The monitoring medicines project: a multinational pharmacovigilance and public health project.

The Monitoring Medicines project (MM), funded by the FP-7 EU framework, was carried out between 2009 and 2013 by a consortium of 11 partners. The objectives were to support and strengthen consumer reporting of adverse drug reactions (ADRs); expand the role and scope of national pharmacovigilance centres concerning medication errors; promote improved use of pharmacovigilance data; and develop methods to complement spontaneous reporting. The work was organised into four themes: patient reporting; medication errors; drug dependence, counterfeit and substandard medicines and clinical risk estimation; and active and targeted spontaneous pharmacovigilance. MM differed from some other major pharmacovigilance initiatives by having participants from developing countries in Asia and Africa and in leaning towards public health and communicable diseases. MM brought together stakeholders including WHO, drug regulators, pharmacovigilance centres, consumers, public health and disease specialists and patient safety networks. Resources and methodologies developed directly by, or with support from, MM include electronic systems/tools for consumer ADR reporting and cohort event monitoring; publication by WHO of handbooks on consumer reporting, medication errors and pharmacovigilance for TB medicines; methodologies for detecting drug dependence and substandard or counterfeit medicines in ADR databases; and a database on HIV treatment risks with a risk assessment tool. MM enabled stakeholders to achieve more than if they had worked alone in pursuit of patient safety.

Using MedDRA: implications for risk management.

The introduction of MedDRA, the Medical Dictionary for Regulatory Activities, as a standardised terminology may have a major impact on the performance of risk management. Thus, MedDRA is likely to have an important effect on the analysis of clinical trial safety data. Review of the most commonly used terms in clinical trial tables from the labelling of ten products indicated that each adverse event could be represented by many MedDRA preferred terms; this might theoretically lead to failure to identify differences in adverse event incidence between treatment arms. Possible solutions are proposed. The use of MedDRA in spontaneous reporting systems is a regulatory requirement in some countries. Variability in modes of implementation and use of the terminology are discussed; these may impose additional limitations on any use of spontaneous data for comparative purposes. There are important differences in the ways that safety databases interface with MedDRA and uncertainty about the most appropriate way to manage version changes. The characteristics of MedDRA must be taken into account when establishing methods for signal detection and its use will affect the retrieval of similar cases as required for signal evaluation. The use of MedDRA in the periodic safety update report is discussed. The possible use of MedDRA in pharmacoepidemiology is highly relevant to risk management, and some issues are briefly outlined. With regard to communication of risk, if MedDRA is introduced into existing product labelling, care must be taken that the change itself does not cause misunderstanding; the most appropriate use of MedDRA in this regard remains to be determined. There is a need for careful evaluation of MedDRA in fulfilling its various functions in pharmacovigilance, followed by definitive regulatory guidance on its use.

Methods and pitfalls in searching drug safety databases utilising the Medical Dictionary for Regulatory Activities (MedDRA).

The Medical Dictionary for Regulatory Activities (MedDRA) is a unified standard terminology for recording and reporting adverse drug event data. Its introduction is widely seen as a significant improvement on the previous situation, where a multitude of terminologies of widely varying scope and quality were in use. However, there are some complexities that may cause difficulties, and these will form the focus for this paper. Two methods of searching MedDRA-coded databases are described: searching based on term selection from all of MedDRA and searching based on terms in the safety database. There are several potential traps for the unwary in safety searches. There may be multiple locations of relevant terms within a system organ class (SOC) and lack of recognition of appropriate group terms; the user may think that group terms are more inclusive than is the case. MedDRA may distribute terms relevant to one medical condition across several primary SOCs. If the database supports the MedDRA model, it is possible to perform multiaxial searching: while this may help find terms that might have been missed, it is still necessary to consider the entire contents of the SOCs to find all relevant terms and there are many instances of incomplete secondary linkages. It is important to adjust for multiaxiality if data are presented using primary and secondary locations. Other sources for errors in searching are non-intuitive placement and the selection of terms as preferred terms (PTs) that may not be widely recognised. Some MedDRA rules could also result in errors in data retrieval if the individual is unaware of these: in particular, the lack of multiaxial linkages for the Investigations SOC, Social circumstances SOC and Surgical and medical procedures SOC and the requirement that a PT may only be present under one High Level Term (HLT) and one High Level Group Term (HLGT) within any single SOC. Special Search Categories (collections of PTs assembled from various SOCs by searching all of MedDRA) are limited by the small number available and by lack of clarity about criteria applied in their construction. Difficulties in database searching may be addressed by suitable user training and experience, and by central reporting of detected deficiencies in MedDRA. Other remedies may include regulatory guidance on implementation and use of MedDRA. Further systematic review of MedDRA is needed and generation of standardised searches that may be used 'off the shelf' will help, particularly where the same search is performed repeatedly on multiple data sets. Until these enhancements are widely available, MedDRA users should take great care when searching a safety database to ensure that cases are not inadvertently missed.

Effects of coding dictionary on signal generation: a consideration of use of MedDRA compared with WHO-ART.

To support signal generation a terminology should facilitate recognition of medical conditions by using terms which represent unique concepts, providing appropriate, homogeneous grouping of related terms. It should allow intuitive or mathematical identification of adverse events reaching a threshold frequency or with disproportionate incidence, permit identification of important events which are commonly drug-related, and support recognition of new syndromes. It is probable that the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) or high level terms (HLTs) will be used to represent adverse events for the purposes of signal generation. A comparison with 315 WHO Adverse Reaction Terminology (WHO-ART) PTs showed that for about 72% of WHO-ART PTs, there were one or two corresponding MedDRA PTs. However, there were instances where there were many MedDRA PTs corresponding to single WHO-ART PTs. In many cases, MedDRA HLTs grouped large numbers of PTs and sometimes there could be problems when a single HLT comprises PTs which represent very different medical concepts, or conditions which differ greatly in their clinical importance. Further studies are needed to compare the way in which identical data sets coded with MedDRA and with other terminologies actually function in generating and exploring signals using the same methods of detection and evaluation.