Few words convey the ability of modern medicine to do harm like “Thalidomide.” It wasn’t the first time that a supposedly harmless medicine wreaked havoc: in 1937, improperly prepared “Elixir sulfanilamide” killed more than a hundred people, serving as the impetus for the 1938 amendments to the Federal Food, Drug and Cosmetic Act, which gave the FDA its first true power to regulate medicines, including requiring all drugs be tested on animals before marketing, with the data sent to the FDA for review. But the Thalidomide birth defects crisis put a new face on the dangers of modern pharmacology, revealing to the world that dangerous medicines could not only poison, but could alter humans’ very structure, causing birth defects like shortened or missing limbs, heart defects, and damage to ears, eyes, and the brain.
The United States was spared the worst of the damage; though millions of doses had been given to patients in clinical trials, Dr. Francis Oldham Kelsey, one of the few physicians at the FDA reviewing drugs at that time, refused to approve the drug — despite considerable corporate pressure — for use in the United States without further testing. The rest of the world wasn’t so lucky, with an estimated 10-20,000 victims born with congenital deformities.
Last Friday, Gruenethal, the German pharmaceutical firm responsible for the drug, claimed to be making public apology for its sins a half-century ago, but it left out the most basic component of a genuine contrition: the admission of fault. Instead, as Sir Harold Evans explains:
“Grünenthal acted,” [the company’s chief executive] said, “in accordance with the state of scientific knowledge and all industry standards for testing new drugs that were relevant and acknowledged in the 1950s and 1960s.” That was flatly untrue, a product of either deep-rooted cynicism, belying his whole apology, or of appalling ignorance. Grünenthal has propagated the big lie for 50 years, retailing the notion that reproductive tests were unnecessary because nobody could possibly have realized in the fifties that a drug could penetrate the placental barrier and reach the fetus. …
It is 39 years since, as editor of the Sunday Times of London in the early seventies, I was associated with thalidomide investigations. Our survey of the scientific literature, consultations with reputable pharmaceutical companies and independent specialist advice swiftly found that reproductive studies were routinely done in the 1950s, because it was widely recognized that a drug could indeed reach the fetus. The tranquilizers in direct competition with thalidomide were all tested for teratogenic effects and the results published. If reproductive tests had been done on thalidomide, they would not necessarily have shown precisely what deformities would be produced, dependent on the time of ingestion in relation to the development of the fetus, but they would certainly have shown that drugs could endanger unborn children in some way.
As much as the teratology of drugs shocked the world, it certainly wasn’t news to pharmaceutical researchers. Hoffman-LaRoche, Pfizer, SmithKline, and all the pharmaceutical companies had done reproductive testing routinely since the 1940s. The need for the testing and the methods for doing so were all well-known and well-published. Grunenthal didn’t bother, and led licensees in other countries to believe the testing had been done, misrepresented the conclusions of its own internal researchers, many of whom said that more testing was needed, and ignored how one of its own employees had given birth to a child without ears. The company, Sir Evans concludes, “covered up a crime against humanity for more than 60 years.”
Journalist Geoff Adams-Spink, himself a victim of thalidomide, notes that Gruenthal hasn’t promised any compensation along with its “apology.” In essence, we’re sorry, not that we did anything wrong, and not like we’re going to help.
The silver-lining of the Thalidomide disaster was, just like with Elixir sulfanilamide, improved regulation of pharmaceutical drugs. The Kefauver Harris Amendment or “Drug Efficacy Amendment” in 1962 required drug manufacturers provide proof of the claimed efficacy and safety of their drugs. The new laws more strictly regulated how drug manufacturers could describe their products; no more “completely safe” and “completely atoxic” branding without some proof.
Unfortunately, in the two generations since Thalidomide, many of those safeguards have been weakened. I have already talked about the dangers of Pradaxa before. Just this month the Journal of the American Medical Association published an article questioning the “Expedited Drug Development Pathway,” raising an example the disturbing tale of Pradaxa:
Dabigatran, the first new oral anticoagulant approved in 56 years, benefited from 3 different FDA policies promoting innovation. This drug received both Fast Track and Priority Reviews and was studied in a single large phase 3 trial rather than in at least 2 pivotal trials, as normally requested. Dabigatran was considered significantly easier to use than warfarin for reducing the risk of stroke in patients with atrial fibrillation, because regular monitoring is not recommended. In the phase 3 trial of dabigatran, the risk of serious bleeding was similar for the 2 drugs. The FDA approved only a single primary dose of 150 mg. Unlike regulatory agencies in Canada, Japan, and Europe, the FDA did not approve a lower 110 mg dose and commented that the drug might be usefully studied at a dose higher than 150 mg.
The limitations of a one-size-fits-all strategy for a treatment as inherently risky as anticoagulation in elderly patients soon became apparent. Within less than a year of approval, 1 survey showed that dabigatran accounted for more serious adverse drug events reported to the FDA during the second quarter of 2011 than any other regularly monitored drug. Risk of hemorrhage was prominent in older patients (median age, 80 years), a subgroup for whom declining kidney function or other factors may have increased bleeding risk. Both a manufacturer package insert revision and the European Medicines Agency have called for closer monitoring of kidney function, a needed step because even moderate kidney impairment increases dabigatran levels more than 2-fold. In addition, unlike warfarin, no antidote is available for use in bleeding emergencies related to dabigatran. Evidence was beginning to emerge that dabigatran-related bleeding – whether from trauma or as an adverse effect – may be more difficult to treat than warfarin-related bleeding.
Every week, I talk with the children and spouses of Pradaxa victims, and they all end up telling me roughly the same story: their loved one was on Coumadin, their doctor recommended switching to Pradaxa because it was more convenient (not because it was safer or more effective) and because “the doctor said it could be stopped at any time.” After a couple days or weeks on Pradaxa, their loved one started vomiting blood or passing it in their stool and so were taken to hospital, where baffled doctors tried a couple variations of standard bleeding treatments that didn’t work. At that point, after 10 or more transfusions over the next 48 hours, the patient either got better, needed surgery, or passed away. The patient’s primary care physician or cardiologist then tells the family that they had no idea of the problem, and that they’ll never prescribe it again.
I’m not exaggerating; I had that same conversation with three different families last week. The part that shocks me is that, like thalidomide, nobody needs Pradaxa. It doesn’t cure cancer. It doesn’t treat heart attacks. It’s not even unique. It’s a drug of convenience, a medication that’s supposed to be easier to use (but not more effective) than Coumadin for preventing strokes. That’s it.
All of which makes me wonder what’s going on at the FDA, and if we as a society need to take a closer look at the way we rush into novel treatments. In The Cost of Hope, Amanda Bennett made a powerful argument in favor of insurers and Medicare paying for novel treatments of fatal diseases, even treatments where the benefit was doubtful and cost extraordinary, because the benefits extended far beyond merely adding time to a terminally ill patient’s life by giving that person and everyone around them hope. But we need to be honest about Pradaxa and other medicines like it that are not unique life-extending drugs, but instead are different modalities of existing treatments. When a drug offers marginal or similar efficacy to existing treatments, safety, not expediency, should be paramount.