This section provides help and advice regarding advanced therapy medicinal products (ATMPs). It aims to provide clarification of the specific areas where the MHRA can provide advice.
If the answer to your question is not here please email info@mhra.gsi.gov.uk
1. Where can I find information about legislation in respect of licensing of medicines and procurement of tissues and cells?
2. Is my product a medicine?
3. s my product an advanced therapy medicinal product (ATMP)?
4. Is my product a combination product?
5. Is my product a medical device?
6. Is there a fee reduction available for ATMPs that are authorised under the Regulation?
7. Does the Human Tissue Authority (HTA) regulate any steps in the manufacture and supply of ATMPs?
8. What are the requirements for using an ATMP in a clinical trial?
9. Is my clinical study sufficient to support a marketing authorisation application (MAA) for an ATMP that falls within the transitional provisions?
10. Where can I find further guidance specific to ATMPs?
11. Can I manufacture and supply an ATMP without the need to hold a marketing authorisation?
12. Is the hospital exemption scheme restricted to the same Member State?
13. Is a manufacturing licence required to operate under the hospital exemption or the specials exemption?
14. Does my MAA require an environmental risk assessment (ERA)?
15. What data is needed to support an ERA?
16. If an ATMP containing a genetically modified organism (GMO) is to be used within the hospital exemption, what additional licences are required?
17. Can the MHRA advise on the position other regulators may take on my product?
18. What guidelines are available?
19. Can the MHRA provide an explanation of the EMA guidelines that have been developed?
20. Can I get scientific advice from MHRA about product development?
21. How do I find out if my product is covered by the transitional provisions?
22. Can the MHRA provide advice about the regulatory regime that will apply to products containing or derived from stem cells?
23. I can’t find the answer to my question. Who should I contact in the MHRA to ask?
24. Are there any useful publications on the MHRA website?
1. Where can I find information about legislation in respect of licensing of medicines and procurement of tissues and cells?
Directives and Regulations relevant to licensing of medicines and ATMPs in particular are:
- Regulation (EC) No 1394/2007
- Regulation (EC) No 726/2004
- Directive 2001/83/EC
- Directive 2001/20/EC
- Directive 2003/63/EC
- Directive 2004/27/EC
- Directive 2008/29/EC
These are published on the European Commission website (external link).
Directives relevant to procurement of human tissues and cells are:
- Directive 2004/23/EC
- Directive 2006/17/EC
- Directive 2006/86/EC
These Directives were formally adopted into UK law by the Human Tissue (Quality and Safety for Human Application) Regulations 2007 and are published by the Human Tissue Authority (external link).
2. Is my product a medicine?
The MHRA provides classification advice for products which are to be placed on the market in the UK. Requests for advice may be directed to the MHRA’s Borderline Section in the first instance. Information, including contact information, is available in the Borderline Section.
Further information is available in A Guide To What Is A Medicinal Product
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Scientific advice on classification of products may also be obtained from the European Medicines Agency (EMA) (external link).
The answer to this question is the first step in determining the appropriate regulatory system for your product. If the product is not medicinal then none of the following FAQs are applicable. If the product is derived from human tissues and cells further information should be sought from the Human Tissue Authority (external link).
3. Is my product an advanced therapy medicinal product (ATMP)?
If, based on the answer to Q2, your product is a medicine and you are seeking advice from the MHRA as to whether the product would fall within the definition of an ATMP please use the ATMP Advice Form. If your product is an ATMP, the immediate next step is to determine which type of ATMP regulatory scheme it will fall under. There are 3 options:
1. licensed (ie the product requires a marketing authorisation)
2. clinical trial – see below and Q8
3. unlicensed – see below and Q11.
In cases where a marketing authorisation is envisaged, the centralised procedure will apply and enquiries should be directed to the EMA. Under the Regulation (No.1394/2007), the centralised authorisation procedure will apply to ATMPs which are intended to be placed on the market in the Community. A new committee, the committee for advanced therapies (CAT) (external link) has been established at the EMA.
The CAT is responsible for preparing a draft opinion on the quality, safety and efficacy of each ATMP for which a marketing authorisation application is submitted. The CAT’s opinion will be submitted to the EMA’s Committee for Medicinal Products for Human Use (CHMP) for final approval.
In the UK, the MHRA is the supervisory authority for UK manufacturers or importers of centrally authorised ATMPs, as well as the competent authority for ATMPs which are prepared and used under the hospital exemption and under the UK’s “specials” scheme. The MHRA is also the competent authority for the assessment of applications for clinical trial authorisations and the associated manufacturer’s licence for investigational medicinal products.
Information about requirements of clinical trials
4. Is my product a combination product?
A combined ATMP is defined as an ATMP that fulfils the following conditions:
- it must incorporate, as an integral part of the product, one or more medical devices within the meaning of Article 1 (2) (a) of Directive 93/42/EEC or one or more active implantable medical devices within the meaning of Article 1 (2) (c) of Directive 90/385/EEC, and
- its cellular tissue or tissue part must contain viable cells or tissues, or
- its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to.
The MHRA can provide advice for combination products in circumstances where a combination product may be supplied without a marketing authorisation. In cases where a marketing authorisation is envisaged, the centralised procedure will apply and enquiries should be directed to the EMA. The EMA will evaluate combination products that are to be authorised under the centralised procedure. Information about the EMA’s responsibilities can be found in the ATMP Regulation (external link).
5. Is my product a medical device?
Specfic information about the regulation of medical devices.
6. Is there a fee reduction available for ATMPs that are authorised under the Regulation?
There are a range of incentives under the Regulation. A 90% reduction for small and medium sized enterprises (SMEs) and 65% for other applicants will apply to the fees payable to the EMA for scientific advice.
The fee payable for a marketing authorisation (MA) shall be reduced by 50% if the applicant is a hospital or a SME and can prove that there is a particular public health interest in the Community in the ATMP. This reduction shall also apply to fees charged by the EMA for post authorisation (external link) activities during the first year following the granting of the MA.
7. Does the HTA regulate any steps in the manufacture and supply of ATMPs?
The HTA is the UK’s competent authority under the Human Tissue Regulations 2007. The HTA regulates donor selection, donor testing, consent and procurement and all steps within these stages which could affect the quality and safety of cells used to manufacture ATMPs. The regulatory requirements also cover the conditions used to transport and store cells used to manufacture ATMPs. Information on the regulatory remit of the HTA (external link).
8. What are the requirements for using an ATMP in a clinical trial?
Clinical trials on ATMPs must be conducted in accordance with the principles laid down in the Clinical Trials Directive (2001/20/EC). The MHRA is responsible for authorising clinical trials and inspecting and issuing the manufacturer’s licence for an investigational medicinal product (IMP) in the UK.
The EMA has been tasked with developing guidance specific to ATMPs. This guidance will be within Annex 2 to EU GMP which is currently being revised to include this and other new guidance.
9. Is my clinical study sufficient to support a marketing authorisation application (MAA) for an ATMP that falls within the transitional provisions?
The MHRA can provide scientific advice on the extent of clinical data that might be necessary to support a MAA for a product that falls within the transitional provisions, and on the suitability of proposed clinical trial protocols. It is not the role of the MHRA, in this situation, to pre-assess the results of clinical trials in support of the medicinal claims. Further information on procedures for applying for MHRA scientific advice can be found using the link in Q19.
Alternatively a similar service is available at the EMA. The appropriate link is provided in Q20.
10. Where can I find further guidance specific to ATMPs?
Scientific guidance specific to ATMPs can be accessed on the EMA’s website (external link).
11. Can I manufacture and supply an ATMP without the need to hold a marketing authorisation?
There are two narrowly drawn exemption schemes available in the UK that may allow the supply of unlicensed ATMPs (ie ATMPs that are not the subject of a marketing authorisation granted by the European Commission).
1) The hospital exemption
If an ATMP is prepared within the UK on a non-routine basis for use in the UK only in a hospital in accordance with a medical prescription for an individual patient it may fall under the hospital exemption inserted as Article 3 (7) of Directive 2001/83/EC by Article 28 (2) of the ATMP Regulation.
2) The 'specials' exemption
The existing exemption from the requirement to hold a marketing authorisation provided by Schedule 1 (the 'specials' exemption) of the Marketing Authorisation Regulations (SI 1994/3144) as amended, may also apply to an unlicensed ATMP if it is “supplied in response to a bona fide unsolicited order, formulated in accordance with the specification of a doctor, dentist or supplementary prescriber and for use by his individual patients on his direct responsibility in order to fulfil the special needs of those patients…”
It should be noted that a qualified person (QP) is not required under either of these schemes. If you consider the activity you are carrying out may fall under one or both of these exemptions you should contact for regulatory advice the MHRA Inspection Enforcement and Standards Division at gmpinspectorate@mhra.gsi.gov.uk
12. Is the hospital exemption scheme restricted to the same Member State?
Under the Regulation, the hospital exemption scheme is restricted to ATMPs that are prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital.
13. Is a manufacturing licence required to operate under the hospital exemption or the specials exemption?
In order to operate under the hospital exemption or the 'specials' exemption within the UK, manufacturers must obtain a manufacturer’s licence from the MHRA. The licence will authorise the manufacture of particular categories of ATMPs (gene therapy, somatic cell therapy or tissue engineered product) rather than individual products. Manufacturer’s licence holders must comply with the principles of good manufacturing practice (GMP) and the specific guidelines on GMP for ATMPs to be issued by the European Commission. The MHRA will inspect for compliance with GMP before granting such a licence and throughout the tenure of the licence.
For further information on manufacturer’s licences for unlicensed ATMPs contact for regulatory advice the MHRA – Inspection Enforcement and Standards Division – gmpinspectorate@mhra.gsi.gov.uk
14. Does my MAA require an environmental risk assessment (ERA)?
An ERA must accompany an application for a marketing authorisation for an ATMP. An ERA is required for all new marketing authorisation applications (external link).
If your product contains a genetically modified organism (GMO) the marketing of that product will be considered deliberate release.
15. What data is needed to support an environmental risk assessment (ERA)?
Specific guidance is available for gene therapy medicinal products (external link).
More general advice for an ERA is given in the following document ‘Guideline on the environmental risk assessment of medicinal products for human use' (external link).
Pre-MAA submission questions (external link) in relation to an ERA are addressed by the EMA.
16. If an ATMP containing a GMO is to be used within the hospital exemption, what additional licences are required?
The use of a product containing or consisting of a GMO will be considered either contained-use or deliberate release, and its use will need to be approved in accordance with the relevant directives. This will be assessed on a case by case basis. The applicant is advised to contact the HSE in the first instance (external link).
17. Can the MHRA advise on the position other regulators may take on my product?
The MHRA is not able to provide advice about the position taken by other regulators. If you have a particular query about placing an ATMP on the market in a specific Member State, you should contact the regulator in that Member State or the EMA if you are intending to apply for a centralised authorisation.
18. What guidelines are available?
The European Commission and the EMA are responsible for developing the guidelines specific to ATMPs which underpin the new Regulation. Information about the guidelines that have been developed are on the EMA’s website (external link).
19. Can the MHRA provide an explanation of the EMA guidelines that have been developed?
The MHRA can provide scientific advice during any stage of the initial development of the product (see Q20) though it is not generally appropriate for the MHRA to provide an explanation of the EMA guidelines. Operators are advised to read the guidelines and if necessary seek the services of a consultant.
20. Can I get scientific advice from the MHRA about product development?
MHRA advice is available on product development which can be sought at any stage during development. There is a fee charged for this advice.
Scientific advice is also available via the EMA (external link).
21. How do I find out if my product is covered by the transitional provisions?
A three year transitional period applies to somatic cell and gene therapy products which were legally on the Community market in accordance with existing arrangements at the time of application of the Regulation.
A four year transitional period applies to tissue engineered products which were legally on the market in accordance with national or Community legislation at the date of application of the Regulation.
Information about transitional arrangements (external link)
22. Can the MHRA provide advice about the regulatory regime that will apply to products containing or derived from stem cells?
In cases where stem cells are to be used in a medicinal product, the donation, procurement and testing of the cells are covered by the Tissues and Cells Directive (2004/23/EC). The Human Tissue Authority (HTA) is the competent authority for the Directive in England, Scotland, Wales and Northern Ireland (www.hta.gov.uk) .
The processing activities (such as work in derivation laboratories) leading up to the point where a Master Cell Bank has been established with a reasonable expectation of clinical utility in a medicinal product will also be covered under the Tissues and Cells Directive. Thereafter medicines legislation applies with the MHRA and the EMA as the national and European regulators.
The MHRA participated in the production of a stem cell tool kit for stem cell research and manufacture which has been developed by the Department of Health with the support of regulatory bodies and the Gene Therapy Advisory Committee.
This stem cell tool kit is intended to be a reference tool for those who wish to develop a programme of stem cell research and manufacture ultimately leading to clinical application.
UK regulatory route map for stem cell research and manufacture (external link)
23. I can’t find the answer to my question. Who should I contact in the MHRA to ask?
Please contact the MHRA’s central enquiry point. The email address is info@mhra.gsi.gov.uk.
24. Are there any useful publications on the MHRA website?
Questions and Answers on Regulation (EC) No.1394/2007
How we regulate advanced therapy medicinal products
UK regulatory route map for stem cell research and manufacture (external link)
