This post is an attempt to provide an information resource for Advance Therapy Medicinal Product (ATMPs) in the EU. The information provided is by no means exhaustive.
Click on the ‘+’ sign next to each heading to access the information under each heading.
This post will be be updated on an ad hoc basis. It was last updated on 8 September 2021. See the section on history of updates at the end of the post.
Advanced therapy medicinal products (ATMPs) are medicines for human use that are based on on genes, tissues or cells. They offer groundbreaking new opportunities for the treatment of disease and injury. They can be used to treat diseases or injuries e.g. skin in burns victims, Alzheimer’s, cancer, muscular dystrophy etc.
In the EU, ATMPs are classified into three main types as shown in the table below:
|Medicine type||Where you can find a precise legal definition?||About the medicine type||What are medicines used for?|
|Gene therapy medicines||Defined in Part IV of Annex I to Directive 2001/83/EC, as amended.||They work by inserting ‘recombinant’ genes into the body, with a view to regulating, repairing, replacing, adding or deleting a genetic sequence.|
A recombinant gene is a stretch of DNA that is created in the laboratory, bringing together DNA from different sources.
|These medicines contain genes that lead to a therapeutic, prophylactic or diagnostic effect.|
Usually used to treat a variety of diseases, including genetic disorders, cancer or long-term diseases.
|Somatic-cell therapy medicines||Defined in Part IV of Annex I to Directive 2001/83/EC, as amended.||These medicines contain cells or tissues that have been manipulated to change their biological characteristics or cells or tissues not intended to be used for the same essential functions in the body.|
Stems cells can be somatic-cell therapy products depending on how the medicine works in the body.
|They can be used to treat, diagnose or prevent diseases.|
|Tissue-engineered medicines||Article 2(1)(b) of Regulation (EC) No. 1394/2007||These medicines contain cells or tissues that have been modified.|
Stems cells can be tissue-engineered products, depending on how the medicine works in the body.
|They can be used to repair, regenerate or replace human tissue.|
Some ATMPs may contain one or more medical devices as an integral part of the medicine, or one or more active implantable medical devices. An example of this is cells embedded in a biodegradable matrix or scaffold. These are known as combined ATMPs.
Basic definitions of DNA, Genes, Chromosomes, somatic cells and stem cells are provided below, with links to video clips to facilitate further understanding:
- DNA, or deoxyribonucleic acid, is the hereditary material in humans and almost all other organisms.
- Nearly every cell in a person’s body has the same DNA.
- Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).
- The information in DNA is stored as a code made up of four chemical bases: adenine (A), guanine (G), cytosine (C), and thymine (T).
- Human DNA consists of about 3 billion bases, and more than 99% of those bases are the same in all people.
- The order, or sequence, of these bases determines the information available for building and maintaining an organism, similar to the way in which letters of the alphabet appear in a certain order to form words and sentences.
- DNA bases pair up with each other, A with T and C with G, to form units called base pairs. Each base is also attached to a sugar molecule and a phosphate molecule. Together, a base, sugar and phosphate are called a nucleotide.
- Nucleotides are arranged in two long strands that form a spiral called a double helix. The structure of the double helix is somewhat like a ladder, with the base pairs forming the ladder’s rungs and the sugar and phosphate molecules forming the vertical sidepieces of the ladder.
This video clip may to help you understand more about DNA.
- Genes are made up of DNA
- Some genes act as instructions to make molecules called proteins. However, many genes do not code for proteins.
- A gene is a small section of DNA on a chromosome that codes for a particular sequence of amino acids, to make a specific protein. It is the unit of heredity, and may be copied and passed on to the next generation.
- In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases.
This video clip may to help you understand more about genes.
- Chromosomes are contained inside a cell’s nucleus. These are long threads of DNA, which are made up of many genes.
- Chromosomes in a body cell are found in pairs.
- One chromosome is inherited from the mother and one is inherited from the father. The chromosomes in each pair carry the same gene in the same location.
This video clip may help you understand more about chromosomes.
- A somatic cell is any cell of the body except sperm and egg cells. Somatic cells are diploid, meaning that they contain two sets of chromosomes, one inherited from each parent. Mutations in somatic cells can affect the individual, but they are not passed on to offspring.
- To put it in another way, “Somatic cells” is a fairly general term which refers to essentially all the cells of the body except for the germ line; the germ line being the cells in the sexual organs that produce sperm and eggs. So anything that doesn’t have the job of producing sperm or eggs is a somatic cell.
Stem cells are naturally occurring cells in the body that have the ability to divide and produce a range of different cell types. Stem cells are important in the growth and development of the body, as well as in repair after injury.
Stems cells are categorised as ATMPs when these cells undergo substantial manipulation or are used for a different essential function. They can be somatic-cell therapy products or tissue-engineered products, depending on how the medicine works in the body.
Regulation (EC) No 1394/2007 provides the overall framework on ATMPs. It entered into force on 30 December 2007 and became applicable from 30 December 2008. It lays down rules for authorising, supervising and monitoring advanced therapy medicinal products( ATMPs).
Regulation (EC) No 1394/2007 amended the following legislation with regards to ATMPs:
- Directive 2001/83/EC relating to medicinal products for human use;
- Regulation (EC) No 726/2004 on procedures for the authorisation and supervision of medicines for human and veterinary use and establishing the European Medicines Agency.
In addition, Commission Directive 2009/120/EC (amending Directive 2001/83/EC) updated the definitions and detailed scientific and technical requirements for gene-therapy medicinal products and somatic cell-therapy medicinal products. It also established detailed scientific and technical requirements for tissue-engineered products, as well as for ATMPs containing devices and combined ATMPs.
Further information on the legal framework is available here.
The main elements of the regulation are:
- A centralised marketing authorisation procedure.
- A multidisciplinary expert Committee (Committee for Advanced Therapies), within the European Medicines Agency (EMA), to assess advanced therapy products.
- Technical requirements adapted to the particular characteristics of these products.
- Special incentives for small and medium-sized enterprises.
- Combination products – The Regulation recognises that some advanced therapy products combine biological materials, such as tissues or cells, with chemical elements such as metal implants or polymer scaffolds. These combination products require adapted regulatory requirements.
The European Commission adopted:
- Guidelines on Good Manufacturing Practice (GMP) specific for Advanced Therapy Medicinal Products (ATMP) in November 2017. The Guidelines provide a specific GMP framework that is adapted to the specific characteristics of ATMP. YOu can view the guidelines here.
- Guidelines on Good Clinical Practice (GCP) specific for Advanced Therapy Medicinal Products (ATMP) in October 2019. You can view them here.
Source: Europa website
This Q&A document provides practical guidance to developers of ATMPs on the application of the concept of “similar active substance”. Throughout the document, the term “similarity” is used to refer to the assessment whether two active substances are similar within the meaning of Commission Regulation (EC) No 847/2000. The content of the document cannot be extrapolated to products other than ATMPs, or to draw conclusions regarding comparability between two ATMPs in a context other than the application of the orphan legislation.
The document will be updated to reflect new scientific developments.
Source: Europa website
- The CAT was established in accordance with Regulation (EC) No 1394/2007 on ATMPs as a multidisciplinary committee, consisting of some of the best available experts in Europe.
- It is the European Medicines Agency’s (EMA) committee responsible for assessing the quality, safety and efficacy of advanced therapy medicinal products (ATMPs) and following scientific developments in the field.
- Its main responsibility is to prepare a draft opinion on each ATMP application submitted to the EMA, before the CHMP adopts a final opinion on the marketing authorisation of the medicine concerned.
- At the request of EMA’s Executive Director or the European Commission, the CAT can also draw up an opinion on any scientific matter relating to ATMPs.
More information on the CAT and its functions is available here.
On this page, you can find the following:
- CAT Agendas – See example here.
- Minutes of the monthly CAT meetings – See example here.
- Monthly reports- See example here.
A range of useful information is provided in the above documents and includes the following:
- Evaulation of ATMPs
- Certification of ATMPs
- Scientific recommendation on classification of ATMPs
- Scientific advice
- Pre-authorisation activities
- application procedures
The European Medicines Agency (EMA) offers a range of advisory services and incentives to support the development of ATMPs. They include the following:
- Scientific advice and protocol assistance – Both are available for ATMPs, from the European Medicines Agency. Further information is available here.
- Orphan designation -Information on orphan designation is available here.
- the micro, small and medium-sized enterprise (SME) office – The legislation provides for scientific and financial incentives to encourage research and development in the area of advanced therapies. Detailed information is available here.
- Classification of advanced therapy medicinal products (ATMPs) – Further information is provided below under the relevant heading.
- Certification of quality and non-clinical data for SMEs – Further information is provided below under the relevant heading.
- PRIME Scheme – This voluntary scheme from the EMA offers enhance support for the development of medicines that target an unmet medical need. The scheme is based on enhanced interaction and early dialogue with developers of promising medicines, to optimise development plans and speed up evaluation so these medicines can reach patients earlier. Further detailed information is available here.
This infosheet from the EMA summarises the tools available to medicines’s developers from the academic sector. Although it is aimed at the academic sector, the sheet would useful for any developer as a starting point to understand the tools available.
About the ATMP classification procedure
In line with Article 17 of Regulation 1394/2007, any applicant developing a product based on genes, cells or tissues may request a scientific recommendation of the Agency (EMA) with a view to determining whether the referred product falls, on scientific grounds, within the definition of an advanced therapy medicinal product. The Agency shall deliver this recommendation after consultation with the Commission and within 60 days after receipt of the request.
The EMA’s Committee for Advanced Therapies (CAT) delivers scientific recommendations on ATMP classification after consultation with the European Commission within 60 days after receipt of the request.
EMA established the ATMP classification procedure in order to address, as early as possible, questions of borderline cases where classification of a product based on genes, cells or tissues is not clear.
The ATMP classification is based on the evaluation of whether a given product fulfils one of the following definitions and whether the product fulfils the definition of a combined ATMP or not:
- gene therapy medicinal product (GTMP),
- somatic cell therapy medicinal product (sCTMP) or
- tissue engineered product (TEP)
It is possible that, due to the complex nature of these therapeutic products, the limited data package at an early stage of product development and the rapid evolution of science and technology, questions of borderline may arise.
EMA publishes the outcome of the assessment of the classification of ATMPs and these can be viewed here.
You can read more here about the classification procedure, including procedural advice and how to apply.
Is the classification procedure mandatory and is there a fee for it?
The ATMP classification procedure is voluntary and it is free of charge.
Who requests the classification procedure?
Upon the request of and on basis of information provided by a developer of a product based on genes, cells or tissues, the ATMP classification is conducted by the CAT. The outcome of the classification is therefore specific to the product under development.
Is the CAT recommendation provided on an ATMP classification binding?
The recommendation on classification provided by the Agency is not binding. The procedure can help developers to clarify the applicable regulatory framework. It also provides clarity on the development path and scientific-regulatory guidance to be followed.
What happens if additional information becomes available after the original ATMP classification?
If additional scientific information becomes available after the original ATMP classification that may impact the classification of the product, the applicant can submit a follow-up request. This should follow the same procedure as the original submission.
The ATMP classification as a useful tool
The ATMP classification may:
- sometimes be a useful tool for applicants to initiate a tailored dialogue on the product development with regulators. Indeed, the ATMP classification, along with other tools (e.g. ITF briefing meetings), should be seen as a first opportunity to engage with regulators. Once the candidate ATMP classification has been clarified and confirmed, the dialogue can continue with the use of other regulatory procedures such as scientific advice and ATMP certification (for small and medium enterprises only)
- also help developers to gain access to all relevant services and incentives offered by the EMA.
- help when submitting a clinical trial dossier, as the applicant and the concerned competent authorities will be made aware of a European classification position which can clarify and facilitate identification of the most relevant criteria and procedure to be applied. Additionally, the ATMP classification can be applied for at any stage of the product development, even when non-clinical and clinical data are not available
In line with Article 18 of Regulation (EC) No 1394/2007 (the ‘ATMP Regulation’), the EMAs Committee for Advanced Therapies (CAT) provides a certification procedure for ATMPs under development by micro-, small- and medium-sized enterprises (SMEs). This provides an opportunity for SMEs to get an assessment of the data they have generated and check that they are on the right track for successful development.
What does the certification procedure involve?
It involves the scientific evaluation of the quality data non-clinical data (when available) that SMEs have generated at any stage of the ATMP development process. It aims to identify any potential issues early on, so that these can be addressed prior to the submission of a marketing-authorisation application.
- After assessment, the CAT may recommend issuing a certification confirming the extent to which the available data comply with the standards that apply for evaluating a marketing-authorisation application.
- Following the CAT recommendation, the Agency issues a certification.
The evaluation and certification procedure takes 90 days.
Where can you find further information on the certification procedure?
Further information is available here for SMEs on the procedures, timelines and practical steps for the submission, evaluation and certification of quality and non-clinical data
From the date when the ATMP Regulation became applicable (30 Dec 2008) until July 2021, Marketing Authorisations (including Conditional Marketing Authorisations for a very small number of products) valid throughout the EU have been granted for nineteen products.
Of the nineteen originally granted Marketing Authorisations:
- three were withdrawn (i.e. Chondrolect, Provenge and Zalmoxis) at the request of the MA holder due to commercial reasons
- two expired , Glybera because the MA Holder did not wish to renew and MACI due to the fact that the MA had been suspended because of the absence of an authorised manufacturing site for the finished product, active substance and batch release. The suspension had not been lifted prior to the expiry of the marketing authorisation.
The table below provides further details for each of the products. The therapy types are:
- Gene therapy medicinal product (GTMP)
- Somatic cell therapy medicinal product (sCTMP)
- Tissue engineered product (TEP)
|Product||Therapy type||MA Holder||Therapeutic area||Date of issue of MA valid throughout EU||Conditional marketing authorisation||Orphan medicine||MA withdrawn||MA expired|
|Abecma||Gene therapy medicinal product (GTMP)||Celgene Europe BV||Intended for the treatment of relapsed and refractory multiple myeloma||18 Aug 2021||Yes||Yes||–||–|
|Skysona||(GTMP)||Bluebird bio, Inc.||early cerebral adrenoleukodystrophy||16 July 2021||Yes||–||–|
|Libmeldy||GTMP||Orchard Therapeutics (Netherlands) BV, The Netherlands||Leukodystrophy, Metachromatic||17 Dec 2020||Yes||–||–|
|Tecartus||GTMP||Kite Pharma EU B.V.||Lymphoma, Mantle-Cell||14 Dec 2020||Yes||Yes||–||–|
|Zolgensma||GTMP||Novartis Gene Therapies EU Limited, Ireland||Muscular Atrophy, Spinal||18 May 2020||Yes||Yes||–||–|
|Zynteglo||Bluebird bio (Netherlands) B.V., The Netherlands||beta-Thalassemia||29 May 2019, |
During its July 2021 meeting, the CAT concluded that the benefit risk balance of Zynteglo, which is
indicated for the treatment of beta thalassaemia, is unchanged.
|Luxturna||GTMP||Novartis Europharm Limited, Ireland||Leber Congenital Amaurosis|
|22 Nov 2018||Yes||–||–|
|Yescarta||GTMP||Kite Pharma EU B.V., The Netherlands||Lymphoma, Follicular|
-Lymphoma, Large B-Cell, Diffuse
|23 Aug 2018||Yes||–||–|
|Kymriah||GTMP||Novartis Europharm Limited, Ireland||-Precursor B-Cell Lymphoblastic Leukemia-Lymphoma|
-Lymphoma, Large B-Cell, Diffuse
|22 Aug 2018||Yes||–||–|
|Alofisel||Somatic cell therapy medicinal product (sCTMP)||Takeda Pharma A/S, Denmark||Rectal Fistula||23 Mar 2018||Yes||–||–|
|Spherox||TEP||CO.DON AG, Germany||Cartilage Diseases||10 July 2017||–||–|
|Zalmoxis||MolMed SpA, Italy||-Hematopoietic Stem Cell Transplantation|
-Graft vs Host Disease
|18 Aug 2016||Yes||Withdrawn on 9 Oct 2019 at the request of the MA holder.||–|
|Strimvelis||GTMP||Orchard Therapeutics (Netherlands) BV||Severe Combined Immunodeficiency||26 May 2016||Yes||–||–|
|Imlygic||GTMP||Amgen Europe B.V., The Netherlands||Melanoma||16 Dec 2015||–||–|
|Holocar||Tissue engineered product (TEP)||Holostem Terapie Avanzate s.r.l., Italy||-Stem Cell Transplantation|
|17 Feb 2015||Yes||Yes||–||–|
Dendreon UK Ltd
|Prostatic Neoplasms||6 Sept 2013||Withdrawn on 6 May 2015 at request of MA holder, for commercial reasons.||–|
|MACI||TEP||Vericel Denmark ApS||Fractures, Cartilage||27 June 2013||–||Expired on 1 July 2018.|
MA had been suspended since 19 Nov 2014
|Glybera||GTMP||uniQure biopharma B.V., The Netherlands||Hyperlipoproteinemia Type I||25 Oct 2012|
This medicine was authorised under exceptional circumstances,
|–||Expired in Oct 2017, following MA Holders decision not to renew.|
|Chondrocelect||TEP||TiGenix N.V., Belgium||Cartilage Diseases||5 Oct 2009||Withdrawn on 29 July 2016 at request of MA holder, for commercial reasons||–|
|8 September 2021||Section entitled Information on ATMPs already granted a marketing authorisation or awaiting a marketing authorisation, since the ATMP regulation became applicable updated for the following reasons:|
1) No of ATMPs for which approval was originally granted, updated to nineteen.
2) Table updated to include information and link to grant of authorisation for Abecma.
|28 August 2021||Section entitled EMA advisory services and incentives to support the development of ATMPs, including the PRIME scheme updated to include information on the EMA infosheet.|
|28 August 2021||History of updates to this post section added.|