A mathematical crystal ball gazes into future of prostate cancer treatmentAugust 04, 2017
The chemotherapy docetaxel is widely accepted as a standard therapy for metastatic castration-resistant prostate cancer. But 10-20 percent of patients will have adverse side effects that force discontinuation of treatment. These patients may have been better off with another treatment or alternative dosing of docetaxel in the first place, but who's to know before trying the drug which patients will go on to experience debilitating side effects? A crowdsourced competition asked this as an open question. Today in the Journal of Clinical Oncology Clinical Cancer Informatics, competition organizers and participating teams report their findings: Using open data from four previously conducted clinical trials, teams of international researchers designed mathematical models predicting the likelihood that a patient will discontinue docetaxel treatment due to adverse events. These results represent the first comprehensive effort to make such predictions based on patient clinical characteristics.
Specifically, the challenge was to connect any of 129 baseline clinical measurements to the chance of docetaxel discontinuation. In all, 34 international teams submitted 61 models. Seven of these teams submitted models with similarly high predictive ability and so technically "won" the challenge. The five clinical factors that were most predictive were measures of hemoglobin, alkaline phosphatase, aspartate aminotransferase, prostate specific antigen, and ECOG performance status. The seven successful models all integrated these five factors into various computational frameworks.
Interestingly, after the competition officially ended, these top seven teams decided to collaborate outside the framework of the competition, resulting in refinements that led to a combined model that was more predictive than any of the submissions alone.
"The seven groups from around the world -- Finland, Germany, Canada, Israel and the U.S. -- had never formally met before the challenge. It's a really exciting example of the power of scientific collaboration," says James Costello, PhD, senior author of the paper, investigator at the University of Colorado Cancer Center, assistant professor in the Department of Pharmacology at the CU School of Medicine, and director of Computational and Systems Biology Challenges within the Sage Bionetworks/DREAM organization.
The combined model stratified patients into groups with low and high risk of discontinuing docetaxel due to adverse events, with the high group having more than double the likelihood of discontinuation as the low group.
"Not only could a model like this help identify patients who might benefit more from a different treatment, it also has the potential to immediately impact future clinical trials by improving patient selection through the use of novel patient selection designs. In doing so, the number of patients needed for clinical trials could be reduced, making more efficient use of available resources," says Devin Koestler, PhD, assistant professor of Biostatistics at the University Kansas Medical Center, and one of the first authors of the paper.
The challenge was built to promote and capitalize on the potential of an open question paired with open data.
"The field is definitely moving toward a much more open sharing model of clinical trial data. This project is a great example of how you can gain new knowledge from existing data and how making clinical data open and freely accessible can maximize the use of these valuable data for the benefit of patients," says Laura Elo, PhD, one of the senior authors of the paper, adjunct professor in Biomathematics and research director in Computational Biomedicine and Bioinformatics at Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Finland.
The project was overseen as a collaborative effort between 16 institutions, led by academic research institutions including CU Cancer Center, open-data initiatives including Project Data Sphere, Sage Bionetworks, and the DREAM Challenges, and industry and research partners including Sanofi, AstraZeneca, and the Prostate Cancer Foundation.
Because only 10-20 percent of patients discontinue treatment due to adverse events, no single trial has enrolled enough patients to predict with statistical significance who would discontinue docetaxel - commonly, these trials tested the effectiveness of treatments in the population that was able to finish the regimen and were not designed to answer this secondary question of who would be unable to finish. Had clinical trial results remained firewalled by the academic or industry sponsors, this secondary question would have remained unanswered; however, the decision to open these clinical trial data allowed the current researchers to combine the numbers from four previous trials, pooling over 2,000 patients - enough to start identifying statistically significant patterns.
"The number of clinical trials in Project Data Sphere continue to grow. At the time of this study, there were about 10,000 patients in their database. Now there are over 70,000, meaning that we will be able to explore future questions with even greater accuracy and ask questions that have been unaddressable due to restricted data access," Costello says.
The project takes place in the context of a debate between research factions, one of which holds that studies should generate new data designed to specifically explore study questions, and another faction that sees value in mining previously generated data for new insights. While antagonizing terms, such as "research parasites," have been used to describe such data scientists, this study bridges the gap between these factions to develop a necessary research symbiosis. The clinicians who helped generate the original data from clinical trials worked with the researchers to develop new tools and draw novel conclusions from these data.
"Ultimately what we'd like to do is have a much more dynamic interaction with the clinical trial design. As patients are coming in, we could use these statistical models to help match the right person with the right trial," Costello says.
Chalk one up for research symbiosis: International, multi-institution research collaboration to mine previously generated, open data now offers a tool that can better leverage patient clinical characteristics and ease the process of clinical trials.
University of Colorado Anschutz Medical Campus
Related Clinical Trials Articles:
Children as young as 8 years old with incurable cancer can reliably characterize the impact an experimental therapy has on their symptoms and quality of life -- even at the earliest stages of drug development -- making self-reported patient outcomes a potential new clinical trial endpoint.
Women who participate in obstetric and gynecology clinical trials experience improved health outcomes compared to those who are not involved in trials, according to research by Queen Mary University of London.
Clinical trials are now enrolling to provide the final tests for a University of Virginia-developed artificial pancreas to automatically monitor and regulate blood-sugar levels in people with type 1 diabetes.
Standards for authorizing first-time trials of drugs in humans are lax, and should be strengthened in several ways, McGill University researchers argue in a paper published today in Nature.
The National Cancer Institute (NCI) today launched a new drug formulary (the 'NCI Formulary') that will enable investigators at NCI-designated Cancer Centers to have quicker access to approved and investigational agents for use in preclinical studies and cancer clinical trials.
Racial and ethnic groups can be underrepresented in medical research.
Researchers at the University of Liverpool have developed a new international guideline to help standardize how results from clinical trial studies are reported.
The number of cardiovascular drugs in the research pipeline has declined across all phases of development in the last 20 years even as cardiovascular disease has become the No.
Clinical research often excludes females from their trials under the assumption that 'one size fits all,' that a painkiller or antidepressant will be equally effective in subjects of either sex, but a growing number of scientists are criticizing this approach.
Clinical trials in children commonly go either uncompleted or unpublished, finds a comprehensive study conducted by researchers at Boston Children's Hospital.
Related Clinical Trials Reading:
Fundamentals of Clinical Trials
by Lawrence M. Friedman (Author), Curt D. Furberg (Author), David L. DeMets (Author), David M. Reboussin (Author), Christopher B. Granger (Author)
This is the fifth edition of a very successful textbook on clinical trials methodology, written by recognized leaders who have long and extensive experience in all areas of clinical trials. The three authors of the first four editions have been joined by two others who add great expertise. A chapter on regulatory issues has been included and the chapter on data monitoring has been split into two and expanded. Many contemporary clinical trial examples have been added. There is much new material on adverse events, adherence, issues in analysis, electronic data, data sharing and... View Details
Clinical Trials, Second Edition: Study Design, Endpoints and Biomarkers, Drug Safety, and FDA and ICH Guidelines
by Tom Brody PhD (Author)
Clinical Trials, Second Edition, offers those engaged in clinical trial design a valuable and practical guide. This book takes an integrated approach to incorporate biomedical science, laboratory data of human study, endpoint specification, legal and regulatory aspects and much more with the fundamentals of clinical trial design. It provides an overview of the design options along with the specific details of trial design and offers guidance on how to make appropriate choices. Full of numerous examples and now containing actual decisions from FDA reviewers to better inform trial... View Details
A Concise Guide to Clinical Trials
by J. Rick Turner PhD (Author)
Biopharmaceutical drugs improve the health and well-being of people across the globe on a scale that is unrivaled by any other medical intervention. Before these drugs can be prescribed for patients by their doctors, they have to be approved for marketing by a regulatory agency. To gain marketing approval, drugs must go through an extremely rigorous process that investigates their safety and efficacy, the process of New Drug Development. The last stage of this long, complex, and expensive process involves conducting clinical trials, the topic of this book. Successfully conducting clinical... View Details
Clinical Trials: A Methodologic Perspective (Wiley Series in Probability and Statistics)
by Steven Piantadosi (Author)
Presents elements of clinical trial methods that are essential in planning, designing, conducting, analyzing, and interpreting clinical trials with the goal of improving the evidence derived from these important studies
This Third Edition builds on the text’s reputation as a straightforward, detailed, and authoritative presentation of quantitative methods for clinical trials. Readers will encounter the principles of design for various types of clinical trials, and are then skillfully guided through the complete process of planning the experiment, assembling a... View Details
A Clinical Trials Manual From The Duke Clinical Research Institute: Lessons from a Horse Named Jim
by Margaret Liu (Author), Kate Davis (Author)
"The publication of the second edition of this manual comes at an important juncture in the history of clinical research. As advances in information technology make it possible to link individuals and groups in diverse locations in jointly seeking the answers to pressing global health problems, it is critically important to remain vigilant about moral and ethical safeguards for every patient enrolled in a trial. Those who study this manual will be well aware of how to ensure patient safety along with fiscal responsibility, trial efficiency, and research integrity."
—Robert... View Details
Fundamentals of Clinical Trials
by Lawrence M. Friedman (Author), Curt D. Furberg (Author), David DeMets (Author)
This book addresses the fundamentals of randomized control clinical trials, devoting a chapter to each of the critical areas of a protocol. The new edition is revised and expanded, with the number of examples illustrating the fundamentals considerably increased.View Details
Designing Clinical Research
by Dr. Stephen B Hulley MD MPH (Author), Steven R Cummings MD (Author), Warren S Browner MD MPH (Author), Deborah G Grady MD MPH (Author), Thomas B Newman MD MPH (Author)
Publisher’s Note: Products purchased from 3rd Party sellers are not guaranteed by the Publisher for quality, authenticity, or access to any online entitlements included with the product.
Designing Clinical Research has been extensively revised and continues to set the standard as a practical guide for doctors, nurses, pharmacists, and other health professionals involved in all forms of clinical, translational, and public health research. It presents advanced epidemiologic concepts in a reader-friendly way, and suggests common sense approaches to the challenging... View Details
Fundamentals of Clinical Trials
by Lawrence M. Friedman (Author), Curt D. Furberg (Author), David L. DeMets (Author)
The randomized control clinical trial has become the gold standard scientific method for the evaluation of pharmaceuticals, biologics, devices, procedures and diagnostic tests. This trial design has been successfully used in both therapeutic and disease prevention trials. It is superior to alternative designs by eliminating several sources of bias which exist in those designs. This role has evolved over the past three decades in a number of disease areas including cardiology, opthalmology, cancer and AIDS. While the specifics of using the randomized control design for a specific intervention... View Details
Economic Evaluation in Clinical Trials (Handbooks in Health Economic Evaluation)
by Henry A. Glick (Author), Jalpa A. Doshi (Author), Seema S. Sonnad (Author), Daniel Polsky (Editor)
It is becoming increasingly important to examine the relationship between the outcomes of a clinical trial and the costs of the medical therapy under study. The results of such analysis can affect reimbursement decisions for new medical technologies, drugs, devices or diagnostics. It can aid companies seeking to make claims about the cost-effectiveness of their product, as well as allowing early consideration of the economic value of therapies which may be important to improving initial adoption decisions. It is also vital for addressing the requirements of regulatory bodies.... View Details
Design and Analysis of Clinical Trials: Concepts and Methodologies
by Shein-Chung Chow (Author), Jen-Pei Liu (Author)
Praise for the Second Edition:
“...a grand feast for biostatisticians. It stands ready to satisfy the appetite of any pharmaceutical scientist with a respectable statistical appetite.” —Journal of Clinical Research Best Practices
The Third Edition of Design and Analysis of Clinical Trials provides complete, comprehensive, and expanded coverage of recent health treatments and interventions. Featuring a unified presentation, the book provides a well-balanced summary of current regulatory requirements and recently developed statistical methods... View Details