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Wednesday, 23 November 2011

Fundamentals of EU Drug Regulatory Affairs


The history of pharmaceutical legislation in the European Union (EU) is intricately linked with legislation and harmonisation across other socioeconomic sectors as well as ever-increasing membership of the EU. The unique strength of the European system of licensing and monitoring medicinal products lies in the scrutiny a new drug, or the safety of an approved drug, receives from the national authorities of all its Member States. A major advantage of this pan- European system is that it can draw on the expertise of all its Member States and, invariably, each application is closely scrutinised by all the experts and advisory committees of each of its Member States. The EU system, through initiatives of its Member States, has provided important leads to other regulatory authorities of the world, either indirectly or formally through the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
The websites of the EU and the European Medicines Agency (EMEA) include all legislation and guidelines as well as a vast amount of information related to pharmaceutical procedures and medicinal products.
I. Member states: Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Liechtenstein, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovak Rep., Slovenia, Spain, Sweden, United Kingdom.
II. Regulatory Agencies and Pharmaceutical Organizations in EU:
1. EMA: The European Medicines Agency (EMA) is a decentralized body of the European Union, located in London. The Agency is responsible for the scientific evaluation of applications for European marketing authorizations for both human and veterinary medicines (centralized procedure).
Further information: European Medicines Agency
2. HMA: The Heads of Medicines Agencies is a network of the Heads of the National Competent Authorities whose organizations are responsible for the regulation of Medicinal Products (Mutual reorganization procedure and Decentralized procedure) for human and veterinary use in the European Economic Area.
Further information: Heads of Medicines Agencies
3. EGA: The EGA is the official representative body of the European generic and biosimilar pharmaceutical industry, which is at the forefront of providing high-quality affordable medicines to millions of Europeans and stimulating competitiveness and innovation in the pharmaceutical sector.
Further Information: European Generic Medicine Association
4. Eudralex: "The rules governing medicinal products in the European Union" called as Eudralex. It consists 10 volumes; each volume describes each pharmaceutical activity.
a. Concerning Medicinal Products for Human use:
Volume 1 - Pharmaceutical Legislation.
Volume 2 - Notice to Applicants.
Volume 2A deals with procedures for marketing authorisation.
Volume 2B deals with the presentation and content of the application dossier.
Volume 2C deals with Guidelines.
Volume 3 - Guidelines.
b. Concerning Medicinal Products for human use in clinical trials (investigational medicinal products):
Volume 10 - Clinical trials.
c. Concerning Veterinary Medicinal Products:
Volume 5 - Pharmaceutical Legislation.
Volume 6 - Notice to Applicants.
Volume 7 - Guidelines.
Volume 8 - Maximum residue limits.
d. Concerning Medicinal Products for Human and Veterinary use:
 Volume 4 - Good Manufacturing Practices.
Volume 9 - Pharmacovigilance.
e. Miscellaneous:
Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03)
Further information: Eudralex
5. National Competent Agencies
Further information: EU Members states Agencies
III. European pharmaceutical legislation: The EU has a set of legal instruments known as either the Regulations or the Directives. In addition, the European Commission (EC) issues communications to clarify its legal understanding of the legislation or requirements. There are also guidelines issued by various EU regulatory bodies. Legislation is two types:
1. Legally binding acts
a) Regulation: A regulation is an act of general application, binding in its entirety and directly applicable in all Member States. It does not require any transposition by the national authorities.
Ex: Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products
b) Directive: A Directive is a legal instrument that is binding, as to the result to be achieved, upon each Member State to whom it is addressed. However, the national authorities are left the choice of form and methods to achieve their objectives. Directives may be addressed to individual, several or all Member States. In order to ensure that the objectives laid down in Directives become applicable to individual citizens, an act of transposition by national legislators is required, whereby national law is adapted to the objectives laid down in Directives.
Ex: Directive 2001/83/EC relating to medicinal products for human use
c) Decision: A decision is a legal act binding in its entirety upon those to who it is addressed (Member State or natural or legal person).
Ex: Council Decision 1999/468/EC with regard to the regulatory procedure with scrutiny Adaptation to the regulatory procedure with scrutiny
2. Soft law
a) Resolution: A resolution is a declaratory act not provided for by the EC Treaty that is published by the Council and the European Parliament in order to inform of their positions on a specific subject, and, where necessary, that invites the Commission to propose the appropriate measures.
A resolution is rather a political than a legal act, it does not create a legal obligation.
Ex: Council Resolution on a global approach to conformity assessment
b) Communication: A Communication is an act not provided for by the EC Treaty, which is without binding legal effect.
It indicates to governments and economic actors how the Commission is planning to apply or wishes to see applied a given Community rule.
The Court of Justice of the European Communities often supports its interpretation of legally binding acts with Commission communications.
Ex: Communication from the Commission - Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies
c) Guidelines
Community guidelines (EMA – Applicable to total Member states)
Guidelines are texts covering technical topics, their legal status may differ:
- Guidelines resulting from a formal request laid down in a Community Directive or Regulation are binding when those acts so provide, and must be complied with when the corresponding Directive or Regulation is implemented.
The Commission publishes them, e.g. the “Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products”.
National guidelines (Applicable to single member state only).
Ex: Netherlands (MEB): Duplex marketing authorization
Ireland (IMB): Human medicines gudiance
d) Notice to applicants
The Commission publishes this guidance in “The rules governing medicinal products in the European Union”. Popularly known as EudraLex.
IV. Types of procedures: There are currently four different procedures that can be used to submit a medicinal product for marketing approval in the European Union.
  • Centralized Procedure (CP)
  • Mutual Recognition Procedure (MRP)
  • Decentralized Procedure (DCP)
  • National procedure
V. Types of applications: As per directive 2001/83/EC, following types of applications are available for registration of pharmaceuticals.
  • Full application
  • Generic application
  • Hybrid application
  • Similar biological application
  • Well-established use application
  • Fixed combination application
  • Informed consent application
VI. Variations:
Variations are by definition any amendment (i.e. addition/deletion/changing the content) to the documentation representing the legal basis for each Marketing Authorisation (MA) of a medicinal product. Variations classifed as Type I (A & B) and Type II. EU variation regulation has been revised and main changes are:
  • Introduction of a European annual reporting system (do and tell procedure)
  • Possibility for grouping of variations
  • Reduction of duplicate work by using a worksharing procedure
  • Implementation of design space concept according ICH.
  • Type IB by default for previously not defined variations and safeguard clause
Further information: Variation guidelines

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