Ethical and Biosafety Oversight of Gene Transfer Clinical Research: What Sponsors and CROs Need to Know

Overview

All human gene transfer clinical trials inside or outside the USA, if subject to the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acids, require approval by an Institutional Biosafety Committee (IBC). Moreover, 2024 changes to the NIH Guidelines have expanded the requirement for IBC oversight of gene editing. Planning for IBC oversight is a critical and often neglected initiation step for gene transfer clinical research. Sponsors and CROs who plan for IBC at an early stage can ensure safe, compliant, and efficient site initiation, startup, and execution. This article details some of the complexities of human gene transfer (HGT) research and tips for sponsors and CROs conducting HGT clinical trials.

Introduction

The number of drug products under development that incorporate recombinant or synthetic DNA or RNA, viral vectors, genetically modified organisms (“GMOs”), and/or gene editing continues to rapidly expand. Since 2023, oversight of cellular and gene therapy products has been under the Office of Therapeutic Products (OTP) within the Center for Biologics Evaluation and Research (CBER). As of August 2024, there are 21 gene therapy products with approval from the U.S. Food and Drug Administration (FDA).

Compared to clinical trials with older classes of drug products, such as small molecules or monoclonal antibodies, there are important similarities and differences in requirements for safe and ethical conduct of clinical trials of gene therapy and related modalities. Any research teams conducting clinical trials in the U.S. will be very familiar with the requirement for ethical oversight by an Independent or Institutional Review Board (IRB), and the requirement for IRB review extends to all gene therapy trials. In addition to IRB review, gene therapy, gene transfer, and gene editing clinical trials also generally require review by an Institutional Biosafety Committee (IBC) at some or all sites.

Broadly speaking, IRBs are tasked with protecting the rights of research participants in clinical trials. IBCs are tasked with mitigating risks posed by gene transfer research to clinical staff, public health, and the environment. With proper planning, IRBs and IBCs can work together to ensure safe, efficient, and compliant study start-up.

Although the FDA has never published a precise definition of “gene therapy,” according to CBER, human gene therapy “seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use.”¹ This definition is based on the drug product’s primary mechanism of action (PMOA), and encompasses viral vectors, genetically modified cellular therapies, and DNA and mRNA products other than prophylactic vaccines for infectious diseases.

In contrast to FDA classification, which primarily depends on the PMOA and indication, the NIH categorizes genetically modified products according to the technology used to produce them. These rules are spelled out in the NIH Guidelines. Specifically, NIH Guidelines Section III-C-1 provides a definition of Human Gene Transfer (HGT) research: HGT research is the deliberate transfer — into one or more human research participants — of recombinant or synthetic or gene-edited nucleic acid molecules, or the deliberate editing of chromosomal DNA in one or more human research participants, with certain exceptions such as research with products incorporating only small or inert DNA or RNA molecules.² In practice, this means that most investigational products that contain genetically modified or synthesized DNA or RNA are HGT products. Exceptions include small, transient molecules such as most short, interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). Any product that incorporates a “viral vector” will be considered an HGT product. Sponsors and CROs should consult a biosafety professional or a molecular biologist to determine whether a particular investigational product meets the NIH definition of an HGT product. Inquiries of this type may also be directed to the NIH Office of Science Policy.

The definition of HGT research is important to understand because any HGT clinical trial inside or outside the USA, if subject to the NIH Guidelines, must have IBC approval prior to initiation. Clinical research is subject to the NIH Guidelines if any of the following apply: i) the clinical trial site receives relevant NIH funding; ii) the investigational product was developed with NIH funding; iii) the clinical trial sponsor receives relevant NIH funding; iv) voluntary compliance is chosen per best practices recommended by the NIH Guidelines.

Below are a few considerations when determining whether the research involves HGT.

1. T cells expressing synthetic Chimeric Antigen Receptor (CAR-T cells): Yes, it is HGT.
2. Biopsy T cells isolated as Tumor Infiltrating Lymphocytes (TILs) and expanded without genetic modification prior to infusion: No, it is not HGT.
3. T cells transduced with T Cell Receptor (TCR) genes cloned from TILs prior to infusion: Yes, it is HGT.

Recent Amendments to the NIH Guidelines

Over the first 40 years that the NIH Guidelines were in effect, the Guidelines required that each HGT protocol be reviewed, or considered for review, by an NIH committee known as the Recombinant DNA Advisory Committee (RAC) prior to approval at individual sites. In April 2019, a final action was announced, whereby the RAC review was eliminated. In addition, various reporting requirements were removed. For example, it is now recommended that IBCs reduce or eliminate consideration of study subject safety, as this is an IRB responsibility. In 2024, the NIH announced further amendments to the Guidelines, expanding the definition of HGT to include certain gene and genome editing technologies.

A segment of DNA encoding the sequence of a protein is called a gene; genes are a subset of the entire chromosomal DNA sequence, also known as the “genome.” The term “genome editing” is sometimes used to encompass the editing of DNA sequences outside of a gene. These sequences may encode a broad array of regulatory functions that affect gene expression. The process used to produce Casgevy is classified as genome editing.

A variety of techniques may be used to accomplish gene editing in human cells. These include zinc-finger-, TALEN-, and most prominently, CRISPR-enabled technologies. A large variety of editing approaches inspired by early CRISPR successes is being deployed in preclinical and clinical research.

Because of the fundamental role played by DNA in human health and disease, gene and genome editing are expected to play ever-increasing roles in medical research over the next decade.

IBC Review of Clinical Trials

Each institution conducting clinical trials subject to the NIH Guidelines must have an IBC registered with the NIH Office of Science policy. IBC membership must include scientific experts qualified to evaluate the research under study and two community representative members who live near the clinical trial site and are not affiliated with the clinical trial site. Clinics and hospitals frequently lack the scientific and regulatory expertise to independently register and maintain an IBC. Even IBCs administered by major academic medical centers can struggle to find the time and attention required to adequately review gene transfer research. Therefore, many sponsors, CROs, clinics, hospitals, and universities find that it is beneficial to partner with an IBC service provider to staff and administer an IBC on behalf of each clinical trial site.

The NIH Guidelines require that a clinical trial protocol be approved by the respective IBC at each clinical trial site prior to initiation of research under that protocol. IBC approval must be issued from a convened public meeting of the IBC. IBCs may convene in person or remotely. IBCs must assess and deliberate on the suitability of the site and the investigator for safe conduct of the proposed research. After IBC approval, the NIH Guidelines require continuing IBC oversight at each site for as long as dosing occurs at that site. Changes in research require prior IBC approval, and unexpected events such as loss of containment or lab-acquired illness must be promptly reported to the IBC.

IRB Review of Gene Transfer Research

In many aspects, IRB review of gene transfer research addresses all the same questions as IRB review of any clinical trial, especially regarding the general concerns of risk/benefit assessment and informed consent. However, some gene transfer studies do pose unique challenges that not all IRBs may be prepared to address. For example, certain classes of gene transfer agents are known to pose a risk of creating cancer-causing chromosomal abnormalities through insertional oncogenesis. As another example, experimental treatment with a first-generation version of a gene transfer vector may induce an immune response that precludes future treatment with subsequent more advanced versions of the product. Proper risk-benefit assessments in these cases require that IRBs include members with a sufficient understanding of the molecular and immunological issues involved. Reviewing informed consent and recruitment materials to address the complex nature of gene transfer research is also a special challenge for IRBs.

IRBs must be prepared to accept primary responsibility for ensuring proper technical and ethical review of gene transfer protocols. Because IBCs necessarily include members with advanced technical understanding of molecular methods, an ideal solution is a system whereby the IBC and IRB work together to provide efficient and comprehensive oversight.

Conclusions: Plan Ahead and Seek Expert Advice

Sponsors and CROs planning Phase I, II, III, or IV clinical trials or multi-patient expanded access protocols should keep in mind that a review of HGT research by the FDA and the IRB is necessary but not sufficient. Requirements for IBC review should be included in project planning at the earliest possible stage while considering product handling, investigator qualifications, and site selection. Proper planning and coordination with gene transfer experts can ensure safe, compliant, and efficient site initiation and clinical trial startup and execution. Consult WCG’s IBC experts for your HGT research by completing the form below.

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References

[1] https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products.

[2] Section III-C-1. Experiments Involving the Deliberate Transfer of Recombinant or Synthetic Nucleic Acid Molecules, or DNA or RNA Derived from Recombinant or Synthetic Nucleic Acid Molecules, into One or More Human Research Participants.