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Streamlining safety

The European Commission is aiming for a simplified, risk–benefit approach to pharmacovigilance

books_hammer Between 5 December 2007 and 1 February 2008, the European Commission consulted stakeholders on legislative changes to strengthen and rationalise the EU system of pharmacovigilance. Following the outcome of the consultation, on December 10 2008, the EU Commission announced proposals to change the legislation (provisions in Regulation EC No 72–6/2004 and Directive 2001/83/EC). The overall objectives being to better protect public health, ensure proper functioning of the internal market and simplify current procedures.

At the heart of the changes is a move towards a risk-based, streamlined approach to pharmacovigilance. It is put forward that the reporting of adverse drug reactions (ADRs) should be made directly to the Eudravigilance database, and periodic safety update reports (PSURs) should be simplified to reflect the risk–benefit profile of the relevant medicine. This should avoid much of the current duplication between ADR reporting and the submission of PSURs. The proposals also envisage patients being able to make ADR reports.

Fifteen specific policy options were selected by the EU Commission. These can be summarised as:
• clarification and codification of the tasks and responsibilities required of all involved parties and the setting of standards
• establishing a clear European Medicines Agency (EMEA) committee structure for pharmacovigilance, scientific assessment and decision making that will coordinate activities and make recommendations on the safety of medicines at EU level
• rationalising the EU pharmacovigilance referral procedures
• increasing drug safety transparency
• improving EU coordination of communication about major new or changing safety issues and launch of an EU portal on the safety of medicines
• introduction, with a transitional implementation period, of a new section in the Summary of Product Characteristics and in patient information leaflets on key information
• introduction of a "Pharmacovigilance System Master File" to ensure robust but less bureaucratic supervision of companies' pharmacovigilance systems
• provision of a clearer legal basis for risk management plans for new and authorised products where there are safety concerns, including post-authorisation safety studies
• codification of guiding principles for overseeing the conduct of non-interventional post-authorisation safety studies
• simplification of ADR reporting using the EU Eudravigilance database as a central tool
• scanning of the scientific literature by the EMEA within a clearly defined scope
• exchange of data, on medication errors that result in an adverse reaction, including between the competent authorities for medicines and those for patient safety
• removal of the current routine requirement for industry PSURs for low risk, old and established products
• provision of the legal basis for the new EMEA pharmacovigilance committee structure to require submission and coordinate assessment of PSURs and make consequent recommendations for product labelling
• provision of the legal basis for patients to report suspected ADRs.

Industry obligations
Companies' pharmacovigilance responsibilities will be clarified. This includes obligations to continuously monitor the safety of products and to bring all relevant information to the attention of the authorities.

One specific change involves the creation of the Pharmacovigilance System Master File. The current legislation requires a "detailed description of the pharmacovigilance system" to be submitted in marketing authorisation applications. The new proposals aim to simplify this. Only key elements of the pharmacovigilance system will need to be submitted, with more detailed information stored in the Pharmacovigilance System Master File on the relevant company's site.

ADR reporting
The Commission aims to strengthen the reporting system for ADRs. At the moment the regime applies to all medicinal products, irrespective of their known risks. Where there is more than one member state in which the product is authorised, ADRs are submitted to more than one authority – leading to duplication. ADR focuses on side effects where a product is used under normal conditions. Other side effects, including those from medication errors or overdose, are not necessarily reported.

If suggested changes are made law, reporting will be proportionate to risk, patients will be able to report side effects and overdoses and medication errors will be noted. ADR reporting will be simplified with data reported, by marketing authorisation holders and member states, directly to the Eudravigilance database. This database should become the single point of receipt of pharmacovigilance information for medicinal products authorised in the EU.

Simple and safe
PSURs currently comprise listings of adverse reactions and, like ADRs, are submitted for all medicinal products. There is no scope for group submissions or assessments by products or substances, which results in duplication.

The Commission proposes simplifying PSUR submission and making it proportional to the knowledge about the safety/risk of the product. It would introduce work-sharing mechanisms for assessments and there will be a prominent role in all cases for a new scientific committee responsible for pharmacovigilance – the Pharmacovigilance Risk Assessment Advisory Committee.

Establishing clear procedures should lead to faster updating of product information. With all ADR data submitted directly to the Eudravigilance database, the scope of PSURs would be amended to become an analysis of the risk-benefit of a medicinal product rather than a detailed presentation of individual case reports. Routine reporting will no longer be necessary where products are considered low risk or where such reporting would be a duplication.

The new proposals envisage a single assessment of PSURs for medicinal products authorised in more than one member state, including for products containing the same active ingredient. A single assessment would also be conducted when there are pharmacovigilance issues about products authorised by member states and products authorised by the Commission.

Risk management
Another proposal is to rationalise the risk management planning by basing evaluation of medicinal products on risk management and ensuring that high-quality, non-promotional safety studies are carried out, when justified by safety concerns.

Currently applicants for a marketing authorisation may provide a risk management system for specific medicinal products if considered appropriate, but there is no express legal basis for authorities to request it. The new proposals will require a risk management system for each new medicinal product (or for existing products on the basis of safety concerns). The risk management system should be proportionate to:
• the identified risks
• potential risks
• the need for additional information on the product in question.

There is also provision for harmonised guiding principles, and a procedure for the supervision of "non-interventional post-authorisation safety studies" which are studies of authorised products not clinical trials. In particular, to ensure that such studies are non-promotional, and that there is follow-up of any safety data generated.

Cost reduction
The Commission has described the proposed changes as creating a "win-win" situation with increasing clarity, efficiency and quality of the EU system of pharmacovigilance.

Estimates, in Commission Staff Working Document SEC(2008)2671, state that as a result of the new proposals, between 591 and 5,910 lives will be saved each year and save society between €237m and €2.4bn.

Meeting current EU regulatory requirements for pharmacovigilance costs pharma €833m. The new proposals are anticipated to redirect the industry spend from duplicative ADR, periodic, literature and system reporting to more proactive monitoring, with higher quality data collection through risk management planning and post authorisation studies. Overall, the proposals will reduce the cost to EU pharma by about 17.4 per cent – a saving of €145m each year.

There are estimated one off costs of €3.9m for the EMEA and €3.9m across the EEA national competent authorities. The proposals foresee industry fees covering these costs, however it has been stated by the Commission that these costs will not necessarily result in direct fee increases as, at least for the EMEA, fee income is in surplus.

The new proposals are not yet law. They will now be discussed and voted upon by the European Parliament and the Council. The pharma industry should keep a close eye on the proposals' progress, and be ready to comment on their implementation at a national level.

The Authors
Tim Worden is senior associate and Dr Loretta Pugh is associate at Taylor Wessing LLP
To comment on this article, email


In Brief

CAT elects chair
Dr Christian Schneider has been appointed chair of the European Medicines Agency's (EMEA) new Committee for Advanced Therapies (CAT). The main responsibility of this multidisciplinary committee is to draft an opinion on advanced therapy medicinal products (ATMP) applications for consideration by the Committee for Medicinal Products for Human Use (CHMP) before marketing authorisation is granted, revoked, varied or suspended. ATMP regulation applies to gene therapy medicinal products, somatic cell therapy medicinal products and tissue-engineered products.

Dr Schneider is head of the division for EU cooperation/microbiology at the Paul Ehrlich Institut in Langen, Germany. He is a member of the CHMP and the Scientific Advice Working Party (SAWP). He also chairs of the Biosimilar Medicinal Products Working Party (BMWP).

Dr Paula-Anneli Salmikangas has been elected as vicechair of CAT. She is a senior researcher at the National Agency for Medicines in Finland and an associate professor in biochemistry at the University of Helsinki. She chairs the EMEA's Cell-based Products Working Party (CPWP) and is a member of the Biologics Working Party (BWP).

Commenting on their appointment Dr Schneider said: "Our common goal is to establish the CAT as a strong and internationally highly recognised independent committee. A committee that fosters innovative medicines, gathers scientific expertise and skills, whilst it collaborates effectively with the other scientific committees at the EMEA to perform top-level assessment in the best interest of patients." 


13th March 2009


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