Managing Risk in Cell and Gene Therapy Clinical Development

Conducting clinical trials for innovative gene therapy products that include viral vector-based products and gene-modified cells is not entirely straightforward.  Operationally, there are special considerations that involve: 1) special handling of the product at the clinical site to ensure product quality; and 2) safety protections for patients, healthcare workers, and caregivers.

Recently, FDA has published several new guidance documents, which discuss special considerations for gene therapy products that include the regulatory requirements for patient follow-up, viral shedding studies, and testing of the final drug product for replication competent viruses.

Although these guidance documents contain important general information about the design and conduct of gene therapy trials, it is important to point out that logistical considerations, such as handling, containment, and disposal of gene therapy products, which are specifically intended to protect the safety of patients, healthcare workers, and close patients contacts, including caregivers and patient family members, are not addressed comprehensively in the FDA guidance documents.  Traditionally, these and other risk mitigation and safety considerations related to gene therapy have fallen under the oversight and guidance of NIH’s RAC (Recombinant DNA Advisory Committee). 

At Parexel, clients often ask us the following type of question: “We’re designing the protocol for a gene therapy trial, and we were wondering what issues the RAC might have with our protocol.”  In recent years, we’ve replied that the RAC has been progressively moving away from overseeing non-novel gene therapy trials, since the accumulating data for the maturing field has led to a higher comfort level with the safety profile of gene therapy products.  However, the question and our answer will both need to be modified, since the NIH recently announced that the RAC has been transformed into the Novel and Exceptional Technology and Research Advisory Committee (NExTRAC).  

As stated in its charter, the NExTRAC’s purpose is to provide advice to the Director of NIH on matters involving novel and exceptional technology.  This committee consists of 25 voting members who are appointed by the Director of NIH based on their knowledge of gene therapy, gene editing and synthetic biology, with ad hoc experts providing additional expertise and perspectives, as needed.   

With this reworking of the organizational charter for the former iteration of RAC, IBCs (Institutional Biosafety Committees) are now fully at the forefront of overseeing the nuts and bolts of safety precautions for gene therapy products at a study site.  The IBC came into being under a mandate from NIH.  An IBC’s responsibilities include enforcement of policies and guidelines that govern use of all biological agents that pose potential hazards.  

A non-exhaustive list of such potentially hazardous products includes: gene therapies, infectious agents, stem cell products and cell lines that are derived from human and non-human primate source material, recombinant nucleotide-based products, and genetically-modified animals that may be zoonotic reservoirs.  The IBC oversees this type of research to protect the safety of researchers, laboratory and healthcare workers, subjects in clinical trials, the public, and the environment.

Specific product characteristics (i.e., the platform, such as AAV- or lentiviral vector-based gene therapy or gene-modified cellular therapy, and the exact physiochemical properties of the delivered transgenes) will require tailoring of risk mitigation strategies for individual products. We at Parexel can provide support to clients in interacting with IBCs prior to trial initiation, for example, reviewing the adequacy of protocol-specified risk mitigation procedures, including handling methods for the gene therapy product, for satisfying IBC requirements.  

References:

https://osp.od.nih.gov/biotechnology/nih-guidelines/
https://osp.od.nih.gov/biotechnology/biosafety-and-recombinant-dna-activities/