Explanatory Memorandum to COM(2005)567 - Advanced therapy medicinal products - Main contents
Please note
This page contains a limited version of this dossier in the EU Monitor.
| dossier | COM(2005)567 - Advanced therapy medicinal products. |
|---|---|
| source | COM(2005)567  |
| date | 16-11-2005 |
Contents
- The current picture
- Advanced therapies: a coherent ensemble
- The current regulatory gap and its implications on public health
- JUSTIFICATION
- Scope, legal basis and procedure
- Legal basis and procedure
- Subsidiarity and proportionality
- Legislative and administrative simplification
- Consistency with other Community policies
- Outside consultation
- Evalu ation of the proposal: Impact Assessment
- PRESENTATION: KEY ELEMENTS OF THE PROPOSAL
- Scope
- Marketing Authorisation Procedure
- Committee for Advanced Therapies (CAT)
- Evaluation procedure
- Marketing Authorisation Requirements
- Technical requirements
- Other requirements
- Post-authorisation issues
- Ethical aspects
- Voluntary and unpaid donation
- Competitiveness aspects
The advancement of science in the fields of biology, biotechnology and medicine, has fuelled the development of promising gene- and cell-based approaches for the prevention and treatment of diseases or dysfunctions of the human body. A number of gene therapy and somatic cell therapy products are already being tested at clinical level for the treatment of inherited diseases, cancer, diabetes, Parkinson's disease and other neurodegenerative disorders.
In addition, a new biotechnology area has emerged: tissue engineering, which combines various aspects of medicine, cell and molecular biology, materials science and engineering, for the purpose of regenerating, repairing or replacing human tissues. Current applications of this nascent field of “regenerative medicine” include treatment for skin, cartilage and bone diseases or injuries. More complex products are already in development, and could reach the Community market in a near future i.
These three kinds of advanced therapies (gene therapy, somatic cell therapy, and tissue engineering) are expected to have a major impact on public health, by improving the quality of life of patients and changing medical practice significantly. Moreover, they constitute a coherent ensemble insofar as they share several key scientific, regulatory and economic features:
- They are based on complex, highly innovative manufacturing processes. The specificity of the product precisely lies in the process.
- Regulatory and scientific expertise for the evaluation of advanced therapies is scarce: pooling of that expertise at Community level is therefore essential to ensure a high level of public health protection.
- Traceability from the donor to the patient, long-term patient follow-up and a thorough post-authorisation risk management strategy are crucial aspects to be addressed when evaluating advanced therapies.
- Advanced therapy products are usually developed by innovative small and medium-sized enterprises, highly-specialised divisions of larger operators in the Life Science sector (biotechnology, medical devices and pharmaceuticals), hospitals or tissue banks. They are subject to rapid and often radical innovation.
Despite these common elements, the regulatory picture for advanced therapies remains incomplete. In particular, while products intended for gene and somatic cell therapy have been classified as medicinal products and regulated as such in the Community i, tissue-engineered products currently lie outside of any Community legislative framework. This leads to divergent, national approaches as to their legal classification and authorisation, thereby impairing the free movement of tissue engineered products in the Community, and hindering patients’ access to these innovative therapies.
There is therefore a need to bridge the regulatory gap by addressing all advanced therapies -including in particular tissue engineering- within a single, integrated framework, fully taking into account their scientific and technical characteristics as well as the specificities of the economic operators concerned.
Objectives
The overall policy objective is to improve patients’ safe access to advanced therapies by increasing the research, development and authorisation of gene therapy, somatic cell therapy, and tissue engineered products.
More specifically, the main objectives are:
- To guarantee a high level of health protection for European patients treated with advanced therapy products;
- To harmonise market access and to improve the functioning of the internal market by establishing a tailored and comprehensive regulatory framework for the authorisation, supervision and post-authorisation vigilance of advanced therapy products;
- To foster the competitiveness of European undertakings operating in this field;
- To provide overall legal certainty , while allowing for sufficient flexibility at technical level , in order to keep the pace with the evolution of science and technology.
Scope
The proposal covers all advanced therapy products (gene therapy medicinal products, somatic cell therapy medicinal products, and tissue engineered products) falling within the global scope of the pharmaceutical legislation (Article 2 i of Directive 2001/83/EC i), i.e. intended to be placed on the market in Member States and either prepared industrially or manufactured by a method involving an industrial process.
The proposal is based on Article 95 of the EC Treaty. Article 95, which prescribes the co-decision procedure described in Article 251, is the legal basis for achieving the aims set out in Article 14 of the Treaty, which includes the free movement of goods (Article 14(2)), in this case advanced therapy medicinal products for human use.
While taking account of the fact that any regulation on the manufacture and distribution of medicinal products must be fundamentally aimed at safeguarding public health, this aim must be achieved by means that do not impede the free movement of medicinal products within the Community. Since the Amsterdam Treaty came into force, all legislative provisions adopted by the European Parliament and the Council in this field have been adopted on the basis of that Article, since the differences between the national legislative, regulatory and administrative provisions on medicinal products tend to hinder intra-Community trade and therefore directly affect the operation of the internal market. Action to promote the development and authorisation of advanced therapy medicinal products is hence justified at a European level, with a view to preventing or eliminating these obstacles.
Given the particularities of advanced therapy products, it is essential to provide a robust and comprehensive regulatory framework, which is directly applicable in all Member States. A Regulation is therefore considered as the most appropriate legal instrument. It should indeed ensure uniform and timely application of the provisions, for the benefit of all actors, including patients, industry and other stakeholders involved in this emerging sector. In addition, the ‘centralised’ marketing authorisation procedure is also laid down in a Regulation (Regulation (EC) No 726/2004) i .
The proposal builds on the experience gained with the existing regulatory framework for medicines in Europe. On the basis of the available evidence, it is concluded that it is unlikely that the current public health issue regarding advanced therapy medicinal products, in particular tissue engineered products, will be resolved in the EU until a specific legislative system is put in place.
Community action allows the best possible use of the instruments set up in Community legislation (in particular in the pharmaceutical sector) to complete the internal market. In addition, authorisation and availability of innovative therapies is a Europe-wide issue. Nevertheless, Member States will have a crucial role in the fulfilment of the proposal’s objectives.
The proposed rules aim at harmonising an area in which application of existing Community legislation and additional national measures have proven insufficient. However, the proposal will create additional regulatory requirements only when this appears necessary to achieve the intended objectives. In this respect, the scope of the proposal has been carefully designed and discussed with all stakeholders, in order to avoid imposing an unnecessary regulatory burden on certain economic operators ( e.g. hospitals, universities and research community). The proposal does not go beyond what is necessary to achieve the objectives pursued.
The proposed approach is based on a single, integrated regulatory framework for all advanced therapy products. The aim of this strategy is to avoid any re-drafting of already-existing and applicable concepts, while focusing exclusively on the key regulatory and technical specificities of the field.
The approach is based on 3 levels:
1. A Regulation on Advanced Therapy Medicinal Products, which lays down tailored regulatory principles for the evaluation and authorisation of these products: marketing authorisation procedure, post-authorisation vigilance, traceability, etc. Such Regulation builds on already-existing legislation, in particular:
2. Directive 2004/23/EC, which lays down quality and safety standards in respect of human tissues and cells i . It is important to bear in mind that these standards would apply to the donation, procurement and testing of human tissues and cells contained in advanced therapy products;
3. Regulation (EC) No 726/2004, which establishes the so-called ‘centralised procedure’ and the role/structure of the European Medicines Agency (EMEA, hereinafter “the Agency”);
4. Directive 2001/83/EC on medicinal products;
5. Council Directive 93/42/EEC concerning medical devices i and Council Directive 90/385/EEC on active implantable medical devices i.
6. Technical requirements. It is well acknowledged that advanced therapy products are neither medical devices nor conventional medicines: therefore, the technical requirements necessary to demonstrate their quality, safety and efficacy ( e.g. the type of pre-clinical and clinical data required) will be highly specific, and should depend on the level of risks associated with these products. As regards gene and somatic cell therapy products, those high-level requirements are already laid down in Annex I to Directive 2001/83/EC i (which is amendable by ‘comitology’) and further complemented by guidelines i. In order to provide for the same level of flexibility, it is proposed to follow a similar approach regarding tissue engineered products, i.e. to lay down the main technical requirements that are specific to these products in Annex I to Directive 2001/83/EC, and to further complement them with guidelines.
7. Detailed guidelines. As for gene and somatic cell therapy products, it is proposed to establish detailed technical guidance for tissue engineered products through guidelines. The fact that expertise is still scarce in this fast-growing, fast-evolving area highlights the importance of extensive and thorough consultation with all interested parties for the drafting of these guidelines.
It is important to note that the current, existing requirements for gene therapy medicinal products and somatic cell therapy medicinal products are not affected by the proposal. The only main change related to these products concerns the introduction of a new Committee (Committee for Advanced Therapies).
As described in Section 2.4, the proposed Regulation is consistent with Community policy in the field of public health ( e.g. quality and safety of human tissues and cells) and medical devices. Consistency will also be sought with other activities related to health and consumer protection, as well as in the area of research and development.
All interested parties (patients associations, industry, hospitals, research community…) have been widely consulted on this proposal, through various means: internet-based consultation, workshops, bilateral meetings, interviews. Details on the consultations conducted by the Commission are included in the Impact Assessment attached to the proposal.
The proposed Regulation has been the subject of a Commission Impact Assessment, which is attached to the proposal .
Definitions and Scope
Definitions
Advanced therapy products are defined as medicinal products being either:
- gene therapy medicinal products, as defined in Annex I to Directive 2001/83/EC; or
- somatic cell therapy medicinal products, as defined in Annex I to Directive 2001/83/EC; or
- tissue engineered products, as defined in the proposal.
Products which do not qualify as advanced therapy medicinal products, even if based on or consisting of tissues and cells, will not be regulated under this framework.
It must be acknowledged that even the best possible definition of advanced therapy medicinal products may not fully eliminate the risk of grey areas, given the highly innovative and rapidly evolving nature of the advanced therapies sector. To address this, the proposal foresees the possibility for applicants to request a scientific recommendation from the EMEA on the classification of any product based on cells or tissues, with a view to resolving borderline issues.
Within the Community legislation on pharmaceuticals, products intended for gene therapy and somatic cell therapy are already classified as biological medicinal products. Tissue engineered products are also considered from a legal viewpoint as medicinal products for at least one of the following reasons:
- They are presented as having properties for treating or preventing disease in human beings;
- They are used in or administered to human beings with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action;
- In accordance with the jurisprudence of the European Court of Justice (ECJ) on the matter, they are capable of having a significant effect on the actual functioning of the body i.
Furthermore, the existence of health risks is traditionally one of the criteria employed by the ECJ for classifying a product as medicinal i. It follows from the aim of health protection pursued by the Community pharmaceutical legislation that products presenting potential health risks (as is clear for advanced therapy medicinal products) should be covered by the rigorous requirements of that legislation in case of doubt as to their classification i.
However, this does not mean that advanced therapy medicinal products will be subject to the same technical requirements as ‘conventional’ medicines. On the contrary, the type and amount of pre-clinical/clinical data necessary to demonstrate their quality, safety and efficacy should be highly specific, fully taking into account their biological, functional and structural characteristics.
The proposal addresses all advanced therapy medicinal products falling within the general scope of the Community legislation on medicinal products i, i.e. “ intended to be placed on the market in Member States and either prepared industrially or manufactured by a method involving an industrial process” . Products which are both prepared in full and used in a single hospital, in accordance with a medical prescription for an individual patient, are excluded from the scope of the proposal. Detailed examples related to this aspect of the proposal are provided in the Impact Assessment.
General principles
Experience gained in the area of modern biotechnology, where scientific expertise is often limited, highlights the necessity to establish centralised procedures for the authorisation of biotechnology-derived therapeutic products. This pooling of expertise from all Member States enables to guarantee a high level of scientific evaluation across the European Union, and thus to preserve the confidence of patients and medical practitioners in their evaluation. This is all the more important for advanced therapy medicinal products, which often result from highly innovative, not-yet-well-established processes and technologies.
The principle of a compulsory Community marketing authorisation is already established for gene therapy medicinal products and somatic cell therapy medicinal products resulting from any biotechnology process referred to in the Annex to Regulation (EC) No 726/2004. It is proposed to apply the same principle of a compulsory, ‘centralised’ Community marketing authorisation to all advanced therapy medicinal products, including tissue engineered products, in order to ensure the effective operation of the internal market in the biotechnology sector, and to enable undertakings to benefit from direct access to the Community market. As for other ‘centrally-authorised’ products, the scientific evaluation would be carried out by Member States experts, within the network coordinated by the EMEA.
Within the EMEA, the Committee for Medicinal Products for Human Use (CHMP) holds the responsibility for drawing up the Agency’s opinion on any scientific matter concerning the evaluation of medicinal products for human use, and for ensuring consistency in the risk-benefit assessment of all categories of medicinal products.
Nevertheless, the assessment of advanced therapy medicinal products often requires very specific expertise, which goes beyond the traditional pharmaceutical field and covers borderline areas related to other sectors, such as biotechnology or medical devices. For this reason, it is proposed to create, within the EMEA, a Committee for Advanced Therapies (CAT), which the CHMP should consult on the assessment of data related to advanced therapy medicinal products, whilst retaining responsibility for the final scientific opinions issued.
Thus, the main task of the CAT will be to advise scientifically on any data related to advanced therapy medicinal products.
The CAT will work in close cooperation with, and under the general supervision of, the CHMP. A clearly-defined procedure, with strict deadlines, is established in order to avoid any delays in the marketing authorisation of these products. The composition of this new Committee should reflect the multidisciplinary nature of the field and ensure appropriate coverage of the scientific areas relevant to advanced therapies. Patient associations and medical surgeons with scientific experience of advanced therapy medicinal products should also be represented.
The CHMP will consult the CAT for any evaluation of advanced therapy medicinal products. A number of mechanisms are foreseen in the proposal to avoid divergent opinions between the CHMP and the CAT. The CAT may also be consulted for other medicinal products which, although not classified as advanced therapy medicinal products, may require specific, CAT-related expertise for the evaluation of their quality, safety or efficacy.
General principles
Broadly speaking, advanced therapy medicinal products are biotechnology-derived products. They should therefore be subject to the same overarching regulatory principles as other types of biotechnology-derived medicines, such as products developed by means of recombinant DNA technology.
‘Conventional pharmaceutical’ technical requirements are not directly relevant for advanced therapy medicinal products, due to their specific structural, functional and biological properties. Special considerations related to the viability or proliferation of cells, to the clinical circumstances where the products are used, or to their particular mode of action, may be required.
In respect of gene and cell therapy, the type and amount of quality-related, pre-clinical and clinical data necessary to demonstrate the quality, safety and efficacy of the products are already laid down in Annex I to Directive 2001/83/EC and through EMEA guidelines.
It is proposed to follow the same approach for tissue engineered products: to amend Annex I to Directive 2001/83/EC in order to lay down technical requirements that are specific to these particular products, and to further complement those requirements with guidelines, drawn up in consultation with all interested parties.
Directive 2004/23/EC lays down standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. As for human tissues and cells contained in advanced therapy medicinal products, Directive 2004/23/EC should apply only as far as donation, procurement and testing are concerned, since the further aspects are regulated by the proposed Regulation.
Advanced therapy medicinal products may also include, as an integral part of the product, medical devices or active implantable medical devices, as defined in Directive 93/42/EEC and Directive 90/385/EEC, respectively. In that case, the ‘device’ part should meet the essential requirements laid down in those Directives. The EMEA, through the CAT, would provide a ‘one-stop shop’ system, by evaluating all aspects (including ‘device’ aspects) of the product. However, if the device part has already been evaluated and certified by a notified body, this certification should be fully taken into account by the CAT for the final evaluation of the concerned product.
By their very nature, advanced therapy medicinal products can stay in the human body for a longer time than ‘conventional’ medicines. Thus, long-term patient follow-up and post-authorisation monitoring are crucial aspects of these products. It is hence essential to ensure, where justified on public health grounds, that the applicant puts in place a suitable risk management system, in order to address these critical issues.
Likewise, a system allowing complete traceability of the patient, as well as the product and its starting materials, is essential to monitor the safety of advanced therapy medicinal products in a long-term perspective, and should therefore be required. This traceability system should be compatible with the requirements laid down in Directive 2004/23/EC as regards the donation, procurement and testing of human tissues and cells, including the aspects related to data protection, confidentiality, and anonymity of both donor and recipient.
General principles
The proposed Regulation respects fundamental human rights and observes the principles reflected in the Charter of Fundamental Rights of the European Union i. It also takes into account, as appropriate, the Convention for the protection of human rights and dignity of the human being with regard to the application of biology and medicine: Convention on human rights and biomedicine (‘Oviedo’ Convention i).
The issue of embryonic stem cells was extensively debated during the adoption of the Directive on the quality and safety of human tissues and cells (Directive 2004/23/EC). In this context, the legislators have recognised that there is, to date, no consensus among Member States upon which harmonised decisions at EU level could be taken on the use or prohibition of embryonic stem cells. Thus, regulating such use or prohibition should remain a national responsibility. If, however, any particular use of these cells is authorised in a given Member State, it should be ensured that all provisions necessary to protect public health and guarantee respect for fundamental rights are effectively applied, in a harmonised way throughout the Community i.
It is suggested to follow the same logic in this proposal. The proposed Regulation does not interfere with national legislation prohibiting or restricting the use of any specific type of human or animal cells, or the sale, supply or use of medicinal products based on such cells. Explicit provisions have been introduced in the proposal to clarify this point.
As outlined in Directive 2004/23/EC, human tissue- and cell- based products should be founded on the philosophy of voluntary and unpaid donation, anonymity of both donor and recipient, altruism of the donor and solidarity between donor and recipient. Voluntary and unpaid tissue and cell donations are a factor which may contribute to high safety standards for tissues and cells, and hence to the protection of human health.
The fact that advanced therapy medicinal products fall under the overall regulatory framework for medicinal products implies that all already-existing incentives and competitiveness-related provisions of this framework directly apply to these products. This includes:
- Direct and harmonised access to the Community market through a Community marketing authorisation, without prejudice to national prohibitions as referred to in section 3.5;
- A harmonised data protection period (the so-called ‘8+2+1’ rule) i;
- The possibility to be designated as an orphan medicinal product i;
- The possibility of an accelerated assessment procedure i;
- The option to get conditional marketing authorisations or marketing authorisations in exceptional circumstances i;
- Specific financial incentives and administrative assistance in respect of small and medium-sized enterprises (SMEs) i.
Besides, the proposal foresees additional, specific incentives:
- a 90% fee reduction for the provision of scientific advice by the EMEA in respect of advanced therapies, regardless of the economic size of the applicant;
- A system of early evaluation and certification of quality and non-clinical safety data by the Agency, independently of any marketing authorisation application, for SMEs developing advanced therapy medicinal products. This system is designed to help SMEs which focus on the early development aspects, but do not conduct the subsequent clinical trials themselves. The certification of ‘early-development’ data by the Agency should provide an important selling argument to those companies who wish to license out their technology to bigger undertakings.