Outcome selection for tissue-agnostic drug trials for immune-mediated inflammatory diseases: a systematic review of core outcome sets and regulatory guidance

Background Tissue-agnostic drug development provides a paradigm shift in precision medicine and requires innovative trial designs. However, outcome selection for such trials can prove challenging. The objectives of this review were to: Identify and map core outcome sets (COS), across 11 immune-mediated inflammatory diseases (IMIDs) in order to facilitate the selection of relevant outcomes across the conditions for innovative trials of tissue-agnostic drug therapies. Compare outcomes or endpoints recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to identify and highlight similarities and differences. Methods The Core Outcome Measures in Effectiveness Trials (COMET), International Consortium for Health Outcomes Measurement (ICHOM), FDA and EMA databases were searched from inception to 28th December 2019. Two reviewers independently screened titles and abstracts of retrieved entries and conducted the subsequent full text screening. Hand searching of the reference lists and citation searching of the selected publications was conducted. The methodological quality of the included peer-reviewed articles was independently assessed by the reviewers based on the items of the COS–Standards for Development recommendations (COS–STAD) checklist. Core outcomes from the included publications were extracted and mapped across studies and conditions. Regulatory guidance from FDA and EMA, where available for clinical trials for the IMIDs, were obtained from their databases and recommendations on outcomes to measure directly compared. Results Forty-four COS publications were included in the final analysis. Outcomes such as disease activity, pain, fatigue, quality of life, physical function, work limitation/productivity, steroid use and biomarkers were recommended across majority of the conditions. There were significant similarities and differences in FDA and EMA recommendations. The only instance where either regulatory body directly referenced a COS was for jSLE—both referenced the Paediatric Rheumatology International Trials Organization (PRINTO) COS. Conclusions The findings from this systematic review provide valuable information to inform outcome selection in tissue-agnostic trials for IMIDs. There is a need for increased collaboration between regulators and COS developers and inclusion of regulators as key stakeholders in COS development to enhance the quality of COS. Trial registration Not registered.

Development of Core Outcome Sets for Clinical Trials in Temporomandibular Disorders

Background Temporomandibular Disorder (TMD) is a generic term applied to describe musculoskeletal disorders that affect the temporomandibular joint (TMJ), the masticatory muscles and the related structures. TMD comprises two groups of disorders, namely intra-articular TMD and masticatory muscle disorders. There is still difficulty in establishing the effectiveness of different therapeutic modalities for TMD with robust evidence, despite the large volume of publications in the area. The lack of outcomes standardization may represent a limiting factor in the search for scientific evidence. Objective This study aims to develop a core outcome sets (COS) for clinical trials in intra-articular TMD and masticatory muscle disorders. Methods The protocol for determining the COS-TMD will consist of three phases: 1. Synthesis of TMD Management Intervention Outcomes. The identification of outcomes will be carried out through a systematic review, which will include randomized clinical trials that evaluated the effectiveness of interventions used in TMD management. 2. Through a two-round international Delphi survey, the list of outcomes will be scored by three panels of stakeholders. 3. A representative sample of key stakeholders will be invited to participate in a face-to-face meeting where they can discuss the results of the Delphi survey and determine the final core set. Conclusions The implementation of this protocol will determine the COS-TMD, which will be made available for use in all TMD clinical studies. The use of COS when planning and reporting TMD clinical trials will reduce the risk of publication bias and enable proper comparison of results found by different studies.

Outcome reporting in randomized controlled trials (RCTs) on the pharmacological management of idiopathic overactive bladder (OAB) in women; a systematic review for the development of core outcome sets (COS)

Introduction and hypothesis Evidence on OAB management remains suboptimal and methodological limitations in randomized control trials (RCTs) affect their comparability. High quality meta-analyses are lacking. This study aimed to compare selection and reporting of outcomes and outcome measures across RCTs as well as evaluate methodological quality and outcome reporting quality as a first stage in the process of developing core outcome sets (COS). Methods RCTs were searched using Pubmed, EMBASE, Medline, Cochrane, ICTRP and Clinicaltrials.gov from inception to January 2020, in English language, on adult women. Pharmacological management, interventions, sample size, journal type and commercial funding were documented. Methodological and outcome reporting quality were evaluated using JADAD and MOMENT scores. Results Thirty-eight trials (18,316 women) were included. Sixty-nine outcomes were reported, using 62 outcome measures. The most commonly reported outcome domains were efficacy (86.8%), safety (73.7%) and QoL (60.5%). The most commonly reported outcomes in each domain were urgency urinary incontinence episodes (UUI) (52.6%), antimuscarinic side effects (76.3%) and change in validated questionnaire scores (36.8%). A statistically significant correlation was found between JADAD and MOMENT (Spearman’s rho = 0.548, p < 0.05) scores. This indicates that higher methodological quality is associated with higher outcome reporting quality. Conclusions Development of COS and core outcome measure sets will address variations and lead to higher quality evidence. We recommend the most commonly reported outcomes in each domain, as interim COS. For efficacy we recommend: UUI episodes, urgency and nocturia episodes; for safety: antimuscarinic adverse events, other adverse events and discontinuation rates; for QoL: OAB-q, PPBC and IIQ scores.

Minimum data and core outcomes for subacute rehabilitation: A scoping review

Objective In clinical practice and research, standardised sets of data and outcomes are routinely collected to facilitate data comparison, benchmarking and quality improvement. Most existing data sets are condition-specific and cannot be applied to all patients in a given clinical setting. This review aimed to determine whether the development of a minimum data set for subacute rehabilitation is feasible by collating and comparing existing rehabilitation minimum data sets and core outcome sets. Data sources Published literature was identified through database searches (Scopus, PubMed, EMBASE, CINAHL and the COMET Initiative) in September 2021. Additional data sets were identified through a grey literature search. Review methods This review was conducted in alignment with the PRISMA-ScR recommendations. Datasets were included if they were published in English, designed for adults, and intended for use in subacute rehabilitation. Data were extracted and taxonomically organised to identify commonalities. Items present in ≥50% of data sets were considered common. Results Twenty minimum data sets and seven core outcome sets were included. There were 29 common minimum data set domains, with 19 relating to Patient Information, seven relating to Outcomes, two relating to Service Delivery and one relating to Provider Demographics. Four common domains were identified within the Core Outcome Set analysis, which all related to Life Impact, specifically Physical Functioning (86%) , Emotional Functioning/Wellbeing (57%) , Social Functioning (86%) and Global Quality of Life (100%). Conclusion Common item domains in conditions requiring subacute rehabilitation have been identified, suggesting that development of a dataset for subacute rehabilitation may be feasible.

State of the art of patient-reported outcomes in acromegaly or GH deficiency: a systematic review and meta-analysis

Context Insight into the current landscape of patient-reported outcome (PRO) measures (PROM) and differences between PROs and conventional biochemical outcomes is pivotal for future implementation of PROs in research and clinical practice. Therefore, in studies among patients with acromegaly and growth hormone deficiency (GHD), we evaluated: I) used PROMs, II) their validity, III) quality of PRO reporting, IV) agreement between PROs and biochemical outcomes, and V) determinants of discrepancies. Evidence acquisition We searched eight electronic databases for prospective studies describing both PROs and biochemical outcomes in acromegaly and GHD patients. Quality of PRO reporting was assessed using the ISOQOL criteria. Logistic regression analysis was used to evaluate determinants. Evidence synthesis Ninety studies were included (acromegaly: n=53; GHD: n=37). Besides non-validated symptom lists (used in 37% of studies), 36 formal PROMs were used (predominantly AcroQoL in acromegaly [43%] and QoL-AGHDA in GHD [43%]). Reporting of PROs was poor, with a median of 37-47% of ISOQOL items being reported per study. Eighteen (34%) acromegaly studies and twelve (32%) GHD studies reported discrepancies between PROs and biochemical outcomes, most often improvement in biochemical outcomes without change in PROs. Conclusions Prospective studies among patients with acromegaly and GHD use a multitude of PROMs, often poorly reported. Since a substantial proportion of studies report discrepancies between PROs and biochemical outcomes, PROMs are pivotal in the evaluation of disease activity. Therefore, harmonization of PROs in clinical practice and research by development of Core Outcome Sets is an important unmet need.

A survey of knowledge, perceptions and use of core outcome sets among clinical trialists

Background Core outcome sets (COS) are standardised sets of outcomes, which represent the minimum outcomes that should be measured and reported in clinical trials. COS can enhance comparability across health trials by reducing heterogeneity of outcome measurement and reporting and potentially minimising selective outcome reporting. Examining what researchers involved in trials know and think about COS is essential to increase awareness and promote COS uptake. The aim of this study is therefore to examine clinical trialists’ knowledge, perceptions and experiences of COS. Methods An online survey design was used. Participants were clinical trialists, operationalised for the current study as researchers named as the contact person on a trial registered on the International Standard Randomised Controlled Trial Number (ISRCTN) Trial repository between 1 January 2019 and 21 July 2020. Survey items assessed clinical trialists’ familiarity with and understanding of COS, along with experiences of COS use and development. Results Of 1913 clinical trialists contacted to participate, 62 (3%) completed the survey. Forty (65%) participants were familiar with COS and, of those familiar with COS, 21 (55%) had been involved in a trial that used a COS. Of clinical trialists who used COS in a trial(s), less than half (n = 9, 41%) reported that all COS outcomes were used. The main barriers to using COS are poor knowledge about COS (n = 43, 69%) and difficulties identifying relevant COS (n = 42, 68%). Clinical trialists also reported perceptions of COS as restrictive and often containing too many outcomes. The main enablers to using COS are clear understanding (n = 51, 82%) and perceived importance of COS (n = 44, 71%). Conclusions Enhancing clinical trialists’ use of all COS outcomes is needed to reduce outcome heterogeneity and enhance comparability across trial findings. Enhancing awareness of COS importance among researchers and funders is needed to ensure that COS are developed and used by clinical trialists. Education and training may further promote awareness and understanding of COS.