Being too cautious can kill you. And the U.S. Food and Drug Administration (FDA) is the avatar of bureaucratic caution.
Consider the FDA's recent responses to setbacks in gene therapy research. In September 1999, 18-year-old Jesse Gelsinger died four days after receiving a novel gene therapy aimed at correcting a genetic disease that prevented his liver from processing proteins properly. His disease, ornithine transcarbamylase deficiency, occurs in one in 40,000 births and usually kills babies born with it within a few days after birth.
The physician scientists at the Institute for Human Genetic Therapy (IHGT) at the University of Pennsylvania infused attenuated cold viruses containing the normal gene directly into Gelsinger's liver. This phase one clinical trial was designed to check on the safety of the treatment -- it was not expected to cure Gelsinger or other participants in the study.
After the gene therapy was administered, Gelsinger suffered an immediate strong immune reaction that led to his death four days later. The Gelsinger family later claimed that they were not given enough information for adequate informed consent. The IHGT researchers argue that they had informed the family, but later settled out of court for unspecified damages.
The FDA went into panic mode after the Gelsinger story broke in The New York Times and The Washington Post. The FDA began hastily scrutinizing all gene therapy trials with an eye to finding not just egregious violations, but even technical paperwork missteps. Spooked bureaucrats who want to stop something that they fear might get them in trouble tend to bury those they regulate in mounds of paper and interrogatories. .
Unfortunately, the research of Dr. Jeffrey Isner fell victim to this FDA ass-covering effort. Dr. Isner and his colleagues at St. Elizabeth's Medical Center in Boston and at Tufts University had begun very promising gene therapy research designed to repair hearts damaged by atherosclerosis. Isner began clinical trials in 1998 in which the gene for vascular endothelial growth factor (VEGF) was inserted directly into the blocked arteries of patients suffering from angina.
The idea is that the VEGF gene would cause the patient's heart to start growing new blood vessels to go around the blocked ones, essentially growing their own heart bypasses without surgery. The patients chosen for the research had tried all other treatments for their heart disease, including heart bypasses and balloon angioplasty. Most could barely walk 100 feet before experiencing crushing chest pain.
Despite some very positive preliminary results the FDA shut down Isner's gene therapy research because of technicalities in March 2000, leaving many patients untreated. The FDA closed him down because two patients in one of his clinical trials had died, but not from side effects of the gene therapy. Since he had not reported those deaths, the FDA bureaucrats couldn't be sure that the treatment hadn't killed them. They followed the motto: When in doubt, shut it down. That some patients died should not have been a surprise considering that only very desperately ill people had been accepted into the trials in the first place. Isner and his patients begged the FDA to reconsider, but the agency took its time.
After being shut down, Isner and his colleagues reported that in one trial 70 percent of the patients had a significant decrease in angina symptoms. For example, one patient, the Rev. Charles Wilson of Charlotte, N.C., told the Boston Herald that before the gene therapy, he suffered "20 to 25 severe angina episodes a day. Something as simple as shaving would bring on angina. Now, I'm back in the pulpit." Rev. Wilson said that he was "baffled" by the FDA's action against Isner.
A year and a half after the FDA stopped the research, Isner published in the scientific journal Circulation the results of one particular protocol in which all 13 patients treated with VEGF were still alive, and nine had increased blood flow to damaged parts of their hearts. In November, at the American Heart Association annual convention, Isner's colleagues reported a double-blind study of 19 patients in which 12 patients received VEGF and seven did not. Eight of the 12 treated with VEGF had increased blood flow to their hearts. In other words, gene therapy worked.
Tragically, Isner didn't get to savor his triumph over the bureaucrats. He dropped dead of a heart attack on October 31. And it is very likely that many patients who might have benefited directly from participating in this clinical trial also dropped dead while the FDA dithered. That's not to mention the deaths that will result from the delay in eventually rolling this treatment out to the more than 250,000 Americans who suffer from angina.
"Among bureaucrats, the costs of errors are thought to exceed the gains from risky choices, so excessive caution or prudence is the norm," public choice economists Randy Simmons and William Mitchell explained in their article "Pathological Politics" in Society.
A frequent critic of the FDA, Sam Kazman from the Competitive Enterprise Institute (CEI) in Washington, D.C., puts it more pointedly. "From a bureaucrat's point of view, it's a lot more important to worry about preventing a single highly publicized death like Jesse Gelsinger's than to worry about the unreported dozens or even hundreds of nameless patients who die because the FDA is delaying approval of a new life-saving therapy."
As bad as the current FDA regulatory system is with regard to getting novel gene therapies to patients, worse may be in store for the age of individualized medicine now dawning. Researchers are hard at work developing treatments that will be tailored for individual patients, not just drugs that can be sold to millions. For example, one type of cancer vaccine can be created using cells taken from each individual patient's tumor. Those vaccines will work, if at all, only for that specific patient.
Dr. Robert Oldham, CEO of Cancer Therapeutics, Inc., says, "Individualized therapies don't fit well into the FDA's mass drug development paradigm." He believes that conducting the double-blind studies using hundreds of patients that the FDA now requires for new drugs would be inappropriate for such individualized treatments.