SACHRP Recommendations on Revisions to “NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules,” Appendix M
Approved by SACHRP October 26, 2016
Background
Oversight of gene transfer research using HHS funding is provided by the “NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules.” Appendix M of these guidelines addresses oversight of such research by IBCs and IRBs, among other parties including the Recombinant DNA Advisory Committee (RAC), an advisory committee to the National Institutes of Health.
The process of RAC review has changed several times through the years. For example, approximately the first 400 protcools to be registered with NIH (which arguably included some of the most novel) were required to have been reviewed and approved by IRBs and IBCs prior to submission to NIH. In the most recent prior process, after NIH had received a complete protocol, that protocol was sent to RAC members for their individual input on whether public review of the protocol was warranted. Only about a quarter of submitted protocols were then reviewed publicly at a RAC meeting. The most recent prior process did not designate at which stage IRB review should occur.
Effective April 27, 2016, however, the National Institutes of Health (NIH) again began to require initial review by IBCs and IRBs, instead of having a prior NIH assessment of whether or not review by the Recombinant DNA Advisory Committee (RAC) was necessary (Federal Registry, Vol. 81, No. 55, Pgs. 15315 – 15322). Although the immediately preceding process had required the majority of clinical trials involving human gene transfer in the United States to undergo initial review by RAC members (regarding whether public review is warranted) prior to receiving IBC and IRB review, the April 27, 2016 revisions reversed that order; initial review by IBCs and IRBs now must precede registration with NIH. Under this new process, the RAC now will review human gene transfer clinical trials only in two situations: (1) Following a recommendation for RAC review made by the IBC or IRB at the first clinical site(s), with subsequent vetting by staff at the NIH Office of Science Policy (OSP, or (2) at the direction of the NIH Director. This change was designed to reduce the regulatory burden on gene transfer research, but SACHRP notes that this has added an additional burden on IBCs and IRBs to opine whether RAC review is warranted or not. Moreover, SACHRP believes that IRBs and IBCs have concerns that they may lack the expertise to make these determinations given the difficulty of determining the novelty and risk of a new gene transfer protocol.
Because NIH has adopted the requirement that both IRBs and IBCs at “initial site(s)” consider and make recommendations on whether RAC review is indicated, SACHRP offers some recommendations on how this requirement might best be managed and implemented.
Regulatory Language
The revised Appendix M Section III-C-1 now reads as follows, with IRBs and IBCs referred to as “oversight bodies” in this section:
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 One or More Human Research Participants
Human gene transfer is the deliberate transfer into human research participants of either:
1. Recombinant nucleic acid molecules, or DNA or RNA derived from recombinant nucleic acid molecules, or
2. Synthetic nucleic acid molecules, or DNA or RNA derived from synthetic nucleic acid molecules, that meet any one of the following criteria:
a. Contain more than 100 nucleotides; or
b. Possess biological properties that enable integration into the genome (e.g., cis elements involved in integration); or
c. Have the potential to replicate in a cell; or
d. Can be translated or transcribed.No research participant shall be enrolled (see definition of enrollment in Section I-E-7) until the NIH protocol registration process has been completed (see Appendix M-I-B, Selection of Individual Protocols for Public RAC Review and Discussion).
In its evaluation of human gene transfer protocols, the NIH will make a determination, following a request from one or more oversight bodies involved in the review at an initial site(s), whether a proposed human gene transfer experiment meets the requirements for selecting protocols for public RAC review and discussion (See Appendix M-I-B). The process of public RAC review and discussion is intended to foster the safe and ethical conduct of human gene transfer experiments. 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 of the research.Public RAC review and discussion of a human gene transfer experiment will be initiated in two exceptional circumstances: (1) Following a request for public RAC review from one or more oversight bodies involved in the review at an initial site(s), the NIH concurs that (a) the individual protocol would significantly benefit from RAC review and (b) that the submission meets one or more of the following NIH RAC review criteria: i) the protocol uses a new vector, genetic material, or delivery methodology that represents a first-in-human experience, thus presenting an unknown risk; ii) the protocol relies on preclinical safety data that were obtained using a new preclinical model system of unknown and unconfirmed value; or iii) 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 and federal regulatory bodies to evaluate the protocol rigorously. However, if one or more oversight bodies involved in the review at an initial site(s) requests public RAC review, but the NIH does not concur that (a) the individual protocol would significantly benefit from RAC review and (b) that the submission meets one or more of the RAC review criteria (listed in i, ii, or iii), then the NIH OSP will inform, within 10 working days, the requesting and other oversight bodies involved in the review at an initial site(s) that public RAC review is not warranted. (2) The NIH Director, in consultation (if needed) with appropriate regulatory authorities, determines that the submission: (a) meets one or more of the NIH RAC review criteria (listed in i, ii, or iii) and that public RAC review and discussion would provide a clear and obvious benefit to the scientific community or the public; or (b) raises significant scientific, societal, or ethical concerns.
Issues of Concern
1. Review by “Initial Site(s)”
The final paragraph of section entitled, “A Criteria and process for selecting protocols for RAC review” states:
The chair of an oversight body or an authorized oversight body representative may submit a request for RAC review by sending the request to the NIH as part of the submission materials provided by the Principal Investigator. Requests for RAC review must originate from oversight bodies involved in the initial site(s) review. This request must include the rationale for why the protocol satisfies both items 1 and 2 of the NIH RAC review criteria. The NIH will review the request and notify the requestor of a decision within 10 working days.
The term “the initial site(s) review,” which is used in several of the new sections, has been confusing to the regulated community. In particular, it has appeared unclear whether only the IRB or IBC from the first site or sites to review the research can send a request for RAC review to NIH, or whether IRBs and IBCs from subsequent sites can also do so.
In guidance issued in October 2016, NIH has clarified that it expects the “oversight bodies” in all sites initially participating in a study to consider and submit a recommendation on the need for RAC review. These “initial site(s)” might be one site or a number of sites, as long as they are included in the initial submission to NIH OSP. The IRB(s) and IBC(s) present this recommendation to the institution or investigator who is submitting the protocol to NIH, and the institution or investigator includes the recommendations in its submission to NIH OSP. As long as the sites are submitted to OSP as part of the initial review documentation, they are an initial site.
As this requirement that IRBs and IBCs at all initial sites consider and make recommendations regarding RAC review has now already been implemented by NIH, SACHRP would encourage NIH to evaluate, over time, the benefits and costs of having multiple IRBs and IBCs make these determinations, as opposed to a more restricted and targeted requirement that one IRB and/or IBC at a lead site undertake this review. Further, with NIH’s emphasis on, and requirements for, the widespread use of single IRBs, NIH should clarify that the single IRB designated for the study review under 45 CFR 46 is also the IRB “of the initial site(s)” for purposes of the assessment regarding whether RAC review is warranted under Appendix M. Otherwise, institutions may mistakenly believe that the institution’s local IRB has to provide the recommendation regarding RAC review despite the fact that a different and external single IRB is the IRB of record.
2. Site Review by Designated Members of IRB and/or IBC
The revised NIH Guidelines indicate that the submission package for registration of new human gene transfer clinical trials must include written recommendations from the local IRB(s) and IBC(s) regarding the need for full public review by the RAC. The Federal Registry announcement indicates that, “The chair of an oversight body or an authorized oversight body representative may submit a request for RAC review by sending the request to the NIH as part of the submission materials provided by the Principal Investigator.” SACHRP understands that there has been some confusion in the regulated community as to whether this required review can be undertaken by the full IRB and IBC, with the result communicated to NIH via the protocol submission by the committee chairs, or whether the chairs themselves, or other committee members, may perform review as delegates of the entire committees.
In official guidance issued in October 2016, NIH clarified that the “oversight bodies” are not required to hold convened meetings to determine whether RAC review will be requested. Instead, the chair of an “oversight body” or an institutionally authorized representative of an IRB or IBC may consider and submit a request for RAC review. NIH leaves to the discretion of the institution the process by which an oversight body makes such a determination
3. Review by Designated Members of an IRB “Oversight Body” as a Formal IRB Action
In regard to 2., above, when a designated representative of an IRB considers and submits to NIH the IRB’s determination as to whether RAC review should be requested, it is unclear whether this constitutes a formal board action under 45 CFR 46 and 21 CFR 56, and thus an expedited action subject to various rules and procedures applicable to such action. In these cases, it would appear that such an action by an IRB chair would not constitute a regulatory function under 45 CFR 46 and 21 CFR 56. SACHRP recommends that OHRP and FDA issue guidance to this effect to clarify the issue.
4. Continued RAC-Related Oversight Responsibilities by “Oversight Bodies”
There appear to be no additional IRB oversight responsibilities under the revised Appendix M guidelines, other than continuing to ensure that adequate expertise is available for the IRB review and providing a letter for an initial site indicating whether or not the IRB is requesting RAC review. In response to SACHRP requests that NIH confirm this, NIH has indicated that indeed, these NIH Guidelines do not require any other additional responsibility of an IRB and do not require a determination at the time of IRB continuing review of whether the protocol should have RAC review.
5. IRB and IBC opinion of whether or not RAC review is required
SACHRP understands that some IRBs and IBCs believed that they only had to provide a letter regarding an opinion that RAC review is required, but did not have to provide a letter if they did not believe that RAC review was required. NIH clarified that in either situation, the IRB and IBC must communicate their opinion.
6. IRB and IBC each must document an opinion
It was also unclear to some IRBs and IBCs whether assessment of the need for RAC review must be undertaken by both the IRB and the IBC, or only by one of those committees. Appendix M states, “In its evaluation of human gene transfer protocols, the NIH will make a determination, following a request from one or more oversight bodies involved in the review at an initial site(s), whether a proposed human gene transfer experiment meets the requirements for selecting protocols for public RAC review and discussion.” This could be interpreted to mean that Appendix M thus requires only the opinion of one oversight body. NIH has clarified that there must be documentation that both oversight bodies have addressed the issue.
7. IRB Deferral to IBC within an Institution
SACHRP believes that it is reasonable to allow the IRB to defer to the IBC regarding the decision about RAC review. In its October 2016 guidance, NIH clarified that, “An assessment must originate from all oversight bodies involved in the review at initial sites(s). The IRB may, however, defer its assessment to the IBC or abstain from making this assessment. The decision of an IRB to defer or abstain must be provided to NIH in writing.” As long as the deferral is documented, it is acceptable for the IRB to defer to the IBC.
SACHRP recommends that, to streamline the administrative implementation of this requirement, NIH should allow the IRB chair or designated representative to co-sign a letter from that initial site’s IBC, either concurring with the IBC recommendation, or deferring to that recommendation. This would simplify the implementation of this requirement, while still assuring an explicit IRB statement of its concurrence with or deferral to an IBC determination. On the other hand, if an IRB disagreed with its own site’s IBC determination, the IRB would, under this recommendation, file its own independent recommendation.
8. Disagreement among Initial Sites’ “Oversight Bodies” about Appropriateness of RAC Review
When there is more than one initial site in a study, then it is entirely possible that IRBs and IBCs at those sites may issue divergent views of the appropriateness of and need for RAC review. SACHRP has been concerned as to how such a disagreement would be handled by institutions and by NIH itself.
In response to this concern, NIH has indicated that only the oversight bodies of initial sites may request review, and that a request from one oversight body is sufficient to be considered a request for RAC review. In the initial submission, statements from all oversight bodies of all initial sites are required. Therefore, NIH has asserted, if there is disagreement regarding RAC review, it will be evident from the submitted material. Under Appendix M, NIH must concur that both criteria are met in order to initiate RAC review. If one or more oversight bodies request RAC review but the NIH does not concur that both criteria are met, NIH has indicated that it will inform the submitter within 10 working days that RAC review is not warranted. NIH has further indicated that after the completion of registration, subsequent sites do not have the authority to request RAC review.
SACHRP also recommends that the NIH OSP consider making the rationale for its decisions to pursue RAC review or not available to the regulated community, particularly in circumstances where this decision conflicts with the conclusion of the local oversight committees.
SACHRP would like to commend the NIH OSP for being available to the regulated community to answer questions about the oversight of gene transfer research.
