Posts Tagged drug approval

Whither the randomized controlled clinical trial?

Whither the randomized controlled clinical trial?

One of the most frequent complaints about evidence-based medicine (EBM), in contrast to science-based medicine (SBM), is its elevation of the randomized clinical trial as the be-all and end-all for clinical evidence for an intervention for a particular disease or condition. Unknown but enormous quantities of “digital ink” have been spilled explaining this distinction right here on this blog, beginning with our founder’s very first post, continuing with Kimball Atwood’s series of posts explaining the shortcomings of EBM’s reliance on clinical trials über alles using homeopathy as his example, to my referring to this aspect of EBM as “methodolatry,” defined as profane worship of the randomized controlled clinical trial (RCT) as the only valid method of clinical investigation. The problem, of course, with methodolatry, is that it completely ignores prior plausibility, and when that prior plausibility is as close to zero as you can imagine (e.g., for clinical trials of homeopathy), then the only positive results that you see in such trials can reasonably be concluded to be due to noise, shortcomings in trial design, and bias. Unfortunately, a failure to realize this has led to many pointless clinical trials and contributed to the rise of a whole new “specialty” known as integrative medicine, dedicated to “integrating” quackery and pseudoscience into science-based medicine.

So we know that practitioners of “complementary and alternative medicine” (CAM), now referred to more frequently as integrative medicine, don’t like RCTs. They love pragmatic trials, because such trials are usually unblinded, often not randomized, and generally face a lower bar of evidence. That pragmatic trials are intended to test the “real world” use of medical and surgical interventions that have already been shown to be safe and effective in RCTs and that the vast majority of CAM nostrums have not met that standard appears not to concern them in the least. However, CAM practitioners are not the only ones critical of RCTs, as I learned when, via Steve Novella, I came across an article in The New England Journal of Medicine entitled “Assessing the Gold Standard — Lessons from the History of RCTs” by Bothwell et al. Given that the article is two weeks old, I wonder how I missed it. Be that as it may, although Bothwell et al make some good points, I tend to agree with Steve that the overall gist of the article is overly critical, to the point of, as Steve put it, portraying the RCT as broken rather than flawed and advocating revolution rather than reform.

Posted in: Clinical Trials, Pharmaceuticals, Politics and Regulation

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Lessons from the History of Insulin

On my recent trip to Nashville for CSICon, I took advantage of the long hours on the plane to read Breakthrough: Elizabeth Hughes, the Discovery of Insulin, and the Making of a Medical Miracle, by Thea Cooper and Arthur Ainsberg. One of our commenters recommended it. I’m not sure who (was it Chris?), but I want to thank you.

It’s the history of insulin told from the perspective of the scientists and of a typical patient, and it touches on a number of issues that we have addressed on SBM. It shows how science works to save lives, in stark contrast to the empty promises of CAM. (more…)

Posted in: Book & movie reviews, History, Pharmaceuticals

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Dabigatran: A Promising Alternative to Warfarin

On October 19, 2010, the FDA approved a long-awaited new drug, dabigatran, expected to replace warfarin (Coumadin) as a better way to prevent blood clots in susceptible patients. This provides an opportunity to re-visit several issues that we have addressed before, including Big Pharma tactics, drug approval by the FDA, deciding what is adequate evidence, applying science to clinical practice, and making individual health care decisions based on evidence that is sometimes incomplete.


Patients with atrial fibrillation, artificial heart valves, deep vein thrombosis, pulmonary embolism, antiphospholipid syndrome, and people undergoing certain types of surgery are at risk of blood clots, embolism, and stroke. They are currently being treated with rat poison. Warfarin (Coumadin) is an anticoagulant originally intended to kill rats. It inhibits the vitamin K dependent synthesis of several clotting factors. It saves human lives but is a mixed blessing. It takes several days to achieve therapeutic levels. Patients must be monitored with frequent blood tests to ensure that their prothrombin levels stay between an INR (international normalized ratio) of 2 and 3. When starting out, this means blood tests every couple of days. For some patients, dosage fluctuates and requires frequent adjustments; others can eventually drop down to a monthly blood test. Warfarin interacts with a long list of other drugs that raise or lower its blood levels. It interacts with many foods, and patients have to modify their diet. It can cause serious bleeding complications; while preventing thrombotic strokes it can cause hemorrhagic strokes. It is taken once daily. There is an antidote, vitamin K, that can reverse its effects promptly.

Warfarin is the 11th most prescribed drug in the US. Its benefits clearly outweigh its risks, but we wish the risks were fewer. We have yearned for a better option: something safer, something that would not require monitoring with blood tests, something that foods wouldn’t interfere with, something that would not interact with every other drug in the book. And now it seems we have it: a direct thrombin inhibitor called dabigatran.


Posted in: Pharmaceuticals

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