A plea to provide best evidence in trials under sample-size restrictions: the example of pioglitazone to resolve leukoplakia and erythroplakia in Fanconi anemia patients

Lasch, Florian; Weber, Kristina; Chao, Mwe Mwe; Koch, Armin

doi:10.1186/s13023-017-0655-8

Cited by 5 publications

(6 citation statements)

References 16 publications

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“…In supplemented SATs, external comparators provide the sole source of controls. While supplemented SATs cannot replace RCTs [28], our opinion is that when performing a SAT it is preferable to supplement with an external comparator to inform safety and efficacy than not to have any comparator. While some qualities of exchangeability can be, and should be, assessed for a supplemented SAT, the assessment is limited to variables measured in both the internal trial and the RWD comparator patients, thus only partial exchangeability can be achieved.…”

Section: Supplemented Single-arm Trialsmentioning

confidence: 99%

“…Unmeasured confounding can arise when there is differential selection not captured in the eligibility criteria or from important patient characteristics not included in the study, e.g. when there are gaps in RWD availability and not all relevant variables are captured [28]. Misclassification and measurement error could result from using different procedures for the measurement of any variable in the RWD vs the trial.…”

Section: Step 1: Identification Of Key Factors Affecting Biasmentioning

confidence: 99%

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A Framework for Methodological Choice and Evidence Assessment for Studies Using External Comparators from Real-World Data

et al. 2020

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Several approaches have been proposed recently to accelerate the pathway from drug discovery to patient access. These include novel designs such as using controls external to the clinical trial where standard randomised controls are not feasible. In parallel, there has been rapid growth in the application of routinely collected healthcare 'real-world' data for post-market safety and effectiveness studies. Thus, using real-world data to establish an external comparator arm in clinical trials is a natural next step. Regulatory authorities have begun to endorse the use of external comparators in certain circumstances, with some positive outcomes for new drug approvals. Given the potential to introduce bias associated with observational studies, there is a need for recommendations on how external comparators should be best used. In this article, we propose an evaluation framework for real-world data external comparator studies that enables full assessment of available evidence and related bias. We define the principle of exchangeability and discuss the applicability of criteria described by Pocock for consideration of the exchangeability of the external and trial populations. We explore how trial designs using real-world data external comparators fit within the evidence hierarchy and propose a four-step process for good conduct of external comparator studies. This process is intended to maximise the quality of evidence based on careful study design and the combination of covariate balancing, bias analysis and combining outcomes.

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Section: Supplemented Single-arm Trialsmentioning

confidence: 99%

Section: Step 1: Identification Of Key Factors Affecting Biasmentioning

confidence: 99%

A Framework for Methodological Choice and Evidence Assessment for Studies Using External Comparators from Real-World Data

et al. 2020

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“…Firstly, despite historical agreement on the suitability of single-arm designs for rare cancers, whether this should be universally accepted has recently been challenged (83,84). It has been argued that the field of oncology performs a disservice to patients with rare tumors when we accept medications using inferior levels of evidence.…”

Section: Contemporary Factors Influencing Phase II Designmentioning

confidence: 99%

A Review of Perspectives on the Use of Randomization in Phase II Oncology Trials

Grayling¹,

Dimairo²,

Mander³

et al. 2019

JNCI: Journal of the National Cancer Institute

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Historically, phase II oncology trials assessed a treatment’s efficacy by examining its tumor response rate in a single-arm trial. Then, approximately 25 years ago, certain statistical and pharmacological considerations ignited a debate around whether randomized designs should be used instead. Here, based on an extensive literature review, we review the arguments on either side of this debate. In particular, we describe the numerous factors that relate to the reliance of single-arm trials on historical control data and detail the trial scenarios in which there was general agreement on preferential utilization of single-arm or randomized design frameworks, such as the use of single-arm designs when investigating treatments for rare cancers. We then summarize the latest figures on phase II oncology trial design, contrasting current design choices against historical recommendations on best practice. Ultimately, we find several ways in which the design of recently completed phase II trials does not appear to align with said recommendations. For example, despite advice to the contrary, only 66.2% of the assessed trials that employed progression-free survival as a primary or coprimary outcome used a randomized comparative design. In addition, we identify that just 28.2% of the considered randomized comparative trials came to a positive conclusion as opposed to 72.7% of the single-arm trials. We conclude by describing a selection of important issues influencing contemporary design, framing this discourse in light of current trends in phase II, such as the increased use of biomarkers and recent interest in novel adaptive designs.

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“…This is preferable to a non‐randomised trial comparing the responses from a contemporary population to those from a historical population, which may differ in characteristics. Although single‐arm trials are more common in small populations and in rare disease settings, randomised designs should still be preferred when at all possible, as using historical information may provide less robust evidence 4,5 . Thus, it has been argued that in almost all instances, two‐arm randomised trials should be preferred to single‐arm trials, with two‐arm randomised trials considered to be the gold standard in trial design 6,7 .…”

Section: Introductionmentioning

confidence: 99%

“…Although single-arm trials are more common in small populations and in rare disease settings, randomised designs should still be preferred when at all possible, as using historical information may provide less robust evidence. 4 , 5 Thus, it has been argued that in almost all instances, two-arm randomised trials should be preferred to single-arm trials, with two-arm randomised trials considered to be the gold standard in trial design. 6 , 7 Nevertheless, single-arm trials remain popular in phase II oncology, accounting for 57% of trials in a recent review of 557 trials.…”

Section: Introductionmentioning

confidence: 99%

A stochastically curtailed two‐arm randomised phaseIItrial design for binary outcomes

Law

Grayling

Mander

2020

Pharmaceutical Statistics

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Summary Randomised controlled trials are considered the gold standard in trial design. However, phase II oncology trials with a binary outcome are often single‐arm. Although a number of reasons exist for choosing a single‐arm trial, the primary reason is that single‐arm designs require fewer participants than their randomised equivalents. Therefore, the development of novel methodology that makes randomised designs more efficient is of value to the trials community. This article introduces a randomised two‐arm binary outcome trial design that includes stochastic curtailment (SC), allowing for the possibility of stopping a trial before the final conclusions are known with certainty. In addition to SC, the proposed design involves the use of a randomised block design, which allows investigators to control the number of interim analyses. This approach is compared with existing designs that also use early stopping, through the use of a loss function comprised of a weighted sum of design characteristics. Comparisons are also made using an example from a real trial. The comparisons show that for many possible loss functions, the proposed design is superior to existing designs. Further, the proposed design may be more practical, by allowing a flexible number of interim analyses. One existing design produces superior design realisations when the anticipated response rate is low. However, when using this design, the probability of rejecting the null hypothesis is sensitive to misspecification of the null response rate. Therefore, when considering randomised designs in phase II, we recommend the proposed approach be preferred over other sequential designs.

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A plea to provide best evidence in trials under sample-size restrictions: the example of pioglitazone to resolve leukoplakia and erythroplakia in Fanconi anemia patients

Cited by 5 publications

References 16 publications

A Framework for Methodological Choice and Evidence Assessment for Studies Using External Comparators from Real-World Data

A Framework for Methodological Choice and Evidence Assessment for Studies Using External Comparators from Real-World Data

A Review of Perspectives on the Use of Randomization in Phase II Oncology Trials

A stochastically curtailed two‐arm randomised phaseIItrial design for binary outcomes

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