PARIS – Refinement of the EMA's rules for advanced therapy medicinal products (ATMPs), which came into effect in 2009, is ongoing, but, so far at least, there is little evidence to suggest that the legislation has been an enabler for companies developing cell therapies or gene therapies.

Just five ATMPs have gained approval under the EMA's centralized procedure, which is overseen by the Committee of Advanced Therapies (CAT), an expert panel drawn from the European Union's member states. The most recent to get a green light is Holoclar, a stem cell therapy marketed by Parma, Italy-based Chiesi Farmaceutici SpA, which gained a conditional approval in February for treating limbal stem cell deficiency in the eyes, due to physical or chemical burns.

A key issue for the company – and for the sector as a whole – will be the level of success it achieves in obtaining reimbursement across Europe's fragmented health care market. That issue has been a heavy drag on the commercial prospects of several earlier cell therapies, notably those approved for cartilage repair such as Chrondrocelect, originally developed by Tigenix NV but now marketed by Swedish Orphan Biovitrum International (SOBI) AB, and MACI, originally developed by the Genzyme arm of Sanofi SA but now marketed by Aastrom Biosciences Inc. (See BioWorld Today, April 4, 2014.)

Speaking during a DIA EuroMeeting session on the ATMP legislation, Klaus Maleck, CEO of Tissue Engineering Technologies AG (Tetec), of Reutlingen, Germany, offered a gloomy prognosis for the sector. "I think the situation is not limited to cartilage repair," he told BioWorld Today. "It is a general situation that reimbursement is uncertain and regulation is very difficult."

For that reason, Tetec has opted not to seek an EMA authorization for its cartilage repair products Novocart 3D and its successor Novocart Inject. The company has a hospital exemption for those products in Germany, and it can obtain a reasonable level of reimbursement – about €3,500 (US$3,745) from that limited use without the additional burden of engaging with the EMA's central procedure.

That, he said, adds extra costs because of the higher levels of product validation and quality data the EMA requires. "It's a difficult investment case," he said. The present clinical development requirements – for an autologous cell therapy that may have been successfully used in patients for up to 10 years – are on a par with those for a new protein therapeutic, he said. "I would question whether that is always the best solution."

The situation is further complicated by the absence of any guarantee that a centrally approved product will find favor with national payers. "Although you have a centralized approval, the market is not harmonized," Maleck said.

WORKING THROUGH ISSUES

Speaking during a later session on translational medicine, CAT member Darius Sladowski suggested that the present difficulties are part of the normal process of technology adoption. It took 30 years for bone marrow transplants to become accepted, he said. "Today, I don't think we'd get this through," he said.

Companies developing ATMPs do need more support – from investors and from research funders, he suggested. "The bottleneck in my view is the first three years, when they have the product on the market but don't have market penetration." Investing in automation could also help to improve quality, he suggested. "You eliminate the human factor," he said.

However, Maleck has already run the numbers and for companies with small-scale manufacturing processes, the investment case does not hold up, he argued. Direct labor costs only form a small fraction of the cost of goods of autologous therapies in Europe, he said. Because of a quirk of U.S. quality requirements, where two staffers need to perform certain tasks, firms can make greater savings by moving to automation.

Meanwhile, further development of guidance around the core ATMP legislation is ongoing. A GMP specification for ATMPs in the offing, Patrick Celis, a member of the EMA secretariat that supports the CAT, told delegates. A first draft will come in the summer, while a first draft on good clinical practice has already been completed and more work will follow in that area, too. Next year, CAT will publish a guideline on minimally manipulated ATMPs.

Celis stressed that the ATMP rules are flexible. Two of the five approvals granted so far were obtained with unconventional data, such as retrospective data. Most of CAT's work has been on early development rather than the approval process, he said, given the immaturity of the sector. ATMP certification, scientific advice and other forms of interaction have formed the bulk of its workload to date. Celis encouraged developers to continue that engagement, given the diversity of the individual therapies and the complexity of the rules. "When CAT is looking at files, we see shortcomings in almost all parts," he said. That includes quality documentation, characterization and potency assays, manufacturing changes made during development, as well as clinical development, which, he said, "are made more difficult by the nature of the products themselves." There is, for ATMP developers seeking a European approval, no alternative to working through those issues. "The current regulatory framework is what it is," Celis said. "It may change – we do not know."

The meeting continues Wednesday.