IntroductionAdditional risk minimisation measures (aRMMs) for medicinal products are necessary to address specific important safety issues which may not be practically achieved through routine risk management measures alone. The implementation and determination of effectiveness for aRMMs can be a challenge as it involves multiple stakeholders. It is therefore important to have concise objectives to avoid undue burden on patients, healthcare professionals and the healthcare system.AimThe aim of this study was to examine how aRMMs are implemented and how effectiveness is assessed in the European Union (EU) using practical examples from Roche Products Limited in the United Kingdom (UK) (referred to as the ‘Company’).MethodsThree centrally authorised products were selected from the Company’s portfolio, each of which had aRMMs to address important safety concerns; specifically, teratogenicity, medication error and infections. The implementation of EU aRMMs, effectiveness checks and specific UK activities were analysed. Hard copy folders and electronic sites for Company aRMMs were used to assess process indicators. Periodic benefit-risk evaluation reports for specified time intervals and the Company safety database was used in checking safety outcomes for the selected products. For each product, the effectiveness of aRMMs was analysed based on specific process indicators and the subsequent safety outcomes. Literature searches were performed on scientific databases for the purposes of the broader study.ResultsThe main process indicators in measuring effectiveness of Company aRMMs were distribution metrics for educational materials, assessment of awareness and clinical actions among healthcare professionals (HCPs). Case reports of pregnancy, medication errors and progressive multifocal leukoencephalopathy (PML) were the outcome indicators for Erivedge®▼, Kadcyla®▼ and MabThera® (the latter specifically in autoimmune indications: rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis) respectively. No pregnancy, one medication error and 10 confirmed PML cases were reported for Erivedge®▼, Kadcyla®▼ and MabThera® respectively.ConclusionsFor the chosen products, a reasonable awareness of aRMMs amongst HCPs is a positive indicator of success in the use of educational materials. However, low response rates from surveys indicate that voluntary feedback may not always achieve the desired level of response in measuring effectiveness. There is a challenge in determining overall effectiveness of aRMMs due to a lack of defined success thresholds. Further regulatory guidance to outline the elements and desired outcomes of aRMMs will be useful for consistency in achieving successful outcomes.

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A risk stratification strategy for DXA scanning using a fracture risk assessment tool (FRAX) and a 10-year fracture risk threshold of 10% leads to a significant reduction in scan rates without compromising osteoporosis detection rates.

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Background The Nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 3 (NLRP3) inflammasome is a driver of caspase 1-dependent release of IL-1β and IL-18 and has been identified as a potential drug target for ulcerative colitis (UC) (Tourkochristou et al. 2019). Selnoflast (RO7486967) is an orally active, potent, selective, and reversible small molecule NLRP3 inhibitor. To assess whether NLRP3 is a driver of inflammation and more specifically of IL-1β production and signaling in UC, we performed a Phase 1b study (BP43099) with selnoflast in patients with UC. Methods A randomized, placebo-controlled, double blind study assessed safety, tolerability, PK and PD of selnoflast in patients with active, moderate to severe UC. 19 patients were recruited: 6 were treated with placebo and 13 were treated with 450 mg selnoflast QD for 7 days. Stool and blood samples were taken at baseline, during and at the end of treatment. Sigmoidal tissue samples were taken at baseline and at the end of treatment. Adverse events were assessed throughout the study. https://www.isrctn.com/ISRCTN16847938 Results Selnoflast was well tolerated in all patients, with mainly mild AEs. No serious or severe AEs were reported. Plasma PK was in line with PK data from previous studies in healthy subjects. In addition, selnoflast demonstrated a good distribution in sigmoidal tissue in all treated patients. The gene signature of 8 genes (i.e. CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CCL2, IL-6, TNFAIP6) downstream of IL-1β, known to be responsive to IL-1β stimulation across different cell types and differentially expressed in colonic biopsies (UC vs healthy), was assessed and showed on average a slight decrease from baseline after treatment with selnoflast compared to placebo (log2 fold change mean (sd) = -1.14 (1.8) and +0.38 (3.26) respectively, t-test p-value = 0.206) in sigmoidal tissue biopsies. Single-cell RNA sequencing showed minimal differences between the two treatment arms. Conclusion Selnoflast was well tolerated and achieved the plasma and tissue exposure predicted to inhibit NLRP3. Expression of IL-1β gene signature in sigmoidal tissue biopsies, single-cell RNA sequencing and additional biomarker analyses showed no robust differences between the two treatment arms, suggesting that targeting the NLRP3 inflammasome with selnoflast may be of limited therapeutic benefit to reduce inflammation in UC. Tourkochristou E, Aggeletopoulou I, Konstantakis C, Triantos C. Role of NLRP3 inflammasome in inflammatory bowel diseases. World J Gastroenterol. 2019