by Michelle Grienauer

Final Action under the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)

On April 27, 2016, an updated model for National Institutes of Health (NIH) oversight of human gene transfer protocols will go into effect, changing a process in place since 1974.  Currently, all NIH-supported gene transfer research requires review by a federal committee called the NIH Recombinant DNA Advisory Committee (RAC).  After April 27, RAC review will only be required in “exceptional circumstances” that meet specified criteria.  The revisions to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) arose from recommendations of the Institute of Medicine (IOM) that the current level of NIH oversight is no longer justifiable given the accumulation of decades of safety data; increased experience with recombinant DNA technology; and concurrent oversight from the U.S. Food and Drug Administration (FDA), institutional review boards (IRBs), and institutional biosafety committees (IBCs).

Under the new “streamlined” NIH protocol review process, RAC review of a human gene transfer experiment will only be initiated in two circumstances:

  • An oversight body (an IBC or an IRB) involved in the initial site review determines that a protocol would significantly benefit from RAC review and one or more of the following criteria are satisfied:
    1. The protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk.
    2. The protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value.
    3. The proposed vector, gene construct, or method of delivery is associated with possible toxicities that are not widely known and that may render it difficult for oversight bodies to evaluate the protocol rigorously.
  • Human gene transfer protocols may also be selected for RAC review if the NIH Director determines the research may present significant scientific, societal, or ethical concerns.

In an effort to reduce administrative burden associated with the protocol registration process, NIH is also reducing its document submission requirements; however, as part of the submission, the Principal Investigator must include written assessments from all oversight bodies involved in the review at an initial site(s) as to whether or not RAC review is warranted.

The amended process does not affect:

  • the requirement that all human gene transfer protocols subject to NIH guidelines must be registered with the NIH;
  • the responsibility of the Principal Investigator to submit documentation to his or her local oversight bodies and to the NIH;
  • the requirement to submit appropriate documentation to the NIH when new clinical trial sites are registered; and
  • the responsibility of a Principal Investigator (or a delegated clinical trial sponsor) to submit appropriate and timely follow up information to the NIH as outlined in theNIH Guidelines (g., protocol amendments, serious adverse events, annual reports with cumulative safety data).

The revised NIH guidelines shift responsibility onto IRBs and IBCs to act as gatekeepers for RAC review of gene transfer protocols.  As such, IRBs need to be aware of when a gene transfer study is subject to NIH guidelines and what its obligations are in that circumstance.  Generally, the NIH guidelines are mandatory for all recombinant or synthetic nucleic acid research that is conducted at or sponsored by an institution that receives any support for recombinant or synthetic nucleic acid research from NIH.  This means that even if a particular study does not receive NIH funding, the NIH guidelines apply if the institution receives any NIH support for gene transfer research.

IRB policies and processes should therefore be developed for handling gene transfer protocols, including processes for:

  • identifying when a study is subject to the NIH guidelines and whether the board is reviewing for an initial site;
  • obtaining input from a gene transfer consultant (if necessary for board review);
  • making the determination as to whether RAC review is warranted;
  • providing the Principal Investigator with a written assessment of whether RAC review is required;
  • clarifying whether a determination that RAC review is required necessitates an IRB “deferral” or “modifications required to secure an approval;” and
  • reviewing RAC recommendations.

Quorum Review IRB has a mission to safeguard the rights and well-being of research participants while enhancing clinical research processes.  We therefore commend the NIH for streamlining its gene transfer review process while leaving the option for increased oversight, when warranted by unknown or uncertain risks to participants.

The Quorum independent review boards (IRBs) and research ethics boards (REBs) include a diverse membership with a comprehensive range of experience.  Our scientific members have expertise in general research as well as key therapeutic specialties such as gene transfer research, and we maintain a network of consultants to provide additional insights when necessary.  Quorum regularly reviews recombinant and synthetic nucleic acid research, as well as NIH-supported research.  As of April 27, 2016, our boards will begin making RAC review assessments for research subject to the NIH guidelines.

A complete description of the revised review process for human gene transfer protocols is available here:  https://www.federalregister.gov/articles/2016/03/22/2016-06448/final-action-under-the-nih-guidelines-for-research-involving-recombinant-or-synthetic-nucleic-acid

 

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