Friday, 30 October 2015

Registration procedure (Marketing Authorization) of drugs in Europe


Registration procedure (Marketing Authorization) of drugs in Europe



   A medicinal product may only be placed in the European union, when a marketing authorization (MA) has been issued by the competent authority. Drug registration process in Europe is considered to be a little complicated in comparison with US, as it involves  multiple member states, multiple agencies (i.e EMEA, CHMP, National Health Agencies) and multiple registration process (i.e Centralized, Decentralized, Mutual recognition process).
The European union (EU) is a union of twenty-eight independent states, which was founded in 1st November, 1993. Member states details are listed in the below table.

EU Member states
United Kingdom
Czech Republic

Along with 28 member states, Norway, Iceland and Liechtenstein forms European economic area (EEA). Once a marketing authorization is granted, it is valid for all EU and EEA states.
After the formation of European Union, European community faced many problems in connection with the free circulation of medicinal products due to different national procedures for marketing authorization.

At present, drug registration process in European Union can be done under any one of the following procedure. 

1. Centralized Procedure (CP)
2. Decentralized Procedure (DCP)
3. Mutual Recognition Procedure (MRP)
4. National Procedure (NP)

1.The Centralized Procedure (CP)

This procedure results in a single marketing authorization that is valid in all EU countries. European medicines agency (EMEA) is responsible for scientific evaluation of applications for centralized marketing authorizations. Once marketing authorization is granted by the European commission the centralized marketing authorization is valid in all EU and EEA – EFTA states.

Upon submission of a valid application, the evaluation takes up to 210 days, at the end of which the committee for medicinal products for human use (CHMP) must issue a scientific opinion on whether the medicine may be authorized or not. This opinion is then communicated to the European commission, which has the ultimate authority for granting the marketing authorization within 67 days after the receipt of the CHMP opinion. 

The centralized procedure is compulsory for:
  • human medicines for the treatment of human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS), cancer, diabetes, neuro degenerative diseases, auto-immune and other immune dysfunctions, and viral diseases;
  • veterinary medicines for use as growth or yield enhancers;
  • medicines derived from biotechnology processes, such as genetic engineering;
  • advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines;
  • officially designated 'orphan medicines' (medicines used for rare human diseases).
 For medicines that do not fall within these categories, companies have the option of submitting an application for a centralized marketing authorization to the Agency. This is possible for medicines:
  • that are a significant therapeutic, scientific or technical innovation, or;
  • Whose authorization would be in the interest of public or animal health.
For medicines falling outside the scope of the centralized procedure, the decentralized procedure, mutual-recognition procedure or purely national authorization procedures should be used, depending on the number of countries in which authorization is sought.

To find out whether a product can be evaluated under the centralized procedure, companies should submit to the CHMP an 'eligibility request', accompanied by a justification that the product falls under one of the categories described above.
Companies should inform the Agency in writing approximately 7 months in advance of their intended submission date. About the same time, a per-submission meeting with the Agency's product team may be requested. It is strongly recommended that applicants take this opportunity to obtain procedural, regulatory and legal advice from the Agency.

The evaluation of centrally authorized products is done by the CHMP, with input from the Pharma-covigilance Risk Assessment Committee (PRAC) on aspects of the risk-management plan and the Committee for Advanced Therapies (CAT) for advanced-therapy medicines. The committees are composed of members from each of the 28 EU Member States and from Iceland and Norway along with co-opted members who provide additional expertise in particular scientific areas. 

For each product, the CHMP/PRAC/CAT appoints (co-) rapporteurs to lead and coordinate the evaluation. The appointment is usually initiated at the earliest 7 months before submission, following receipt of the letter of intention to submit a marketing-authorization application.

Steps involved in obtaining an EU marketing authorization (CP)
  • Submission of eligibility request. (At the earliest 18 months and at the latest 7 months in advance of submission.)
  •  Notification of intention to submit an application. (Approx. 7 months in advance of submission.)
  • Appointment of rapporteurs. (Approx. 7 months in advance of submission.)
  •   Pre -submission meeting. (Approx. 7 months in advance of submission.)
  •   Submission of the application.
  •   Scientific evaluation. (210 days of assessment.)
  • CHMP scientific opinion
  •  European Commission decision on the marketing authorization.
 2. Decentralized Procedure (DCP)

The new DCP came in to effect in the EU in 2005.Objective of this procedure is to obtain MA in several member states. For medicinal products not falling within the mandatory scope of the centralized procedure, identical dossiers are filed in multiple member state (MS) where a marketing authorization is sought. Applicant may designate a country to act as the reference member state. Selection of RMS depends on many considerations including work load, previous experience, interests etc. RMS selected by applicant will prepare a preliminary assessment report on the dossier to the CMS(s) and the applicant within 70 days. The CMS(s) is asked to give comments on the proposed national prescription status and to inform RMS. On day 105, the RMS will forward all comments to the applicant and stops the clock necessary, until the applicant prepares a response document. The RMS prepares a draft assessment report on day 120 and may close the procedure if a consensus has been reached between the CMS(s) and the RMS. Otherwise; the CMS(s) has 90 more days to approve the draft assessment report and other documents. Competent authorities of the RMS and the CMS(s) adopt a decision within 30 days after acknowledgement of their agreement to the assessment report and other documents. At the  end of the decentralized procedure with a positive agreement, a national marketing authorization will be issued in the RMS and each CMS(s).

RMS – Reference Member State Roles:
  •        Acts as a link between the applicant and concerned member states.
  •        Allocation of procedure number.
  •        Starting the procedure.
  •       Involved in the preparation of preliminary and draft assessment reports, initial comments on – SmPc (summary of product characteristics), labelling and package leaflets provided in the dossier.
  • Stopping and restarting the procedure, before and after clock stop period.
  •   Closing the procedure if consensus is reached.
CMS – Concerned Member State Roles:
  • Involved in the approval/disapproval of RMS’s – preliminary and draft-assessment reports, initial comments on – SmPc (summary of product characteristics),labeling and package leaflets.
  • Involved in earlier stages of DCP to avoid disagreements between CMS and RMS.
  • Upon submission of a valid application, the evaluation takes up to 210 days and MA will be granted in accordance with the decision taken by RMS and CMS.
3. Mutual Recognition Procedure (MRP)

Mutual recognition procedure allows applicants to obtain a marketing authorization in the member states (concerned member state) other than the member state (reference member state) where the drug is previously approved (i.e the applicant requests one more CMS(s) to mutually recognize the authorization granted by the RMS.)

The MA should submit an application to the competent authorities of the RMS and each CMS(s). With 90 days of receipt of a valid application, the RMS provides the assessment report, or if necessary, updates any existing one and sends it together with other documents to CMS(s) and applicant. The RMS launches the clock after receipt of the assessment report and validation of the applicant by each of the CMS(s). Within 90 days CMS(s) recognize the decision of the RMS. 30 days after the close of the procedure, the competent authorities of the CMS(s) adopts a decision to grant MA.

4. National Procedure (NP)
Nationalized procedure is one which allows applicants to obtain a marketing authorization in one member state only. Time line for this procedure is 210 days. Generally NP is not used now a days. 

Important Facts to Remember.....
·       European Commission, the European Medicines Agency and national competent authorities (medicines regulatory authorities in Member States). together, make up the EU regulatory network.

·       Marketing authorization will have initial validity of 5 years, after these five years, marketing authorization may be renewed on the basis of re evaluation, once renewed marketing authorization will be valid for unlimited period. Any authorization which within three years of its granting is not followed by the actual placing on the market of the authorized product, the authorization for that product will be ceased.
·       The centralized procedure allows applicants to obtain a marketing authorization that is valid throughout the EU (28 member states).

·       Centralized procedure for the approval of drugs, is coordinated by EMEA.

·       EMEA was established in 1995,it works as a scientific body. It does not have any execution power. Its evaluations are submitted to European commission, which issues marketing approval.

·       Using decentralized procedure, manufacturer can apply for simultaneous authorization in more than one EU country.

·       The competent authorities of the member states are responsible for granting MA for medicinal products which are placed on their markets.

CAT: Committee for Advanced Therapies
CHMP: Committee for Medicinal Products for Human Use
CMS: Concerned Member State
EEA: European Economic Area
EFTA: European Free Trade Association
EMEA: European Medicines Agency
MA: Marketing Authorization
PRAC: Pharma-covigilance Risk Assessment Committee
RMS: Reference Member State
SmPc : Summary of Product Characteristics

1. 'EMA pre-submission procedural advice for users of the centralized procedure' (EMA/339324/2007).
2. Regulation (EC) No 726/2004.

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