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Home » Ask the Experts: Risk Groups versus Biosafety Levels for DNA/RNA Therapies
Ask the Experts: Risk Groups versus Biosafety Levels for DNA/RNA Therapies
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March 11, 2024
This monthly feature presents questions from clinical trial professionals with answers from experts. In this issue, we feature insights from Christopher Doyle, WCG IBC chair and director of IBC services, and Amy Michaud, WCG biosafety analyst lead.
Question: For investigational drugs needing institutional biosafety committee (IBC) review, what is the difference between a risk group (RG) and a biosafety level (BSL)?
Answer: 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 an 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
RGs range from one to four, with level one for the lowest-risk agents and level four for the highest-risk agents.
BSLs are similar to RGs in that they are used to classify research based on risk. BSLs also range from levels one to four, with one for low-risk research and four 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.
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. 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 at which 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.
See all risk groups and biosafety levels and accompanying examples here.
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