Pharmaceutical Product Registration and Pharmacovigilance Rules and Guidelines

Product Registrationpharmacovigilance it is most relevant to products
Getting marketing authorisation for medicinal productsauthorised by the national, mutual recognition and
in more than one Member State in the EU is done bydecentralised procedures. The Member States are
using one of three procedures:the licensing authorities in these procedures.
Regulation 726/2004. This concerns centrally
"Mutual Recognition Procedure" andauthorised products. The European Commission is the
"Decentralised Procedure" - Directive 2001/83/EC.licensing authority for these products.
As well as these, national authorisations still allowDirective 2001/20. This is the Clinical Trials Directive
products to be marketed in individual countries in theand includes extensive coverage of pharmacovigilance
EU. Products could be authorised separately in severalfor interventional clinical trials pre- and
Member States by a number of nationalpost-authorisation.
authorisations, alternatively one of theseGuidelines
authorisations could be used to apply forA word to the wise here. The guidelines tends to be
authorization using the Mutual Recognition Procedure.suggestions or recommended methods. When it
Where products have national authorisation, thecomes to EU pharmacovigilance law the guidelines are
regulatory agency of the country concerned has toconsidered to be compulsory as far as pharmaceutical
monitor and assess the safety of any products thatcompanies are concerned.
have national authorisation.The European Commission guidelines provide detail
Centralised Procedureand interpretation as to how the directives and
The EMEA administers the centralized procedure,regulations should be followed.The guidelines are also
where a single application, if approved, grantsaimed at regulatory authorities and provide detailed
marketing authorisation for all the countries in therequirements for the way that they must carry out
European Union (and the European Economic Area,pharmacovigilance as well. The guidelines are:
that's the EU countries plus Iceland, Norway andVolume 9A of the Rules Governing Medicinal Products
Liechtenstein). The European Commission becomesin the European Community - for post-authorisation
the responsible authority for products which come topharmacovigilance
market through the centralised procedure. ThisVolume 10 of the Rules Governing Medicinal Products
procedure is available to all new or innovativein the European Community. This applies to clinical
pharmaceuticals and is the only way to authorisetrials pre- and post-authorisation and incorporates the
biotechnology medicines. Where products containguideline Detailed guidance on the collection,
new substances for treating serious diseases, theyverification and presentation of adverse reaction
would use the centralised procedure.reports arising from clinical trials on medicinal products
The regulatory agency of one Member State is thenfor human use
appointed as the Rapporteur and they will then carryAs well as these laws and regulatory guidelines there
out initial assessments of the application forare also various voluntary guidelines, generated for
Marketing Authorisation; a second agency isthe most part by two organizations:
appointed as Co-Rapporteur. These countries will thenThe Council for International Organizations of Medical
be responsible for leading the monitoring andSciences (CIOMS)
assessment of safety of the product when it isThe International Conference on Harmonization of
subsequently marketed.Technical Requirements for the Registration of
Mutual Recognition ProcedurePharmaceuticals (ICH).
In the Mutual Recognition Procedure the marketingCIOMS is a body set up under the World Health
authorisation of one member State is recognised andOrganization and UNESCO. It has developed a series
copied by the other member states. In thisof guidelines on pharmacovigilance, drawn up by a
procedure, the 'Reference Member State', is "mutuallycommittee of volunteers from Industry, regulatory
recognised" by other 'Concerned Member States'.authorities, WHO and others. The main guidelines
Once the application for mutual recognition has goneconcern the international reporting form (CIOMS I);
in, there is a 90 day assessment period. After theperiodic safety update reports (CIOMS II); core data
assessment period the Member States grant asheets (CIOMS III); benefit-risk assessments (CIOMS
marketing authorisation with an identical summary ofIV); practical issues in pharmacovigilance (CIOMS V);
product characteristics to the one in the Referenceclinical trial safety data (CIOMS VI); and development
Member State as long as they accept the originalsafety update reports (CIOMS VII).
assessment of the product. If a Member State raisesWhilst CIOMS guidelines are very influential they are
objections and does not recognise the originalnot "official" regulatory guidelines, they have no legal
marketing authorisation then the matter may beforce and are generally there just to provide a
referred to the EMEA for discussion among theconsensus on good practices and new methodologies.
parties: if this fails, binding arbitration is imposed.ICH consists of representatives of the regulatory
Decentralised Procedureauthorities from the EU, Japan and US, with
The decentralised procedure can apply where there isrepresentatives of the corresponding industry regional
no authorisation yet in any of the Member States.organizations and Health Canada and WHO as
The same dossier is submitted to all Member Statesobservers. ICH establishes guidelines applicable to the
where a marketing authorisation is needed. TheEU, US and Japan through a series of expert working
applicant selects a Reference Member State andgroups. There is a stepwise development of the
prepares a preliminary assessment report within 120guidelines. At Step 4, there is consensus
days and sends it to the other states, the Concernedinternationally and at Step 5, an agreement by the
Member States. They then approve the assessmentregulators that they will introduce the guidelines into
or the application will continue into a facilitation or, iflegislation, although there may be some divergence
this fails, a binding arbitration procedure applies.when these are actually put into effect in the
Laws and guidelinesdifferent regions.
LawsThe three areas covered by ICH guidelines are
In the EU there are EU laws which are directives andEfficacy, Safety and Multidisciplinary. Paradoxically, the
regulations, and national laws. Once an EU regulation"Efficacy" guidelines include clinical (human) safety,
comes into effect it is in force in all the Memberwhereas the "Safety" guidelines concern only
States of the European Union. However EU directivespre-clinical (animal toxicology) safety.
are different, once an EU directive comes into forceThe main guidelines concerning pharmacovigilance are:
it must first be enacted in national law in each EUE1: populations to be studied for safety and efficacy
Member State within a specified time-frame. As wellE2A: reporting on safety in clinical trials
as the national laws that put EU directives into action,E2B: electronic reporting of adverse events
there may also be national laws governingE2C: periodic safety update reports
pharmacovigilance practice.E2D: reporting on safety post-marketing
The principal EU laws concerning pharmacovigilanceE2E: pharmacovigilance planning
are:E2F: development safety update reports
Directive 2001/83, amended by Directive 2004/27.M1: Medical Dictionary for Regulatory Activities
This concerns all medicinal products, although forM4: the Common Technical Document (i.e.