The US Food and Drug Administration (FDA) has announced the final release of a guidance intended to clarify the processes by which cellular and gene therapy (CGT) products should be assessed prior to human testing.

Background

CGTs are essentially used to make therapeutic changes to a person's cells, tissue or genes by injecting a patient with altered DNA, cells or entire organs. The products include cellular therapies, gene therapies, therapeutic vaccines, xenotransplantation and other drug products, including devices used in combination with them. Regardless of their physical composition, they are required to undergo preclinical testing before they are able to be used in humans as part of a Phase 1 trial.

But as FDA explained in its November 2012 draft iteration of the guidance, Preclinical Assessment of Investigational Cellular and Gene Therapy Products, conducting preclinical assessments of CGTs is far more difficult than it is for chemical drugs.

Because the composition of the products, as well as their mechanism of action, vary so greatly from chemical and biological drugs, standardized toxicology testing and other preclinical testing methods are often "not appropriate" for evaluating the products, FDA explained.

"The diverse biology and clinical indications and the rapid and fluid state of the evolving scientific research into these product areas pose unique scientific challenges in terms of regulatory review," FDA wrote in its guidance. "As a consequence the regulatory review process for evaluation of investigational CGT products necessitates a careful risk-benefit analysis performed in the context of the particular clinical indication under study."

FDA's Office of Cellular, Tissue and Gene Therapies (OCTGT), the office in charge of regulating the products, said it uses a "flexible, science-driven" review approach to address preclinical safety issues to ensure a product is sufficiently safe to begin clinical testing. However, "Although flexible, such an approach incorporated the basic toxicological principles that underlie more traditional, standardized preclinical testing."

Final Guidance

FDA has now released a final version of the same guidance, reflecting what FDA said were several reorganizations of content but no major changes relative to the draft.

The final guidance is divided into four main sections: Preclinical study considerations, recommendations for investigational cell therapy products, recommendations for investigational gene therapy products, and recommendations for investigational therapeutic vaccines.

The extensive framework largely avoids specifics and instead focuses on areas of generally applicable principles. For example, if animals are used, they should be selected based on a biological response that is expected to be the same in humans. These expectations should be backed up through a detailed assessment and made available to FDA in the investigational new drug (IND) submission, FDA said.

But the key to the entire approach, which FDA concedes can vary wildly among product types, is communication.

The agency said it recommends "early and ongoing" communication with OCTGT staff to avoid any surprises or delays in approval. "These communications help to ensure that regulatory expectations related to safety, demonstration of potential activity, and understanding of possible MOA(s) are addressed," FDA explained.

"Useful general information can be gained from FDA guidances and presentations at scientific meetings.  However, preclinical testing programs for CGT products often need to be highly individualized; therefore, a sponsor may need discussions with OCTGT regarding CBER expectations for the specific product and indication."

FDA said this information could be obtained through ultra-early interactions it deemed "pre-pre-IND interactions," though it cautioned that this advice is non-binding.

Preclinical Assessment of Investigational Cellular and Gene Therapy Products

Federal Register