The placebo problem Big Pharma's desperate to solve
This article was taken from the October issue of Wired UK magazine. Be the first to read Wired's articles in print before they're posted online, and get your hands on loads of additional content by subscribing online
Merck was in trouble. In 2002, the pharmaceutical giant was falling behind its rivals in sales. Even worse, patents on five of its blockbuster drugs were about to expire, a development that would allow cheaper generics to flood the market. The company hadn't introduced a truly new product in three years and its stock price was plummeting.
In interviews with the press, Edward Scolnick, Merck's research director, laid out his battle plan to restore the firm to pre-eminence. Key to his strategy was expanding the company's reach into the antidepressant market, where Merck had lagged while competitors like Pfizer and GlaxoSmithKline created some of the best-selling drugs in the world. "To remain dominant in the future," he told Forbes, "we need to dominate the central nervous system."
His plan hinged on the success of an experimental antidepressant codenamed MK-869. Still in clinical trials, it looked like every pharma executive's dream: a new kind of medication that exploited brain chemistry in innovative ways to promote feelings of well-being. The drug tested brilliantly early on, with minimal side effects, and Merck touted its game-changing potential at a meeting of 300 securities analysts.
Behind the scenes, however, MK-869 was starting to unravel. True, many test subjects treated with the medication felt their hopelessness and anxiety lift. But so did nearly the same number who took a placebo, a look-alike pill made of milk sugar or another inert substance given to groups of volunteers in clinical trials to gauge how much more effective the real drug is by comparison. The fact that taking a faux drug can powerfully improve some people's health - the so-called placebo effect - has long been considered an embarrassment to the serious practice of pharmacology.
Ultimately, Merck's foray into the antidepressant market failed. In subsequent tests, MK-869 turned out to be no more effective than a placebo. In the jargon of the pharmaceutical industry, the trials "crossed the futility boundary".
MK-869 wasn't the only highly anticipated medical breakthrough to be undone in recent years by the placebo effect. From 2001 to 2006, the percentage of new products cut from development after Phase II clinical trials, when drugs are first tested against placebo, rose by 20 per cent. The failure rate in more extensive Phase III trials increased by 11 per cent, mainly due to surprisingly poor showings against placebo. Despite historic levels of industry investment in R&D, the US Food and Drug Administration (FDA) approved only 19 first-of-their-kind remedies in 2007 - the fewest since 1983 - and just 24 in 2008. Half of all drugs that fail in late-stage trials drop out because of their inability to beat sugar pills.
The upshot is fewer new medicines available to ailing patients and more financial woes for the beleaguered pharmaceutical industry. Last November, a new type of gene therapy for Parkinson's disease, championed by the Michael J Fox Foundation, was abruptly withdrawn from Phase II trials after unexpectedly tanking against placebo. A stem-cell startup called Osiris Therapeutics got a drubbing on Wall Street in March, when it suspended trials of its pill for Crohn's disease, an intestinal ailment, citing an "unusually high" response to placebo. Two days later, Eli Lilly broke off tests on a new schizophrenia drug when volunteers showed double the expected level of placebo response.
It's not only trials of new drugs that are crossing the futility boundary. Some products that have been on the market for decades, like Prozac, are faltering in more recent follow-up tests. In many cases, these are the compounds that, in the late 90s, made Big Pharma more profitable than Big Oil. But if these same drugs were vetted now, regulators might not approve some of them. Two comprehensive analyses of antidepressant trials have uncovered a dramatic increase in placebo response since the 80s. One estimated that the so-called effect size (a measure of statistical significance) in placebo groups had nearly doubled over that time. It's not that the old meds are getting weaker, drug developers say. It's as if the placebo effect is somehow getting stronger.
The fact that an increasing number of medications are unable to beat sugar pills has thrown the industry into crisis. The stakes could hardly be higher. In today's economy, the fate of a long-established company can hang on the outcome of a handful of tests.
Why are inert pills suddenly overwhelming promising new drugs and established medicines alike? The reasons are only just beginning to be understood. A network of independent researchers is doggedly uncovering the inner workings - and potential therapeutic applications - of the placebo effect. At the same time, drugmakers are realising they need to fully understand the mechanisms behind it so they can design trials that differentiate more clearly between the beneficial effects of their products and the body's innate ability to heal itself. A special task force of the Foundation for the National Institutes of Health (a US-government research organisation) is seeking to stem the crisis by quietly undertaking one of the most ambitious data-sharing efforts in the history of the drug industry.
The roots of the placebo problem can be traced to a lie told by a US Army nurse during World War II as Allied forces stormed the beaches of southern Italy. The nurse was assisting an anaesthetist named Henry Beecher, who was tending to US troops under heavy German bombardment. When the morphine supply ran low, the nurse assured a wounded soldier that he was getting a shot of potent painkiller, though her syringe contained only salt water. Amazingly, the bogus injection relieved the soldier's agony and prevented the onset of shock.
Returning to his post at Harvard after the war, Beecher became one of the nation's leading medical reformers. Inspired by the nurse's healing act of deception, he launched a crusade to promote a method of testing new medicines to find out whether they were truly effective. At the time, the process for vetting drugs was sloppy at best: pharmaceutical companies would simply dose volunteers with an experimental agent until the side effects swamped the presumed benefits. Beecher proposed that if test subjects could be compared to a group that received a placebo, health officials would finally have an impartial way to determine whether a medicine was actually responsible for making a patient better.
In a 1955 paper titled "The Powerful Placebo", published in the Journal of the American Medical Association, Beecher described how the placebo effect had undermined the results of more than a dozen trials by causing improvement that was mistakenly attributed to the drugs being tested. He demonstrated that trial volunteers who got real medication were also subject to placebo effects; the act of taking a pill was itself somehow therapeutic, boosting the curative power of the medicine. Only by subtracting the improvement in a placebo control group could the actual value of the drug be calculated.
The article caused a sensation. By 1962, reeling from news of birth defects caused by thalidomide, the US Congress amended the Food, Drug and Cosmetic Act, requiring trials to include enhanced safety testing and placebo control groups. Volunteers would be assigned randomly to receive either medicine or a sugar pill, and neither doctor nor patient would know the difference until the trial was over. Beecher's double- blind, placebo-controlled, randomised clinical trial - or RCT - was enshrined as the gold standard of the emerging pharmaceutical industry. Today, to win FDA approval, a new medication must beat placebo in at least two trials.
Beecher's prescription helped cure the medical establishment of outright quackery, but it had an insidious side effect. By casting placebo as the villain in RCTs, he ended up stigmatising one of his most important discoveries. The fact that dummy capsules can kick-start the body's recovery engine became a problem for drug developers, rather than something that could guide doctors toward a better understanding of the healing process.
Beecher also overreached by seeing the placebo effect at work in curing ailments like the common cold, which wane without intervention. But the triumph of his gold standard was a generation of safer medications that worked for nearly everyone.
What Beecher didn't foresee, however, was the explosive growth of the pharmaceutical industry. The blockbuster success of mood drugs in the 80s and 90s emboldened Big Pharma to promote remedies for a growing panoply of disorders that are intimately related to higher brain function. By attempting to dominate the central nervous system, Big Pharma gambled its future on treating ailments that have turned out to be particularly susceptible to the placebo effect.