CBER’s Experience With Adaptive Design Clinical Trials

Lin, Min; Lee, Shiowjen; Zhen, Boguang; Scott, John; Horne, Amelia Dale; Solomon, Ghideon; Russek‐Cohen, Estelle

doi:10.1177/2168479015604181

Cited by 35 publications

(36 citation statements)

References 31 publications

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“…Recently, an arm of the Food and Drug Administration reviewed submission protocols and found 136 phase II or III ADs [23], highlighting underestimation of our review though the ClinicalTrials.gov [18] register. However, one point of reassurance is that based on our review, the frequency of certain types of AD, such as GSDs and SSRs, is consistent with this regulator review.…”

Section: Discussionmentioning

confidence: 99%

Adaptive designs undertaken in clinical research: a review of registered clinical trials

Hatfield

Allison

Flight

et al. 2016

Trials

103

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Adaptive designs have the potential to improve efficiency in the evaluation of new medical treatments in comparison to traditional fixed sample size designs. However, they are still not widely used in practice in clinical research. Little research has been conducted to investigate what adaptive designs are being undertaken. This review highlights the current state of registered adaptive designs and their characteristics. The review looked at phase II, II/III and III trials registered on ClinicalTrials.gov from 29 February 2000 to 1 June 2014, supplemented with trials from the National Institute for Health Research register and known adaptive trials. A range of adaptive design search terms were applied to the trials extracted from each database. Characteristics of the adaptive designs were then recorded including funder, therapeutic area and type of adaptation. The results in the paper suggest that the use of adaptive designs has increased. They seem to be most often used in phase II trials and in oncology. In phase III trials, the most popular form of adaptation is the group sequential design. The review failed to capture all trials with adaptive designs, which suggests that the reporting of adaptive designs, such as in clinical trials registers, needs much improving. We recommend that clinical trial registers should contain sections dedicated to the type and scope of the adaptation and that the term ‘adaptive design’ should be included in the trial title or at least in the brief summary or design sections.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1273-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Adaptive designs undertaken in clinical research: a review of registered clinical trials

Hatfield

Allison

Flight

et al. 2016

Trials

103

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“…Consider a simple setting, where no early rejection of the null hypothesis is allowed at the end of the first stage but an adaptation of the design such as sample size reassessment or nonbinding futility stopping can be performed (Bauer, Bretz, Dragalin, König, & Wassmer, ; Bretz et al., ; Lin et al., ). The adaptive combination test rejects the null hypothesis of interest if

Z^{*} > z_{1 - α}

.…”

Section: Sample Size Reassessment Based On Conditional Powermentioning

confidence: 99%

“…During an interim analysis an ongoing trial can be stopped early for efficacy or futility, or some designs adaptations, such as sample size reassessment or dropping of treatment arms can be performed. Consideration of futility stopping of a trial is seen to be important and useful for both ethical and economic reasons, and therefore widely used (Elsäßer et al., ; Hatfield, Allison, Flight, Julious, & Dimairo, ; Lin et al., ). It is also possible for different endpoints to be considered during an interim analysis and an example of that could be the use of shorter observations on patients.…”

Section: Introductionmentioning

confidence: 99%

Interim analysis incorporating short‐ and long‐term binary endpoints

2019

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Designs incorporating more than one endpoint have become popular in drug development. One of such designs allows for incorporation of short‐term information in an interim analysis if the long‐term primary endpoint has not been yet observed for some of the patients. At first we consider a two‐stage design with binary endpoints allowing for futility stopping only based on conditional power under both fixed and observed effects. Design characteristics of three estimators: using primary long‐term endpoint only, short‐term endpoint only, and combining data from both are compared. For each approach, equivalent cut‐off point values for fixed and observed effect conditional power calculations can be derived resulting in the same overall power. While in trials stopping for futility the type I error rate cannot get inflated (it usually decreases), there is loss of power. In this study, we consider different scenarios, including different thresholds for conditional power, different amount of information available at the interim, different correlations and probabilities of success. We further extend the methods to adaptive designs with unblinded sample size reassessments based on conditional power with inverse normal method as the combination function. Two different futility stopping rules are considered: one based on the conditional power, and one from P‐values based on Z‐statistics of the estimators. Average sample size, probability to stop for futility and overall power of the trial are compared and the influence of the choice of weights is investigated.

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“…These reviews are consistent with the earlier review by Morgan et al (2014). Lin et al (2016) summarized the adaptive trial proposals that were received by the Center for Biologics Evaluation and Research at the FDA from 2008 to 2013. This centre regulates vaccines, blood products, allergenic products, cellular, tissue and gene therapies, and related medical and diagnostic devices.…”

Section: Types Of Adaptation In Clinical Trialsmentioning

confidence: 99%

“…These include modifying treatment dose, randomization probabilities, enrolment criteria and/or follow-up time (based on unblinded data), sample size (other than group sequential designs or based on blinded analyses) or end points. Lin et al (2016), whose authors are all from the Center for Biologics Evaluation and Research at the FDA, clarified that less-well-understood methods can still be used in confirmatory trials for FDA approval; however, they generally require additional justification and discussion with the FDA before formal submission. It is beyond the scope of our paper to present examples of each type of less-well-understood adaptation; instead, we give an example of one such adaptation type that has shown promise in oncology trials.…”

Section: Modifying Enrolment Criteria Dose Sample Size Follow-up Tmentioning

confidence: 99%

Adaptive Design in Surveys and Clinical Trials: Similarities, Differences and Opportunities for Cross-fertilization

Rosenblum

Miller

Reist

et al. 2018

Journal of the Royal Statistical Society Series A: Statistics in Society

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Summary Adaptive designs involve preplanned rules for modifying an on‐going study based on accruing data. We compare the goals and methods of adaptation for trials and surveys, identify similarities and differences, and make recommendations for what types of adaptive approaches from one domain have high potential to be useful in the other. For example, clinical trials could benefit from recently developed survey methods for monitoring which groups have low response rates and intervening to fix this. Clinical trials may also benefit from more formal identification of the target population, and from using paradata (contextual information collected before or during the collection of actual outcomes) to predict participant compliance and retention and then to intervene to improve these. Surveys could benefit from stopping rules based on information monitoring, applying techniques from sequential multiple‐assignment randomized trial designs to improve response rates, prespecifying a formal adaptation protocol and including a data monitoring committee. We conclude with a discussion of the additional information, infrastructure and statistical analysis methods that are needed when conducting adaptive designs, as well as benefits and risks of adaptation.

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CBER’s Experience With Adaptive Design Clinical Trials

Cited by 35 publications

References 31 publications

Adaptive designs undertaken in clinical research: a review of registered clinical trials

Adaptive designs undertaken in clinical research: a review of registered clinical trials

Interim analysis incorporating short‐ and long‐term binary endpoints

Adaptive Design in Surveys and Clinical Trials: Similarities, Differences and Opportunities for Cross-fertilization

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