Human Guinea Pigs on the Frontiers of Medicine

By Marie McCullough

Paul Gelsinger, made an activist by the death of his son, addresses the Association of Clinical Research Professionals. Photo by Derek Oliver, ACRP.

Paul Gelsinger stood before an audience of thousands of doctors and clinicians who test experimental treatments on humans to make a heartwrenching plea: Don't let what happened to my son happen to others. Gelsinger's son, Jesse, 18, died in a gene-therapy experiment at the University of Pennsylvania in September 1999.

Since then, revelations of accidents and abuses at other respected research institutions have made it clear Jesse's tragedy was not an isolated one. Step-by-step testing of new treatments on humans is essential to medical progress, and about 3 million Americans a year now sign up for 80,000 "clinical trials." But critics say these experiments have become so numerous, commercialized and hard to monitor that it is too easy for researchers who are arrogant, reckless or just plain sloppy to harm people.

Enhancing patient safety is crucial because clinical research, by its nature, involves risk, even when scrupulous care is taken. Deaths are rare - only about 1 in 10,000 subjects die. But "serious adverse events" - those that are life-threatening or require hospitalization - happen to 1 in 30 subjects in studies of new drugs, according to an analysis by CenterWatch, a Boston firm that tracks the clinical-trials industry.

Proposals for reform have come from Congress, the drug industry, academia and government. Still, overhauling the vast, varied clinical-trials system is proving to be tough. The federal Office of Human Research Protections has been reorganized and beefed up under former Harvard researcher Greg Koski. Beyond that, critics say, there has been more debate than decisive action.

Paul Gelsinger, 49, has become an outspoken advocate of change. He was in Toronto last month to address the Association of Clinical Research Professionals, using his son's story to personalize an often-impersonal process.

He described Jesse, the second of four children, as an exuberant, good-hearted teenager, despite a rare liver-enzyme disorder, which was controlled with diet and drugs. Jesse was also, Paul said ruefully, an unabashed slacker. One day, while driving Jesse to work at a supermarket near their Tucson, Ariz., home, Gelsinger sternly told him to find a job with health insurance if he wasn't going to college.

In a huff, Jesse jumped from the moving vehicle. "As I cradled him in my arms" afterward, Gelsinger recalled, "I cried, 'You idiot! What were you thinking?' "

Several months later, the same headstrong teenager made a thoughtful decision, with his father's guidance, to volunteer for the study at Penn. Both realized Jesse wouldn't benefit and would likely suffer flulike symptoms. But Jesse wanted to help find a cure for babies with a deadly form of his disorder, ornithine transcarbamylase deficiency.

"Words cannot express how proud I was of this kid," Gelsinger said, recalling the day Jesse flew to Philadelphia. "Just 18, he was going off to help the world. I gave him a big hug and told him he was my hero." That was their last hug.

Paul Gelsinger had planned to go to Philadelphia a week after the treatment for what he figured would be the most dangerous part, a liver biopsy. Within a day of getting the genes, Jesse was gravely ill. His father and family members rushed to Philadelphia to find Jesse in a coma, his organs failing. On the third day, they held a bedside prayer service. Then life support was shut off.

"Jesse was bloated beyond recognition," Gelsinger said. "The only way to be sure it was Jesse was the battle scar on his elbow" from jumping out of the van, and a small tattoo.

The researchers, federal investigators found, had violated their own protocol and federal safety rules, while ignoring signs the treatment could be harmful - breaches Gelsinger initially denied.

"I believed that their intent was nearly as pure as Jesse's. They had promised to tell me everything. I had bonded with these men. We shared personal experiences, spiritual things."

In the last three years, at least two more healthy volunteers have died in trials at other institutions. The most recent was Ellen Roche, 24, who inhaled a toxic chemical in June as part of an asthma experiment at Johns Hopkins University in Baltimore.

Penn, Johns Hopkins and at least five other prestigious centers, including Duke University Medical Center and Rush-Presbyterian-St. Luke's Medical Center in Chicago, have had trials temporarily shut down by federal regulators concerned that patients were being endangered. Dozens of other centers have been faulted for lapses.

Invariably, the wayward institutions have made swift, sweeping changes. Penn set up a $1.5 million, 13-member Office of Human Research to train, assist and monitor researchers.

Still, the clinical-research industry is leery of proposals for tighter federal control.

"One of the reasons there hasn't been anything concrete is that no one has come up with a really good solution that's workable," said Leonard Glantz, a professor at Boston University School of Public Health.

Although most people don't know what clinical trials are, such studies are crucial to evaluating the safety and effectiveness of new treatments. Before trials became standard in the mid-20th century - using control groups, placebos and other mechanisms to prevent distortion of outcomes - the healing arts relied heavily on superstition, folk tradition and doctors' experiences.

"Clinical trials are not only essential to medical progress, but in the overwhelming majority of cases, they also offer participants the opportunity to receive top-quality care and the best available treatments," said Narberth oncologist Marisa Weiss, president of, an Internet support group.

The number and complexity of trials have grown as research has shifted from lone scientists testing patients at individual medical centers to global, multicenter studies sponsored by the government, academic institutions and drug firms. In 1985, a new drug approved by the FDA involved 36 trials and 3,200 patients; now, the average is 75 trials and 4,800 patients, according to Parexel, a clinical trials-management company. Only one in five drugs ultimately wins approval.

Considering the system's sheer size, "you don't hear about many problems with clinical trials. I think it's been one of the great worldwide success stories," said Thomas L. Adams, head of the Association of Clinical Research Professionals.

Indeed, about 77 percent of patients in trials say they would volunteer again, CenterWatch surveys show.

On the other hand, even top-notch centers have made news with ethically questionable studies or disastrous errors: In 1996 at the University of Rochester, a healthy 19-year-old student had lung cells collected in a study of smoking and air pollution. When she complained of pain, she was mistakenly given a deadly dose of the anesthetic lidocaine.

In 1999 at Children's Hospital of Pittsburgh, a 9-month-old baby died of a heart arrhythmia after being given an experimental medicine for acid reflux; a coroner blamed the arrhythmia on the drug, which had been linked to adult deaths.

Last year at Case Western Reserve University, a healthy retired nurse died during tobacco industry-sponsored research. Investigators concluded that she was given a fatal overdose of methionine, a normally harmless dietary supplement.

Too often, critics say, patients don't understand or aren't told about risks, despite signing a statement of informed consent. At Penn, two volunteers preceding Jesse Gelsinger suffered from temporary liver toxicity that should have halted the trial. They were not informed. The Gelsingers were not told, either, even though Jesse's liver functioning was the weakest and his dose the highest.

Another problem is that the system is unevenly regulated. Drug industry-sponsored trials are regulated by the FDA, which conducts impromptu on-site audits and requires reports of virtually all subject deaths and adverse events.

But government-funded studies at academic institutions are regulated by the Office of Human Research Protections. The OHRP wants to know about "unanticipated problems involving risks to subjects," a rule that compliance-oversight director Michael Carome said has "ambiguity."

Moreover, until Koski took over the OHRP, it rarely checked on institutions unless someone complained. Now, his staff of 47 seeks to visit 70 sites each month - although 60 of these will be "quality-improvement consultations," not hunts for violations.

"We must move from a culture of compliance to a culture of conscience," Koski said.

Outside FDA and OHRP purview are studies with no regulation, including some infertility, dietary-supplement and stem-cell trials. "I could have children inhale lighter fluid, and the OHRP and FDA would have nothing to say about it, if I'm not a drug company and I don't work at an institution," said Glantz.

When rules are unclear, some researchers err on the side of not reporting. After Jesse Gelsinger's death, "the National Institutes of Health received 652 reports of previously unreported serious adverse events [from gene therapy trials] that sparked a series of congressional hearings on patient safety oversight," noted the CenterWatch analysis.

Adil E. Shamoo, a University of Maryland biochemist and editor of the journal Accountability in Research, says non-disclosure is common. "I'm not accusing them of conspiring not to report," Shamoo added. "I'm saying what happens is, nobody is going to... say, 'Hey, guys, I've read the federal regulations, and we have to report this.' " The system is not supposed to be so vulnerable.

Local institutional panels are supposed to ensure that every trial has proper oversight, an ethical design, and that each patient signs an informed-consent document. Called Institutional Review Boards (IRBs), or ethics boards, the panels were mandated in 1974 by federal law following revelations about abuse of human subjects - including government-sponsored radiation experiments and the notorious Tuskegee syphillis study, in which African American men were secretly left untreated for the venereal disease.

But ethics boards, which must have at least one community representative, are not trained or paid for what is often a crushing workload. A government report found a typical university medical center IRB had less than two minutes per agenda item during a 21/2-hour meeting - hardly conducive to careful deliberation.

Under current rules, ethics boards may wind up with boxes full of adverse-event reports from many testing sites, but no way to make sense of them.

"We get a report, but without context... , we often cannot determine if it is referring to one event in a population of 10 patients or 300 patients," said Erica Heath, president of Independent Review Consulting, a for-hire ethics board. "Was the subject assigned to the study drug or placebo?"

Ethics boards have not been effective in dealing with another problem - financial conflicts of interest. In the gene therapy trial, for example, both James Wilson, Penn's lead gene-therapy researcher, and the university held stock in Genovo, a company that Wilson founded to develop therapies. Paul Gelsinger says he was not aware of this when Jesse volunteered, although it was disclosed on the informed-consent form.

A year after Jesse died, Targeted Genetics Corp., of Seattle, acquired Genovo. Wilson got $13.5 million in Targeted stock and the university got $1.4 million in stock. (Wilson quit last month as head of Penn's gene-therapy institute, and the FDA has begun a process that could bar him from human research overseen by the agency.)

Money influences the system in other ways, critics say. Drug companies often pay patients to take part in studies, and pay researchers to recruit them.

Harvard Medical School faculty member Marcia Angell, former editor of the New England Journal of Medicine, says financial deals that could compromise objectivity should be banned, not just disclosed. Disclosure is "neither fair nor helpful to the patient, who may be both sick and desperate." A typical reaction to her unequivocal stance: Get real.

"I think [a ban] would bring, particularly in biotechnology, a lot of research to a complete halt," said Adams. "And I don't think that would be in the interest of public health."

In Toronto, a nurse from the University of Texas asked Gelsinger, "How are we supposed to find a balance between the industry pressures... and the patients and advocacy groups on the other side? Patients don't care about the details. They just want the new drug now."

Gelsinger said he sympathized. An advocacy group for patients with Jesse's disorder had pushed for the Penn trial.

"People pour so much hope in that they become blind," he said. "But that's why we need independent oversight. Somebody needs to be stepping back, and being careful and unbiased."