Sleep deficiency and untreated sleep disorders threaten the health of 20-30 percent of US adults through an increased risk of stroke, hypertension, diabetes, inflammatory disease, and all-cause mortality. Developing the scientific evidence-base of validated interventions will enhance the management of cardiometabolic and pulmonary risks to health, present new opportunities for secondary prevention, and reduce associated burden on health care systems.

Improving sleep health through informed public recognition of decision-relevant science, and relatively low cost therapies for management of sleep disorders are available for immediate assessment of impact in appropriate clinical trials to demonstrate efficacy and effectiveness.
Discovery research advances implicate an array of cellular sleep and circadian mechanisms in pathophysiological pathways leading to cardiometabolic and pulmonary disease.

Irregular and disturbed sleep impairs cellular biological rhythm in all tissues and organs leading to oxidative stress, unfolded protein responses, and impaired cell function. The pathophysiological findings juxtaposed with epidemiological evidence of disease risk indicate that sleep deficiency contributes to an erosion of health across the lifespan over and above the effects of aging.

A primary focus on principles of psychology may result in significantly improved control of the obesity epidemic. Effective interventions could reduce the risk of diabetes, sleep apnea, and hypertension. This research could also affect clinical practice guidelines for weight loss and obesity treatment.

Psychological science has been successful in developing effective treatments for a number of conditions, including sleep disorders, depressive symptoms, anxiety and phobias. Many of the behavioral principles employed in such interventions (e.g., cognitive restructuring, motivational methods) could be translated for the prevention and treatment of obesity within a reasonable time frame. Additional attention should be directed to the needs of population subgroups in which obesity is most prevalent.
In their Viewpoint article on weight loss intervention research, Pagoto and Appelhans (JAMA, 2013, see attachment) question whether a continued focus on dietary factors in research on weight loss and obesity is warranted. Their commentary raises the importance of attention to the individual psychological characteristics that influence adherence to weight loss interventions rather than dietary composition.

Many of the malignant and non-malignant blood diseases that fall under the purview of the NHLBI are uncommon though, in aggregate, important contributors to the burden of disease in the US population. Although in some areas, like blood and marrow transplantation (BMT), there exists an infrastructure for multicenter trials, in many areas there does not. This makes testing potentially effective therapies very difficult. The large increase in the number of national BMT trials following the implementation of that network indicates the effectiveness of the approach, which could be expanded to include cellular therapies and other novel approaches.

The current R01 process does not lend itself to efficient and rapid implementation of trials to test new approaches or to the time needed to complete trials that focus on long-term survival and quality of life endpoints. Even within the existing transplant network, efficiencies could be gained by infrastructural enhancements like a common IRB or government-assisted contracting (i.e., CRADAs), a streamlined process for protocol review (e.g. a one- versus two-step process), etc. Additionally, enhanced ability to collaborate with other organizations or institutes, without undue bureaucratic burden, would allow better use of NIH funds so that more trials could be done.

The work and support provided to date have allowed for the creation of an infrastructure for both the CTSN and PHN. Each network is now providing valuable results to the cardiothoracic surgery specialty which will allow an increase in quality patient care in the years and decades to come. The continued support is essential for the success of these networks as any reduction will limit the resources available for site participation and ultimately results. Due to the existing infrastructure for each network, the financial burden associated with de-funding and then restarting the networks in future years would be at least triple the financial commitment currently in place.

Conducting multi-center clinical trials is a substantial financial commitment but a vital part for the future of the cardiothoracic surgery specialty.

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.

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.

Efficient translation of clinical observation into discovery science, and, particularly, the timely translation of potential therapeutic target identification into the treatment of rare diseases has been impeded by the reality that rare disease populations are often too small to be studied using “classical” epidemiology, clinical trial, and implementation science methodology. Overcoming these barriers will require both the adaptation of current clinical research methods and the development of novel methodologies. The requirement for better methods in rare disease clinical science will become even more urgent with time as systems biology more specifically defines and sub-characterizes ‘common’ heart, lung, blood, and sleep disease populations

This problem has been recently addressed through special initiatives in the application of small trial methodology into the planning and design of clinical trials in rare hemostatic disorders and sickle cell disease. Furthermore, small clinical trial methodologists have begun to populate the CTSAs and Regulatory Agencies. Their expertise in clinical trial design and biostatistical methods, and their creative ideas can be brought to bear in the clinical trials required to advance NHLBI scientific priorities.

Developing tools to facilitate and streamline the day-to-day performance of clinical trials would help investigators and NHLBI alike. Trials would recruit more quickly, at less cost. We could, therefore, potentially fund more trials. In addition, if we have common templates, this would facilitate a number of things ranging from peer review to IRB submissions, and would also be beneficial to new investigators by providing a framework for them to use.

Some of it will involve 'just doing it' - for example, we have the capability now to require common protocol and informed consent formats. We have sufficient data to develop performance milestones and implement them. The hardest part will be figuring out how to develop pools of patients, or with which organizations to collaborate in order to achieve this. However, 5-10 years should be ample for this and related activities.
For example, we need to emulate and collaborate with other organizations in figuring out how to identify large numbers of patients willing to participate in our trials. We need performance milestones and metrics, and we need tools like common templates for protocols and informed consent forms that all NHLBI-funded trials would use.

The failure to resolve the debate about what is the appropriate goal for treatment of systolic hypertension could adversely effect the progress we have made in reducing the level of systolic blood pressure among the one third of adults with hypertension. At the heart of this debate is what is the optimal balance between lowering systolic blood pressure versus causing adverse consequences in those who are being treated for hypertension.

Because the existence of large clinical research networks with electronic medical records and use of generic drugs, all mean that a large pragmatic trial is definitely feasible.
Despite fifty years of clinical trial research and forty years of national guideline activity, important clinical questions remain under intense scientific debate. The importance of these questions is underlined by the scientific consensus that hypertension is the most important cardiovascular risk factor globally, in fact, more important than even tobacco use. Further hypertension research could be important because of the role of hypertension not only in CVD, but also in chronic kidney disease, stroke, and possibly in dementia and age related cognitive decline.

• Reduce mortality and morbidity
• Improved quality of life
• Higher proportion of people receiving evidence-based care and at goal for that care
• Reduced disparities in health and healthcare

Challenges:
• Lack of research methodology in this area – may need new scientific approaches

• Lack of current capacities and capabilities in this area

• Current silos that separate research enterprise from industry, as well as NHLBI from other ICs

• Divisions between performance of clinical trials and implementation research

• Lack of clarity which federal agencies and NIH Institutes are ‘in charge’ of implementation and/or prioritize this as part of their mission and budget

• Lack of wide sharing of best practices of other implementation models

• Improving the science in this area needs to include methods and metrics development

• The accumulated knowledge of clinical trialists and implementation researchers is often not shared

In various blood disorders, including hematologic malignancies, there are both inherited and somatic genetic alterations that contribute to predisposition, transformation, disease progression, responsiveness to therapy, and treatment complications. The presence of such genetic alterations underscore the need for the identification of rare but traceable mutations as well as the integration of such genomic information into clinical trials. By implementing a few structural changes in the healthcare sector, a clinical trial infrastructure can be established that accounts for proper application of sequencing technology. Some examples include the creation of genome diagnostic networks that address accrual of sufficient patients, procurement of suitable tumor/non-tumor material for sequencing, as well as pharmacodynamic and correlative biology studies in hematologic diseases.

The ability to identify factors, both ahead of time, and during the trial, that will predict the success of the trial would permit considerable efficiencies for NHLBI. We should be able to select a group of trials that will be able to recruit on time and within budget. For others where there may be less chance of success, we may want to invest time and resources in mentoring the investigators (e.g., in the case of new investigators), or in helping to redesign the trial. This latter function could be especially helpful during the pre-application process.

NHLBI has developed a critical mass of expertise in portfolio analysis, and is working on developing the IT tools to match. This area was identified as a high priority by the internal IMPACT Task Forces at their recent retreat, so there is also widespread interest in this approach as well.

Improve the efficiency of clinical trials and a return on research investments

Yes, this is feasible.

• Assure that early stage translation research will be suitable for implementation in real world setting
• Aligns the research interventions from T1-T3 research to those appropriate to T4 research
• Potential to focus early stage research in key high burden areas
• Provides research community an understanding of the connections from early stage to late stage translation research which will potentially refine research strategies and directions at all levels

• Promote the importance of translation to population of heart, lung, blood, and sleep researcher to broader research community
• Potential for more T4 research contributions for guiding investment into translation research from T1-T3
• Provide avenues for T1-T3 investigators to translate their ideas into positive outcomes for population health
• Successful T4 research will stimulate feedback loop and identify opportunities for early translation research

If successful this approach should enable the conduct of cheap pragmatic trials that are fueled by data from clinical care. The integration into clinical care helps assure efficiency and generalizability of results.

The advent of electronic medical records and the explosion of big data technology has made it possible to gain access to and analyze data in a manner that would have been unthinkable 10 years ago. This is already going on in other fields.
Health care systems are increasingly using "big data" approaches to track outcomes in the patients treated with different strategies and drugs, and apply the knowledge gained from outcomes in previous patients to inform decision making in subsequent patients ("learning"). This approach could be used to personalize treatment. A recent example from cancer is to genotype lung tumors, and tailor the treatment of a new patients to drugs producing good results in patients with similar tumor genotypes. When two or more treatments produce similar results, one could randomize. Cardiovascular disease presents a challenge in using genotyping information to personalize treatment, because the manifestations are the results of complex genetic and environmental risk factors.