Different strategies have been studied to allow a better characterization of the safety profile of orphan drugs soon after their approval. At the end of the development phases only few data are available because of the small number of subjects exposed to an orphan medicine for the treatment of rare or ultra-rare conditions. As a consequence, the evaluation of the safety profile is limited at the time of the first approval. In the post-marketing period, all available sources should be combined for a better understanding of the safety of orphan drugs. These sources, include outputs from large databases such as the European Medicines Agency’s EudraVigilance database. Analyses of data from this source are required to be performed by marketing authorization holders (MAHs) as part of their signal management activities. In 2018, the Pharmacovigilance Risk Assessment Committee (PRAC) assessed 114 confirmed signals, 79% of which included data from EudraVigilance. MAHs have access to statistical calculations for drug–event combinations (DECs) from EudraVigilance, provided in the form of measures of disproportionality of ratios of the observed proportion of spontaneous cases for a DEC in relation to the proportion of cases that would be expected if no association existed between the drug and the event. However, such statistical summaries for orphan drugs could be misleading because of the very limited safety data available for orphan drugs (under-reporting together with low numbers of exposed patients). In addition, the applied statistical methodology in most instances is constrained by different confounding factors such as indications of specific medicines and the wide spectrum of medical conditions/diseases of patients from whom reporting of disproportionality ratios are derived (i.e. proportions of DECs for orphan drugs (ODECs) from a small patient population suffering the rare disease and the proportion of DECs in the rest of the population represented in the whole database who have been treated with other medicines for a wide range of indications, and prescribed to treat completely different medical conditions). As expected, these statistical calculations produced not only signals of disproportionate reporting (SDRs) that are false positives, but also not sensitive enough to detect certain SDRs, thus resulting in false negatives. In the context of rare/ultra-rare life-threatening diseases where new molecules have been made available on the market on the basis of their proven efficacy, but with only limited safety data at the time of approval, false negatives could be a special concern since unlikely converted in positives or becoming positives with notable delay. Subgroup analyses (using a limited dataset comprising ADRs within specific individual case safety reports (ICSRs), sorted by indication/disease relevant to the drug of interest could, at least in part, possibly reduce some of the weaknesses resulting from the abovementioned confounding factors. On the other hand it could also cause the loss of some identification of SDRs that would be captured if no database restrictions had been undertaken. Therefore, data subgroup analysis should not be selected as a preferred approach to quantitative signal detection for orphan drugs but rather evaluated as complementary possibly to confirm negatives or to further characterize detected SDRs. Some examples of false negatives originating from quantitative signal detection in EudraVigilance applied to orphan drugs are discussed in this article.

The collection and assessment of individual case safety reports (ICSRs) is important to detect unknown adverse drug reactions particularly in the first decade after approval of new chemical entities. However, regulations require that these activities are routinely undertaken for all medicinal products, including older medicines such as generic medicinal products with a well-established safety profile. For the latter, the risk management plans no longer contain important risks, considered important safety concerns, on the basis that routine pharmacovigilance activity would not allow their further characterisation. Society assumes that unexpected adverse reactions causally related to pharmacological activity are very unlikely to be detected for such well-established medicines, but important risks can still occur. For these products, a change in the safety profile which is brand or source specific and usually local in nature, associated with failures with the adequate control of quality of manufacturing or distribution are important safety issues. These may be the consequence of manufacturing and pharmacovigilance quality systems that are not fully integrated over the product life cycle (e.g. inadequate control of quality defects affecting one or multiple batches; inadequate impact assessment of change/variation of manufacturing, quality control testing, storage and distribution processes; inadequate control over the distribution channels including the introduction of counterfeit or falsified products into the supply chain). Drug safety hazards caused by the above-mentioned issues have been identified with different products and formulations, from small molecules to complex molecules such as biological products extracted from animal sources, biosimilars and advanced therapy medicinal products. The various phases of the drug manufacturing and distribution of pharmaceutical products require inputs from pharmacovigilance to assess any effects of quality-related issues and to identify proportionate risk minimisation measures that often have design implications for a medicine which requires a close link between proactive vigilance and good manufacturing practice. To illustrate our argument for closer organisational integration, some examples of drug safety hazards originating from quality, manufacturing and distribution issues are discussed. Plain language summary Monitoring the manufacturing and quality of medicines: the fundamental task of pharmacovigilance Pharmacovigilance is the science relating to the collection, detection, assessment, monitoring, and prevention of adverse reactions with pharmaceutical products. The collection and assessment of adverse reactions are particularly important in the first decade after marketing authorisation of a drug as the information gathered in this period could help, for example, to identify complications from its use which were unknown before its commercialization. However, when it comes to medicines that have been on the market for a long time there is general acceptance that their safety profile is already well-established and unknown adverse reactions unlikely to occur. Nevertheless, even older medicines, such as generic drugs, can generate new risks. For these drugs a change in the safety profile could be the result of inadequate control of their quality, manufacturing and distribution systems. To overcome such an obstacle, it is necessary to fully integrate manufacturing and pharmacovigilance quality systems in the medicine life-cycle. This could help detect safety hazards and prevent the development of new complications which may arise due to the poor quality of a drug. Pharmacovigilance activities should indeed be included in all phases of the drugs’ manufacturing and distribution process, regardless of their chemical complexity to detect quality-related matters in good time and reduce the risk of safety concerns to a minimum.

European Directives and Regulations introduced between late 2010 and 2012 have substantially overhauled pharmacovigilance processes across the European Union (EU). In this review, the implementation of the pharmacovigilance legislative framework by EU regulators is examined with the aim of mapping Directive 2010/84/EU and Regulation EC No. 1235/2010 against their aspired objectives of strengthening and rationalizing pharmacovigilance in the EU. A comprehensive review of the current state of affairs of the progress made by EU regulators is presented in this paper. Our review shows that intense efforts by regulators and industry to fulfil legislative obligations have resulted in major positive shifts in pharmacovigilance. Harmonized decision making, transparency in decision processes with patient involvement, information accessibility to the public, patient adverse drug reaction reporting, efforts in communication and enhanced cooperation between member states to maximize resource utilization and minimize duplication of efforts are observed.