Hospital exemption (HE) is an alternative access route for Advanced Therapeutic Medicinal Products (ATMPs) that does not require central marketing authorisation (MA) by the European Medicine Agency (EMA). An introduction to the regulatory framework, challenges, and opportunities of HE pathway here . In the current blog we dive deeper into implementation of HE across four European Union (EU4) countries (France, Germany, Italy and Spain) and the United Kingdom (UK) and explore real-world examples to understand the impact of HE ATMPs on the access and pricing of centrally approved ATMPs.
How do European countries apply the Hospital Exemption pathway?
The HE pathway presents several challenges, most of which stem from the variations in its implementation across European countries.The key differences in how major European markets (EU4 and UK) interpret the HE regulation are highlighted in Table 1. Although the UK is no longer a member of the EU, it continues to recognise the HE scheme.
Table 1.Different Hospital Exemption interpretation across the EU4 and the UK
Notes: *Mostly used by hospitals; **Except when clinical data is available; ^Not required for non-pharmaceutical establishments only.
Abbreviations: AEMPS, Spanish Agency of Medicines and Medical Products; AIFA, Italian Medicines Agency; ANSM, National Agency for the Safety of Medicines and Health Products; HE, Hospital Exemption; MHRA, Medicines and Healthcare Products Regulatory Agency; PEI, Paul-Ehrlich-Institute.
The difference in interpretation and implementation of the HE pathway across the major European countries exists on multiple levels. For instance, the EU4 and UK lack a uniform definition for the term “non-routine basis”, so it is determined on a case-by-case basis. Additionally, France, Germany, and the UK do not restrict the type of organizations eligible for licenses, whereas Italy and Spain limit eligibility to hospitals and public institutes, respectively.
Validity periods for HE licenses vary across the EU4 and the UK as well. France and Italy restrict licenses if a centrally approved ATMP is already available, while Germany, Spain, and the UK lack clear restrictions. Some countries impose additional requirements, such as evidence of high unmet medical need or requirement of clinical data before issuing the HE licenses.
The UK, though no longer part of the European Union, continues to use “Specials” scheme for production and supply of unlicensed medicinal products. Unlike HE in EU4, the “Specials” are not specific to ATMPs and can be exported out of the UK for use in other countries (both within and outside the EU) that have a similar scheme. The “Specials” scheme also enables the import of products not licensed in the UK.
The lack of harmonisation of HE regulation has led to divergent motivation for it’s use. In France, healthcare providers use HE alongside clinical trials to treat patients who are ineligible or missed the recruitment window. On the other hand, Germany and Spain adopt a broader approach, for data collection towards obtaining a MA via centralized European registration.
In early 2023, the UK government announced its intentions to introduce a new framework for therapies manufactured at the point-of-care. ATMPs are specifically mentioned as a focus of this new framework. Although there are currently no further details, it could provide a stronger regulatory position on this issue.
Impact of Hospital Exemption ATMPs on Access to Centrally Approved ATMPs
As per regulation, HE ATMPs currently address the need of patients when centrally approved ATMPs are either not available or not commercially feasible. However, when a centrally approved ATMP are either not available authorization for the same or similar indication in which a HE product already exists, it creates an uneven playing field. There are few examples where centrally approved ATMPs faced challenges due to availability of similar HE ATMPs at local level.
One example is ChondroCelect, a tissue engineered product indicated to treat symptomatic cartilage defects. Despite being the first EMA approved in 2009, It faced delays before successfully entering the EU market, due to market acceptance and reimbursement negotiations. ChondroCelect was eventually withdrawn from the EU market in 2016 for commercial reasons.
One commercial reason was related to the presence of other chondrocyte products in Germany operating under the HE, as depicted in Table 2. According to TiGenix, the manufacturer of ChondroCelect, this situation created unfair competition, ultimately resulting in the withdrawal of their product which would otherwise be authorised for used throughout the EU. In order to avoid this, the industry is demanding that HE is limited to situations where there is no centrally authorised treatment available. Similarly to ChondroCelect, the availability of HE ATMPs in the EU market posed challenges for another ATMP, MACI (matrix-induced autologous chondrocyte implantation), leading to product’s withdrawal.
These examples showcase how the presence of HE ATMPs can hamper access to centrally approved ATMPs. While France and Italy have regulation to restrict use of HE ATMPs when a centrally approved ATMP is available, there is a lack of periodic status checks to effectively monitor compliance.
In summary, the inconsistencies in implementation of the HE pathway across European countries pose significant challenges. The presence of HE ATMPs can create unfair competition and potentially discourage the development of centrally approved ATMPs Stakeholders must work together to create a system where the use of the HE pathway is focused on filling gaps where commercial ATMPs are lacking. They should also work towards harmonizing its application and interpretation across Europe to ensure sustainable and equal access to safe and potentially lifesaving treatments.
Table 2. ATMPs currently available under HE pathway in EU
Abbreviations: ATMP, Advanced Therapeutic Medicinal Product; CAR-T, Chimeric Antigen Receptor Cell Therapy; GTMP, Gene Therapy Medicinal Products; HE, Hospital Exemption; sCTMP, Somatic Cell Therapy Medicinal Products; TEP, Tissue Engineered Product
Impact of Hospital Exemption ATMPs on Future Development of Centrally Approved ATMPs
EU regulations contain stringent requirements for the development of ATMPs. However, for the HE pathway it is up to the individual Member States and the competent authorities to establish or maintain the quality requirements of the production processes. This leads to lighter quality control criteria and consequently leads to a reduction in costs of HE ATMPs.
A recent example of such a low cost HE ATMP is ARI-0001. Spain developed and approved this, making it the first Chimeric Antigen Receptor Cell Therapy (CAR-T) to progress from bench to bedside in the EU. ARI-0001 is indicated for the treatment of patients aged >25 years with relapsed/refractory acute lymphoblastic leukemia, where no other treatments are available. The EU ATMP Regulation for centrally approved ATMPs.
The development of ARI-0001 was jointly financed by public authorities and civil society, and it is now reimbursed in Spain at one-third of the cost other CAR-T therapies marketed in Spain. The low cost could raise concerns for manufacturers of centrally authorised ATMPs. ON I-0001 is expected to expand it’s label to include multiple myeloma in the future, where centrally approved CAR-T therapies (Abecma and Carvykti) are already available.
The low cost of HE ATMPs could provide a disincentive for multinational development of centrally authorised ATMPs, due to differences in quality requirements leading to a non-level playing field. Industry organisations have proposed that ATMPs with a HE should be excluded from the benchmarks for price determination of centrally approved ATMPs. However, it remains to be seen whether payers will refer to the price of HE ATMPs.
In summary, the inconsistencies in implementation of the HE pathway across European countries pose significant challenges. The presence of HE ATMPs can create unfair competition and potentially discourage the development of centrally approved ATMPs. Stakeholders must work together to create a system where the use of the HE pathway is focused on filling gaps where commercial ATMPs are lacking. They should also work towards harmonizing its application and interpretation across Europe to ensure sustainable and equal access to safe and potentially lifesaving treatments.