The Tribulation of Trials
Earlier this month, six healthy young men in London fell ill all at once and in a matter of hours landed in the critical care unit of Northwick Park Hospital on life support with multiple body organs failing. The villain: an experimental medicine administered as part of a research study.
The collapse came after injection with a drug code-named TGN 1412, a presumed anti-inflammatory agent that might help those with diseases like multiple sclerosis and leukemia. But it had the opposite effect. The drug triggered a massive inflammatory response. The robust bodies of all these men were flooded with immune chemicals gone toxic and killer blood cells all of their own making, dropping them like soldiers on a battlefield hit with friendly fire. Three prime suspects lead the list as explanations for why things went so terribly wrong in this trial. One is a contaminant; endotoxins made by bacterial growth can do this. Or the doses may have been miscalculated; too much of any drug is poison. Lastly, it might have been a species thing; a drug bioengineered to specifically mimic a human antibody might be harmless in test animals but poisonous to humans. An investigation is being carried out by the British equivalent of the U.S. Food and Drug Administration, which should get this all sorted out.
Understandably, this saga, splashed all over the front pages of newspapers and on TV, has riveted the British public. Who could not relate to these young college-age men, described variously as a waiter, a television technician, an apprentice plumber who signed up to earn money to take his mom on holiday, and a regular bloke who did many of these trials to help mankind? It's been surprising to me that here, across the pond, this still ongoing human tragedy has barely made a ripple.
This is not just a British problem. These boys might as well have been our own. Gone are the days of Kalamazoo when American drugs were American made. Drug development and the human studies that bring them to sick patients are global efforts. Look at TGN 1412: developed by a small German biotechnology company, TeGenero in Wurzburg; manufactured by a large multinational German pharmaceutical house, Boehringer Ingelheim. Both British and German regulatory authorities, using procedures similar to our own, approved its human testing. And an American clinical research company, Massachusetts-based Parexel International, carried out the trial in England.
But enough about borders. What's important is that the investigation might well turn up a problem of species incompatibility. In that scenario, the London experiment will cast a shadow over that crucial crossroad in the development of new drugs, the Phase I clinical trial. Phase I is the point in drug development when a new drug is finally ready to be tried in humans. Extensive prior testing in our furry friends has traditionally made this supremely safe.
Roulette. John Jenkins, director of the Office of New Drugs at the FDA, said no one there could recall a Phase I human trial that resulted in such serious toxicity. But most worrisome to him is the possibility that animal testing failed to pick up the problem in this particular class of drugs and thus might be falsely reassuring as new drugs in the biotech pipeline are tested.
Then who goes first? For most first-in-human studies, it's healthy volunteers who step up to take the risks with absolutely no medical benefit to themselves. But the hazard is tempered by proven safety in animals, the promise of a few days of R&R, watching TV, or playing pool, with an honorarium of a few hundred or a few thousand dollars tossed in. But if the risks become high-stakes roulette with a ticket to the ICU or worse on the table, no amount of psychic return or cold cash will do, and good drugs could pile up at the crossroads.
We all have a stake in what's happening in Britain. And development of technology that simulates human systems to test drugs before human exposure now takes on some urgency. The FDA just this month announced a new Predictive Safety Testing Consortium for companies to share technology that would more reliably predict human safety before drugs enter clinical study. The London event only highlights its importance.
Look into your own medicine chest. Walk the corridors of any hospital. Standing silently behind every one of our therapies is an army of human volunteers who have gone first or gone early. They have courageously taken risks for all of us, and in their hands is tomorrow's medicine.
This story appears in the April 3, 2006 print edition of U.S. News & World Report.