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.

scholarly journals Novel Clinical Trial Designs to Improve the Efficiency of Research

2020 ◽  
Vol 132 (1) ◽  
pp. 69-81 ◽  
Author(s):  
Daniel I. Sessler ◽  
Paul S. Myles
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Real Time ◽  
Randomized Trials ◽  
Clinical Evidence ◽  
Adaptive Designs ◽  
Large Numbers ◽  
Clinical Trial Designs ◽  
Study Sites ◽  
Trial Efficiency

Abstract SUMMARY Large randomized trials provide the highest level of clinical evidence. However, enrolling large numbers of randomized patients across numerous study sites is expensive and often takes years. There will never be enough conventional clinical trials to address the important questions in medicine. Efficient alternatives to conventional randomized trials that preserve protections against bias and confounding are thus of considerable interest. A common feature of novel trial designs is that they are pragmatic and facilitate enrollment of large numbers of patients at modest cost. This article presents trial designs including cluster designs, real-time automated enrollment, and practitioner-preference approaches. Then various adaptive designs that improve trial efficiency are presented. And finally, the article discusses the advantages of embedding randomized trials within registries.

A Bayesian Hybrid Adaptive Randomisation Design for Clinical Trials with Survival Outcomes

2016 ◽  
Vol 55 (01) ◽  
pp. 4-13
Author(s):  
M. Moatti ◽  
S. Zohar ◽  
W. F. Rosenberger ◽  
S. Chevret
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adaptive Design ◽  
Hazard Ratio ◽  
Adaptive Designs ◽  
Stopping Rules ◽  
Phase Iii ◽  
Optimal Criterion ◽  
Fully Bayesian

SummaryBackground: Response-adaptive randomisation designs have been proposed to im -prove the efficiency of phase III randomised clinical trials and improve the outcomes of the clinical trial population. In the setting of failure time outcomes, Zhang and Rosen -berger (2007) developed a response-adaptive randomisation approach that targets an optimal allocation, based on a fixed sample size. Objectives: The aim of this research is to propose a response-adaptive randomisation procedure for survival trials with an interim monitoring plan, based on the following optimal criterion: for fixed variance of the esti -mated log hazard ratio, what allocation minimizes the expected hazard of failure? We demonstrate the utility of the design by re -designing a clinical trial on multiple myeloma. Methods: To handle continuous monitoring of data, we propose a Bayesian response-adap -tive randomisation procedure, where the log hazard ratio is the effect measure of interest. Combining the prior with the normal likelihood, the mean posterior estimate of the log hazard ratio allows derivation of the optimal target allocation. We perform a simu lationstudy to assess and compare the perform -ance of this proposed Bayesian hybrid adaptive design to those of fixed, sequential or adaptive – either frequentist or fully Bayesian – designs. Non informative normal priors of the log hazard ratio were used, as well as mixture of enthusiastic and skeptical priors. Stopping rules based on the posterior dis -tribution of the log hazard ratio were com -puted. The method is then illus trated by redesigning a phase III randomised clinical trial of chemotherapy in patients with multiple myeloma, with mixture of normal priors elicited from experts. Results: As expected, there was a reduction in the proportion of observed deaths in the adaptive vs. non-adaptive designs; this reduction was maximized using a Bayes mix -ture prior, with no clear-cut improvement by using a fully Bayesian procedure. The use of stopping rules allows a slight decrease in the observed proportion of deaths under the alternate hypothesis compared with the adaptive designs with no stopping rules. Conclusions: Such Bayesian hybrid adaptive survival trials may be promising alternatives to traditional designs, reducing the duration of survival trials, as well as optimizing the ethical concerns for patients enrolled in the trial.

scholarly journals Racial disparities in cancer clinical trials.

2020 ◽  
Vol 38 (29_suppl) ◽  
pp. 97-97
Author(s):  
Pushti Khandwala ◽  
Devashish Desai ◽  
Devika Govind Das ◽  
Aakash Desai
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Demographic Data ◽  
Racial Minorities ◽  
Phase Iii ◽  
Cancer Clinical Trials ◽  
Adequate Representation ◽  
Race Ethnicity ◽  
Demographic Distribution ◽  
Phase Iii Studies

97 Background: Cancer-related mortality has been found to be disproportionately higher in racial minorities and medically underserved populations.[1] This necessitates adequate representation of these subgroups in clinical trials for these practices to become an acceptable benchmark for all.However, this has been historically challenging and various studies have failed to show the equitable representation of various ethnic groups in these trials that ultimately guide clinical practice. Methods: We reviewed all abstracts presented at the 2020 ASCO Virtual meeting, from which we selected abstracts discussing results from phase III trials. Of these, we included phase III studies that provided explicit information on the demographic distribution of the clinical trial participants with respect to their race/ethnicity. We then extracted information on the demographic data of participants in the clinical trial using the slides or posters available on the ASCO website. Further, we utilized descriptive statistics to analyze and compare the clinical trial population with the general cancer population using the 2020 ACS Cancer statistics. However, our analysis was potentially limited by the absence of full demographic distribution when previously described elsewhere and the lack of uniform reporting of different ethnicities among these abstracts. Results: Of the total 476 abstracts studied, 120 described phase III studies. Among these, 23 did provide detailed demographic (race/ethnicity) distribution. However, 98 studies did not include standardized subgroups (White, African American, and Others) and 6 studies provided data only on Whites. A total of 9 studies were included in the final analysis. Overall, the following was found: White 7083 (76.8%), African Americans 675 (7.3%), and “Others” 1466 (15.9%). Meanwhile, a comparison of cancer demographic data from the American Cancer Society (ACS) demonstrates the overall cancer incidence rates from 2012-2017 was found to be 464.6/100,000 in non-Hispanic whites and a comparable 460/100,000 in Non-Hispanic Blacks. However, our analysis shows that these ethnic minorities continue to be severely underrepresented in these phase III clinical trials. Conclusions: Despite several efforts, health care disparities persist and racial minorities continue to be underrepresented in cancer clinical trials. Further measures are needed to ensure adequate representation, healthcare equity and the generalizable nature of these “practice-changing” trials. References: 1. https://seer.cancer.gov/csr/1975_2017/results_merged/topic_race_ethnicity.pdf .

Current Advances in Clinical Trials for Rare Disease Populations: Spotlight on the Patient

2021 ◽  
Vol 16 ◽  
Author(s):  
Erica Winter ◽  
Scott Schliebner
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Development ◽  
Rare Disease ◽  
Rare Diseases ◽  
Statistical Analyses ◽  
Clinical Trial Designs ◽  
Novel Approaches

: Characterized by small, highly heterogeneous patient populations, rare disease trials magnify the challenges often encountered in traditional clinical trials. In recent years, there have been increased efforts by stakeholders to improve drug development in rare diseases through novel approaches to clinical trial designs and statistical analyses. We highlight and discuss some of the current and emerging approaches aimed at overcoming challenges in rare disease clinical trials, with a focus on the ultimate stakeholder, the patient.

scholarly journals The case for introducing pre-registered confirmatory pharmacological pre-clinical studies

2018 ◽  
Vol 38 (5) ◽  
pp. 749-754 ◽  
Author(s):  
Olivia Kiwanuka ◽  
Bo-Michael Bellander ◽  
Anders Hånell
Keyword(s):  
Clinical Trial ◽  
Traumatic Brain Injury ◽  
Clinical Trials ◽  
Brain Injury ◽  
Network Analysis ◽  
Clinical Studies ◽  
Phase Iii ◽  
Phase Iii Clinical Trial ◽  
Phase Iii Clinical Trials ◽  
Experimental Drugs

When evaluating the design of pre-clinical studies in the field of traumatic brain injury, we found substantial differences compared to phase III clinical trials, which in part may explain the difficulties in translating promising experimental drugs into approved treatments. By using network analysis, we also found cases where a large proportion of the studies evaluating a pre-clinical treatment was performed by inter-related researchers, which is potentially problematic. Subjecting all pre-clinical trials to the rigor of a phase III clinical trial is, however, likely not practically achievable. Instead, we repeat the call for a distinction to be made between exploratory and confirmatory pre-clinical studies.

scholarly journals A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

2007 ◽  
Vol 89 (3) ◽  
pp. 207-211 ◽  
Author(s):  
JF Thorpe ◽  
S Jain ◽  
TH Marczylo ◽  
AJ Gescher ◽  
WP Steward ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Prevention ◽  
Age Of Onset ◽  
Cancer Chemoprevention ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Prostate Cancer Prevention ◽  
Phase Iii Trials

INTRODUCTION Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. PATIENTS AND METHODS All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords ‘clinical trial, prostate cancer, chemoprevention’. RESULTS In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5α-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention – the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium – are also reviewed. CONCLUSIONS At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

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