Product Registration

Getting marketing authorisation for medicinal products in more than one Member State in the EU is done by using one of three procedures:

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

“Mutual Recognition Procedure” and

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

As well as these, national authorisations still allow products to be marketed in individual countries in the EU. Products could be authorised separately in several Member States by a number of national authorisations, alternatively one of these authorisations could be used to apply for authorization using the Mutual Recognition Procedure. Where products have national authorisation, the regulatory agency of the country concerned has to monitor and assess the safety of any products that have national authorisation.

Centralised Procedure

The EMEA administers the centralized procedure, where a single application, if approved, grants marketing authorisation for all the countries in the European Union (and the European Economic Area, that’s the EU countries plus Iceland, Norway and Liechtenstein). The European Commission becomes the responsible authority for products which come to market through the centralised procedure. This procedure is available to all new or innovative pharmaceuticals and is the only way to authorise biotechnology medicines. Where products contain new substances for treating serious diseases, they would use the centralised procedure.

The regulatory agency of one Member State is then appointed as the Rapporteur and they will then carry out initial assessments of the application for Marketing Authorisation; a second agency is appointed as Co-Rapporteur. These countries will then be responsible for leading the monitoring and assessment of safety of the product when it is subsequently marketed.

Mutual Recognition Procedure

In the Mutual Recognition Procedure the marketing authorisation of one member State is recognised and copied by the other member states. In this procedure, the ‘Reference Member State’, is “mutually recognised” by other ‘Concerned Member States’. Once the application for mutual recognition has gone in, there is a 90 day assessment period. After the assessment period the Member States grant a marketing authorisation with an identical summary of product characteristics to the one in the Reference Member State as long as they accept the original assessment of the product. If a Member State raises objections and does not recognise the original marketing authorisation then the matter may be referred to the EMEA for discussion among the parties: if this fails, binding arbitration is imposed.

Decentralised Procedure

The decentralised procedure can apply where there is no authorisation yet in any of the Member States. The same dossier is submitted to all Member States where a marketing authorisation is needed. The applicant selects a Reference Member State and prepares a preliminary assessment report within 120 days and sends it to the other states, the Concerned Member States. They then approve the assessment or the application will continue into a facilitation or, if this fails, a binding arbitration procedure applies.

Laws and guidelines

Laws

In the EU there are EU laws which are directives and regulations, and national laws. Once an EU regulation comes into effect it is in force in all the Member States of the European Union. However EU directives are different, once an EU directive comes into force it must first be enacted in national law in each EU Member State within a specified time-frame. As well as the national laws that put EU directives into action, there may also be national laws governing pharmacovigilance practice.

The principal EU laws concerning pharmacovigilance are:

Directive 2001/83, amended by Directive 2004/27. This concerns all medicinal products, although for pharmacovigilance it is most relevant to products authorised by the national, mutual recognition and decentralised procedures. The Member States are the licensing authorities in these procedures.

Regulation 726/2004. This concerns centrally authorised products. The European Commission is the licensing authority for these products.

Directive 2001/20. This is the Clinical Trials Directive and includes extensive coverage of pharmacovigilance for interventional clinical trials pre- and post-authorisation.

Guidelines

A word to the wise here. The guidelines tends to be suggestions or recommended methods. When it comes to EU pharmacovigilance law the guidelines are considered to be compulsory as far as pharmaceutical companies are concerned.

The European Commission guidelines provide detail and interpretation as to how the directives and regulations should be followed.The guidelines are also aimed at regulatory authorities and provide detailed requirements for the way that they must carry out pharmacovigilance as well. The guidelines are:

Volume 9A of the Rules Governing Medicinal Products in the European Community - for post-authorisation pharmacovigilance

Volume 10 of the Rules Governing Medicinal Products in the European Community. This applies to clinical trials pre- and post-authorisation and incorporates the guideline Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use

As well as these laws and regulatory guidelines there are also various voluntary guidelines, generated for the most part by two organizations:

The Council for International Organizations of Medical Sciences (CIOMS)

The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals (ICH).

CIOMS is a body set up under the World Health Organization and UNESCO. It has developed a series of guidelines on pharmacovigilance, drawn up by a committee of volunteers from Industry, regulatory authorities, WHO and others. The main guidelines concern the international reporting form (CIOMS I); periodic safety update reports (CIOMS II); core data sheets (CIOMS III); benefit-risk assessments (CIOMS IV); practical issues in pharmacovigilance (CIOMS V); clinical trial safety data (CIOMS VI); and development safety update reports (CIOMS VII).

Whilst CIOMS guidelines are very influential they are not “official” regulatory guidelines, they have no legal force and are generally there just to provide a consensus on good practices and new methodologies.

ICH consists of representatives of the regulatory authorities from the EU, Japan and US, with representatives of the corresponding industry regional organizations and Health Canada and WHO as observers. ICH establishes guidelines applicable to the EU, US and Japan through a series of expert working groups. There is a stepwise development of the guidelines. At Step 4, there is consensus internationally and at Step 5, an agreement by the regulators that they will introduce the guidelines into legislation, although there may be some divergence when these are actually put into effect in the different regions.

The three areas covered by ICH guidelines are Efficacy, Safety and Multidisciplinary. Paradoxically, the “Efficacy” guidelines include clinical (human) safety, whereas the “Safety” guidelines concern only pre-clinical (animal toxicology) safety.

The main guidelines concerning pharmacovigilance are:

E1: populations to be studied for safety and efficacy

E2A: reporting on safety in clinical trials

E2B: electronic reporting of adverse events

E2C: periodic safety update reports

E2D: reporting on safety post-marketing

E2E: pharmacovigilance planning

E2F: development safety update reports

M1: Medical Dictionary for Regulatory Activities

M4: the Common Technical Document (i.e. the international registration dossier)

Pharmacovigilance is the practice of maximizing the safety and benefit of drugs and minimizing the risks and adverse effects. Pharmacovigilance techniques are employed during trials and afterward once a product is on the market to monitor any adverse events and side effects in order to protect the public. Effective pharmacovigilance is a legal requirement of any pharmaceutical company and the penalties for failing to implement good pharmacovigilance practice are severe.

When a pharmaceutical company is granted a license to release a drug onto the market, the license is granted on the back of several phases of clinical trials where the drug will have been tested firstly on healthy volunteers and then on patients suffering from the condition that the drug is designed to treat. In many cases the drug will have been tested for extensive periods of time on thousands of people the intention being that as many of the adverse effects of the drug will have been spotted during the clinical trials.

The licensing authorities have a balancing act - on the one hand medicines must be as safe as possible, on the other hand they need to make sure that diseases are treated. In order to help achieve this balance there are procedures in place to ensure safety once a drug is on the market. This may be necessary if there are unforeseen long-term consequences of using the medicine or if the medicine interacts in unusual or unexpected ways with other medicines or if the medicine turns out to be less suitable for use in certain populations than was previously suspected - for example in the elderly or infirm. Also very rare and potentially serious side-effects may only be spotted after the drug has been taken by a much larger number of people than could have been on the trials.

In order to almost guarantee finding a side effect that occurs in 1 in 10 patients, you have to give the drug to 30 patients just to be sure of finding that effect. In order to almost guarantee finding an adverse effect that is extremely rare and only affects 1 in 10,000 patients, you need to give it to 30,000 patients. No clinical trial would ever be that extensive and therefore pharmacovigilance is the way to detect these rarer events.

Pharmacovigilance is the science of drug safety, a combination of pharmacoepidemiology and pharmacology it provides the tools to help assess risk vs benefit, to detect signals in data that point to an adverse event and to help assess the significance of these signals. You can read more about it in other articles on here or at the site for the Pharmacovigilance Information Service.

Even large pharmaceutical companies struggle to find suitable expertise in-house. Running a search in Google for “pharmacovigilance job” will show you just how desperate the shortage it. This shortage of talent brings consequent problems when they are inspected by the competent authorities, such inspections being an inevitable part of the pharmacovigilance process. The demands on medium and small companies are such that they can not comply economically in-house and must outsource parts or all of their pharmacovigilance and drug safety operations. They are then left trying to find a reliable pharmacovigilance resource that they can trust.

For small and medium-sized pharmaceutical companies the cost of running a pharmacovigilance system is prohibitive - they simply can’t afford to do it, however worthwhile and important it might be. For larger companies pharmacovigilance systems may be something that they would wish to outsource for reasons of efficiency. There are a number of contract organizations who can run your pharmacovigilance system for you. Again there are many factors to consider, cost being just one of them.

With an outsourced pharmacovigilance systems, the regulator will consider you liable for any problems rather than the company you contract to, so you will want to make sure that the staff are properly trained and fluent in the relevant languages that they will need, most predominantly English. They will be taking in reports from medical professionals and processing them, expediting them where necessary, adding them to the pharmacovigilance database, dealing with and liasing with medical professionals and regulatory bodies on your behalf and also taking calls and queries from members of the public. Remember, when any member of your company or the company acting on your behalf hears of a potentially serious adverse reaction, they have 15 days to get that report confirmed and submitted to the regulator. Outsourcing is a serious matter. Your marketing authorization depends on it. What steps are you taking to make sure that your pharmacovigilance outsourcing is validated and compliant? Is your qualified person available at all times when they need to be? Are they experienced in responding to queries from regulators?

There are many companies out there offering pharmacovigilance services but very few that have been set up as dedicated pharmacovigilance contract research organizations by some of the people who have been in the industry since the start. PrimeVigilance were established as a joint venture between Ergomed, a CRO, and Elliot Brown Consulting whose managing director was one of the authors of MedDRA the Medical Dictionary for Regulatory Authorities, now used worldwide by all regulators, pharmaceutical companies and most recently the WHO. A similar consultancy service is offered by Pietrek Associates. The other option is to go with one of the big CROs such as Parexel, but costs with companies such as this can be prohibitive.