Biological Safety Manual - Chapter 18: NIH Oversight of Research Involving Recombinant Biosafety Issues

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Biological Safety Manual - Chapter 18: NIH Oversight of Research Involving Recombinant Biosafety Issues

Introduction

The National Institutes of Health (NIH) Office of Science Policy (OSP) serves as primary advisor to the NIH Director regarding biomedical policy issues. In order to effectively promote safe and ethical practices within the research community, the OSP integrates reports from several specialized offices to develop comprehensive and pragmatic policies. The locus for oversight of research involving recombinant or synthetic nucleic acids (rsNA) is the Biosafety and Recombinant DNA Policy Program overseen by the Biosafety, Biosecurity, and Emerging Biotechnology Policy Division of the OSP. The Biosafety and Recombinant DNA Policy Program is responsible for ensuring research performed at NIH funded institutions is conducted in accordance with the highest biosafety standards to protect research personnel, the public, and the environment. Two tools that the program uses to advise the scientific community are the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) and the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC).

The NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines)

The NIH Guidelines were first published in 1976 and have been amended as needed to keep pace with developing technology, policies, and data, with the most recent version being released April 2019. The NIH Guidelines outline the roles and responsibilities of various entities associated with recombinant DNA research, (e.g., institutions, investigators, the NIH) and describe the appropriate containment practices and review requirements for different types of rsNA components.

The NIH Guidelines are applicable to all rsNA work at an institution that receives any funding from the NIH for research involving:

1. Recombinant or synthetic nucleic acid molecules (rsNA), which includes:
   1. Molecules that are constructed by joining nucleic acid molecules and which are able to replicate in a living cell;
   2. Nucleic acid molecules that are synthetized, amplified, or modified (chemically or by other means); and/or
   3. Molecules that result from the replication of (a) or (b).
2. Cells, organisms, and viruses containing rsNA.

Compliance with the NIH Guidelines is mandatory for investigators conducting rsNA research that is directly funded by the NIH, and rsNA research or sponsored by or at any institution that receives NIH funding for recombinant DNA research. This broad reach of the NIH Guidelines is intended to instill biosafety practices throughout the institution and ensure the implementation of an effective and comprehensive oversight program. There are researchers at UNC-Chapel Hill that do receive NIH funding, therefore all rsNA research on campus is subject to NIH Guidelines.

The Principal Investigator is responsible for ensuring that research performed under them maintains compliance with the NIH Guidelines. Non-compliance with the Guidelines can have far-reaching consequences, and may include:

1. suspension, limitation, or termination of financial assistance for the noncompliant NIH-funded research project and of NIH funds for other recombinant or synthetic nucleic acid molecule research at the institution; or
2. a requirement for prior NIH approval of any or all recombinant or synthetic nucleic acid molecule projects at the institution. See Section IV of the NIH Guidelines for detailed information regarding your position’s role and responsibilities.

The Institutional Biosafety Committee (IBC)

Institutions that receive NIH funding for rsNA research are required to establish or commission an Institutional Biosafety Committee. The IBC’s membership and functional requirements are described in section IV-B-2 of the NIH Guidelines. The primary responsibility of the IBC is to review rsNA research proposals and verify that the safety precautions and procedures are appropriate for the agent described. The NIH Guidelines defines six rsNA categories, numbered Section A-F, that differ in the level of review required before an experiment can be initiated.

* UNC-Chapel Hill utilizes WCG’s IBC services for these experiments. 

See Section III of the NIH Guidelines for additional details. Information regarding UNC-Chapel Hill’s IBC is available on UNC-Chapel Hill's Environment, Health and Safety website.

Incident Reporting

NIH Guidelines require reporting of any research related accidents or illnesses involving recombinant or synthetic nucleic acid molecules. Principal Investigators must immediately report any incidents involving recombinant or synthetic nucleic acids to the Biological Safety section within the Department of Environment, Health and Safety. The Biological Safety Officer will investigate the incident and report to the NIH OSP.

Incidents may include needlesticks, cuts/scratches, contact with broken skin, animal bites, splashes to eyes, nose, mouth, lost animals or spills outside of a biological safety cabinet, breached personal protective equipment, inappropriate waste disposal, theft, or illness/symptoms related to an exposure.

Contact the Biological Safety Officer or the Associate Biological Safety Officer to report incidents involving recombinant or synthetic nucleic acids.

EHS_BioSafety@ad.unc.edu
Tel: 919-962-5507
After-hours pager: 919-216-3963

Changes to the NIH Guidelines for Research Involving Recombinant DNA Molecules

Effective: August 2018

The NIH Director issued a statement describing a proposal to streamline the federal framework for oversight of gene therapy. This proposal, which was developed in conjunction with the Food and Drug Administration, included amending the NIH Guidelines to eliminate duplicative review and reporting requirements for human gene transfer protocols. The statement also describes NIH’s effort to refocus the role of the NIH Recombinant DNA Advisory Committee (RAC) to be closer to its original mandate - a transparent forum for science, safety, and ethics of emerging biotechnologies. After a 60-day public comment period, the NIH Guidelines have been updated to reflect these changes and the RAC has been renamed the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC).

The charter of the NExTRAC reflects the shift in focus of the committee while embracing the continuity of this important advisory committee.

Effective: January 2011

The NIH Guidelines address two pathways for generation of a transgenic rodent: altering the animal’s genome using recombinant DNA technology, or breeding one or more transgenic rodents to create a new transgenic rodent (i.e., breeding of two different transgenic rodents or the breeding of a transgenic rodent and a non-transgenic rodent). On 20 July 2010 the NIH Office of Biotechnology Activities (OBA) published a proposed action (75-FR 42114) to amend Section III-E-3 and to add a new section to Appendix C (Appendix C-VII) of the NIH Guidelines so as to exempt breeding of almost all rodents that can be housed at BSL-1, with the exception of rodents that contain a transgene encoding more than 50% of an exogenous eukaryotic virus and transgenic rodents in which the transgene is under the control of a gamma retroviral promoter. These two categories of breeding experiments will continue to require IBC registration.

Appendix C-VII. Generation of BSL-1 Transgenic Rodents via Breeding

Creating a new strain of transgenic rodent through either the breeding of two different transgenic rodents or the breeding of a transgenic rodent and a non-transgenic rodent will be exempt from the guidelines if:

1. Both parental rodents can be housed under BSL-1 containment; and
2. Neither parental transgenic rodent contains the following genetic modifications:
   1. Incorporation of more than one-half of the genome of an exogenous eukaryotic virus from a single family of viruses; or
   2. Incorporation of a transgene that is under the control of a gamma retroviral long terminal repeat (LTR); and
3. The transgenic rodent that results from this breeding is not expected to contain more than one-half of an exogenous viral genome from a single family of viruses; and
4. The resulting rodent can be housed at BSL-1 containment.

 The OSP FAQ section for the NIH Guidelines contains a summary table for animal work that lists a variety of research aims and provides the minimum containment level and corresponding section of the NIH Guidelines for each activity. This table can be viewed and downloaded on the NIH website. Other questions regarding transgenic animal work can be directed to ibc@office.unc.edu.

For additional information about the requirements of the NIH Guidelines, please visit the NIH OSP website or write to SciencePolicy@od.nih.gov.

Transgenic Animals and the Use of Recombinant DNA in Animals

FAQs for Research Subject to the NIH Guidelines

Q: Under which section of the NIH Guidelines does the generation of transgenic rodents fall?
A: The creation of transgenic rodents falls under one of two portions of the NIH Guidelines depending on the containment level required to house the rodents. Experiments involving the creation of transgenic rodents that can be housed under Biosafety Level 1 conditions are covered under Section III-E-3. Experiments involving the generation of transgenic rodents requiring BL2, BL3 and BL4 containment are covered under Section III-D-4.

Q: Under which section of the NIH Guidelines does the generation of transgenic animals other than rodents fall?
A: The creation of all transgenic animals (other than rodents that can be housed under BL1 containment conditions) is covered under Section III-D-4 of the NIH Guidelines.

Q: Would the breeding of two different strains of knock-out mice require IBC approval under the NIH Guidelines?
A: The techniques used initially to create knock-out animals involve the stable introduction of recombinant DNA into the animal’s genome, and thus these animals are considered transgenic. As the breeding of two different strains of knock-out mice will potentially generate a novel strain of transgenic animal, the work is covered under the NIH Guidelines and as such requires IBC review and approval. Sections in the NIH Guidelines that cover work with rodents include III-E-3 for work that requires Biosafety Level (BL) 1 containment and III-D-4 for work that requires BL2, BL3 and BL4 containment.

Q: Is IBC registration and approval needed for the maintenance of a transgenic animal colony?
A: The maintenance of a transgenic rodent colony (i.e. breeding within a particular transgenic strain) at BL1 is an activity that is exempt from to the NIH Guidelines and, as such, does not require IBC registration and approval. The maintenance of a transgenic rodent colony at BL2 or higher falls under Section III-D-4-b and requires IBC approval. The breeding of all other transgenic animals is subject to the NIH Guidelines under Section III-D-4-a or III-D-4-b depending on the containment level required.

Q: Is the purchase and transfer of transgenic rodents exempt from the NIH Guidelines?
A: Under Appendix C-VI of the NIH Guidelines, the purchase or transfer of transgenic rodents may be maintained at BL1 containment are exempt from the NIH Guidelines. The purchase or transfer of transgenic rodents that require BL2 or higher containment is not exempt from the NIH Guidelines. These animals are covered under Section III-D-4, and purchase and transfer of such animals requires IBC registration and approval.

It should be noted that the subsequent use of transgenic rodents may not be exempt from the NIH Guidelines. Experiments using transgenic rodents at BL1 are exempt from the NIH Guidelines if the experiment does not involve the use of recombinant DNA. If the protocol does involve the use of recombinant DNA or is conducted at BL2 or higher than the work falls under III-D-4 of the NIH Guidelines and as such requires IBC review and approval prior to initiation.

Q: Is the purchase and transfer of transgenic animals other than rodents exempt from the NIH Guidelines?
A: No, only the purchase or transfer of transgenic rodents that may be maintained at BL1 containment is exempt from the NIH Guidelines. The purchase or transfer of any other animal for research purposes at any biosafety level (including BL1) is not exempt, nor is the purchase and transfer of transgenic rodents that require BL2 or higher containment.

Q: Are gene ablation studies covered by the NIH Guidelines?
A: The answer to this question depends on the technique employed in the study. If recombinant techniques are used to knock out the gene, then work would be covered under the NIH Guidelines.

Q: Who has the responsibility to review the generation of transgenic animals if an institution is generating animals for investigators who are not affiliated with that institution?
A: The generation (creation) of transgenic animals is an activity covered under the NIH Guidelines. The IBC at the institution where that activity is occurring has the responsibility to review and approve that activity (if the institution is subject to the requirements of the NIH Guidelines). The subsequent use of the animals by investigators not at that institution would need to be reviewed and approved by the IBC at the investigator’s institution if that institution conducts or supports recombinant DNA research that receives NIH support and the activity covered under the NIH Guidelines.

Q: When a core facility generates transgenic mice as a “fee for service” for Principle Investigators (PIs), is it the responsibility of the PI or the core facility to register the generation of the mice with the IBC?
A: Section IV-B-7-a-(1) of the NIH Guidelines articulates one of the responsibilities of the PI as ‘initiating no recombinant DNA research which requires IBC approval prior to initiation until that research has been approved by the IBC and has met all other requirements of the NIH Guidelines.’ It would be acceptable for either the PI of the core facility or the PI purchasing the transgenic animals to fulfill the responsibility to register the generation of the animals. In many cases, the animals being generated will be subsequently used in experiments that are subject to the NIH Guidelines, and the registration of the research with the IBC may encompass both the generation and subsequent experimentation with the animals.

Q: When existing transgenic animals at an institution are purchased or transferred to an investigator outside the institution, who should review and approve the use of these animals?
A: An institution’s IBC does not need to review and approve the use of transgenic animals at another institution. If the receiving institution is subject to the NIH Guidelines (i.e. conducts or supports recombinant DNA research that receives NIH support), then the purchase and transfer of animals (other than rodents that can be housed under BL1 containment), along with any experiments subject to the NIH Guideline, would require review and approval by the IBC at that institution.

Q: What are the NIH Guidelines requirements for research with large transgenic animals (sheep, pigs, etc.), or research with recombinant DNA microorganisms in such animals?
A: When conducting recombinant DNA work with large animals, the work is covered under Appendix Q of the NIH Guidelines. Appendix Q specifies containment and confinement practices when animals are of a size or have growth requirements that preclude the use of laboratory containment of animals. The NIH Guidelines include provisions for tracking and inventorying these animals (Appendix Q-1-B-2 states that a permanent record must be maintained of the experimental use and disposal of each animal). Animal carcasses must be disposed of as to avoid their use as food for human beings or animals unless food use is specifically authorized by an appropriate federal agency (Appendix Q-1-B-1). An acceptable method, for example, would be incineration.

Q: Are recombinant DNA modifications to the somatic cells of non-transgenic animals subject to the NIH Guidelines?
A: Yes, these experiments are subject to the NIH Guidelines.

• Sections III-D-1-a through III-D-1-d cover experiments using Risk Group 2, 3, 4, or restricted agents in whole animals. See the NIH Guidelines for the appropriate containment for such experiments.
• Section III-D-4-a covers experiments involving viable recombinant DNA-modified microorganisms tested on whole animals. DNA from any source except for greater than one-half (50%) of eukaryotic viral genome may be transferred to any animal and propagated under conditions of physical containment comparable to BL1 or BL1-N and appropriate to the organism under study.
• Section III-D-4-b covers recombinant DNA, or DNA or RNA derived therefrom, involving whole animals, including transgenic animals that are not covered by Sections III-D-1 or III-D-4-a. The appropriate containment for these experiments is determined by the IBC.
• Experiments not included in Sections III-A, III-B, III-C, III-D, III-F, fall into Section III-E. Experiments covered by Section III-E may be conducted at BL1 containment.

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