On April 25th, NIH Director Francis Collins announced the release of the amended NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines). This amendment is the final implementation of the proposed changes that were announced in August 2018, as covered in our previous post. The announced changes are consistent with what we expected to see based on comments from NIH leadership leading up to this announcement.
Following are the changes that are of greatest interest to sponsors and investigators engaged in clinical studies—i.e. human gene transfer (HGT) research. In a future post I will review changes that affect nonclinical research.
Requirement for IBC approval at each clinical trial site remains unchanged
The most important take-home message for clinical trial sponsors and investigators is that the April 2019 amendment to the NIH Guidelines does not alter the fundamental requirement for IBC approval at each clinical trial site prior to initiation of human gene therapy research at that site. For any clinical trial subject to the NIH Guidelines, investigators and sponsors still must ensure that IBC approval is obtained at each clinical trial site from an IBC registered with the NIH on behalf of that site.
As expected, the April 2019 amendment does introduce some changes that may affect how clinical investigators interact with their IBCs.
- New definition of “initiation” of HGT research. Previously, the NIH Guidelines required IBC approval prior to enrollment, where enrollment was defined as requesting consent from prospective study participants. Under the new amendment, “no human gene transfer experiment shall be initiated… until Institutional Biosafety Committee (IBC) approval (from the clinical trial site) has been obtained” [emphasis added]. For clinical research, the operational definition of initiation in most cases will now be administration of the investigational product to study subjects. In other words, under the previous rules IBC approval was required prior to seeking consent, while under the new amendment, in most cases participants may be consented prior to IBC approval, as long as IBC approval is secured prior to dosing. In some cases IBC approval may also be required prior to certain manufacturing or product preparation steps.
- New guidance on the suggested scope of IBC review. The amended guidelines state that IBC oversight of HGT research may focus on “biosafety issues” (e.g., administration, shedding). Previous NIH guidance recommended more overlap between IRB and IBC review with respect to the protection of human subjects and review of informed consent forms (ICF) and adverse events. Furthermore, the amended guidelines are now explicit in stating that “IBC oversight may conclude after the last participant is administered the final dose of product.” Notably the Guidelines emphasize that an IBC may choose to set alternative end points for oversight, based on its biosafety assessment.
- Clarification that expanded access treatment does not require IBC approval. Previously the NIH Office of Science Policy (OSP) frequently treated expanded access protocols as research subject to the NIH Guidelines. The amended Guidelines clarify that an “FDA-regulated individual patient expanded access IND or protocol, including for emergency use, is not research subject to the NIH Guidelines.”
- Final Action: Deletion of Appendix M. The previous Appendix M (points to consider in the design and submission of HGT research) is deleted in its entirety. This formalizes the NIH Director’s announcement of August 2018 that all requirements for Appendix M submission and reporting were rescinded.
- Final Action: No RAC assessment required. Prior to August 2018, the assessment of new HGT protocols for review by the Recombinant DNA Advisory Committee (RAC) was required before an IBC could approve the protocol. Consistent with the NIH Director’s announcement of August 2018, this requirement is removed. The RAC will have a new name: Novel and Exceptional Technology and Research Advisory Committee (NExTRAC) and will serve the NIH Director in an advisory capacity. NExTRAC will not have a role in routine review of new HGT protocols.
In summary, the changes announced this week did not include any real surprises and are consistent with previous comments from NIH leadership. This amendment will not involve a major change in IBC operations or IBC review of HGT research. For questions about the impact of this announcement on your HGT research, please contact our Institutional Biosafety Committee Services.
[This post was edited on April 30, 2019]