title: Regulatory considerations for novel gene therapy products: a review of the process leading to the first clinical lentiviral vector.
abstract: This review is intended to exemplify the roles and responsibilities of the two agencies under the Department of Health and Human Services, the National Institutes of Health and the Food and Drug Administration, that have oversight for human gene transfer clinical protocols, as seen through our experience of bringing a first-in-its-class lentiviral vector to clinical trials. In response to the changing circumstances in gene therapy research between 1999 and 2002, the concerns of these agencies regarding gene therapy have been evolving. This review provides an overview of the major safety concerns regarding insertional oncogenesis, the generation of a replication- competent lentivirus (RCL), and vector mobilization thought to be related to lentiviral vectors, which had to be addressed during the regulatory review process before initiating the clinical trial. Specific monitoring assays to address these concerns were established to test for RCL generation, vector mobilization, persistence of vector-modified cells, and abnormal clonal expansion of modified cells. We hope to provide a basic understanding and appreciation of the regulatory process and major safety concerns, toward providing useful insight to those presently embarking on the development of clinical application of lentiviral vectors.
authors.affiliation: VIRxSYS, 200 Perry Parkway, Gaithersburg, MD 20877, USA. peter@virxsys.com
authors.forename: Peter
authors.initials: P
authors.lastname: Manilla
authors.forename: Tessio
authors.initials: T
authors.lastname: Rebello
authors.forename: Cathleen
authors.initials: C
authors.lastname: Afable
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Lu
authors.forename: Vladimir
authors.initials: V
authors.lastname: Slepushkin
authors.forename: Laurent M
authors.initials: LM
authors.lastname: Humeau
authors.forename: Kathy
authors.initials: K
authors.lastname: Schonely
authors.forename: Yajin
authors.initials: Y
authors.lastname: Ni
authors.forename: Gwendolyn K
authors.initials: GK
authors.lastname: Binder
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Rob-Roy
authors.initials: RR
authors.lastname: MacGregor
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Boro
authors.initials: B
authors.lastname: Dropulic
mesh_terms: D035843:Biomedical Research / Q000331:legislation & jurisprudence; D002986:Clinical Trials as Topic; D015316:Genetic Therapy; D005822:Genetic Vectors; D033161:Government Regulation; D006805:Human Experimentation / Q000592:standards; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*