An Industry Survey on Managing the Pharmacovigilance System Master File in a Global Environment: The Need for a Pragmatic Approach.

BACKGROUND: Legislative requirements for Marketing Authorisation Holders (MAHs) to maintain a Pharmacovigilance System Master File (PSMF) were introduced in the European Union (EU) in 2010, operationalised in 2012 and subsequently introduced in other territories. There are no internationally agreed standards for the PSMF and country/regional requirements vary, leaving room for interpretation. This creates complexities for MAHs in implementing and maintaining multiple PSMFs. OBJECTIVES: The approaches taken towards the creation and maintenance of PSMFs in a global environment were investigated using a survey in order to gain a better understanding of the impact of the PSMF for MAHs. METHODS: A structured benchmarking survey was conducted during September and October of 2019 and the responses were analysed. A questionnaire with open-ended questions was designed to elicit detailed information on PSMF management and provide insights into company experiences. Companies affiliated to the EU Federation of Pharmaceutical Industries and Associations (EFPIA) and industry stakeholders with experience of PSMFs were contacted ensuring a broad representation including small, medium and large pharmaceutical companies, contract organisations/consultants and research-driven and generic organisations. RESULTS: Thirty companies responded; of these, 29 provided information relating to their PSMF practices. Respondents acknowledged that the PSMF is a valuable document that has helped to create greater awareness of pharmacovigilance within companies. Complex and varying international requirements were recognised as burdensome, especially in the context of consistent development and maintenance of multiple PSMFs. The respondents indicated that companies use the EU PSMF to manage requirements in other territories. Similar areas for standardisation were identified across respondents. CONCLUSION: The survey results highlight both the value of the PSMF and the challenges in maintaining it. Building on these responses, the paper offers pragmatic solutions to the challenges faced by MAHs and proposes a continued dialogue with key stakeholders in industry and national regulatory authorities about PSMF globalisation, harmonisation and simplification of requirements.

Betahistine: a retrospective synopsis of safety data.

Betahistine is a structural analogue of histamine that is prescribed for the treatment of vestibular disorders such as Ménière's disease and the symptomatic treatment of vertigo. It is estimated from sales information that >130 million patients have been exposed to the drug since its registration in 1968. In this review we analyse the safety profile of betahistine based on data obtained during >35 years of worldwide postmarketing surveillance. Until 31 December 2005, 554 adverse drug reaction (ADR) reports with 994 individual signs and symptoms were received by the marketing authorisation holder from worldwide sources and were reviewed and evaluated. Signs and symptoms of cutaneous hypersensitivity reactions during betahistine therapy were the most frequently reported complaints. They consisted of usually mild and self-limiting rash, pruritus and urticaria, and all symptoms were reversible after drug discontinuation. Betahistine was reported to be involved in one anaphylactoid reaction and one case of Stevens-Johnson syndrome. Anaphylactic reactions with fatal outcome were not reported. The reports that describe gastrointestinal complaints mostly concern nausea and vomiting or unspecific abdominal pain. These were typically non-serious complaints. Hepatobiliary involvement was reported 25 times, including increases in alkaline phosphatase, gamma-glutamyltransferase, and alanine and aspartate aminotransferase levels. None of the patients concerned developed severe liver failure or died. ADRs related to the nervous system predominantly reveal heterogeneous events that are not suggestive of a specific adverse reaction profile for betahistine. A clinical intolerance to betahistine that gave rise to asthma or bronchospasm was only reported in eight ADRs. A total of three cases of neoplasm have been reported. One case concerned a male patient of unknown age who experienced weight loss, insomnia, impatience and irritability soon after the start of betahistine therapy. An undiagnosed phaeochromocytoma was suspected. The remaining two cases were assessed as being unrelated to betahistine by the reporter. Finally, four deaths have been reported during the course of postmarketing surveillance for betahistine. The reporter assessed the causal relationship to betahistine in two as unrelated, in one as unlikely and the other as unassessable. In summary, clinical and postmarketing studies have revealed a good safety profile of betahistine that was confirmed by the safety surveillance data presented.