If animal models can faithfully predict the outcomes in human clinical trials of new medicines and treatments, it will reduce the economic burden for the failure of drug development.

Identification of current available animal models;
Development of new animal models with recent advances in mammalian genome projects and gene targeting technologies could be done over the next 5-10 years
Medical research, especially in basic discovery, has benefited significantly from the use of various animal models, such as gene-targeted and transgenic mouse models. However, many discoveries from animal models (e.g. mouse models) failed to translate into human applications.

During the past several decades there have been revolutionary changes in technology that have enabled an unprecedented understanding of basic biologic and pathobiologic phenomena. However, there has not been a concomitant increase in novel technologies to prevent, diagnose, and treat disease. While NHLBI funds thousands of R01 grants that support mechanistic research, only a small percentage moves the basic discoveries into the pre-clinical space, a critical step in fulfilling NHLBI’s mission. An analysis of the Division of Blood Diseases applications for the FY 2012, showed that while 32% (174/541) of the unsolicited applications (RO1, R21, PO1) had at least one early translational component, only 15% went beyond proof of concept and only 3% included early phase clinical trials. Patent filings, a main gateway to translation, are another way to estimate the translation of NHLBI discovery science. A survey of 90 NHLBI investigators, randomly selected across all three Divisions, found 76% of the investigators had no patent activity over a 10 year period and 12% accounted for 82% of all the patent activity. These data suggest that there may be barriers to investigators being able to realize the translational potential of promising discoveries beyond proof of concept. NHLBI needs an overarching, coordinated, and efficient plan to encourage and support investigators in their independent pursuit of translational research.

The creation of an integrated, facilitative programmatic pathway at NHLBI that would leverage existing NIH resources to ease the major barriers to translation of scientific discovery in the investigator community by:
•Providing skills development training and guidance for investigators wishing to do translational research
•Coordinating the support of all pre-IND phases of translational science
Facilitating reproducible pre-clinical research in animals, including animal and humanized models, medical chemistry, pharmacological toxicology
•Providing support for early phase or adaptive design clinical trials
•Ensuring scientific review that is available and tailored to all phases of investigator-initiated translational science
•Establishing a robust system for ongoing portfolio analysis and program evaluation as well as metrics for evaluating programmatic outcomes

The creation of an integrated, facilitative programmatic pathway at NHLBI that would leverage existing NIH resources to ease the major barriers to translation of scientific discovery in the investigator community by:
•Providing skills development training and guidance for investigators wishing to do translational research
•Coordinating the support of all pre-IND phases of translational science
Facilitating reproducible pre-clinical research in animals, including animal and humanized models, medical chemistry, pharmacological toxicology
•Providing support for early phase or adaptive design clinical trials
•Ensuring scientific review that is available and tailored to all phases of investigator-initiated translational science
•Establishing a robust system for ongoing portfolio analysis and program evaluation as well as metrics for evaluating programmatic outcomes

The overwhelming response to NHLBI translational initiatives suggests a critical mass of investigators willing and able to explore the translational potential of their discoveries. The barriers to the continuous receipt of translational applications outside of the RFA mechanism have been identified and the proposed model for a competitive peer-reviewed process that spans the early translational pipeline has already been successfully implemented in at least one other NIH Institute. Adopting this model, the pipeline, as envisioned, would mostly consist of facilitative PAs and Review would not require a major up front expenditure of NHLBI targeted funding.

Continuity of research discoveries requires that outstanding mentors impart their passion and research skills to the next generation. Opportunities and incentives must be provided to ensure that highly qualified scientists can devote adequate time and effort to mentor promising junior colleagues, as well as enhance their own research output.

Mentor-directed opportunities can be immediately made available to provide protected time and salary for scientists with a passion for mentoring.
The current K24 mechanisms have been shown to be quite beneficial, not only for the mentor who can advance his career in the academe, but more so for the trainees who are exposed to the science that the mentor brings. However, K24 awards are primarily for patient-oriented research which enhance clinical skills. Non-clinical biomedical research will also benefit from similar programs.

What is the nature of scientific knowledge? Are there enough opportunities for young scientists?

Funding of young scientists and of generalists is a challenge.

Survival of the enterprise and maintaining US competitiveness.

NIGMS has some interesting approaches that help their funding rates. Can any of these approaches be adopted more readily by NHLBI?

This would allow for rapid exploration of novel concepts. Would reduce the time and cost of doing research in the HCT field. Would allow to explore questions related to best supportive care practices in HCT

Very feasible. Last year we prepared a proposal in response to an RFA demonstrating that all elements are in place.
The CIBMTR has already shown that prospective observational studies are feasible and useful

The state of NHLBI funding rates for R01s are so low that we are undoubtedly loosing many young researchers as the fail to obtain adequate support for their research. Funding R21 grants will allow new, innovative, and perhps risky projects to proceed, while keeping less established researchers in the field. Re-establishing R21 funding may prevent the impression that NHLBI is more interested in supporting established labs and not advocating for and supporting new investigators.

Given the limited budget of R21s, they will not have as large an impact on the overall budget of NHLBI as the equivalent number of funded R01 grants. Therefore, this change is feasible from a financial standpoint. Obviously, funding R21s will decrease funding for other mechanisms. Finally, it is possible that many of these grants will not lead to advances in the field, but it is my understanding that studies show the same thing about R01s.

The current status of research training in sleep and circadian disorders suggest that new approaches are needed. The field has developed one multi-center training grant to bring training to different institutions. This is focused on genetic/genomic approaches. It is run by the University of Pennsylvania which has a well developed program in this area. The fellows in training are, however, at other institutions, i.e., Johns Hopkins, University of Michigan and Stanford. Web-based approaches are used for work-in-progress seminars, grant development workshops and group mentorship, and didactic lectures. This strategy could be used more broadly to develop research training in other areas of sleep and circadian research. Stimulating this would have a major impact on research training in this new field of medicine.

Another relevant strategy would be to encourage adding slots in a competitive way for sleep/circadian research to other existing institutional T32 grants.

There are multiple mechanisms in place to communicate opportunities to the sleep/circadian academic community, i.e., Sleep-L, administered by the National Center for Sleep Disorders Research; Sleep Research Society biweekly blog; the Sleep Research Network. Specific encouragement of this approach would broaden the base for research training and would be of high impact.

The field of sleep and circadian research has had a long commitment to facilitating research training. The Sleep Research Society has hosted Trainee Day at our annual meeting for 20 years. The Sleep Research Society is funding early-stage investigators through its Foundation. The American Academy of Sleep Medicine runs, in collaboration with the NHLBI, an event at NIH for early-stage investigators in clinical research. The American Academy of Sleep Medicine Foundation has a “Bridge to K Award” program that provides funds to early-stage investigators who just missed funding on their first application for a K award. The Sleep Research Society has provided travel funds for early-stage investigators to attend recent workshops held by different NIH Institutes including National Heart, Lung and Blood Institute. Thus, there is no doubt of the commitment of the field and its professional organizations.

The impact of these new initiatives would be to broaden the base for research training beyond a few institutions. The number of institutions with a critical mass of investigators to mount successful T32 institutional training grants is not sufficient to provide the necessary future biomedical research workforce in this area. Novel approaches, based on modern communication IT technology, are needed.

The most cost effective scientific procedure ever utilized to answer the risk benefit question posed by a new intervention to be used in humans is a clinical trial. Major clinical trials are their most effective when planted in controversial ground (MRFIT, CAST, ALLHAT). Like these studies, which were caught in a controversial dynamic of uncertainties and disparate sets of expectations, a clinical trial network to assess cell therapy is precisely what is needed.
Experienced researchers recognize the current inimical environment of cell therapy. Now - as before - some forces argue that new therapy offers no benefits, while other equally vehement constituents contend that the benefits of therapy are so great, and the risks so small, that the treatment requires little if any regulation and should be available at once to the US public. Each side provides thunder, but little light.
It is precisely in this contentious environment where passions argue beyond the data that clinical trials are required. Their construction of the most objective view of the strengths and weaknesses of the intervention comes at a cost, but the answers these well designed and concordantly executed studies provide is the clearest illuminations of the benefits and risks of human cell therapy.

Based on the unmet clinical needs in the treatment of cardiovascular disease and the compelling early evidence for the promise of cell therapy, NHLBI created the Cardiovascular Cell Therapy Research Network in 2007. Now in its ninth year, the Network has completed three major clinical trials in cell therapy. It has published 35 manuscripts in prestigious clinical journals including JAMA, Circ, and Circ Research. Its biorepository has published two manuscripts relating baseline phenotype findings to measures of left ventricular function. A fourth clinical trial is underway assessing the effect of cell therapy on peripheral vascular disease. The Network is also proceeding with the largest effort to assess the effect of CSC cells in patients with heart failure - the first clinical trial that will assess the effect of combined cell therapy in heart failure patients. In addition, CCTRN will study the effect of allogeneic mesenchymal stem cells in patients with anthracycline-induced cardiomyopathy. Each of these protocols is NHLBI and FDA approved.
CCTRN’s reputation of conducting and then promulgating the results of high quality clinical trials makes it the most effective mechanism to assess the benefits of cell therapy in cardiovascular disease. It is important to continue to fund the infrastructure already in place to ensure its continued high quality operation and its place as the cornerstone of cardiovascular clinical cell therapy research in the United States.

• Provide new knowledge for implementing strategies that will tackle inequities
• Provides opportunity to create multidiscipline research communities focused on health inequities
• Will gain momentum from federal and national implementation institutions to promote effective interventions to address health inequities

• Capitalizing on new methods, metrics and tapping big data could provide a promising platform to use systems science to better understand the barriers to eliminating health inequities in a short timeframe
• Identifying barriers will allow investigators to devise innovative implementation strategies that can reduce health inequities
• NHLBI could encourage communities of researchers to use team science to both identify barriers and link with other teams to implement strategies to reduce and eliminate barriers
• Established NHLBI health inequities Think Tank and space for developing innovative strategies to address health inequities.

We will start solving relevant clinical issues using the support of basic science

infrastructure within NIH

Congenital heart disease (CHD) is the most common congenital malformation and the most common cause of mortality during the first year of life. Approximately 70% of cases occur sporadically without a strong family history or identifiable genetic syndrome, and the primary heritable basis of most non-syndromic CHD has yet to be identified. Studies of affected kindreds, syndromic disease, and more recently genome wide association studies (GWAS) have shed light on a handful of causal loci, while exome sequencing and studies of structural variation uncovering rare de novo variants in trios have yielded only an 8-10% rate of diagnosis in cohorts with CHD. Despite the application of contemporary techniques and study design to genetic discovery in CHD, the majority of the genetic risk for human cardiac malformations remains unexplained.

One key challenge is that many of the stakeholders including those affected with congenital heart disease (children), along with the physicians make a diagnosis and referral (obstetricians, neonatologists, general pediatricians), are generally funded by other agencies (NICHD). Trans-agency collaboration and cooperation is necessary to improve the translational research structures necessary to improve disease.

Obesity and non-adherence are two of the most important yet challenging behavioral problems contributing to cardiovascular morbidity and mortality. One way to address this challenge is to fund a network of “behavior change labs,” each of which bring together teams of basic behavioral scientists who are investigating the bases of behavior and behavior change with clinical researchers interested in designing, optimizing and testing novel ideas for tackling the difficult behavior problems of obesity and non-adherence to cardiac medications.

Pain is the most common clinical manifestation of sickle cell disease (SCD) and accounts for a large proportion of emergency department visits and hospitalizations. Due to its impact on the patients’ quality of life, there is a need for more basic and clinical research studies focused on understanding the mechanisms of different pain syndromes as well as the role of neurotransmitters and inflammation in acute and chronic SCD pain. Also, comparative effectiveness studies in the management of chronic pain will be crucial in helping to improve the patients’ overall quality of life.