Statistical Considerations in Design, Execution, and Analysis of Multiregional Clinical Trials: Consistency Evaluation and Adaptive Trials

2021 ◽  
pp. 229-252
Author(s):  
Lanju Zhang ◽  
Weining Z. Robieson
Keyword(s):  
Clinical Trials ◽  
Adaptive Trials ◽  
Consistency Evaluation

scholarly journals Adaptive design clinical trials: a review of the literature and ClinicalTrials.gov

BMJ Open ◽  
2018 ◽  
Vol 8 (2) ◽  
pp. e018320 ◽  
Author(s):  
Laura E Bothwell ◽  
Jerry Avorn ◽  
Nazleen F Khan ◽  
Aaron S Kesselheim
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Interim Analysis ◽  
Adaptive Design ◽  
Drug Application ◽  
Adaptive Designs ◽  
European Medicines Agency ◽  
Product Approval ◽  
New Drug ◽  
Adaptive Trials

ObjectivesThis review investigates characteristics of implemented adaptive design clinical trials and provides examples of regulatory experience with such trials.DesignReview of adaptive design clinical trials in EMBASE, PubMed, Cochrane Registry of Controlled Clinical Trials, Web of Science and ClinicalTrials.gov. Phase I and seamless Phase I/II trials were excluded. Variables extracted from trials included basic study characteristics, adaptive design features, size and use of independent data monitoring committees (DMCs) and blinded interim analyses. We also examined use of the adaptive trials in new drug submissions to the Food and Drug Administration (FDA) and European Medicines Agency (EMA) and recorded regulators’ experiences with adaptive designs.Results142 studies met inclusion criteria. There has been a recent growth in publicly reported use of adaptive designs among researchers around the world. The most frequently appearing types of adaptations were seamless Phase II/III (57%), group sequential (21%), biomarker adaptive (20%), and adaptive dose-finding designs (16%). About one-third (32%) of trials reported an independent DMC, while 6% reported blinded interim analysis. We found that 9% of adaptive trials were used for FDA product approval consideration, and 12% were used for EMA product approval consideration. International regulators had mixed experiences with adaptive trials. Many product applications with adaptive trials had extensive correspondence between drug sponsors and regulators regarding the adaptive designs, in some cases with regulators requiring revisions or alterations to research designs.ConclusionsWider use of adaptive designs will necessitate new drug application sponsors to engage with regulatory scientists during planning and conduct of the trials. Investigators need to more consistently report protections intended to preserve confidentiality and minimise potential operational bias during interim analysis.

scholarly journals Adapt to Translate

2021 ◽  
Vol 17 (2) ◽  
pp. 5-24
Author(s):  
Daria Jadreškić
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Clinical Research ◽  
Pharmaceutical Research ◽  
Lessons Learned ◽  
Operational Conditions ◽  
Medical Interventions ◽  
Adaptive Trials ◽  
Adaptive Clinical Trials ◽  
Normative Argument

The article presents the advantages and limitations of adaptive clinical trials for assessing the effectiveness of medical interventions and specifies the conditions that contributed to their development and implementation in clinical practice. I advance two arguments by discussing different cases of adaptive trials. The normative argument is that responsible adaptation should be taken seriously as a new way of doing clinical research insofar as a valid justification, sufficient understanding, and adequate operational conditions are provided. The second argument is historical. The development of adaptive trials can be related to lessons learned from research in cases of urgency and to the decades-long efforts to end the productivity crisis of pharmaceutical research, which led to the emergence of translational, personalized, and, recently, precision medicine movements.

scholarly journals The Bayesian Design of Adaptive Clinical Trials

2021 ◽  
Vol 18 (2) ◽  
pp. 530
Author(s):  
Alessandra Giovagnoli
Keyword(s):  
Clinical Trials ◽  
Adaptive Design ◽  
Recent Literature ◽  
Adaptive Designs ◽  
Bayesian Design ◽  
High Expectations ◽  
Reading Material ◽  
Adaptive Trials ◽  
Adaptive Clinical Trials ◽  
Interesting Reading

This paper presents a brief overview of the recent literature on adaptive design of clinical trials from a Bayesian perspective for statistically not so sophisticated readers. Adaptive designs are attracting a keen interest in several disciplines, from a theoretical viewpoint and also—potentially—from a practical one, and Bayesian adaptive designs, in particular, have raised high expectations in clinical trials. The main conceptual tools are highlighted here, with a mention of several trial designs proposed in the literature that use these methods, including some of the registered Bayesian adaptive trials to this date. This review aims at complementing the existing ones on this topic, pointing at further interesting reading material.

P4-004: Planning Dose Escalation in Phase III Clinical Trials May Prevent Underpowered Trials and Mitigate the Increase in Sample Size or Duration of Adaptive Trials

2016 ◽  
Vol 12 ◽  
pp. P1015-P1015
Author(s):  
Guoqiao Wang ◽  
Eric McDade ◽  
Randall Bateman ◽  
Jason Hassenstab ◽  
Martin R. Farlow ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Sample Size ◽  
Dose Escalation ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Adaptive Trials

scholarly journals Costs and staffing resource requirements for adaptive clinical trials: quantitative and qualitative results from the Costing Adaptive Trials project

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Nina Wilson ◽  
Katie Biggs ◽  
Sarah Bowden ◽  
Julia Brown ◽  
Munyaradzi Dimairo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Data Management ◽  
Adaptive Design ◽  
Adaptive Designs ◽  
Great Promise ◽  
Percentage Increase ◽  
Trial Management ◽  
High Quality ◽  
Adaptive Trials ◽  
Adaptive Trial

Abstract Background Adaptive designs offer great promise in improving the efficiency and patient-benefit of clinical trials. An important barrier to further increased use is a lack of understanding about which additional resources are required to conduct a high-quality adaptive clinical trial, compared to a traditional fixed design. The Costing Adaptive Trials (CAT) project investigated which additional resources may be required to support adaptive trials. Methods We conducted a mock costing exercise amongst seven Clinical Trials Units (CTUs) in the UK. Five scenarios were developed, derived from funded clinical trials, where a non-adaptive version and an adaptive version were described. Each scenario represented a different type of adaptive design. CTU staff were asked to provide the costs and staff time they estimated would be needed to support the trial, categorised into specified areas (e.g. statistics, data management, trial management). This was calculated separately for the non-adaptive and adaptive version of the trial, allowing paired comparisons. Interviews with 10 CTU staff who had completed the costing exercise were conducted by qualitative researchers to explore reasons for similarities and differences. Results Estimated resources associated with conducting an adaptive trial were always (moderately) higher than for the non-adaptive equivalent. The median increase was between 2 and 4% for all scenarios, except for sample size re-estimation which was 26.5% (as the adaptive design could lead to a lengthened study period). The highest increase was for statistical staff, with lower increases for data management and trial management staff. The percentage increase in resources varied across different CTUs. The interviews identified possible explanations for differences, including (1) experience in adaptive trials, (2) the complexity of the non-adaptive and adaptive design, and (3) the extent of non-trial specific core infrastructure funding the CTU had. Conclusions This work sheds light on additional resources required to adequately support a high-quality adaptive trial. The percentage increase in costs for supporting an adaptive trial was generally modest and should not be a barrier to adaptive designs being cost-effective to use in practice. Informed by the results of this research, guidance for investigators and funders will be developed on appropriately resourcing adaptive trials.

scholarly journals Adding flexibility to clinical trial designs: an example-based guide to the practical use of adaptive designs

BMC Medicine ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Thomas Burnett ◽  
Pavel Mozgunov ◽  
Philip Pallmann ◽  
Sofia S. Villar ◽  
Graham M. Wheeler ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Adaptive Designs ◽  
Phase Iii ◽  
Scientific Interest ◽  
Clinical Community ◽  
Adaptive Trials ◽  
Clinical Trial Designs ◽  
Phase Iii Studies ◽  
Confirmatory Phase

AbstractAdaptive designs for clinical trials permit alterations to a study in response to accumulating data in order to make trials more flexible, ethical, and efficient. These benefits are achieved while preserving the integrity and validity of the trial, through the pre-specification and proper adjustment for the possible alterations during the course of the trial. Despite much research in the statistical literature highlighting the potential advantages of adaptive designs over traditional fixed designs, the uptake of such methods in clinical research has been slow. One major reason for this is that different adaptations to trial designs, as well as their advantages and limitations, remain unfamiliar to large parts of the clinical community. The aim of this paper is to clarify where adaptive designs can be used to address specific questions of scientific interest; we introduce the main features of adaptive designs and commonly used terminology, highlighting their utility and pitfalls, and illustrate their use through case studies of adaptive trials ranging from early-phase dose escalation to confirmatory phase III studies.

Localization of Gallium-67 in Peritoneal Cells by Electron Microscopic Autoradiography

1973 ◽  
Vol 31 ◽  
pp. 404-405
Author(s):  
D. C. Swartzendruber ◽  
Norma L. Idoyaga-Vargas
Keyword(s):  
Clinical Trials ◽  
Soft Tissue ◽  
Tumor Tissue ◽  
Soft Tissue Tumors ◽  
Clinical Usefulness ◽  
Electron Microscopic ◽  
Normal Cells ◽  
Electron Microscopic Autoradiography ◽  
Peritoneal Cells ◽  
Gallium 67

The radionuclide gallium-67 (67Ga) localizes preferentially but not specifically in many human and experimental soft-tissue tumors. Because of this localization, 67Ga is used in clinical trials to detect humar. cancers by external scintiscanning methods. However, the fact that 67Ga does not localize specifically in tumors requires for its eventual clinical usefulness a fuller understanding of the mechanisms that control its deposition in both malignant and normal cells. We have previously reported that 67Ga localizes in lysosomal-like bodies, notably, although not exclusively, in macrophages of the spocytaneous AKR thymoma. Further studies on the uptake of 67Ga by macrophages are needed to determine whether there are factors related to malignancy that might alter the localization of 67Ga in these cells and thus provide clues to discovering the mechanism of 67Ga localization in tumor tissue.

Sign in / Sign up

Export Citation Format

Share Document