Defining control considerations for CRISPR reagents is key
The FDA recently released draft guidance on Investigational New Drug (IND) applications for Human Gene Therapy Drug Products Incorporating Human Genome Editing technology to edit human somatic cells. This much-anticipated draft highlights manufacturing, quality, and regulatory considerations for drug developers preparing IND filings for novel, gene-modified cell therapies.
The new guidance covers many cutting-edge, gene-modified cell therapy approaches, including allogeneic and autologous human T cell, hematopoietic stem cell (HSC), and induced pluripotent stem cell (iPSC) treatments. As a key supplier in support of the cell and gene therapy industry, Aldevron immediately keyed in on implications for raw materials and drug substances used by our clients.
Clarifying reagent requirements
For developers applying gene editing technology such as CRISPR, this guidance helps to clarify some key requirements around Chemistry, Manufacturing, and Control (CMC) for the gene-editing reagents as well as the gene-modified cellular Drug Product. For the first time, the FDA has defined key control considerations for CRISPR reagents. Method of delivery for the genome editing reagent is key:
- When delivered in vivo (e.g., by viral vector or nanoparticle), the final formulation is a drug product and the gene editing technology itself is considered as a drug substance.
- When a cellular drug product is administered ex vivo, the gene modification technology (e.g., CRISPR reagents) are considered to be critical raw materials that require a full Drug Substance section in IND filings.
Editing under control
Control of off-target gene editing is also a major theme of this guidance. There are repeated requirements throughout the document for developers to demonstrate an affirmative strategy to minimize these off-target effects (OTEs). These approaches to reduce OTEs can include:
- Optimizing the target and sgRNA sequences
- Choosing a high-fidelity gene editing nuclease (such as SpyFiTM Cas9 Nuclease, manufactured by Aldevron)
In my next post on the new guidance, I’ll discuss two common categories of gene-modified cell therapies, and how they could be affected by the FDA guidance.