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The objective of this Funding Opportunity Announcement (FOA) is to support the development of a point of care (POC) device for the diagnosis of sickle cell disease (SCD) including HbSS, HbSC, HbS/ßthal0 in infants and young children in low-income and low-resource settings.
The genetic disorders of hemoglobin are the most common monogenic diseases. Approximately 5% of the world’s population carries trait genes for hemoglobin disorders, primarily sickle cell disease and the thalassemias. Although these disorders occur mainly in tropical regions, population migration has spread these diseases to most countries. The health burden of hemoglobin disorders can be effectively reduced through management and prevention programs.
The World Health Organization (WHO) has declared SCD a public health priority. The greatest burden of SCD is in sub-Saharan Africa, where 75% of the 300,000 annual global births of affected children live, and estimates suggest that 50-80% of these patients will die before reaching adulthood. The WHO estimates that 70% of SCD deaths in Africa are preventable with simple, cost-effective interventions such as early identification of SCD patients by newborn screening (NBS) and the subsequent provision of comprehensive care.
SCD can be diagnosed in newborns and infants as well as older persons by methods such as zone electrophoresis, isoelectric focusing electrophoresis, high-performance liquid chromatography (HPLC) or DNA analysis. However, these methods all require expensive equipment and are performed by highly trained laboratory technologists. On the other hand, solubility testing methods such as Sickledex and concentrated phosphate buffer are simple and inexpensive, but are not appropriate for screening purposes due to interfering factors. Currently there are no simple and inexpensive screening tests for SCD that are free of interferences or can differentiate patients with sickle cell trait (HbAS) from sickle cell disease conditions (HbSS, HbSC and HbS ß-thalassemias).
Due to advances in the diagnosis and management of SCD, there has been a reduction of morbidity and mortality in developed countries. There is evidence that neonatal screening for SCD based on timely diagnostic testing including parental education and comprehensive care, markedly reduces morbidity and mortality from the disease in infancy and early childhood. In rural parts of Africa, particularly Sub-Saharan Africa where SCD is most prevalent, many women do not give birth in medical facilities. Consequently, a SCD diagnosis is rarely made before the age of 2-3 years and many undiagnosed children die in early infancy due to potentially treatable diseases such as meningitis, pneumonia or acute anemia. Barriers to screening for SCD include the need for sophisticated and expensive equipment and the training of qualified laboratory technologists both of which are not practical due to limited health care fiscal resources in those regions.
Traditional neonatal screening for SCD would not be an effective diagnostic intervention in these low resource settings due to the high number of out of hospital births. A more pragmatic use of limited health care dollars in low income countries would involve the widespread integration of highly sensitive and specific POC testing during the infant’s/child’s first acute care visit at a local medical clinic. The implementation of a low-cost and accurate POC diagnostic device would overcome the current barriers. To accomplish this, the initial approach will be to test children for SCD at the time of acute illness, and if the child is found to have the disease, s/he will be given appropriate acute therapy and integrated into the local/national SCD healthcare system for longer term care to reduce the risk of some future complications. Once the test is developed and evaluated at the medical clinic level, POC testing could be expanded to local geographies to provide early diagnosis to a much larger group of children. In either the acute medical or local community setting, our current understanding of the disease would allow for molecular or biochemical technologies to be explored to distinguish normal, carrier and disease states.
A POC device should efficiently, inexpensively and rapidly diagnose a patient with SCD. POC testing is currently defined as testing performed close to the patient, at the time care is required. The result should enable a clinical decision to be made, leading to clinical action (e.g., treatment) if required. For POC testing to be effective, it should allow for timely intervention that leads to an improved health outcome.
Accepted technologies in this program will provide (1) high specificity to detect HbS, (2) high sensitivity by identifying HbS in the presence of elevated fetal hemoglobin (HbF), and (3) capacity to distinguish patients with sickle trait (heterozygous HbAS) from those with SCD (homozygous HbSS, heterozygous HbSC and HbS ß-thalassemias). Development of a POC device based on such technologies will allow basic health care workers to perform the assay in the field and to quickly and appropriately manage those patients with SCD.
Specifications: Specific requirements for an appropriate POC device are:
Research examples include, but are not limited to:
Phase I Activities:
Phase II Applications:
Phase II applications are required to include a steering committee consisting of appropriate experts to provide oversight and critical evaluation of the clinical development plan and its components.
Phase II Activities:
Phase II and Fast-Track applicants interested in pursuing clinical trials in low resource regions are encouraged to contact the NHLBI program staff.