Futility stopping in clinical trials, optimality and practical considerations

Chang, Yen Chung; Song, T.; Monaco, Jane; Ivanova, Anastasia

doi:10.1080/10543406.2020.1818253

Cited by 10 publications

(3 citation statements)

References 16 publications

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“…Deciding whether and how to define stop criteria for future studies is extremely complex but nevertheless very important to avoid unnecessary studies in the case of a very conclusive and robust findings. Stop statements for additional studies are per definition a form of IfR statements and should not be confused with stopping rules of interim analyses within clinical trials, e.g., stopping for futility [ 18 ]. Our findings suggest that reasons for stopping further studies were worded in a very generic way and may trigger questions on explicit criteria to justify such stop statements.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of ‘implications for research’ statements in systematic reviews of interventions in advanced cancer patients – a meta-research study

Siemens,

Bantle,

Ebner

et al. 2023

BMC Med Res Methodol

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Background Implications for research (IfR) sections are an important part of systematic reviews (SRs) to inform health care researchers and policy makers. PRISMA 2020 recommends reporting IfR, while Cochrane Reviews require a separate chapter on IfR. However, it is unclear to what extent SRs discuss IfR. We aimed i) to assess whether SRs include an IfR statement and ii) to evaluate which elements informed IfR statements. Methods We conducted a meta-research study based on SRs of interventions in advanced cancer patients from a previous project (CRD42019134904). As suggested in the Cochrane Handbook, we assessed if the following predefined variables were referred to in IfR statements: patient, intervention, control, outcome (PICO) and study design; concepts underlying Grading of Recommendations, Assessment, Development and Evaluation (GRADE) domains: risk of bias, inconsistency, indirectness, imprecision, publication bias. Data were independently extracted by three reviewers after piloting the data extraction form. Discrepancies were resolved in weekly in-depth discussions. Results We included 261 SRs. The majority evaluated a pharmacological intervention (n = 244, 93.5%); twenty-nine were Cochrane Reviews (11.1%). Four out of five SRs included an IfR statement (n = 210, 80.5%). IfR statements commonly addressed ‘intervention’ (n = 121, 57.6%), ‘patient ‘ (n = 113, 53.8%), and ‘study design’ (n = 107, 51.0%). The most frequent PICO and study design combinations were ‘patient and intervention ‘ (n = 71, 33.8%) and ‘patient, intervention and study design ‘ (n = 34, 16.2%). Concepts underlying GRADE domains were rarely used for informing IfR recommendations: ‘risk of bias ‘ (n = 2, 1.0%), and ‘imprecision ‘ (n = 1, 0.5%), ‘inconsistency ‘ (n = 1, 0.5%). Additional elements informing IfR were considerations on cost effectiveness (n = 9, 4.3%), reporting standards (n = 4, 1.9%), and individual patient data meta-analysis (n = 4, 1.9%). Conclusion Although about 80% of SRs included an IfR statement, the reporting of PICO elements varied across SRs. Concepts underlying GRADE domains were rarely used to derive IfR. Further work needs to assess the generalizability beyond SRs in advanced cancer patients. We suggest that more specific guidance on which and how IfR elements to report in SRs of interventions needs to be developed. Utilizing PICO elements and concepts underlying GRADE according to the Cochrane Handbook to state IfR seems to be a reasonable approach in the interim. Registration CRD42019134904.

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Section: Discussionmentioning

confidence: 99%

Evaluation of ‘implications for research’ statements in systematic reviews of interventions in advanced cancer patients – a meta-research study

Siemens,

Bantle,

Ebner

et al. 2023

BMC Med Res Methodol

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“…All hypothetical RCTs were designed as superiority trials; if a noninferiority trial had to be designed, then hypothetical sample sizes would have also differed ( 27 ). Additionally, if a treatment is felt to be futile, at interim analysis, then a trial could be stopped early, requiring a smaller sample size than originally proposed ( 28 ). Follow-up duration for the time-to-event endpoints for hypothetical RCTs was set as twice the median life expectancy for the disease condition.…”

Section: Discussionmentioning

confidence: 99%

Feasibility of Randomized Controlled Trials for Cancer Drugs Approved by the Food and Drug Administration Based on Single-Arm Studies

Rittberg

Czaykowski

Niraula

2021

JNCI Cancer Spectrum

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Background The United States (US) Food and Drug Administration (FDA) introduced an Accelerated Approval (AA) pathway to expedite patient access to new drugs. AA accepts less rigorous trial designs, including single arm studies (SAS), owing to perceived lack of feasibility of timely RCTs. Methods We designed hypothetical RCTs with endpoints of objective response rate (ORR), progression free survival (PFS), and overall survival (OS) for FDA approvals based on SAS for solid tumors during 2010–2019. Existing standards of care served as controls. RCTs were designed to detect a difference with power of 0.80, α-error of 5% (two-sided), and 1:1 randomization. Accrual duration was estimated based on participation by < 5% of eligible patients derived from cancer-specific incidence and mortality rates in the US. Results Thirty-one of 172 (18.0%) approvals during the study period were based on SAS. Median sample size was 104 (range = 23–411), and 77.4% were AA. All studies reported ORR, 55% reported duration of response, 19.4% reported PFS, and 22.5% reported OS. Median sample size needed to conduct RCTs with endpoints of ORR, PFS and OS were 206, 130, and 396 respectively. It would have been theoretically possible to conduct RCTs within duration comparable to that required by SAS for 84.6%, 94.1%, and 80.0% of approvals with endpoints of ORR, PFS and OS respectively. Conclusion An overwhelming majority of FDA approvals based on SAS should be feasible as RCTs within a reasonable time-frame. Given the collateral harms to patients and to scientific rigor, drug approval based on SAS should only be permitted under exceptional circumstances.

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“…A single interim futility analysis is planned for each intervention (independently of the others) after test treatment and placebo (matched or unmatched) data are available on 60 participants in the a priori best subgroup. To set up a futility rule for this trial with crossover allocation we investigated various futility rules and optimal timing to stop for futility (Chang et al 2020).…”

Section: Precision Medicine and Adaptive Design Featuresmentioning

confidence: 99%

The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations

Ivanova

Israel

LaVange

et al. 2020

Journal of Biopharmaceutical Statistics

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Futility stopping in clinical trials, optimality and practical considerations

Cited by 10 publications

References 16 publications

Evaluation of ‘implications for research’ statements in systematic reviews of interventions in advanced cancer patients – a meta-research study

Evaluation of ‘implications for research’ statements in systematic reviews of interventions in advanced cancer patients – a meta-research study

Feasibility of Randomized Controlled Trials for Cancer Drugs Approved by the Food and Drug Administration Based on Single-Arm Studies

The precision interventions for severe and/or exacerbation-prone asthma (PrecISE) adaptive platform trial: statistical considerations

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