Question:
For investigational drugs needing IBC review, what is the difference between a Risk Group and a Biosafety Level? Are they always equivalent?
- Regulatory Coordinator, Oncology Clinic
Answer:
Institutional Biosafety Committees (IBCs) exist to protect research staff, the public, and the environment from risks posed by research with biological agents containing recombinant or synthetic nucleic acids (i.e. DNA/RNA). As part of these responsibilities, the National Institutes of Health (NIH) requires IBCs to comprehensively assess biosafety-related risks associated with the research, and outlines a number of items IBCs should consider when conducting these risk assessments. As a starting point, investigational agents are assigned to a Risk Group (RG) based on several criteria related to the agent itself, or for genetically modified agents, the parental organism from which the agent was derived:
- Ability to cause disease in healthy adult humans;
- Anticipated disease severity;
- Availability of preventative or therapeutic interventions.
Risk Groups range from 1-4, with level 1 for the lowest-risk agents and level 4 for the highest-risk agents (Table 1).
Biosafety Levels (BSL) are similar to RGs in that they are used to classify research based on risk. Biosafety Levels also range from levels 1-4, with 1 for low-risk research and 4 for the highest-risk research. In contrast to RGs, however, which generally do not dictate behaviors or work practices, BSLs are used to identify and characterize specific work practices, facilities, and safety equipment required for the research in question. In general, BSLs and RGs are aligned, meaning RG2 agents are usually approved by IBCs for handling at BSL-2. The NIH also requires certain BSLs for several categories of research, including BSL-4 for all work with RG4 agents (Table 2).
However, there are also times that the IBC-determined BSL and the RG of the agent being worked with do not align. This can happen because risk assessments and BSL determinations are not based solely on an agent’s assigned RG. In addition to RG, IBCs also consider the agent’s “virulence, pathogenicity, infectious dose, environmental stability, route of spread, communicability, operations, quantity, availability of vaccine or treatment, and gene product effects such as toxicity, physiological activity, and allergenicity”, and as a result, BSLs “may be raised or lowered as a result of [these] considerations”1. This is a common occurrence for certain agents; for example, many IBCs approve research with lentivirus-modified chimeric antigen receptor (CAR) T cells at BSL-2 despite lentiviruses being RG3 agents. Similarly, IBCs often approve research at a BSL higher than the RG of the agent being handled, particularly if it harbors genetic modifications or transgenes that increase biosafety risks.
It should be noted that nearly all clinical trial research can be safely conducted at BSL-1 or BSL-2. At many institutions, the pharmacies, laboratories, and patient rooms used for clinical research are set up such that they meet the requirements of both BSL-1 and BSL-2; in these cases the distinction between BSL-1 and BSL-2 may be largely administrative. Whatever the case, communication between investigators and their staff with the IBC is one of the most effective ways of ensuring biosafety. Lastly, as certain genetic engineering technologies advance to the point where they can be used without infectious microbial vectors (and therefore have no assigned RG), it will be critical that IBCs and research staff fully understand the nature of each agent so that risk assessments and the research can be conducted appropriately.
| Risk Group | Description | Example(s) |
|---|---|---|
| None | Not Based on an infectious agent | mRNA |
| 1 | Based on an infectious agent that is not associated with disease in healthy adult humans | Adeno-associated virus Lactococcus lactis Saccharomyces cerevisiae |
| 2 | Based on an infectious agent that is associated with human disease, which is rarely serious and for which preventive or therapeutic interventions are often available | Adenovirus Herpes simplex virus Listeria monocytogenes Rhinovirus Salmonella typhi |
| 3 | Based on an infectious agent that is associated with serious or lethal human disease for which preventive or therapeutic interventions may be available (high individual risk but low community risk) | Bacillus anthracis Francisella tularensis HIV-1 SARS-CoV |
| 4 | Based on an infectious agent that is likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available (high individual risk and high community risk) | Ebola virus Lassa virus |
| Research Type | Required BSL | NIH Guidelines Citation |
|---|---|---|
| Research with RG4 agents | BSL-4 | Section III-D-1-c |
| Research with agents containing DNA from RG4 agents unless the agent is defective relative to the parental RG4 agent | BSL-4 | Section III-D-2-a |
| Research conducted in a lab where other BSL-3 research is conducted | BSL-3 | Appendix G-II-C-1-h |
| Research with certain pandemic or highly-transmissible avian influenza viruses | BSL-3 enhanced | Sections III-D-7; III-D-7-a; III-D-7-b; III-D-7-c |
| Research with large animals infected with certain influenza viruses | Animal BSL-3 | Appendix G-II-C-5-b-(2) |
| Research with recombinant/ synthetic influenza viruses | Equal to the RG of the strain from which a majority of genes are derived | Section III-D-7 |
| Research with restricted agents | As determined by NIH | Sections III-D-1-d; III-D-2-b; III-D-3-d |
References
- Comprehensive Risk Assessment. NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines). April 2019. National Institutes of Health. Available at https://osp.od.nih.gov/wp-content/uploads/NIH_Guidelines.pdf. Accessed 12 November 2023.