires who pretty much single-handedly created a multi-million dollar market for pomegranate juice where none existed before. Or, as LA Times columnist Michael Hilzik wrote,

It has long been clear that the most wonderful thing about Pom Wonderful pomegranate juice is the spectacular marketing skill that persuades consumers to fork over their hard-earned cash for a liquid that sells for five to six times the price of, oh, cranberry juice.

He’s right about the expense: a daily 8 oz. dose of POM Wonderful juice costs about $780 annually according to a recent Federal Trade Commission case, which we’ll get to soon.

The Resnicks parlayed their success selling pomegranate juice into two additional products, both dietary supplements, in the form of POMx pills and POMx liquid. The Resnicks and their companies have shelled out $35 million in sponsored research to determine what health benefits might arise from ingesting pomegranate juice or its components, research they have not been shy about using in touting their products. The couple apparently has a flair for taking the mundane and making it appear, well, wonderful to the consumer – they also own Fiji Water and the Franklin Mint, among other business interests.

In 2010, the Federal Trade Commission (FTC) filed a complaint against Resnicks, one of their business partners, and two of their companies (which I’ll refer to collectively as “POM”), alleging unfair and deceptive trade practices. POM, according to the FTC complaint, made false and misleading claims that its POM products treat, prevent, and reduce the risk of heart disease, prostate cancer and erectile dysfunction.

An Administrative Law Judge (ALJ) agreed with the FTC and on May 17, 2012, issued a 335-page decision and cease and desist order, ruling POM lacked competent and reliable scientific evidence that drinking 8 ounces of POM Wonderful Juice daily, or taking one POMx pill, or one teaspoon of POMx liquid, treats, prevents or reduces the risk of heart disease, prostate cancer, or erectile dysfunction. In the Matter of POM Wonderful, LLC, et al., F.T.C. No. 9344 (May 17, 2012).


Posted in: Clinical Trials, Herbs & Supplements, Legal, Nutrition, Politics and Regulation

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Plausibility bias? You say that as though that were a bad thing!

On Friday, you might have noticed that Mark Crislip hinted at a foreshadowing of a blog post to come. This is that blog post. He knew it was coming because when I saw the article that inspired it, I sent an e-mail to my fellow bloggers marking out my territory like a dog peeing on every tree or protecting my newfound topic like a mother bear protecting her cubs. In other words, I was telling them all to back off. This article is mine.

Mine! Mine! Mine! I tell you!

My extreme territorial tendencies (even towards my friends and colleagues) notwithstanding on this issue aside, if you read Mark’s post (and if you didn’t go back and read it now—seriously, go now), you might also remember that he was discussing a “reality bias” in science-based medicine (SBM), a bias that we like to call prior plausibility. In brief, positive randomized clinical trials (RCTs) testing highly implausible treatments are far more likely to be false positives than RCTs testing more plausible treatments. That is the lesson that John Ioannidis has taught us and that I’ve written about multiple times before, as have other SBM bloggers, most prominently Kimball Atwood, although nearly all of us have chimed in at one time or another about this issue.

Apparently a homeopath disagrees and expressed his disagreement in an article published last week online in Medicine, Health Care, and Philosophy entitled Plausibility and evidence: the case of homeopathy. You’ll get an idea of what it is that affected us at SBM like the proverbial matador waving his cape in front of a bull by reading this brief passage from the abstract:

Prior disbelief in homeopathy is rooted in the perceived implausibility of any conceivable mechanism of action. Using the ‘crossword analogy’, we demonstrate that plausibility bias impedes assessment of the clinical evidence. Sweeping statements about the scientific impossibility of homeopathy are themselves unscientific: scientific statements must be precise and testable.

Scientific. You keep using that word. I do not think it means what you think it means. Of course, his being a homeopath is about as close to a guarantee as I can think of that a person doesn’t have the first clue what is and is not scientific. If he did, he wouldn’t be a homeopath. Still, this particular line of attack is often effective, whether yielded by a homeopath or other CAM apologist. After all, why not test these therapies in human beings and see if they work? What’s wrong with that? Isn’t it “close-minded” to claim that scientific considerations of prior plausibility consign homeopathy to the eternal dustbin of pseudoscience?

Not at all. There’s a difference between being open-minded and being so “open-minded” that your brains threaten to fall out. Guess which category homeopaths like Rutten fall into. But to hear them tell it, homeopathy is rejected because because we scientists have a “negative plausibility bias” towards it. At least, that’s what Rutten and some other homeopaths have been trying to convince us. This article seems to be an attempt to put some meat on the bones of their initial trial balloon of this argument published last summer, which Steve Novella duly deconstructed.

Before I dig in, however, I think it’s necessary for me to “confess” my bias and why I think it should be your bias too.

Posted in: Basic Science, Clinical Trials, Homeopathy, Science and Medicine

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Funding CAM Research

Paul Offit has published a thoughtful essay in the most recent Journal of the American Medical Association (JAMA) in which he argues against funding research into complementary and alternative therapies (CAM). Offit is a leading critic of the anti-vaccine movement and has written popular books discrediting many of their claims, such as disproved claim for a connection between some vaccines or ingredients and risk of developing autism. In his article he mirrors points we have made here at SBM many times in the past.

Offit makes several salient points – the first being that the track record of research into CAM, mostly funded by the NCCAM, is pretty dismal.

“NCCAM officials have spent $375,000 to find that inhaling lemon and lavender scents does not promote wound healing; $750,000 to find that prayer does not cure AIDS or hasten recovery from breast-reconstruction surgery; $390,000 to find that ancient Indian remedies do not control type 2 diabetes; $700,000 to find that magnets do not treat arthritis, carpal tunnel syndrome, or migraine headaches; and $406,000 to find that coffee enemas do not cure pancreatic cancer.”

The reason for the poor track record is fairly simple to identify – by definition CAM includes treatments that are scientifically implausible, which means there is a low prior probability that they will work. If the treatments were scientifically plausible then they wouldn’t be alternative.


Posted in: Clinical Trials, Herbs & Supplements, Medical Ethics, Politics and Regulation, Science and Medicine

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