Advanced Therapies: Stakeholders Call for EMA Changes on Regulations, Manufacturing

The European Medicines Agency (EMA) on Friday released a report outlining the concerns and regulatory changes described by developers, manufacturers and investors in advanced therapy medicinal products (ATMPs), which include gene therapies, tissue-engineered products and somatic cell therapies, at a meeting last week.

The report notes that recurring themes included the need for early interaction with regulators and guidance, more transparency, greater harmonization between EU member states with regard to ATMP regulation, as well as a proposal from industry calling on EMA to be more flexible with manufacturing ATMPs.

“Although no decisions have yet been made, the European Commission, national competent authorities, and EMA have already started discussing the feasibility of these proposals,” EMA said.

Background

In the EU, the regulatory framework for ATMPs was established under Regulation (EC) No 1394/2007, which has been in force since 2008.

The regulation allows automatic access to a central route for the authorization of ATMPs across the EU and established the Committee for Advanced Therapies, which brings together expertise and established, among other processes, the classification and certification procedures to aid the early development of ATMPs.

EMA convened a meeting covering ATMPs on 27 May 2016, which was attended by academics and researchers, incubators and consortium organizations, as well as representatives from patients and healthcare organizations, small and large pharmaceutical companies, investors, health technology assessment bodies, national competent authorities (NCAs) and the European Commission.

Manufacturing Proposal

“A major proposal at the meeting was for licensing requirements to take account of the unique particularities of ATMP manufacture,” the report says. “For example, participants noted that ATMP manufacture can take place at various sites and that, for some products, the later stages of production may need to take place close to the bedside. The implication is that all sites involved – hospitals included – would need to hold a manufacturing licence.”

However, with a lack of harmonization at the national level, as only some member states allow hospitals to hold a manufacturing license, stakeholders “requested authorities to make requirements more flexible during early developmental phases. Specific proposals for cell-based products included adapting requirements for low-risk (non-substantially manipulated) products, as these could be considered to fall on the borderline between transplants and ATMPs.

“Similarly, a more pragmatic approach should be used to address process validation requirements for many ATMPs, given the difficulty in producing the required number of batches for standard pharmaceuticals,” the report says.

Other manufacturing proposals include promoting new technologies (e.g. bedside manufacturing and closed systems) and manufacturing models (e.g. decentralized manufacture), which would require more flexibility.

“Regulators could also promote development of manufacturing sites, as a service, using small and medium-sized enterprises (SME) and other funding, so capability is available to several parties developing different ATMPs,” the report notes. “These suggestions were considered timely, given that the European Commission is currently revising the guideline on GMP requirements for ATMPs and will shortly be launching a public consultation.”

GMOs

Another major topic at the meeting revolved around genetically modified organisms (GMOs), which have had a chilly reception in the EU.

Stakeholders noted that the GMO Directive (Directive 2001/18/EC) “is not specifically designed for medicinal products and its shortcomings in this respect are compounded by divergences in implementation in Member States. Since requirements differ among Member States, the integration of GMO assessment in clinical trials authorisation poses a challenge, particularly in the context of multicentre clinical trials.”

Developers of these gene therapies called for more uniformity and suggested, as an initial step, the setting up of a central repository in English, listing the requirements and timelines for GMO assessment in every member state.

“Some stakeholders also called for changes to the GMO directive itself,” the report says. “Another area that could benefit from further harmonisation relates to cells and tissues used as starting materials for the manufacture of ATMPs, with stakeholders asking for a more streamlined implementation of the Tissues and Cells Directive (Directive 2004/23/EC) and other relevant legislation.”

Other Issues

Those weighing in also called for further harmonization to “facilitate the movement of starting materials between areas with different requirements (within and outside the EU) and reduce the burden of having to re-test the cells and tissues prior to starting the manufacture of ATMPs. Testing can then be focused on aspects relevant to the nature of ATMPs.”

Industry also called for specific guidance on excipients and a master file system for marketing authorization purposes in relation to excipients and raw materials.

In addition, stakeholders proposed novel development tools (e.g. organoids, extrapolation, modelling/simulation, biomarkers, etc.) to address non-clinical requirements.

“On the question of the benefit-risk balance of products in development, stakeholders noted that current practice focuses mainly on risks and called for additional emphasis to be placed on expected but realistic benefits, particularly where patients have incurable diseases or where suitable treatments are lacking,” the report added.

“If ATMPs are to fulfil their promise of providing innovative treatments for patients, regulators must nurture a regulatory environment that encourages innovation, safeguards public health and, ultimately, facilitates timely patient access to new therapies,” the report says.

Advanced therapy medicines: exploring solutions to foster development and expand patient access in Europe