Multimorbidity and polypharmacy are emerging health priorities and the care of persons with these conditions is complex and challenging. The aim of the present guidelines is to develop recommendations for the clinical management of persons with multimorbidity and/or polypharmacy and to provide evidence-based guidance to improve their quality of care. The recommendations have been produced in keeping with the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Overall, 14 recommendations were issued, focusing on 4 thematic areas: (1.) General Principles; (2.) target population for an individualized approach to care; (3.) individualized care of patients with multimorbidity and/or polypharmacy; (4.) models of care. These recommendations support the provision of individualized care to persons with multimorbidity and/or polypharmacy as well as the prioritization of care through the identification of persons at increased risk of negative health outcomes. Given the limited available evidence, recommendations could not be issued for all the questions defined and, therefore, some aspects related to the complex care of patients with multimorbidity and/or polypharmacy could not be covered in these guidelines. This points to the need for more research in this field and evidence to improve the care of this population.

Primary Biliary Cholangitis, previously known as Primary Biliary Cirrhosis, is a rare disease, which mainly affects women in their fifth to seventh decades of life. It is a chronic autoimmune disease characterized by a progressive damage of interlobular bile ducts leading to ductopenia, chronic cholestasis and bile acids retention. Even if the disease usually presents a long asymptomatic phase and a slow progression, in many patients it may progress faster toward cirrhosis and its complications. The 10year mortality is greater than in diseases such as human immunodeficiency virus/Hepatitis C Virus coinfection and breast cancer. Ursodeoxycholic acid is the only treatment available today, but even if effective in counteracting the disease progression for the majority of patients, in approximately 40% is not able to decrease effectively the alkaline phosphatase, a surrogate marker of disease activity. Recently, obeticholic acid received the European Medicines Agency conditional approval, as add on treatment in patients non responders or intolerant to ursodeoxycholic acid. The present paper illustrates the opinion of a working group, composed by clinical pharmacologists, gastroenterologists/hepatologists with specific expertise on Primary Biliary Cholangitis and patient associations, on the state of the art and future perspectives of the disease management. The agreement on the document was reached through an Expert Meeting.

Nurses, pharmacists, doctors and patients each hold a piece of the puzzle and only by placing the pieces together will we be able to see the big picture at last. Everyone-patients includedneeds to be invited to the big round table of medicine safety 1. Of the 59 approved new molecular entities in 2018, 48 include a table summarizing whether

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.

Background The effective impact of patient engagement (PE) across the medicines development continuum is widely acknowledged across diverse health stakeholder groups, including health authorities; however, the practical applications of how to implement meaningful and consistent PE are not always addressed. Guidance for the practical implementation of PE requires granularity, and the need for such guidance has been identified as a priority. We describe the co-production and summarize the content of how-to guides that focus on PE in the early stages of medicines development. Methods Multi-stakeholder working groups (WGs) were established by Patient Focused Medicines Development (PFMD) for how-to guide development. How-to guides were co-produced with patients for PE activities identified as priorities through public consultation and by WGs. Guides were developed by applying PE quality guidance and associated quality criteria in an iterative process. How-to guides underwent internal review and validation by experts (ie, those with relevant experience in the particular PE activity or focus area) in specific focus groups and external review and validation through appropriate events and public consultation. Results Overall, 103 individual contributors from 38 organizations (representing eight stakeholder groups, including patients/patient organizations) and from 14 countries were organized into WGs and workstreams. Each WG comprised 15–30 contributors with PE experience relevant to the specific how-to guide. How-to guides were developed for PE in the early discovery and preclinical phases; PE in the development of a clinical outcomes assessment strategy; and PE in clinical trial protocol design. The how-to guides have a standardized format and structure to promote user familiarity. They provide detailed guidance and examples that are relevant to the individual PE activity and aim to facilitate the practical implementation of PE. Conclusions The how-to guides form a comprehensive series of actionable and stepwise resources that build from and integrate the PE quality criteria across the medicines continuum. They will be made freely available through PFMD’s Patient Engagement Management Suite (pemsuite.org) and shared widely to a variety of audiences in different settings, ensuring access to diverse patient populations. Implementation of these guides should advance the field of PE in bringing new medicines to the market and ultimately will benefit patients. Plain English summary Medicines are developed to help patients improve their health and lives. Many organizations and individuals want to ensure that medicines are developed to meet real patient needs and to address what is most important to patients. Finding out what patients need and what patients want requires good patient engagement, but knowing how to do patient engagement is not always clear. This is because medicines development is complicated, and a lot of different steps, people, and organizations are involved. Patient Focused Medicines Development (PFMD) was established in 2015 to connect individuals and organizations that are committed to making medicines not just for patients but with patients. To do this, PFMD brought together patients and other groups of people with relevant experience and good ideas on how to achieve patient engagement in the real-world setting. Together, PFMD has developed “how-to guides” for patient engagement that cover the main activities along the medicines development process. The guides are free to use and provide practical advice and examples that anyone can use in their patient engagement activities. The how-to guides will also help patients to understand medicines development and how best they can participate in this process to address their needs.