ADVANCED THERAPY MEDICINAL PRODUCTS (ATMPs)
The EMA has a Committee for Advanced Therapies (CAT), which is responsible for assessing the quality, safety and efficacy of ATMPs and following scientific developments in the field. The committee is responsible for carrying out classifications of ATMPs. Classification is a non-mandatory, free of charge, legally non-binding procedure. The classification helps developers to clarify the applicable regulatory framework. It provides clarity on the development path and scientific-regulatory guidance to be followed. ATMP classification is based on the evaluation of whether a given product fulfils one of the definitions of a gene therapy medicinal product (GTMP), somatic cell therapy medicinal product (sCTMP) or tissue engineered product (TEP) and whether the product fulfils the definition of a combined ATMP or not. Classification focuses on the proposed mechanism of action of the ATMP.
The EMA publishes the assessment of ATMP classification as summary reports; EMA: definition of the classification. If you need to classify the product (not necessary) an application for classification can be submitted; apply for the classification. The CAT delivers scientific recommendations on ATMP classification after consultation with the European Commission within 60 days from receipt of the request.
The EMA has published the following guidance for help in classifying ATMPs:
Reflection paper on the classification of advanced therapy medicinal products
European Medicines Agency – advanced therapy classification – summaries of scientific recommendations for the classification of advanced therapy medicinal products
When preparing a submission for the classification of a combined ATMP (according to the EMA’s advice):
1) The device part has a CE mark
- include administrative information regarding the medical device on the ‘presubmission request form’. (p. 5)
- In the ‘briefing document’ (Word document), include sufficient information for the CAT to judge whether the device is integral with the cells/tissues (include this information in section 1.4 of the document). Also include in section 2.3, your rationale regarding how your product fulfils the definition of a combined ATMP.
2) The device part has no CE mark
- on the presubmission request form, complete the top part of page 5 which refers to ‘medical device incorporated’
- in the briefing document, as above, include sufficient information for the CAT to judge whether the device is integral with the cells/tissues (include this information in section 1.4 of the document). Also include in section 2.3, your rationale regarding how your product fulfils the definition of a combined ATMP. Furthermore, clearly state that the structural component would fulfil the definition of a medical device (and justify your reasoning).
The regulatory framework for ATMPs is designed to give access to the EU market and guarantee health protection for patients. The regulatory aspects for ATMPs can be found on the EMA’s web page: regulatory framework. Legislation on ATMP: (Regulation 1394/2007/EC) and Directive 2001/83/EC
Läkemedelsverket also provides guidance on ATMPs on its homepage:
- ATMP (in Swedish) – Läkemedelsverket
- Quality and safety regulations for human cell and tissue handling (in Swedish) – Läkemedelsverket
For procurement and manufacturing, permits are required from national authorities (Läkemedelsverket):
- For clarification of the tissue establishment – authorisation and inspection: Tissue establishment: authorisation and inspection (in Swedish)
- Donation and procurement of tissue and cells necessitates: SOSFS 2009:30 (in Swedish)
- For handling human tissues and cells to be used as raw material in the production of ATMPs, a tissue establishment authorisation (LVFS_2011-4 (in Swedish) and LVFS_2008-12 (in Swedish)) and manufacturing permit LVFS_2004-7 (in Swedish) are needed.
- A qualified person (QP) is needed; the necessary qualifications and responsibilities are described in LVFS 2004:7 (in Swedish) and GMP vol. 4 Annex 16).
- Clinical trials for an ATMP require a permit from Läkemedelsverket (clinical approval (in Swedish) – Läkemedelsverket.
- For the protection of persons with regard to the processing of personal data, the General Data Protection Regulation GDPR directive must be followed.
GXP IN RELATION TO ATMPs
Generally, pivotal non-clinical safety studies should be performed under good laboratory practice (GLP). However, this may prove difficult due to the nature of ATMPs. It is recommended to seek advice from the relevant authority on the non-clinical safety programme before initiation, which also should include the GLP status of the intended studies or part of studies.
THE PRINCIPLES OF GLP THAT NEED TO BE TAKEN INTO ACCOUNT IN RELATION TO ATMPS ARE DESCRIBED HERE: GLP IN RELATION TO ATMPS
QUALITY (INCLUDING MANUFACTURING)
The good manufacturing practice (GMP) guideline is a quality system that provides guidance for the production of pharmaceuticals (incl. manufacturing, testing and quality assurance). EudraLex (the rules governing medicinal products in the European Union) Volume 4 (EU guideline on good manufacturing practice for medicinal products for human and veterinary use) is useful for ATMPs:
The following guidelines are specific for ATMPs: GMP for ATMPs. Other documents developing GMPrequirements for medicinal products which are contained in Volume 4 are not applicable to ATMPs, unless specific reference to them is made in these guidelines.The following documents are referenced and hence are applicable to ATMPs:
- Manufacture of biological active substances and medicinal products for human use: Annex 2
- Investigational medicinal products: Annex 13
- Certification by a qualified person and batch release: Annex 16
DOCUMENTS RELATING TO ATMPS
The following essential documents apply to quality.
- Setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells: Directive 2004/23/EC, Directive2006/17/EC, Commission Directive (EU) 2015/566
- Community code relating to medicinal products for human use regarding ATMPs: Directive2009/120/EC
- Use of bovine serum in the manufacture of human biological medicinal products: Guideline CHMP/BWP/457920/2012 Rev. 1
- Good distribution practice (GDP) applies for medical products (Commission guideline 2013/C 343/01).
Detailed guidelines on good clinical practice specific to ATMPs, GCP for ATMPs (EudraLex), and investigational medicinal products for human use, as well as the requirements for authorising the manufacture or import of such products: GCP Directive2005/28/EC