Risk Assessment for use of Engineered Genetic Materials in Clinical Research

The use of engineered genetic materials in clinical trials is rapidly expanding, with potential applications for genetic vaccines, gene-modified cellular therapies, and gene therapies.

This trend came to the forefront during the COVID-19 pandemic, as the three most popular vaccines developed in response to the coronavirus contained engineered genetic materials in the form of mRNA or a genetically engineered virus.

A similar phenomenon has taken place in oncology, as gene-modified chimeric antigen receptor (CAR) T cells have become popular for treating refractor or resistant B cell malignancies.

Among the various regulatory bodies providing oversight on clinical research, only the institutional biosafety committee (IBC) has a purview specific to research involving engineered genetic materials. IBC review ensures compliance with biosafety guidelines, issued by the National Institutes of Health (NIH) as well as the Centers for Disease Control and Prevention (CDC), intended to protect the health and safety of research personnel as well as the community and environment around the research site. A key part of the IBC’s evaluation is assessing the risks posed by the engineered genetic materials.

Why Does the IBC Need to do a Risk Assessment?

Any investigational product (IP) comprised of engineered genetic materials administered to a human subject, and whose development has received support from the NIH, must receive review and approval from an IBC registered with the NIH.

IBC review boils down to assessing the risks associated with engineered genetic materials. The committee is also charged with ensuring an appropriate risk mitigation plan is in place to protect research staff, the community, and the environment around the research site.

IPs containing engineered genetic materials may pose risks potentially not anticipated by the clinic’s standard infection control policies. With a membership comprised of subject matter experts in genetic engineering, microbiology, and biosafety, an IBC fills this gap with a comprehensive risk assessment tailored to the specific IP and the procedures performed as part of the clinical trial.

IBCs also include community members (who may or may not have a science background) to address the concerns of the general public and ensure representation is not purely scientific. These individuals provide a perspective that is equally important for consideration when evaluating the risks to the study participants and clinicians, as well as to the community where the study is conducted.

Gene Delivery Systems

Genetic material, in the form of DNA or RNA, does not easily enter cells without the aid of a delivery system. For example, the Pfizer and Moderna mRNA COVID vaccines utilize lipid nanoparticles, while other approaches utilize genetically engineered viruses. Either way, occupational exposure to these gene delivery systems bears potential risks to the research staff.

The diverse array of viruses capable of infecting humans leads to a menagerie of potential gene delivery vectors (also known as viral vectors) with diverse possibilities for uses, as well as potential toxicities or risks. To mitigate the latter, these viruses are typically genetically modified with built-in safety features to limit their ability to reproduce in human cells (while still delivering their genetic payload).

Although attenuated, these viral vectors can retain their potential to replicate under the right circumstances and cause disease in exposed individuals, which can also be transmitted to others. Further, the genetic modifications themselves, or the inserted potentially therapeutic transgene, have the potential to increase the virulence of the delivery system given the right context. In its risk assessment, the IBC considers all these aspects inherent to the recombinant IP.

Risk Assessment

The IBC also evaluates the research clinic’s policies and practices for handling the recombinant IP. These include the following:

• Unpacking and storing the IP after receipt from the sponsor
• Preparing and diluting the IP for administration
• Administering the IP to subjects
• Destruction or removal of contaminated waste and unused IP from the clinic
• The clinic’s incident response plans in the event of a spill or release of the IP
• The location where each of the above procedures will be conducted
• Personal protective equipment (PPE) to be worn during each of the above procedures
• The disinfectants to be used for decontaminating surfaces throughout the above procedures

At Advarra, this information is captured in the safety standard operating procedure (SOP) each clinic completes prior to IBC review and includes photos of the individual rooms. Every clinic receives a comprehensive facility inspection, which is normally performed remotely via live video, between one of Advarra’s biosafety experts and the clinic’s staff.

Then, at the convened IBC meeting when the clinic’s protocol is reviewed, the SOP and photos are presented to the committee by the biosafety experts who performed the inspection. This allows the IBC to assess whether the clinic has the facilities to safely handle the IP and prevent exposure or release at that site. Finally, the principal investigator (PI) of every protocol is evaluated for their competency to comply with the IBC’s recommended safety practices and to train the clinic’s staff on those practices.

For deficiencies identified with any of these practices, the IBC will typically recommend safety plan revisions to satisfy the committee’s concerns, rather than disapproving the protocol completely. The research clinic must satisfy these conditions of approval before the IBC releases full protocol approval.

The risk assessment is meant to be a collaborative process between the clinic/PI and the IBC, such that the risk mitigation procedures approved by the IBC are reasonable and practical for each clinic.

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