BETHESDA, Md.—Aimed first at improving the measurement of, then subsequently the function of, beta cells—insulin-producing cells within the pancreas—a major public-private biomedical research partnership led by the National Institutes of Health (NIH) has launched a landmark clinical study of patients at risk for rapid beta cell function deterioration that may inform future studies of diabetes progression.
Like many current studies in the new era of personalized medicine, this one focuses on the promise that biomarker discovery holds for our understanding of disease incidence, progression and prevention—specifically, type 2 diabetes and the many health conditions that are often associated with it.
Researchers in the study—called the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium—will spend $5.1 million over the next three years to develop standardized tests for measuring beta cell function in the clinical setting. Founded by the FNIH, the U.S. Food and Drug Administration (FDA) and the Pharmaceutical Research and Manufacturers of America, the consortium has broad participation from a variety of stakeholders, including government, industry, academia, patient advocacy and nonprofit and private -sector organizations.
The consortium's diverse partners include Amylin Pharmaceuticals Inc., the Biotechnology Industry Organization (BIO), the Centers for Medicare & Medicaid Services, Eli Lilly & Co., Johnson & Johnson Pharmaceutical Research and Development LLC, the Juvenile Diabetes Research Foundation, Merck & Co. Inc., Merck Sharp & Dohme Corp., Novartis Institutes for BioMedical Research Inc., Pfizer Inc., Sanofi-Aventis and Takeda Global Research & Development Center Inc.
All of these parties have come together in a quest to rapidly identify, develop and qualify potential biomarkers that could impact the detection, prevention, diagnosis and treatment of disease, explains Jenna Mills, communications manager for the FNIH. The current project, "Diabetes Drug Development: Identification and Validation of Markers that Predict Long-Term Beta Cell Function and Mass," will be managed by the Metabolic Disorders Steering Committee (MDSC) of the FNIH Biomarkers Consortium.
"Biomarker research already has identified biological indicators that have had immense impact in the identification, prevention and treatment of disease," Mills says. "Body temperature, for example, is considered an effective biomarker for fever, and blood pressure is considered an effective biomarker for predicting the risk of stroke and coronary heart disease. Cholesterol is accepted as a biomarker of cardiovascular risk. Effective identification and deployment of biomarkers is essential to achieving a new era of predictive, preventive and personalized medicine."
Results from the consortium's first completed project, "Evaluate the Utility of Adiponectin as a Biomarker Predictive of Glycemic Efficacy by Pooling Existing Clinical Trial Data from Previously Conducted Studies," were published in June 2009. Conducted entirely with in-kind contributions from F. Hoffman LaRoche, GlaxoSmithKline (GSK), Merck and Quintiles, the project involved aggregating data from clinical trials of peroxisome proliferator-activated receptor (PPAR) agonists at GSK, Lilly, Merck and Roche. The pooled data was then analyzed by statisticians at Quintiles and at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Among the project's results was evidence that adiponectin is a robust predictor of glycemic response to PPAR agonists in type 2 diabetes patients, and that adiponectin has potential utility across the spectrum of glucose tolerance. In addition, this project established that cross-company collaboration is a feasible and powerful approach to biomarker qualification.
But Mills notes that although there are many proposed testing regimens that reportedly estimate beta cell function, there is no standardized "gold standard" for doing so. Each investigator has his or her preferred way of conducting the testing as well as analyzing the data and reporting the results. In addition, many of the more widely accepted testing regiments are technically challenging and complex, making the unsuitable for large, multi-center clinical studies.
Consequently, there have been no large longitudinal trials in which specific measurement of beta cell function has shown to predict or track with clinical status over several years.
In the current study, biomarkers will enable the undertaking of consistent studies of the pathophysiology and natural history of diabetes, as well as the study of therapeutic effects of new interventions in a more effective manner, says Mills. The consortium's main objective is to appropriately characterize the Meal Tolerance Test and Maximum Stimulation Methods for measuring beta cell function and make data-driven decisions about whether these two tests are the best methodologies to include in a longitudinal clinical trial studying diabetes progression.
Subjects who are healthy, pre-diabetic and have type 2 diabetes will be identified and recruited for observational study at one to three clinical sites in the United States, which will be selected by the project team. The request for proposals (RFP) for the clinical sites is open until June 6, and the award will be announced during the summer.
This series of fundamental clinical studies, says Mills, will provide the foundation for effective and confident use of selected methodologies in long-term, multi-center clinical trials.
"One of the next steps of diabetes therapeutic development is to enable a change in the rate of progression of beta cell failure," she adds. "To do so, there is a need to identify those individuals whose beta cell function will deteriorate rapidly as well as short-term markers that predict long-term changes of beta cell function in response to an intervention. This would be the next phase which would come after the methodological studies are completed by the Biomarkers Consortium."
The project will make great strides in addressing a disease area with significant patient need. According to the Centers for Disease Control and Prevention, diabetes affects 25.8 million Americans, or more than 8 percent of the population. The prevalence of type 2 diabetes, in particular, is expected to rise due to longer life expectancy, an aging population and higher risk rates within minority groups. Diabetes can often lead to other critical or life-threatening conditions, such as kidney failure, lower-limb amputations, blindness, heart disease and stroke.
The consortium's diverse partners include Amylin Pharmaceuticals Inc., the Biotechnology Industry Organization (BIO), the Centers for Medicare & Medicaid Services, Eli Lilly & Co., Johnson & Johnson Pharmaceutical Research and Development LLC, the Juvenile Diabetes Research Foundation, Merck & Co. Inc., Merck Sharp & Dohme Corp., Novartis Institutes for BioMedical Research Inc., Pfizer Inc., Sanofi-Aventis and Takeda Global Research & Development Center Inc.
All of these parties have come together in a quest to rapidly identify, develop and qualify potential biomarkers that could impact the detection, prevention, diagnosis and treatment of disease, explains Jenna Mills, communications manager for the FNIH. The current project, "Diabetes Drug Development: Identification and Validation of Markers that Predict Long-Term Beta Cell Function and Mass," will be managed by the Metabolic Disorders Steering Committee (MDSC) of the FNIH Biomarkers Consortium.
"Biomarker research already has identified biological indicators that have had immense impact in the identification, prevention and treatment of disease," Mills says. "Body temperature, for example, is considered an effective biomarker for fever, and blood pressure is considered an effective biomarker for predicting the risk of stroke and coronary heart disease. Cholesterol is accepted as a biomarker of cardiovascular risk. Effective identification and deployment of biomarkers is essential to achieving a new era of predictive, preventive and personalized medicine."
Results from the consortium's first completed project, "Evaluate the Utility of Adiponectin as a Biomarker Predictive of Glycemic Efficacy by Pooling Existing Clinical Trial Data from Previously Conducted Studies," were published in June 2009. Conducted entirely with in-kind contributions from F. Hoffman LaRoche, GlaxoSmithKline (GSK), Merck and Quintiles, the project involved aggregating data from clinical trials of peroxisome proliferator-activated receptor (PPAR) agonists at GSK, Lilly, Merck and Roche. The pooled data was then analyzed by statisticians at Quintiles and at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
Among the project's results was evidence that adiponectin is a robust predictor of glycemic response to PPAR agonists in type 2 diabetes patients, and that adiponectin has potential utility across the spectrum of glucose tolerance. In addition, this project established that cross-company collaboration is a feasible and powerful approach to biomarker qualification.
But Mills notes that although there are many proposed testing regimens that reportedly estimate beta cell function, there is no standardized "gold standard" for doing so. Each investigator has his or her preferred way of conducting the testing as well as analyzing the data and reporting the results. In addition, many of the more widely accepted testing regiments are technically challenging and complex, making the unsuitable for large, multi-center clinical studies.
Consequently, there have been no large longitudinal trials in which specific measurement of beta cell function has shown to predict or track with clinical status over several years.
In the current study, biomarkers will enable the undertaking of consistent studies of the pathophysiology and natural history of diabetes, as well as the study of therapeutic effects of new interventions in a more effective manner, says Mills. The consortium's main objective is to appropriately characterize the Meal Tolerance Test and Maximum Stimulation Methods for measuring beta cell function and make data-driven decisions about whether these two tests are the best methodologies to include in a longitudinal clinical trial studying diabetes progression.
Subjects who are healthy, pre-diabetic and have type 2 diabetes will be identified and recruited for observational study at one to three clinical sites in the United States, which will be selected by the project team. The request for proposals (RFP) for the clinical sites is open until June 6, and the award will be announced during the summer.
This series of fundamental clinical studies, says Mills, will provide the foundation for effective and confident use of selected methodologies in long-term, multi-center clinical trials.
"One of the next steps of diabetes therapeutic development is to enable a change in the rate of progression of beta cell failure," she adds. "To do so, there is a need to identify those individuals whose beta cell function will deteriorate rapidly as well as short-term markers that predict long-term changes of beta cell function in response to an intervention. This would be the next phase which would come after the methodological studies are completed by the Biomarkers Consortium."
The project will make great strides in addressing a disease area with significant patient need. According to the Centers for Disease Control and Prevention, diabetes affects 25.8 million Americans, or more than 8 percent of the population. The prevalence of type 2 diabetes, in particular, is expected to rise due to longer life expectancy, an aging population and higher risk rates within minority groups. Diabetes can often lead to other critical or life-threatening conditions, such as kidney failure, lower-limb amputations, blindness, heart disease and stroke.
