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Regulatory: ATMPs and the EUTCD

The Potential of Advanced Therapies

Rapid and cutting-edge developments in the field of biotechnology, cell biology, (bio)material science and regenerative medicine have led to the development of what are now defined as advanced therapy medicinal products (ATMPs). They offer the opportunity for the treatment of diseases and injuries that currently have limited or no effective therapeutic options.

ATMPs are medicinal products for human use and include gene therapy, somatic cell therapy and tissue engineering products.They are regulated under the new consolidated regulatory framework for advanced therapies. Human tissue and cells that are a constituent of an ATMP must also comply with the requirements of the European Union Tissue and Cells Directive (EUTCD) with respect to their donation, procurement and testing.This article outlines a regulatory perspective of the ATMP regulation and the embedded EUTCD. In addition, the complexity and clinical challenges of ATMPs will be discussed.

Advanced Therapy Medicinal Products

The ATMP regulation was drafted to control and improve patient access to novel cell-based medicinal products, as well as to ensure the safety and quality of these products. It clarifies the regulatory position, marketing authorisation and pharmacovigilance requirements for three specific categories of ATMPs: gene therapy medicinal products, somatic cell therapy products and tissue engineered products.

ATMP Definitions
Gene and somatic cell therapy products have been defined in Part IV of Annex I to Directive 2001/83/EC.Gene therapy medicinal products (GTMPs) aim to transfer genes to cells and, through their subsequent expression, to achieve a therapeutic effect in patients. Somatic cell therapy medicinal products (SCTMPs) are cell-based products intended to prevent, treat or diagnose a disease and achieve their principle mode of action via pharmaceutical, metabolic or immunological means.

Tissue engineered products (TEPs) have only been recently defined in the ATMP regulation.They are medicinal products intended for the structural regeneration, repair or replacement of human tissue or tissue defects.TEPs contain ‘engineered’ cells or tissue, meaning they have been subjected to substantial manipulation and/or that they are not intended for the same essential function in the recipient as in the donor. Appendix I to the ATMP regulation provides an overview of processing steps that are not considered substantial manipulation. Cell centrifugation and separation, for example, are considered non-substantial manipulations, whereas cell expansion is not. Examples of TEPs include tissue engineered skin, cartilage and heart valves.There are similarities between TEPs and SCTMPs in that the origin of the cells for both products may be autologous, allogeneic or xenogenic. In addition, the same substantial manipulation and essential function principles apply.

Combined ATMPs are also defined in the regulation.They comprise viable cells and, as an integral part, a medical device or active implantable device within the meaning of Directive 93/42/EEC or 90/385/EC, respectively. Importantly, the devices must conform to the applicable essential requirements of the Medical Device Directives.

Regulatory Framework for ATMPs

The ATMP regulation is an amendment to Directive 2001/83/EC on medicinal products for human use.Although there are small differences when compared to the classical pharmaceutical regime, the general marketing authorisation requirements for drug products will have to be followed.The main aspects of the advanced therapy regulation are the centralised marketing authorisation, the establishment of the Committee for Advanced Therapies (CAT), the hospital exemption ruling, specific GMP regulations, incentives for small and medium sized enterprises (SMEs) and post-authorisation vigilance systems. The CAT, Hospital Exemption, and specific GMP aspects will be outlined in greater detail below.

Committee for Advanced Therapies
This committee at EMA is comprised of multidisciplinary scientific experts representing all EU member states as well as patient and medical associations (1). CAT’s main responsibilities include the primary evaluation of the quality, safety and performance of ATMPs in marketing authorisation applications (MAA) and providing scientific advice. The scientific advice procedure offers the opportunity to obtain valuable feedback on the ATMP classification as well as on the required and proposed preclinical and clinical development programmes to demonstrate quality, safety and performance of the ATMP.

Hospital Exemption
This relates to ATMPs which are exempted from the centralised marketing authorisation procedure. It was included in the regulation in recognition of the small scale and developmental nature of cell-related activities within hospitals.The exemption applies to ATMPs which are prepared on a non-routine basis, according to specific quality standards, and used within the same member state in a hospital in accordance with a medical prescription for an individual patient. As such, it is basically analogous to the ‘Magisterial Formula’ for classic medicinal products for human use.

ATMPs are regulated at EMA level.Member states, however, are responsible for the implementation of the hospital exemption. To date, only a few member states have taken a proactive role and published guidance for the hospital exemption including the UK (MHRA) and the Netherlands (Dutch Health Care Inspectorate). However, under no circumstances should the hospital exemption be considered to be a facilitated pathway for bringing ATMPs to the clinic. Competent authorities of the member states need to ensure that national pharmacovigilance and traceability requirements are met. In addition, specific quality standards for ATMPs under the hospital exemption are equivalent to those for which a centralised procedure would be mandatory.These include, but are not limited to, GMP manufacturing and product release by a qualified person. Furthermore, it should be noted that the hospital exemption is not intended for the initiation of clinical trials.Treatments of patients under this exemption are case studies and will not replace the need for clinical studies should a centralised marketing authorisation be considered.

GMPs
ATMPs need to be manufactured in accordance with the GMP guidelines for human medicinal products, as laid down in Directive 2003/94/EC. Satisfactory consistency and uniformity of the manufacturing process of the final ATMP product will add to the clinical performance of ATMPs. Annex 2 of the EU Guidelines for Good Manufacturing Practices for Medicinal Products for Human and Veterinary Use (Eudralex Vol 4) has been updated to include GMP specific to ATMPs.The annex further recognises the inherent variability and increased risks for microbial contamination and transfer of pathogens associated with biological culturing processes and materials. Quality risk management principles are thus of importance in the development of the manufacturing control strategy.Where animal derived materials are used during manufacture, the ATMPs must comply with the guidance to minimise the risk of transmitting transmissible spongiform encephalopathies (TSE).

European Union Tissue and Cells Directives

The EUTCD provide a harmonised framework for the regulation of the quality and safety of human tissues and cells across Europe. It is intended to safeguard public health, prevent the transmission of infectious diseases and facilitate the exchange of human tissues by ensuring the same high quality and safety across the EU.The EUTCD is comprised of the parent Directive 2004/23/EC and the two implementing technical Directives 2006/17/EC and 2006/86/EC which accompanied it. Specifically, these Directives set the standards for the quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. In addition, they provide a system for the traceability of tissues from donor to patient, including the requirements for tissue establishment accreditation for aforementioned tissue activities.Directive 2004/23/EC came into force in April 2006 and was transposed into national law by majority of the Member States in 2008. National law, however, allows for the inclusion of additional local requirements, such as those dealing with serological testing, making it a nonuniform interpretation of the Directive.

Overlap ATMP and EUTCD

There is an overlap between the ATMP regulation and the EUTCD with respect to human tissues and cells.Where an ATMP contains human tissue or cells, the EUTCD applies in relation to the donation, procurement and testing of the starting human tissue and cells. Aspects such as processing, preservation, final product release, storage and distribution are covered by the ATMP regulation. Figure 1 provides an overview of the applicable regulatory framework for cell-based products for human use.

Traceability
Each ATMP should be traceable from tissue donation to the recipient and vice versa. The product should thus be traceable through the sourcing, testing, manufacturing, packaging, storage, transport to the hospital and final administration to the patient or disposal. Both the ATMP and the EUTCD cover a traceability system and the traceability system for ATMPs must be complementary and compatible with that of the EUTCD. A schematic overview of the regulatory framework for ATMPs is provided in Figure 2.

Complexity and Challenges of ATMPs

Complexity
While advanced therapies have been categorised as medicinal products, it is recognised that the conventional medicinal product authorisation requirements are not always applicable to ATMPs due to its added complexity and diverse structural and biological properties. Cells are complex and labile active substances.They are dependent on – and reactive to – their exposed micro-environment. Aspects like cell heterogeneity, stability, identity, purity, viability, potency, persistence, sterility and potential tumourgenicity need to be addressed. With combined ATMPs, a particular emphasis should also be given to matrix biodegradation aspects and matrix-cell interactions.

Clinical Challenges
For the clinical development of ATMPs, the same requirements as for medicinal products generally apply. Aspects like pharmacokinetics, mechanism of action studies, dose finding studies and randomised clinical trials should be performed in accordance to Directive 2001/20/EC. However, classical dose finding studies to define the clinical target dose may not be applicable and require alternative approaches to establish at least a minimally effective dose. Conventional ADME studies are usually not relevant. In addition, as a result of specific biological characteristics of cell-based products, alternative approaches to Phase 1 to Phase 3 trials may be required. Furthermore, appropriate comparator therapies or products may not always be available (1).

When the ATMP that is being used in clinical trials contains human tissue or cells, the donor requirements (involving consent, eligibility of donors, compensation, data protection and confidentiality, selection, evaluation and procurement) outlined in the EUTCD should be met. As well as ensuring compatibility of the traceability systems of both the ATMP regulation and EUTCD, the GCP requirements for accountability of investigational medicinal products also needs to be incorporated. Requirements for pharmacovigilance are laid down in Directive 2001/20/EC, Regulation (EC) 726/2004 and 1394/2007 and the GCP guidelines for ATMPs. Safety issues of particular concern include adverse events related to the product application procedure or product failures, including those due to medical devices as part of combination ATMPs, suspected or confirmed infections, and unexpected reactions.

Clinical study concepts are particularly challenging as clinical efficacy or safety might only be apparent after several years. Measurement of clinical outcomes and long-term safety issues such as infections, immunogenicity and malignant transformations therefore need to be considered. In case of combined ATMPs, the durability of the medical device and its influence on the cells must also be addressed. A particular challenge may be the functional integration and/or remodelling of the cell-based product with the host tissue; ideally, these products should persist in the recipient to achieve a sustained therapeutic effect. Follow-up of efficacy and reporting of adverse reactions are thus crucial aspects. Depending on the nature of the ATMP and its risks, follow-up may even be necessary after the end of the clinical trial to monitor specific safety issues. Furthermore, the timely sampling and testing to demonstrate compliance with serological, (micro)biological or final product requirements is often an issue due to the limited stability of cell-based products and warrants the development and validation of rapid test methods. It frequently requires the conditional release of ATMPs and their starting tissue alike. Clearly, consultation with regulatory authorities such as CAT is recommended to establish the clinical development programme.

Risk Based Approach
Due to the inherent complexity of ATMPs, it is the riskbased approach that determines to a substantial degree the nature and extent of the quality and (pre)clinical data to be included in the MAA. Risk factors to be considered include the nature and indication of the ATMP product, route of administration, starting dose, origin of cells, phenotype stability, initiation of immune response, level of cell manipulation as well as the combination with biomolecules or structural (bio)materials. Long-term safety issues such as infections, immunogenicity and device durability for combination ATMPs should also be considered. Raw materials sourced directly or indirectly (feeder cells) from animal material may introduce adventitious agents in the ATMP and alternatives should be evaluated. Furthermore, the long-term functionality and implementation of relevant safety endpoints in the clinical trials needs to be addressed. The available safety, quality and efficacy data should finally enable a favourable risk-benefit assessment by CAT to recommend towards marketing authorisation approval.

Conclusion

Advanced therapy products offer enormous potential for the treatment of a wide range of diseases where traditional medicines have proven unsuccessful. The consolidated regulatory framework for ATMPs will unequivocally contribute to the availability of safe and effective ATMPs on the EU market. The establishment of dedicated committees, working parties and scientific advice procedures has facilitated interactions between EMA and the industry. Various incentives will stimulate market introduction of advanced products by SMEs. In spite the promising potential of ATMPs, however, few marketing authorisation applications have been submitted with only one approval to date (an autologous cultured chondrocytes product for cartilage repair). CAT recognises that the traditional regulatory framework for human medicines does not fully address the requirements for ATMPs. As such, in November 2010 it presented a five-year work programme aimed at increasing the number ATMP approvals in which training, early dialogue and increased accessibility to the regulatory framework for SMEs, academia and hospitals play a central role.

Challenges, nevertheless, will remain. While the number of CAT scientific recommendations on ATMP classification is increasing, and thus at least partially providing precedents, borderline ATMPs will remain. Since member states are responsible for the implementation of the hospital exemption, differences in interpretation of the competent authorities are likely to occur. In addition, the hospital exemption lacks specificity in its associated requirements and definitions such as on ‘non-routine use’. Constant monitoring and communication between member states will therefore be key to ensure similar requirements at the EU level for both industry and hospitals, and especially to avoid companies from diverting their clinical trial strategies and activities to a certain member state.

As much as the field of advanced therapies is dynamic, so is its regulatory framework. Future amendments to directives can be expected to further clarify ATMP specifics and to keep abreast of new and emerging developments in the advanced therapy area. It will broaden the scope of ATMPs and offer the opportunity to fully exploit the potential of advanced therapies.

ATMP Regulatory Framework

When human tissue and cells are used for the manufacturing of ATMPs, the European Directive for Tissue and Cells (2004/23/EC) is applicable as far as donation, procurement and testing is concerned. These aspects are covered by the technical implementing Directive 2006/17/EC of the EUTCD. Regulation (EC) 1394/2007 is at the heart of the regulatory ATMP framework. It is an amendment to Directive 2001/83/EC on human medicinal products for human use and establishes the requirements for the market authorisation, supervision and pharmacovigilance of ATMPs. Tissue engineered products and combined ATMPs are newly defined in this regulation.

Regulation (EC) 726/2004 provides the legal basis for the EMA centralised procedure. It established the Committee for Medicinal Products for Human Use within EMA and outlines the centralised marketing authorisation, supervision and pharmacovigilance of medicinal products. Instead of the centralised procedure, applicants may also seek an orphan designation for the ATMP product to treat or prevent a rare disease in the EU in accordance with Regulation (EC) No 141/2000. ATMPs need to be manufactured in accordance with GMP as laid down in Directive 2003/94/EC. Volume 4 of the Eudralex will in the future contain an updated Annex 2 to cover GMP specific to ATMPs. ATMPs may include the use of blood derived components. Requirements for the suitability of human donors and the testing of donations of starting materials for plasma-derived medicinal products are laid down in Directive 2002/98/EC and its implementing directives. This Directive thus ensures the safety and quality of blood and blood components used in human medicinal products.

Directive 2003/63/EC is an amendment to Directive 2001/83/EC and provides a revision for the marketing authorisation application dossier requirements (Part IV of Annex I to 2001/83) to include ATMPs and specifically gene therapy and somatic cell therapy medicinal products. A further amendment of definitions and authorisation requirements for ATMPs is laid down in Directive 2009/120 (Part IV of Annex I to 2001/83) to also include tissue engineered products and combined ATMPs. Regulation (EC) 668/2009 implements the ATMP Regulation with respect to the requirements for the certification of quality and non-clinical data for SMEs. Combined ATMPs are defined in the ATMP regulation as ATMPs containing as an integral part a medical device or active medical device. For these combined products, the medical device and the active medical device need to conform to the Essential Requirements of Directives 93/42/EEC and 90/385/EC, respectively.

Finally, the performance of clinical studies with ATMPs needs to comply with Directive 2001/20/EC on good clinical practice for medicinal products for human use. Detailed guidelines have been developed to specifically address issues related to good clinical practice for trials involving ATMPs. 

Reference

  1. CAT, Challenges with advanced therapy medicinal products and how to meet them, Nat Rev Drug Discov 9(3): pp195-201, 2010

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Jeroen Pieper has well over 10 years of experience in the life science and biomedical industry. He is specialised in research, product development and regulatory affairs in the areas of medical devices, orthobiology and advanced therapies. Jeroen acquired his PhD in Medical and Life Sciences at the University Medical Centre Radboud, Nijmegen, Netherlands. Previously, he has held Senior Scientist, Project Manager and Manager R&D positions at IsoTis and Integra OrthoBiologics. He is currently a Senior RA/QA consultant at Signifix BV, focusing on US and EU regulatory strategies for borderline medical devices, combination products and advanced therapy medicinal products.
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