Cell Therapy
Clinical Trials
Gene Editing
Gene Therapy
Regulatory & Standards

Genetically Engineered Product Guidelines put under the FDA Microscope

Anna Osborne
22 March 2022

After a wave of FDA activity featuring advanced therapy products – some positive and some not so much – gene edited and CAR-T cell therapies’ guidelines are in the spotlight as the FDA announces the release of two draft guidance documents.

The first document – ‘Human Gene Therapy Products Incorporating Human Genome Editing’ – provides recommendations for the development of products based on gene edited human somatic cell and the information required for the submission of Investigational New Drug (IND) applications, regarding: product design, manufacturing, testing, preclinical safety assessments and clinical trial designs.

The second of the new draft guidance documents – ‘Considerations for the Development of CAR T Cell Products’ – describes recommendations for the chemistry, manufacturing and control of CAR-T cell products, including advice concerning their pharmacology, toxicology and clinical study design. Although built in relation to CAR-T cell-specific products, the guidance can be applied to alternative genetically engineered lymphocyte therapies such as CAR NK cells and TCR-modified cells.

But what does this new guidance actually mean for the clinical development of genetically engineered therapies? And how will this affect the already complex approval process to get these therapies to market?

There is no shying away from the fact that these are still relatively new and relatively complex advanced therapy medicinal products, resulting in equally as new and complex regulatory concerns. As a rapidly evolving field the guidelines will take a provisional nature adjusting as more clinical evidence regarding safety of these products emerges.

The gene editing guidelines included a recommendation for initial proof of concept studies to support the rationale for progression to administration in a clinical trial. Providing preclinical data presents an opportunity to examine the feasibility, safety and benefit of an investigational clinical trial.

This guideline also outlines conditions for patient long-term follow-ups, with a recommendation of a 15-year protocol, to which patients will provide voluntary informed consent prior to the study. This will allow the FDA to build a wider picture of the unknown long-term effects of such therapeutics.

Additionally, recommendations for study primary end-points include reporting on the proposed indication or clinically meaningful effect.

The guidelines referring to CAR-T cell-specific products, the more extensive of the two documents, highlight a key area of difficulty when it comes to FDA submissions and approvals of these new and evolving therapies; change.

Changes to CAR-T cell product design, life cycle and manufacturing processes are common during developmental stages and could affect product quality, safety and stability. Therefore, changes are to be assessed on a case-by-case basis. In such an event, providing extensive comparability data is essential to avoid a clinical hold or request for a new IND submission.

Initial characterization studies were recommended to support comparability assessments. This cellular data can be referred to in order to assess product and process consistency throughout development.

The guidelines suggest for therapeutic developmental information to be collected and submitted following the product life cycle approach, with an emphasis of CMC to be placed on product safety and manufacturing control and, of course, all CAR-T cells and their vectors are to be manufactured under GMP conditions throughout development. Providing in depth CMC information as part of the IND submission will allow for the product development to be aligned against the proposed clinical development.

Over the last few years, arguably in light of the attention and success of the Covid-19 vaccine scale-up and roll-out, the FDA is recognising and responding to the potential of advanced therapies.

Recently the FDA has given the green light to a plethora of gene-edited and CAR-T products. Most notably an approval of Janssen’s CAR-T cell immunotherapy for relapsed or refectory multiple myeloma, as well as a flurry of RMAT designations, for example Fate Theraputics product for r/r DLBCL, and Orphan Drug Designation’s including Innovent and IASO Bio’s BCMA CAR-T cell therapy.

Whilst successful approvals have held a light to the FDA’s willingness to grasp these novel life-saving therapies, the agency remains understandably tentative. The new guidelines magnify the importance of safety precautions for gene-edited and CAR-T cell therapies approval and highlight potential risks.

Such untoward risks have been seen in recent months in a spate of clinical holds placed onto gene-edited and CAR-T cell therapies clinical trials, including Celyad Oncology’s Phase Ib trail for RMCC.

The FDA guidelines are built to provide thorough investigations and highlight necessary precautions. Advancing gene-edited and CAR-T cell specific measures outlines the extensive evidence required to gain product approval. Although it may appear this puts all aspects of preclinical and clinical research under harsher spotlights, the attention the FDA has given gene-edited and CAR-T cell therapies in these documents will hopefully serve to enhance clearer means for ensuring patient safety and enlighten the path for biotechs seeking product approval.

Source – FDA Press Release