June 2005 

I. Definitions

Cells Subject to Gene Transfer:

Allogeneic: Being genetically different although belonging to or obtained from the same species.

Autologous: Of or relating to a transfer of cells or tissue in which the donor and recipient are the same individual.

Xenogeneic: Derived or obtained from an organism of a different species.

Genetic Engineering:   The process of manipulating the genetic material of organisms, also known as biotechnology.

Gene Transfer: The introduction of new DNA into an existing organism’s cell, usually by vectors such as plasmids and modified viruses. Cells may be modified ex vivo for subsequent administration to humans, or may be altered in vivo by gene therapy given directly to the subject. The genetic manipulation of cells may be intended to have a therapeutic or prophylactic effect, or may provide a way for marking cells for later identification. Cells may be delivered in various ways, for example, by infusion, injection at various sites, or surgically implanted in aggregated form or along with solid supports or encapsulating materials.

Excipients, Additional Active Components, or Medical Devices: Any matrices, beads, fibers, polymers, or other materials which are used in addition to the cells in the delivery of genetically modified cells into the body.

Ex Vivo: Literally, “out of or from life,” i.e., refers to tissues or cells removed from an organism .

In Vitro: Literally, “in glass,” i.e., in a test tube or Petri dish; the opposite of in vivo; describes biological reactions that take place in laboratory containers.

In Vivo:   Literally, “in life,” i.e., in the body. In a living organism; a reaction, process, or experiment in a living organism or cell.

Recombinant DNA: DNA which has been altered from its original form by joining genetic material from two different sources. It usually involves putting a gene or part of a gene obtained from one organism into the genome of a different organism. The alteration and recombination in the laboratory often involves cutting up DNA molecules and splicing together specific DNA fragments. The DNA may be natural or synthetic. The altered DNA may be inserted into the receiving DNA chain by chemical, enzymatic, or biologic means.

Somatic Cell Gene Therapy: The repair or replacement of a defective gene within somatic (body) tissue by administration to humans of autologous, allogenic, or xenogeneic living cells which have been manipulated or processed ex vivo.

II. Introduction

Human gene transfer (therapy) is the process of transferring genetic material (DNA or RNA) into a person. Gene therapy is a medical intervention based on modification of the genetic material of living cells which is then given to humans. Cells may be modified ex vivo for subsequent administration to humans, or may be altered in vivo by gene therapy given directly to the subject. When the genetic manipulation is performed ex vivo on cells which are then administered to the patient, this is also a form of somatic cell therapy. The genetic manipulation may be intended to have a therapeutic or prophylactic effect, or may provide a way of marking cells for later identification. Recombinant DNA materials used to transfer genetic material for such therapy are considered components of gene therapy and as such are subject to regulatory oversight.

The hope is that gene transfer can help improve genetic disorders or treat complex diseases (i.e. cancer, heart disease) and certain infectious diseases (i.e. AIDS). This document summarizes important aspects of the NIH and FDA guidances on human gene transfer research.

III. Regulatory Requirements

Participants may not be enrolled into a gene transfer study until all regulatory requirements have been met. Under the NIH Guidelines, patient enrollment is considered to begin with the process of obtaining informed consent from prospective participants.  This process cannot begin until: (1) the RAC review process has been completed; and (2) IBC, IRB and FDA approvals and other applicable regulatory authorization(s) have been obtained.

A.IBC

Institutional Biosafety Committee (IBC) approval must be obtained from each institution at which recombinant DNA material will be administered to human subjects.   At Johns Hopkins, Investigators who wish to submit gene transfer protocols to the JHM IRB must first contact the Biosafety Officer at the IBC for submission details for that committee, Stephen C. Dahl, Ph.D. [email protected]. The JHM IRB cannot approve a gene transfer project until the IBC has approved it. 

B. OBA and RAC

Investigators conducting gene transfer research at, or sponsored by, an institution that receives NIH support for recombinant DNA research must comply with Appendix M of the NIH Guidelines. Appendix M outlines the main points for Investigators to consider when submitting a protocol to the federal Office of Biotechnology Activities (OBA). If a protocol is subject to the NIH Guidelines, the Investigator must register the protocol with OBA and, usually, with the NIH Recombinant DNA Advisory Committee (RAC). Factors that may contribute to RAC decision to hold public discussion of a human gene transfer experiment include: (i) new vectors/new gene delivery systems, (ii) new diseases, (iii) unique applications of gene transfer, and (iv) other issues considered to require further public discussion.

Once a protocol is approved and initiated, continued specified submissions are required to be filed with OBA. If registered with the RAC, a filing must be made again 20 days after the first patient is enrolled into a clinical trial. Additionally, OBA and the RAC require Principle Investigators to submit annual reports in accordance with Appendix M. Adverse events are required to be submitted both to the JHM IRB (http://irb.jhmi.edu/Guidelines/Event_Deviation_Reporting.html) as well as the OBA in accord with Appendix M.

C. FDA

The FDA is responsible for the review and approval of gene therapy products as Investigational New Drugs (INDs). Full copies of the FDA guidelines are available at http://www.fda.gov. The FDA's primary objective in the review of INDs is to assure the safety and rights of subjects in all phases of the investigation, and, in Phase 2 and 3 trials, to assure that the quality of the scientific evaluation of the investigational product is adequate to permit an evaluation of its safety and effectiveness. The FDA also requires related serious adverse event reporting and annual reports. 

IV. Informed Consent

Gene transfer research concepts are often difficult for potential participants to understand. Thus, the Office of Biotechnology Activities (OBA) has developed guidance on the issue of informed consent in gene transfer studies. The guidance focuses on the issues of conflict of interest, comprehension, time of consent, and assent. The guidance can be used as a resource for Investigators in developing an informed consent document for a gene transfer protocol by discussing each topic that should be covered.