by Michael Firgens
Advanced Therapy Medicinal Products (ATMPs) bear game changing potential for the treatment of severe conditions for which we have no appropriate therapies today. The product class of ATMPs comprises gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (sCTMPs), tissue-engineered products (TEPs) as well as combined ATMPs. ATMPs are complex products, and ATMP developing companies face diverse challenges during development as well as for commercialization.
Hospital Exemption Legislation - Background
Following the implementation of the ATMP Regulation (EC) 1394/2007 on 30 December 2008 by EMA, it became mandatory for ATMPs to follow the centralised procedure to obtain a marketing authorisation pursuant to Regulation (EC) No. 726/2004. As a consequence, ATMPs had to fulfil the same high regulatory standards as other pharmaceuticals, including manufacturing in compliance with GMP, pivotal clinical trials and paediatric investigation plans (PIP). These requirements have put a significant regulatory burden on ATMP developers and manufacturers who are mainly represented by SMEs and academic institutions with only limited regulatory expertise, budget and personnel.
However, an exemption from the centralised procedure was introduced into the ATMP Regulation to allow marketing of certain ATMPs in individual EU member states: the so-called “hospital exemption”. EU member states are allowed to permit the use of ATMPs in their respective territories without the need for a marketing authorisation (Figure 1). Hospital exemption can only be applied for custom-made ATMPs used in a hospital setting for a specific patient. Such products are produced under the responsibility of a physician and are only to be used within the member state where it is produced. In addition, a competent authority must authorise hospital exemption for ATMPs. The hospital exemption products must comply with the same national requirements concerning quality, traceability and pharmacovigilance that apply to authorised medicinal products.
Hospital exemption for ATMPs has implications for patients, ATMP developers, healthcare professionals, regulators, and other stakeholders. The following topics are currently under discussion among these stakeholder groups:
1. Implementation of Hospital Exemption in the EU
The hospital exemption legislation is implemented differently in EU member states (Table 1). As a consequence, industry and academia request clarification on what constitutes hospital exemption and greater uniformity of its implementation. These observed differences are partially resulting from vague terminology used in the legislation; terms such as “non-routine production” or “industrial preparation” are not clearly defined.
As a consequence, divergent implementation of the hospital exemption legislation can negatively impact patient access to treatments, its use in certain indications and development of new ATMPs. Therefore, stakeholder groups request a harmonisation for hospital exemption criteria across the EU and more guidance from EU member states.
2. Patient access
The hospital exemption’s obvious advantage is that patients can receive much needed ATMP treatments in situations when no product has been authorised. Hospital exemptions also allow patients to benefit from ongoing clinical research, particularly in areas of unmet medical need.
On the other hand, as hospital exemption products can only be used within the respective EU member state, the use of hospital exemption instead of the central marketing authorisation to the market deprives large groups of patients across Europe of the benefits of therapy. Some consider that this creates unequal access to new treatments for patients within the EU.
3. Clinical Data Requirements
Data collected from the use of hospital exemption products can be a valuable source of clinical experience supporting future marketing authorisation applications. When the hospital exemption is applied for, clinical trial data demonstrating a favourable benefit-risk balance are usually not available yet. Considering this uncertainty in clinical practice, some urge to carefully outweigh the use of hospital exemption products against evidence-based medicinal products with established safety, efficacy, and quality data.
In relation to information sharing, it has been proposed to systematically collate clinical efficacy and safety data and experiences from hospital exempted ATMPs. It was also argued that better data collation could help move products along the path to marketing authorisation. On the other hand, other stakeholder emphasize that clinical trials should remain the relevant route for generating clinical data and for the basis of a marketing authorisation.
To better control hospital exemption products, certain stakeholders request that the hospital exemption license holder or physician is obliged to collect and report all clinical safety and efficacy data to the national competent authority.
4. Commercialization & Competition
Originally, hospital exemption has not been intended as the primary route for marketing ATMPs. However, for certain types of ATMPs, it has been claimed that hospital exemption is currently the preferred route for marketing instead of obtaining a marketing authorisation.
Considering their lack of adequate data on efficacy and safety, hospital exemption products are best used in situations of high unmet medical need and where no authorised products are available. In case new authorised medicinal products become available in a specific indication, some stakeholder groups demand that hospital exemptions for equivalent products should cease to exist. This approach would minimise competition between licensed medicinal products and hospital exemption products and incentivise the development of therapies with demonstrated quality and clinical benefit. ATMPs that obtain marketing authorisation first would significantly benefit from such a regulation.
Stakeholder groups call for more transparency on the use of exemption products in the EU, so that industry, academia, regulators and patients, can obtain information on the number, type and indication of hospital exemption products, e.g. in publicly accessible registries and other electronic databases.
In summary, the regulatory environment and pathways of ATMPs are still dynamic fields, which likely will be sharpened over the next years. While patient representatives stress the importance of ensuring that patients have good access to necessary treatments and that clinical research is not impeded, other stakeholders request a strict limitation of hospital exemptions to exceptional cases. Overall, clear and practical guidance is still required for moving ATMPs from hospital exemption to marketing authorisation.
Biopharma Excellence has in-depth expertise in the development of ATMPs. Please let us know if we can support you with
- Preparation and submission of the hospital exemption dossier
- Planning of the ATMP development strategy and regulatory pathways to hospital exemption or marketing authorization
- Preparation and conduct of scientific advice meetings with national EU agencies or with EMA