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.
Although I’m one of the few non-clinicians writing here at SBM, I think about clinical trials a great deal – especially this week.
First, our colleague, Dr. David Gorski, had a superb analysis and highly-commented post on The Atlantic story by David H. Freedman about the work of John Ioannadis – more accurately, on Freedman’s misinterpretation of Ioannadis’s work and Dr. Gorski’s comments. While too rich to distill to one line, Dr. Gorski’s post struck me in that we who study the scientific basis of medicine actually change our minds when new data become available. That is a GoodThing – I want my physician to guide my care based on the latest data that challenges or proves incorrect previously held assumptions. However, this concept is not well-appreciated in a society that speaks in absolutes (broadly, not just with regard to medicine), expecting benefits with no assumption of risk or sacrifice in reaping those benefits. Indeed, the fact that we change our minds, evolving and refining disease prevention and treatment approaches, is how science and medicine move forward.
Then, I had the opportunity to hear an excellent talk on pharmaceutical bioethics by Ross E. McKinney, Jr., MD, Director of the Trent Center for Humanities, Bioethics, and History of Medicine at Duke University School of Medicine. McKinney is a pediatrics infectious disease specialist who led and published landmark Phase I and Phase II trials zidovudine (AZT) for pediatric AIDS patients. While he continues working in this realm, McKinney also studies clinical research ethics, conflicts of interest, and informed consent. I was absolutely fascinated and refreshed by hearing from an expert who while describing and citing major ethical lapses in our system of drug development is also willing to propose solutions and do the hard thinking required for us to maximize the benefits we derive from pharmaceuticals while minimizing unethical behavior.
In my group practice, the Yale Medical Group, drug-company sponsored lunches and similar events have been banned. This is part of a trend, at least within academic medicine, to create some distance between physicians and pharmaceutical companies, or at least their marketing divisions. The justifications for this are several, and are all reasonable. One reason is the appearance of being too cozy, which compromises the role of academic physicians as independent experts.
But the primary reason is the belief that “detailing” by pharmaceutical sales representatives has a negative effect on the prescribing habits of physicians. There is reason to believe this may be the case because of cases of bad behavior on the part of pharmaceutical marketing divisions – ghost writing white papers, for example. The concern, backed by evidence, is that pharmaceutical companies introduce spin and bias into the information they provide to physicians, whether though CME, detailing, literature, or sponsored lectures. Even when the information itself is not massaged, it is cherry picked, so in the end physicians are not getting a thorough and unbiased assessment of the facts.
The FDA does heavily regulate the marketing of information about pharmaceuticals, but marketers are very clever about exploiting loopholes and seem to be one step ahead of the regulators.
On the other hand there are those who argue that physicians can handle access to information and they are equipped to take it with a grain of salt and put it into context. Certainly most physicians I speak to believe this about themselves. Further, information provided by pharmaceutical companies may actually improve prescribing habits if it makes physicians aware of new products on the market and new information about the drugs they prescribe. The information itself is FDA approved (or at least should be), even if it is selective and wrapped in spin.
Chelation is the provision of a substance to increase the body’s excretion of heavy metals. In poisoning situations (lead, aluminum, iron, etc.), chelation is medically necessary, objectively effective, and approved for use. But the same term has a completely different meaning in the alternative medicine universe, where proponents often believe heavy metal toxicity is the “one true cause” of disease, and chelation can undo microvascular inflammation, atherosclerosis, and even aging itself. From early days as an unproven treatment of coronary artery disease, its use has expanded to include autism, Alzheimer’s disease, cancer, and dozens of other diseases. Today, chelation is widely available. Regrettably, my own profession, pharmacy, facilitates this pseudoscience by manufacturing and selling chelation products.
Provoked urine tests are a common entry point to chelation therapy. Patients are given a product to provoke heavy metal excretion. The urine is tested and the patient is informed that they’re “toxic” and require chelation. Unfortunately, these results are meaningless and provide no evidence that chelation is medically necessary. But that’s the justification used for advocating a treatment regimen that will be useless at best and fatal at worst. A recent Medical Letter review concluded:
Medical Letter consultants believe that the use of chelation therapy in non-standard protocols for unsubstantiated indications should be discouraged. The results of provoked urine testing are not an acceptable basis for such treatment.
Providing chelation to patients isn’t a straightforward matter. It’s typically an intravenous infusion (though there are some oral products). Unless you’re part of the dubious TACT trial, which has administration centres across the United States and Canada, there are few products commercially available. For example, edetate calcium disodium (EDTA) is approved for sale in the United States but not Canada. Edetate disodium (also called EDTA) is not approved for sale in either country. But these products are widely available: they’re manufactured by pharmacists in pharmacies.
An article in the latest issue of PLOS Medicine, The Haunting of Medical Journals: How Ghostwriting Sold “HRT”, details the use of ghostwriting as a marketing tool for pharmaceutical companies. It is a chilling discussion of how at least one pharmaceutical company, Wyeth, used the peer-reviewed literature as a method of distributing marketing messages to physicians.
The author, Adriane J. Fugh-Berman, details a practice that cuts at the heart of science-based medicine – the exploitation and distortion of the literature. The medical profession needs to jealously guard the legitimacy and purity of the peer-review process and the medical scientific literature. I am never one to gratuitously bash “Big Pharma” – this is often used as a method of casually dismissing inconvenient scientific evidence. But at the same time, pharmaceutical companies are in the business of making money. While they are a carefully regulated industry, some in the industry seek ways to skirt around regulations that limit their ability to market their products.
While most physicians consider themselves savvy with respect to pharmaceutical marketing, the story told by Fugh-Berman is one of profound naivete. I guess it should not be a surprise that some academics were bamboozled by expert salespersons who spent a lot of time and effort, apparently, figuring out ways to deceive and manipulate them. But now that the story is out, naivete is no longer an excuse. Here is what happened:
I’m only a monthly contributor here but between being a SBM reader and having my own blogs, I often grow weary of the blind criticism that researchers and drug companies couldn’t care less about traditional folk medicines as drug products. My laboratory spends every single day working on natural product extracts in the search for compounds that may have selective effectiveness against cancer. So, this is a bit of a sore spot for me.
Two papers this week from Cancer Prevention Research on the potential anticancer effects of a diabetes drug (Nathan Seppa story here) remind me to tell the story of a Middle Ages European herbal medicine used to treat polyuria that gave rise to one of the most widely prescribed drugs in the world, metformin (Glucophage in the US). Metformin, known chemically as a biguanide, dimethylguanide to be precise, traces its roots to the plant Galega officinalis. Known as goat’s rue, French lilac, or professor weed, this plant was shown to be a rich source of guanidine and a less toxic compound later called galegin or galegine (isoamyline guanidine).
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.
The week of 12-16 July saw an FDA Advisory Panel meet to decide the fate of an important drug. Along the way, the FDA charted new territory in using drug comparisons to judge safety, amidst external allegations of corporate malfeasance and patient harm.
Avandia, or rosiglitazone, is one of a new class of anti-diabetes drugs approved for marketing by the FDA in 1999. It, and its competitor, Actos (pioglitazone), are thiazolidinediones (TZD’s), a class of drugs that act to decrease insulin resistance. A third TZD, troglitazone, was withdrawn after studies showed a 1:20,000 incidence of hepatitis and potential liver failure.
Avandia was a clear market success, with sales peaking at $2.5B in 2006, the year prior to the first research “shot across the bow” regarding patient safety.
Among scientists, the mid-July review capped a rising level of concern. Among the public, a tide of safety concern had been rising for several years, flowing from the scientific community into the legal and political arena.
On the car radio, I have several times happened upon “infomercial” programs touting the benefits of testosterone replacement therapy for men, broadcast by doctors who specialize in prescribing the drugs. They have lots of wonderful stories about men who feel younger, happier, and more vigorous because of their macho remedies. It’s a tribute to the power of the placebo.
I have been reviewing John Brinkley’s goat gland scam for a presentation on medical frauds. In an era before the isolation of the hormone testosterone, Brinkley transplanted goat testes into human scrotums in an attempt to treat impotence and aging. We are more sophisticated today … but not much. Longevity clinics and individual practitioners are offering testosterone to men as a general pick-me-up and anti-aging treatment. Their practice is not supported by the scientific evidence. (more…)
There are two topics about which I am a crank. The first, as you might have guessed, is alternative medicine. The other is pharmaceutical reps. Drug companies are somewhat schizophrenic. They have amazing scientists who invent drugs that treat an astounding array of diseases. Then, they take these drugs and turn them over to marketing, to be sold with all the enthusiasm and truthiness of a late night infomercial.
In the spirit of openness, I will say that I have not talked to a drug rep in 20 years. As far as industry supported gifts and food, I have not taken a pen or eaten pizza from industry in almost 30 years, since I was a fourth year medical student. I have accepted one gift over the years. Years ago, when the Pfizer rep left, he sent me Fleets enema with a Unasyn sticker on it. I still have it in my office, unused. But you never know when it might come in handy.
Being an absolutist about industry gifts does have downsides. It is distracting to sit in an auditorium filled with the smell of pizza and not eat any; somehow the PB&J I bring with me doesn’t smell as sweet. Administration has received one letter complaining about me that was ostensibly from an employee, but curiously was printed from a windows folder that had the same name as the levofloxacin rep. Just a coincidence, I am sure.