The experience of conducting clinical trials with advanced therapy medicinal products (ATMPs) in a real-world clinical setting, according to a new European Medicines Agency (EMA) summary of a conference discussion, can mean “battling multiple and often ridiculous barriers.”

The summary of a December regulatory conference in London on ATMPs notes that after a decade of having Regulation (EC) No 1394/2007 in force to speed access to ATMPs, “real progress has been made,” though a range of issues, from a lack of sustainable funding to problems with running trials to insufficient transparency and regulatory guidance, is still hampering greater uptake of ATMPS.

Challenges

The report uses the example of an ex vivo autologous cell and gene therapy product and of a centralized facility versus decentralized, regional manufacturing hubs, where more processes can be automated, and hones in on three critical challenges:

• "Vector scale-up, moving from adherent culture (small batch sizes) to fully disposable and scalable suspension platformss, eliminating the need for ongoing plasmid manufacture
• Ex vivo cell processing, currently a manual process (extraction) requiring highly skilled operators and where scale-out needs can be significant since patient populations, particularly in oncology, can be large
• Change management and comparability for manufacturing changes aiming to enable the treatment of larger populations.

“Key questions arising from the discussed example included agreeing what and how to measure (changes, cycles, processes), how a change in one process will affect (an)other(s), the need for in vivo comparability studies, how robustness can be compared between sites, understanding the variability of cells (inherent in people) and its impact, and analytics and methodologies,” the report says.

It also touches on the use of patient or treatment registries, which “offer opportunities to generate new data, for label expansion, and to study changes in mode of use or administration, which is particularly useful for ATMPs. However, the dichotomy between academic registries (concerned with data quality and integrity, GCP compliance, regulatory accountability and pharmacovigilance) and industry registries (concerned with the commitment of investigators, duplications, multiple investigations and questions of independence) makes their use difficult.

“Other challenges include implementing clinical trial standards (a registry is a living creature so data change with the patient’s health journey), study complexity; country or site activation; and restricted access and reimbursement based on payment by result. A solution could be to have different types of platforms for registries in the hands of specialised data platform providers (guardians), with patients owning the data (users) and other stakeholders having access,” the report notes.

And while investors provided over $80 billion of available venture capital in 2016 (year to date) and €100 billion in 2015, the report cautions that only “a tiny percentage of deal proposals are successful each year, however, due mainly to insufficiently novel products being offered, or failure to adequately address an unmet need. The biggest problem for promising start-ups is the lack of venture capital funding in Europe. While they often receive initial support, they lack follow-up finance for the next phases, which means they have to go to the US or elsewhere and Europe fails to reap the benefit.”

As far as these “multiple and often ridiculous barriers” to running ATMP trials, the report offers the example of bio-safety levels (BSL) attributed to an ATMP candidate by different competent authorities in EU member states, which can differ widely.

“In the case of TalimogeneLaherparepvec (TVEC) immunotherapy treatment, a BSL2 designation was given in Austria and Germany, but BSL1 in Spain. While BSL2 information is well defined for the laboratory research, there is no available information on its requirements in clinical settings to aid healthcare professionals with their hands-on work with patients. Study start-up was also markedly quicker in countries without BSL2 designation, it was noted.”

Summary