Committee review, public review part of gene therapy oversight process

Federal panel examines safety of gene therapy research

Genetic therapies are rapidly moving from the laboratory into the clinical setting, with more investigators testing experimental gene delivery systems and therapies designed to fundamentally alter our bodies to prevent or treat disease.

But gene therapy trials involve a complex review process that includes a federal panel examination of the study protocol and technologies involved and — possibly — submission of the proposed treatment or therapeutic process for review and comment by the public.

"There are many, many trials going on all over the country, and there are lots of layers of rules and regulations — so much so that it takes a very long time to get anything done," says Darwin J. Prockop, MD, PhD, director of the Center for Gene Therapy at Tulane University in New Orleans. The center focuses on research involving adult stem cell therapies, providing standardized adult stem cells to laboratory researchers across the country, and advising a current clinical trial involving an experimental stem cell treatment for osteogenesis imperfecta that currently is under way at St. Jude’s Children’s Research Hospital in Memphis, TN.

The state of the science — and regulation — has come a long way since the controversy surrounding the 1999 death of research participant Jesse Gelsinger during a gene therapy trial at the University of Pennsylvania.

Now, Prockop contends, gene therapy experiments are much more closely regulated, and the oversight process is very stringent.

"Ten or 15 years ago, things might have been much looser, but that is not the case now," he states. "Even in privately funded research, no investigator really wants to contemplate a shortcut or bypass of the protections required."

All gene therapy research in any way sponsored by the NIH must be reviewed by the institutes’ Recombinant DNA Advisory Committee (RAC), a panel of up to 21 national experts in various fields of science, medicine, genetics, ethics, and patient perspectives.

"If the sponsor of the research, the institution where the trial is to be conducted, or the testing materials containing the recombinant DNA have received any NIH funding, then the human gene therapy trial must be reviewed by RAC," says Terence R. Flotte, MD, professor of molecular genetics and microbiology at the University of Florida in Gainesville, director of the university’s Genetics Institute and Gene Therapy Center, and a member of the clinical and regulatory affairs committee of the American Society of Gene Therapy. "And privately funded gene therapy research may also be submitted for review."

RAC’s purpose is to advise the NIH director and the NIH’s Office of Biotechnology Activities (OBA) on appropriate policies to ensure safe and ethical research using recombinant DNA molecules, he explains. RAC recommends changes to the current NIH Guidelines for Research Involving rDNA Molecules, which outlines responsible research practices in both basic and clinical rDNA research.

"The process of public RAC review and discussion is intended to foster the safe and ethical conduct of human gene transfer experiments," Flotte says. "Public review and discussion of a human gene transfer experiment [and access to relevant information] also serves to inform the public about the technical aspects of the proposal, the meaning and significance of the research, and any significant safety, social, and ethical implications the research might have."

Appendix M of the NIH guidelines outlines the requirements for the design and conduct of gene therapy trials and the requirements for submitting a protocol for RAC review.

Submissions are made to the OBA and must include:

  • A cover letter on institutional letterhead that acknowledges that the documentation complies with the requirements set forth in Appendix M, section I, subsection A (M-I-A) "Requirements for Protocol Submission" and identifies the institutional biosafety committee (IBC) and IRB responsible for local review and approval of the protocol.
  • A scientific abstract.
  • A nontechnical abstract.
  • The proposed clinical protocol with relevant manuscripts.
  • The proposed informed consent document.
  • The curriculum vitae of the principal investigators (PIs).

The initial review is made by the RAC membership, which may request additional information or clarifications. RAC also may make specific comments or suggestions. All of this information is then forwarded to the PI or investigators, Flotte says.

The investigators also may be required to submit their protocol for public review at the RAC’s quarterly public meetings if the OBA director initiates a public review following the recommendations by at least three RAC members or another federal agency or the NIH director initiates a public review. Factors warranting public review include:

  • unique applications of gene transfer research;
  • use of new vectors or delivery systems;
  • unique clinical, social, or ethical concerns.

"If public review is requested, the principal investigator will be invited to make a 15-minute presentation of the submission at the meeting," Flotte says. "Several RAC members assigned to conduct an in-depth review will comment and ask questions. Questions may also be sent to the PI and responses received prior to the meeting. Other experts and ad hoc reviewers may be consulted and the public is also invited to comment and ask questions at the meeting."

The outcome of the RAC review is recommendations for the safe and ethical conduct of the trial. A letter summarizing the recommendations is sent to the principal investigator, the local IRB and IBC reviewing the protocol, and the FDA, which must issue the required IND approval before the trial begins.

IBC examines local safety issues

Once the RAC review is complete, investigators can seek local review by the IBC. The specific responsibilities of the IBC, with respect to gene therapy research include:

• Review of all proposals regarding recombinant DNA research conducted or sponsored by the institution to ensure compliance with the appropriate regulations and guidelines.

• Establishing and implementing university policies that ensure the safe conduct of rDNA research.

• Certification of research support agencies that personnel, facilities, procedures, and practices have been reviewed and are in compliance with the appropriate regulations.

• Creation and maintenance of a central reference file and library of communications related to all aspects of rDNA research at their institution.

The difference between IRB review and IBC review is that the IRB is primarily concerned with the safety of individuals involved as subjects in the proposed trial, and the IBC is charged with ensuring that procedures to protect the public, the researchers themselves, and others are put in place and adhered to, Flotte says.

IRBs are concerned with the protocol’s informed consent process, risk-benefit ratio for subjects, recruitment of study subjects, confidentiality and privacy issues, and adherence to good clinical practice.

The IBC will examine procedures related to the safety of the subjects, as well as clinical personnel and the surrounding community. The IBC also will want to see evidence of the training of research personnel in the procedures and practices of rDNA research, he says.

Coordination within the facility 

Prior to the initiation of the protocol, investigators also must work collaboratively with other groups at the hospital or center where the clinical trial visits will take place.

Gene therapy often involves the use of an altered virus as a vector for delivering the gene therapy inside the tissues of the subjects. These virus vectors can pose a hazard to researchers and other health care workers or patients if the vector is mishandled. In some instances, the potential may exist for the vector to be transmitted to close contacts of the person undergoing therapy.

Investigators must develop a plan in conjunction with facility infection control professionals, waste management, and engineering to ensure that procedures are in place to keep the vector secure and that the trial is safely conducted.

Plans must be in place regarding the handling, preparation, and administration of the vector, protection of sexual partners of trial participants, protection of close contacts and offspring, and the protection of health care workers and the work environment, Flotte says.

Once the protocol has been reviewed by the RAC and IBC, it can be submitted for review by the IRB and submitted to the FDA as an IND application, he says. "The IRB is responsible for the protection of the rights and welfare of human subjects in all human subject research. They are regulated by the CFR to oversee all human research in their designated area."

Although the IRB and IBC monitor the conduct of the trial locally, investigators must also file annual reports and safety reports with the RAC. In particular, any serious adverse events that are unexpected and associated with the use of the gene transfer product must be reported to the OBA. Relevant findings from tests in laboratory animals that suggest a significant risk for a human research participant also must be reported to OBA. Assessments of the trial’s safety are performed by a working group of the RAC known as the NIH Gene Transfer Assessment Board.

"The IRB and FDA may review the protocol before or after the RAC review, but both the IRB and FDA will be informed of the RAC recommendations, Flotte says. "The RAC review occurs before the final IBC approval to ensure that committee is informed of the RAC’s recommendations."