Unknown adverse drug reactions from spontaneous reports in a hospital setting: characterization, follow-up, and contribution to the pharmacovigilance system.

Introduction: Post-marketing identification and report of unknown adverse drug reactions (ADRs) are crucial for patient safety. However, complete information on unknown ADRs seldom is available at the time of spontaneous ADR reports and this can hamper their contribution to the pharmacovigilance system. Methods: In order to characterize the seriousness and outcome of unknown ADRs at the time of report and at follow-up, and analyze their contribution to generate pharmacovigilance regulatory actions, a retrospective observational study of those identified in the spontaneous ADR reports of patients assisted at a hospital (January, 2016-December, 2021) was carried out. Information on demographic, clinical and complementary tests was retrieved from patients' hospital medical records. To evaluate the contribution to pharmacovigilance system we reviewed the European Union SmPCs, the list of the pharmacovigilance signals discussed by the Pharmacovigilance Risk Assessment Committee, and its recommendations reports on safety signals. Results: A total of 15.2% of the spontaneous reported cases during the study contained at least one unknown drug-ADR pair. After exclusions, 295 unknown drug-ADR pairs were included, within them the most frequently affected organs or systems were: skin and subcutaneous tissue (34, 11.5%), hepatobiliary disorders (28, 9.5%), cardiac disorders (28, 9.5%) and central nervous system disorders (27, 9.2%). The most frequent ADRs were pemphigus (7, 2.4%), and cytolytic hepatitis, sudden death, cutaneous vasculitis and fetal growth restriction with 6 (2%) each. Vaccines such as covid-19 and pneumococcus (68, 21.3%), antineoplastics such as paclitaxel, trastuzumab and vincristine (39, 12.2%) and immunosuppressants such as methotrexate and tocilizumab (35, 11%) were the most frequent drug subgroups involved. Sudden death due to hydroxychloroquine alone or in combination (4, 1.4%) and hypertransaminasemia by vincristine (n = 3, 1%) were the most frequent unknown drug-ADR pairs. A total of 269 (91.2%) of them were serious. Complementary tests were performed in 82.7% of unknown-ADR pairs and helped to reinforce their association in 18.3% of them. A total of 18 (6.1%) unknown drug-ADR pairs were evaluated by the EMA, in 8 (2.7%) the information was added to the drug's SmPC and in 1 case the risk prevention material was updated. Conclusion: Identification and follow-up of unknown ADRs can be of great relevance for patient safety and for the enrichment of the pharmacovigilance system.

Premature termination of clinical trials in Spain: reasons, characteristics, and opportunities to improve.

PURPOSE: The aim of this study is to determine the rate of prematurely terminated clinical trials (CTs) and describe primary reasons and characteristics, and suggest strategies to improve. METHODS: We performed a retrospective, observational, cross-sectional study including all CTs registered in the Spanish Registry of Clinical Studies (REec) from January 1, 2013 to November 31, 2021. A descriptive analysis of reasons for premature termination was made. To assess characteristics associated with a premature termination, the relative risks (RR) with a 95% confidence interval were calculated. RESULTS: In total, 21% (718) of CT were prematurely terminated. Reasons for premature termination included patient recruitment issues in 25% (179) of cases, efficacy or futility problems in 18% (132), and commercial or strategic decisions from the sponsor in 12% (87). Characteristics significantly associated with an increased risk of premature termination included the following: presence of placebo (RR 2.08); multiple study sites (RR 1.32); pediatric and geriatric populations (RR 1.29 children; RR 1.47 preschoolers; RR 1.92 newborns; RR 1.27 > 64 years of age). In addition, circumstances such as investigations in phase II (RR 1.21), of cancer (RR 1.37), and of digestive pathology (RR 1.65) were also associated with increased risk of premature termination. CONCLUSION: Recruitment of the study subjects in a CT must be meticulous and account for age of participants. In addition, CT study sites should be evaluated to ensure they have appropriate resources and the desired patient population. Based on intermediate analyses, CT protocols should describe the criteria to terminate a study due to futility. These approaches are essential to avoid harm to participants, ensure internal validity of studies, and improve the use of resources in CT development.

Aggressive Pituitary Macroadenoma Treated With Capecitabine and Temozolomide Chemotherapy Combination in a Patient With Nelson's Syndrome: A Case Report.

Nelson's syndrome is considered a severe side effect that can occur after a total bilateral adrenalectomy in patients with Cushing's disease. It usually presents with clinical manifestations of an enlarging pituitary tumor including visual and cranial nerve alterations, and if not treated, can cause death through local brain compression or invasion. The first therapeutic option is surgery but in extreme cases of inaccessible or resistant aggressive pituitary tumors; the off-label use of chemotherapy with capecitabine and temozolomide can be considered. However, the use of this treatment is controversial due to adverse events, lack of complete response, and inability to predict results. We present the case of a 48-year-old man diagnosed with Nelson's syndrome with prolonged partial response and significant clinical benefit to treatment with capecitabine and temozolomide.