This Funding Opportunity Announcement (FOA) invites applications for a Central Primary Reference Laboratory (CPRL) to provide support for the harmonization and standardization of laboratory measurements critical for clinical research in type 1 diabetes. The CPRL will provide administrative functions to coordinate harmonization efforts among clinical laboratories and commercial suppliers of reagents and methods, and will provide measurements of reference values for C-peptide and HbA1c measurements.
HbA1c measurement standardization has become even more important in recent years. There is increased use of the test, with rising rates of diabetes. The FDA has utilized improvements in HbA1c as an outcome measure for approval of new therapies for diabetes. In 2010, the ADA sanctioned the use of HbA1c as one option for diagnosis of diabetes and pre-diabetes. Thus, there is now a critical need for accuracy and precision near the normal range in addition to the clinical target range for diabetes treatment.
In an effort to standardize these methods and to reduce the variation among them, the American Association for Clinical Chemistry established the National Glycohemoglobin Standardization Program (NGSP). The NGSP evaluates, sets accuracy standards, and certifies methods for the measurement of HbA1c with the goal of standardizing the glycohemoglobin test. This initiative has resulted in a substantial improvement in the comparability, reliability, and precision of assay methods. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) work group on Standardization of HbA1c then developed a reference measurement procedure that has been approved by all IFCC member societies. The fact that HbA1c is now recommended for diagnosis of diabetes and prediabetes reinforces the requirement that HbA1c results be accurate. More specifically, constant monitoring of the analytical performance of the assay and quality control is needed to achieve the goals of intra-laboratory CV <2% and inter-laboratory CV <3.5%.
The DCCT established the importance of another key laboratory measurement in type 1 diabetes. C-peptide is a stable and detectable non-functional cleavage product of insulin found in serum. Measurement of C-peptide is used to monitor endogenous insulin production in people with diabetes who are receiving exogenous insulin as therapy. There is increasing evidence, including data from the DCCT study, that preservation of even a low level of endogenous insulin production in people with type 1 diabetes is associated with significantly fewer diabetes complications. DCCT participants with measurable C-peptide were able to achieve better glycemic control with less risk of hypoglycemia and had fewer long-term complications of diabetes. These data suggest that functional preservation of endogenous insulin production as assessed by C-peptide has clinical benefit. Typically, the new onset type 1 diabetes patient can expect to see their endogenous insulin production (as measured by mixed meal-stimulated C-peptide) decline over the first 1-2 years after diagnosis, as residual insulin producing beta cells are lost to autoimmune destruction. Therefore, recent trials of clinical interventions in new onset subjects are designed to delay progression of beta cell loss and preserve C-peptide production or to delay its decline over 1 to 2 years. Preservation of C-peptide production at 1 or 2 years as a clinical trial endpoint has been accepted by the FDA.
Measuring C-peptide levels with highly sensitive and standardized methods is therefore important now to accurately implement and interpret clinical trials to identify therapeutic interventions capable of reversing or delaying progression of the disease at onset. C-peptide measurements are also important for research that seeks to disrupt the disease process before symptoms appear. It has been recently demonstrated that the new therapeutic, teplizumab, first shown to preserve C-peptide in new onset clinical trials, also delays progression to symptoms when given at the prodromal Stage 2. Improving, harmonizing, and standardizing C-peptide measurements continue to be important as additional interventions and combination of agents are tested for clinical benefit.
To assist in C-peptide assay harmonization, an ADA endorsed C-peptide standardization committee was established and international C-peptide comparison studies were conducted. As a result of many years of comparison studies using pure C-peptide standards and patient samples, the committee concluded that patient samples work best to improve comparability and calibration among assays, and to reduce variability. More recently, a LC/MS reference method for C-peptide was developed and used to improve comparability of results. A second reference laboratory procedure is also underway to fulfill the requirements of manufacturer acceptability to list the reference method with the Joint Commission on Traceability in Laboratory Medicine. Newer studies seek to develop improved direct detection methods including LC/MS and make them applicable to research clinical laboratory settings.
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