T H E   N I H    C A T A L Y S T      M A R C H  –   A P R I L   2000



by Fran Pollner

It was almost business as usual at the first meeting of the year of the NIH Recombinant DNA Advisory Committee (RAC), held here March 8–10; members of the press attended but in nowhere near the numbers that overwhelmed the preceding RAC meeting in December. That meeting, convened in the wake of the death of Jesse Gelsinger, had focused on gene therapy oversight, the safety of adenoviral vectors in general, and the conduct of the trial in which Gelsinger was a volunteer in particular (see "Gene Therapy Trial and Errors Raise Scientific, Ethical, and Oversight Questions," The NIH Catalyst, January–February 2000).

In the three-month interval between the two RAC meetings, the Food and Drug Administration suspended all clinical gene therapy trial sponsored by investigator James Wilson and the Institute for Human Gene Therapy at the University of Pennsylvania, where Gelsinger died; NIH and FDA have been revisiting their gene therapy oversight roles; a Senate panel held a hearing on the issue; and the RAC continued its daily business of scrutinizing novel gene therapy protocols and advising investigators on needed modifications.

On the Hill

At the Senate hearing before the Public Health Subcommittee, chaired by Bill Frist (R-Tenn.), lawmakers challenged FDA and NIH to improve gene therapy oversight procedures. The system, they said, is "failing." They were especially miffed by the failure of investigators to report adverse events to NIH and suggested that researchers may have misinterpreted the RAC’s loss of protocol approval authority as license to ignore reporting regulations.

Paul Gelsinger, the father of Jesse, appeared with his lawyers and testified that he and his son had been misled, that his consent had been "informed" by documents and talks with the investigators that downplayed risks, omitted past adverse results, and implied unrealistic benefit. He called for the establishment of an independent body of knowledgeable persons who could serve as advisors in the informed consent process. Other witnesses and, later, Sen. Ted Kennedy (D-Mass.) called for the establishment of a national independent Data Safety and Monitoring Board for all gene therapy trials.

Missing from the Senate hearing were the investigators in the UPenn trial. Wilson and his colleagues had been invited to attend, according to a Senate staffer, but had declined, and Frist chose not to exercise his subpoena authority. Frist plans to hold additional hearings and followed up on the first one with written questions for FDA and NIH. Those directed to NIH focused on site visits to gene therapy grantees and financial conflicts of interest, progress in developing an interactive gene therapy database, the RAC’s role, and adverse event reporting requirements.

At the RAC

The death of Jesse Gelsinger colored nearly every item on the RAC’s packed three-day agenda—from the review of nine novel gene therapy protocols to discussions of adverse events reporting and the boundaries of RAC authority. The adverse events issue proved thorny, with RAC members in a "stalemate," in the words of RAC chair Claudia Mickelson, over which adverse events ought to be reported to the group and how quickly. Mickelson insisted agreement be reached by the RAC’s June meeting.

Regarding RAC’s authority, most members appeared satisfied with the value of their work and the influence it has on the field of gene therapy. Although there were a few comments on the need for "teeth"—in the form of protocol-approval authority—to ensure compliance with RAC requests for protocol changes or additional preclinical studies, there was general consensus that the FDA, investigators, institutional review boards (IRBs), legislators, and the public take the RAC’s advice very seriously. Some members wanted more formal feedback procedures to learn whether their advice had actually been followed, and several emphasized the need for optimal timing of RAC protocol deliberations—namely, before approval by other bodies, such as an IRB or FDA.

RAC Chair
Claudia Mickelson

RAC scientific and ethical expertise, as well as power of persuasion, was much in evidence during protocol reviews. The lead-off protocol actually served as a prototype for extended scrutiny of a new vector–the gutless (internally deleted) adenoviral vector—in this case carrying the gene for factor VIII. The FDA had requested the RAC review; both the principal investigator and the sponsor said they would not proceed with the trial without RAC approval. Indeed, two other unrelated protocols originally on the agenda had received such extensive preliminary comments from RAC reviewers that the sponsors had withdrawn their submissions before the meeting.

Most of the remaining protocols were Phase I studies involving cancer patients or patients with monogeneic deficiency conditions, such as hemophilia; several used adenoviral or adeno-associated vectors to deliver the transgene. In response to RAC requests, often informed by the lessons of the Gelsinger case, investigators variously agreed to institute arithmetic rather than half-log increments in the higher dosage ranges in their dose-escalation studies, to monitor cytokine levels and other immune parameters, and to do more preclinical studies on biodistribution of the vector. Attention was paid to explicit criteria for stopping a study to assess adverse effects, as well as to full disclosure of risks in informed consent documents.

Much of the discussion was in conformity with the recommendation of a RAC working group that clinical trials using adenoviral vectors "continue with caution" while vector standards and characterizations are further developed. The working group also endorsed the idea of having "patient advocates" to address conflicts of interest and to optimize informed decision making—similar to the proposal made earlier
at the Senate hearing and repeated at the RAC meeting by Paul Gelsinger.

The RAC rejected a proposal by Jeremy Rifkin, of the Washington-based Foundation for Economic Trends, to halt the use of all viral
vectors in gene therapy protocols, except as a last resort in life-threatening illness.

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Jeremy Rifkin (left) confers with Paul Gelsinger (middle) and Gelsinger’s attorney during a break in the RAC proceedings