Monitoring the manufacturing and quality of medicines: a fundamental task of pharmacovigilance.

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.

Pharmacovigilance of medicines for rare and ultrarare diseases.

The assessment of the safety of medicines for rare diseases during the development phase is often limited by the few data available from small numbers of patients. This also applies to a lesser extent during the postmarketing phase of the lifecycle of a medicine. By using all available sources of data for rare diseases drugs, and by carefully assessing these data, the most informed safety profile can be obtained. This should also allow a clear view of data that are not available at any given time point and facilitates planning of strategies to obtain data through appropriate postmarketing risk management. Although it is not always easy, there are possibilities to increase the speed by which data in the postmarketing period can be generated by better use of data from ongoing formal clinical trials, by early planning of drug or disease registries and leveraging the power of both disease patient support groups, which are often well established, and networks to facilitate international research, specifically in rare diseases. The future may offer approaches using personal medical monitoring data tools and 'big data' to further facilitate the availability of information and to determine the effectiveness and safety profiles of drugs used for rare diseases and thus allow the benefit/risk of these drugs to be optimized. These issues will be discussed here.

Safety and tolerability of pioglitazone, metformin, and gliclazide in the treatment of type 2 diabetes.

This analysis compares the safety and tolerability of pioglitazone (a thiazolidinedione), metformin (a biguanide), and gliclazide (a sulfonylurea). Data collected from four 1-year, double-blind studies comparing treatment of over 3700 patients with type 2 diabetes with pioglitazone, metformin, or gliclazide have been combined to provide comparative tolerability and safety profiles. All treatments were well tolerated with approximately 6% of patients withdrawing from treatment because of side-effects. The side-effects profile varied between treatments, with pioglitazone being associated with edema, metformin with gastrointestinal side-effects, and gliclazide with hypoglycemia. Cardiovascular outcome was similar with all treatments, with no excess reports of cardiac failure with pioglitazone treatment. Both pioglitazone and gliclazide resulted in mean weight gain, whilst with metformin there was mean weight loss. Mean liver enzyme values decreased with pioglitazone and to a lesser extent with metformin. With gliclazide, mean liver enzyme values increased. The expected small decreases in mean hemoglobin and hematocrit seen with pioglitazone also occurred with metformin and to a lesser degree with gliclazide. The results show that all three drugs are safe, but that tolerability profiles vary. Each treatment provides an alternative therapy for type 2 diabetes, dependent on the particular needs of individual patients.