Washington Editor

SILVER SPRING, Md. - Development of leukemia in two French gene therapy patients coupled with limited data prompted an FDA panel of advisers to conclude that gene therapy trials in X-linked severe combined immunodeficiency (SCID) should not go forward unless there are no other treatment options available.

The FDA's Biological Response Modifiers Advisory Committee (BRMAC) voted unanimously on the question about X-SCID trials, but in a second, 20-3 vote, the committee said the FDA should the lift the "clinical hold" placed on trials using retroviral vectors in hematopoietic stem cells and review the trials on a case-by-case basis. The FDA is not bound by the panel's recommendation.

"We don't know if those trials are dangerous or not. We haven't seen the data and we don't want to make a decision without the data," Daniel Salomon, committee chairman and associate professor at the department of molecular and experimental medicine at The Scripps Research Institute in La Jolla, Calif., told BioWorld Today after the meeting. "We are recommending that the FDA look at each one of these and make a decision."

At issue is a number of gene therapy trials that were halted (stopped from enrolling new patients) after two children participating in a gene therapy trial in France for X-SCID ("bubble-boy" disease) developed leukemia. The first child, a 3-year-old boy, developed the adverse event after 30 months of treatment and the second child developed it late last year. (See BioWorld Today, Jan. 16, 2003.)

Keeping in mind that the French investigators did not conduct their trial based on FDA guidelines, regulators here took that matter seriously, particularly since the science community faced a similar scenario in 1999 when gene therapy patient Jesse Gelsinger died. Gelsinger, an 18-year-old, was participating in a University of Pennsylvania gene therapy study using an adenoviral vector.

The clinical hold has been in place since mid-January pending advice from BRMAC.

For the most part in reference to the X-SCID trials, panel members were wary.

"Any sponsor who wants to do these types of studies better have a darn good reason not to choose an alternative," Salomon said.

In agreement, Joanne Kurtzberg, professor of pediatrics at Duke University Medical Center in Durham, N.C., added that in most instances, patients have options other than gene therapy. While also risky, she recommended transplants.

After the leukemia event in the first child was discovered last August, BRMAC held an emergency meeting to take up the issue.

At that time the panel recommended that trial sponsors revise informed consent materials and that they implement a plan to monitor peripheral blood samples from trial subjects for the clonality of vector integrants over time.

Subsequently, the National Institutes of Health's Recombinant DNA Advisory Committee (RAC) studied the issue and determined that "there's not enough evidence of adverse events attributed to the vectors to warrant halting other human gene transfer studies, including those for non-X-linked SCID." (See BioWorld Today, Feb. 14, 2003.)

Furthermore, RAC said retroviral gene transfer studies for X-SCID should be limited to patients who have failed identical or haploidentical stem cell transplantation or for whom no suitable stem cell donor can be identified.