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GENETIC MEDICINE
Prescription for Conflict

The Topic In-Depth #1: The Safety of Clinical Trials

by Sally Lehrman
October 2001

Paul Gelsinger lost his son to science.

The boy had inherited a rare metabolic disease, though he looked and felt healthy as long as he took his pills and maintained a strict diet. He held down a part-time job, rode his motorcycle in the Arizona desert and dreamed about creating a new world wrestling federation. Four days after his 18th birthday, he volunteered to join a clinical trial of gene therapy, telling his father he hoped to help babies whose lives were threatened by the same condition he had.

He flew to the Institute for Human Gene Therapy at the University of Pennsylvania in Philadelphia, where doctors injected him with a test treatment for ornithine transcarbamylase (OTC) deficiency, which harms the liver's ability to break down nitrogen and can lead to a dangerous buildup of ammonia. Four days later, Jesse Gelsinger died.

His father learned later that four other patients had experienced serious problems with the therapy. He found out no one had yet shown the treatment worked in humans. He discovered that other researchers had voiced concerns about using an adenovirus, one of the causes of the common cold, to carry the repair gene into patients' livers. He learned that the lead scientist on the project had a financial stake in the outcome through a gene therapy company called Genovo he helped found.

"I'm a pretty average guy and going into it, I just wanted to trust the system," Paul Gelsinger says now. "People have to know you can't do that."

After Jesse Gelsinger's death in 1999, problems with gene therapy tests throughout the country came to light. The National Institutes of Health discovered that scientists had reported only 39 - not even six percent - of 691 incidents of severe side effects or deaths in gene therapy studies using adenoviruses. Researchers using another type of gene therapy to regenerate blood vessels had failed to tell the agency that six patients had died.

It wasn't just high-tech treatments that turned out to be problematic.

Throughout the academic clinical trial system, regulators, bioethicists and many scientists agreed, oversight and patient protection policies are outdated, ignored and generally in need of repair. Patients often misunderstand the purpose of a trial, expecting treatment when in fact medical effectiveness is far from certain. Demand is building to repair weak oversight, improve communication with patients, and uncover conflict-of- interest on the part of institutions and researchers.

"It's a mess, it really is," says Michael Baram, director of the Center for Law and Technology at Boston University. The immense promise of biotechnology and genetics has pushed research rapidly forward, sometimes leaving safety measures behind, he says.

"Maybe we're putting a lot of pressure on something that needs more time," he adds.

In August and September 2001, several medical journals including the Journal of the American Medical Association and the New England Journal of Medicine published editorials that decried the way commercial interests had influenced clinical trials and pledged to hold scientists reporting their research accountable for ethical behavior. Recent government proposals would toughen rules about the way patients are recruited, require researchers to disclose financial conflicts of interest and improve the capacity of university-level oversight committees to do their job.

In September 2001, the National Bioethics Advisory Commission, which reports to the White House, recommended that an independent federal office be created to develop, monitor, and enforce regulations for all types of human clinical research.

The committee emphasized two big weaknesses in the current system: (1) the lack of independent review of risks and benefits, and (2) the use of legalistic forms to replace direct communication between researchers and prospective patients. Commission members recommended that university-level review boards receive training and prove their competence; they also asked for rules to contain financial conflict-of-interest.

"I don't think any of the researchers are evil people. They think they're going to be doing something good. The problem is in the design of the research and (potential study participants) aren't going to be able to judge that," says Patricia Backlar, a commission member and assistant director for the Center for Ethics and Health Care at Oregon Health Sciences University.

"You're preying on people who are so desirous of help - and in a climate where people may not have access to health care."

People who want to participate in studies must navigate a very complicated system with little access to information, experts agree. No one is certain, but it's estimated that about half of clinical trials don't fall under any federal regulations because they're privately funded, unrelated to drug approval applications or performed at government agencies, including the Department of Labor and the Nuclear Regulatory Commission, that don't follow generally accepted guidelines.

Even researchers who are covered by the federal rules have great discretion and only must report unanticipated problems they deem to be associated with the studies. The information they do provide is then kept within agency offices and even other scientists rarely have access.

"Obviously, something has to be done with the adverse event reporting system because no one seems to be following it," says Baram. He says the regulations are impenetrable to most researchers, who treasure their academic freedom and so sometimes simply refuse to follow the rules.

Indeed, reports about safety problems in clinical trials are sorely lacking, according to Adil E. Shamoo, a molecular biologist and ethicist at the University of Maryland who made a Freedom of Information Act request for all "adverse events" submitted to the Office of Human Research Protection over a ten-year period.

From 1990 to August 2000, out of studies that involved more than an estimated 70 million patients, researchers reported only eight deaths and 386 adverse events in all.

"It's obscene," he says. "I can give you all the excuses in the world and bend backward, and there still are not going to be just eight deaths."

Institutional review boards, university-level groups charged with keeping track of a study's design and safety, often are understaffed, poorly funded and filled with the colleagues and fellow-employees of those doing the study, critics say. "They don't have filing cabinets to store the work, for example," Shamoo says. "They're riddled with conflict-of-interest. The IRBs are the gatekeepers and they're structurally flawed."

Before a patient even decides to join a study, research doctors are supposed to describe the possible dangers in detail, but the exchange often boils down to a signature on a set of legalistic documents.

Universities and companies have changed the purpose of consent forms to protect themselves instead of the patient, says anthropologist Barbara Koenig, Executive Director of the Stanford Center for Biomedical Ethics.

"The problem is this is has been put in a bureaucratic compliance box when it's really meant to make people think about these things and to talk about them," she says.

Koenig also points out that patients often view clinical trials as an opportunity for treatment when in fact, doctors are only testing dosage levels or possible effectiveness.

Researchers may unintentionally contribute to the problem. The website for the Eastern Cooperative Oncology Group, for example, tells people with cancer, "Volunteering for research studies can give patients access to promising new drugs long before they are available to the general public." It does, however, go on to point out that the new treatment might be disappointing.

Robert Catalano, a regulatory officer of the research consortium, says that patients should learn the difference between a study and a treatment in discussions that are part of the informed consent process.

"You have access to a promising new drug, but no guarantee," he explains.

Paul Gelsinger considers such talk the sort of sleight-of-hand that lured his family into tragedy. Jesse became a lot more interested in participating in the gene therapy trial when researchers told him the treatment seemed destined to be a success, his father says. "We were led to believe the treatment was working when it was in fact not. It was wishful thinking on their part."

Despite the widespread acceptance of deep problems within the clinical trial system, no one suggests that patients should simply opt-out on principle. They do suggest, however, going into studies with open eyes and asking lots of questions.