A quick guide to EU's new pharmacovigilance package: what pharma companies should do

Jul 28, 2009

Over the last couple of decades, advances in biomedical science have generated more new and complex medicines to treat a broader range of diseases and conditions than ever before. The number of people taking medications has increased dramatically, and, as a result, governments, patient groups and health advocates are demanding stronger regulatory practices and procedures, to assure the safety of medicines before and after they reach the market.

In particular, pharmacovigilance — defined by WHO as the science of detecting, assessing, understanding and preventing adverse effects of drugs or other drug-related problems1 — is taking on greater importance in the safety management of a product through its life cycle. Despite this increased scrutiny and the additional requirements to monitor products on the market, however, safety problems continue to plague the healthcare system. A case in point: approximately 5% of all hospital admissions in Europe are due to an adverse drug reaction (ADR), and ADRs are the fifth most common cause of hospital deaths.2

In fact, an impact assessment carried out for the European Commission has estimated that ADRs cause 197,000 deaths per year in the EU, at a total cost of €79 billion.2

For these and other reasons, the European Commission is rolling out systemic changes in its drug oversight programme, designed to improve ADR monitoring and the risk assessment of medicines on the market.

After a number of years of stakeholder consultations, the EU pharmaceutical sector believes the old system is too complex and potentially confusing, leading to a duplication of effort and a lack of clarity on who's responsible for what. In addition, the existing system of oversight does not sufficiently take into account the different characteristics and risk profiles of medicines or make the best use of knowledge about adverse effects.

Improving patient safety through better monitoring and simpler rules and procedures, therefore, is at the heart of Europe's pharmacovigilance package — new legislative proposals and guidance designed to reform drug regulation and provide patients with a central source of safety information.

The proposals centre on updating existing directives and regulations governing pharmacovigilance in the EU.3,4 Once implemented, the new measures are expected to save between 600 and 6000 lives a year across the EU, and achieve annual cost savings of between €237 million and €2.4 billion.

In addition, one co-ordinated, efficient and robust EU procedure will deal with safety issues in a centralised manner, rather than disparate national reviews, studies and actions. Public health is expected to benefit by freeing up resources and reducing duplication of effort. There also should be faster product safety assessment and faster updating of product information; clearer, more co-ordinated messages about specific safety risk issues to improve the safe use of medicines; and greater transparency to benefit public health in general.

To realise these goals, the emerging plans are expected to lay out clearer roles for member states, the European Medicines Agency (EMEA) and Marketing Authorisation Holders (MAHs), and to reinforce EMEA's position as a co-ordinating body. A new independent scientific panel within the EMEA, the Pharmacovigilance Risk Assessment Advisory Committee (PRAAC), is being formed to oversee pharmacovigilance assessments, working alongside the EMEA’s Committee for Medicinal Products for Human Use (CHMP) and other assessment bodies. Member states will remain central to the operation of pharmacovigilance in the EU, with increased co-operation and work-sharing mechanisms. But the new package is also designed to clarify the responsibility of companies, particularly the scope of their obligation to continuously monitor product safety so that all relevant information is brought to the attention of the authorities in a timely fashion.

Other planned changes include increasing the functionality of the Eudravigilance database and making it the single point of receipt of pharmacovigilance information on medicines author ised in the EU. The creation of a new web site for the public, dedicated to communicate safety issues, is also in the works.

Over the last few years there have been efforts to improve and streamline the use of available EU resources. These include:
• Work-sharing by the member states
• Harmonisation of European birth dates and report submission schedules
• Reduced duplication of some requirements, ie, third parties
• Screening the literature on behalf of companies (especially generics).

As part of a more proactive approach to safety monitoring in the EU, some of the new changes affecting both regulators and industry will include:
• Establishing good pharmacovigilance practice guidelines and requirements for the Pharmacovigilance System Master File for each
• Introducing an EU list of medicines under intensive monitoring
• Enforcing risk management and post-authorisation commitments
• Increasing patient reporting, including patient-specific report forms within the product packaging
• Developing new safety warnings/messages within packaging (similar to Black Box warnings).

Specifically, below is an outline of the proposed new pharmacovigilance activities and how companies should prepare for and implement appropriate responses:

1. Provide clear roles and responsibilities for responsible parties.
Member states will remain central to pharmacovigilance operations, with increased co-operation and work-sharing mechanisms and streamlined procedures for assessing serious safety issues for nationally authorised products. The EMEA's new Pharmacovigilance Risk Assessment Advisory Committee, composed of a number of pharmacovigilance experts from across the EU, will play a key role in EU pharmacovigilance safety assessments for both new and established products.

To do:
With clarified responsibilities, companies must understand and carry out their obligation to monitor the safety of products so all relevant available information is brought to the attention of the authorities.

The individual responsible for monitoring the safety profile of the MAHs' marketed products, the EU QPPV, must take an even more active role to ensure that quality safety information is provided in a timely fashion. (The EU QPPV is the Qualified Person for Pharmacovigilance, who is legally responsible for the functioning of the system on behalf of the Market Authorisation Holder).

2. Strengthen transparency and communication on product safety to increase the understanding and trust of patients and health professionals and extend the reach of key warnings.
The Eudravigilance database will become the single source of pharmacovigilance information for medicinal products authorised in the EU. The EU will co-ordinate communication about safety issues and establish a European medicines safety web portal.

To do:
Companies must provide a new 'key information' section in the summary of the product characteristics and the package leaflet.

Close collaboration with all parties involved in the preparation of the new style of SmPC will be of paramount importance. (The SmPC is the EU Summary of Product Characteristics — legally approved information that every authorised product must have on its packaging or is made available on a web site etc.) The key safety information must be presented in the context of the product's benefit and is likely to make product packaging and labelling more user-friendly.

3. Strengthen and improve company pharmacovigilance systems, while reducing their administrative burden.
Generally, companies in the EU should find it easier to provide pharmacovigilance system information under the new regulation and the new directive. Rather than filing a comprehensive description of the system they intend to use (currently called the Detailed Description of the Pharmacovigilance System), companies will now be able to follow a pharmacovigilance 'master file' similar to those already used for active ingredients.

To do:
In the new applications, companies only need to submit key elements of the pharmacovigilance system, but this is balanced with a requirement to maintain a detailed file on site.

Companies will benefit from a decrease in the number of variations required to update the Detailed Description of the Pharmacovigilance System. However, the EU QPPV will need to make sure the file is updated regularly and is ready to submitted to the regulatory authorities within seven days, if required.

4. Introduce risk management planning for each new medicinal product and non-interventional safety studies.
In the existing provisions, companies may provide a risk management system for specific medicinal products if considered appropriate, and there is no explicit legal basis for competent authorities to request it.

To do:
In the new proposals, companies must have a risk management system for each new medicinal product (or for existing products with safety concerns), which should be proportionate to the identified risks, potential risks, and the need for additional information on the product.

With increased focus on risk management planning, companies must ensure that their RMPs (a given product's Risk Management Plans, which must follow an EU-sanctioned template) are of high-quality and fit-for purpose and that specific measures for follow-up milestones are attached.

Companies will also be required to develop a procedure for supervising non-interventional- post-interventional authorisation safety studies (ie safety studies of authorised products not in clinical trials) and any safety data generated in such studies).

It will be important for companies to establish systems that identify safety issues from such studies at any point in the process, not just at study-end. This must be transmitted to the EU QPPV for signal detection purposes and for consideration for impact on the benefit-risk profile of the marketed product.

5. Strengthen the reporting system for adverse reactions by rationalising the current system and involving all stakeholders in pharmacovigilance.
Currently, adverse reaction reports are submitted to several authorities if a product is authorised in more than one member state. To eliminate the duplication of these assessments under the new system, reports of all adverse reaction data would be sent directly to the Eudravigilance database. Other elements of the proposals will make reports proportionate to risks, empower patients to report side effects, and ensure that overdoses and medication errors are reported.

To do:
Robust systems will need to be implemented in all companies to make sure mechanisms are in place to collect, evaluate and report patient reports, as well as data on such areas as accidental and intentional misuse/abuse/overdose.

6. Ensure the proactive and proportionate collection of high-quality data relevant to the safety of medicines through risk management and structured data collection.
Several proposals address the issues of proportionality and quality, including the use of simplified periodic safety update report submissions by industry. These reports would be proportional to the knowledge about the safety/risk of each product, with a focus on the risk-benefit balance. Regulatory authorities will follow up on assessments of periodic safety update reports to ensure a clear link between pharmacovigilance evaluations and the review and updating of marketing authorisations in the EU.

To do:
Companies will be able to focus their resource on aggregate report preparation and review for those products that warrant it. It will therefore become even more important to demonstrate a proactive approach to updating product information whenever such a review is carried out at all stages of the product life cycle.

Although these changes are far-reaching and comprehensive — and will take some getting used to — there is no doubt that a streamlined and harmonised approach will benefit all stakeholders. Companies and regulators alike will have access to better tools that will help them provide and receive safety information more quickly, and manage the risks associated with their product more effectively and efficiently.

With a greater understanding of the importance of safety monitoring, along with better utilisation of all the available technologies, everyone connected with these initiatives will ultimately play a more substantial role in helping patients and further safeguarding public health throughout the EU.


1. The Importance of Pharmacovigilance, World Health Organisation, 2002
2. http://ec.europa.eu/enterprise/pharmaceuticals/pharmacos/pharmpack_en.htm
3. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, as amended.
4. Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency.

lorem ipsum