European Patients’ Academy on Therapeutic Innovation Marketing authorisation.

European Patients’ Academy on Therapeutic Innovation

Marketing authorisation


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.

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Marketing authorisation: Main principles (1)


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.

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Marketing authorisation: Main principles (2)


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.

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MA application dossier and Common Technical Document (CTD)


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

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Common Technical Document (CTD)


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

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Common Technical Document: Modules (1)


3. Quality Chemical, pharmaceutical, and/or biological information

4. Non-clinical Non-clinical study reports (pharmacology/toxicology)

5. Clinical Clinical study reports

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ICH (2015). The CTD Triangle. Retrieved 7 September, 2015, from http://www.ich.org/products/ctd.html

http://www.ich.org/products/ctd.html


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)

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Regulatory procedures for obtaining a Marketing Authorisation (MA)


z

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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


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’

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Centralised Procedure (CP) (1)


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.

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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

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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)

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Non-centralised procedures


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

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National procedures


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.

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Mutual Recognition and Decentralised Procedures (1)


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))

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Mutual Recognition and Decentralised Procedures (2)


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

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Mutual Recognition Procedure (MRP)


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).

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Objections to mutual recognition


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

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Decentralised Procedure (DCP)


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

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Types of applications for an MA of a medicinal product


‘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.

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Extension of an MA


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

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Variation procedures (1)


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.

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Variation procedures (2)


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.

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Renewals


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

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Refusal of an MA


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

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Options for granting an MA


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).

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Further reading

http://ec.europa.eu/health/documents/eudralex/index_en.htm

http://ec.europa.eu/health/documents/eudralex/index_en.htm


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

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Further Reading

http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1441700788112&uri=CELEX:32001L0083

http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1441700788112&uri=CELEX:32001L0083

http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1441697290872&uri=CELEX:32004R0726

http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1441697290872&uri=CELEX:32004R0726

European Patients’ Academy on Therapeutic Innovation Marketing authorisation.

Documents

Transcript of European Patients’ Academy on Therapeutic Innovation Marketing authorisation.