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International Clinical Trials

A Safer Europe

In 1961, the Australian physician William McBride reported that he had noted an increased frequency of limb malformation among babies. He found that a common denominator seemed to be the intake of a new hypnotic and antiemetic drug, thalidomide, by their mothers during pregnancy.

As about 10,000 children were born with severe malformations, this ‘thalidomide disaster’ prompted governments in several countries to set up procedures for a systematic collection of information about adverse drug reactions, and the first pharmacovigilance centres arose.

Over subsequent decades, despite all the benefits of modern medicines, evidence has continued to mount that adverse reactions to drugs are a common, yet often preventable, cause of illness, disability and even death. Pharmacovigilance and drug safety management measures have subsequently evolved, as reflected by industry systems for reporting adverse reactions and by the latest legislation introduced in the European Union (EU) in 2012.

Pharmacovigilance
Pharmacovigilance has been defined by the World Health Organization as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem.

Before a drug becomes commercially available, it has to go through various phases of clinical development to establish its safety and efficacy. However, at the time of authorisation, information on the safety of a medicinal product is relatively limited. This is due to many factors, including the relatively small number of subjects in clinical trials compared with the intended treatment population; restrictions in age, co-morbidity, co-medication and conditions of use; and relatively short duration of exposure and follow-up.

Consequently, some side-effects or adverse reactions may only be detected when the product is used in the real world. It is therefore vital that the safety of all medicines is monitored throughout their use in healthcare practice.

The pharmacovigilance system in the EU operates with the management and involvement of regulatory authorities in member states, the European Commission and the European Medicines Agency (EMA). In some member states, regional centres are in place under the coordination of the national competent authority. Within this system, the EMA’s role is to coordinate the EU pharmacovigilance system and ensure the provision of advice for the safe and effective use of medicines.

Adverse Event Reporting
The activity that is most commonly associated with pharmacovigilance, and which consumes a significant amount of resources for drug regulatory authorities (or similar government agencies) and drug safety departments in pharmaceutical companies, is that of adverse event (AE) reporting.

The source of AE reports, in which data on adverse reactions are captured, may include spontaneous reports from healthcare professionals, patients or other intermediaries; solicited reports from patient support programmes; reports from clinical or post-marketing studies; literature sources; reports from the media, including social media and websites; and reports to drug regulatory authorities.

For pharmaceutical companies, AE reporting is a regulatory requirement in most countries. It also provides data to these companies and drug regulatory authorities that play a key role in assessing the benefit-risk profile of a given medicine.

Managing Risks
Risk management is the discipline within pharmacovigilance that is responsible for signal detection and the monitoring of the benefit-risk profi le of medicines. A risk management system is put in place which consists of a set of pharma-covigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products.

In the EU, the risk management system will be described in detail in the risk management plan (RMP), and will further be addressed in aggregate reports such as the periodic safety update report (PSUR) and development safety update report (DSUR).

The RMP describes the medicine’s safety profile, including the identified and potential risks for developing side-effects; how its risks will be prevented or minimised in patients; plans for studies and other activities to gain more knowledge about the safety and efficacy of the medicine; and the effectiveness of risk minimisation measures.

Risk-Based Approach
An initial RMP will be compiled and submitted as part of the dossier to obtain marketing authorisation for a medicinal product. Taking the described risks into account, authorisation will only be granted when the benefit-risk balance is judged to be positive for the target population.

Once the medicine is authorised for marketing, there is no automatic requirement to update RMPs on a fixed-time basis, but rather a risk-based approach should be used. Throughout the lifetime of the medicine, an updated RMP will have to be submitted whenever its risk management system is modified, particularly when there is new information that could lead to a change in the medicine’s benefit-risk profile, or when important pharmacovigilance or risk minimisation milestones are reached.

Updates may occur at the request of the EMA, or at the initiative of the marketing authorisation holder in the case of a significant change to an existing marketing authorisation – for example, a change in indication, new dosage or route of administration – or in the case of a licence renewal.

Legislative Update
Since July 2012, new EU pharmacovigilance legislation has been put in place by the EMA, including Good Pharmacovigilance Practice (GVP) guidelines and a new RMP template. One of the main changes in the new template is its modular structure: the RMP now consists of seven parts.

Certain parts of the RMP, in particular the safety specification, are subdivided into modules, so the content can be tailored to the specifics of the medicinal product and modules can be added, removed or reused in other documents, such as the PSUR. The modular structure also means that the RMP can easily be updated.

As the product matures, some RMP modules or sections will no longer change and can effectively be ‘locked’ until new data needs to be added. In addition, certain RMP modules may be omitted in specific circumstances. Instead of submitting a complete RMP each time an update is required, companies will only need to submit the modules that have changed so that the EMA can build a complete RMP based on the latest version of each module. The move to a modular format should also facilitate submission to different regulatory authorities.

Another change to the RMP template is the inclusion of a public summary – a scientific summary of the RMP written for the lay reader, which will be made publically available. The summary must include key elements of the RMP with a specific focus on risk minimisation activities. With regard to the safety specification of the medicinal product concerned, it should contain information on important identified and potential risks, as well as missing information.

Safety Update Reports
A PSUR is mandated for submission at periodic intervals from the time of marketing authorisation, and will consider the overall benefit-risk profile of the medicinal product. It is anticipated that only a small proportion of the adverse reactions described in the PSUR will be classified as important identified or potential risks, and become a safety concern discussed within the RMP.

When a PSUR and an RMP are to be submitted together, the RMP should reflect the conclusions of the accompanying PSUR – for example, with regard to a new identified risk. The PSUR also has a modular format, allowing common sections/modules to be used in both documents in order to minimise duplication.

A DSUR should be prepared after the first authorisation of a clinical trial worldwide. It will describe the current understanding and management of identified and potential risks, and new safety issues that could have an impact on the protection of clinical trial subjects. It will also examine whether the information obtained by the pharmaceutical company during the reporting period is in accordance with previous knowledge of the product’s safety; and will provide an update on the status of the clinical investigation or development programme.

Although the focus of the DSUR is on investigational drugs, there can be overlap between the content of the DSUR and PSUR; some repetition is expected. For example, information from marketing experience (reported in the PSUR) might be relevant to clinical development, and therefore reported in the DSUR. Safety findings from clinical trials conducted using marketed drugs would be included in both the DSUR and PSUR.


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About the author

Mieke Notenbaert started her career as a medical writer in 1997 at an international contract research organisation, where she worked for nearly five years. In 2001, Mieke co-founded Emtex, an independent company that offers worldwide professional scientifi c writing services. She is currently Head of Medical Writing. Among other activities, Mieke educates and trains others in the skills needed to be a successful medical writer.

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Mieke Notenbaert
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