Setting-up a high quality and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for industrials. Generating high-quality safety data, compliant with legal and regulatory standards such as European or World Health Organization (WHO), places special requirements on the PV system. The scenario becomes more complicated when dealing with multi-country European clinical trials where heterogeneity on safety process can be encountered. Some Sponsors face these challenges are even more difficult for pediatric trials. A possible solution to ensure that the safety of all participants is equally guaranteed and the PV system fulfills all regulations could be to set up a centralized PV system. This paper introduces the key points to consider when implementing and organizing such system in multi-national European clinical trials. It is based on the Inserm-ANRS MIE pharmacovigilance department’s experience and aims to harmonize and anticipate the needs, in particular by implementing safety procedures and a network of local safety officers. This system is very useful to respond to the challenges of a European clinical trial, notably when considering the complexity of local safety requirements of each country, signal management and the specificities of paediatric regulation.

Background: Infections are common complications after stroke and associated with unfavorable outcomes. We evaluated the efficacy and safety of prophylactic antibiotics for post-acute stroke infection. Methods: We searched PubMed, Embase, the Cochrane Library, SinoMed, China National Knowledge Infrastructure, and WanFangData from inception to February 15th, 2022. We calculated the pooled risk ratio (RR) and mean differences (MDs) with 95% confidence interval (CI), evaluated the risk of bias and conducted sensitivity analysis with RevMan version 5.4.1 and Stata version 14.0 software. The overall quality of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Results: Twelve studies (4809 participants) were included in this meta-analysis. There was no significant difference in the mortality rate [RR 1.03 (95% Cl: 0.91-1.16)], pneumonia [RR 0.94 (95% CI: 0.79-1.11)], and the incidence of adverse events between the prophylactic antibiotics and control groups. Prophylactic antibiotics significantly reduced the incidence of infections [RR 0.72 (95% Cl: 0.58-0.89)], and urinary tract infections [RR 0.39 (95% Cl: 0.3-0.49)] in patients with acute stroke. We performed a subgroup analysis and found a decreasing trend in pneumonia in patients with early prophylactic use of antibiotics within 24 hours after admission [RR 0.81 (95%CI: 0.62-1.07)] as compared with those using prophylactic use of antibiotics within 48 hours after admission [RR 0.94 (95%CI: 0.79-1.11)]. Conclusions: Prophylactic antibiotics did not significantly reduce the mortality rate and pneumonia in patients with acute stroke but reduced the incidence of infections and urinary tract infections.

Reactivation of the scar resulting from intracutaneous injection of Bacillus Calmette-Guérin (BCG) is a common specific reaction in Kawasaki’s Disease. It has also sporadically been associated with viral infections, Multisystem Inflammatory Syndrome in Children, influenza vaccination and mRNA COVID-19 vaccination. Since the start of the COVID-19 vaccination campaign in January 2021, the Netherlands Pharmacovigilance Centre Lareb has received 22 case reports of BCG reactivation after vaccination with a COVID-19 vaccine. In 20 case reports it concerned mRNA COVID-19 vaccines Moderna (14) and Pfizer (6). In 2 case reports the viral vector COVID-19 vaccine AstraZeneca was administered. Erythema and pain were the most frequently reported symptoms and the size of the inflammation was between 1.5 to 5 cm. BCG reactivation occurred with a median time to onset of 2 days after the second or booster COVID-19 vaccination, whereas the median time to onset was 7 days after the first COVID-19 vaccination. None of the BCG reactivations were treated. The exact mechanism of the occurrence of this specific reaction remains unknown, however involvement of heat shock protein 65 is suggested. BCG reactivation is a non-serious, self-limiting reaction that can occur after vaccination with both mRNA and viral vector COVID-19 vaccines.

Aim: Quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate. Methods: Hmong participants (n=34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. Serum urates (SU) were obtained pre- and post-allopurinol. Serum oxypurinol concentrations were obtained at times 0, 2, 4, and 6 hours after the last dose. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed-effects modeling evaluated the impact of anthropometrics, concomitant medications, and genetic variants on oxypurinol PKPD parameters. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model. Results: A one-compartment model with first order absorption and elimination best described the oxypurinol concentration-time data. Inhibitory of SU by oxypurinol was described with a direct inhibitory Emax model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype. Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus alternative medications. Conclusion: The proposed allopurinol dosing guide uses individuals’ fat-free mass, renal function, and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.

AIMS Doxorubicin-induced cardiotoxicity (DIC) is a significant cause of mortality in cancer care. This study was conducted to establish the frequency of DIC in Zimbabwean breast cancer patients on doxorubicin and to test the DIC predictive power of genetic biomarkers. METHODS A cohort of 50 Zimbabwean breast cancer patients treated with doxorubicin were followed up for 12 months with serial echocardiography and genotyped for UGTA1A6*4, SLC28A3 and RARG. 11% of the patients experienced DIC. RESULTS The frequency of SLC28A3 (rs7853758), UGT1A6*4 (rs17863783) and RARG (rs2229774) was 60.7%, 17.9% and 14.3% respectively. No association between DIC and the three variants was observed. CONCLUSIONS This is the first study on the prevalence of DIC and associated genetic biomarker predictive evaluation in Zimbabwean breast cancer patients. The genetic frequencies observed in our study was different to that reported in other populations. A larger sample size with a longer follow up time will be necessary in future studies.

Background: TMS-007, an SMTP family member, modulates plasminogen conformation and enhances plasminogen-fibrin binding, leading to promotion of endogenous fibrinolysis. Its anti-inflammatory action mediated by soluble epoxide hydrolase inhibition contributes to the efficacy. Evidence suggests that TMS-007 can effectively treat experimental thrombotic and embolic strokes with a wide time window while reducing hemorrhagic transformation. Aims: To evaluate the safety, pharmacokinetics, and pharmacodynamics of TMS-007 in healthy volunteers. Methods: A randomized, placebo-controlled, double blind, dose-escalation study, administered as a single intravenous infusion of TMS-007 in cohorts of healthy male Japanese subjects. There were 6 cohorts planned, but 5 were completed. In each cohort (n = 8), individuals were randomized to receive one of 5 doses of TMS-007 (3, 15, 60, 180, or 360 mg; n = 6) or placebo (n = 2). Results: TMS-007 was generally well-tolerated, and no serious adverse events attributed to the drug. A linear dose-dependency was observed for plasma TMS-007 levels. No symptoms of bleeding were observed in brain MRI analysis, and no bleeding-related responses in laboratory testing were found. The plasma levels of the coagulation factor fibrinogen and the anti-fibrinolysis factor 2-antiplasmin levels were unchanged after the TMS-007 dosing. A slight increase in the plasma level of plasmin-α2-antiplasmin complex, an index of plasmin formation, was observed in some subjects who received 360 mg of TMS-007 (≈ 6 mg kg−1). Conclusions: TMS-007 is generally well-tolerated and exhibits favorable pharmacokinetic profiles that warrant further clinical development.

A document by Thomas Svare Ehlers. Click on the document to view its contents.

The European Medicines Agency (EMA) started operating under its new legal mandate on 1 April 2022. The mandate brings new responsibilities to the Agency in three different areas: • Reinforcement of the role and activities of the EMA pandemic Task Force(which is now known as the Emergency Task Force (ETF)). • A stronger role of EMA in the monitoring of shortages of critical medicines, medical devices and in-vitro diagnostics, both in anticipation of and during a crisis. • A more coordinated mechanism of European Union (EU) experts advice on medical devices classified as high-risk (class IIa and III or class D (1)) and in-vitro diagnostic medical devices. Here we consider the impact of the COVID-19 pandemic on the operations of EMA and the European medicines regulatory network, and how EMA’s new mandate will strengthen the Agency’s and the Network’s ability to face crises. EMA’s extended mandate brings clear benefits in terms of response to public health emergencies at EU level, which ranges from improvements in crisis management to avoiding medicine shortages and improving access to diagnostics and medical devices that are safe and conform to their expected function.

Aims: This study aims to evaluate the drug-drug interaction（DDI） between hetrombopag and cyclosporine in healthy Chinese subjects. Methods: Twenty-six eligible subjects enrolled in this single-center, single-sequence, open-label, DDI study with three treatment periods, receiving 5 mg hetrombopag once on day 1, 100 mg cyclosporine twice daily from day 11 to day 15, and 5 mg hetrombopag + 100 mg cyclosporine on day 16. Serial blood samples were collected for pharmacokinetic evaluation. Adverse events were monitored throughout the study. Results: The plasma hetrombopag geometric mean ratios (GMRs) (90% CI) of Cmax, AUC0-t and AUC0-∞ of co-administration of hetrombopag with cyclosporine vs hetrombopag alone are 95.97% (70.08%, 131.43%), 105.75% (75.04%, 149.04%) and 104.19% (74.71%, 145.32%), respectively, indicating multiple doses of cyclosporine had minimal effects on hetrombopag exposure. The GMRs (90% CI) of Cmax and AUCss,tau for blood cyclosporine of co-administration vs cyclosporine alone were 100.49% (91.89%, 109.89%) and 100.81% (107.88%, 103.82%), respectively, suggesting a single dose of hetormbopag had no impact on the exposure of cyclosporine. Co-administration of hetormbopag with cyclosporine was generally well tolerated. Conclusion: No clinically significant DDI was observed when co-administration of hetrombopag with cyclosporine. No additional dose adjustment is warranted for this combination.

Aim: Cisplatin causes acute kidney injury (AKI) in approximately one-third of patients. Serum creatinine and urinary output are poor markers of cisplatin-induced (AKI). Metabolomics was utilized to identify predictive or early diagnostic biomarkers of cisplatin-induced AKI. Methods: Thirty-one adult head and neck cancer patients receiving cisplatin (dose ≥ 70 mg m2 -1) were recruited for metabolomics analysis. Urine and serum samples were collected prior to cisplatin (pre), 24-48 hours after cisplatin (24-48h), and 5-14 days (post) after cisplatin. Based on serum creatinine concentrations measured at the post timepoint, 11/31 patients were classified with clinical AKI. Untargeted metabolomics was performed using liquid chromatography-mass spectrometry. Results: Metabolic discrimination was observed between “AKI” patients and “no AKI” patients at all timepoints. Urinary glycine, hippuric acid sulfate, 3-hydroxydecanedioc acid, and suberate were significantly different between AKI patients and no AKI patients prior to cisplatin infusion. Urinary glycine and hippuric acid sulfate were lower (-2.22-fold and -8.85-fold), whereas 3-hydroxydecanedioc acid and suberate were higher (3.62-fold and 1.91-fold) in AKI patients relative to no AKI patients. Several urine and serum metabolites were found to be altered 24-48 hours following cisplatin infusion, particularly metabolites involved with mitochondrial energetics. Conclusion: We propose glycine, hippuric acid sulfate, 3-hydroxydecanedioc acid, and suberate as predictive biomarkers of predisposition to cisplatin-induced AKI. Metabolites indicative of mitochondrial dysfunction may serve as early markers of subclinical AKI.

Hyperbaric oxygen should not be used routinely for carbon monoxide poisoning: CONDavid N. Juurlink, MD, PhDDepartments of Medicine, Pediatrics, and Health Policy, Management and Evaluation, University of Toronto, the Ontario Poison Centre, and Sunnybrook Research InstituteWord count: 2036

Olanzapine pamoate is an intramuscular depot injection for the treatment of schizophrenia. Approximately 1.4% of patients develop a serious adverse event called Post Injection Delirium/Sedation Syndrome (PDSS); characterised by drowsiness, anticholinergic and extrapyramidal symptoms. The objective is to investigate olanzapine PDSS presentations including clinical features and treatment approach. This is a retrospective review of olanzapine PDSS patients from three toxicology units and the NSW Poisons Information between 2017 and 2022. Adult patients were included if they had intramuscular olanzapine then developed PDSS criteria. Clinical symptoms, treatment, timing and length of symptoms were extracted into a preformatted Excel database. There were 18 patients included in the series, with a median age of 49 years (IQR: 38-58) and male predominance (89%). Median onset time post injection was 30 minutes (IQR: 11-38). PDSS symptoms predominate with drowsiness, confusion and dysarthria. Median length of symptoms was 24 hours (IQR: 20-54). Most common treatment included supportive care without any pharmacological intervention (n=10), benzodiazepine (n=4) and benztropine (n=3). In one case, bromocriptine and physostigmine followed by oral rivastigmine were given to manage anti-dopaminergic and anti-cholinergic symptoms respectively. This proposed treatment combination could alleviate some of the symptoms. In conclusion, this case series supports the characterisation of PDSS symptomology predominantly being anti-cholinergic with similar onset (<1 hour) and duration (<72hours). A combination of bromocriptine and physostigmine followed by rivastigmine is proposed to manage PDSS if patients develop severe dopamine blockade or anti-cholinergic delirium.

Population pharmacokinetic (PK) and pharmacokinetic- pharmacodynamic (PK-PD) models were used to quantify the exposure-response (E-R) relationship between nalbuphine exposure and 2 widely used rating scales for itch: the Numerical Rating Scale for the subject’s ‘average’ itch experience (NRS-AV) and the Worst Itch (WI-NRS), with 24-hour recall. Simulations based on the model E-R relationship were used to support dose selection for future clinical investigations and were evaluated with a target of reducing the 7-day average of the 24-hour WI-NRS by at least 30% from baseline in the majority of the analysis population. Data from two clinical trials (NCT02373215: 9 healthy subjects; NCT02174419: 62 subjects with PN), in patients with Prurigo Nodularis (PN) with moderate to severe itch who received treatment with either of 2 doses of Nalbuphine ER versus placebo, were used for the analysis. A two-compartment PK model with serial zero and first-order oral absorption was used to describe drug exposure. A sigmoidal maximum effect (Emax) model with a placebo effect was used to model the itch response endpoints (NRS-AV, WI-NRS). The PK/PD model adequately predicted the exposure-related reduction in both NRS-AV and WI-NRS over time with approximately 63% and 27% of Emax, respectively. Exposures associated with 80% of Emax were achieved in about 78% of the patients at 162 mg BID compared to 35% at 81 mg BID. Simulated dose-response indicated that 108 and 162 mg BID doses result in the highest proportion of patients achieving at least a 30% reduction in NRS-AV and WI-NRS, respectively.

Aim To clarify the incidence and risk factors of infusion-related reactions (IRRs) to trastuzumab in breast cancer patients and verify the preventive effects of glucocorticoids. Methods The electronic medical record data at the time of trastuzumab administration were retrospectively reviewed. The following exclusion criteria were applied to 229 breast cancer patients who received trastuzumab at Osaka Medical and Pharmaceutical University Hospital during the 4-year study period: missing information on human epidermal growth factor receptor type 2 (HER2) status (n=1); missing information on eosinophils (n=11); or use of treatments other than trastuzumab (n=41). Results The 176 patients included in the study received 2,320 infusions. Fifty-eight patients (33.0%) experienced IRRs, and IRRs occurred in 80 (3.4%) of the 2,320 infusions. Owing to the hierarchical structure of the data, the independence of the observed values was evaluated using the intraclass correlation coefficient. Multivariate multilevel logistic regression analysis showed that premedication with dexamethasone was effective in lowering IRR risk with trastuzumab (mg; per unit; odds ratio, OR=0.62; 95% confidence interval, 95% CI, 0.44‒0.86; p=0.005). Preoperative status (OR=34.7; 95% CI, 5.0–242.0; p<0.001) and high doses of trastuzumab (mg/kg; per unit; OR=59.6; 95% CI, 19.7–180.0; p<0.001) were independent risk factors for IRRs. Conclusion The results of this study suggest that premedication with dexamethasone has a protective effect against IRRs caused by trastuzumab in breast cancer treatment. Future studies are needed to determine the optimal dosing of dexamethasone to prevent IRRs and the impact of dexamethasone on the efficacy of trastuzumab treatment.

Abstract Objective To compare the Liverpool Causality Assessment Tool versus Naranjo Scale for screening suspected adverse drug reaction (ADR) cases. Methods We retrospectively reviewed patient charts with a history of suspected ADR, scored using both instruments and determined how each correlates with laboratory and other investigations. 924 charts from the Clinical Pharmacology Clinic at the London Health Sciences Centre were reviewed and 529 charts contained objective findings to support or against the diagnosis of ADR. The participant age ranged from 1 month old to 93 years. We determined the sensitivity and specificity of Liverpool and Naranjo tools for predicting ADRs with scores ranging from “Possible” to “Definite” were considered positive and “Unlikely/Doubtful” as negative for ADR. These results were confirmed by laboratory or clinical (re-challenge) testing in 529 cases. Results Liverpool causality tool had sensitivity (SN) of 97.2% ± 2.4% and specificity (SP) of 2.3% ± 1.57%. The positive (PPV) and negative predictive values (NPV) were 34.1% and 61.5%, respectively. The Naranjo scale had SN of 81.2% ± 5.69% and SP of 13.2% ± 3.56%. PPV and NPV were 32.7% and 57.5%, respectively. Conclusions The Liverpool Causality Assessment Tool is a more sensitive tool than the Naranjo Scale in the assessment of possible ADRs but both tools have poor specificity. The Liverpool Tool can be a useful screening tool in settings where other tests may not be readily available. However the low PPV and NPV of both instruments suggests pursue further testing is needed to confirm or deny an ADR.

Aim: To identify older patients’ risk factors for drug-related readmissions and assess the preventability of older patients’ drug-related revisits. Methods: Post-hoc analysis of a randomised clinical trial with patients aged ≥ 65 years at eight wards within four hospitals in Sweden. The primary outcome used to identify risk factors was drug-related readmission within 12 months post-discharge. A Cox proportional hazards model was made with sociodemographic and clinical baseline characteristics. Four hundred trial participants were randomly selected and their revisits (admissions and emergency department visits) were assessed to identify potentially preventable drug-related revisits, related diseases and causes. Results: Among 2,637 patients (median age (interquartile range) 81 (74–87) years), 582 (22%) experienced a drug-related readmission within 12 months. Sixteen risk factors (hazard ratio > 1, p < 0.05) related to age, previous hospital visits, medication use, multimorbidity and cardiovascular, liver, lung and peptic ulcer disease were identified. The 400 patients experienced a total of 522 hospital revisits, of which 85 (16%) were potentially preventable drug-related revisits. The two most prevalent diseases and causes related to preventable revisits were heart failure (n=24, 28%) and chronic obstructive pulmonary disease (n=13, 15%), and inadequate treatment (n=23, 27%) and insufficient or no follow-up (n=22, 26%). Conclusion: Risk factors for drug-related readmissions in older hospitalised patients were age, previous hospital visits, medication use and multiple diseases. Potentially preventable drug-related hospital revisits are common and might be prevented through adequate medication use and follow-up in older patients with cardiovascular or lung disease.

Background There is evidence gastrointestinal (GI) motility may play a role in the development of GI cancers. Weak opioids (codeine and dihydrocodeine) decrease GI motility, but their effect on GI cancer risk has not been assessed. Aim To assess the association between weak opioids and cancers of the GI tract. Methods A series of nested case-control studies was conducted using Scottish general practice records from the Primary Care Clinical Informatics Unit Research database. Oesophageal (n=2,432), gastric (n=1,443), and colorectal cancer (n=8,750) cases, diagnosed between 1999 and 2011, were identified and matched with up to five controls. Weak opioid use was identified from prescribing records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression, adjusting for relevant comorbidities and medication use. Results There was no association between weak opioids and colorectal cancer (adjusted OR=0.96, CI 0.90, 1.02, p=0.15). There was an increased risk of oesophageal (adjusted OR=1.16, CI 1.04, 1.29, p=0.01) and gastric cancer (adjusted OR=1.26, CI 1.10, 1.45, p=0.001). The associations for oesophageal cancer, but not gastric cancer, were attenuated when weak opioid users were compared with users of another analgesic (adjusted OR=1.03 CI 0.86, 1.22, p=0.76 and adjusted OR=1.29 CI 1.02, 1.64, p=0.04 respectively). Conclusion In this large population-based study, there was no consistent evidence of an association between weak opioids and oesophageal or colorectal cancer risk, but a small increased risk of gastric cancer. Further investigation is required to determine whether this association is causal or reflects residual confounding or confounding by indication.

The recent introduction of the European Medical Device Regulation poses stricter legislation for manufacturers developing medical devices in the EU. Many devices have been placed into a higher risk category, thus requiring more data before market approval, and a much larger focus has also been placed on safety. For implantable and Class III devices, the highest risk class, clinical evidence is a necessity. However, the requirements of clinical study design and developmental outcomes are only described in general terms due to the diversity of devices. A structured approach to determining the requirements for the clinical development of high-risk medical devices is introduced, utilising the question-based development framework, which is already used for pharmaceutical drug development. An example of a novel implantable device for haemodialysis demonstrates how to set up a relevant target product profile defining the device requirements and criteria. This can then be used to define specific questions to be answered during clinical development, based upon 5 general questions as specified by the question-based framework. The result is a clear and evaluable overview of requirements and methodologies to verify and track these requirements in the clinical development phase. Development organisations will be guided to the optimal route, also to abandon projects destined for failure in an early stage to minimise development risks. Moreover, the framework facilitates communication with funding agencies, regulators and clinicians, while highlighting remaining “known unknowns” that are to be answered in the post-market phase after sufficient benefit has been established relative to the risks.