Proposed Changes to the NIH Guidelines for Human Gene Transfer Experiments

1. Rae Hintlian

Associate Editor

Loyola University Chicago School of Law, J.D. 2019

 

The National Institute of Health (NIH) has submitted a proposal to amend the NIH Guidelinesfor research involving recombinant or synthetic nucleic acid molecules.  The proposed amendmentseeks to streamline the oversight for human gene transfer clinical research protocols and reduce duplicative reporting requirements already captured within existing regulatory framework.  The amendment specifically seeks to delete the NIH protocol registration submission and reporting requirements under Appendix M of the NIH Guidelines, and modify the roles and responsibilities of entities involved in human gene transfer or the Recombinant DNA Advisory Committee(RAC).

Human Gene Transfer

The NIH Guidelinedefinition of human gene transfer is the deliberate transfer of recombinant or synthetic nucleic acid, or DNA or RNA derived from recombinant or synthetic nucleic acid molecules into one or more human participants.  This can further be dissected to the deliberate transfer into human research participants of either recombinant nucleic acid molecules, or DNA or RNA derived from recombinant molecules, or synthetic nucleic acid molecules, or DNA or RNA derived from synthetic nucleic acid molecules that meet certain criteria.  In its evaluation of protocols involving human gene transfer the NIH makes a determination, following a request from one or more oversight bodies involved in the review, whether the proposed experiment meets the requirement for selecting the protocol for a public RAC review and discussion.  This process is intended to foster the safe and ethical conduct of human gene transfer experiments. Further, the public review informs the public about the ethical aspects of the proposal, as well as the meaning and significance of the research, and any significant safety, social, and ethical implications.

Current Guidelines

The purpose of the NIH Guidelines is to specify the biosafety practices and containment principles in the construction and handling of recombinant nucleic acid molecules, synthetic nucleic acid molecules, (including those that are chemically or otherwise modified but can base pair with naturally occurring nucleic acid molecules), and cells, organisms, and viruses containing those molecules.  Under the current guidelinesany nucleic acid molecule experiment requires approval by the NIH, and must be submitted to the NIH or another federal agency with the jurisdiction to review and approve the experiment.  Once approved the experiment may proceed without further NIH review or approval. For experiments involving the deliberate transfer of recombinant or synthetic nucleic acid molecules, or DNA or RNA derived from recombinant or synthetic nucleic acid molecules, into human research participants (human gene transfer), no research participant may be enrolled until certain requirements have been met.  Under the NIH protocol the registration process must be completed, Institutional Biosafety Committee (IBC) approval must be obtained, Institutional Review Board (IRB) approval needs to be obtained, and all applicable regulatory authorization(s) must be received.

Experiments with Recombinant or Synthetic Nucleic Acid Molecules

There are six categories of experiments involving recombinant or synthetic nucleic acid molecules covered by the NIH Guidelines.  They include: (i) those that require Institutional Biosafety Committee(IBC) approval, RAC review, and NIH Director approval before initiation, (ii) those that require NIH Office of Science Policy (OSP) and Institutional Biosafety Committee approval before initiation, (iii) those that require IBC and IRB approvals and RAC review before participant enrollment, (iv) those that require IBC approval before initiation, (v) those that require IBC notification simultaneous with initiation, and (vi) those that are exempt from the NIH Guidelines.  Any change in containment level, which differs from those approved may not be initiated without the express approval of the NIH OSP.

Experiments which are considered as Major Actionsunder the NIH Guidelines cannot be initiated without submission of relevant information on the proposed experiment to the Office of Science Policy, National Institutes of Health.  The containment conditions or stipulation requirements for such experiments are recommended by the RAC and set by the NIH at the time of approval. These experiments may include the deliberate transfer of a drug resistant trait to one or more microorganisms that are not known to acquire the trait naturally, more information may be found in Section V of the NIH Guidelines, if the acquisition of the traits could compromise the ability to control the disease agent in humans, veterinary medicine, or agriculture.  Further consideration must be given as to whether the drug resistant trait, if used in the experiment, would render the microorganisms resistant to the primary drug available to and/or indicated for certain population (i.e.children or pregnant women).  The NIH OSP will make a determination regarding whether a specific experiment involving the deliberate transfer of a drug resistant trait requires further review by the RAC and NIH Director approval.

Public RAC Review and Discussion

In order to qualify a human gene transfer experiment for public RAC review and discussion one of two exceptional circumstances must be met. The first requires that after a request for a public RAC review from one of the oversight bodies, the NIH concurs that the individual protocol would benefit significantly from the RAC review, and the submission meets one or more of the NIH RAC review Criteria.  The NIH RAC review criteria include the protocol uses a new vector, genetic material, or delivery methodology that represents an first-in-human experience, and therefore presents unknown risk; the protocol relies on preclinical model systems of unknown and unconfirmed value, or; the proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and may render it difficult for oversight and federal regulatory bodies to evaluate the protocol rigorously.  If one or more of the oversight bodies involved in the review at an initial site requests the public review but the NIH does not agree then the NIH OSP will inform, within 10 business days the review is not warranted.

The second requires that the NIH Director, in consultation (if needed) with the appropriate regulatory authorities, determines that the submission meets one or more of the NIH RAC review criteria (supra) and that public RAC review and discussion would provide a clear and obvious benefit to the scientific community or public; or raises significant scientific, societal, or ethical concerns then the RAC review is warranted.

Proposed Changes

The proposed changes to the NIH Guidelines seek to make the oversight of Human Gene Transfer research protocols commensurate with oversight afforded to other areas of clinical research given the robust infrastructure in place to oversee this area of research.  The NIH proposes to amend the guidelines to eliminate the RAC review and reporting requirements to the NIH for HGT protocols.  The amendments would modify the roles and responsibilities of investigators, institutions, IBCs, the RAC, and the NIH to be consistent with the previously mentioned goals, such that the roles of the IBCs reviewing HGT to be consistent with review of other covered research; eliminating references to the RAC, including its roles in HGT and biosafety.  This would eliminate the duplicative review of oversight provided by the FDA and IRBs. The IBC would retain responsibility of reviewing and approving HGT protocols, but the responsibilities would be modified to be similar to those of other research subject to the NIH Guidelines. This would allow the IBC’s to focus on providing local biosafety oversight of basic and clinical research involving recombinant or synthetic nucleic acids.  The RAC roles and responsibilities will be modified to focus on emerging biotechnologies in research, rather than focusing solely on research involving recombinant or synthetic acids.

The NIH has put forth a series of actions within the NIH Guidelines to streamline oversight of human gene transfer (HGT) research, and focus the NIH guidelines more specifically on biosafety issues associated with research involving recombinant or synthetic nucleic acid molecules.  The field of HGT has recently experienced a series of advances which resulted in the translation or research into clinical practice, includes the U.S. Food and Drug Administration approvals for licensed products. Oversight mechanisms for ensuring HGT proceeds safely have sufficiently evolved to keep pace with the new discoveries in this field.  The new NIH guidelines seek to solve the delays and issues caused by the prior requirements which resulted in duplication in submitting protocols, annual reports, and serious adverse events for HGT clinical protocols.