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Rare Diseases Drug Development
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
Shein-Chung Chow, Shutian Zhang, Wei Zhang
Another useful innovative trial design for rare disease clinical trials is an adaptive trial design. In its draft guidance on adaptive clinical trial design, FDA defines an adaptive design as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of (usually interim) data from subjects in the study (FDA 2010, 2019c). The FDA guidance has been served as an official document describing the potential use of adaptive designs in clinical trials since it was published in 2019. It, however, should be noted that the FDA draft guidance on adaptive clinical trial design is currently being revised in order to reflect pharmaceutical practice and FDA's current thinking.
Bayesian Adaptive Designs in Drug Development
Published in Emmanuel Lesaffre, Gianluca Baio, Bruno Boulanger, Bayesian Methods in Pharmaceutical Research, 2020
Adaptive clinical trial designs allow the trial to change in response to accumulating data. The most common adaptive design is a sequential design that includes interim analyses of the accruing data. So-called group sequential studies allow for early termination of a randomized clinical trial once there is clear evidence of the superiority of one treatment over the other treatments in the study. A group sequential trial might also incorporate early stopping for futility. Futility in this context is usually defined as a low probability of ultimately finding a “significant” difference between the treatments if the study continues to its planned end.
Sequential Multiple Assignment Randomized Trials
Published in Anastasios A. Tsiatis, Marie Davidian, Shannon T. Holloway, Eric B. Laber, Dynamic Treatment Regimes, 2019
Anastasios A. Tsiatis, Marie Davidian, Shannon T. Holloway, Eric B. Laber
SMARTs are sometimes confused with adaptive clinical trial designs with a single point of randomization for which the randomization probabilities are adjusted over time as information about treatment effects accrues (e.g., Berry and Fristedt, 1985; Whitehead, 1997). However, although SMARTs comprise a sequence of randomizations, these randomizations are within a subject over time and are conducted for the purpose of evaluating treatment sequences. In contrast, an adaptive clinical trial applies a sequence of randomizations across participants, driven by the perspective that randomization probabilities should be informed by current evidence from previous participants of each candidate treatment’s efficacy. SMARTs also may be confused with crossover designs, as both involve randomly assigning treatment sequences to each patient (Jones and Kenward, 2014). However, the primary goal of a crossover trial is the identification of a single best treatment option, and such designs use assignment of the same subject to multiple treatments as a mechanism to control for subject-specific characteristics and thereby reduce variance. Thus, in a crossover design, treatment sequences are a means to compare fixed treatments efficiently rather than a reflection of clinical interest in such sequences.
Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for ultra-rare inherited bleeding disorders
Published in Expert Review of Hematology, 2023
Diane Nugent, Suchitra S. Acharya, Kimberly J. Baumann, Camille Bedrosian, Rebecca Bialas, Kai Brown, Deya Corzo, Amar Haidar, Catherine P. M. Hayward, Peter Marks, Marzia Menegatti, Margaret E. Miller, Kate Nammacher, Roberta Palla, Skye Peltier, Rajiv K. Pruthi, Michael Recht, Benny Sørensen, Michael Tarantino, Alisa S. Wolberg, Amy D. Shapiro
The centralized national, or harmonized international data collection proposed above would support accumulating the evidence base to understand a number of key factors, such as how existing therapeutics are being used (including off-label), their real-world safety and efficacy outcomes, and the need for novel therapeutics and indications. Clearly demonstrating the absence of effective treatment options for specific populations may prompt regulators to consider adjusting endpoint/outcome thresholds for provisional approval. A therapeutic currently approved for a different indication could be accepted to treat a high-need population upon demonstration of its safety and potential benefits. Under provisional approval, further information supporting use could be captured with ongoing data collection to further elucidate and confirm benefits. Adaptive clinical trial designs, as explored by WG6 [57], may facilitate maximization of the impact of data generated from a limited number of participants.
Novel immune targets for the treatment of triple-negative breast cancer
Published in Expert Opinion on Therapeutic Targets, 2021
Chiara Corti, Eleonora Nicolò, Giuseppe Curigliano
Importantly, the appropriate trial design to evaluate the therapeutic benefit of many novel immunotherapeutics may distance itself from the traditional phase 3 trial design. In fact, conventional two-arm clinical trials often require a long period of time for quantification of durable survival and cost [25]. In this regard, ‘platform’ trials that are clinical trials with a single master protocol in which multiple treatments are evaluated simultaneously, may be a solution [25]. However, since the advantages and disadvantages of adaptive clinical trial design can vary according to the clinical setting, their application in a particular field should be clearly justified.
Clinical trial design for unmet clinical needs: a spotlight on sepsis
Published in Expert Review of Clinical Pharmacology, 2019
Jean-Louis Vincent, Yasser Sakr
RCTs are difficult to conduct in critically ill patients with sepsis, largely because of the complexity and heterogeneity of sepsis. The multiple RCTs that have been conducted and have failed to demonstrate a beneficial effect of the intervention on survival should be used to encourage new approaches to sepsis trials with better patient selection and additional primary endpoints, rather than the widely used strategies targeting primarily 28-day mortality in large unselected populations. New adaptive clinical trial designs should also be considered.