Assessing the reporting quality of early phase dose-finding trial protocols: a methodological review

Villacampa, Guillermo; Patel, Dhrusti; Zheng, Haiyan; McAleese, Jessica; Rekowski, Jan; Solovyeva, Olga; Yap, Christina

doi:10.1016/j.eclinm.2023.102020

Cited by 5 publications

(4 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The prevalence and importance of early phase trials in the clinical development pipeline, as well as the increasing complexity of the designs used, necessitate thorough, precise, and transparent efforts to ensure that the work can be accurately evaluated and, if necessary, reproduced. The methodological review findings of inconsistent and inadequate reporting of important methodological features in design, conduct, and analysis confirm the need for robust, consensus-driven extensions of SPIRIT 2013 [ 139 ] and CONSORT 2010 [ 9 ] to provide the research community with the tools needed to accurately report and assess EPDF trials while meeting the standards achieved by the original checklists [ 4 , 8 ] and existing extensions in the broader clinical trials reporting landscape [ 140 ].…”

Section: Discussionmentioning

confidence: 90%

Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study

Solovyeva

Dimairo

Weir

et al. 2023

BMC Med

Self Cite

View full text Add to dashboard Cite

Background Early phase dose-finding (EPDF) trials are crucial for the development of a new intervention and influence whether it should be investigated in further trials. Guidance exists for clinical trial protocols and completed trial reports in the SPIRIT and CONSORT guidelines, respectively. However, both guidelines and their extensions do not adequately address the characteristics of EPDF trials. Building on the SPIRIT and CONSORT checklists, the DEFINE study aims to develop international consensus-driven guidelines for EPDF trial protocols (SPIRIT-DEFINE) and reports (CONSORT-DEFINE). Methods The initial generation of candidate items was informed by reviewing published EPDF trial reports. The early draft items were refined further through a review of the published and grey literature, analysis of real-world examples, citation and reference searches, and expert recommendations, followed by a two-round modified Delphi process. Patient and public involvement and engagement (PPIE) was pursued concurrently with the quantitative and thematic analysis of Delphi participants’ feedback. Results The Delphi survey included 79 new or modified SPIRIT-DEFINE (n = 36) and CONSORT-DEFINE (n = 43) extension candidate items. In Round One, 206 interdisciplinary stakeholders from 24 countries voted and 151 stakeholders voted in Round Two. Following Round One feedback, one item for CONSORT-DEFINE was added in Round Two. Of the 80 items, 60 met the threshold for inclusion (≥ 70% of respondents voted critical: 26 SPIRIT-DEFINE, 34 CONSORT-DEFINE), with the remaining 20 items to be further discussed at the consensus meeting. The parallel PPIE work resulted in the development of an EPDF lay summary toolkit consisting of a template with guidance notes and an exemplar. Conclusions By detailing the development journey of the DEFINE study and the decisions undertaken, we envision that this will enhance understanding and help researchers in the development of future guidelines. The SPIRIT-DEFINE and CONSORT-DEFINE guidelines will allow investigators to effectively address essential items that should be present in EPDF trial protocols and reports, thereby promoting transparency, comprehensiveness, and reproducibility. Trial registration SPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network (https://www.equator-network.org/).

show abstract

Section: Discussionmentioning

confidence: 90%

Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study

Solovyeva

Dimairo

Weir

et al. 2023

BMC Med

Self Cite

View full text Add to dashboard Cite

show abstract

“…The use of model assisted and model based designs, which have been reported to be more efficient but also more complex than algorithm based designs,428 rose from 1.6% (20/1235) of phase 1 cancer trials published in 1991-200629 to 8.6% (68/788) in 2014-19 4. Most recent data confirm this trend with the rate of advanced designs in cancer trials reported to be 19% (11/58) based on protocols posted on ClinicalTrials.gov in 2017-23 30. The complexity of these designs is reflected in a more multifaceted implementation and the requirement to specify more details on design features,313233 which mandates more detailed protocols for EPDF trials to improve precision and transparency, and to facilitate understanding of trial design and decision making processes.…”

mentioning

confidence: 82%

“…It might also lead to unnecessary amendments and associated costs, as well as inadequate or biased reporting resulting in erroneous conclusions on safety and efficacy. The overall quality of EPDF protocols from ClinicalTrials.gov in 2017-23 was reported to be substantially variable and poor, with insufficient reporting in many applicable SPIRIT 2013 items 30. For example, sections on ethics and dissemination strategy were frequently found to be dealt with insufficiently.…”

mentioning

confidence: 99%

Enhancing quality and impact of early phase dose-finding clinical trial protocols: SPIRIT Dose-finding Extension (SPIRIT-DEFINE) guidance

Yap,

Rekowski,

Ursino

et al. 2023

BMJ

Self Cite

View full text Add to dashboard Cite

SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 provides guidance for clinical trial protocol writing. However, neither the original guidance nor its extensions adequately cover the features of early phase dose-finding trials. The SPIRIT Dose-finding Extension (DEFINE) statement is a new guideline that provides recommendations for essential items that should be provided in the protocols of these trials. It details extensions to the SPIRIT 2013 guidance, incorporating 17 new items and modifying 15 existing items. The purpose of this guideline is to promote transparency, completeness, reproducibility of methods, and interpretation of early phase dose-finding trial protocols. It is envisioned that the resulting improvements in the design and conduct of early phase clinical trials will ultimately reduce research inefficiencies and inconsistencies, driving transformational advances in clinical care.

show abstract

“…The current landscape reveals a notable gap in understanding how to effectively embed PPIE within statistical methodology [ 11 ]. There has been a rise in the adoption of advanced model-based and model-assisted trial designs in DFOTs [ 12 ]. While these designs enhance efficiency, they come at the cost of increased complexity [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Patient and public involvement and engagement in the development of innovative patient-centric early phase dose-finding trial designs

Alger,

Van Zyl,

Aiyegbusi

et al. 2024

Res Involv Engagem

Self Cite

View full text Add to dashboard Cite

Background In light of the FDA’s Project Optimus initiative, there is fresh interest in leveraging Patient-reported Outcome (PRO) data to enhance the assessment of tolerability for investigational therapies within early phase dose-finding oncology trials. Typically, dose escalation in most trial designs is solely reliant on clinician assessed adverse events. Research has shown a disparity between patients and clinicians when assessing whether an investigational therapy is tolerable, leading to the recommendation of potentially intolerable doses for further investigation in subsequent trials. It is also increasingly recognized that patient and public involvement and engagement (PPIE) plays a pivotal role in enriching trial design and conduct. However, to our knowledge, no PPIE has explored the optimal integration of PROs in the development of advanced statistical trial designs within early phase dose-finding oncology trials. Methods A virtual PPIE session was held with nine participants on 18th October 2023 to discuss the incorporation of PROs within a dose-finding trial design. This cross disciplinary session was developed and led by a team of statisticians, clinical specialists, qualitative experts, and trial methodologists. Following the session, in-depth perspectives were provided by two patient advocates who actively engaged in the PPIE session. We discuss the importance of PPIE in shaping advanced dose-finding trial designs, share insights from patients on integrating PROs to inform treatment tolerability, and present a template for meaningful patient involvement in trial design development. Results Participants generally supported the introduction of PROs within dose-finding trials but showed some apprehensiveness as to how PROs may reduce the size of the recommended dose (and potentially efficacious effect). Some participants shared that they may be reluctant to record the real severity of their symptoms via PROs if it would mean that they would have to discontinue treatment. They discussed that PROs could be used to assess tolerability rather than toxicity of a dose. Conclusions Amplifying patient voice in the development of patient-centric dose-finding trial designs is now essential. This paper offers an exemplary illustration of how trialists and methodologists can effectively incorporate patient voice in the future development of advanced dose-finding trial designs.

show abstract

Assessing the reporting quality of early phase dose-finding trial protocols: a methodological review

Cited by 5 publications

References 15 publications

Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study

Development of consensus-driven SPIRIT and CONSORT extensions for early phase dose-finding trials: the DEFINE study

Enhancing quality and impact of early phase dose-finding clinical trial protocols: SPIRIT Dose-finding Extension (SPIRIT-DEFINE) guidance

Patient and public involvement and engagement in the development of innovative patient-centric early phase dose-finding trial designs

Contact Info

Product

Resources

About