Recombinant DNA Advisory Committee- 9/12-13/94 
initiatives. FDA initiatives are very much in response to hazards that have been known. 
In 1902, the Biologies Control Act was enacted following an episode of contamination of 
diphtheria antisera with tetanus, resulting in 11 deaths in St. Louis. For most biologies, 
the efficacy has never been in doubt; the regulation is mainly to ensure safety. In 1981, it 
was demonstrated that a recombinant protein could be produced in bacteria, and very 
shortly a recombinant growth hormone was produced. On the other hand, the RAC was 
created following a moratorium on recombinant DNA research at the Asilomar 
Conference and approved its first gene transfer protocol in 1988. The FDA responded in 
1991 by issuing its own Points to Consider for human gene transfer studies; and in 1992, 
created the Division of Cellular and Gene Therapies within the Center for Biologies 
Evaluation and Research of FDA. A recent notice on Application of Current Statutory 
Authorities to Human Somatic Cell Therapy was published in the Federal Register on 
October 14, 1993, and on Regulation of Somatic-Cell Therapy by the FDA was published 
in the New England Journal of Medicine, Volume 329, pp. 1169-1173, October 14, 1993. 
Dr. Noguchi noted that in the last couple of years, NIH and FDA had started productive 
interactions, and the RAC has provided a public forum to discuss gene therapy issues. 
Under the Biologies Control Act and the Food, Drug, and Cosmetic Act is a large body of 
proprietary information that FDA has to protect. Dr. Noguchi said that in gene therapy 
area, this should not be an issue since the crucial development is the biology of gene 
transfer which can be discussed in public rather than the proprietary information of vector 
preparation. In response to concerns raised by Dr. Miller and Ms. Meyers, Dr. Noguchi 
said that in the revised FDA proposal, the Appendix M, Points to Consider, will be 
retained in the NIH Guidelines and will be allowed to continuously evolve as new ethical 
and societal issues are raised. The investigators will submit responses to the Points to 
Consider simultaneously to both FDA and ORDA in order to determine its need for RAC 
review. 
Dr. Noguchi used a slide to illustrate adverse reactions encountered in clinical trials of 
biologies. Dr. Jonas Salk personally immunized over 100,000 individuals with his polio 
vaccine without any adverse events. It was not until the company started to produce this 
vaccine en masse for the polio campaign that large-scale contamination by simian virus 40 
(SV40) occurred. The amount of formalin used in the large scale production process was 
not sufficient to inactivate SV40, and hundreds of thousands of individuals were exposed 
to this virus. Fortunately, no sequelae have been directly linked to that exposure. Yellow 
fever vaccine was contaminated by retroviruses. Many fatalities were associated with the 
vaccine for respiratory syncytial virus. Most recently, an incidence of outbreak of 
replication competent retroviruses has been experienced in the production of retroviral 
vectors, and there were instances of adverse events in gene therapy trials with adenovirus 
vector and in the treatment of brain tumors with retrovirus producer cells. 
Addressing concern that RAC will cede its oversight role to FDA, Dr. Noguchi suggested 
that RAC continues to provide public review of the emerging issues. Dr. Noguchi 
mentioned a concern about the prohibitive cost of biosafety testing of retroviral vectors 
raised by the public testimony in the retroviral production meeting held by FDA following 
the RAC meeting. The high cost of vector testing will hinder access of "orphan" disease 
[54] 
Recombinant DNA Research, Volume 20 
