FDA aims to speed gene therapy development with prior scientific knowledge guidance

The US Food and Drug Administration (FDA) has proposed guidance on the types of scientifically valid prior knowledge sponsors should consider when developing certain gene therapies (GT). The agency said the recommendations in the guidance are intended to improve review efficiency and help accelerate product development.

On 2 June, FDA published a draft guidance that details the agency’s thinking on how to leverage chemistry, manufacturing, and controls (CMC), and nonclinical and clinical prior knowledge when developing GT products that incorporate ex vivo and in vivo genome editing (GE) of human somatic cells. The agency said the information may be especially helpful when developing GT products for rare diseases.

“This guidance is being released as part of a [Prescription Drug User Fee Amendments (PDUFA VII)] commitment to publish guidance on leveraging prior knowledge for cell and GT (CGT) products,” said FDA. “While this draft guidance specifically focuses on GE products, some of the recommendations, when finalized, are or may be applicable to other CGT products, such as adeno-associated viral (AAV) vectors, nanoparticle-based GT products, and ex vivo-modified cell-based GTs that do not incorporate GE.

“However, additional considerations may also apply to these related product types, based on the specific product and manufacturing process, that are beyond those recommended in this guidance,” the agency added.

FDA has provided a list of terms in the guidance and how regulators define them, including public knowledge, platform knowledge, and prior knowledge. The agency also addressed the scientific soundness of leveraging prior knowledge, stating that it depends on several factors, such as the similarities in the molecular structure of a component or product and its manufacturing process.

For nonclinical data for GE products, the extent of leveraging prior knowledge may depend on the similarity in on-target genomic edits between products, cell source(s), manufacturing processes, formulation, and intended therapeutic mechanism. For in vivo GE products, leveraging the knowledge may depend on similarities and differences in the products, manufacturing processes, final formulations, route of administration (ROA), proposed clinical dosing regimens, and dose levels.

Regulators also emphasized that the recommendations in the guidance are not exhaustive, and they are open to other means of leveraging the necessary prior knowledge.

“Sponsors should submit any leveraging proposals to FDA for consideration, and, if desired, discussion (see section IV),” said FDA. “Furthermore, it may be possible to leverage additional knowledge throughout the product lifecycle as product specific experience and knowledge in the field is gained.

“However, in all cases, when leveraging any kind of prior knowledge, a sponsor should provide a justification for the applicability of the data being leveraged,” the agency added. “Additional recommendations, also applicable to GE products, can be found in other FDA guidance documents.”

When considering CMC data for prior knowledge to support the development of GE products, FDA provided examples that sponsors can consider that address analytical methods, method qualification, and validation data. The agency also addressed the use of lot release specification data, stability data, comparability data, process characterization and process validation data, and data from manufacturing facilities. It also similarly addressed gathering clinical and nonclinical data.