Major Actions under Section III-A of the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules – May 2019

Under the NIH Guidelines, the term “Major Action” means that NIH Director approval is required. Only one type of experiment requires NIH Director approval – the deliberate transfer of a drug resistance trait to a microorganism when such resistance could compromise the ability to control the disease agent in humans, veterinary medicine, or agriculture (see Section III-A-1-a of the NIH Guidelines).

An experiment may be considered a Major Action if: 1) it involves the use of recombinant or synthetic nucleic acids to introduce drug resistance into a microorganism, and 2) the drug in question is used to treat disease caused by the organism in humans, veterinary medicine, or agriculture. The experiment would not be considered a Major Action if there is sufficient documentation that resistance to a therapeutically useful concentration of that drug exists in the agent outside of a laboratory setting. Such evidence should be in the form of articles published in the scientific literature.

A drug is therapeutically useful if it is effective in the treatment of the disease caused by the microorganism. It does not have to be the ‘first line’ agent but should be recognized in the scientific literature as a useful drug. In vitro sensitivity to the drug is not sufficient; it must be useful in vivo.

In addition, if a drug is not therapeutically useful but will confer cross resistance to a therapeutically useful drug, then this also is considered a III-A-1-a experiment.

A drug is considered to be useful for treatment even if its use is limited to the treatment of a specific patient population (for example, children or pregnant women), or it is primarily used for treatment outside of the United States where alternative drugs are not available (e.g., chloramphenicol is not in common use in the U.S. but is used in many other countries).

The investigator should make an initial assessment regarding whether a particular experiment constitutes a Major Action, with confirmation by the IBC. IBCs are encouraged to contact the NIH Office of Science Policy (OSP) if they need assistance in assessing whether a specific experiment involving the deliberate transfer of a drug resistance trait falls under Section III-A-1-a and therefore requires NIH Director approval. IBCs may also consult with NIH OSP regarding experiments that raise important public health issues but do not meet the criteria of Section III-A-1-a (e.g., because there is low frequency of resistance to a drug). NIH OSP will consult, as needed, with appropriate experts, as needed.

The IBC may initiate its review of these experiments before or after submission to and approval/denial from NIH. The IBC’s final determination should occur after approval by the NIH Director, because the IBC must take into account any special conditions that the NIH Director has stipulated as a condition of approval and ensure that they are implemented. Research that meets the criteria for Section III-A-1-a cannot be initiated unless approval is granted by the NIH Director (or NIH OSP in the case of an equivalent experiment).

Information about the proposed experiment that NIH requires to determine whether the experiment meets the criteria of Section III-A-1-a of the NIH Guidelines includes technical information about the proposed transfer of drug resistance (e.g., the vector(s), gene(s) encoding the resistance, degree(s) of resistance, cross-resistance to other drugs, and other pertinent characteristics of the recombinant construct).

If the experiment is considered to be a III-A-1-a experiment, the following additional information must be submitted to NIH OSP:

• Rationale for why the work should go forward, including an assessment of how the scientific and public health benefits outweigh the potential risks for humans, animals, or agriculture.
• A discussion of whether there are alternative approaches to this research that would not involve conferring resistance to a drug that has utility in the treatment of disease caused by the organism in question. This should include a statement indicating whether the submitting investigator or others have considered any alternatives.
• A description of the proposed risk mitigation strategies that will be implemented to minimize risk to laboratory personnel as well as to the public.
• Minutes, if available, of any IBC discussion of the research in question (IBC review is not required prior to NIH review and NIH Director approval/denial, but a preliminary review is desirable).
• IBC contact information

In addition, NIH may also request that the following information be submitted:

• Description of the biosafety features of the room(s) in which the research will be conducted.
• Most recent inspection report(s) of the room(s) in which the research will be conducted, including any reports of biosafety equipment failures or biosafety-related problems that have occurred in these rooms in the last two years.
• Biosafety manual for the proposed work.
• Description of any additional biosafety training that laboratory personnel will receive specific to the research question.
• Description of any special occupational health requirements for the laboratory personnel involved in the research (e.g., vaccination, medical surveillance).

Submission of relevant information on a proposed Section III-A-1-a experiment should be made to NIHGuidelines@od.nih.gov

The NIH Director approves these experiments. These experiments may not proceed unless approved by the NIH Director and the IBC.

Once a Section III-A-I-a experiment has been approved by the NIH Director, equivalent experiments may not need to follow the same approval process to determine the appropriate biosafety containment level for the work. Under Section III-B-2 of the NIH Guidelines (Experiments that Require NIH and IBC Approval Before Initiation), NIH may determine that a proposed experiment is equivalent to one that has previously been approved by the NIH Director as a Major Action. An experiment will be considered equivalent only if, as determined by NIH, there are no substantive differences in methodology and other pertinent information has not emerged since submission of the initial III-A-1-a experiment that would change the biosafety and/or public health considerations for the proposed experiment. If NIH makes such a determination, experiments deemed to be equivalent will not require review and approval under Section III-A-1-a. These experiments will have been approved by NIH and may proceed once approved by the appropriate IBC.

Experiments utilizing recombinant or synthetic nucleic acid molecules that involve the deliberate transfer of a drug resistance trait into a Select Agent (that meet the definition of a restricted experiment) may be subject to the regulatory authority of, and review by, HHS and/or USDA under their respective rules (found in 42 CFR Part 73, 7 CFR Part 331, and 9 CFR Part 121). Review and approval by the appropriate Federal agency (HHS or USDA) supersedes the requirement for approval under the NIH Guidelines. However, other provisions of the NIH Guidelines for example, IBC review and approval are still applicable.