By Kim Coghill

Washington Editor

BETHESDA, Md. - The FDA told an advisory committee Thursday that feedback from the scientific community on gene therapy showed that researchers are increasing efforts to comply with government guidelines.

In a two-day meeting of the Biological Response Modifiers Advisory Committee, representatives of the FDA presented gene therapy data collected through a March 6, 2000, letter sent to clinics and sponsors around the country involved in the research. The agency mailed 156 letters regarding 276 investigational new drug applications.

Gene therapy and its safety in recent years entered the forefront of FDA discussion following the death of 18-year-old Jesse Gelsinger, a gene therapy patient in a University of Pennsylvania study. And although gene therapy is considered by the FDA to be a promising field of clinical research, other areas that have fueled concern are the risk of transmission of infectious agents by inadequately tested products and numerous violations that the agency uncovered on direct inspections.

Daniel Salomon, associate professor at the Department of Molecular and Experimental Medicine at Scripps Research Institute in La Jolla, Calif., and chairman of the FDA's Biological Response Modifiers Advisory Committee, said generally, based on response of the letters, "things are not going bad out there. I think we need more education out there if you want sponsors to understand. We want to hold investigators up to our standards and I think there needs to be more understanding on the part of the sponsors."

The Center for Biologics Evaluation and Research regulates human gene therapy products - products that introduce genetic material into the human body to replace faulty or missing genetic material, thus treating or curing a disease or abnormal medical condition. CBER uses both the Public Health Service Act and the Federal Food Drug and Cosmetic Act as enabling statutes for oversight.

The FDA has not yet approved any human gene therapy product for sale. However, the amount of gene-related research and development occurring in the U.S. continues to grow at a fast rate and the FDA is actively involved in overseeing this activity. The FDA has received many requests from medical researchers and manufactures to study gene therapy and to develop gene therapy products. Such research could lead to gene-based treatments for cancer, cystic fibrosis, heart disease, hemophilia, wounds, infectious diseases, such as AIDS, and graft-vs.-host disease.

Among the requests in the March 6, 2000, letter, sponsors were asked to submit a list of gene therapy products, cell banks, viral banks, date of manufacturing of each, investigational new drug files, summary of product manufacturing and quality assurance and quality control files.

In reviewing the responses, the FDA determined that there are several areas of regulation that are misunderstood by many sponsors.

For example, Mary Malarkley, director of the FDA's Division of Case Management for the Office of Compliance and Biologics Quality, said many of the respondents apparently misunderstand the division of responsibilities between the IND sponsor and a multiuse facility contracted to conduct product manufacturing. Sponsors often assume that the contract lab will provide necessary quality assurance and quality control manufacturing and testing information to the Center for Biologics Evaluation and Research and do not involve themselves sufficiently in the design of the testing, examination of the data and answering of questions.

"But sponsors are ultimately responsible for their products and submission of the appropriate data," she said. "These issues apply to the sponsors and not just the lab."

In other areas, Patricia Keegan, the FDA's deputy director of the Division of Clinical Trial Design and Analysis, said it is possible that the FDA was not clear in the type of information it was seeking from sponsors because so much of the data returned falls short of what was needed.

She said the FDA also was looking for information on monitoring procedures, adherence to protocol and auditing procedures. "Generally we got procedures used at the beginning of the protocol, but we didn't get how they implemented [them] or adherence to the protocol."

In other areas, she said sponsors failed to name a person or position ultimately responsible for the research and they did not say how the person would be removed if there were problems in the research.

The due date for the letters was June 6, 2000 - three months after they were sent. However, Keegan said days before the due date, only a handful of letters had been returned so the FDA extended the deadline another month. Overall, much of the information returned by sponsors in the first round was inadequate and had to resubmitted. The FDA is continuing to review the data.

The committee today is scheduled to discuss the proposed rule on public disclosure and submission to the FDA of certain data and information related to human gene therapy and xenotransplantation. n