By Lisa Seachrist

Washington Editor

BETHESDA, Md. ¿ A flood of adverse event reports poured into the National Institutes of Health¿s Office of Biotechnology Activities in the aftermath of the death of University of Pennsylvania gene therapy patient Jesse Gelsinger.

That deluge highlighted the fact that many gene therapy investigators weren¿t complying with regulations requiring all investigators whose institutions receive research money from NIH to immediately report all serious adverse events in gene therapy trials. As a result, a working group of the Recombinant DNA Advisory Committee (RAC) presented new reporting standards at a meeting Thursday of the entire RAC.

The proposed reporting standards, however, met with resistance from within the working group and among members of the full committee.

Much of the working group¿s proposal called for harmonizing the reporting requirements between the FDA and the NIH in order to create an atmosphere in which investigators report the same data at the same time to both agencies. However, the working group¿s proposal, while harmonizing the definitions of serious adverse events, calls for more stringent reporting requirements than currently in place at FDA and suggests the formation of a national gene therapy data safety monitoring board (DSMB).

¿We did agree that is desirable to harmonize reporting with the FDA requirements,¿ said RAC member and working group chair Ruth Macklin, professor of bioethics at Albert Einstein University in New York. ¿However, several factors stand in the way.¿

The proposal calls for using the FDA¿s definition of a serious adverse event: any adverse event occurring at any dose that results in death, a life-threatening event, in-patient hospitalization or prolongation of existing hospitalization, a persistence of significant disability/incapacity, or a birth defect. The working group would have investigators immediately report ¿all serious adverse events that are possibly associated with the use of the gene transfer product, whether expected or unexpected, and all unexpected adverse events that are possibly associated with the use of the gene transfer product, whether serious or not.¿

The working group would also require an independent monitor to make the determination whether an adverse event is possibly associated with the gene transfer product to ensure the reliability of such judgments.

Working group and RAC member M. Louise Markert, associate professor of pediatrics at Duke University Medical Center in Durham, N.C., questioned whether the RAC really wanted to receive such a volume of data when FDA requires only immediate reporting for unexpected serious adverse events. The rest of the adverse events show up in annual reports submitted by a study sponsor to FDA.

¿I don¿t see the point of reporting serious expected adverse events,¿ Markert said. ¿They are stated in the consent form. Why do we need to verify those adverse events in real time? When you are treating patients who are very sick, they have innumerable adverse events. This would be a great burden to the investigator.¿

RAC member C. Estuardo Aguilar-Cordova, director of the gene therapy laboratories at Baylor College of Medicine in Houston, agreed with Markert. ¿Our desire to collect the data on all of these adverse events is to assure as much as possible the safety of the public,¿ Aguilar-Cordova said. ¿But, data isn¿t equivalent to information. We don¿t have the expertise or personnel to turn this data into information. The FDA does.¿

Macklin noted one of the concerns raised by a number of working group members was the information at FDA is confidential, not public. Philip Noguchi, director of cellular and gene therapies at FDA, said the agency is in the process of promulgating a rule that would permit more disclosure of adverse events in certain situations.

Jay Siegel, director of FDA¿s Office of Therapeutics Research and Review for the Center for Biologics Evaluation and Research, noted while NIH experienced a deluge of adverse event reports, FDA had received all necessary reports in time. In fact, FDA was notified of Jesse Gelsinger¿s reaction to the gene therapy product before Gelsinger died. The agency then scoured all similar clinical trials to share the information with the investigators.

¿With respect to adverse event reporting, we don¿t have any evidence to date that there is a significant problem,¿ Siegel said. ¿Still, we have good reason to believe there are areas in good clinical practice and manufacturing where compliance isn¿t what it should be and we are looking at education and outreach efforts as well as increased oversight to bring those investigators into compliance.¿

No Comments