european patients’ academy on therapeutic innovation marketing authorisation
DESCRIPTION
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)TRANSCRIPT
European Patients’ Academy on Therapeutic Innovation
Marketing authorisation
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)
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)
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)
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)
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)
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)
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.html
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)
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
One or more EU member
states
Only one EU member
state
EU Marketing Authorisation procedures
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)
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)
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)
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 procedureMutual 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
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
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)
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)
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)
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
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)
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
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
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)
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)
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
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
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
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).
28
Further reading
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: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:32004R0726
29
Further Reading