Developing generic templates to shape the future for conducting integrated research platform trials.

BACKGROUND: Interventional clinical studies conducted in the regulated drug research environment are designed using International Council for Harmonisation (ICH) regulatory guidance documents: ICH E6 (R2) Good Clinical Practice-scientific guideline, first published in 2002 and last updated in 2016. This document provides an international ethical and scientific quality standard for designing and conducting trials that involve the participation of human subjects. Recently, there has been heightened awareness of the importance of integrated research platform trials (IRPs) designed to evaluate multiple therapies simultaneously. The use of a single master protocol as a key source document to fulfill trial conduct obligations has resulted in a re-examination of the templates used to fulfill the dynamic regulatory and modern drug development environment challenges. METHODS: Regulatory medical writing, biostatistical, and other members of EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) developed the suite of templates for IRPs over a 3.5-year period. Stakeholders contributing expertise included academic hospitals, pharmaceutical companies, non-governmental organizations, patient representative groups, and small and medium-sized enterprises (SMEs). RESULTS: The suite of templates for IRPs based on TransCelerate's Common Protocol Template (CPT) and statistical analysis plan (SAP) should help authors navigate relevant guidelines as they create study design content relevant for today's IRP studies. It offers practical suggestions for adaptive platform designs which offer flexible features such as dropping treatments for futility or adding new treatments to be tested during a trial. The EU-PEARL suite of templates for IRPs comprises a preface, followed by the actual resource. The preface clarifies the intended use and underlying principles that inform resource utility. The preface lists references contributing to the development of the resource. The resource includes TransCelerate CPT guidance text, and EU-PEARL-derived guidance text, distinguished from one another using shading. Rationale comments are used throughout for clarification purposes. In addition, a user-friendly, functional, and informative Platform Trials Best Practices tool to support the setup, design, planning, implementation, and conduct of complex and innovative trials to support multi-sourced/multi-company platform trials is also provided. Together, the EU-PEARL suite of templates and the Platform Trials Best Practices tool constitute the reference user manual. CONCLUSIONS: This publication is intended to enhance the use, understanding, and dissemination of the EU-PEARL suite of templates for designing IRPs. The reference user manual and the associated website ( http://www.eu-pearl ) should facilitate the designing of IRP trials.

Quantifying Site Burden to Optimize Protocol Performance.

BACKGROUND: The increase in protocol complexity and the resulting rise in the effort required by investigative sites to implement protocols have been well documented, but existing measures of site burden only offer an incomplete view of the burden experienced by site personnel. The introduction of Decentralized Clinical Trials-trials supported by remote and virtual technologies and services-is expected to impact the burden imposed on sites, but this impact has not yet been systematically measured. METHODS: The Tufts Center for the Study of Drug Development conducted an online survey among clinical research sites worldwide and gathered 355 responses assessing the burden associated with distinct activities and procedures related to the implementation of clinical trial protocols using traditional and decentralized approaches. RESULTS: A high percentage of investigative sites (50.5%) have had no experience with DCT solutions and only a small percentage (6.6%) have participated in fully decentralized clinical trials. Overall, half of respondents view DCT solutions as more burdensome than traditional clinical trials. In general, activities related to operational and managerial aspects of trial implementation were viewed as less burdensome when done remotely, while clinical procedures or elements that require study team-patient interactions were viewed as more burdensome when using DCT approaches versus in-person or traditional methods.

Strengthening Reporting of Neonatal Trials.

BACKGROUND AND OBJECTIVES: There is variability in the selection and reporting of outcomes in neonatal trials with key information frequently omitted. This can impact applicability of trial findings to clinicians, families, and caregivers, and impair evidence synthesis. The Neonatal Core Outcomes Set describes outcomes agreed as clinically important that should be assessed in all neonatal trials, and Consolidated Standards of Reporting Trials (CONSORT)-Outcomes 2022 is a new, harmonized, evidence-based reporting guideline for trial outcomes. We reviewed published trials using CONSORT-Outcomes 2022 guidance to identify exemplars of neonatal core outcome reporting to strengthen description of outcomes in future trial publications. METHODS: Neonatal trials including >100 participants per arm published between 2015 to 2020 with a primary outcome included in the Neonatal Core Outcome Set were identified. Primary outcome reporting was reviewed using CONSORT 2010 and CONSORT-Outcomes 2022 guidelines by assessors recruited from Cochrane Neonatal. Examples of clear and complete outcome reporting were identified with verbatim text extracted from trial reports. RESULTS: Thirty-six trials were reviewed by 39 assessors. Examples of good reporting for CONSORT 2010 and CONSORT-Outcomes 2022 criteria were identified and subdivided into 3 outcome categories: "survival," "short-term neonatal complications," and "long-term developmental outcomes" depending on the core outcomes to which they relate. These examples are presented to strengthen future research reporting. CONCLUSIONS: We have identified examples of good trial outcome reporting. These illustrate how important neonatal outcomes should be reported to meet the CONSORT 2010 and CONSORT-Outcomes 2022 guidelines. Emulating these examples will improve the transmission of information relating to outcomes and reduce associated research waste.

Comparison of Availability of Trial Results in ClinicalTrials.gov and PubMed by Data Source and Funder Type.

This study examines the dissemination of trial results by data source (ie, ClinicalTrials.gov and PubMed) and funder type (ie, industry and nonindustry).

A meta-analytic investigation of cognitive remediation for mood disorders: Efficacy and the role of study quality, sample and treatment factors.

BACKGROUND: The number of randomized, controlled studies of cognitive remediation (CR) for mood disorders (major depressive disorder [MDD] and bipolar illness [BD]), has grown substantially over the past 10 years. The role of study quality, participant characteristics, and intervention features in CR treatment effects remains largely unknown. METHODS: Electronic databases were searched up to February 2022 using variants of the key words: "cognitive remediation", "clinical trials", "major depressive disorder" and "bipolar disorder". This search produced 22 unique randomized, controlled trials that met all inclusion criteria for the study. Data were extracted by 3 authors with strong reliability (>90 %). Primary cognitive, and secondary symptom and functional outcomes were assessed with random effects models. RESULTS: The meta-analysis (993 participants) revealed that CR produced significant small-to-moderate size effects in attention, verbal learning and memory, working memory and executive function (Hedge's g = 0.29-0.45). CR produced a small-moderate effect on one secondary outcome: depressive symptoms (g = 0.33). CR programs that used an individualized approach produced larger effects on executive function. Samples with lower baseline IQ were more likely to benefit from CR on measures of working memory. Sample age, education, gender, or baseline depressive symptomatology did not serve as barriers to treatment gains, and observed effects were not epiphenomena of poorer design quality. LIMITATIONS: The number of RCTs remains low. CONCLUSIONS: CR produces small to moderate improvements in cognition and depressive symptoms in mood disorders. Future research should study how CR might be optimized to help generalize CR-related cognitive and symptom improvements to function.

Overview of literature monitoring practice of clinical trials vigilance units in French institutional sponsors - A study from the REVISE working group.

INTRODUCTION: The evaluation of clinical trial (CT) safety is the main task of CT vigilance units. In addition to the management of adverse events, the units must review the literature to identify information that may impact the benefit-risk assessment of studies. In this survey, we investigated the literature monitoring (LM) activity of French Institutional Vigilance Units (IVU) from the working group "REflexion sur la VIgilance et la SEcurite des essais cliniques" (REVISE). MATERIAL AND METHODS: We sent a questionnaire of 26 questions, divided into four themes, to the 60 IVU: (1) Presentation of the IVU and the LM activity; (2) Used sources, queries and criteria for selecting articles; (3) Valuation of the LM and (4) Practical organisation. RESULTS: Of the 27 IVU that responded to the questionnaire, 85% of them carried out LM. This was mainly provided by medical staff to improve general knowledge (83%), to detect Adverse Reactions (AR) not listed in the reference documents (70%) and to detect new safety information (61%). Due to lack of time, staff, available recommendations and sources, only 21% of IVU conducted LM for all CT. On average, units reported four sources: ANSM information (96%), PubMed database (83%), EMA alerts (57%) and the subscription to APM international (48%). The LM had an impact on the CT of 57% of the IVU such as changing the conditions of a study (39%) or suspending a study (22%). DISCUSSION/CONCLUSION: LM is an important but time-consuming activity with heterogeneous practices. According to the results of this survey, we proposed seven ways to improve this practice: (1) Target the highest risk CT; (2) Refine the PubMed queries; (3) Use other tools; (4) Create a decision flowchart for the selection of PubMed articles; (5) Improve training; (6) Value the activity and (7) Outsource the activity.

A call for clinical trial globalization in Alzheimer's disease and related dementia.

BACKGROUND: The burden of Alzheimer's disease and related dementia (ADRD) is projected to disproportionally impact low-middle-income countries (LMICs). However, there is a systematic under-representation of LMICs in ADRD clinical trial platforms. METHODS: We aimed to determine the global distribution of ADRD clinical trials and identify existing barriers for conducting clinical trials in LMICs. Primary data sources to identify trial distribution in LMICs included ClinicalTrials.gov and the International Trials Registry Platform. An additional systematic review and expert consensus interviews were conducted to identify barriers for conducting clinical trials in LMICs. FINDINGS: Among 1237 disease-modifying therapies tested in ADRD clinical trials, only 11.6% have been or are conducted in emerging economies (upper-middle income [9.6%] and low-middle income [2.0%]). We identified several limitations for trial implementation including a lack of financial resources, low industry presence, regulatory obstacles, and operational barriers INTERPRETATION: Although LMICs bear the greatest burden of ADRD globally, substantial development of clinical trial platforms to address this inequity and health disparity is lacking.

Conditional Power: How Likely Is Trial Success?

This JAMA Guide to Statistics and Methods article examines conditional power, calculated while a trial is ongoing and based on both the currently observed data and an assumed treatment effect for future patients.

A Proposal for Post Hoc Subgroup Analysis in Support of Regulatory Submission.

BACKGROUND: In clinical trials, it is not uncommon that the primary analysis fails to achieve the study objective for demonstrating the safety and efficacy of a test treatment under investigation, while a specific sub-population analysis shows a significant positive result. In this case, whether the observed positive sub-population analysis results can be used in support of regulatory submission of the test treatment under investigation is an interesting question to both the investigator(s) and the regulatory medical/statistical reviewers. METHODS: In this article, several statistical evaluations for confirming the integrity and validity of the observed sub-population analysis results were proposed in support of the regulatory submission. Selection bias caused by looking at one subgroup is adjusted before all statistical evaluations, including reproducibility, consistency between sub-population and the entire population, generalizability between the promising sub-population and other sub-populations, and sensitivity index when there are shifts in mean and/or variability between sub-populations. The multiplicity issue is also addressed in measuring generalizability. RESULTS: A numerical example of a global (multi-regional) clinical trial was presented for illustration purposes. The choice of applying which estimation approach relies on the scale of test statistics. Recommendations for incorporating statistical evaluations in measuring sub-population analysis are provided. Finally, we proposed possible solutions such as real-world data and real-world evidence for regulatory concerns, which may increase the insufficient power. CONCLUSION: Sub-population analysis can contribute to regulatory submission if it passes the evaluation. This analysis can also support hypothesis generation and the planning of future clinical trials, though it fails to pass the measurement process.