Goal 2: Reduce Human Disease

Risk-benefit of oral hypoglycemic medication in type 2 diabetes

Is an increase in macrovascular endpoints outweighed by the benefit in microvascular end points in new oral type 2 diabetes drugs?

 

It would go against the current regulatory paradigm in type 2 diabetes. Although drug companies do not like the current paradigm, they would prefer to go back to the pre-rosiglitazone state of affairs, in which new drugs had only to prove that they lowered blood glucose and HbA1c.

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Trials along this line would create a new and more rational paradigm to evaluate the cardiovascular safety of new oral hypoglycemic agents in type 2 diabetes in the context of their incremental benefit in preventing microvascular complications.

Feasibility and challenges of addressing this CQ or CC :

Some of the newer oral meds for treating type 2 diabetes, starting with rosiglitazone, have shown no benefit on clinical macrovascular end points, particularly heart failure. The FDA has responded to this by requiring new drugs to undergo large non-inferiority trials demonstrating that these drugs cause no more than a 30% increase in macrovascular endpoints as a precondition for approval. Yet there is no requirement that microvascular events (renal dysfunction and failure, neuropathy, retinopathy and visual loss) even be documented in these trials. So we are allowing new agents like alogliptin and sitogliptin to be marketed without any direct evidence that they do anything good for patients other than lowering glucose and HbA1c levels and with some evidence of adverse CV effects. While it is reasonable to assume that surrogates like lower glucose and HbA1c will translate to reduction in microvascular events, this assumption is based on old studies using different classes of drugs in a different disease population and environment. Even if HbA1c and glucose remain good qualitative surrogates, there is no way to quantitatively compare benefits versus risks of new hypoglycemic drugs compared to placebo or other drugs. Novel statistical methods to look at weighted composites of microvascular and macrovascular endpoints would enable the key question of net benefit to be addressed with a reasonable sample size.

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

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9 up votes
16 down votes
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Goal 2: Reduce Human Disease

Utilizing Competition to Enhance NHLBI’s Clinical Trial Enterprise

During this period of diminishing Federal resources and funding, what novel methods can be employed to effectively conduct clinical trials that address existing and emerging medical and public health issues?

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

Addressing thecritical challenge would improve clinical trial design, clinical trial efficacy and ultimately completion and reporting of trial results. This approach would most likely save money.

Feasibility and challenges of addressing this CQ or CC :

The Other Transaction Authority already exists within the PHS and NIH and this method has been tested at NCI.

Competition is an important element of successful achievement in everything from sports rivalries to scientific innovation. Examples of this can be cited for the Larry Bird and Magic Johnson hoops competition, Muhammad Ali versus Joe Frazier boxing duels, and the contest between the Human Genome Project and Celera for completion of the mapping of the human genome. The US Defense Advanced Research Project Agency (DARPA http://www.darpa.mil) has used the concept of competition to advance the development of never before imagined scientific and technological innovations including development of the internet, the SIRI voice recognition system, UNIX and the cloud, and the global positioning system, among many products and innovations. Under this paradigm great advances are initiated through a public challenge which brings competitors together to achieve a goal set by the government. This is accomplished through the use of the Other Transaction Authority (OTA), which has been extended to the NIH. Subsequent management of the challenge involves the setting of milestones and utilization of “go/no go” decision making. The NCI has used a “DARPA-like” approach to instill competition for the design and conduct of clinical trials and as a result has substantially improved the performance of its clinical trials networks / cooperative groups.

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

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-1 net votes
6 up votes
7 down votes
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Goal 2: Reduce Human Disease

Life-Course Approach to Science

We encourage the NHLBI to include research focused on children as a priority in their strategic vision. We encourage them to consider the implications of a life-course approach, where childhood presents a unique opportunity to set the trajectory for health risk as an adult. This also implies that interventions targeting children may have the greatest impact on the population as a whole in the long term.

Submitted by (@nhlbiforumadministrator)

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

Name of idea submitter and other team members who worked on this idea : American Society of Pediatric Nephrology (ASPN)

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2 net votes
2 up votes
0 down votes
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Goal 3: Advance Translational Research

Multicenter trials of therapies for rare diseases.

Infrastructure for performing research in rare diseases should be enhanced to allow efficient accrual to multicenter trials.

Submitted by (@marymh)

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

Details on the impact of addressing this CQ or CC :

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.

Feasibility and challenges of addressing this CQ or CC :

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.

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

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80 net votes
114 up votes
34 down votes
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Goal 1: Promote Human Health

Non-opioid management of pain

The use of opioid agents has increased dramatically in the United States. Prescription drug overdoses now account for more deaths than traumatic injuries in the 1-44 age group. There is a need for more high level evidence to target optimal pain management strategies in the acute (ED) and non-acute settings (office practice) especially for chronic disorders such as low back pain, headaches, fibromyalgia, acupuncture etc. ...more »

Submitted by (@dayam0)

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

Details on the impact of addressing this CQ or CC :

Huge problem in the US compared to other countries where opioid use is more restricted. Potential to enhance population health and reduce accidental death.

Feasibility and challenges of addressing this CQ or CC :

Complex since affecting by many factors and groups that would need to work together in conjunction with patients to change the way we approach pain.

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

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6 net votes
6 up votes
0 down votes
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Goal 3: Advance Translational Research

Improving Drug Safety through Precompetitive Research

The lack of transparency in Pharma clinical studies and the incomplete knowledge of the effect of genetic profiles and pharmacological factors on drug toxicities are challenges in decreasing drug development costs and increasing drug safety.

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Precompetitive research and collaborations directed at improving our understanding of the factors underlying adverse patient responses to investigational heart, lung, blood, sleep drugs will help to expedite the drug development process, increase probabilities of success and reduce product development costs.

Feasibility and challenges of addressing this CQ or CC :

Several public-private initiatives such as The Predictive Safety Testing Consortium and the Cardiac Safety Research Consortium are underway that address components of this problem. NHLBI can join existing initiatives or formulate its own. In either case, NHLBI’s participation as either an honest broker or a funding source will enable substantive progress on several fronts over a 5-10 year period.

Clinical safety complications and chronic exposure toxicities are a major cause of drug trial failures and recalls and thereby contribute to the high cost of pharmaceutical product development and the rising prices of commercial medicines. Safety problems can usually be attributed to the off-target biological effects of drug compounds or their metabolites. Reducing the safety risks associated with drug development will therefore require us to expand our knowledge around the pharmacological and pharmacogenomic factors underlying adverse safety events. Furthermore, adverse events that occur during clinical studies that are conducted by pharmaceutical companies are not usually shared publicly. This lack of transparency contributes to unnecessary inefficiencies and costs in the drug development process.

Mechanisms for minimizing safety hurdles in drug development include funding precompetitive applied research and promoting collaborations among companies to encourage sharing of clinical failure data.

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

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-4 net votes
13 up votes
17 down votes
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Goal 3: Advance Translational Research

Obstacles to the timely completion of clinical trials

There are numerous obstacles to the timely completion of trials, and there is a crisis in US enrollment rates. Overcoming barriers to timely completion of clinical trials would have a profound impact on accelerating research translation to improving health. Clinical investigations are necessary to advance the prevention, diagnosis, treatment and cures of human disease. The rate of basic scientific discovery has overwhelmed ...more »

Submitted by (@rebecca.lehotzky)

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

Feasibility and challenges of addressing this CQ or CC :

For comparative effectiveness trials, incentives are misaligned; it is often easier, financially advantageous and benefits practice/hospital metrics to perform tests/procedures clinically than in the context of a trial. A collaboration between NHLBI, FDA and CMS would markedly accelerate many trials by aligning incentives. There are a few small examples with some success eg, Carotid stenting. Regulatory burdens should be reduced.

 

Solutions to enrollment challenges need to address physician and participant related barriers. NHLBI and AHA could lead a public private partnership and with patient advocacy groups (eg, Research America) and the media to enhance the understanding and acceptance of participation in clinical research.

 

To advance the efficiency of clinical trials NHLBI should support investigation of methodologies such as event driven trials, adaptive design, Bayesian approaches, multiple randomized groups, group/cluster randomized trials, maximizing information from subgroup analyses.

Name of idea submitter and other team members who worked on this idea : AHA Staff & Volunteers

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6 net votes
8 up votes
2 down votes
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Goal 2: Reduce Human Disease

Adequately powered clinical trials

Pragmatic and adequately powered clinical trials are an ongoing challenge.

­Develop new tools to facilitate identification and recruitment of subjects, remote/wireless data collection, and functional measures.

Submitted by (@societyforvascularsurgery)

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

Name of idea submitter and other team members who worked on this idea : Society for Vascular Surgery

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4 net votes
5 up votes
1 down votes
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Goal 3: Advance Translational Research

Using Single Patients for Clinical Trials

To foster the IOM recommendation that every healthcare encounter contribute to a learning healthcare system, would clinical practice structured as N-of-1 trials and documented via EHR/EMR provide strong practice-based evidence?

Submitted by (@nhlbiforumadministrator1)

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

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

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-20 net votes
9 up votes
29 down votes
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Goal 3: Advance Translational Research

Advancing the science of translating evidence into practice

What are the best ways for the NHLBI to advance the evolving science of translating robust evidence into clinical practice domestically and globally? How to personalize broad research evidence for individual patients? How to predict and evaluate the impact of evidence-based interventions? How to identify implementation methods available in industry and elsewhere that work best and are most translatable in healthcare? ...more »

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

• 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

Feasibility and challenges of addressing this CQ or CC :

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

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

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13 net votes
27 up votes
14 down votes
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Goal 2: Reduce Human Disease

New Clinical Research Methodologies for Rare Diseases

What innovative methodologies applicable to small cohorts and rare outcomes can better ensure the success of clinical and implementation studies in the rare diseases affecting heart, lung, blood, and sleep?

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

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

Feasibility and challenges of addressing this CQ or CC :

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.

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

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24 net votes
37 up votes
13 down 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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66 net votes
76 up votes
10 down votes
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