Goal 1: Promote Human Health

Study wellness instead of diseases by longitudinal follow-up of frequent and long term blood donors

Blood donors (especially young donors) in general represent healthy populations. Longitudinal follow-up of frequent and long term blood donors can be useful to establish data and sample sources for the study of wellness, instead of disease (especially for blood diseases). Not only it can be used as healthy controls, it can also be used to predict the wellness factors such as genetic variation, life style, exercise patterns, ...more »

Submitted by (@yanyunw)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Once such study is established, it can be used as a wellness model/control for many diseases and conditions. The longer we have the study, more useful it will become. This can help us to change or optimize our health care model, from treating diseases to maintain wellness.

Feasibility and challenges of addressing this CQ or CC :

This can be quite feasible as there are many frequent and long term donors. They care about others’ health as well as their own health. They are also very willing to support research. Follow-up can start from early adulthood.

 

With funding support this can be achieved.

Name of idea submitter and other team members who worked on this idea : Yanyun Wu

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Goal 2: Reduce Human Disease

Mitigating risks due to the RBC storage lesion and vulnerable patients

What are the underlying dependencies (genomic, metabolic, disease) in individual donors that either accelerate or delay the changes to red blood cells during refrigerated storage? What methods of preparation might protect patients from the risks posed by the accelerated degradation of RBCs provided by "poor storers"? What characteristics of individual patients make them particularly vulnerable to transfusion of red ...more »

Submitted by (@andrew.dunham)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The changes in red blood cells during refrigerated storage have been well documented and associated with negative clinical sequelae in the peer reviewed literature. While the impact of this so-called storage lesion does not impact every patient during every transfusion it is reasonable to expect that when a unit of blood is transfused to a particularly vulnerable patient from a donor that has red blood cells pre-disposed to degradation, stored in a manner that has allowed significant change to occur, the risk of a negative clinical sequelae is increased. In this case it will be important to understand what underlies the likelihood of a donors blood to store poorly, the changes that occur during storage that could impact vulnerable patients and design approaches to mitigate the degradation that could result.

Feasibility and challenges of addressing this CQ or CC :

We believe mitigating the impact of the storage lesion is feasible by reducing and controlling the oxygen concentration in the RBC unit prior to refrigerated storage. We are continuing our development of a device to do this and to generate the data demonstrating the effect of deoxygenation and anaerobic storage.

Name of idea submitter and other team members who worked on this idea : Andrew Dunham

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Goal 3: Advance Translational Research

Comprehensive Assessment of Cardiovascular Physiology: Imaging of Structure, Function and Blood Flow

The development of cardiovascular disease is associated with changes in structure, function and blood flow within a complex and highly interconnected system. Current diagnostic tools focus on individual elements of the cardiovascular system and/or relatively simple parameters which do not reflect the true underlying pathophysiology. A novel multi-modular and multi-parametric approach based on new and promising imaging ...more »

Submitted by (@mmarkl)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

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Goal 3: Advance Translational Research

To find specific medical therapies to treat the wide array of human vascular malformations and vascular tumors.

Vascular malformations and vascular tumors, together referred to as vascular anomalies, comprise a complex and wide array of diseases in which there is a fundamental disruption in blood and lymphatic vasculature. The lesions disrupt organ function, destroy tissue, cause bleeding, increase infections and can threaten life. At present, there are some medical therapies but none are specifically targeted to an underlying ...more »

Submitted by (@joyce.bischoff)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Deciphering the cellular and molecular basis of human vascular anomalies will have a critical impact for patients with these lesions and it will also have a broad, far-reaching impact on cardiovascular research because the mechanisms and insights learned from these specific vascular anomalies will teach us the fundamental rules that are needed, and must be followed, to build and maintain a stable functional vasculature in humans. This will have an impact on a variety of areas of research including regenerative medicine.

Feasibility and challenges of addressing this CQ or CC :

With the enormous advances in next generations sequencing technologies, the time is ripe for a concerted push to find the gene mutations that cause human vascular malformations and vascular tumors, both the most common and the rare. Cellular models for human endothelial cells are vastly improved and far superior to murine endothelial models, making research on patient-derived cells highly feasible.

The challenges will be to develop animal models of the individual human vascular anomalies that reflect as closely as possible the critical and specific features of the vascular malformation or vascular tumor. Such animal models, as well as relevant cellular in vitro models, would then be ideal for screen drug libraries for ability to reverse or slow the formation of the malformation or tumor. Such drugs might then be candidates to test in pilot clinical trials.

Name of idea submitter and other team members who worked on this idea : Joyce Bischoff

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20 up votes
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Goal 3: Advance Translational Research

Tools to facilitate availability and safe use of innovative blood products and their analogs

Novel blood products are being developed based on innovative science (e.g., ex vivo manufactured RBC and platelets, and platelet and plasma derived hemostatic products). However, there is a significant lag in the development of appropriate tools and model systems, which poses a challenge when evaluating such products for regulatory approval.

Submitted by (@chintamani.atreya)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

The rapid advancement in science and technology has identified pathways for ex vivo manufacturing of RBC and platelets; platelet and plasma derived hemostatic products and recombinant coagulation factors, etc. However, these novel products have to be evaluated for their safety, efficacy, purity and potency as part of regulatory approval process. Because the new products are manufactured using innovative technologies some of the existing tools for their evaluation are inadequate. Therefore, future investments in the development of necessary predictive tools (I.e. regulatory science tools) in areas such as the following will positively impact the availability and safe use of innovative blood products and their analogs: 1) the development of analytical and biochemical assays, 2) animal models for product safety and efficacy, 3) product quality-associated biomarkers to characterize storage lesions of RBC and platelets and 4) functional assays and molecular and bioinformatics models that can predict the success of novel blood products both during manufacturing and with respect to clinical patient outcomes.

Feasibility and challenges of addressing this CQ or CC :

This initiative is feasible as investigators in blood organizations, academia and government are already working independently towards this goal in their defined areas of study. However, a coordinated effort among these independent entities could help in the faster development of necessary regulatory science tools to optimize care of individual patients and patient groups.

Name of idea submitter and other team members who worked on this idea : Office of Blood Research and Review, CBER, FDA

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Goal 3: Advance Translational Research

Develop alternatives for patients for whom routine red cell transfusion is unavailable or impractical

There is a compelling need to advance research to understand the physiology governing the safety and efficacy of hemoglobin-based oxygen therapeutics functioning outside the red cell.

Submitted by (@chintamani.atreya)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Adequate numbers of red blood cells are required to sustain human life. Neurocognitive deficits and mortality in acutely anemic humans increase significantly at a hemoglobin level of below 5 g/dL even in the absence of significant cardiovascular disease. At extremely low hemoglobin levels, alternative treatments (supplemental or hyperbaric oxygen, sedation, muscle paralysis and mechanical ventilation) are of only limited benefit and are not without risk. Several classes of patients cannot be routinely transfused with red blood cells. These classes of patients for whom blood is not an option would include patients who will not accept transfusion for religious or personal reasons, patients who due to multiple prior transfusions have developed red cell antibodies without the option for compatible red cells, and massive trauma patients needing treatment in a remote location. The development of cell-free hemoglobin-based oxygen carriers, stable at room temperature and not requiring cross-matching prior to transfusion as a red cell substitute, has been a sought after goal for several decades, yet to date all attempts have met with failure during clinical trials. There is a compelling need to advance research to understand the physiology governing the safety and efficacy of hemoglobin-based oxygen therapeutics functioning outside the red cell.

Feasibility and challenges of addressing this CQ or CC :

Multiple physiologic insults and adverse events seen with earlier modified hemoglobins, compared to banked red blood cells, have been described and are now better, but not completely, understood. Advances in hemoglobin modification could allow for successful use in a variety of clinical scenarios with life-saving results. Additional clinical indications could be investigated and established, such as identification of clinical situations where additional oxygen delivery could modulate the effects of chronic ischemic conditions. In addition, the hemoglobin molecule could be modified to deliver additional therapeutic benefit.

Name of idea submitter and other team members who worked on this idea : Office of Blood Research and Review, CBER, FDA

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Goal 2: Reduce Human Disease

Development of right ventricular-targeted therapies in pulmonary arterial hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. A great increase in the treatment armamentarium has been noted for this rare disease in the past 20 years, with 12 new PAH-targeted therapies. Though these therapies do improve cardiac performance, this is most likely due to their primary ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Since 2006, 12 medical therapies for PAH have been approved by the FDA, which have increased survival of this rare disease from around 2.8 years to approximately 9 years; these therapies primarily act by dilating the pulmonary arteries in order to reduce pulmonary vascular resistance to blood flow. However, patients continue to die from right ventricular failure, highlighting the important relationship of the pulmonary arterial system and right ventricle (RV). Despite patients ultimately dying from RV failure, little is known about the effect of the currently available PAH-targeted therapies on RV functional support. Prostacyclins, PDE5i, and sGC agonists are thought to enhance RV contractility—though the long-term effects remain unknown—while ERAs are thought to reduce it. The direct RV effect of some potential therapies targeting the pseudo-malignancy theory of PAH is a concern, as these therapies seek to reduce the hypertrophy and angiogenesis that may actually be supporting the adapting RV. Further, therapies targeting the ventricle directly have historically been centered on the LV—for example β-adrenergic receptor blockers and RAS inhibition—and either remain controversial or without data in the RV. There remains no identified RV-specific therapy to either provide support through increase contractility or molecularly prevent the progression from RV hypertrophy to ultimate failure.

Feasibility and challenges of addressing this CQ or CC :

The primary challenge of addressing this CC on the lack of RV-targeted therapies for the treatment of PAH is the comprehensive analysis and support that will need to be provided, spanning from basic to clinical science. To begin, strong support of biologic characterization of the right ventricle needs to be provided. The RV is distinctly different from the more comprehensively studied left ventricle, and subsequently responds differently to autocrine, paracrine, neuroendocrine, pressure, and pharmaceutical changes to name only a few. However, when identified, these RV biologic distinctions can be translated and tested clinically to more comprehensively and appropriately treat the RV-arterial uncoupling ultimately leading to right heart failure: through both reduction in afterload and an increase in contractility.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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75 up votes
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Goal 2: Reduce Human Disease

In pulmonary arterial hypertension (PAH), how can right ventricular function be improved in the setting of increased afterload

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. Significant improvements have been made in medical management with through approved pulmonary vasodilator therapies. However, long-term right ventricular afterload reductions have still not yet been achieved. The process by which the ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Understanding of many components of the PAH disease state have evolved significantly in the past thirty years. When initially described by an NIH registry, in a time where pulmonary transplantation was the only treatment for PAH, the average life expectancy of PAH patients was estimated to be 2.8 years. Since then, 12 PAH-targeted therapies have been approved by the FDA; these therapies primarily act by dilating the pulmonary arteries in order to allow blood to flow easier through the pulmonary vascular system. Despite these advances and complex therapies, long-term afterload reduction is not achievable in most PAH patients. Patients continue to die from right ventricular failure, highlighting the important relationship of the pulmonary arterial system and right ventricle. Little is known about how and why the RV progresses from hypertrophy to full RV failure, the diagnostic signs indicating early RV failure, and how best to intervene to support the failing ventricle. Knowledge in this area is critical, however, as the RV is able to recover in many patients with severe PAH after lung transplantation. The relationship between the lung vasculature and cardiac function, and specifically a characterization of RV failure, was included as a research opportunity in the Strategic Plan for Lung Vascular Research in an NHLBI-ORDR Workshop Report (Erzurum S, et al. 2010).

Feasibility and challenges of addressing this CQ or CC :

The primary challenge of addressing this CQ on how right ventricular function can be improved in the setting of increased afterload is the comprehensive analysis and support that will need to be provided, spanning from basic to clinical science. To begin, strong support of biologic characterization of the right ventricle needs to be provided. The RV is distinctly different from the more comprehensively studied left ventricle (LV), and subsequently responds differently to changes in pressure, neurotransmitters, hormones, and pharmaceutical therapies to name only a few. However, when identified, these RV biologic distinctions can be further explored to develop a better understanding of RV failure and potential points of intervention.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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72 up votes
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Goal 2: Reduce Human Disease

How can we increase the pharmaceutical clinical research of targeted therapies in pediatric PAH patients, including encouraging

Clinical research, especially randomized pharmaceutical clinical trials, poses many unique challenges compared to research in adult subjects. In pulmonary arterial hypertension, a disease characterized by high blood pressure of the lungs with increased pulmonary vascular resistance leading to right ventricular failure, there are 12 FDA-approved PAH-targeted therapies for adults. None of these medications are currently ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Pulmonary arterial hypertension is a heterogeneous condition generally characterized by high blood pressure in the lungs and increased pulmonary vascular resistance that leads to right heart failure if left untreated. Though some causes of PAH are seen in both adult and pediatric populations, some etiologies are seen exclusively in pediatric populations, including persistent pulmonary hypertension of the newborn, bronchopulmonary dysplasia, lung hypoplasia, and alveolar capillary dysplasia. Despite these differences in disease etiology, and known physiologic differences in pediatric populations, inhaled nitric oxide (iNO) in the acute setting is the only approved medication for PAH treatment in children. A number of issues have decreased pediatric PAH pharmaceutical research, including protection of the pediatric population as vulnerable subjects, principle of scientific necessity, balance of risk and potential benefit, parental consent/child assent, and feasibility of pediatric clinical trial design and implementation. Encouraging clinical trials of existing adult medications and potentially emerging, novel agents specifically for pediatrics—either through direct sponsorship or regulatory incentives—would not only lead to better outcomes for pediatric PAH patients, but potentially to a better and more comprehensive characterization of the developing pulmonary vascular system and right ventricle.

Feasibility and challenges of addressing this CQ or CC :

Several challenges exist for addressing this critical challenge. First, there are a number of differences between conducting clinical research in pediatric populations compared to adult populations. This not only includes the broad items referenced above, but items as noted by Rose and colleagues related to clinical trial design and analysis including (1) accepted age-matched normal ranges for laboratory values; (2) requirements for the validation of clinical endpoints for the assessment of efficacy and safety; and (3) standards for long-term safety monitoring and pharmacovigilance (Rose K, et al. NEJM 2005). Sponsorship of this type of clinical research is a second concern, which could either be mitigated by direct support from the National Institutes of Health of pediatric PAH clinical trials or in regulatory changes incentivizing pediatric clinical research in rare diseases.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Goal 2: Reduce Human Disease

Would patients with pulmonary arterial hypertension (PAH) benefit from background anticoagulation in addition to their PAH-targe

Pulmonary hypertension (PH) is a complex, progressive condition characterized by high blood pressure in the lungs. For several decades, oral anticoagulation has been recommended by some societies for patients with a specific form of PH called pulmonary arterial hypertension. However, the evidence currently supporting this recommendation is very limited. To date, no prospective randomized clinical trial has been completed ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The evolution of the anticoagulation recommendation in pulmonary arterial hypertension (PAH) is a relatively logical one at face value. Early in the modern era of PAH management, a “thrombosis” in the small pulmonary arteries was identified and described; studies since then have demonstrated hypercoagulability in patients with severe disease. Together, these observations led to a theory that in-situ thrombosis contributed to the PAH disease progression and a belief that anticoagulation should be beneficial. The empirical evidence currently supporting this recommendation comes mostly from a retrospective cohort study of the European COMPERA PH registry and a systematic review of 7 retrospective cohort studies that are at least 10 years old—2 of which did not suggest a survival benefit—and in a time where only 4 of the widely used PAH-targeted therapies were approved by the FDA. Purely based on observational evidence with a number of potential biases, warfarin (Coumadin) is widely used in PAH management to this day. Warfarin in this patient population is not without its risks, as some subgroups of PAH patients are at increased risk of bleeding complications based on their disease process alone. Assessing the true benefit of this widely used background therapy could allow clinicians and patients to more accurately weigh the risks and burden of anticoagulation with a true understanding of the survival benefit.

Feasibility and challenges of addressing this CQ or CC :

Addressing this compelling question is indeed feasible through an NIH-sponsored randomized, double-blind, placebo-controlled trial of anticoagulation in patients with certain types of pulmonary arterial hypertension.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Goal 2: Reduce Human Disease

How can we non-invasively, but still accurately, measure blood pressure in the pulmonary arteries?

Pulmonary hypertension (PH) is a complex, progressive condition characterized by high blood pressure in the lungs. The gold standard for measuring pressures in the pulmonary arteries is a right heart catheterization, where a special catheter is guided through the right side of the heart and into the pulmonary artery, the main vessel carrying blood to the lungs. This measurement is essential, as it allows physicians and ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

i. In patients with pulmonary hypertension, the use of multiple tests to characterize the type and severity has long been recommended by global experts; one commonly used diagnostic algorithm recommends more than ten different tests to accurately define this complex, heterogeneous disease. Despite the algorithm used, to confirm a diagnosis of one specific type of PH, pulmonary arterial hypertension (PAH), one must always directly measure the pressures in the heart and pulmonary artery through a right heart catheterization (RHC). Complications for this procedure are rare, but not non-existent with potentially 1 in every 100 patients having a right heart catheterization experiencing a serious adverse event (Hoeper MM 2006). Patients would significantly benefit from a non-invasive method of quantifying their pulmonary artery pressures and/or disease progression, but to date this has not been possible with echocardiography due to measurement errors (Laver 2014), CT scan due in part to measurement inconsistencies (Alhamad 2011), and cardiac MRI due to lack of standardization and multicenter trials (Peacock 2013). Not only would wider utilization of a non-invasive method of measuring pulmonary artery pressures and disease progression potentially reduce the risk from RHC, depending on the modality it could lead to earlier diagnosis of this progressive disease and/or application in countries where RHC is less common.

Feasibility and challenges of addressing this CQ or CC :

Addressing a non-invasive method of measuring pulmonary artery pressures requires investment in both technology and multicenter clinical trials to validate these measures.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Goal 1: Promote Human Health

Nefarious substances in the US blood supply

Prescription and illicit drug is everpresent in the US, which can potentially result in controlled substances entering the US blood supply. Passive transfer of immune allergens is only anecdotally been reported as peanut allergens, fish allergens, and contrast material. However, US blood donors are only screened for a limited number of medications on the universal donor health questionnaire at time of collection. What, ...more »

Submitted by (@garrett.s.booth)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Of the nearly 15 million blood products collected in the US (National Blood Collection and Utilization Survey), what percent of donations capture additional substances like medications and illicit substances. Healthcare providers may be unaware of potential adverse transfusion reactions that could arise from potent allergens within the products themselves.

If additional donor screening is required to reduce the number of medications/drugs entering the US blood supply, how best to do this? Via blood toxicology, urine toxicology, hair toxicology? Is there a need to marry the donor drug history with the recipient allergy list?

Feasibility and challenges of addressing this CQ or CC :

These questions would require blood collection centers to potentially revise how they screen blood donors. How and when to probe donations or donors will require extensive medical-legal investigation.

Name of idea submitter and other team members who worked on this idea : LostInNashville

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