EMA updates advanced therapy guidelines for developers

Regulatory NewsRegulatory News | 18 December 2020 |  By 

The European Medicines Agency (EMA) has updated its guidance to industry on the development of new medicines with genetically modified cells, including a special section on considerations for developing chimeric antigen receptor (CAR) T-cell therapies.
“It is recognised that this is an area under constant development and the guideline should be applied to any novel product as appropriate,” the EMA wrote in the new guideline.
The 36-page guideline provides recommendations covering the quality, non-clinical, and clinical aspects, as well as pharmacovigilance and environmental risk assessment related to medicines with genetically modified cells. It goes into effect on 1 June 2021, replacing a 2012 version developed before the first gene therapy medicinal product using genetically modified cells was authorized. The revisions are based on the agency’s experience with novel technologies, including CAR T-cells, induced pluripotent stem cells, and genome editing. (RELATED: Convergence: EMA close to finalizing guidance for advanced therapies, Regulatory Focus 17 September 2020)
The quality section of the guideline was updated to include information related to starting materials, comparability, and validation. For instance, EMA advised that when using pre-complexed ribonucleoprotein, which is needed for some genome editing procedures, the same amount of data is needed for each starting material – such as recombinant protein and guide RNA – as is required for the drug substances of a biologic medicinal product and a chemical medical product.
The guideline has also been updated to include current thinking on requirements for conducting non-clinical studies, as well as the scientific principles for CAR T-cell and T-cells with engineered T-cell receptors. For example, the guideline states that in the case of CAR T-cells, there should be pharmacodynamic assessment of immune effector mechanisms, cytokine levels, and tumor cell kills. Drug developers should also monitor the duration of the pharmacodynamic effect.
In the guideline’s special CAR T-cell section, EMA recommends that exploratory pharmacokinetic clinical studies should characterize CAR T-cell levels, as well as their expansion and persistence in blood and target tissues, at various relevant time points. Dose-finding studies should be conducted to examine safety, toxicity, and anti-tumor activity at different dose levels and to define the recommended dose or dose range for phase 2 studies.
Conventional drug-drug interaction studies and renal/hepatic impairment studies are less likely to be applicable to CAR T-cells and should be considered on a case-by-case basis, EMA advised.
In terms of efficacy for CAR T-cells, dose-selection and timing of response assessment should be based on the results of exploratory trials. In planning confirmatory trials, EMA recommends adhering to the intention-to-treat (ITT) principle in assessing efficacy. The agency suggests defining the ITT population as all patients enrolled in the trial, including the CAR T-cell and the comparator arm.
A randomized controlled trial design is preferred and comparison to best supportive care or investigator’s choice treatment is preferred to single-arm trials. “Exceptionally and when scientifically justified, an uncontrolled single arm setting might be acceptable for marketing authorization,” EMA wrote. “In such cases, it is expected that the treatment effect is exceptionally compelling, and the usual course of the disease is highly predictable.”
For safety evaluation of CAR T-cell products, EMA advises that drug developers assess the cause of adverse events from the CAR T-cell product and related procedures, such as the lymphodepleting regimen or the apheresis procedure. Sponsors should consider defining expected and unexpected adverse events, choosing an algorithm for detecting and treating potential life-threatening toxicities, and planning a study duration that allows for the detection of late toxicities, according to the guideline.
Commenters on a draft version of the new guideline generally welcomed the update, given the significant changes in science that have occurred around cellular and gene therapies. But bluebird bio suggested that the EMA consider making regular updates every 2-3 years.
Autolus Limited commented that there should be more details on CAR T-cell therapies, specifically on improving CAR T-cell efficacy and safety during clinical development or the post-marketing period.
The Alliance for Regenerative Medicine called for closer alignment with requirements from the US Food and Drug Administration (FDA). “In particular, it would be helpful if there could be common agreement between the FDA and the EMA on how the different components and products used during the manufacturing process are evaluated and classified as starting materials, raw materials, drug substance or intermediates, especially for ex vivo gene therapies,” the group wrote.
In response, EMA said that they had received input from the FDA on the guideline and that they are seeking alignment when possible.


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