CAR T-Cells, Helping US Firms & An “Ambitious” Plan For Advanced Therapies In The EU

If all goes to plan, developers of drugs based on chimeric antigen receptor (CAR) T-cell technology should soon start to get a better understanding of what will be required of them on the regulatory front in Europe.

CAR T-cells, classified in the EU as advanced therapy medicinal products (ATMPs), are showing promise in clinical trials as a new paradigm for treating cancers such as leukemia and lymphoma that have not responded to standard therapies.

These types of genetically-modified cells pose a number of scientific and regulatory challenges but, as yet, there is no EU guidance on how to develop and evaluate them. Remedying this is high up on the to-do list of Martina Schüssler-Lenz, the new chair of the European Medicines Agency’s Committee for Advanced Therapies. “We have to make sure that these products get to the patient,” Schüssler-Lenz told the Pink Sheet.

Martina Schüssler-Lenz, the new chair of the European Medicines Agency’s Committee for Advanced Therapies

Schüssler-Lenz spoke about what she said was an “ambitious” work plan for the CAT – and ATMPs in general – under her three-year mandate as chair; she was elected chair in February this year. “An increased workload lies ahead of us,” she said, and her aim is to “come up with adequate regulatory strategies to cope.”

ATMPs, which are based on genes or cells, represent a fast-growing field. But they are complex products and their development has been hampered by myriad scientific, technical and manufacturing challenges. Since EU legislation (Regulation (EC) No 1394/2007) governing advanced therapies came into force in 2008, just 15 ATMP marketing authorization applications (MAAs) have been filed. Only eight products have been approved and launched, and three of these have since been withdrawn.

Considerably More MAAs Forecast

That said, forecasts indicate that the CAT will receive considerably more MAAs over the next two years, Schüssler-Lenz said, noting that her committee was currently evaluating two MAAs (the CAT drafts an opinion on each ATMP application before the EMA’s Committee for Medicinal Products for Human Use (CHMP) adopts a final opinion). In addition, a study published in the Journal of Market Access & Health Policy in 2016 said that around 1,000 clinical trials were being conducted for ATMPs, of which 65 were in Phase III, suggesting they had a successful Phase II and a chance of reaching the market in the coming five years.

CAT members will have to keep pace with a scientific field that moves very quickly. “This means that in parallel to our work on procedures and marketing authorizations, we will need to adapt to the regulatory challenges that the evolving science poses and draft new guidelines or revise existing ones,” Schüssler-Lenz explained.

For example, the CAT will be revising its scientific guidance document on products containing genetically-modified cells so that it factors in guidelines on the development and evaluation of medicines that contain CAR T-cells.

The committee is also revising its ATMP guideline on safety and efficacy follow-up and risk management (EMEA/149995/2008) to include information on the use of registries. A revised document has been prepared and is scheduled to be released for consultation by the summer. Health technology assessment bodies are expected to be consulted proactively during the consultation phase, and the EMA also plans to work on an ATMP-specific risk management plan template and guidance that would reduce the administrative burden for ATMP developers.

The European Commission is shortly expected to publish new guidance on good manufacturing practices for ATMPs, which was developed with input from the CAT. The document has been some time in the making and there have been concerns over the fact that it is being developed as a stand-alone document rather than as an annex to the existing EU GMP guideline (EudraLex Volume 4) for medicines in general. Regulatory authorities participating in the international Pharmaceutical Inspection Co-operation Scheme, for example, issued a statement in February warning that it diverges from PIC/S requirements and would result in lower regulatory standards.

Schüssler-Lenz disagrees. She is “very much in support of the document” and says that accusations that it will reduce safety are wrong. The CAT chair said the guidance is a very good example of a collaborative effort that was developed in response to requests from stakeholders who wanted a document that outlined the GMP requirements, was readable, did not require people having “to look in five different annexes,” and addressed the flexibility needed for ATMPs and the risk-based approach required.

Other activities on the CAT’s agenda include dealing with applications from sponsors for early regulatory support under the EMA’s priority medicines (PRIME) scheme: over half of the 19 products that have been granted PRIME designation so far are ATMPS, including CAR T therapies. In addition, forecasts suggest the CAT will receive more than 50 requests for a scientific recommendation on ATMP classification in 2017. The committee will also be dealing with scientific advice procedures and certifying quality and non-clinical data for SMEs. A CAT work plan for 2017 is expected to be published in the second quarter of this year.

Gearing Up For CAR T-Cells

Schüssler-Lenz, a physician by training, is the deputy head of the Advanced Therapy Medicinal Products Section at the Paul-Ehrlich Institute in Germany, and had been vice-chair of the CAT since March 2014. She used CAR T-cell therapies as an example to illustrate the challenges her team deals with when it comes to ATMPs.

CAR T-cell therapies are under investigation for different types of cancer by several companies including Novartis, Kite Pharma, Juno Therapeutics, bluebird bio/Celgene, Cellectis/Servier/Pfizer, Bellicum Pharmaceuticals and Celyad (formerly Cardio3 BioSciences). They involve taking T-cells from a patient’s blood and then genetically engineering them in the laboratory to allow them to recognize cancer cells through specific receptor proteins. After the modified cells are returned to the patient, they can identify cancer cells and destroy them.

“As a physician, I worked in the clinic with terminally ill leukemia patients where, after several lines of treatment, there was nothing else to offer,” Schüssler-Lenz said. “Now with the CAR T-cells coming, we are seeing in clinical trials that they might offer a new treatment modality.”

But while CAR T-cells are demonstrating efficacy, there are concerns over their toxicity. “So these are quite challenging products for which we have no guidelines available yet,” Schüssler-Lenz said.

“We have to make sure that our regulatory frame is suitable to deal with new developments and with evolving new treatment modalities,” the CAT chair stressed. Just as important, “we have to make sure that our regulatory frame does not inhibit the timely access to these new types of treatments.”

As well as working on scientific guidance for CAR T-cells, the committee will continue to take on board conclusions from a workshop it hosted last November that explored how to facilitate development of cancer treatments based on genetically-modified T-cells.

Work on the CAR T-cell guidance is all the more pressing, given that companies expect soon to start filing EU marketing applications for such therapies. For example, Novartis, which appears to be on track to getting the first CAR T therapy to market in the US after revealing on March 29 that the Food and Drug Administration had accepted its MAA filing for CTL019 (tisagenlecleucel-T), plans to submit an MAA for the product to the EMA later this year.

Supporting Developers

Schüssler-Lenz also wants to make sure that ATMP developers who might be unfamiliar with EU drug requirements, such as those from academia or the US, get the support they need to navigate Europe’s regulatory procedures.

“We have to see, for example, that we guide US-based developers of CAR T-cells through our European system, which is more complex than that in the US both procedure- and diversity-wise.” For instance, it might not be clear to some sponsors that clinical trial applications must be submitted to national competent authorities, while marketing applications are submitted to the EMA. Also, sponsors might need help in understanding how to go about the business of setting up manufacturing for these cells in Europe.

To some extent, the CAT is already offering drug makers more help via the PRIME scheme, under which the EMA provides early and proactive support to developers of medicines that target an unmet medical need so that they might reach patients faster.

“I think it’s an important task of the CAT, and of course in cooperation with the rest of the EMA, national agencies and the European Commission, that we help people work with our system,” Schüssler-Lenz said.

There is also a need to ensure that hospitals and physicians understand how to use CAR T-cells and other ATMPs properly by, for example, requiring that companies establish appropriate post-authorization measures and risk management plans.

“So taking care of these products – the science and the adaptation of the regulatory system to make them available to patients – is something that I am dedicated to working on.”

Focusing On Clinical Data

The CAT’s focus has traditionally been on quality, non-clinical and clinical issues. As part of her strategy for the next three years, Schüssler-Lenz plans to have an even stronger focus on bringing products to patients by looking at efficacy, safety and benefit-risk from a clinical perspective. This does not mean neglecting quality or non-clinical issues, according to the CAT chair.

“I am really excited to focus on what the disease is and which clinical data we will need to achieve a positive benefit-risk assessment,” Schüssler-Lenz said. This is “very important,” and sometimes challenging in the area of ATMPs. For instance, where an orthopedic surgeon might be randomizing patients in a trial to treatment with either a cartilage-repairing, tissue-engineered chondrocyte-containing product or to a traditional surgical procedure, “we need adequate clinical expertise to judge the clinical data, to reach a conclusion on efficacy and safety and how to deal with, for example, remaining quality issues.”

Schüssler-Lenz wants to make sure she has the right expertise on her team. She is satisfied with the multidisciplinary composition of the CAT, but knows there is room for improvement. “We need good clinical expertise and good expertise in trial methodology,” the CAT chair said, adding that she has had “very fruitful” discussions with Europe’s Heads of Medicines Agencies network about support on this front. Schüssler-Lenz is also planning to streamline discussions in committee meetings and foster closer interaction with the EMA’s other scientific committees and working parties.

Schüssler-Lenz replaced Paula-Anneli Salmikangas, who chaired the CAT between February 2014 and February 2017.

From the editors of Scrip Regulatory Affairs.