Contributed Commentary by Daniel Kavanagh, PhD

August 31, 2021 | The goal of biosafety in research is the management of risk to people and the environment associated with exposure to biological agents and toxins and to genetically modified vectors, DNA or RNA. There are two ways that biosafety oversight of clinical trials could be improved to become more consistent and transparent. First, federal rules governing which clinical trials require biosafety approval should be broadened and clarified. Second, the National Institutes of Health (NIH) could restore certain aspects of central risk assessment and guidance that were eliminated in recent changes to the NIH Guidelines for Research Involving Recombinant and Synthetic Nucleic Acid Molecules (NIH Guidelines), while taking care not to institute burdensome duplicative review requirements.  

Biosafety Risk Assessment

Biosafety professionals consider many different kinds of risk when assessing oversight needs in a clinical trial. Some of these issues overlap with those addressed by a traditional infection control department, for example exposure to airborne pathogens. Other issues arise from specific aspects of novel biotechnologies not traditionally considered by medical professionals such as exposure to an adventitious replicating recombinant viral vector through accidental spillage or needlestick injury. Risk assessment for the latter scenario requires an in-depth understanding of molecular techniques used to construct various classes of viral vectors, as well as manufacturing control considerations for determining replication capacity within each vector preparation and an understanding of which disinfectants are effective against what types of viral vectors. Because of the complex and specialized expertise required for these assessments, many institutions require approval of cell and gene therapy clinical trials by an Institutional Biosafety Committee (IBC) prior to initiation of the research. In many cases such review is required by federal rules per the NIH Guidelines. To comply with those guidelines, the membership of each IBC must be approved by, and registered with, the NIH Office of Science Policy (OSP).

The concept of the NIH Guidelines arose from the 1975 Asilomar Conference on Recombinant DNA Molecules. Scientists and regulators were especially concerned that inappropriate molecular experimentation might lead to release of novel infectious agents, posing a serious threat to public health and the environment. The original concept of those guidelines was focused on basic science, but application to human clinical trials eventually became an important aspect of oversight. The essential requirements for local IBC oversight have remained largely unchanged through the years, although the Guidelines themselves have been amended many times, most recently in 2019. With respect to clinical trials, the Guidelines mandate IBC oversight when two criteria are met: i) the research involves administration of recombinant or synthetic DNA or RNA meeting a technical definition of Human Gene Transfer (HGT); and ii) the institution, the clinical trial, or investigational product development involve applicable NIH funding. I argue that each of these criteria is too narrow with respect to IBC oversight in the interest of protecting public welfare.

Change to the NIH Guidelines

One very notable recent change in the Guidelines is the removal of the NIH Recombinant DNA Advisory Committee (RAC) from routine biosafety oversight of clinical and nonclinical research. Until 2018, every HGT trial subject to the NIH Guidelines was reviewed by (or considered for review by) the RAC prior to receiving IBC approval at any clinical trial site. These reviews created a useful national database of HGT trials and prompted illuminating public discussions of critical biosafety issues among national experts. On the other hand, the RAC review process was often seen as redundant with FDA and IRB reviews, especially for a large number of trials all involving very similar investigational gene transfer technologies and products. For these reasons, the RAC was renamed and repurposed in 2019 and no longer conducts routine reviews of clinical trials. The former RAC is now known as the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC) and deals with a broader array of “scientific, safety, and ethical issues associated with emerging biotechnologies.” The elimination of central federal biosafety assessment of HGT research was a loss for the research community, and I suggest that NIH consider ways for such oversight to be restored without requiring redundant or superfluous assessments.

Gaps in NIH Review Requirements

To illustrate the potential significance of gaps in NIH review requirements, consider some gaps and their potential biosafety significance.

The section of the NIH Guidelines that defines HGT (Section III-C) was written before the advent of the latest gene editing techniques, such as CRISPR-Cas9 technologies. As written, the definition of HGT research includes genetic modifications that add (integrate) new DNA code into a cell’s chromosome, but Section III-C does not address gene editing that only removes or deletes portions of a chromosome. It is not obvious from first principles that such deletions are necessarily benign. I believe a revised version of Section III-C should include a more expansive definition of HGT, to include genetic modifications that delete portions of the genome using modern techniques such as gene editing.

On a more basic level, our current national biosafety regime for clinical trials is based on NIH Guidelines, which only apply to studies with certain types of NIH funding attached. Thus, a genetically modified investigational product developed with private funding, or with non-NIH public funding, may be tested in humans without IBC oversight. An identical product developed with NIH funding must have IBC approval prior to initiation of the research. In this scenario, the identical products present identical risk to the public and the environment. Given that the purpose of IBC review is protection of public health and general welfare, a more rational IBC oversight regime would apply equally to all clinical trials irrespective of funding. Such requirements could be instituted by a variety of approaches, possibly requiring statutory changes. For example, requirements for IBC review could be attached to FDA allowance of Investigational New Drug (IND) applications.

Comprehensive biosafety review of clinical trials must involve a study-level risk assessment (risks associated with investigational product and protocol), and also a site-specific risk assessment (risks associates with facilities, training, and procedures on site). Elimination of RAC review in 2019 resulted in devolution of study-level risk assessments to each IBC, even for multicenter trials with many sites under one protocol. There is no reason to expect that risks associated with investigational product and protocol should be significantly different from site to site. Therefore, a federal-level consideration of such risks would benefit the public at large as well as reviewers charged with oversight at each site. To avoid trivial and duplicative reviews of individual protocols, the federal assessments could be applied to general classes or categories of genetically modified biologics and thus provide centralized guidance and public discussion of important new technologies. This type of engagement could be added to the scope and charge of the current NExTRAC committee—perhaps with the addition of more committee members and subcommittees to tackle the additional work.

Potential Public Health Risks

As a speculative example of potential public health risks associated with new technologies, consider the case of transmissible tumors, such as have been observed in wild dogs and Tasmanian devils. In Tasmanian devils, transmissible tumors are an existential threat that have driven the species to the edge of extinction. Transmissible tumors are a kind of infectious cancer cells that can be passed from one individual to the next. Transmissible tumors are not currently considered a public health risk for humans; in general mammals are protected from transmissible cancer by the same immune rejection reaction that prevents us from receiving bone marrow transplants from genetically distinct donors.

A category of biologic under development in various labs involves “universal donor” cells that have been genetically engineered to evade those immune mechanisms that block tissue transplant to genetically mismatched recipients. This technology presents very promising possibilities for regenerative medicine and cellular therapy of cancer. However, it is not clear that the biosafety risks associated with this category of agents have been systematically assessed. Could such a cellular product mutate and become a transmissible tumor in humans? Consideration of such low-probability but potentially highly significant public health risks is not obviously within the purview of FDA or IRB oversight as currently defined. Furthermore, it is not logical that such risks should be assessed on a site-by-site basis by local IBCs. Finally, for products developed without NIH funding, they may be tested in humans without any IBC oversight at all. Overall, this class of products involves a category of risks that would benefit from public discussion and centralized engagement of biosafety experts from around the country.

In conclusion, our current system of IBC review for clinical trials as required by the NIH Guidelines is robust and useful, but also has gaps that prevent comprehensive assessment of risks to public welfare. Some changes and improvements in the current regime will lead to increased public safety and public confidence in clinical research in the coming decades.

Daniel Kavanagh, PhD, is Senior Scientific Advisor, Gene Therapy at WCG. Dr. Kavanagh serves as scientific lead in WCG’s IBC Services division. Previously, Dr. Kavanagh was assistant professor of medicine at Harvard Medical School (HMS) engaged in preclinical and clinical vaccine development, assistant immunologist at the Massachusetts General Hospital (MGH), IBC Vice Chair, HMS/ MGH, and a principal investigator studying infectious diseases at the Ragon Institute of MGH, MIT, and Harvard. He has a PhD in molecular microbiology and immunology from the Oregon Health and Science University, and RAC credential through the Regulatory Affairs Professionals Society. He can be reached at dkavanagh@wcgclinical.com.