TERMIS PAP: Session 3 — Regulation of Advanced Therapeutic Medicinal Products (ATMPs) in Europe
Directives and Regulations
The legal framework for market approval in Europe is provided by EU directives and regulations. This legal framework tries to categorise medical/medicinal products, devices and procedures into their own distinct areas with their own separate directives and regulatory agencies. However, in reality there is often an overlap, resulting in a situation where more than one directive and regulatory agency may apply to your product. In these cases, more often than not, the directives related to medicines take precedence.
As always, there are some exceptions: For example, a medical device that may contain some small amount of medicinal product that only has an ancillary role would go (mainly) under the medical device directives and regulations and not the medicinal ones.
When it comes to Advanced Therapeutic Medicinal Products (ATMPs), the category that regenerative medicine and tissue engineering products fall under, the following directives and regulations are relevant:
There are two fundamental pieces of regulation:
- The European Tissue and Cells Directive (EUTCD) [Directive 2004/23/EC and implementing directives]
- Advanced Therapy Medicinal Product (ATMP) Regulations (1394/2007 and 668/2009)
Further important regulations:
3. Medicinal Products Directive (2001/83)
4. Medicinal Products Regulation (726/2004)
May be relevant:
5. Medical Devices Directive (93/42)
6. Active Implantable Medical Devices Directive (90/385)
7. GMO Release Directive (2001/18)
These are available from the Eur-Lex website: http://eur-lex.europa.eu/homepage.html
The European Tissue and Cells Directive (EUTCD) [Directive 2004/23/EC and implementing directives]
This EU directive sets the quality and safety of tissues and cells that are used in the clinic during the path from acquisition through testing, storage, and distribution to grafting.
The framework is set out in Directive 2004/23. The technical details are described in Directive 2006/17 and 2006/86.
Tissues and cells used as an autologous graft within the same surgical procedure are exempt from under the EUTCD (Article 2(2)(a) Directive 2004/23).
Advanced Therapy Medicinal Product (ATMP) Regulations (1394/2007 and 668/2009) apply across the EU and whole European Economic Area.
There is a continuum between medical devices and medicinal products. Since the 90s it became apparent that some medical products might fall between the two when it comes to mode of action. This is what the ATMP Regulations were developed to govern.
The ATMP regulations do not derogate from the basic principles laid down in the EUTCD. Therefore, all the regulation described in the EUTCD regarding quality and safety remains intact. However, processing, storage and distribution of ATMPs are defined by the ATMP regulations.
What are ATMPs from the perspective of regulation?
As defined by the Medicinal Products Directive (2001/83)
The following products are defined to fall under the category of advanced therapeutic medicinal product:
Gene therapy medicinal products (GTMPs): Including both genetically-modified cells (Ex vivo GTMP) and “directly application” where the gene modifying active substance is injected, i.e. active substance consists of a recombinant nucleic acid/virus (In vivo GTMP). The speciation is independent of whether viral or nonviral vectors are used.
Vaccines against infectious diseases are not GTMPs.
Gene therapy products are GMOs independent of whether in vivo or ex vivo. This is why the GMO Directive 2001/18 is relevant. Don’t be alarmed by this. The key thing is to create a risk management plan and to seek further advice.
Somatic cell therapy medicinal products: A biological medicinal product that contains or consists of cells that have been subject to substantial manipulation. For guidelines on what qualifies as “substantial manipulation” please see the Medicinal Products Directive (2001/83). Cutting, grinding, shaping, centrifugation, sterilization, freezing, filtering, etc. do not qualify as “substantial”.
Tissue engineered products: A product that contains or contains engineered cells or tissues with a view to regenerating, repairing or replacing human tissue. When is a tissue “engineered”? It has to have been subject to substantial manipulation, and it is not intended to fulfil the same essential function or functions in the recipient as in the donor.
It is important to note that a product may fall under one of these categories “scientifically” in the opinion of their creators, but it may not do so legally. It is important to seek advice from the Committee for Advanced Therapies (more information below) if in any doubt.
Mononuclear cells used in myocardial infarction are an ATMP.
Coronary artery bypass graft (CABG) surgery is not an ATMP.
Cryo-preserved adipocytes used as a lipofiller are not an ATMP.
The relevant regulatory bodies
Committee for Advanced Therapies
A multidisciplinary expert body that was created to assess ATMP products and follow scientific developments in the field. It is a scientific rather than a legislative body. It provides scientific recommendations on the regulatory classification on the ATMP in question: Is it an ATMP?
The classification procedure has no fee; it isn’t mandatory; and is open to all applicants. The procedure takes 60-days, but is often shorter.
Committee for Healthcare Medicinal Products
The Committee for Medicinal Products for Human Use (CHMP) is the European Medicines Agency’s (EMA) committee responsible for human medicines.
European Medicines Agency (EMA)
The EMA established under the Medicinal Product Regulation 726/2004. It is the top medicinal regulatory agency in the European Economic Area. It is responsible for the evaluation, supervision and pharmacovigilance of medicinal products.
CAT, CMPH and other committees form a part of EMA.
The market authorisation procedure
When is it a requirement?
Only ATMPs that are industrially produced for human use and are intended to be placed on the market (“making available in return for payment with a view to distribution and/or to be used in the community market”) fall under the Medicinal Products Directive, and are, therefore, subject to market authorisation. However, other legislation, regulations and ethical guidelines (may) still apply even if market authorisation is not necessary.
There are further “exemptions” that make market authorisation unnecessary. These are the “Hospital Use” and the “Specials” exemptions. The “Specials” exemption is relatively common in Europe. The “Hospital Use” exemption has only been applied for once in the UK, but is more commonly used in other EU member states.
How to apply for market authorisation?
Generally speaking, market authorisation can be sought nationally; through mutual recognition in a number of states; or centralised in the EU through the European Medicines Agency.
Centralised market authorisation is mandatory for:
· Orphan medicinal products
· Biotechnology products
· Certain indications, e.g. viral diseases
· and ATMPs.
Centralised market approval by the EMA is beneficial for other products as well, as it grants market authorisation for the whole of the EEA.
The procedure for centralised market authorisation can either be started with a “Full Application” (all the data from a complete development programme has to be submitted) or through one of the “abridged routes” ( Where less data is necessary, for example due to referencing data already provided for previous products).
What are the basic requirements for the data that has to be submitted/demonstrated?
The requirements for ATMPs are not different from those for other medicines. The actual data that is required depends on the underlying science, but quality, safety and efficacy will have to be demonstrated somehow:
Quality: One has to be able to demonstrate good quality, that should be consistent, and that the product is pure or contains only few (and safe) levels of impurities.
Safety: Step-wise approach (animals to man) established in a carefully considered way must be demonstrated. Risks must be identified and mitigated as far as possible. Safety must be evaluated such that risks are understood and controlled.
Efficacy: The product must be shown to work within the stated limitations. A risk/benefit assessment must be completed: E.g. toxicity/side effects and risk of disease transmission have been balanced against treatment or cure of a disease/symptoms and any secondary benefits.
The regulators can advise on what type and quantity of data they will require, but may not have all the answers at the beginning, for example, if you are using a new technology like CRISPR. Early discussions with regulatory bodies can be helpful, but premature discussion can backfire by confusing the regulator. Be prepared for these discussions. Early discussion with independent regulatory experts, however, is recommended.
If available, follow the guidelines. If not, then provide a case as best as possible based on scientific knowledge/common sense/logic. As we are at the forefront of science, a prescribed tick-box system is not always possible, but this also provides flexibility to the system. Early adopters of new technology need to work with the regulators to figure out the data requirements.
PAS-83 (BSI, 2012) Developing human cells for clinical applications in the European Union and the United States of America. Guide. — http://shop.bsigroup.com/forms/PASs/PAS-83/
PAS 93 (BSI, 2011) Characterisation of cells and cell products. — http://shop.bsigroup.com/forms/PASs/PAS-93/
PAS 84 (BSI, 2012) Cell therapy and regenerative medicine glossary. — http://shop.bsigroup.com/forms/PASs/PAS-84/
All are free downloads!
Eur-Lex website for the directives and regulations: http://eur-lex.europa.eu/homepage.html
European Medicines Agency: http://www.ema.europa.eu/ema/
Committee for Advanced Therapies: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000266.jsp
Committee for Healthcare Medicinal Products: http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000094.jsp