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Biomarker-adaptive clinical trial designs

Published on Dec 1, 2010in Pharmacogenomics2.27
· DOI :10.2217/pgs.10.153
Boris Freidlin35
Estimated H-index: 35
(NIH: National Institutes of Health),
Edward L. Korn51
Estimated H-index: 51
Cite
Abstract
Advancements made in molecularly targeted therapeutics have focussed increasing attention on biomarker-adaptive clinical trial designs as a means of improving the efficiency of drug development and advancing medical care. Here, we focus on randomized clinical trial (RCT) designs aimed at developing/validating clinically relevant pharmacogenomic biomarkers capable of identifying patients sensitive to a given therapy(s), and thereby, selecting the best therapy for a given patient. The term ‘biomarker-adaptive’ refers to biomarker trials that incorporate adaptive clinical trial method ology to modify the trial according to the accumulating outcome data. While some adaptive methods (e.g., interim monitoring) have been an integral part of traditional clinical trial design for decades, these methods can be particularly advantageous in biomarker studies that evaluate molecularly targeted therapies. Here, we briefly review the main clinical trial methods that are used in designing adaptive trials. We then discuss how these methods can be used to improve the efficiency of biomarker RCT designs.
  • References (16)
  • Citations (26)
Cite
References16
Newest
Published on Feb 20, 2011in Journal of Clinical Oncology28.25
Edward L. Korn51
Estimated H-index: 51
,
Boris Freidlin35
Estimated H-index: 35
Outcome-adaptive randomization is one of the possible elements of an adaptive trial design in which the ratio of patients randomly assigned to the experimental treatment arm versus the control treatment arm changes from 1:1 over time to randomly assigning a higher proportion of patients to the arm that is doing better. Outcome-adaptive randomization has intuitive appeal in that, on average, a higher proportion of patients will be treated on the better treatment arm (if there is one). In both the...
Published on Oct 1, 2010in Clinical Trials2.26
Sumithra J. Mandrekar38
Estimated H-index: 38
(Mayo Clinic),
Daniel J. Sargent76
Estimated H-index: 76
(Mayo Clinic)
Background With the advent of targeted therapies, biomarkers provide a promising means of individualizing therapy through an integrated approach to prediction using the genetic makeup of the disease and the genotype of the patient. Biomarker validation has therefore become a central topic of discussion in the field of medicine, primarily due to the changing landscape of therapies for treatment of a disease and these therapies purported mechanism(s) of action.Purpose In this report, we discuss th...
Published on Oct 1, 2010in Clinical Trials2.26
Aiyi Liu27
Estimated H-index: 27
(NIH: National Institutes of Health),
Chunling Liu8
Estimated H-index: 8
(NIH: National Institutes of Health)
+ 2 AuthorsVivian Yuan3
Estimated H-index: 3
(CDER: Center for Drug Evaluation and Research)
Background Large comparative clinical trials usually target a wide-range of patients population in which subgroups exist according to certain patients’ characteristics. Often, scientific knowledge or existing empirical data support the assumption that patients’ improvement is larger among certain subgroups than others. Such information can be used to design a more cost-effective clinical trial.Purpose The goal of the article is to use such information to design a more cost-effective clinical tri...
Published on Feb 3, 2010in Journal of the National Cancer Institute10.21
Boris Freidlin35
Estimated H-index: 35
,
Lisa M. McShane56
Estimated H-index: 56
,
Edward L. Korn51
Estimated H-index: 51
Clinical biomarker tests that aid in making treatment decisions will play an important role in achieving personalized medicine for cancer patients. Definitive evaluation of the clinical utility of these biomarkers requires conducting large randomized clinical trials (RCTs). Efficient RCT design is therefore crucial for timely introduction of these medical advances into clinical practice, and a variety of designs have been proposed for this purpose. To guide design and interpretation of RCTs eval...
Published on Jan 15, 2010in Clinical Cancer Research8.91
Boris Freidlin35
Estimated H-index: 35
(NIH: National Institutes of Health),
Wenyu Jiang4
Estimated H-index: 4
,
Richard T. Simon1
Estimated H-index: 1
Purpose: Many anticancer therapies benefit only a subset of treated patients and may be overlooked by the traditional broad eligibility approach to design phase III clinical trials. New biotechnologies such as microarrays can be used to identify the patients that are most likely to benefit from anticancer therapies. However, due to the high-dimensional nature of the genomic data, developing a reliable classifier by the time the definitive phase III trail is designed may not be feasible. Experime...
Published on Jan 1, 2010in Personalized Medicine1.41
Richard M. Simon64
Estimated H-index: 64
(NIH: National Institutes of Health)
Physicians need improved tools for selecting treatments for individual patients. Many diagnostic entities hat were traditionally viewed as individual diseases are heterogeneous in their molecular pathogenesis and treatment responsiveness. This results in the treatment of many patients with ineffective drugs, incursion of substantial medical costs for the treatment of patients who do not benefit and the conducting of large clinical trials to identify small, average treatment benefits for heteroge...
Published on Oct 1, 2009in Clinical Cancer Research8.91
Sally Hunsberger31
Estimated H-index: 31
,
Yingdong Zhao37
Estimated H-index: 37
,
Richard M. Simon64
Estimated H-index: 64
The traditional oncology drug development paradigm of single arm phase II studies followed by a randomized phase III study has limitations for modern oncology drug development. Interpretation of single arm phase II study results is difficult when a new drug is used in combination with other agents or when progression free survival is used as the endpoint rather than tumor shrinkage. Randomized phase II studies are more informative for these objectives but increase both the number of patients and...
Published on Jul 1, 2009in Clinical Pharmacology & Therapeutics6.34
Anna Barker8
Estimated H-index: 8
,
Caroline C. Sigman42
Estimated H-index: 42
+ 3 AuthorsLaura Esserman64
Estimated H-index: 64
(UCSF: University of California, San Francisco)
I-SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) is a process targeting the rapid, focused clinical development of paired oncologic therapies and biomarkers. The framework is an adaptive phase II clinical trial design in the neoadjuvant setting for women with locally advanced breast cancer. I-SPY 2 is a collaborative effort among academic investigators, the National Cancer Institute, the US Food and Drug Administration, and the ...
Published on Feb 1, 2009in Journal of Clinical Oncology28.25
Boris Freidlin35
Estimated H-index: 35
,
Edward L. Korn51
Estimated H-index: 51
To balance patient interests against the need for acquiring evidence, ongoing randomized clinical trials are formally monitored for early convincing indication of benefit or lack of benefit. In lethal diseases like cancer, where new therapies are often toxic and may have limited preliminary efficacy data, monitoring for lack of benefit is particularly important. We review the complex nature of stopping a randomized trial for lack of benefit and argue that many cancer trials could be improved by ...
Published on Jul 15, 2008in Clinical Cancer Research8.91
Boris Freidlin35
Estimated H-index: 35
,
Edward L. Korn51
Estimated H-index: 51
+ 1 AuthorsAlison Martin1
Estimated H-index: 1
A major challenge in the development of anticancer therapies is the considerable time and resources needed for conducting randomized clinical trials (RCT). There is a need for more efficient RCT designs that accelerate development, minimize costs, and make trials more appealing to patients. We review the statistical and logistical characteristics of multi-arm designs that compare several experimental treatments to a common control arm. In particular, we present a rationale for not requiring mult...
Cited By26
Newest
Published on Sep 13, 2019in Nature Reviews Cancer51.85
Christine A. Iacobuzio-Donahue77
Estimated H-index: 77
(MSK: Memorial Sloan Kettering Cancer Center),
Chelsea Michael1
Estimated H-index: 1
(MSK: Memorial Sloan Kettering Cancer Center)
+ 3 AuthorsTravis Hollman2
Estimated H-index: 2
(MSK: Memorial Sloan Kettering Cancer Center)
A research autopsy is a post-mortem medical procedure performed on a deceased individual with the primary goal of collecting tissue to support basic and translational research. This approach has increasingly been used to investigate the pathophysiological mechanisms of cancer evolution, metastasis and treatment resistance. In this Review, we discuss the rationale for the use of research autopsies in cancer research and provide an evidence-based discussion of the quality of post-mortem tissues co...
Published on Sep 8, 2017in Clinical Cancer Research8.91
Shigeyuki Matsui19
Estimated H-index: 19
(Nagoya University),
John Crowley91
Estimated H-index: 91
Among various design approaches to phase III clinical trials with a predictive biomarker, the marker-stratified all-comers design is advantageous because it allows for establishing the utility of both treatment and biomarker, but it is often criticized for requiring large sample sizes, since the design includes both marker-positive and marker-negative patients. In this paper, we propose a simple but flexible subgroup-focused design for marker-stratified trials that allows both sequential assessm...
Published on Sep 1, 2017in Clinical Cancer Research8.91
Janice M. Mehnert21
Estimated H-index: 21
(RU: Rutgers University),
Arta M. Monjazeb18
Estimated H-index: 18
(UC Davis: University of California, Davis)
+ 3 AuthorsLyndsay Harris50
Estimated H-index: 50
The development of immunotherapy is an important breakthrough for the treatment of cancer, with antitumor efficacy observed in a wide variety of tumors. To optimize immunotherapy use, approaches must be developed to identify which patients are likely to achieve benefit. To minimize therapeutic toxicities and costs, understanding the ideal choice and sequencing of the numerous immuno-oncology agents available for individual patients is thus critical, but fraught with challenges. The immune tumor ...
Steffen Ventz6
Estimated H-index: 6
(URI: University of Rhode Island),
Giovanni Parmigiani69
Estimated H-index: 69
(Harvard University),
Lorenzo Trippa16
Estimated H-index: 16
(Harvard University)
Published on Feb 1, 2017in Critical Reviews in Oncology Hematology5.01
Charlotte Wilhelm-Benartzi12
Estimated H-index: 12
(Imperial College London),
Shahrul Mt-Isa15
Estimated H-index: 15
(Imperial College London)
+ 2 AuthorsDeborah Ashby44
Estimated H-index: 44
(Imperial College London)
tBiomarkers can be used to establish more homogeneous groups using the genetic makeup of the tumourto inform the selection of treatment for each individual patient. However, proper preclinical work andstringent validation are needed before taking forward biomarkers into confirmatory studies. Despitethe challenges, incorporation of biomarkers into clinical trials could better target appropriate patients,and potentially be lifesaving. The authors conducted a systematic review to describe marker-ba...
Published on Jan 25, 2017in Journal of Personalized Medicine
Miranta Antoniou2
Estimated H-index: 2
,
Ruwanthi Kolamunnage-Dona16
Estimated H-index: 16
,
Andrea Jorgensen25
Estimated H-index: 25
Biomarker-guided treatment is a rapidly developing area of medicine, where treatment choice is personalised according to one or more of an individual’s biomarker measurements. A number of biomarker-guided trial designs have been proposed in the past decade, including both adaptive and non-adaptive trial designs which test the effectiveness of a biomarker-guided approach to treatment with the aim of improving patient health. A better understanding of them is needed as challenges occur both in ter...
Published on Feb 24, 2016in PLOS ONE2.78
Miranta Antoniou2
Estimated H-index: 2
(University of Liverpool),
Andrea Jorgensen25
Estimated H-index: 25
(University of Liverpool),
Ruwanthi Kolamunnage-Dona16
Estimated H-index: 16
(University of Liverpool)
Background Personalized medicine is a growing area of research which aims to tailor the treatment given to a patient according to one or more personal characteristics. These characteristics can be demographic such as age or gender, or biological such as a genetic or other biomarker. Prior to utilizing a patient’s biomarker information in clinical practice, robust testing in terms of analytical validity, clinical validity and clinical utility is necessary. A number of clinical trial designs have ...
Published on Jan 1, 2016in American Journal of Therapeutics1.13
Sanjay G. Gokhale2
Estimated H-index: 2
,
Sankalp Gokhale8
Estimated H-index: 8
Published on Jan 1, 2016in Neurotherapeutics5.55
Afsaneh Shirani13
Estimated H-index: 13
(UTSW: University of Texas Southwestern Medical Center),
Darin T. Okuda24
Estimated H-index: 24
(UTSW: University of Texas Southwestern Medical Center),
Olaf Stüve47
Estimated H-index: 47
(UTSW: University of Texas Southwestern Medical Center)
Identifying effective therapies for the treatment of progressive forms of multiple sclerosis (MS) is a highly relevant priority and one of the greatest challenges for the global MS community. Better understanding of the mechanisms involved in progression of the disease, novel trial designs, drug repurposing strategies, and new models of collaboration may assist in identifying effective therapies. In this review, we discuss various therapies under study in phase II or III trials, including antiox...
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