Use of pragmatic randomized trials in multiple sclerosis: A systematic overview.

BACKGROUND: Pragmatic trials are increasingly recognized for providing real-world evidence on treatment choices. OBJECTIVE: The objective of this study is to investigate the use and characteristics of pragmatic trials in multiple sclerosis (MS). METHODS: Systematic literature search and analysis of pragmatic trials on any intervention published up to 2022. The assessment of pragmatism with PRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary-2) is performed. RESULTS: We identified 48 pragmatic trials published 1967-2022 that included a median of 82 participants (interquartile range (IQR) = 42-160) to assess typically supportive care interventions (n = 41; 85%). Only seven trials assessed drugs (15%). Only three trials (6%) included >500 participants. Trials were mostly from the United Kingdom (n = 18; 38%), Italy (n = 6; 13%), the United States and Denmark (each n = 5; 10%). Primary outcomes were diverse, for example, quality-of-life, physical functioning, or disease activity. Only 1 trial (2%) used routinely collected data for outcome ascertainment. No trial was very pragmatic in all design aspects, but 14 trials (29%) were widely pragmatic (i.e. PRECIS-2 score ⩾ 4/5 in all domains). CONCLUSION: Only few and mostly small pragmatic trials exist in MS which rarely assess drugs. Despite the widely available routine data infrastructures, very few trials utilize them. There is an urgent need to leverage the potential of this pioneering study design to provide useful randomized real-world evidence.

Meta-research on pragmatism of randomized trials: rationale and design of the PragMeta database.

BACKGROUND: Pragmatic trials provide decision-oriented, real-world evidence that is highly applicable and generalizable. The interest in real-world evidence is fueled by the assumption that effects in the "real-world" are different to effects obtained under artificial, controlled, research conditions as often used for traditional explanatory trials. However, it is unknown which features of pragmatism, generalizability, and applicability would be responsible for such differences. There is a need to provide empirical evidence and promote meta-research to answer these fundamental questions on the pragmatism of randomized trials and real-world evidence. Here, we describe the rationale and design of the PragMeta database which pursues this goal ( www.PragMeta.org ). METHODS: PragMeta is a non-commercial, open data platform and infrastructure to facilitate research on pragmatic trials. It collects and shares data from published randomized trials that either have a specific design feature or other characteristic related to pragmatism or they form clusters of trials addressing the same research question but having different aspects of pragmatism. This lays the foundation to determine the relationship of various features of pragmatism, generalizability, and applicability with intervention effects or other trial characteristics. The database contains trial data actively collected for PragMeta but also allows to import and link existing datasets of trials collected for other purposes, forming a large-scale meta-database. PragMeta captures data on (1) trial and design characteristics (e.g., sample size, population, intervention/comparison, outcome, longitudinal structure, blinding), (2) effects estimates, and (3) various determinants of pragmatism (e.g., the use of routinely collected data) and ratings from established tools used to determine pragmatism (e.g., the PRagmatic-Explanatory Continuum Indicator Summary 2; PRECIS-2). PragMeta is continuously provided online, inviting the meta-research community to collaborate, contribute, and/or use the database. As of April 2023, PragMeta contains data from > 700 trials, mostly with assessments on pragmatism. CONCLUSIONS: PragMeta will inform a better understanding of pragmatism and the generation and interpretation of real-world evidence.

The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020.

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I2  = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

Clinical trial research on COVID-19 in Germany - a systematic analysis.

Background: In 2020, the COVID-19 pandemic led to an unprecedented volume of almost 3,000 clinical trials registered worldwide. We aimed to describe the COVID-19 clinical trial research agenda in Germany during the first year of the pandemic. Methods: We identified randomized clinical trials assessing interventions to treat or prevent COVID-19 that were registered in 2020 and recruited or planned to recruit participants in Germany. We requested recruitment information from trial investigators as of April 2021. Results: In 2020, 65 trials were completely (n=27) or partially (n=38) conducted in Germany. Most trials investigated interventions to treat COVID-19 (86.2%; 56/65), in hospitalized patients (67.7%; 44/65), with industry funding (53.8%; 35/65). Few trials were completed (21.5%; 14/65). Overall, 187,179 participants were planned to be recruited (20,696 in Germany), with a median number of 106 German participants per trial (IQR 40 to 345). From the planned German participants, 13.4% were recruited (median 15 per trial (IQR 0 to 44). Conclusions: The overall German contribution to the worldwide COVID-19 clinical trial research agenda was modest. Few trials delivered urgently needed evidence. Most trials did not meet recruitment goals. Evaluation and international comparison of the challenges for conducting clinical trials in Germany is needed.

SPHN - Development and Usability Testing of an Electronic General Consent Prototype.

BACKGROUND: According to the Swiss Law on Research in Humans, the reuse of routinely collected genetic and non-genetic data and samples from patients for research purposes requires the consent of patients. Unfortunately, the so far established paper-based processes are intrinsically linked to the hospital admission process, labour intensive and not yielding the targeted return rates. Therefore, the overall goal of the presented SPHN project is to increase patient reach by providing hospitals with a patient-centric, user-friendly and admission-independent electronic general consent pathway. As part of the project, feasibility of different digital pathways was evaluated in a usability testing. METHODS: Based on a nationwide harmonised template, a mobile centric progressive web application was developed by the Department of Clinical Research Basel. Usability of the application and according user journeys were evaluated at all partner hospitals. Two options of giving consent were explored using 1) patients' smartphones without any involvement of hospital personnel and 2) a hospital device (tablet) with explicit confirmation of patient identity by hospital personnel. Participant signatures were captured as a picture of a handwritten signature on paper taken with the camera of the smartphone or tablet. Usability issues and feedback of participants were documented directly after usability testing. RESULTS: In total, 122 users agreed to participate in the usability testing using a tablet or smartphone. The general consent request workflow on the smartphone or tablet was regarded as user friendly and easy to navigate by 96% of all participants. However, capturing a picture of a handwritten signature resulted in usability issues in multiple cases, i.e. due to missing pen or paper. CONCLUSION: Usability testing of our prototype application showed a broad acceptance of participants regarding the use of mobile electronic devices to give general consent. Therefore, we believe that easy-to-use digital general consent processes provide effective means to increase the patient pool for health-related research. Further discussions with legislative bodies are required to find patient centric, feasible and legally acceptable solutions in the specific case of electronic general consent for the near future.