Very Critical of Clinical Trials-Part I

TIME Magazine article, 2002

Human Guinea Pigs

Some patients join clinical trials out of desperation. Others to help medicine advance. Whom do you blame if they get sick—or even die?

By MICHAEL D. LEMONICK and ANDREW GOLDSTEIN/TULSA

By the time Cherlynn Mathias was ready to blow the whistle on Dr. Michael McGee two years ago, it had been clear for quite a while that something fishy was going on.

For one thing, there were the hokey infomercials touting his experimental vaccine for malignant melanoma, a particularly nasty form of cancer, as if it were a Veg-O-Matic. Thanks to the vaccine, a patient declared onscreen, my cancer is in total remission. Then there was the sales pitch McGee delivered in person. When she and the doctor met with a prospective patient, says Mathias, who worked as his research nurse, he would come on like a used-car salesman: "'We have the best vaccine out there,'" she remembers his saying.

"'Two-thirds of my patients have responded to the treatment.'" He was even giving the drug to his father-in-law, he would tell people; that's how good it was.But what they got, once they joined McGee's clinical trial, many patients say, was a different story.

According to Mathias, more than a third developed severe side effects, including uncontrollable nausea, fevers, rashes, swelling and terrible headaches. Some thought the doctor's behavior was odd. While on the vaccine, one patient, Dawanna Robertson, discovered she was pregnant; she panicked when she recalled the warning on the consent form she had signed: "The potential effects of these drugs on the growing fetus ... may include serious birth defects."

Yet when she voiced her fears, Robertson says, McGee assured her that the vaccine couldn't pass through the placenta. She received another injection that day. Still, Mathias says, most of McGee's patients believed that this vaccine was their best chance for recovery from what is usually a fatal disease.

That's why they were so shocked when McGee sent them a letter that read, in part, "Patients have enrolled in this study more rapidly than originally expected ... Due to this interest, the sponsor has exceeded its capacity to supply the experimental Melanoma Vaccine and is unable to provide material for further injections at this time."The letter was devastating enough, but Mathias knew it was a lie.

The truth was that the trial had been suspended out of a growing concern among McGee's supervisors that it may have been doing more harm than good. So after agonizing for days about what to do, she wrote a long, detailed letter to what is now called the federal Office for Human Research Protections (OHRP), describing McGee's multiple lapses.

Her letter reported that McGee had, among other things, stored the vaccine improperly, exposing it to potential contamination; failed to maintain adequate records and track its consistency from batch to batch; mislabeled vials of the stuff; and, worst of all, kept most of the data on adverse side effects secret.

An investigation by the Food and Drug Administration confirmed her suspicions and ultimately revealed more than 20 separate deficiencies. "We were doing nothing right," says Mathias. "It was a perfect lesson in how not to run a clinical trial."The lesson would have been a lot less shocking if McGee's vaccine trial had been run out of a back-alley clinic or a storefront in Tijuana.

In fact, the study was conducted at the St. John Medical Center in Tulsa, Okla., and co-sponsored by the respected University of Oklahoma Health Sciences Center. It had been approved by the university's institutional review board, or irb, a body set up to ensure that such trials meet federal standards for experimental design—including the obligation to inform participants of any safety issues.

And it had been given the green light by the FDA itself.Unusual as it is, the Oklahoma case isn't an isolated incident—and in many ways, it isn't even the worst. Clinical trials are usually pretty safe; the vast majority of subjects are not hurt in any way. But so many problems—and such serious problems—have surfaced in recent years that doctors and hospital administrators are starting to wonder whether there is something dangerously wrong with the clinical-trial system. Nobody is suggesting that it be shut down completely.

Clinical trials are a vital and necessary part of America's vaunted medical research system. They are its primary mechanism for testing potential drugs and separating the ones that work from the ones that are useless or actively harmful.

Yet the very nature of human testing involves risk; nobody can tell in advance whether a new medicine carries unforeseen dangers. And so clinicians are forced to walk an ethical and scientific tightrope. Make the rules protecting patients too lax, and subjects will suffer and even die needlessly.

Make them too strict, and lifesaving medications won't make it out of the lab quickly enough to help the people who need them most.But precisely where the balance lies is a matter of serious, even bitter debate. At one extreme are those who believe that most trials are tainted because they play on the fears of desperately ill patients, involve some sort of subtle coercion like money or free medicine or fail to warn patients of the very real dangers they face.

Some critics argue as well that there are simply too many trials, as pharmaceutical companies looking for a share of the blockbuster drug market pump out copycat medicines that no one really needs. On the other side are clinicians who feel they are already burdened with too much regulatory paperwork.

Tighter rules will just take time and energy away from what they should be doing—developing and testing desperately needed medications. A few mishaps today, they say, may be the price we pay to save thousands of lives tomorrow.

Still, something is clearly wrong with the system as it now operates. Over the past three years, more than 60 institutions, including several of the world's most prestigious research centers, have been criticized by the U.S. government for failing to protect human subjects adequately. McGee's patients were very sick, so in a sense they couldn't be made much worse by his treatments.

But federal records show that since 1999 at least four people who entered clinical trials in reasonably good health wound up dead—including two infamous cases, at Johns Hopkins Medical Center and the University of Pennsylvania. The actual number of such deaths may be considerably higher, but nobody really knows.

The monitoring of clinical research in the U.S. is so piecemeal, and the reporting of problems so haphazard, that it's almost impossible to find out what is really happening. Thanks to a patchwork regulatory system, perhaps a quarter of all clinical research—including some studies on reconstructive surgery, dietary supplements, stem cells and infertility treatments, for example—gets no federal oversight whatsoever.

And even where oversight is mandated, it's often applied loosely, if at all. And it can only get worse as the number of trials increases. According to CenterWatch, a patient information group that monitors clinical research, 80,000 clinical trials were conducted in the U.S. last year alone.

Adil Shamoo, a bioethicist from the University of Maryland School of Medicine who sits on the National Human Research Protection Advisory Committee, estimates that some 20 million people were enrolled as research subjects last year—three times the number a decade ago.

That figure is expected to grow astronomically in the next few years, as drug companies prepare record quantities of new medicines for market and as the budget of the National Institutes of Health—the government's primary research agency—continues to grow. Says Thomas Murray, president of the Hastings Center, a bioethics think tank: "Our human-subject-protection apparatus is simply not equipped to deal with this demand.

We're going to potentially face 100 Oklahomas, 100 Hopkinses."But what to do about it isn't at all clear. Some experts favor tighter enforcement of existing rules and greater resources for the understaffed, overworked review boards that too often let shoddy research proceed. Others think patients need to be told more clearly and forcefully what the dangers and limitations of clinical trials really are. Still others are convinced that financial conflicts of interest—drug companies sponsoring trials and paying doctors—are the root of all evil.

Bills are being introduced in both houses of Congress in the next few weeks that are designed to better protect research subjects, and OHRP, the main research regulatory agency, is rewriting its rules.

What's clear to nearly everyone, though, is that without uniform, federally mandated regulations, the situation will only get worse.


TIME Magazine article -Part II

Part II

TIME Magazine Part III

Part III


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