1. European Patients’ Academy on Therapeutic Innovation Marketing authorisation

2. European Patients’ Academy on Therapeutic Innovation  A medicinal product may only be placed on the market in the European Economic Area (EEA) after a marketing authorisation (MA) has been issued by the competent authority of that Member State (MS) or by the European Commission after scientific assessment by the European Medicines Agency (EMA).  The process for obtaining a marketing authorisation is very complex and is highly regulated. 2 Marketing authorisation: Main principles (1)

3. European Patients’ Academy on Therapeutic Innovation  The main principle underlying pharmaceutical legislation is the protection of public health.  MAs for medicinal products are dynamic; the dossier supporting an MA must be regularly updated in order to ensure that scientific progress and new regulatory requirements are respected.  Any new information that may influence the evaluation of the benefits and risks of the medicinal product must be promptly supplied to the competent authority. 3 Marketing authorisation: Main principles (2)

4. European Patients’ Academy on Therapeutic Innovation  The applicant submits an MA application (MAA) dossier to the competent authority which must demonstrate that the medicinal product has the required quality, that it is safe, and that it is efficacious.  The dossier must adhere to the common technical document (CTD), a set of specifications for the MAA dossier. The CTD is an internationally agreed format that must be followed for applications intended to be submitted to regulatory authorities. 4 MA application dossier and Common Technical Document (CTD)

5. European Patients’ Academy on Therapeutic Innovation  The Common Technical Document (CTD):  Determines an appropriate format for the data required in an application  Is applicable for all types of MAAs, irrespective of the type of application or the procedure  Is organised in five modules -Modules 2-4 constitute the actual CTD; Module 1 differs according to region.  An eCTD guideline specifies how to construct an electronic version of the CTD 5 Common Technical Document (CTD)

6. European Patients’ Academy on Therapeutic Innovation  1. Regional information  Specific administrative data including application form  Risk management plan (RMP)  Summary of Product Characteristics (SmPC)  Labelling and package leaflet (PL)  2. Quality overall summary  Non-clinical overview/summaries and clinical overview/summaries 6 Common Technical Document: Modules (1)

7. European Patients’ Academy on Therapeutic Innovation  3. Quality  Chemical, pharmaceutical, and/or biological information  4. Non-clinical  Non-clinical study reports (pharmacology/toxicology)  5. Clinical  Clinical study reports 7 Common Technical Document: Modules (2)

8. European Patients’ Academy on Therapeutic Innovation 8 Common Technical Document: Modules (3) ICH (2015). The CTD Triangle. Retrieved 7 September, 2015, from http://www.ich.org/products/ctd.htmlhttp://www.ich.org/products/ctd.html

9. European Patients’ Academy on Therapeutic Innovation  There are two pathways for obtaining an MA:  The Centralised Procedure (CP)  Non-centralised procedures -Decentralised Procedure (DCP) -Mutual Recognition Procedure (MRP) -National procedure  Each procedure has its own legal provisions and responsibilities for the competent authorities (the EMA or national competent authorities (NCAs) and MA holders) 9 Regulatory procedures for obtaining a Marketing Authorisation (MA)

10. European Patients’ Academy on Therapeutic Innovation z 10 Centralised Procedure Mutual Recognition Procedure Decentralised Procedure National Procedure All EU member states One or more EU member states Only one EU member state EU Marketing Authorisation procedures

11. European Patients’ Academy on Therapeutic Innovation  The European Medicines Agency (EMA) is responsible for the CP  A single application is submitted to the EMA; all member states (MSs) are involved in the procedure  The Committee for Human Medicinal Products (CHMP) carries out a scientific evaluation of the dossier  A rapporteur and co-rapporteur experts from each MS (usually from the regulatory authority) evaluate the application dossier  The full process takes up to 210 active days, but ‘clock stops are possible’ 11 Centralised Procedure (CP) (1)

12. European Patients’ Academy on Therapeutic Innovation  The CHMP adopts a final opinion with a recommendation to the European Commission as to whether or not the medicine should receive an MA  The MA is then finally granted by the European Commission.  The CP results in a pan-European MA; valid in all states of the European Economic Area (EEA). The same trade name (invented name) is used in all states, and common product information (Summary of Product Characteristics (SmPC), labels, package leaflets) is translated into the 24 official EU languages. 12 Centralised Procedure (CP) (2)

13. European Patients’ Academy on Therapeutic Innovation  The CP is mandatory in the case of:  Medicines for the treatment of ○ HIV or AIDS○ neurodegenerative disease ○ cancer○ auto-immune and other immune dysfunctions ○ diabetes○ viral diseases  Medicines derived from biotechnology products, such as genetic engineering  Advanced-therapy medicines, such as gene-therapy, somatic cell-therapy, or tissue-engineered medicines  Orphan medicines (medicines used for rare human diseases)  The CP is optional for medicines that are:  A significant therapeutic, scientific, or technical innovation  In the interest of public health 13 Centralised Procedure (CP) (3)

14. European Patients’ Academy on Therapeutic Innovation  There are three systems for new applications that are ineligible or which have opted out of the CP:  National procedure  Mutual recognition procedure (MRP) of an already authorised product (one which holds a national MA)  Decentralised procedure (where the product has no existing European MA) 14 Non-centralised procedures

15. European Patients’ Academy on Therapeutic Innovation  National procedures may be followed under two circumstances:  Independent national procedures, strictly limited to medicines that are to be authorised and marketed in only one MS -In case the medicine should be marketed in multiple MSs, the national procedure must be followed by a mutual recognition procedure. Alternatively, a decentralised procedure may be considered to obtain MAs in parallel in several MSs.  For extensions of medicines already authorised nationally -Additional strengths, pharmaceutical forms, or routes of administration 15 National procedures

16. European Patients’ Academy on Therapeutic Innovation  Both procedures are based on the recognition by national competent authorities of an assessment performed by the authorities of one MS.  These procedures aim to facilitate access to a single market by relying on mutual recognition  A reference member state (RMS) and one or more concerned member states (CMSs) are involved  It is not necessary to seek an MA in all 28 MSs to use these procedures – a minimum of two is required. 16 Mutual Recognition and Decentralised Procedures(1)

17. European Patients’ Academy on Therapeutic Innovation  The Marketing Authorisation Application (MAA) dossier is assessed by one member state (the RMS); their review is shared with other involved member states (the CMSs)  The company can choose the RMSs and CMSs  The company can choose trade names  A national MA – including a harmonised SmPC and package leaflet – is issued by each involved MS  These procedures are overseen by the Heads of Medicines Agencies (HMA) via the Coordination Group for Mutual Recognition and Decentralised Procedures (CMD(h)) 17 Mutual Recognition and Decentralised Procedures(2)

18. European Patients’ Academy on Therapeutic Innovation  An identical application for mutual recognition is to be submitted to all CMSs  The RMS prepares an assessment report or updates an existing one within 90 days  Copies of the assessment report are sent to all CMSs with the approved SmPC, package labelling, and package leaflet  CMSs then have 90 days to recognise the decision of the RMS  National MAs will be granted within 30 days after acknowledgement of the agreement 18 Mutual Recognition Procedure (MRP)

19. European Patients’ Academy on Therapeutic Innovation  Objections to recognition can only be raised on the grounds of potential serious risk to public health.*  The issue will be referred to the coordination group (CMD(h)) where MSs will reach a consensus within 60 days. If this case fails, the procedure is submitted to the EMA scientific committee (CHMP) for arbitration. * According to Directive 2001/83/EC the term ‘risk related to the use of the medicinal product’ is defined as ‘any risk relating to the quality, safety or efficacy of the medicinal product as regards to patients' health or public health’ (or any risk of undesirable effects on the environment). 19 Objections to mutual recognition

20. European Patients’ Academy on Therapeutic Innovation  The DCP is available for new products that have not yet been authorised in any EEA country and which do not fall in the mandatory scope of the CP  The application is submitted to all the involved MSs at the same time. The RMS prepares an assessment report. CMSs then recognise the decision of the RMS or raise issues to be resolved.  National MAs will be granted within 30 days after acknowledgement of the agreement  The product is nationally authorised in the RMS and each CMS with a harmonised SmPC, package leaflet, and package labelling 20 Decentralised Procedure (DCP)

21. European Patients’ Academy on Therapeutic Innovation  Stand alone (full) application (all CTD modules)  Mixed application  Generic application  Hybrid application  Similar biological product (biosimilar) application  Well-established use application  Application for a new combination containing active substances used in already authorised products  ‘Informed consent’ application 21 Types of applications for an MA of a medicinal product

22. European Patients’ Academy on Therapeutic Innovation  ‘Extension of an MA’ or ‘extension’ means a variation that is listed in Annex I of Regulation (EC) No 1234/2008 and fulfils the conditions listed there:  1. Changes to the active substance(s) where efficacy and safety characteristics are not significantly different  2. Changes to strength, pharmaceutical form, and route of administration  Such applications are evaluated in accordance with the same procedure as that of granting the initial MA  The extension can either be granted as a new MA or will be included in the initial MA to which it relates. 22 Extension of an MA

23. European Patients’ Academy on Therapeutic Innovation  Article 23 of Directive 2001/83/EC:  Requires the MA holder to continuously update the dossier to take account of technical and scientific progress and to introduce any change that may be required for the manufacture and control of the medicinal product  Updating should be taken up through the variations procedure, and reflected in the dossier and/or Overall Summaries and Overviews, as appropriate 23 Variation procedures (1)

24. European Patients’ Academy on Therapeutic Innovation  Each marketing authorisation holder (MAH) is obligated to update the MA throughout the life of the product as new data emerge. They should do this via the variation procedure  Any application by he MAH to vary the length of an MA that has been granted in accordance with the legislation must be submitted to all the MSs that have previously authorised the medicinal product. 24 Variation procedures (2)

25. European Patients’ Academy on Therapeutic Innovation  The MA may be renewed after five years on the basis of a re-evaluation of the benefit-risk balance by the competent authority of the authorising MS.  At least 9 months before the expiry of the MA, he MAH provides the competent authority with a consolidated version of the file in respect of quality, safety, and efficacy, including all variations introduced since the MA was granted.  Once renewed, the MA is valid for an unlimited period, unless the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. 25 Renewals

26. European Patients’ Academy on Therapeutic Innovation  The MA will be refused if  The risk-benefit balance is not considered to be favourable  Its therapeutic efficacy is insufficiently substantiated by the applicant  Its qualitative and quantitative composition is not as declared.  The MA is also to be refused if any particulars or documents submitted with the application do not comply with the legislation.  The applicant or MAH is responsible for the accuracy of the documents and data submitted 26 Refusal of an MA

27. European Patients’ Academy on Therapeutic Innovation  Depending on the application, the different options are:  For CPs  Marketing Authorisation  Conditional Marketing Authorisation  Marketing Authorisation granted under exceptional circumstances  For National/DCP/MRP procedures  Marketing Authorisation  Marketing Authorisation granted under exceptional circumstances 27 Options for granting an MA

28. European Patients’ Academy on Therapeutic Innovation  Legal Basis – EU Legislation – EUDRALEX  The legislation in the pharmaceutical sector can be found in several volumes of the publication The rules governing medicinal products in the EU. This is available from http://ec.europa.eu/health/documents/eudralex/index_en. htm (Retrieved 8 September, 2015). http://ec.europa.eu/health/documents/eudralex/index_en. htm 28 Further reading

29. European Patients’ Academy on Therapeutic Innovation  Volume 1 – Pharmaceutical legislation of EUDRALEX contains directive, regulations and miscellaneous. There are two fundamental texts:  European Parliament (2001). Directive 2001/83/EC on the Community code relating to medicinal products for human use. Retrieved 8 September, 2015 from http://eur-lex.europa.eu/legal- content/EN/TXT/?qid=1441700788112&uri=CELEX:32001L0083http://eur-lex.europa.eu/legal- content/EN/TXT/?qid=1441700788112&uri=CELEX:32001L0083  European Parliament (2004). Regulation (EC) No 726/2004/EC laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. Retrieved 8 September, 2015 from http://eur-lex.europa.eu/legal- content/EN/TXT/?qid=1441697290872&uri=CELEX:32004R0726http://eur-lex.europa.eu/legal- content/EN/TXT/?qid=1441697290872&uri=CELEX:32004R0726 29 Further Reading