Early phase clinical trials extension to guidelines for the content of statistical analysis plans

Homer, Victoria; Yap, Christina; Bond, Simon; Holmes, Jane; Stocken, Deborah; Walker, Katrina; Robinson, Emily; Wheeler, Graham; Brown, Sarah; Hinsley, Samantha; Schipper, Matthew J.; Weir, Christopher; Rantell, Khadija; Prior, Thomas; Yu, Ly-Mee; Kirkpatrick, John; Bedding, Alun; Gamble, Carrol; Gaunt, Piers

doi:10.1136/bmj-2021-068177

Cited by 20 publications

(31 citation statements)

References 31 publications

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“…15 More recent guidelines for the contents of statistical analysis plans in early phase trials include specification of estimands. 39 However, this review found that some trials defined their estimands in their protocol, which differs from a recent review of protocols published in October 2020 in Trials and BMJ Open, where no protocols explicitly defined the estimand, and estimands could be inferred in only 26% of protocols. 17 Use of estimands in this review might have been higher as we considered the six leading general medical journals and non-published protocols submitted as supplementary material.…”

Section: Research In Contextmentioning

confidence: 61%

“… 15 More recent guidelines for the contents of statistical analysis plans in early phase trials include specification of estimands. 39 …”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we recommend that in any future update, estimands be explicitly incorporated into the CONSORT statement 15. More recent guidelines for the contents of statistical analysis plans in early phase trials include specification of estimands 39…”

Section: Discussionmentioning

confidence: 99%

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Evaluating how clear the questions being investigated in randomised trials are: systematic review of estimands

Cro

Kahan

Rehal

et al. 2022

BMJ

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Objectives To evaluate how often the precise research question being addressed about an intervention (the estimand) is stated or can be determined from reported methods, and to identify what types of questions are being investigated in phase 2-4 randomised trials. Design Systematic review of the clarity of research questions being investigated in randomised trials in 2020 in six leading general medical journals. Data source PubMed search in February 2021. Eligibility criteria for selecting studies Phase 2-4 randomised trials, with no restrictions on medical conditions or interventions. Cluster randomised, crossover, non-inferiority, and equivalence trials were excluded. Main outcome measures Number of trials that stated the precise primary question being addressed about an intervention (ie, the primary estimand), or for which the primary estimand could be determined unambiguously from the reported methods using statistical knowledge. Strategies used to handle post-randomisation events that affect the interpretation or existence of patient outcomes, such as intervention discontinuations or uses of additional drug treatments (known as intercurrent events), and the corresponding types of questions being investigated. Results 255 eligible randomised trials were identified. No trials clearly stated all the attributes of the estimand. In 117 (46%) of 255 trials, the primary estimand could be determined from the reported methods. Intercurrent events were reported in 242 (95%) of 255 trials; but the handling of these could only be determined in 125 (49%) of 255 trials. Most trials that provided this information considered the occurrence of intercurrent events as irrelevant in the calculation of the treatment effect and assessed the effect of the intervention regardless (96/125, 77%)—that is, they used a treatment policy strategy. Four (4%) of 99 trials with treatment non-adherence owing to adverse events estimated the treatment effect in a hypothetical setting (ie, the effect as if participants continued treatment despite adverse events), and 19 (79%) of 24 trials where some patients died estimated the treatment effect in a hypothetical setting (ie, the effect as if participants did not die). Conclusions The precise research question being investigated in most trials is unclear, mainly because of a lack of clarity on the approach to handling intercurrent events. Clear reporting of estimands is necessary in trial reports so that all stakeholders, including clinicians, patients and policy makers, can make fully informed decisions about medical interventions. Systematic review registration PROSPERO CRD42021238053.

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Section: Research In Contextmentioning

confidence: 61%

“… 15 More recent guidelines for the contents of statistical analysis plans in early phase trials include specification of estimands. 39 …”

Section: Discussionmentioning

confidence: 99%

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Evaluating how clear the questions being investigated in randomised trials are: systematic review of estimands

Cro

Kahan

Rehal

et al. 2022

BMJ

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“…As with every large-scale trial, smaller scale feasibility and pilot trials should be conducted to inform final study features including recruitment and retention procedures, fidelity of intervention delivery, selection of primary and secondary outcomes and protocols for outcomes assessment, infrastructure for data management and ethical oversight across multiple sites. Consolidated Standards of Reporting Trials (CONSORT) and other guidelines for the design and reporting of pilot clinical trials are now widely available [221,222].…”

Section: Randomized Controlled Trialsmentioning

confidence: 99%

A systematic review of chiropractic care for fall prevention: rationale, state of the evidence, and recommendations for future research

Grabowska

Burton

Kowalski

et al. 2022

BMC Musculoskelet Disord

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Background Falls in older adults are a significant and growing public health concern. There are multiple risk factors associated with falls that may be addressed within the scope of chiropractic training and licensure. Few attempts have been made to summarize existing evidence on multimodal chiropractic care and fall risk mitigation. Therefore, the broad purpose of this review was to summarize this research to date. Body Systematic review was conducted following PRISMA guidelines. Databases searched included PubMed, Embase, Cochrane Library, PEDro, and Index of Chiropractic Literature. Eligible study designs included randomized controlled trials (RCT), prospective non-randomized controlled, observational, and cross-over studies in which multimodal chiropractic care was the primary intervention and changes in gait, balance and/or falls were outcomes. Risk of bias was also assessed using the 8-item Cochrane Collaboration Tool. The original search yielded 889 articles; 21 met final eligibility including 10 RCTs. One study directly measured the frequency of falls (underpowered secondary outcome) while most studies assessed short-term measurements of gait and balance. The overall methodological quality of identified studies and findings were mixed, limiting interpretation regarding the potential impact of chiropractic care on fall risk to qualitative synthesis. Conclusion Little high-quality research has been published to inform how multimodal chiropractic care can best address and positively influence fall prevention. We propose strategies for building an evidence base to inform the role of multimodal chiropractic care in fall prevention and outline recommendations for future research to fill current evidence gaps.

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“…It is beyond the scope of this paper to discuss situations where subjects experience either near DLTs or devastating DLTs and clinician's judgments on risk‐benefit are factored into the decision. While inclusion of this type of flexibility in the protocol is permissible, a recent survey by Homer and colleagues 14 shows that dose escalation decisions, stopping criteria, and interim go‐no‐go criteria are often poorly documented, resulting in ambiguous decisions to escalate. Critical assessment of dose escalation is only possible if the design, conduct, and analysis are predefined thoroughly and clearly documented.…”

Section: Practical Considerationsmentioning

confidence: 99%

Rejoinder: Improving the performance of Bayesian logistic regression model with overdose control in oncology dose‐finding studies

Zhang¹,

Chiang

Wang

2022

Statistics in Medicine

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hereafter FGK); Drs. Alexia Iasonos and Graham Wheeler 3 (hereafter IW). We appreciate all of their remarks about our proposed Bayesian logistic regression model (BLRM) with overdose and underdose control design in particular. We (and it seems our discussants) see the main contribution of our article as identifying an important statistical issue with BLRM that had not before been completely recognized and providing one fairly general statistical approach to address it. We recognize that many other dose escalation models could be developed and encourage colleagues and fellow practitioners to pursue these potentially fertile research paths as laid out by the discussants. In our rejoinder, we focus on three general issues raised in the discussions: alternative approaches, practical considerations, and model flexibility and parsimony.

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Early phase clinical trials extension to guidelines for the content of statistical analysis plans

Cited by 20 publications

References 31 publications

Evaluating how clear the questions being investigated in randomised trials are: systematic review of estimands

Evaluating how clear the questions being investigated in randomised trials are: systematic review of estimands

A systematic review of chiropractic care for fall prevention: rationale, state of the evidence, and recommendations for future research

Rejoinder: Improving the performance of Bayesian logistic regression model with overdose control in oncology dose‐finding studies

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