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T2EVOLVE publishes recommendations for cutting CAR-T therapy red tape

The consortium published a series of recommendations for how the regulatory process in the EU for approving cell and gene therapies could be sped up.

18 March 2024
T-Cell binding to a tumor cell using Chimeric Antigen Receptor (CAR). Image credit: Alpha Tauri 3D Graphics via Shutterstock.
T-Cell binding to a tumour cell using Chimeric Antigen Receptor (CAR). Image credit: Alpha Tauri 3D Graphics via Shutterstock.

Selling new cell and gene therapies in the EU is complicated. To gain access to the market, a cell and gene therapy manufacturer must undergo a series of health technology assessments at national level as well as regulatory assessments by the European Medicines Agency (EMA).

The rules vary from country to country, so a treatment might be approved in one country but rejected in another, presenting a headache for drug manufacturers and lengthening the amount of time it takes for a treatment to get to market. This is seen more often in emerging technologies, like cell and gene therapies, where regulation has to catch up with innovation and the best way to perform assessments is not yet obvious. For instance, CAR-T cell therapies are not currently available outside of clinical trials for patients in Belgium or the Netherlands, while patients in France and Germany can already benefit from these treatments.

“The situation in Europe is really scattered,” says Carmen Sanges of Lehrstuhl für Zelluläre Immuntherapie, Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany, who was one of the authors of the paper published by T2Evolve. The complications that arise from this makes it more challenging than it needs to be to get drugs to patients.

Living cells versus traditional medicines

Cell and gene therapies differ from traditional medicines in that they are engineered from living tissues. For instance, in CAR-T cell therapy, a new cancer treatment, a patient’s own cells are harvested from the patient, modified to kill cancer cells, and re-introduced to the patient. By the very nature of this therapy, slight changes or tweaks may be necessary to better suit one patient’s particular needs. Sometimes the need for these changes only becomes clear during the process of removing and editing the cells. But drug manufacturers cannot go ahead and make these tweaks as they see fit – rather, if one CAR-T product differs in any way at all from another, it must undergo the whole regulatory process again from scratch.

“When you’re engineering living cells, you can adapt the therapies and it changes the whole drug development process from one of discovery to one of engineering. As it now stands, if you were to change a little bit in the process of how your cell is made, it has to go through the whole regulatory process again,” says Scott Wagers, a strategy consultant and founder of BioSci Consulting, one of the T2Evolve partners.

T2Evolve’s recommendations

Making adjustments to the regulatory process could reduce the burden on manufacturers and shorten the waiting times for treatments to be approved for clinical trials. As well as that, it could speed up the rate at which new treatments are developed, because multiple versions of a product could be tested simultaneously. The T2EVOLVE project ran a workshop in 2023 with the European Medicines Agency in attendance and came up with a series of recommendations, the main highlights of which are outlined below:

  1. Using an umbrella approach for evaluating multiple versions of a single product

Current regulatory processes for clinical trials make testing several closely-related potential candidate treatments difficult – if an umbrella approach was taken, regulators could evaluate several similar products in a single sweep.

  1. Pioneering the ‘parent-child’ approach in Europe

In the US, the FDA has adopted a ‘parent-child’ approach where several versions of a product are submitted for regulatory approval within one file. One version of the product (dubbed the parent) provides all of the common clinical information while the additional versions’ paperwork just involves the ‘extra’ or ‘different’ information. The approach is not directly translatable to Europe, because the US files are organised product by product and the EU files are organised trial by trial, but the paper published by T2Evolve sets out how it could be applied to the European context.

“The parent-child approach allows you to test different versions so you can cross-reference your new studies with the old ones,” says Rashmi Choudhary of Takeda Pharmaceuticals, T2Evolve’s project leader, who has been working in the US and so is familiar with the American system. “It takes a lot of time to file a new application and we know that our patients are waiting so we don’t want to delay giving them the drugs that they need, or an optimised version of the drug that they need.”

One of the core questions that manufacturers have to ask themselves however is whether the specific change being made to the ‘parent’ or original product actually leads to a new version of the initial product, or is a completely new product. This will have to be defined, and the EMA have already published a draft reflection paper outlining the types of differences that could be used to justify whether a product is completely new, or a new version of an existing original.

The road ahead

“From my perspective we need to compile more use cases that effectively demonstrate the necessity for implementing a parent-child approach here in Europe. Currently, regulatory bodies may not fully appreciate the urgency of introducing a new process,” says Sanges.

“Our first priority is to gather additional use cases. Secondly, we require a valuable tool to assist CAR-T cell producers in assessing the impact of any changes to their products. Such a tool could significantly facilitate discussions with regulatory authorities.”

CAR-T cell therapy has enormous potential to fight some currently incurable diseases, like cancer and autoimmune diseases. However, it also presents challenges due to its potential to cause toxic side-effects, which can be lethal, and it’s not yet possible to predict these in preclinical and animal studies. Because T cells are engineered from the body’s own cells, they also persist and spread in the patient’s body. T2Evolve is investigating new preclinical models which can better predict how CAR-T therapy will impact humans – for instance, looking at how techniques that are used to prepare the body for a CAR-T cell treatment can be improved, determining the quality of the raw materials that should be used for CAR-T cell engineering, or exploring how slight modifications in how the cells are engineered could reduce toxicity.

T2Evolve is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.