HHS SBIR RFA-HL-14-010
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HHS SBIR RFA-HL-14-010
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:
- Low-cost, including materials and reagents.
- Compact, low-weight, portable size that can fit in a back pack or handbag (no large electricity-dependent instruments needed to perform the test).
- Sensitive (very low false-negative rates) and specific (very low false-positive rates), and accurate when there are co-existing conditions such as nutritional anemia (e.g., iron deficiency), and parasitemia due to malaria.
- User friendly design and instructions for use (simple to perform by persons with little training).
- Minimal and either non-invasive (e.g., buccal swab) or minimally invasive (e.g., finger or heel stick to obtain 2-4 drops of blood sample) specimen procurement.
- Rapid analysis at the first visit.
- Robust use without the need for special storage, e.g., provide results within minutes to hours as opposed to days; and able to perform multiple tests in a day.
- Battery-driven or solar-powered devices are especially desirable.
- Device should be operable in extreme temperatures and humidity.
Must provide significant improvement over the currently used solubility test.
- The current solubility method has sensitivity of 45% and a positive predictive value of 33.3% (Okwi et al., 2010 (Clinics in Mother and Child Health, 7(1):1205-1210, 2010). Acceptable devices should provide values exceeding at least 60% for each of these two parameters. The overall diagnostic accuracy should exceed 90%.
- The current solubility test fails to detect HbS in persons with severe anemia (Package Insert from the Sickledex® solubility test). The POC device should overcome this limitation.
Research examples include, but are not limited to:
- Low-cost, high-resolution, portable MRI that can be held adjacent to nail beds or sclera to assess blood rheology.
- Low-cost, easy-to-use, portable lateral flow immunoassay (LFIA) POC blood test cassettes that provide results at the time of testing and use highly specific monoclonal antibodies (MAbs) to sickle hemoglobin (HbS), normal adult hemoglobin (HbA), and potentially HbF and HbC.
- Nucleic acid amplification testing (NAAT) of saliva or blood combined with a simple, compact, low-weight means of detection device.
- Blood Card Technology that facilitates collection of specimens and reading on site or at a “central” laboratory.
- Developing hand-held self contained POC device to perform flow through immunoassay.
- Digital microfluidics.
- Low-cost, low-power, portable, hand-held connective PCR for analysis of blood.
- Density-based cell separation technique for blood samples.
- Lab-on-a-film: combines PCR and microarray hybridization for analysis of blood or saliva samples.
- Handheld pipette (Millipore® Scepter) to analyze RBC morphology or a selected biomarker.
- Use of cell phone or satellite phone technology to analyze specimens and transmit data.
Phase I Activities:
- Development of the essential components of the proposed technology.
- Demonstration of the feasibility of the technology.
- Characterization of the performance characteristics of the device including cross-reactivity, precision, specimen collection and handling conditions, assay cut-off point(s) and accuracy of the method.
- Test the device using a set of standards acceptable to the US regulatory authorities under Premarket Notification (510k) or Premarket Approval (PMA).
- Test the device using samples with known sickling disorders to demonstrate: (1) high specificity to HbS and HbA; (2) high sensitivity by identifying HbS when there are co-existing conditions such as elevated HbF, severe anemia, etc.
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:
- Test the device in low resource settings using a targeted subject population.
Phase II and Fast-Track applicants interested in pursuing clinical trials in low resource regions are encouraged to contact the NHLBI program staff.