Over the past three decades, cell and gene therapies (CGT) have proven their potential for finding new solutions for complicated diseases that cannot be treated with conventional therapeutics. However, the field is young still, requiring work by developers and regulators to further establish product characterization, manufacturing, safety, and regulatory approaches. Much progress has been made, and the future of CGT is bright. Perhaps the most significant facilitator of progress is maturing regulatory constructs that provide developers with more established commercialization pathways.

The FDA has introduced important new CGT guidances most every year for now nearly two decades and 2022 was no exception. In 2022, new draft guidances were released for products incorporating human genome editing (GE) and the development of chimeric antigen receptor (CAR) T cell products, and a final version of human gene therapy (GT) for neurodegenerative diseases guidance for the industry has just recently been published.

Human Gene Therapy Products Incorporating Human Genome Editing

Intending to assist in the transition to clinical trials, the FDA published this draft guidance to provide recommendations that sponsors should include in their Investigational New Drug (IND) applications for GE products, containing information on product design, manufacturing, and testing, along with preclinical safety assessment and clinical trial design.

In general, the FDA recommends that developers use the best available technologies for their GE genomic target and the type of intended modification. Suggestions for INDs include:

  • A description of the design and screening processes.
  • A justification for the overall approach.
  • The sequence of the genome editing components.

Also, it is proposed to optimize the GE components to reduce the potential for off-target modifications. 

Public comments offered by biotechnology-related organizations have expressed concerns about the implied preference of the regulatory agency for the best available technology in a single application. Considering there are many untested novel technologies that might not be ready to be implemented in this field,  existing ones that are eligible to be adapted for GE products should be prioritized to focus efforts on the product itself.

For preclinical studies, the regulatory agency conveys their thoughts on:

  1. In vitro and in vivo proof of concept studies – to establish feasibility and justification for using the product in a clinical trial.
  2. Biodistribution studies – to provide information on the extent of the editing activity in target and non-target tissues.
  3. Preclinical safety studies that can identify potential risks associated with the administration of the GE product. 

Additionally, the authority suggests that clinical trials should enroll patients for whom no other treatment options are available or acceptable. This might present restrictive language that does not reflect a proper benefit-risk assessment for patients, contrary to the real potential of GE. Experts have suggested that enrollment flexibility should be discussed based on a benefit-risk approach.

Finally, it’s worth noting that public comments have expressed the need for a more comprehensive discussion of “how safety, efficacy, durability, and quality of a GE product are factoring into FDA’s regulatory decisions” and the importance of a deeper understanding of the benefit-risk considerations at marketing application review.

For further information about public comments on the guidance, visit the Biotechnology Innovation Organization (BIO) website

Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products

CAR T cells are regulated as a gene therapy product under FDA’s existing framework for biological products. Their complex nature derived from the multiple functional elements contained in CAR T cells is a challenge to product safety, specificity, and efficacy. To facilitate the development of this biotechnology, the FDA has put together this draft guidance to provide general thoughts, CMC recommendations, and preclinical and clinical considerations.

To begin with, the regulatory agency expresses concerns about starting material from patients who have previously received CAR T cells because it may differ from those from patients who have not – leading to unexpected effects on manufacturing, potency, safety, and efficacy. The cellular starting material is critical for CAR T cells’ quality and function, so the FDA recommends evaluating previously administered CAR T cell levels in the starting material. However, this may present a difficult task for developers because of the lack of product-specific assays available to evaluate CAR T cell levels from previous therapies.

Like other guidelines, this one stresses the importance of early-phase clinical trials and the early development of analytical methods to ensure the investigational product’s safety, identity, quality, purity, and strength. The authority states that early approaches like these “are critical to establish safety of the product, response to risk mitigation measures, dose-response relationship, differences in optimal dose based on differences in indication, and preliminary evidence of efficacy and feasibility of manufacturing.” Nevertheless, this statement means setting a far too high bar for early-phase clinical trials, given the complexity and novelty of these CGT products. As much as great efforts are put into early approaches, these will only be able to partially assess these complicated issues.

Furthermore, the guidance recommends calculating the cell dose based on weight or body surface area rather than using a flat dose. However, public comments suggest that dosing based on these measures isn’t always appropriate. This discrepancy needs to be assessed through published references that put up data that support the correlation between body weight and safety/efficacy.

Visit BIO for further information about public comments on the guidance.

Human Gene Therapy for Neurodegenerative Diseases

Neurodegenerative diseases are a varied group of disorders characterized by progressive degeneration of the nervous system’s structure and a wide array of etiology, prevalence, diagnosis, and management. Therefore, to support developers in ensuring the safety, specificity, and efficacy of GT products, the FDA has issued this final guidance focused on considerations for product development, preclinical testing, and clinical trial design.

In this final version, the FDA resolved public requests regarding crossover trials, comparability studies, and residual product-related impurities.

The agency suggests that developers evaluate the effect of manufacturing process changes on the product’s critical quality attributes and be prepared to conduct a proper risk analysis. Then, if necessary and applicable, comparability studies could be performed “depending on the manufacturing change, the ability of analytical method to detect changes in the product, and the stage of clinical development.”

Regarding residual host cell-DNA impurity levels, the draft initially recommended setting a less than 10 ng/dose to avoid immunogenic reactions in patients. However, experts suggested that this limit may be unattainable for GT delivered with some viral vectors. Hence, the final version of the guidance replaces this recommendation with the statement that characteristics of viral vectors that could impact the safety of the final product should be considered carefully, along with limiting residual host cell-DNA levels and DNA size. 

Furthermore, the FDA recognizes that neurodegenerative diseases constitute a heterogeneous group of disorders that can broadly differ on available knowledge of well-characterized pathogenesis and pathophysiology. Thus, the agency suggests that innovative clinical trial designs – if justified and if product development could be facilitated – may be feasible to expedite clinical development when the natural history of the disease is well-characterized and relatively consistent. On the contrary, the guidance recommends sticking to randomized, concurrent-controlled clinical trials with appropriate blinding for disorders with poorly characterized or highly variable natural history.

Closing Comments

While important guidances were released in 2022, regulatory constructs for CGTs will continue to evolve in 2023 and beyond. BioTechLogic’s team of experts is here to help you and your team navigate the changes. Contact us to discuss how we can help.



macon Raine