Gene-therapy death prompts broad civil lawsuit

URL: http://www.nature.com/cgi-taf/DynaPage.taf?file=/nbt/journal/v18/n11/full/nbt1100_1136a.html

 Nature Biotech, November 2000 Volume 18 Number 11 p 1136

Jeffrey L. Fox

                  One year since the death of a volunteer in a gene therapy

                  clinical trial at the University of Pennsylvania (UP; Philadelphia,

                  PA), a broadly framed wrongful death lawsuit has been brought

                  against the university, two local hospitals with which it is

                  associated, and its private sector biotechnology collaborator,

                  Genovo (Sharon Hills, PA). The lawsuit was filed by the patient's

                  father and uncle in mid September in the Philadelphia County

                  Court of Common Pleas. It not only names several UP faculty

                  members who were directly involved in its gene therapy

                  program, but unusually also singles out a bioethicist on the

                  faculty who advised them as well as university trustees and

                  specific administrators for alleged negligence and conflicts of

                  interest.

                  As a civil action, the lawsuit seeks to collect both compensatory

                  and punitive damages in excess of $50,000 on all of several

                  claims that, besides wrongful death, include "assault and

                  battery," "lack of informed consent," "infliction of emotional

                  distress," and "fraud on the Food and Drug Administration."

                  However, in the broad sweep of the lawsuit, it in effect demands

                  higher standards for safety during such clinical trials, insists on

                  more detail and candor when disclosing risks to volunteers who

                  participate in them, and calls for sharply restricting the kinds of

                  conflict of interest that would be permitted among corporate and

                  university partners that undertake gene therapy and other

                  high-risk clinical trials. The demands coincide with espousals

                  from Greg Koski of the new federal Office for Human Research

                  Protections (Washington, DC) of stronger standards, and the

                  American Society of Gene Therapy's (Milwaukee, WI) recent

                  adoption of similarly stringent standards as a way of minimizing

                  conflicts of interest (Nat. Biotechnol. 18, 1029;MEDLINE).

                   Jesse Gelsinger had a mild form of a rare inherited nitrogen

                  metabolism disorder called ornithine transcarbamylase (OTC)

                  deficiency. He died in September 1999 while participating in

                  the phase I clinical trial that was testing an engineered

                  adenovirus vector carrying a gene intended to correct the

                  defect. UP principal investigator James Wilson and other

                  members of the UP team attributed Gelsinger's death to an

                  acute respiratory system collapse and subsequent multiorgan

                  failure induced, at least in part, by his immune system's

                  response to the engineered viral vector (Nat. Biotechnol. 18,

                  377, 2000; 18,143, 2000; 17, 1153, 1999;MEDLINE).

                  The lawsuit claims that Gelsinger died because the members of

                  the UP medical team and other defendants were "careless,

                  negligent, and reckless" and that they failed to "properly and

                  adequately evaluate [Gelsinger's] condition and eligibility for the

                  gene transfer trial." Moreover, it claims that the adenoviral

                  vector that "ultimately caused the death" was "defective" and

                  "unreasonably dangerous." Among other specific claims, it

                  contends that Genovo and UP researchers "allowed vectors to

                  sit and/or be stored on lab shelves for 25 months before being

                  tested on animals, making them less potent than they could

                  have been." Moreover, the way the vector was stored "may

                  have resulted in underestimation of [its] potency in humans."

                  The lawsuit also takes sharp issue with the financial

                  arrangements between UP and Genovo, as well as with the

                  extent to which Wilson has been involved with that company,

                  including the extent of his equity holdings. In addition to naming

                  Wilson and other members of the team who administered

                  vectors to volunteers, the lawsuit names William Kelley, a

                  former dean of the UP Medical School, who along with Wilson

                  holds a broad patent covering several fundamental aspects of

                  gene therapy technology involving use of such vectors. "Dr

                  Kelley, Genovo, and Dr Wilson all stood to gain financially from

                  the successful use of [adenovirus] vectors," the lawsuit states.

                  And, because the university took an equity stake in Genovo, it,

                  too, "stood to gain financially." These arrangements may have

                  contributed to the defendants' alleged failure to notify officials of

                  the FDA of "adverse or unexpected events associated with. .

                  .the study."

                  Although a UP committee said in early 1995 that there

                  appeared to be one or more conflicts of interest surrounding

                  these arrangements with Genovo, university administrators

                  approved them and allowed Wilson and colleagues to hold

                  equity positions in the company and to plan and conduct clinical

                  experiments involving volunteers at UP facilities. The lawsuit

                  claims that these conflicts of interest were not fully disclosed to

                  either Gelsinger or his father and, further, that they led Wilson

                  and his colleagues to understate the clinical experiment's risks

                  and to misrepresent the efficacy to be expected from the

                  procedures.

                  A remarkable element of this lawsuit is the extent to which it

                  cites Arthur Caplan, director of the UP Bioethics Department,

                  who is widely known for his outspoken views on a wide range of

                  ethical issues in modern biomedicine. The lawsuit suggests

                  without explicitly stating so that Caplan was subject to a conflict

                  of interest because Wilson's department helped to fund

                  Caplan's program. Yet the lawsuit also references public

                  statements from Caplan to buttress some of its claims against

                  the defendants. For example, it quotes him as saying that "if you

                  cured anybody from a phase I gene therapy trial, it would be a

                  miracle" and "there was never a chance that anybody would

                  benefit from these experiments."

                  Meanwhile, its more pointed complaint is aimed at Caplan's

                  intervention in the early planning of the OTC deficiency gene

                  therapy clinical trials in which he helped to persuade Wilson and

                  colleagues to conduct their experiments on adults rather than on

                  newborn infants with a more serious form of this deficiency. Part

                  of the reasoning was that such infants cannot give informed

                  consent and that their parents may be too easily persuaded to

                  enroll their seriously ill children in clinical trials that appear to

                  offer such a novel way of combating a potentially deadly and

                  certainly life-long condition.