Bioethics: Gene therapy business: the tragic case of Jesse Gelsingerby News WeeklyNews Weekly
, August 12, 2000
A year ago Christmas, Jesse Gelsinger had a scary brush with death. He suffered from a disorder called partial ornithine transcarbamylase (OTC) deficiency, which kept him perpetually in danger of hoarding toxic levels of ammonia in his blood. Half of all infants born with the condition die within a month.
But Jesse was lucky. Five days of intensive care and a change of medication revived him.
On the day of his 18th birthday, Jesse took off with his family on a vacation to New Jersey — by way of the University of Pennsylvania, where researchers were testing a way to replace the genes that caused his disorder.
Jesse really wanted to participate in the study, says his father, Paul Gelsinger, especially after he had come so close to dying. Not because he thought it would improve his own health — he knew the test would probably make it impossible for gene therapy to help him later. “He wanted to be a hero,” his father says.
Once in Philadelphia, Jesse signed up. Four months later, on September 17 last year, Jesse was dead.
Within hours after doctors shot the normal OTC gene attached to a therapeutic virus into his liver, Jesse developed a high fever. His immune system began raging out of control, his blood began clotting, ammonia levels climbed, his liver hemorrhaged and a flood of white blood cells shut down his lungs.
Jesse’s death — the first reported death ever directly attributable to a gene therapy experiment — triggered an avalanche of revelations. There were questions about the quality of informed consent at University of Pennsylvania. There were accusations that the university had failed to report toxic side effects earlier that could have shut down the study.
And in response to a query from the National Institute of Health (NIH), gene therapy researchers all over the country revealed more than 650 dangerous adverse reactions they also had previously kept secret, including several deaths.
The Food and Drug Administration (FDA) put all gene therapy trials at University of Pennsylvania — plus other experiments ongoing in several other institutions — on hold.
Senator Bill Frist, a physician and transplant surgeon, began hearings to investigate the quality of government oversight and safety enforcement in gene therapy studies. And President Clinton demanded improvements in patient consent procedures and access to information about gene therapy research across the board.
Paul Gelsinger said he did not learn about any of the serious dangers his son was facing until it was too late. He didn’t know that two Rhesus monkeys had died in tests involving a gene delivery system similar to the one used with Jesse; he didn’t know that four other human patients had suffered toxicity to their livers earlier in the study.
For a time after Jesse’s death, Paul Gelsinger had defended the University of Pennsylvania gene therapy team believing they had done their best and had not deliberately risked Jesse’s life. He blamed the FDA for withholding vital information about this experiment from public scrutiny, information that would have made the researchers cautious about conducting the fatal experiment on his son. Now he is angry at both the FDA and the University of Pennsylvania team.
In the wake of the experiment that killed his 18-year-old boy, regulators and academics have scrambled to try to improve patient protections and restore public confidence in medical research.
But truly informed consent may still be impossible. Among other things, it’s very difficult for anyone, whether a member of the general public or a skilled scientist, to learn details about the problems cropping up in gene therapy studies.
Even a new National Institute of Health (NIH) database on clinical trials, if it sticks to requirements for the agency’s existing Clinical Trials Data Bank for serious or life-threatening diseases, will include no information about adverse reactions to gene therapy treatments. Further, financial alliances and conflicts-of-interest will not be included.
The NIH already collects details on serious adverse events quarterly. The terse reports, however, only describe incidents from trials the agency helps fund — leaving out the ones paid for solely by industry — and that the investigators themselves judge to be directly connected to the treatment.
Industry representatives are bridling at proposed rules that would prevent them from wrapping adverse reaction reports in pages of trade secrets as they do now, thus keeping them confidential.
Robert Spiegel of the Schering-Plough Research Institute, for example, implored the NIH at the December 1999 NIH Recombinant DNA Advisory Committee (RAC) meeting to avoid unnecessarily alarming the public with too much negative data. In May this year, industry representatives urged senators not to legislate new procedures or penalties. And up to now, of course, rules for reporting to both FDA and NIH have been widely ignored.
There is no guidance from either agency on when researchers ought to inform prospective participants about studies not directly related to the trial in question. Negative data that could help shape other research rarely make it into scientific journals. And even as new information unfolds, investigators can do little to incorporate it in a study’s design for fear of harming the strength of their results. Informed consent
“We know that informed consent doesn’t work,” says Arthur Caplan, who directs a large bioethics program at University of Pennsylvania. (Caplan did not participate in the Gelsinger study, although he did advise the researchers on ethical questions about whom to include in the research early on. The university recently announced it will move his program into an independent department outside of the Institute for Human Gene Therapy, where it was formerly housed.)
Caplan says the privatisation of science, combined with patients’ ardent desire for a cure, conspire to prevent meaningful protections for participants in all kinds of studies. Trade secrets, financial conflicts of interest and overloaded review committees obstruct informed consent by keeping news about ongoing studies beyond the reach of patients and researchers alike, he and other observers argue.
Paul Gelsinger says that regulators are aiming in the wrong direction if they don’t correct the undue influence of business interests on gene therapy research.
The FDA and the researchers at University of Pennsylvania all knew more about the dangers of the treatment than they let on, Paul Gelsinger says now. The NIH sat by, complacent. “This is all about money, prestige,” he says. “We forgot the basic point of it all: people.”