Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease.

BACKGROUND: Vedolizumab is a gut-selective immunoglobulin G1 monoclonal antibody to α4 ß7 integrin for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Prospective clinical studies of vedolizumab in pregnancy have not been conducted; therefore, existing safety data of vedolizumab in pregnancy were examined. AIM: To assess pregnancy outcomes in females and partners of males who received vedolizumab. METHODS: All pregnancy data collected during the clinical programme (from 14 May 2007 to 27 June 2013) and in the post-marketing setting (to 19 November 2015) were analysed. RESULTS: Across six studies, there were 27 pregnancies in female participants and 19 pregnancies in partners of male participants. Among 24 vedolizumab-treated females (23 with CD/UC, one healthy volunteer), there were 11 live births, five elective terminations, four spontaneous abortions and four undocumented outcomes. A congenital corpus callosum agenesis anomaly was reported in one live birth from a healthy volunteer with extensive obstetric history exposed to single-dose vedolizumab 79 days before estimated conception. Of 19 pregnancies in partners of male participants, there were 11 live births, two spontaneous abortions, three elective terminations and three undocumented outcomes. Post-marketing reports recorded 81 pregnancies, resulting in four live births, 11 spontaneous abortions and 66 pregnancies that were on-going or reported undocumented outcomes. CONCLUSIONS: Initial analysis, limited by sample size and follow-up, identified no new safety concerns for pregnancy outcomes in females directly or indirectly exposed to vedolizumab. However, vedolizumab should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother/unborn child.

Structured assessment for prospective identification of safety signals in electronic medical records: evaluation in the health improvement network.

BACKGROUND: Pharmacovigilance signal detection largely relies on individual case reports, but longitudinal health data are being explored as complementary information sources. Research to date has focused on the ability of epidemiological methods to distinguish established adverse drug reactions (ADRs) from unrelated adverse events. OBJECTIVE: The aim of this study was to evaluate a process for structured clinical and epidemiological assessment of temporally associated drugs and medical events in electronic medical records. METHODS: Pairs of drugs and medical events were selected for review on the basis of their temporal association according to a calibrated self-controlled cohort analysis in The Health Improvement Network. Six assessors trained in pharmacovigilance and/or epidemiology evaluated seven drugs each, with up to 20 medical events per drug. A pre-specified questionnaire considered aspects related to the nature of the temporal pattern, demographic features of the cohort, concomitant medicines, earlier signs and symptoms, and possible confounding by underlying disease. This informed a classification of drug-event pairs as known ADRs, meriting further evaluation, or dismissed. RESULTS: The number of temporally associated medical events per drug ranged from 11 to 307 (median 50) for the 42 selected drugs. Out of the 509 relevant drug-event combinations subjected to the assessment, 127 (25 %) were classified as known ADRs. Ninety-one (24 %) of the remaining pairs were classified as potential signals meriting further evaluation and 291 (76 %) were dismissed. Suggestive temporal patterns and lack of clear alternative explanations were the most common reasons that drug-event pairs were classified as meriting further evaluation. Earlier signs and symptoms and confounding by the underlying disease were the most common reasons that drug-event pairs were dismissed. CONCLUSIONS: Exploratory analysis of electronic medical records can detect important potential safety signals. However, effective signal detection requires that statistical signal detection be combined with clinical and epidemiological review to achieve an acceptable false positive rate.

NSAID use and risk of leukaemia: a population-based case-control study.

PURPOSE: The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of developing colorectal and lung cancer. Studies suggesting similar associations in leukaemia have been small and underpowered. We have conducted a large population-based case-control study to determine whether the use of NSAIDs is associated with a reduced risk of acute and chronic leukaemias, and whether their use has any impact on survival in these patients. METHODS: We identified all the incident cases of leukaemia in 'The Health Improvement Network' (THIN) general practice dataset, along with at least four matched controls per case. We used conditional logistic regression to determine odds ratios for NSAID prescription rates and the risk of developing several leukaemia sub-types. We then used Cox regression to determine the association between NSAID prescription rate and risk of death in leukaemia. Hazard ratios were adjusted for gender, age at diagnosis, smoking status and Townsend Score. RESULTS: The risk of leukaemia overall appears to increase marginally with increased use of NSAIDs prior to diagnosis. This is not seen when individual leukaemia sub-types are examined, however, except perhaps in CLL where patients who had received 2-5 prescriptions/year are 34% more likely to be diagnosed with CLL than those who had not had any NSAID prescriptions (O.R. 1.34, p = 0.03, 95% C.I. 1.02-1.74). There was no statistically significant association between exposure to NSAIDs prior to leukaemia diagnosis and survival. CONCLUSION: The use of NSAIDs does not reduce the risk of developing leukaemia, nor do they improve survival.