The European Medicines Agency is on the verge of releasing revised guidance for advanced therapy medicinal products containing genetically modified cells, which includes chimeric antigen receptor (CAR)-T cell therapies.

The Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells was originally issued in 2012 but underwent revision and consultation from July 2018-July 2019. The revised version is expected to be adopted in October and published in November, according to Ana Hidalgo-Simon, MD, PhD, head of advanced therapies at EMA. She previewed the major changes at RAPS Convergence 2020.

There were an enormous number of comments on the document, Hidalgo-Simon said.The agency is also working on a Q&A document on principles of good manufacturing practices (GMP) for Advanced Therapy Medicinal Products (ATMP) starting material. There will likely be consultation on the document in 2021, she said. (RELATED: Regulation of advanced therapy medicinal products in the EU, Regulatory Focus, 16 July 2020.)

Major changesEMA chose to update the guidance to reflect the increase in clinical experience with these therapies, particularly chimeric antigen receptor-T (CAR-T) cells; to cover new categories of products, such as induced pluripotent stem (iPS) cells; and to allow for consideration of new tools for genetic modification of cells, such as genome editing technologies, she said.

The main quality updates are related to starting materials, the manufacturing process, and characterization and release. For example, the starting materials guidance will now include genome editing tools, while the manufacturing process includes a new section on comparability. The characterization and release portion of the guidance includes specific advice for CAR-T cells.

Additionally, the guidance calls for dose-finding studies to explore safety, toxicity, and anti-tumor activity at different dose levels, to define the threshold dose required for anti-tumor effect, and to define the recommended dose or range for Phase 2 studies. She said sponsors need to show a solid rationale for the criteria being used to find the dose.

The guidance also calls for Phase 3 confirmatory trials to follow a randomized controlled design, comparing the CAR-T cell therapy to a reference regimen, unless otherwise scientifically justified. Single-arm studies will continue to be allowed, but they will be the exception, Dr. Hidalgo-Simon said.

Be very careful with the design of the trials, she advised. The assumptions need to be really, very well backed.

When it comes to safety, the guidance calls for a 15-year follow period. While sponsors wont have all the answers at the time of submission, Hidalgo-Simon said they should have a plan that includes monitoring during the post-authorization period.

Hidalgo-Simon also advised sponsors to think beyond the approval process and consider what evidence will be needed to convince other stakeholders -- from patients to payers -- about the safety and efficacy of the therapy.

Avoiding development pitfallsRichard Dennett, PhD, the senior director of chemistry, manufacturing and controls regulatory affairs at PPD, also participated in the RAPS Convergence 2020 session on advanced therapies. He reviewed development points where companies can run into trouble with advanced therapies, particularly CAR-T cell products.Dennett recommended that product sponsors keep the end in mind when developing advanced therapies by focusing on the target product profile at the beginning of development. That profile includes the indication for which approval will be sought and the incidence of that indication; other considerations include mode of action, demographics, how much of the product needs to be produced, and market access and reimbursement considerations.

He also outlined several areas where developers should focus to create a watertight regulatory package, including sufficient product characterization, potency assay, impurities, formulation, stability, lack of sufficient development batches, and validation strategy.

Dennett urged developers to dive into the growing number of regulatory guidance documents for advanced therapies. In addition to the European guidance documents, developers should consultthe US Food and Drug Administrations Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), which was released in January 2020. (RELATED: Advanced therapies: Trip hazards on the development pathway, Regulatory Focus, 02 August 2020)

Live and breathe the guidances that are out there, Dennett advised. They allow us to understand what expectations we need to meet.

The key to success in advancing CAR-T cell therapies is the mitigation of risk, Dennett said: The biggest risk is the one that you havent thought of.RAPS 2020 Convergence

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Convergence: EMA close to finalizing guidance for advanced therapies - Regulatory Focus