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
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Germany
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Netherlands
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Ireland
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Denmark
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United Kingdom
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Belgium
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Croatia
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Latvia
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France
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Greece
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Lithuania
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Estonia
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Italy
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Czech
Republic
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Slovenia
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Cyprus
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Spain
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Portugal
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Luxembourg
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Malta
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Poland
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Hungary
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Romania
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Sweden
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Finland
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Austria
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Slovakia
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Bulgaria
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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.)
- 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.
- 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.
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Abbreviations
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
References
1. 'EMA pre-submission procedural advice for users of the centralized
procedure' (EMA/339324/2007).
2. Regulation (EC) No 726/2004.
