Clinical Trialists Research Articles

Evaluation of Data Sharing After Implementation of the International Committee of Medical Journal Editors Data Sharing Statement Requirement

The benefits of responsible sharing of individual-participant data (IPD) from clinical studies are well recognized, but stakeholders often disagree on how to align those benefits with privacy risks, costs, and incentives for clinical trialists and sponsors. The International Committee of Medical Journal Editors (ICMJE) required a data sharing statement (DSS) from submissions reporting clinical trials effective July 1, 2018. The required DSSs provide a window into current data sharing rates, practices, and norms among trialists and sponsors. To evaluate the implementation of the ICMJE DSS requirement in 3 leading medical journals: JAMA, Lancet, and New England Journal of Medicine (NEJM). This is a cross-sectional study of clinical trial reports published as articles in JAMA, Lancet, and NEJM between July 1, 2018, and April 4, 2020. Articles not eligible for DSS, including observational studies and letters or correspondence, were excluded. A MEDLINE/PubMed search identified 487 eligible clinical trials in JAMA (112 trials), Lancet (147 trials), and NEJM (228 trials). Two reviewers evaluated each of the 487 articles independently. Publication of clinical trial reports in an ICMJE medical journal requiring a DSS. The primary outcomes of the study were declared data availability and actual data availability in repositories. Other captured outcomes were data type, access, and conditions and reasons for data availability or unavailability. Associations with funding sources were examined. A total of 334 of 487 articles (68.6%; 95% CI, 64%-73%) declared data sharing, with nonindustry NIH-funded trials exhibiting the highest rates of declared data sharing (89%; 95% CI, 80%-98%) and industry-funded trials the lowest (61%; 95% CI, 54%-68%). However, only 2 IPD sets (0.6%; 95% CI, 0.0%-1.5%) were actually deidentified and publicly available as of April 10, 2020. The remaining were supposedly accessible via request to authors (143 of 334 articles [42.8%]), repository (89 of 334 articles [26.6%]), and company (78 of 334 articles [23.4%]). Among the 89 articles declaring that IPD would be stored in repositories, only 17 (19.1%) deposited data, mostly because of embargo and regulatory approval. Embargo was set in 47.3% of data-sharing articles (158 of 334), and in half of them the period exceeded 1 year or was unspecified. Most trials published in JAMA, Lancet, and NEJM after the implementation of the ICMJE policy declared their intent to make clinical data available. However, a wide gap between declared and actual data sharing exists. To improve transparency and data reuse, journals should promote the use of unique pointers to data set location and standardized choices for embargo periods and access requirements.

Uptake of core outcome sets by clinical trialists publishing in major medical journals: Protocol.

Background: Outcome heterogeneity, selective reporting, and choosing outcomes that do not reflect needs and priorities of stakeholders, limit the examination of health intervention effects, particularly in late phase trials. Core outcome sets (COS) are a proposed solution to these issues. A COS is an agreed-upon, standardised set of outcomes that should be measured and reported as a minimum in all trials in a specific area of health or healthcare. COS are intended to increase standardisation of outcome measurement and reporting to better enable comparisons between, and synthesis of findings of trials in a particular health area. Methods: This study will examine late phase trials, published between October 2019 and March 2020 (inclusive), in the following five medical journals: New England Journal of Medicine, Journal of the American Medical Association, Lancet, BMJ, and Annals of Internal Medicine. Trials will be examined to determine if they refer to a COS, and whether they use a COS. Trialists for each identified trial will subsequently be contacted to complete an online survey examining trialists' awareness of, and decisions to search for and use a COS. Discussion: This study will provide important information on uptake of COS by later phase trialists in major medical journals, and the views of these trialists on COS use in trials. These findings will inform approaches to increasing awareness and uptake of COS in future health trials.

A modular framework for early-phase seamless oncology trials.

As our understanding of the etiology and mechanisms of cancer becomes more sophisticated and the number of therapeutic options increases, phase I oncology trials today have multiple primary objectives. Many such designs are now "seamless," meaning that the trial estimates both the maximum tolerated dose and the efficacy at this dose level. Sponsors often proceed with further study only with this additional efficacy evidence. However, with this increasing complexity in trial design, it becomes challenging to articulate fundamental operating characteristics of these trials, such as (1) what is the probability that the design will identify an acceptable, that is., safe and efficacious, dose level? or (2) how many patients will be assigned to an acceptable dose level on average? In this manuscript, we propose a new modular framework for designing and evaluating seamless oncology trials. Each module is comprised of either a dose assignment step or a dose-response evaluation, and multiple such modules can be implemented sequentially. We develop modules from existing phase I/II designs as well as a novel module for evaluating dose-response using a Bayesian isotonic regression scheme. We also demonstrate a freely available R package called seamlesssim to numerically estimate, by means of simulation, the operating characteristics of these modular trials. Together, this design framework and its accompanying simulator allow the clinical trialist to compare multiple different candidate designs, more rigorously assess performance, better justify sample sizes, and ultimately select a higher quality design.

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper from the Fleischner Society.

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others. This article is a simultaneous joint publication in Radiology and CHEST. The articles are identical except for stylistic changes in keeping with each journal's style. Either version may be used in citing this article. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Emerging clinical scientist paradigm: a call for spectrum recognition in team science

Team science1—what a concept! To many, the idea that a group of scientists can work together on a common problem and seek collective answers leading to success seems almost intuitive....

Uptake of core outcome sets by clinical trialists publishing in major medical journals: Protocol

Background: Outcome heterogeneity, selective reporting, and choosing outcomes that do not reflect needs and priorities of stakeholders, limit the examination of health intervention effects, particularly in late phase trials. Core outcome sets (COS) are a proposed solution to these issues. A COS is an agreed-upon, standardised set of outcomes that should be measured and reported as a minimum in all trials in a specific area of health or healthcare. COS are intended to increase standardisation of outcome measurement and reporting to better enable comparisons between, and synthesis of findings of trials in a particular health area. Methods: This study will examine late phase trials, published between October 2019 and March 2020 (inclusive), in the following five medical journals: New England Journal of Medicine, Journal of the American Medical Association, Lancet, BMJ, and Annals of Internal Medicine. Trials will be examined to determine if they refer to a COS, and whether they use a COS. Trialists for each identified trial will subsequently be contacted to complete an online survey examining trialists’ awareness of, and decisions to search for and use a COS. Discussion: This study will provide important information on uptake of COS by later phase trialists in major medical journals, and the views of these trialists on COS use in trials. These findings will inform approaches to increasing awareness and uptake of COS in future health trials.

Data management in substance use disorder treatment research: Implications from data harmonization of National Institute on Drug Abuse-funded randomized controlled trials.

Secondary analysis of data from completed randomized controlled trials is a critical and efficient way to maximize the potential benefits from past research. De-identified primary data from completed randomized controlled trials have been increasingly available in recent years; however, the lack of standardized data products is a major barrier to further use of these valuable data. Pre-statistical harmonization of data structure, variables, and codebooks across randomized controlled trials would facilitate secondary data analysis, including meta-analyses and comparative effectiveness studies. We describe a pre-statistical data harmonization initiative to standardize de-identified primary data from substance use disorder treatment randomized controlled trials funded by the National Institute on Drug Abuse available on the National Institute on Drug Abuse Data Share website. Standardized datasets and codebooks with consistent data structures, variable names, labels, and definitions were developed for 36 completed randomized controlled trials. Common data domains were identified to bundle data files from individual randomized controlled trials according to relevant concepts. Variables were harmonized if at least two randomized controlled trials used the same instruments. The structures of the harmonized data were determined based on the feedback from clinical trialists and substance use disorder research experts. We have created a harmonized database of variables across 36 randomized controlled trials with a build-in label and a brief definition for each variable. Data files from the randomized controlled trials have been consistently categorized into eight domains (enrollment, demographics, adherence, adverse events, physical health measures, mental-behavioral-cognitive health measures, self-reported substance use measures, and biologic substance use measures). Standardized codebooks and concordance tables have also been developed to help identify instruments and variables of interest more easily. The harmonized data of randomized controlled trials of substance use disorder treatments can potentially promote future secondary data analysis of completed randomized controlled trials, allowing combining data from multiple randomized controlled trials and provide guidance for future randomized controlled trials in substance use disorder treatment research.

Identifying individuals with mild cognitive impairment who are at higher genetic risk of further substantial cognitive decline due to Alzheimer's disease

AbstractBackgroundThe development of tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials and cohort studies. The utility of Polygenic Risk Scores (PRS) is gaining increased attention for generating genetic risk profiles and subsequent estimation of future disease risk in Alzheimer’s Disease. We have previously reported on the performance of our PRS to differentiate AD cases from healthy controls in the ADNI cohort using individual's most recent diagnosis. In this work we have analysed whether the PRS is able to predict substantial cognitive decline towards an AD phenotype of individuals with MCI at the point of entering the study. The aim being to demonstrate the utility of PRS approaches in longitudinal studies and future clinical practice.MethodThis longitudinal study explored the performance of the Cytox genoSCORE™ PRS algorithm as measured using ROC, AUC analysis when predicting a change in ADAS‐Cog13 score of 5,10 and 15 points at 2, 3 and 4‐year assessment timepoints. Subjects are included in the analysis based on availability of ADAS‐Cog13 data at those timepoints and availability of genetic data in the ADNI database. Change in cognition as measured by ADAS‐Cog13 was used instead of change of diagnosis given the broad spectrum of baseline cognitive performance in those individuals with MCI.ResultIndividuals with low PRS clearly have a lower likelihood of experiencing substantial cognitive decline (>10 points on the ADAS‐Cog13 scale over 4 years) than those individuals with higher PRS. In a population of 285 individuals with an MCI diagnosis at baseline genoSCORE™ has an accuracy as measured by area under the curve of 74% in predicting those individuals who declined substantially over 4 years, with very high negative predictive values.ConclusionIdentifying individuals of higher risk for substantial cognitive decline towards AD will allow clinical trialists to enrich their studies with more appropriate patients. In addition, use of such risk evaluation techniques in clinical practice will enable clinicians to make more informed decisions on how to manage their patients. Cytox is able to provide a robust end‐to‐end process to provide this comprehensive genetic risk assessment.

Interpretation of clinical studies in electrophysiology: statistical considerations for the clinician.

Atrial fibrillation (AF) outcome studies play an essential role in the development of clinical evidence to improve the management of AF patients. Understanding the statistical considerations involved in study design and interpretation is crucial if electrophysiologists are to change practice. In this review, with the guidance of a medical statistician and a clinical trialist we provide an overview of important statistical issues for the clinician, with a focus on clinical studies in AF ablation. Various types of study designs including randomized controlled trials, superiority, and non-inferiority studies are described, along with their implications and limitations. Appropriate sample size calculation is fundamental to ensure statistical power and efficient resource use. Multiplicity in study endpoints is useful to encapsulate the varied effects of an intervention/treatment, although statistical adjustments are required to account for this. Finally, we discuss the limitations with the current primary endpoint used in AF ablation studies, namely, freedom from atrial tachyarrhythmia of >30 seconds, and propose AF burden as a more relevant primary endpoint, based on findings from recent clinical studies. However, technical challenges need to be overcome before AF burden can be routinely adopted, especially the need for non-invasive, long-term monitoring. The emergence of newer technologies, particularly wearable technology, offers significant promise in filling this gap.

Abstract 13205: Underrepresentation of Women as Clinical Trialists in Heart Failure: A Systematic Review of Randomized Controlled Trials Published in High-impact Medical Journals

Introduction: Clinical trials change practice in cardiology but leading them typically requires advanced research training, mentorship, sponsorship, and networking. Women are underrepresented in cardiology and report challenges in obtaining mentorship and networking opportunities. Objective: To evaluate the gender distribution of first and senior authors in practice-changing clinical trials in heart failure (HF), and explore clinical trial characteristics associated with women as first authors. Methods: We searched MEDLINE, EMBASE and CINAHL databases for randomized controlled trials (RCTs) published January 2000 - May 2019. We included RCTs that recruited adults with HF with reduced ejection fraction that were published in medical journals with an impact factor of > 10. Two reviewers screened and extracted data independently. We determined the gender distribution of the authors, assessed temporal trends in authorship, and used logistic regression to identify characteristics associated with women in first authorship positions. Results: The search identified 10,596 unique studies, of which 317 met eligibility criteria. We found that 15.8%, 11.7%, and 10.7% of first, senior, and corresponding authors, respectively, were women. Multivariable analysis revealed that the first author was more likely to be a woman if the senior author of a clinical trial was a woman (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.04-4.66, p=0.039), and if the trial was conducted at a single rather than multiple centers (OR 1.40, 95% CI 1.09-6.48, p=0.035). Source of funding (public or industry), type of intervention (health service, drug, device, or surgery), and region of trial coordination (Europe, North America, Central and South America, Asia, and Australia) were not associated with gender of first authors. The proportion of trials that included women as authors has decreased from 2000 to present. Conclusion: Women are under-represented as clinical trialists in HF. Adjusting for other trial characteristics, the first author of a clinical trial was more likely to be a woman if the senior author was a woman. Mentoring women as clinical trialists in the present era may be a strategic way to increase the gender diversity of clinical trialists in years to come.

Dexamethasone in hospitalised patients with COVID-19: addressing uncertainties

Dexamethasone in hospitalised patients with COVID-19: addressing uncertainties

Seven decades of chemotherapy clinical trials: a pan-cancer social network analysis

Clinical trials establish the standard of cancer care, yet the evolution and characteristics of the social dynamics between the people conducting this work remain understudied. We performed a social network analysis of authors publishing chemotherapy-based prospective trials from 1946 to 2018 to understand how social influences, including the role of gender, have influenced the growth and development of this network, which has expanded exponentially from fewer than 50 authors in 1946 to 29,197 in 2018. While 99.4% of authors were directly or indirectly connected by 2018, our results indicate a tendency to predominantly connect with others in the same or similar fields, as well as an increasing disparity in author impact and number of connections. Scale-free effects were evident, with small numbers of individuals having disproportionate impact. Women were under-represented and likelier to have lower impact, shorter productive periods (P < 0.001 for both comparisons), less centrality, and a greater proportion of co-authors in their same subspecialty. The past 30 years were characterized by a trend towards increased authorship by women, with new author parity anticipated in 2032. The network of cancer clinical trialists is best characterized as strategic or mixed-motive, with cooperative and competitive elements influencing its appearance. Network effects such as low centrality, which may limit access to high-profile individuals, likely contribute to the observed disparities.

A call for Essays: stories from the frontline during the COVID-19 pandemic

The year 2020 will no doubt be etched in the memory of health-care professionals around the world for many years to come. Doctors, nurses, paramedics, researchers, and many more working in health care have been challenged by the COVID-19 pandemic in many ways, but some positive outcomes have emerged in its wake. Collaborations have sprung up between private companies, public health bodies, and other stakeholders. There has been unprecedented research efforts and cooperation between clinical trialists to publish results in a timely manner and to inform the public and professionals in patient management.

Effect of Bout Length on Gait Measures in People with and without Parkinson's Disease during Daily Life.

Although the use of wearable technology to characterize gait disorders in daily life is increasing, there is no consensus on which specific gait bout length should be used to characterize gait. Clinical trialists using daily life gait quality as study outcomes need to understand how gait bout length affects the sensitivity and specificity of measures to discriminate pathological gait as well as the reliability of gait measures across gait bout lengths. We investigated whether Parkinson’s disease (PD) affects how gait characteristics change as bout length changes, and how gait bout length affects the reliability and discriminative ability of gait measures to identify gait impairments in people with PD compared to neurotypical Old Adults (OA). We recruited 29 people with PD and 20 neurotypical OA of similar age for this study. Subjects wore 3 inertial sensors, one on each foot and one over the lumbar spine all day, for 7 days. To investigate which gait bout lengths should be included to extract gait measures, we determined the range of gait bout lengths available across all subjects. To investigate if the effect of bout length on each gait measure is similar or not between subjects with PD and OA, we used a growth curve analysis. For reliability and discriminative ability of each gait measure as a function of gait bout length, we used the intraclass correlation coefficient (ICC) and area under the curve (AUC), respectively. Ninety percent of subjects walked with a bout length of less than 53 strides during the week, and the majority (>50%) of gait bouts consisted of less than 12 strides. Although bout length affected all gait measures, the effects depended on the specific measure and sometimes differed for PD versus OA. Specifically, people with PD did not increase/decrease cadence and swing duration with bout length in the same way as OA. ICC and AUC characteristics tended to be larger for shorter than longer gait bouts. Our findings suggest that PD interferes with the scaling of cadence and swing duration with gait bout length. Whereas control subjects gradually increased cadence and decreased swing duration as bout length increased, participants with PD started with higher than normal cadence and shorter than normal stride duration for the smallest bouts, and cadence and stride duration changed little as bout length increased, so differences between PD and OA disappeared for the longer bout lengths. Gait measures extracted from shorter bouts are more common, more reliable, and more discriminative, suggesting that shorter gait bouts should be used to extract potential digital biomarkers for people with PD.

What happened to the US cancer cooperative groups? A status update ten years after the Institute of Medicine report.

The US cancer cooperative groups (cooperative groups) were founded in the 1950s to establish a standing infrastructure to conduct multi-institutional cancer clinical trials. Initially funded almost entirely by the US National Cancer Institute (NCI), over the years, the research conducted by the Cooperative Groups has evolved to meet the demands of cancer clinical research, with a scope now encompassing trials to advance cancer treatment, cancer control, biomarker development and validation, and health services research, with a corresponding broadening of their funding sources. The cooperative groups are also a critical mechanism for educating the next generation of cancer clinical trialists from many different disciplines. This review outlines the overall mission, structure, and funding of the cooperative groups, beginning in 1955 when they were first established by the NCI, and describes the considerable progress against cancer achieved over the past decade.

I. Indices of Pain Intensity Derived From Ecological Momentary Assessments: Rationale and Stakeholder Preferences

Pain assessment that fully represents patients’ pain experiences is essential for chronic pain research and management. The traditional primary outcome measure has been a patient's average pain intensity over a time period. In this series of 3 articles, we examine whether pain assessment can be enhanced by considering additional outcome measures capturing temporal aspects of pain, such as pain maxima, duration, and variability. Ecological momentary assessment makes the assessment of such indices readily available. In this first article, we discuss the rationale for considering additional pain indices derived from ecological momentary assessment and examine which are most important to stakeholders. Patients (n = 32), clinicians (n = 20), and clinical trialists (n = 20) were interviewed about their preference rankings for Average, Worst, and Least Pain, Time in High Pain, Time in No/Low Pain, Pain Variability, and Pain Unpredictability. Each stakeholder group displayed a distinct preference hierarchy for different indices, and there were few commonalities between groups. Patients favored Worst Pain and Time in High Pain, followed by Pain Variability and Unpredictability. Trialists favored Average Pain, whereas clinicians favored Worst Pain. Results suggest that multiple temporal aspects of pain are relevant for stakeholders and should be considered when evaluating the efficacy of pain management. PerspectiveExamining which aspects of pain are most important to measure from the perspective of different stakeholders can facilitate efforts to include all relevant treatment outcomes. Our study suggests that multiple temporal aspects of pain intensity are important to stakeholders. This should be considered when evaluating the efficacy of pain management.

Understanding between-cluster variation in prevalence and limits for how much variation is plausible.

In clinical trials and observational studies of clustered binary data, understanding between-cluster variation is essential: in sample size and power calculations of cluster randomised trials, for example, the intra-cluster correlation coefficient is often specified. However, quantifications of between-cluster variation can be unintuitive, and an intra-cluster correlation coefficient as low as 0.04 may correspond to surprisingly large between-cluster differences. We suggest that understanding is improved through visualising the implied distribution of true cluster prevalences - possibly by assuming they follow a beta distribution - or by calculating their standard deviation, which is more readily interpretable than the intra-cluster correlation coefficient. Even so, the bounded nature of binary data complicates the interpretation of variances as primary measures of uncertainty, and entropy offers an attractive alternative. Appealing to maximum entropy theory, we propose the following rule of thumb: that plausible intra-cluster correlation coefficients and standard deviations of true cluster prevalences are both bounded above by the overall prevalence, its complement, and one third. We also provide corresponding bounds for the coefficient of variation, and for a different standard deviation and intra-cluster correlation defined on the log odds scale. Using previously published data, we observe the quantities defined on the log odds scale to be more transportable between studies with different outcomes with different prevalences than the intra-cluster correlation and coefficient of variation. The latter increase and decrease, respectively, as prevalence increases from 0% to 50%, and the same is true for our bounds. Our work will help clinical trialists better understand between-cluster variation and avoid specifying implausibly high values for the intra-cluster correlation in sample size and power calculations.

Stroke rehabilitation research translation in Australia: a survey of clinical trialists

Purpose Translation of findings from stroke trials into clinical practice remains low. Little is known about planned translation activities from the perspective of trialists who generate the evidence. This study aims to investigate perceptions of Australian stroke clinical trialists’ about implementation of their findings into practice, and what translation activities they embedded into trial protocols. Materials and method A descriptive cohort design and electronic survey was conducted. Three databases were searched to identify Australian stroke rehabilitation trials published between 2007 and 2017. Corresponding authors of the included trials were invited to complete an anonymous online survey about implementation of their trial intervention. Results Fifty-one trialists were invited to participate and 38 completed the survey (74% response rate). The majority (79%) considered their trial results to be clinically significant and 68% had pre-planned knowledge translation activities. The most common planned translation activities were publication (89%), conference presentation (87%), and feedback of results to target audiences (58%). Mixed opinions were evident regarding when and how to design knowledge translation activities for inclusion in trial protocols. Stroke rehabilitation trialists rely mostly on anecdotal reports about implementation of trial interventions, with few formally measuring uptake. Implications for rehabilitation The most common knowledge translation activities planned for by researchers are publication of findings in academic journals, and conference presentations. Mixed opinions exist regarding when and how to design for knowledge translation activities in trial protocols. Limited formal measurement of intervention uptake is completed. Further implementation research is required to support and measure effective translation efforts when embedded into trial protocols.

Comparison of freshly cultured versus freshly thawed (cryopreserved) mesenchymal stem cells in preclinical in vivo models of inflammation: a protocol for a preclinical systematic review and meta-analysis

BackgroundMesenchymal stem cells (MSCs) are multipotent cells that demonstrate therapeutic potential for the treatment of acute and chronic inflammatory-mediated conditions. Especially for acute conditions, it is critical to have a readily available freshly thawed (cryopreserved) MSC product for rapid administration. Although controversial, some studies suggest that MSCs may lose their functionality with cryopreservation which in turn could render them non-efficacious.ObjectiveIn controlled preclinical in vivo models of inflammation, to determine if there are differences in surrogate measures of preclinical efficacy between freshly cultured and freshly thawed MSCsMethods/designA systematic search for pre-clinical in vivo inflammatory model studies will compare freshly cultured to freshly thawed MSCs from any source. The primary outcomes will include measures of in vivo preclinical efficacy; secondary outcomes will include measures of in vitro MSC potency. Electronic searches for MEDLINE and EMBASE will be constructed and reviewed by the Peer Review of Electronic Search Strategies (PRESS) process. If applicable, study outcomes will be meta-analyzed using a random effects model. Risk of bias will be assessed by the SYRCLE “Risk of Bias” assessment tool for preclinical in vivo studies.DiscussionThe results of this systematic review will provide translational scientists, clinical trialists, health regulators, and the clinical and public community with the current pre-clinical evidence base related to the efficacy and potency of freshly cultured versus freshly thawed MSCs, help identify evidence gaps, and guide future related research.Systematic review registrationProtocol is submitted to PROSPERO for registration (pending confirmation) and will be submitted to Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) for public posting.

Uptake of core outcome sets by clinical trialists publishing in major medical journals: Protocol

Background: Outcome heterogeneity, selective reporting, and choosing outcomes that do not reflect needs and priorities of stakeholders, limit the examination of health intervention effects, particularly in late phase trials. Core outcome sets (COS) are a proposed solution to these issues. A COS is an agreed-upon, standardised set of outcomes that should be measured and reported as a minimum in all trials in a specific area of health or healthcare. COS are intended to increase standardisation of outcome measurement and reporting to better enable comparisons between, and synthesis of findings of trials in a particular health area. Methods: This study will examine late phase trials, published between October 2019 and March 2020 (inclusive), in the following five medical journals: New England Journal of Medicine, Journal of the American Medical Association, Lancet, BMJ, and Annals of Internal Medicine. Trials will be examined to determine if they refer to a COS, and whether they use a COS. Trialists for each identified trial will subsequently be contacted to complete an online survey examining trialists' awareness of, and decisions to search for and use a COS. Discussion: This study will provide important information on uptake of COS by later phase trialists in major medical journals, and the views of these trialists on COS use in trials. These findings will inform approaches to increasing awareness and uptake of COS in future health trials.