You pharmacovigilance system could consist of an in-house team or an external expert company providing a pharmacovigilance service – either way, one thing is for sure, you will waste time and money without a very basic understanding of EU rules on product pharmaceutical registration and pharmacovigilance. This article succinctly explains the key concepts of marketing authorisation in the EU via the Centralised Procedure, Mutual Recognition Procedure and Decentralised Procedure. This guide to basic concepts allows you to gain entry level understanding of the three main regulatory pathways before moving on to work with consultants from your pharmacovigilance services.

The Three Vital Routes to Pharmaceutical Product Registration

Any pharmaceutical product which needs a marketing authorisation in order to be sold in one or more EU countries is going to need to follow one of the legal routes in order to be registered:

“Centralised Procedure” – Regulation (EC) No 726/2004

“Mutual Recognition Procedure”

“Decentralised Procedure” – Directive 2001/83/EC.

As well as these three routes, there are some national authorisations which could allow a product to be marketed in the particular member state or states granting them. This can be an avenue to pursue in order to apply for authorisation under the Mutual Recognition Procedure. Wherever the single national marketing authorisation is will become the country which assumes responsibility for monitoring and safety assessment for that particular product.

Key Concepts of The Centralised Procedure

Administration of this legal route to marketing authorisation is the responsibility of the EMEA. A single application is made with the aim of gaining marketing authorisation throughout all the countries of the EU, Iceland, Norway and Liechtenstein. Once products meet the market, the European Commission is then the responsible agency. This Centralised Procedure should be used for new products and those containing novel substances which are designed to treat serious illness. It is also the route for all biotechnology medicines,

One EU countries regulatory authority becomes the official  Rapporteur, and will be responsible for the initial assessments for the Marketing Authority application. A second agency is appointed as the official Co-Raportuer and between the two agencies, the responsibility for safety assessment and monitoring is shared once the product is introduced to the market.

The regulations are stringent and as such, it is essential that the applicants company uses an experienced in house or externally hired pharmacovigilance services company throughout the application process- and of course, after the product has reached the market

Key Concepts of  Mutual Recognition Procedure

When a product has had a marketing authorisation issued by a single EU country but is required to be marketed in other EU countered, the Mutual Recognition Procedure may be the answer. Should an application be successful, in essence, the marketing authorisation is copied by the other countries involved. The nation which issued the marketing authorisation on a national level is known as the ‘Reference Member State’. The other countries the product is applying to be sold in are  known as the ‘Concerned Member States’. After an application has been entered, there will be a 90 day period during which the ‘Concerned Member States’. Enter an assessment phase. If the application is successful, the original marketing authorisation issued by the ‘Reference Member State’ is adopted into identical authorisations by the ‘Concerned Member States’.

If the application is not successful due to objections raised by any of the ‘Concerned Member States’, the matter is subject to referral to the EMEA. There will be a debating process to try to resolve any problems, and should this fail the next step would be binding arbitration. Whilst there are mechanisms in place, there is no substitute for the services of competent pharmacovigilance solutions companies.

Key Concepts of The Decentralised Procedure

This concerns when there is a product for which there has not so far been any marketing authorisation granted in any country in the EU. A dossier will be copied and circulated to all the EU countries in which as marketing authorisation is sought. The company who submit the application are able to decide which country should be the ‘Reference Member State’ under this procedure. The company must prepare a preliminary report within 120 days and circulate it to every ‘Concerned Member State’. If the application is not accepted, it does continue, into a facilitation period. If this remedy is still not successful to resolve the problems, binding arbitration will be imposed.

The Decentralised Procedure again obviously requires expert input at every step of the way from the company’s in house or external pharmacovigilance team.

This summary of the nature of the three legal routes to product registration in the EU should help when deciphering some of the industry jargon surrounding gaining EU product registration. This can assist you in dealing with either an in-house pharmacovigilance department or any external pharmacovigilance services provider.

Pre-clinical Research

The research program consists of animal, ex vivo and in vitro experiments, carried out in accordance with the requirements laid down in detailed regulatory guidelines. A number of short-term animal studies must be carried out before the substance can first be tried in single doses in humans. The animal studies comprise: toxicology studies –the effects of large doses; pharmacology studies – the effects of the substance on how the body systems function; and pharmacokinetic studies – looking at how the substance is absorbed, distributed, metabolised and eliminated in the animal.

Longer duration animal toxicology studies must then be performed before multiple doses may be administered in humans, with increasing periods of exposure and a larger range of animals being studied as exposure in humans increases during clinical research.

Alongside the above animal pre-clinical studies, other studies are carried out e.g. mutagenicity studies (effects on chromosomes and on genetic processes), studies of effects on the foetus etc.

This rolling program of pre-clinical studies synchronises with the clinical study programme. At each step in the clinical trial program, there must first have been reassuring information from animal studies. However, even at the time of application for a marketing authoriztion, there may be ongoing long-term animal studies – usually carcinogenicity studies – the results of which may only become available after the product is on the market.

Clinical Research

The clinical trial program in humans can be considered as comprising four phases. In phase 1, generally involving up to about 100 subjects, there is study of the tolerability of increasing single doses of the drug and investigation of its pharmacology and pharmacokinetics. Phase 2, usually includes the first study of efficacy in patients with the disease and studies – commonly in a few hundred patients – to find a dose that is effective and well-tolerated. However, phase 1 studies may continue alongside phase 2 studies. Phase 3 potentially extends the studies into several thousand patients – although the average is around 1,500. The focus is on demonstrating efficacy and acceptable safety in the intended population. If the drug is to be used over long periods of time, there will be long-term studies. At the end of the program comes the assembly and submission of a registration dossier to regulatory authorities. This is the application for marketing authorisation (MAA in Europe, NDA in the US). The dossier is usually submitted electronically but the paper copy of the pharmaceutical, pre-clinical and clinical files often comprises many hundreds of volumes of data, each volume comprising several hundred pages. The clinical trials usually continue during the registration review period, and Phase 4 studies are set up after marketing.

Each step in the clinical research program is heavily regulated. Before first exposure in man, there is assessment by the regulatory authorities of all the animal and in vitro studies. Every trial thereafter has to be approved by the appropriate regulatory authorities –and separately by ethics committees in each country – based on summaries of the available evidence to date. All new relevant safety information arising from animal studies must be submitted to the authorities and the ethics committees during the clinical research program (and to the regulatory authorities if arising thereafter).

An investigator brochure summarising all knowledge to date about the safety and efficacy of the study drug is created by the company and updated at intervals. This is supplied to all investigators and to the ethics committees and regulators.

Serious, unexpected adverse reactions that occur during clinical trials and are suspected of being related to the study drug (SUSARs) must be submitted to the appropriate regulatory authorities within specified short time frames (expedited reports). They must also be notified to all investigators and to ethics committees. Each year during the course of the clinical trial program, annual reports (Annual Safety Reports in the EU, IND Annual reports in the US) including a summary and analysis of all the serious adverse events that have arisen during that period and all new safety findings from animal studies, as well as evaluations of benefit and risk, must be submitted to the regulatory authorities and ethics committees. All of these submissions are required by law and compliance by the companies is checked by a combination of internal company audit and regulatory authority inspection.

The review of safety in clinical trials pre-registration is performed throughout the clinical research program by R&D and pharmacovigilance departments within the sponsor companies. The conduct of the clinical trials is often contracted out to Contract Research Organizations (CROs) – but the responsibility for safety lies with the sponsor company. In addition, safety may be reviewed continuously by independent Drug Safety Monitoring Boards set up for specific studies.