How New FDA Guidelines Can Affect Cell Therapy Development, Part 1

May 18, 2022 / by Max Sellman

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The FDA recently released draft guidance on Investigational New Drug (IND) applications for Human Gene Therapy Drug Products Incorporating Human Genome Editing technology to edit human somatic cells.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.

The guidance also touches on GMP manufacturing considerations for these drug substances. While Phase I trials require components to adhere to the FDA’s Guidance for Industry: CGMP for Phase 1 Investigational Drugs, later phase and approved therapeutics will require cGMP components per 21 CFR Parts 210 and 211.

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 Spy Fi^TM Cas9 Nuclease, manufactured by Aldevron)

To the extent that OTEs are present in the final cellular drug product, these effects should be well characterized and demonstrated to not carry safety risk to patients.

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.

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