Medical Specialists' Perspectives on the Influence of Electronic Medical Record Use on the Quality of Hospital Care:Semistructured Interview Study

Objective: The aim of this study was to examine how, and by which aspects, the relationship between EMR use and the quality of care in hospitals is influenced according to medical specialists. Methods: To answer this question, a qualitative study was conducted in the period of August-October 2018. Semistructured interviews of around 90 min were conducted with 11 medical specialists from 11 different Dutch hospitals. For analysis of the answers, we used a previously published taxonomy of factors that can influence the use of EMRs. Results: The professional experience of the participating medical specialists varied between 5 and 27 years. Using the previously published taxonomy, these medical specialists considered technical barriers the most significant for EMR use. The suboptimal change processes surrounding implementation were also perceived as a major barrier. A final major problem is related to the categories “social” (their relationships with the patients and fellow care providers), “psychological” (based on their personal issues, knowledge, and perceptions), and “time” (the time required to select, implement, and learn how to use EMR systems and subsequently enter data into the system). However, the medical specialists also identified potential technical facilitators, particularly in the assured availability of information to all health care professionals involved in the care of a patient. They see promise in using EMRs for medical decision support to improve the quality of care but consider these possibilities currently lacking. Conclusions: The 11 medical specialists shared positive experiences with EMR use when comparing it to formerly used paper records. The fact that involved health care professionals can access patient data at any time they need is considered important. However, in practice, potential quality improvement lags as long as decision support cannot be applied because of the lack of a fully coded patient record

Pragmatic rules for comparability of biological medicinal products

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Recommendations for the design of small population clinical trials

Background Orphan drug development faces numerous challenges, including low disease prevalence, patient population heterogeneity, and strong presence of paediatric patient populations. Consequently, clinical trials for orphan drugs are often smaller than those of non-orphan drugs, and they require the development of efficient trial designs relevant to small populations to gain the most information from the available data. The International Rare Diseases Research Consortium (IRDiRC) is aimed at promoting international collaboration and advance rare diseases research worldwide, and has as one of its goals to contribute to 1000 new therapies for rare diseases. IRDiRC set up a Small Population Clinical Trials (SPCT) Task Force in order to address the shortcomings of our understanding in carrying out clinical trials in rare diseases. Results The IRDiRC SPCT Task Force met in March 2016 to discuss challenges faced in the design of small studies for rare diseases and present their recommendations, structured around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi-arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients’ engagement in study design. Conclusions Recommendations have been issued based on discussions of the Small Population Clinical Trials Task Force that aim to contribute towards successful therapy development and clinical use. While randomised clinical trials are still considered the gold standard, it is recommended to systematically take into consideration alternative trial design options when studying treatments for a rare disease. Combining different sources of safety data is important to give a fuller picture of a therapy’s safety profile. Multi-arm trials should be considered an opportunity for rare diseases therapy development, and funders are encouraged to support such trial design via international networks. Patient engagement is critical in trial design and therapy development, a process which sponsors are encouraged to incorporate when conducting trials and clinical studies. Input from multiple regulatory agencies is recommended early and throughout clinical development. Regulators are often supportive of new clinical trial designs, provided they are well thought through and justified, and they also welcome discussions and questions on this topic. Parallel advice for multiregional development programs should also be considered

Improving clinical trial efficiency by biomarker-guided patient selection

Background: In many therapeutic areas, individual patient markers have been identified that are associated with differential treatment response. These markers include both baseline characteristics, as well as short-term changes following treatment. Using such predictive markers to select subjects for inclusion in randomized clinical trials could potentially result in more targeted studies and reduce the number of subjects to recruit. Methods: This study compared three trial designs on the sample size needed to establish treatment efficacy across a range of realistic scenarios. A conventional parallel group design served as the point of reference, while the alternative designs selected subjects on either a baseline characteristic or an early improvement after a short active run-in phase. Data were generated using a model that characterized the effect of treatment on survival as a combination of a primary effect, an interaction with a baseline marker and/or an early marker improvement. A representative scenario derived from empirical data was also evaluated. Results: Simulations showed that an active run-in design could substantially reduce the number of subjects to recruit when improvement during active run-in was a reliable predictor of differential treatment response. In this case, the baseline selection design was also more efficient than the parallel group design, but less efficient than the active run-in design with an equally restricted population. For most scenarios, however, the advantage of the baseline selection design was limited. Conclusions: An active run-in design could substantially reduce the number of subjects to recruit in a randomized clinical trial. However, just as with the baseline selection design, generalizability of results may be limited and implementation could be difficult

Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials

Background: Funding and resources for low prevalent neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) are limited, and optimising their use is vital for efficient drug development. In this study, we review the design assumptions for pivotal ALS clinical trials with time-to-event endpoints and provide optimised settings for future trials. Methods: We extracted design settings from 13 completed placebo-controlled trials. Optimal assumptions were estimated using parametric survival models in individual participant data (n=4991). Designs were compared in terms of sample size, trial duration, drug use and costs. Results: Previous trials overestimated the hazard rate by 18.9% (95% CI 3.4% to 34.5%, p=0.021). The median expected HR was 0.56 (range 0.33–0.66). Additionally, we found evidence for an increasing mean hazard rate over time (Weibull shape parameter of 2.03, 95% CI 1.93 to 2.15, p<0.001), which affects the design and planning of future clinical trials. Incorporating accrual time and assuming an increasing hazard rate at the design stage reduced sample size by 33.2% (95% CI 27.9 to 39.4), trial duration by 17.4% (95% CI 11.6 to 23.3), drug use by 14.3% (95% CI 9.6 to 19.0) and follow-up costs by 21.2% (95% CI 15.6 to 26.8). Conclusions: Implementing distributional knowledge and incorporating accrual at the design stage could achieve large gains in the efficiency of ALS clinical trials with time-to-event endpoints. We provide an open-source platform that helps investigators to make more accurate sample size calculations and optimise the use of their available resources

TUBectomy with delayed oophorectomy as an alternative to risk-reducing salpingo-oophorectomy in high-risk women to assess the safety of prevention:the TUBA-WISP II study protocol

BACKGROUND: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy.PRIMARY OBJECTIVE: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk.STUDY HYPOTHESIS: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) or 45-50 (BRCA2) years, compared with the current standard salpingo-oophorectomy at age 35-40 (BRCA1) or 40-45 (BRCA2) years, is non-inferior in regard to tubo-ovarian cancer risk.TRIAL DESIGN: In this international prospective preference trial, participants will choose between the novel salpingectomy with delayed oophorectomy and the current standard salpingo-oophorectomy. Salpingectomy can be performed after the completion of childbearing and between the age of 25 and 40 (BRCA1), 25 and 45 (BRCA2), or 25 and 50 (BRIP1, RAD51C, and RAD51D pathogenic variant carriers) years. Subsequent oophorectomy is recommended at a maximum delay of 5 years beyond the upper limit of the current guideline age for salpingo-oophorectomy. The current National Comprehensive Cancer Network (NCCN) guideline age, which is also the recommended age for salpingo-oophorectomy within the study, is 35-40 years for BRCA1, 40-45 years for BRCA2, and 45-50 years for BRIP1, RAD51C, and RAD51D pathogenic variant carriers.MAJOR INCLUSION/EXCLUSION CRITERIA: Premenopausal individuals with a documented class IV or V germline pathogenic variant in the BRCA1, BRCA2, BRIP1, RAD51C, or RAD51D gene who have completed childbearing are eligible for participation. Participants may have a personal history of a non-ovarian malignancy.PRIMARY ENDPOINT: The primary outcome is the cumulative tubo-ovarian cancer incidence at the target age: 46 years for BRCA1 and 51 years for BRCA2 pathogenic variant carriers.SAMPLE SIZE: The sample size to ensure sufficient power to test non-inferiority of salpingectomy with delayed oophorectomy compared with salpingo-oophorectomy requires 1500 BRCA1 and 1500 BRCA2 pathogenic variant carriers.ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Participant recruitment is expected to be completed at the end of 2026 (total recruitment period of 5 years). The primary outcome is expected to be available in 2036 (minimal follow-up period of 10 years).TRIAL REGISTRATION NUMBER: NCT04294927.</p

Reporting of covariate selection and balance assessment in propensity score analysis is suboptimal: a systematic review

Abstract Objectives: To assess the current practice of propensity score (PS) analysis in the medical literature, particularly the assessment and reporting of balance on confounders. Study Design and Setting: A PubMed search identified studies using PS methods from December 2011 through May 2012. For each article included in the review, information was extracted on important aspects of the PS such as the type of PS method used, variable selection for PS model, and assessment of balance. Results: Among 296 articles that were included in the review, variable selection for PS model was explicitly reported in 102 studies (34.4%). Covariate balance was checked and reported in 177 studies (59.8%). P-values were the most commonly used statistical tools to report balance (125 of 177, 70.6%). The standardized difference and graphical displays were reported in 45 (25.4%) and 11 (6.2%) articles, respectively. Matching on the PS was the most commonly used approach to control for confounding (68.9%), followed by PS adjustment (20.9%), PS stratification (13.9%), and inverse probability of treatment weighting (IPTW, 7.1%). Balance was more often checked in articles using PS matching and IPTW, 70.6% and 71.4%, respectively. Conclusion: The execution and reporting of covariate selection and assessment of balance is far from optimal. Recommendations on reporting of PS analysis are provided to allow better appraisal of the validity of PS-based studies.

Applicability and added value of novel methods to improve drug development in rare diseases

The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports. The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were 'innovative trial designs' (six methods), 'level of evidence' (one method), 'study endpoints and statistical analysis' (four methods), and 'meta-analysis' (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters. Direct applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters. Novel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes. The online version of this article (10.1186/s13023-018-0925-0) contains supplementary material, which is available to authorized users

Room for Improvement in Conducting and Reporting Non-Inferiority Randomized Controlled Trials on Drugs: A Systematic Review

BACKGROUND: A non-inferiority (NI) trial is intended to show that the effect of a new treatment is not worse than the comparator. We conducted a review to identify how NI trials were conducted and reported, and whether the standard requirements from the guidelines were followed. METHODOLOGY AND PRINCIPAL FINDINGS: From 300 randomly selected articles on NI trials registered in PubMed at 5 February 2009, we included 227 NI articles that referred to 232 trials. We excluded studies on bioequivalence, trials on healthy volunteers, non-drug trials, and articles of which the full-text version could not be retrieved. A large proportion of trials (34.0%) did not use blinding. The NI margin was reported in 97.8% of the trials, but only 45.7% of the trials reported the method to determine the margin. Most of the trials used either intention to treat (ITT) (34.9%) or per-protocol (PP) analysis (19.4%), while 41.8% of the trials used both methods. Less than 10% of the trials included a placebo arm to confirm the efficacy of the new drug and active comparator against placebo, and less than 5.0% were reporting the similarity of the current trial with the previous comparator's trials. In general, no difference was seen in the quality of reporting before and after the release of the CONSORT statement extension 2006 or between the high-impact and low-impact journals. CONCLUSION: The conduct and reporting of NI trials can be improved, particularly in terms of maximizing the use of blinding, the use of both ITT and PP analysis, reporting the similarity with the previous comparator's trials to guarantee a valid constancy assumption, and most importantly reporting the method to determine the NI margin

Lithium carbonate in amyotrophic lateral sclerosis patients homozygous for the C-allele at SNP rs12608932 in UNC13A: protocol for a confirmatory, randomized, group-sequential, event-driven, double-blind, placebo-controlled trial

BackgroundGiven the large genetic heterogeneity in amyotrophic lateral sclerosis (ALS), it seems likely that genetic subgroups may benefit differently from treatment. An exploratory meta-analysis identified that patients homozygous for the C-allele at SNP rs12608932, a single nucleotide polymorphism in the gene UNC13A, had a statistically significant survival benefit when treated with lithium carbonate. We aim to confirm the efficacy of lithium carbonate on the time to death or respiratory insufficiency in patients with ALS homozygous for the C-allele at SNP rs12608932 in UNC13A. MethodsA randomized, group-sequential, event-driven, double-blind, placebo-controlled trial will be conducted in 15 sites across Europe and Australia. Patients will be genotyped for UNC13A; those homozygous for the C-allele at SNP rs12608932 will be eligible. Patients must have a diagnosis of ALS according to the revised El Escorial criteria, and a TRICALS risk-profile score between -6.0 and -2.0. An expected number of 1200 patients will be screened in order to enroll a target sample size of 171 patients. Patients will be randomly allocated in a 2:1 ratio to lithium carbonate or matching placebo, and treated for a maximum duration of 24 months. The primary endpoint is the time to death or respiratory insufficiency, whichever occurs first. Key secondary endpoints include functional decline, respiratory function, quality of life, tolerability, and safety. An interim analysis for futility and efficacy will be conducted after the occurrence of 41 events. DiscussionLithium carbonate has been proven to be safe and well-tolerated in patients with ALS. Given the favorable safety profile, the potential benefits are considered to outweigh the burden and risks associated with study participation. This study may provide conclusive evidence about the life-prolonging potential of lithium carbonate in a genetic ALS subgroup