Europe’s Advanced Therapy Medicinal Products: chances and challenges

Regenerative medicine emerged in the early to mid-1990s and holds the promise of treating many serious and disabling diseases by replacing damaged, lost or diseased tissues and organs. Among the numerous applications are heart muscle repair following a myocardial infarction [1], treatment of neurodegenerative disorders including Parkinson’s disease [2], enhancing wound repair and replacing damaged bone and cartilage. In the last 10 years, research has been translated into early clinical trials and the results have been quite encouraging [3]. Today, 20% of the medicines on the market and 50% of those in development are biotech-based products [101]. The potential impact of regenerative therapies is foreseen to radically change healthcare; however, it also challenges existing perceptions, dynamics and standards relating to ethics, safety and governance.

In December 2008, the European Regulation (EC) No. 1394/2007 on Advanced Therapy Medicinal Products (ATMP) came into effect, granting European patients access to safe, efficient and innovative treatments, while ensuring the highest level of protection. It represents a regulatory framework built on the directives laid down for medicinal products (e.g., gene therapy and somatic cell therapy) for human use (Directive 2001/83/EC), quality and safety standards with respect to human tissues and cells (Directive 2004/23/EC), medical devices (Directive 93/42/EEC), active implantable medical devices (Directive 90/385/EEC), and centralized procedures (Regulation No. 726/2004) [4]. The European Medicines Agency is responsible for the scientific evaluation of applications for European marketing authorization for ATMPs. While the marketing authorization procedure has been established by the drafted regulations, technical regulations covering the ATMP development process, from production, handling, storage and transport, up to donor traceability, are still in progress [4]. Hereby, the EU regulatory framework substitutes the existing patchy regulatory situation in the constituent EU member states that resulted in market fragmentation. Consequently, ATMPs can only be placed on the European market after rigorous review and approval. While it is hoped that investment and growth in the European biotechnology industry will be encouraged by the creation of a central marketing authorization, the regulations are subject to a number of provisos [102].

Developers of ATMPs applying human embryonic stem cell technologies may find it impossible to commercialize their product in some EU-member states, even if it has been granted a centralized marketing authorization. According to the ‘subsidiarity’ principle, each member state is entitled to forbid the use of certain cell types and therapies on its territory owing to ethical concerns.

Product accreditation is regulated centrally, but reimbursement has to be negotiated separately with all EU-member states owing to self-contained social insurance systems. New and improved medical treatments, including ATMPs, do not necessarily cost more than traditional treatments, although obviously they can. However, the current standard of care, for chronic diseases and wounds in particular, can be very expensive. Therefore, treatments that replace or modernize the traditional standard of care, occasionally avoiding costly nursing-home care, can reduce the patient’s medical costs, even if the new treatments are themselves very expensive [103]. Nonetheless, for successful clinical implementation of ATMP-based innovative therapies, developers will need to discuss with regulative authorities and health insurance companies which instruments are most suitable for evaluating therapeutic efficiency. Classic randomized, double-blinded clinical trials will not be feasible owing to small patient cohorts or where invasive procedures applying autologous human tissue-engineered products (hTEP) will be involved [4].

The ATMP regulation brings three important innovative medical disciplines under one regulatory text, namely gene therapy, somatic cell therapy and hTEP. The compatibility and feasibility of trying to cover gene therapy and somatic cell therapy on one hand and hTEP on the other, in a single regulation, has been questioned by all stakeholders. The reason for this is that a pharmacological, metabolic or immunological principal intended mode of action is central to gene and somatic cell therapy, whereas hTEPs are generally considered to be much closer to medical devices than pharmaceuticals in their principal intended mode of action. Therefore, the design phase and ongoing risk assessment, clinical investigation and other key technical requirements are quite different.

Essential technical regulations covering the ATMP development process, from production, handling, storage and transport, up to donor traceability, are still in progress. For example, the existing concept of good manufacturing practice cannot be adopted for hTEPs and must be customized for hTEP applications. Appropriate rules have not yet been defined by the EU regulators [4], providing adequate flexibility for future regulations keeping pace with scientific development.

The rules and regulations for market approval are assessed as complex and burdensome by the chiefly small- and medium-sized enterprises involved in research and development, testing, manufacturing and distribution of ATMPs. Here, the regulatory authorities bear the responsibility of guaranteeing patient safety and supporting innovation. Needlessly long or prolongated approval procedures will jeopardize the financial survival of most small- and medium-sized enterprises, which, in most cases, emanated from governmental research programs financed by taxpayers’ money. In contrast to the regulation’s primary intention to afford every European citizen access to ATMPs, an innovation-impeditive approval would, in the worst case, obviate a benefit for the taxpaying European citizen when becoming a patient.

The presently bemoaned approval hurdles are not alike for all ATMPs. The European Medicines Agency has established numerous forms of relief for so-called ‘orphan’ medicinal products [5]. Medicines for rare diseases, the so-called orphan medicinal products, are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions that affect no more than five in 10,000 people in the EU, or are medicines that, for economic reasons, would be unlikely to be developed without incentives. Companies with an orphan designation for an ATMP benefit from scientific advice during the product-development phase, 10-year marketing exclusivity and fee reductions or exemptions. Therefore, it is foreseeable that, in the near future, various ATMPs for primarily orphan applications will make their way into the approval process. On the supposition of continuously increasing expertise in conversion of the regulations on both sides, that is, the industry/academia and the regulatory authorities, nonorphan applications will profit from this process.

Looking into the future, a further diversification of ATMPs is foreseeable, introducing several new regulatory challenges. For example, the potential impact of nanomedicine will radically change medical devices and pharmaceutical therapies, including ATMPs. As nanomedicine evolves and more products and devices enter the pipeline, the current regulations will have to be revised.

In conclusion, the much-anticipated regulation on advanced therapy medicinal products normalizes the regulatory standards for regenerative therapies in the EU, resulting in a coherent European market. As a consequence, market approval sets high standards for small- and medium-sized enterprises and the regulatory authorities. In the coming months, we will hopefully experience an adaptive system that fulfils its superordinate tasks: affording technological innovation and maximum patient protection.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.