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Archive for Clinical Trials

Acupuncture for Macular Degeneration: Why I Reject the Evidence

This post is dedicated to two people who are frequent commenters on SBM, Stephen S. Rodrigues and Peter Moran. Rodrigues is an MD/acupuncturist who tries to persuade us that acupuncture is effective. Moran is a retired surgeon who objects to insulting language and thinks more can be accomplished by trying to better understand why people turn to CAM and by explaining the facts and reasons politely and dispassionately. He has claimed that he “could probably help [Rodrigues] understand better why his views are not having much impact.”

I recently wrote about supplements for age-related macular degeneration (AMD). There is evidence that the supplement mixture tested in the AREDS trial slows the progression of moderate to advanced disease. That is based on a good scientific study, although the study has not been replicated and there is reason to interpret its results with caution. Dr. Rodrigues commented with a link to a website advertising the Santa Fe acupuncture protocol, saying that he uses the method in his office and it helps some of his patients with AMD. The website claims that the Santa Fe acupuncture protocol will reverse vision loss from macular degeneration in 4 days or your money back. That is a bold claim. I will try to explain, as politely as possible, why I reject the claim, and why the evidence for it is unacceptable. (more…)

Posted in: Acupuncture, Clinical Trials, Ophthalmology

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Macular Degeneration and AREDS 2 Supplements

What AMD does to vision

What AMD does to vision

Four years ago I wrote about the premature marketing of a diet supplement for macular degeneration before the results of a trial to test it were available. Now that we know the results of that trial, a follow-up post is in order.

Age-related macular degeneration (AMD) is a leading cause of blindness. The incidence increases with age; it affects 10% of people by age 66-74 and 30% of people by age 75-85. There are known risk factors including genetics and smoking, but there is no effective prevention. There are multiple diet supplement products on the market that are advertised as “supporting eye health.” Some are based on evidence from randomized, controlled studies; but the advertising hype goes beyond the evidence and tends to mislead consumers. There is evidence that supplementation may slow the progression of moderate to severe AMD, but there is no evidence that supplements are effective in milder disease or for preventing AMD from developing in the first place. (more…)

Posted in: Clinical Trials, Herbs & Supplements

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Of the Trial to Assess Chelation Therapy, Bayes, the NIH, and Human Studies Ethics

An experiment is ethical or not at its inception; it does not become ethical post hoc—ends do not justify means.
~ Henry K. Beecher

tact

A couple of weeks ago, Dr. Josephine Briggs, the Director of the National Center for Complementary and Alternative Medicine (NCCAM), posted a short essay on the NCCAM Research Blog touting the results of the Trial to Assess Chelation Therapy (TACT) (italics added):

The authors found that those receiving the active treatment clearly fared better than those receiving placebo. The accompanying editorial in the AHJ reminds readers about the value of equipoise and the need to “test our beliefs against evidence.”

Most physicians did not expect benefit from chelation treatment for cardiovascular disease. I readily admit, initially, I also did not expect we would find evidence that these treatments reduce heart attack, strokes, or death. So, the evidence of benefit coming from analyses of the TACT trial has been a surprise to many of us. The subgroup analyses are suggesting sizable benefit for diabetic patients—and also, importantly, no benefit for the non-diabetic patient. Clearly subgroup analyses, even if prespecified, do not give us the final answer. But it is also clear that more research is needed to test these important findings.

And TACT findings are indeed a reminder of the importance of retaining equipoise [sic], seeking further research aimed at replicating the findings, and neither accepting nor rejecting findings based on personal biases. The scientific process is designed to weed out our preconceived notions and replace them with evidence.

Dr. Briggs concluded:

So, TACT is a reminder—an open mind is at the center of the scientific method.

Dr. Briggs’s title was “Bayes’ Rule and Being Ready To Change Our Minds”, a reference to a recent editorial that had accompanied one of the TACT papers. That editorial, by Dr. Sanjay Kaul, a physician and statistician from UCLA, begins with this quotation:

Preconceived notions are the locks on the door to wisdom.
~ Merry Browne

Here is the relevant passage from Dr. Kaul’s editorial (italics added):

Sixth, it has been argued that the trial was unethical because there was no compelling clinical or preclinical evidence that chelation therapy has significant efficacy against atherosclerotic cardiovascular disease, and given that chelation therapy can cause harm, the risk was not minimal. A Bayesian analysis would not look kindly on the results because of the low prior probability of treatment effect (the so-called implausibility argument).6 This is an uncharitable (and unwarranted) interpretation of the data because previous systematic reviews concluded, “insufficient evidence to decide on the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes among people with atherosclerotic cardiovascular disease.” It is axiomatic that absence of evidence of efficacy is not the same as evidence of the absence of efficacy.

From a Bayesian perspective, the strength of evidence is often summarized using a Bayes factor, which is a measure of how well 2 competing hypotheses (the null and the alternate) predict the data. The Bayes factor and the corresponding strength of evidence for the primary end point result in TACT overall, and diabetic cohorts are shown in Table 1. The p-value of 0.035 for TACT overall cohort translates into a Bayes factor of 0.108, which means the evidence supports the null hypothesis ≈1/9th as strongly as it does the alternative. This reduces the null probability from 50% pretrial (justified by suspension of one’s belief in treatment effect) to 10% post-trial. Although this does not represent strong evidence against the null, it does reduce the level of skepticism surrounding chelation therapy. In the diabetic cohort, the nominal p-value of 0.0002 translates into a Bayes factor of 0.002 (1/500), which reduces the extremely skeptical prior null probability of 95% to 4% post- trial, indicating very strong evidence against the null.

In concluding, Dr. Kaul states:

Finally, TACT highlights the double standard when it comes to accepting inconvenient results not aligned with our preconceived notions on so-called dubious quack cures such as chelation…

Closed minds?

Dr. Kaul’s reference “6” above is to a lengthy article that we published in 2008 titled “Why the NIH Trial to Assess Chelation Therapy Should Be Abandoned”. So, it seems, both Drs. Briggs and Kaul were chastising us for our biased, preconceived beliefs about so-called dubious quack cures. Our minds were, apparently, not open. Let’s examine this contention. (more…)

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

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In which Dr. Gorski is taken to task by an eminent radiologist for his posts on mammography

40F MLO DMMG

Introduction: An unexpected e-mail arrives

One of the consequences of the growing traffic and prominence of this blog over the last few years is that people who would otherwise have probably ignored what I or my partners in blogging write now sometimes actually take notice. Nearly a decade ago, long before I joined this blog as a founding blogger, if I wrote a post criticizing something that a prominent academic said, it was highly unlikely that that person would even become aware of it, much less bother to respond to whatever my criticism was. I was, quite simply, beneath their notice, sometimes happily, sometimes unhappily.

It appears that those days might be over. Last week Dr. Daniel Kopans, a prominent Harvard radiologist and well-known long-time defender of screening mammography, sent me a rather unhappy e-mail complaining about my “attack” on him on this blog, a charge that he repeated in a subsequent e-mail. Before I publish his initial e-mail verbatim (with his permission), I would like to point out that, while it’s true that I did criticize some of Dr. Kopans’ statements rather harshly in my post about the Canadian National Breast Screening Study (CNBSS), even characterizing one statement as a “howler,” I would hardly characterize what I wrote as an “attack.” That to me tends to imply a personal attack. Using Dr. Kopans’ apparent definition, what he has said and written about investigators like those running the CNBSS, as documented in my post, about H. Gilbert Welch, who published a large study in 2012 estimating the extent of overdiagnosis due to mammography, and the U.S. Preventive Services Task Force (USPSTF), the group that in 2009 suggested changing guidelines for routine screening mammography in asymptomatic women to begin at age 50 instead of age 40, would appear to also qualify as “attacks.”

Be that as it may, I also wondered why Dr. Kopans hadn’t noticed my CNBSS post until more than three months after it had originally appeared. Then, the day after I received Dr. Kopans’ e-mail, my Google Alert on mammography popped up an article in the Wall Street Journal by Dr. Kopans entitled “Mammograms Save Lives: Criticism of breast-cancer screenings is more about rationing than rationality.” That’s when I guessed that someone probably had either posted or e-mailed Dr. Kopans a link to my previous post in response to that article. Given the confluence of events, I think it’s a perfect time to discuss both Dr. Kopans’ e-mail and his article, because they cover many of the same issues. (more…)

Posted in: Cancer, Clinical Trials, Diagnostic tests & procedures, Public Health

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What’s in a name?: NCCAM tries to polish a turd

turdpolish

What’s in a name? that which we call a rose
By any other name would smell as sweet;
So Romeo would, were he not Romeo call’d,
Retain that dear perfection which he owes
Without that title. Romeo, doff thy name,
And for that name which is no part of thee
Take all myself.

William Shakespeare, Romeo and Juliet, Act II, Scene 2

You can clean up a pig, put a ribbon on its tail, spray it with perfume, but it is still a pig.

You can paint a turd red, but it’s still a turd.

There’s a colloquial phrase commonly used to describe an effort to sell or promote something that is so inherently awful or at least so flawed as to be unsalvageable without either a radical rethinking or such a major overhaul that it would be impractical or impossible to do: Polishing a turd. In this, advocates of so-called “complementary and alternative medicine” (CAM) have been very successful. Mark Crislip, in his usual inimitable fashion, just reminded us why CAM is a turd that needs polishing. Unfortunately, on Friday, I learned that the National Center for Complementary and Alternative Medicine unveiled a proposal to help it be more efficient in polishing the turd that is CAM through the clever use of language, and it wants your feedback. There were lots of other things that happened over the last few days that tempted me to write about them that will likely have to appear over at my not-so-secret other blog, but this one caught my attention and held it, given that it goes to the very heart of the deceptive use of language that is at the heart of giving CAM the appearance of legitimacy. In this specific case, NCCAM wants a new name. Dr. Briggs wants to rename NCCAM the National Center for Research on Complementary and Integrative Health (NCRCI). (I have no idea why the abbreviation of the proposed new center name isn’t NCRCIH.) Here’s Dr. Briggs explaining the rationale for the proposal and urging feedback by June 6 at http://nccam.nih.gov/about/offices/od/comments. I urge you to watch the whole video, or at least read the transcript:

Thus does Dr. Briggs propose polishing the turd that is NCCAM.
(more…)

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

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More Dialogs

There is no alternative medicine. There is only scientifically proven, evidence-based medicine supported by solid data or unproven medicine, for which scientific evidence is lacking. JAMA

Just just because there are flaws in aircraft design that doesn’t mean flying carpets exist. Ben Goldacre

Wiser heads than I have commented on “Invitation to a Dialogue: Alternative Therapies” in The New York Times. So why add my two cents? Partly because The New York Times wanted brief responses and I don’t do brief. Partly because I write for me; nothing focuses the mind like putting electrons to LCD, except, perhaps, a hanging. Partly we do need a dialog, just not of the kind suggested by the writer. And partly, life has been so busy of late I needed a topic that required no research. (more…)

Posted in: Basic Science, Clinical Trials, Critical Thinking, Science and Medicine

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A formal request for retraction of a Cancer article

I am formally requesting that Cancer retract an article claiming that psychotherapy delays recurrence and extends survival time for breast cancer patients. Regardless of whether I succeed in getting a retraction, I hope I will prompt other efforts to retract such articles. My letter appears later in this post.

In seeking retraction, I cite the standards of the Committee on Publication Ethics (COPE) for retraction. Claims in the article are not borne out in simple analyses that were not provided in the article, but should have been. The authors instead took refuge in inappropriate multivariate analyses that have a high likelihood of being spurious and of capitalizing on chance.

The article exemplifies a much larger problem. Claims about innovative cancer treatments are often unsubstantiated, hyped, lacking in a plausible mechanism, or are simply voodoo science. We don’t have to go to dubious websites to find evidence of this. All we have to do is search the peer-reviewed literature with Google Scholar or PubMed. Try looking up therapeutic touch (TT).

mind-over-body

I uncovered unsubstantiated claims and implausible mechanisms that persisted after peer review in another blog post about the respected, high journal-impact-factor (JIF = 18.03) Journal of Clinical Oncology. We obviously cannot depend on the peer review processes to filter out this misinformation. The Science-Based Medicine blog provides tools and cultivates skepticism not only in laypersons, but in professionals, including, hopefully, reviewers who seem to have deficiencies in both. However, we need to be alert to opportunities not just to educate, but to directly challenge and remove bad science from the literature. (more…)

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

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CureCrowd – Crowdsourcing Science

curecrowd-HAA new website came to my attention that promises to “Discover what truly works.” The idea is to essentially crowdsource anecdotal reports about what treatments work for specific conditions.

This is an interesting idea, that can harness the power of information flow over the internet to do what is essentially an observational, uncontrolled, and unscientific study about treatment effects. At its best, this type of information would consist of what we call a pragmatic study – an open-label study of the real-world application of specific treatments.

Pragmatic studies have their place – they add information about the practical applicability of various treatments. Pragmatic studies, however, are not efficacy trials – they cannot and should not be used to make efficacy claims. It has recently come into vogue for proponents of various CAM treatments to rely on pragmatic studies to make efficacy claims, when actual efficacy trials have failed to show effectiveness. (more…)

Posted in: Clinical Trials, Computers & Internet

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Cochrane Reviews: The Food Babe of Medicine?

There are two topics about which I know a fair amount. The first is Infectious Disease. I am expert in ID, Board Certified and certified bored, by the ABIM. The other, although to a lesser extent, is SCAMs.

When I read the literature on these topics, I do so with extensive knowledge and, in the case of ID, 30 years of clinical experience. The extensive knowledge, and, one hopes, understanding, has led me to read meta-analyses with a grain of salt substitute. They average meta-analysis and systematic review is good for gaining a general understanding of the topic within, as well as, and here is the key phrase, the limitations of the included studies.

And like all the published literature, when writing a meta-analysis, those with an axe to grind will grind it. Even, or perhaps especially, the Cochrane reviews.

Just because something is labelled as a systematic review does not mean it is any good. We have to be just as vigilant now as ever. Even a review with a Cochrane label does not make its true. Four out of 12 Cochrane reviews on acupuncture were wrong. Caveat lector rules, OK? (more…)

Posted in: Basic Science, Clinical Trials, Critical Thinking, Pharmaceuticals, Science and Medicine

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The Compassionate Freedom of Choice Act: Ill-advised “right to try” goes federal

Not too long ago, I expressed alarm at a series of bills that were popping up like so much kudzu in various state legislatures, namely “right to try” bills. Both Jann Bellamy and I warned that these bills gave a false illusion of hope to patients with terminal illnesses. Basically, these laws claim to grant the “right” of patients with terminal illnesses to access promising experimental medicines that have not yet been approved by the FDA. Indeed, these investigational drugs need merely to have passed phase I trials, and these “right to try” laws would allow them to be used in pretty much any human with a terminal illness who can persuade a pharmaceutical company to let them have such drugs. Of course, as I pointed out, such laws are based on a false premise, namely that there are lots of promising drugs out there that could save lots of lives of terminally ill patients, if only the hidebound FDA would get out of the way and let the people try them. The problem (besides the false assumption behind such laws) is that they are all state laws, and the FDA and federal law still trump state laws with respect to drug approval.

Apparently, advocates of “right to try” laws have gotten around to trying to take care of that little obstacle, too. I’m referring to a federal law under consideration in the House of Representatives and championed by the usual suspects, including the Alliance for Natural Health USA, a “health freedom” group that has yet to see a pro-quackery bill it doesn’t like.

In any case, at the time I originally learned about this bill, HR 4475, which was introduced by Rep. Morgan Griffith (R-VA) and entitled “The Compassionate Freedom of Choice Act of 2014,” its text hadn’t yet been published to the Congressional website. I did learn that the bill has been floating around for a while in various forms (for instance, former Representative Ron Paul (R-TX) apparently introduced it.) Now its text has been published, as Guy Chapman has noted. He calls it a “quack’s charter,” and he’s only off by a bit. The bill doesn’t go quite as far as he believes, but the bill is still plenty bad, man. If enacted, HR 4475 would amend the Food, Drug, and Cosmetic Act by inserting after section 561 (21 U.S.C. 360bbb) the text of HR 4475. This section of the Food, Drug, and Cosmetic Act is entitled “Expanded Access to Unapproved Therapies and Diagnostics,” and it’s the section of the act that regulates exactly that. The interesting thing is that this particular section of existing law is the framework under which the whole system of single patient INDs (also known as “compassionate use exemptions”) is already based. As I’ve described before, single patients can receive promising unapproved drugs under what’s known as a single patient IND, which has to be approved by the Institutional Review Board and the FDA and allows single patients to receive unapproved drugs. You can (and many have) argued that the single patient IND process is too cumbersome and restrictive, but HR 4475 seeks to (mostly) nuke this requirement. You’ll see what I mean in a minute.
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Posted in: Clinical Trials, Politics and Regulation

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