Head of Pharmacovigilance Department
Hopital Henri Mondor, Assistance Publique Hôpitaux de Paris, Université Paris-Est Créteil
President of the International Society of Pharmacovigilance
** Prof. Jean-Michel Dogné
Head of the Department of Pharmacy
Namur Thrombosis and Hemostasis Center (NTHC)-Narilis
University of Namur
Rue de Bruxelles, 61
B-5000 Namur, Belgium
In European Union (EU), the Burden of Adverse Drug Reactions (ADRs) is a major concern of public health with 5% of all hospital admissions due ADRs and 5% of all hospital patients suffering an ADR. Today ADRs are the 5th most common cause of hospital death with 197 000 deaths per year for a cost of Euro 79 Billion / year.
To establish Robust Risk Management, robust science methods, robust resources and robust law are necessary.
2) Overview on the European legislation.
The pharmacovigilance legislation, which came into effect in 2012, introduced a range of new tasks and streamlined existing responsibilities for regulators and the pharmaceutical industry in the EU. It had also significant implications for patients, and healthcare professionals. The practical measures to facilitate the performance of pharmacovigilance in accordance with the legislation are available in the guideline on good pharmacovigilance practices (GVP).
The pharmacovigilance legislation aims to reduce the number of ADRs in the EU. It aims to achieve this through:
- The collection of better data on medicines and their safety;
- A rapid and robust assessment of issues related to the safety of medicines;
- An effective regulatory action to deliver safe and effective use of medicines;
- The empowerment of patients through reporting and participation;
- Increased levels of transparency and better communication.
The legislation impacts on marketing-authorisation applicants and holders. It aims to:
- make their roles and responsibilities clear;
- minimise duplication of effort;
- free up resources by rationalising and simplifying reporting on safety issues;
- establish a clear legal framework for post-authorisation studies.
The European Medicines Agency (EMA, the Agency), the EU Member States (MSs) and the European Commission (EC) are responsible for implementing and operating much of the pharmacovigilance legislation. The Agency plays a key role in coordinating activities relating to the authorisation and supervision of medicines, including safety monitoring, across this network.
The Agency is working with a wide range of stakeholders including the EC, pharmaceutical companies, national medicines regulatory authorities, patients and healthcare professionals.
The Agency has now seven scientific committees that carry out its scientific assessments and the new legislation is mainly centred on the Pharmacovigilance Risk Assessment Committee (PRAC).
The other committee are:
- Committee for Medicinal Products for Human Use (CHMP)
- Pharmacovigilance Risk Assessment Committee (PRAC)
- Committee for Medicinal Products for Veterinary Use (CVMP)
- Committee for Orphan Medicinal Products (COMP)
- Committee on Herbal Medicinal Products (HMPC)
- Committee for Advanced Therapies (CAT)
- Paediatric Committee (PDCO)
It is important to understand that in the EU, medicines can be authorised throughout the EU by means of 2 main different procedures, the centralised procedure and the decentralised and mutual recognition procedure.
- The centralised procedure: The Agency is responsible for the scientific evaluation of applications for centralised marketing authorisations. The evaluation is performed by the CHMP, with input from the PRAC on aspects of the risk-management plan and the CAT for advanced-therapy medicines. Once granted by the EC, the centralised marketing authorisation is valid in all EU. This allows the marketing- authorisation holder to market the medicine and make it available to patients and healthcare professionals throughout the EEA. All human medicines derived from biotechnology and other high-tech processes must be evaluated by the Agency via the centralised procedure. The same applies to all advanced- therapy medicines and medicinal products containing new active substances intended for the treatment of HIV/AIDS, cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases, as well as to all designated orphan medicines intended for the treatment of rare diseases.
- The decentralised and mutual recognition procedure: The mutual recognition procedure (MRP) is a European authorisation route resulting in a mutually recognised product. It must be used when a product is already authorised in at least one Member State on a national basis and the Marketing Authorisation Holder wishes to obtain a Marketing Authorisation (MA) for the same product in at least one other Member State.
The decentralised procedure (DCP) is a European authorisation route resulting in a mutually recognised product (MRP). The difference between MRP and DCP is that a product must already be authorised in at least one Member State on a national basis in order for MRP to be used. DCP may be used if the product is not already authorised in any Member State, but does not want to use the centralised procedure.
3) The PRAC
The PRAC is responsible for assessing all aspects of the risk management of medicines for human use. This includes the detection, assessment, minimisation and communication relating to the risk of adverse reactions, while taking the therapeutic effect of the medicine into account. It also has responsibility for the design and evaluation of post-authorisation safety studies and pharmacovigilance audit.
The main responsibility of the PRAC is to prepare recommendations on any questions relating to pharmacovigilance activities related to a medicine for human use and on risk-management systems, including the monitoring of the effectiveness of those risk-management systems.
According to the procedure of registration, the PRAC generally provides these recommendations to the CHMP, the Coordination group for Mutual and Decentralized procedure- Human (CMDh), the EMA secretariat, Management Board and EC, as applicable.
The PRAC can be involved indifferent procedures
- Assessment of signals relating to medicines marketed in the EU. The Report of the Council for International Organisations of Medical Sciences Working group VIII Practical Aspects of Signal Detection in Pharmacovigilance defines a signal as information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action;
- Referral which is a procedure used to resolve issues such as concerns over the safety or benefit-risk balance of a medicine or a class of medicines. In a referral, the Agency is requested to conduct, on behalf of the European Union, a scientific assessment of a particular medicine or class of medicines. There are a number of reasons why a referral may be started, ranging from concerns over the safety of a class of medicine to disagreements among Member States on the use of the medicine. At the end of the referral, the Committee makes a recommendation, and the EC issues a decision to all Member States reflecting the measures to take to implement the PRAC recommendation. The medicine, or the class or medicines, is ‘referred’ to the PRAC, so that the committee can make a recommendation for a harmonised position across the European Union;
- Assessment of medicines’ risk management plans (RMP). A RMP is a detailed description of the activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicines. In the European Union (EU), companies must submit an RMP to the Agency at the time of application for a marketing authorisation. For medicines that do not have an RMP, it is likely that one will be required with any application involving a significant change to the marketing authorisation;
- Assessment of non-interventional safety study protocols and study reports;
- Assessment of the Periodic Safety Update Report (PSUR) where at least one of the Marketing Authorisations (MAs) has been granted in accordance with the centralised procedure. PSURs are pharmacovigilance documents intended to provide an evaluation of the risk-benefit balance of a medicinal product for submission by marketing authorisation holders at defined time points during the post-authorisation phase;
- Establishment of a list of EU Reference Dates (EURD) and frequency of submission of PSURs;
3-2) Composition and meetings.
The members of the PRAC are nominated by European Union Member States, in consultation with the Agency's Management Board. They are chosen on the strength of their qualifications and expertise with regard to pharmacovigilance matters and risk assessments of medicines for human use.
The PRAC is composed of:
- a chair and a vice chair, elected by serving PRAC members;
- one member and an alternate nominated by each of the 28 Member States;
- one member and an alternate nominated by Iceland and by Norway;
- six independent scientific experts nominated by the European Commission;
- one member and an alternate nominated by the European Commission after consultation of the European Parliament to represent healthcare professionals;
- one member and one alternate nominated by the European Commission after consultation of the European Parliament to represent patients organisations.
The PRAC meets once a month and meetings are not public. However, The Agency publishes the agendas and minutes of the meetings on his website. After each PRAC meeting, the Agency also publishes a table highlighting the main decisions taken during the meeting.
During its first Term, from July 2012 to Dec 2014, the PRAC held 26 meetings:
- More than 300 potential signals (193 true signals) have been discussed. It allows a faster detection and management of new and changing safety issues;
- 600 RMPs have been reviewed which supports protection and innovation;
- 1000 PSURs have been revised, allowing an integration of benefit and risk and direct application of new labelling (faster impact)
- 150 PASS protocols have been studied which are better planned and better scrutinised
- 31 safety referrals have been debated, as major assessments delivering labelling for safe and effective use of medicines
Many improvement have been achieved in the field of medication errors with the adoption of good practice guides in 2015 and in transparency concerning committee proceedings, side effect data, RMP summaries and PSUR assessment conclusions
We have come from a situation with reactive monitoring, under-utilisation of structured data collection, overlapping roles and responsibilities, duplication of effort in efficient use of resources, exclusion of patients from safety monitoring, low levels of transparency to a situation with, proactive monitoring, faster safety issue detection, faster warnings to users, increased transparency, engagement of stakeholders, process improvement, and simplification.
The last three years have seen great progress in realising potential of EU Pharmacovigilance legislation & role of PRAC.
Experience has demonstrated areas where a strengthened, clarified or simplified approach are needed and this will be the basis for developing a work plan for 2016 with a clear focus on best evidence and new methodologies.