Clinical trials
Medicines that have not been marketed before must undergo clinical trials to demonstrate their safety and efficacy (effectiveness).
The relevant legislation for the UK is the Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004 no 1031) (external link) which came into force on 1 May 2004.
These regulations implement Directive 2001/20/EC (external link) relating to good clinical practice in the conduct of clinical trials on medicinal products for human use – known as the 'European Clinical Trials Directive'.
More details and links to the legislation and guidance documents can be found in the main Clinical trials section of the website.
Marketing authorisations (MAs)
Marketing authorisations are the European licensing system for medicines. MAs replaced the product licence (PL) system.
Applications for marketing authorisations mainly come from the pharmaceutical industry, but anyone with the necessary supporting data may apply.
There are several routes that applicants can take to obtain a marketing authorisation.
Centralised procedure
In the European Union (EU), a company may submit a single application to the European Medicines Agency (EMA) for a marketing authorisation that is valid simultaneously in all EU Member States, plus Iceland, Liechtenstein and Norway. This is called the centralised (or community) authorisation procedure, and is mandatory for certain types of medicines and optional for others. (The precise scope is set out in Annex I of Regulation (EC) No 726/2004) (external link).
Other authorisation procedures are used for medicines that do not fall within the mandatory scope of the centralised procedure:
National procedure
Each EU Member State has its own procedures for the authorisation of medicines that fall outside the scope of the centralised procedure.
Full details of the procedure in the UK and the various types of application are available in the Marketing authorisations section of the website.
There are also two other routes available to companies for the authorisation of medicines in several EU countries simultaneously.
Decentralised procedure
Using the decentralised procedure, companies may apply for simultaneous authorisation in more than one EU country of products that have not yet been authorised in any EU country and that do not fall within the mandatory scope of the centralised procedure.
Mutual recognition procedure
In the mutual recognition procedure, a medicine is first authorised in one EU Member State, in accordance with the national procedures of that country. Following this, further marketing authorisations can be sought from other EU countries in a procedure whereby the countries concerned agree to recognise the validity of the original, national marketing authorisation.
Further details about the decentralised and mutual-recognition procedures can be obtained from the Coordination Group for Mutual Recognition and Decentralised Procedures – Human, CMD(h) (external link).
More details can be found in the Marketing authorisations section of the website.
Maintaining a marketing authorisation
Renewals
Under the medicines legislation which was implemented on the 30 October 2005, marketing authorisations are be valid for five years and then may be renewed on the basis of a re-evaluation of the risk-benefit balance.
Once renewed, the marketing authorisation will be valid for an unlimited period unless there are justified grounds relating to pharmacovigilance to proceed with one additional five-year renewal. In addition, the five-yearly cycle of Periodic Safety Update Reports (PSURs) with renewal has been replaced by a three-year cycle.
Full details of the renewal procedures, PSURs and guidance documents are available:
Information for licence holders
Variations
The MHRA has revised its procedures for processing applications to vary marketing authorisations in line with the European legislation. (Commission Regulations 1084/2003/EC [external link] and 1085/2003/EC [external link] concern mutual recognition (MR) and centralised procedures, respectively). Information on centralised procedures is available from the European Medicines Agency (EMA) website (external link).
The Mutual Recognition Facilitation Group (MRFG) has revised and brought together all its guidance on variations procedures into a single Best Practice Guide (BPG) which is available on the Heads of Agencies website (external link).
MHRA guidance and fees information is available:
Product Information
The term product information includes the packaging labels and patient information leaflets. Full details of the relevant legislation and guidance documents are available on the webite.
Labels, packaging and patient information leaflets
Advertising
The advertising of medicines is controlled by a combination of statutory measures (with both criminal and civil sanctions) enforced by the MHRA and self-regulation through Codes of Practice for the pharmaceutical industry, administered by trade associations. Full details of the legislation and links to the MHRA guidance and trade associations are available on the website.
Pharmacovigilance
Pharmacovigilance is the process of:
- monitoring the use of medicines in everyday practice to identify previously unrecognised adverse effects or changes in the patterns of adverse effects
- assessing the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use
- providing information to healthcare professionals and patients to optimise the safe and effective use of medicines
- monitoring the impact of any action taken.
The reporting obligations of marketing authorisation holders and sponsors of clinical trials are defined in the Community legislation, in particular Regulation (EC) No 726/2004, Directive 2001/83/EC (external link) as amended and Directive 2001/20/EC (external link).
For more information visit the Eudravigilance website (external link).
Detailed guidance on pharmacovigilance reporting to the MHRA is available on the website.
Good pharmacovigilance practice
Reclassification
New medicines are usually authorised for use as prescription only medicines (POM). After some years' use, if adverse reactions to the medicine are few and minor, it is possible that the medicine may be safely used without a doctor's supervision. If there is sufficient evidence of safety, a medicine may be reclassified for sale or supply under the supervision of a pharmacist (P).
Pharmacy medicines which have been safely used for several years may be suitable for general sale and may be reclassified as GSL.
Reclassification of a substance normally follows a request from the company which holds a marketing authorisation for it. However, requests can be made by any interested party, such as a professional body, or be initiated by the MHRA. Unless the reclassified product is just a different pack size, the new product must have a different brand name to the original product and therefore a separate marketing authorisation. Full details about the procedure are available:
Legal status and reclassification
Manufacture and wholesale dealing
The manufacture and wholesale dealing of medicinal products are licensable activities under UK and EU legislation.
Applications for new licences and variations to existing licences are processed by the Licensing Office in the Inspection and Standards Division of the MHRA. The Licensing Office deals with a range of licences and covers activities including pharmaceutical manufacturing (including the manufacture of investigational medicinal products), pharmaceutical wholesaling, authorisation of blood establishments and administrative tasks for clinical trials and pharmacovigilance.
Licensing Office staff are also responsible for issuing certificates in support of the World Health Organization scheme on the quality of pharmaceutical products moving in international commerce (often referred to as export certificates). When carrying out their role, staff in the Licensing Office work closely with colleagues in the Inspectorate.
European legislation for manufacturers is laid down in:
- Directive 2001/83/EC, Title 4 – Manufacture and Importatio
- Directive 2003/94/EC (external link
- the ‘GMP’ Directive. (see Good Manufacturing Practice
- for wholesalers in Directive 2001/83/EC (external link) Title VII, Wholesale Distribution.
The UK legislation is The Medicines for Human Use (Manufacturing, Wholesale Dealing and Miscellaneous Amendments) Regulations 2005 No. 2789
(164Kb).
The Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2007 - the 'Orange Guide’ provides interpretation and guidance of all the relevant legislation, including official guidelines published by the European Commission.
