National Heart, Lung, and Blood Advisory Council August - September 2021 Meeting Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

NATIONAL HEART, LUNG, AND BLOOD ADVISORY COUNCIL MEETING SUMMARY

August 31 – September 1, 2021

The 294th meeting of the National Heart, Lung, and Blood Advisory Council (NHLBAC) convened virtually on Tuesday, August 31, 2021, and continued on Wednesday, September 1, 2021. In addition to NHLBAC members, the meeting included an ad hoc Board of External Experts (BEE), scientists with research expertise in National Heart, Lung, and Blood Institute (NHLBI) mission areas, who were recruited for this meeting as a special NHLBAC working group. On Day 1, the Council meeting began at 12:02 p.m. and ended at 5:35 p.m., EDT. The meeting was open to the public between 12:02 and 3:15 p.m. Working groups of the NHLBI Council convened between 3:15 and 4:30 p.m. On Day 2, the Council met in open session from 10:00 a.m. to 12:00 p.m., EDT. The working groups met briefly between 12:00 to 1:30 p.m. The open session reconvened from 1:30 to 2:42 p.m. to hear reports and recommendations from each working group. Dr. Gary H. Gibbons, Director of NHLBI, presided as chair.

NHLBAC Members Attending
Jennifer E. DeVoe, D.Phil., M.D.
Grace Ann Dorney Koppel, J.D.
Martha U. Gillette, Ph.D.
Garth Graham, M.D., M.P.H.
David H. Ingbar, M.D.
Monica Kraft, M.D.
Kiran Musunuru, M.D., Ph.D.
Mohandas Narla, D.Sc.
Dean Sheppard, M.D.
Kevin L. Thomas, M.D.
Andrew S. Weyrich, Ph.D.
Zachariah P. Zachariah, M.D.

Ad Hoc BEE Attendees
Michelle A. Albert, M.D., M.P.H.
Judy L. Aschner, M.D.
Timothy S. Blackwell, M.D.
Annetine C. Gelijns, Ph.D., J.D.
Nadia N. Hansel, M.D., M.P.H.
Bertha Hidalgo, Ph.D., M.P.H.
Darrell N. Kotton, M.D.
Elizabeth McNally, M.D., Ph.D.
Brian S. Mittman, Ph.D.
Matthias Nahrendorf, M.D., Ph.D.
Ellis J. Neufeld, M.D., Ph.D.
Laura Kristin Newby, M.D.
Bruce M. Psaty, Ph.D., M.D., M.P.H.
Susan Redline, M.D., M.P.H.
M. Celeste Simon, Ph.D.
Herman A. Taylor, Jr., M.D.
Griffin M. Weber, M.D.

Members of the Public Attending
Some 200 members of the public were present.

NHLBI Employees Attending
Several NHLBI staff members were present.

I. CALL TO ORDER

Dr. Gary H. Gibbons, Director of the National Heart, Lung, and Blood Institute (NHLBI), called the meeting to order at 12:02 p.m. He welcomed members of the National Heart, Lung, and Blood Advisory Council (NHLBAC) and other attendees to this joint meeting.

II. ADMINISTRATIVE ANNOUNCEMENTS

Dr. Laura K. Moen, Director of the Division of Extramural Research Activities at NHLBI, introduced the session, stating that the main topic is optimizing clinical trials and noting that presentations will be web-cast live for the public.

III. DIRECTORS REMARKS

Dr. Gibbons explained that as part of NHLBI’s integrative approach to strategic visioning, this annual meeting was an opportunity to reflect and brainstorm to keep that vision evergreen and shape Institute-initiated priorities. This meeting responds, in part, to the National Institute of Medicine’s assessment of the clinical trial enterprise—namely, that there are long delays from research ideas to proposals to research outcomes; suboptimal participant accrual and retention; and regulatory and risk management challenges. Dr. Gibbons encouraged attendees to challenge the NHLBI in identifying new ways to think about its clinical research enterprise, and how its  investments could be more effective in supporting the NHLBI strategic vision. The overarching charge for this meeting was to consider innovative ways to optimize the clinical research enterprise and enhance efficiency, collaboration, inclusion, and impact.

IV. PCORnet: ENHANCING & EVOLVING COMPARITIVE EFFECTIVENESS RESEARCH

Ms. Penny Mohr, Acting Director of the Patient-Centered Outcomes Research Institute (PCORI), and Dr. Adrian Hernandez, Vice Dean and Executive Director of the Duke University Clinical Research Institute, and Co-Principal Investigator of the PCORnet Coordinating Center, described how PCORnet advances PCORI’s goal of improving decision-making to advance health outcomes while reducing costs. PCORnet is not a repository of data, but a health community of systems and investigators (e.g., people, infrastructure, aggregated data, trust), enabling investigators to avoid having to rebuild infrastructure at the start each new study. PCORnet aims to bring people together and engage patients.

This national research network, comprising more than 70 research organizations in diverse settings, geography and scale, provides the flexibility needed to address particular needs irrespective of disease type. Additionally, the network builds trust by leveraging the distributive data model, which minimizes transfer of individual-level data outside of the network.

Key findings for research infrastructure include: use of templates, hybrid approaches, and a standing community of sites to speed site activation, cohort identification, and outcomes ascertainment; collaborative governance to help build trust; patient and community engagement  early and often; as well as recognizing the critical role of health system leadership. PCORI anticipates hosting webinars to find ways to build out the data network, evaluate social determinants of health (SDOH) and patient-reported outcomes, and enhance access to public claims.

Comments from NHLBAC and attendees were as follows:

• Understanding patient preferences could improve the participation rate, which averages about 2% of those eligible. PCORnet creates teams from that community.
• Investigators should not reach back to people who contributed to their last study, but engage new partners.
• PCORnet’s breadth enables it to funnel tens of millions of people to a study, making it a great resource for research on rare diseases.
• To attract participants, rural or urban, investigators must be able to make the case to the patient that researchers have their best interest in mind.
• The frequently reported data breaches and misinformation campaigns have eroded trust.
• Federally Qualified Health Centers are very under-resourced, and their involvement depends on their priorities in serving their communities.
• A variety of electronic health records (EHRs) are required. A local site must be able to load and transform their data in the common data model. This depends on using local tools, which must be customized.
• One aid to advancing young investigators is having them partner with successful investigators.

V. THE MAKING OF NCI-MATCH

Dr. Alice Chen, Director of the National Cancer Institute (NCI), explained how leveraging the centralized functions in the National Clinical Trials Network supports NCI-Molecular Analysis for Therapy Choice (MATCH), a precision medical trial exploring treatment of patients based on the molecular profile of their tumors. MATCH opened in August 2015 and  is currently evaluating 694 patients, with representation from all ethnic groups, in some 1,100 participating sites throughout the United States, including 30 lead academic sites participating in phase 2 and phase 3 trials.

MATCH’s success relies on involving young investigators as principal investigators (PIs); levels of evidence for drug variants; planned interim analysis; constant oversight (e.g., weekly meetings); biopsy and lab analyses flexibilities; and the ability to close arms as the landscape changes. Correlative studies are ongoing with multiple projects having been developed using the data from this trial.

NHLBAC and attendee comments during the discussion included the following:

• MATCH treated patients individually according to their tumor features, whereas the
  I-SPY network sequentially tested a class of agents as they became available.
• The MATCH arms were designed so that if a drug was approved to treat a particular cancer, it was excluded; if a higher-priority trial was opening, histology was used to determine the trial a patient would join.
• MATCH launched in a time of single-cell sequencing and adapted as technology evolved.

VI. CHARGE FOR THE WORKING GROUPS

Council and expert attendees were asked to consider innovative ways to optimizing clinical trials with the goal of enhancing efficiency, collaboration, inclusion, and impact. Overall, the working groups were charged to weigh in on the structures of clinical trial models and to:

• advise the NHLBI on opportunities to advance and build upon the Strategic Vision in the rapidly evolving and cross-cutting area of the design of clinical trial models 
• engage the NHLBAC and others as representatives of the NHLBI research community in breakout sessions to tackle challenging topics
• develop a series of breakout group report-outs to be presented to the plenary group, which includes a final summary of the forum discussion and anticipated next steps

VII. LESSONS LEARNED FROM THE NHLBI: CONNECTS/ENDEVOR

Dr. Amy Patterson, Deputy Director of Clinical Research and Strategic Initiatives at NHLBI, moderated this panel discussion. Panelists were Dr. Yves Rosenberg, Branch Chief of the NHLBI; Dr. Antonello Punturieri, Program Officer in the Division of Lung Diseases at NHLBI; Dr. Clyde Yancy, Chief of the Division of Cardiology at Northwestern University Feinberg School of Medicine; and Dr. Robert Harrington, Chair of the Department of Medicine at Stanford University.

Prior to the COVID-19 pandemic, NHLBI initiated Enhancing the Design, Evidence Base, and Monitoring of NHLBI Clinical Trials (ENDEVOR), an integrated set of management tools controlling and monitoring the mainframe software development lifecycle. During the COVID-19 pandemic, the Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (CONNECTS) was created in an effort to halt virus progression and speed patients’ recovery. The two are complementary approaches relevant to all NHLBI trials.

CONNECTS succeeded in: accelerating site activation and recruitment; enabling networks capable of site expansion; developing an adaptive platform design that permitted adding and removing potential therapies; supporting a multi-platform approach for analysis of shared therapeutics; real time collaborative interaction with the U.S. Food and Drug Administration; sufficient capitation to expedite study set-up; as well as an infrastructure and methodology that promoted diversity and inclusion.

CONNECTS engaged over 6,000 patients via it’s more than 700 sites, including 20% from underrepresented populations. Human capital made it possible to bring a network of networks together. In effect, the spirit of the investigators for collaboration and cooperation changed the practice of medicine in a single year.

In 2016, NHLBI initially reengineered its clinical trial FOAs to adopt a milestone-driven, biphasic approach to its awards.  In 2019, the FOAs were further revised to emphasize the Institute’s expectations regarding a systemic review of current clinical practices; ample scientific evidence base for trial hypothesis; and justification for proposed clinical trial designs, including equipoise.

VIII. WORK GROUP REPORT-OUTS AND DISCUSSION

Each working group addressed the charge with respect to its given area of focus.

Group A: Optimizing Inclusion in Clinical Trials

Dr. Laura Newby summarized the responses to the key questions for Group A.

• How should the NHLBI think about different clinical trial models to make them more relevant to public health?
  • Facilitate partnering with institutions to share resources, which will also provide investigators early in their careers with opportunities for experience beyond what is available through their home institutions.
  • Use opportunities for nesting clinical trials and participating outside the structure.

• How can the NHLBI promote and support equity in clinical trials for participants; how can infrastructure support rather than impede participants’ ability to participate?
  • Network at both the institution and investigator level, perhaps leveraging Clinical and Translational Science Awards.
  • Partner with less-experienced investigators and make smaller institutions the prime.
  • Use investigators’ medical and research institutions to disseminate knowledge.
  • Provide additional funding to integrate early-stage investigators (ESIs) into clinical trials, as is done with P-grants.
  • Create an infrastructure that minimizes participants’ burden by including indirect costs, such as for centralized resources for administrative support, transportation, and staff to handle recruitment and community engagement.
  • Train investigators in administrative and other management matters.

• How can we access populations and institutions not traditionally included in clinical trials?
  • Recruit from existing epidemiologic cohorts, including older populations.
  • Provide adequate funding to support inclusiveness at all levels.
  • Use personalized behavioral approaches (e.g., a MATCH template).

• How can we address hesitancy and mistrust about clinical trial participation, particularly among underrepresented groups?
  • Establish trust and expand reach through education and information.
  • Increase the budget for community engagement.
  • Reach populations not involved through investigator engagement and commitment.
  • Be prescriptive in application requirements, such as adding a separate criterion score asking that ages of participants reflect the actual epidemiology of the condition.

Group B: Optimizing Clinical Trial Adaptiveness, Efficiency, and Translational Advances

Dr. Ellis Neufeld summarized the responses to the key questions for Group B.

• What are ways to provide support for important changes to increase efficiency and flexibility in trials?
  • Maintain flexibility to study heart, lung, blood, and sleep (HLBS) research questions across diverse populations.
  • Encourage use of master protocols, such as PrecISE.
  • Make technological strategies that have been successful in one area available across the NHLBI.
  • Link clinical trial participants to administrative networks, as important clinical outcomes be 5 to 10 years in the future, so.
  • Apply the same considerations to prevention trials as to treatment trials.
  • Include patients as members of the team designing a trial.

• Are there new infrastructures and technologies that would make each stage of the clinical trial process (recruitment, retention, study visits, virtual assessments, outcome ascertainment, etc.) faster, more efficient, and less burdensome?
  • Include non-technological means because not everyone has access to technology.
  • Use Implementation Science methods in trial designs.
  • Use technology as a conduit for referrals of clinical patients to research.
  • Use master protocols in the outpatient arena.
  • Use remote follow-up for patients.

• Are there lessons learned from the COVID-19 pandemic on opportunities to innovate how clinical trials are conducted?
  • Ensure that development and approval are rapid.
  • Use technology for remote studies.
  • Identify, review, assess, and repurpose existing infrastructure to meet emerging needs.
  • Keep some of this infrastructure ready for future emergencies.

• Can we leverage practice networks, private practices, health systems, EHR, health clinics, and traditional healers to answer important questions?
  • Consider initiatives to investigate innovative ways to use EHRs for research purposes.
  • Leverage large cohorts, such as All of Us.
  • Be sure site leadership reflects the populations of interest.
  • Use practice settings to better reveal SDOH.
  • Engage private practices with networks and leadership from the beginning.

• How can we integrate and/or adapt existing clinical research networks to enhance efficiency and impact?
  • Incorporate lessons and methods of Implementation Science.
  • Improve data access and other network resources for non-network participants.
  • Communicate research goals and outcomes to the community early and often.

• What are the barriers to successful uptake of potential technologies, infrastructure changes, and efficiencies to optimize clinical trials, and what strategies can be implemented by the NHLBI to address those barriers?
  • Invest in capacity-building.
  • Involve patients more.
  • Use infrastructure that includes home visits.
  • Educate and clarify objectives and outcomes to facilitate understanding the process.
  • Streamline contracting needs.
  • Consider funding Implementation Science.
  • Consider having experienced sites serve as mentor sites for investigators and leaders. Develop templates for research agreements, data sharing, bio-specimen collection and sharing, and regulatory cooperation.

Group C: Fostering the Next Generation of HLBS Clinical Trialists

Dr. Bertha Hidalgo summarized the responses to the key questions for Group C.

• How can the NHLBI attract clinical trialists representative of the U.S. demographics?
  • Use virtual technology for mentorship, training, and collaboration.
  • Leverage existing models and partnerships, such as with PCORI.

• How can the NHLBI support the investment and training for a diverse group of investigators to learn how to conduct HLBS clinical trials, and provide them opportunities to do so?
  • Promote stable funding for junior faculty through capitation-independent funding.
  • Use foundation grants, such as from the American Heart Association and the Doris Duke Foundation, or National Institutes of Health mechanisms that do not require U.S. citizenship.

• How should the NHLBI support training of non-traditional staff (e.g. community members) to participate in the conduct of clinical trials?
  • Explicitly state and offer incentives in FOAs to include ESIs and community members.
  • Include funding for community partners.
  • Partner with patient advocacy groups for clinical trials.

• How can the NHLBI support training investigators in approaches to enhance diversity and community engagement in HLBS clinical research?
  • Provide access to experts via national networks to address geographic and racial disparities for training.
  • Bridge the gap between pay and independent grant funding in relation to payment structure.
  • Promote community involvement that provides training opportunities.
  • Fund national networks to include formal plans for training to share expertise.
  • Encourage inclusion of patient advocacy groups in review of FOAs.

• How can we sustain engagement of diverse clinical trial investigators, not only in the early career stages but through mid-career as well?
  • Provide mid-career funding and create mechanisms for trainees to be supported.
  • Create an academic environment that promotes the needed diversity.
  • Recognize support from industry to develop clinical trialists.

• How can the NHLBI nurture the next generation of trialists in developing the skills required to conduct trials across the spectrum of trial types, from early phase, through efficacy, effectiveness, to dissemination and implementation trials?
  • Enhance the flexibility of RO3/R21s and offer mechanisms like K24s or K18s.
  • Offer micro-grants for explicit groups to bolster the science to obtain larger grants.
  • Encourage use of smaller studies or projects so junior investigators can publish manuscripts before the main product is published years later.
  • Include ESIs in larger grants/networks to provide training and experience.

Group D: Optimizing Engagement and Responsiveness to Communities to Enhance the Impact of Clinical Trials

Dr. Garth Graham summarized the responses to the key questions for Group D.

• How can the NHLBI invest in promoting community engagement—including patients, community health centers, and society at large—in all stages of clinical trial design and conduct to enhance understanding and responsiveness to local conditions and community priorities?
  • Identify key phases of the research process, then identify opportunities in each phase and create a framework for ensuring patient and community engagement.
  • Ensure that PIs become advocates.
  • Seek community leadership early and often.
  • Demonstrate and document understanding of and commitment to community needs by taking steps such as establishing advisory boards and holding workshops.

• How and when should the NHLBI seek input from community leadership regarding the research concept, rationale to establish common grounds, and concerns?
  • Engage early and have ongoing relationships with the community.
  • Develop research networks by building on relationships developed during the pandemic.
  • Gain understanding of community needs and existing infrastructures.
  • Ensure that FOAs and the review processes require proof of community input and engagement.
  • Ensure that the NHLBI peer review process is focused on community needs.

• How can the NHLBI support the infrastructure needed to enhance engagement of community members throughout the design and conduct of clinical studies?
  • Establish advisory boards, hold workshops and town halls, expand existing mechanisms, and support community-level bodies.
  • Disseminate FOAs.

• What can the NHLBI do to enhance the understanding of research (“research literacy”) by participants and community?
  • Take guidance from PCORI when developing new approaches.
  • Focus peer review on community needs and resources.

• How can the NHLBI support developing and sustaining partnerships beyond traditional healthcare or public health and its infrastructure?
  • Ensure that those who need funding the most get it.
  • Employ community members.
  • Enhance understanding of the research and create infrastructure to bring the benefits of the research back to the community.
  • Develop and sustain partnerships.
  • Create partnerships to reach people.

DISCUSSION

Several common themes for all four groups include: early and frequent community engagement; importance of establishing trusting relationships; fostering research network transparency; and exploring opportunities to nurture and sustain a well-trained clinical research workforce..

CLOSING REMARKS AND ADJOURNMENT

Dr. Gibbons thanked everyone for the rich dialogue and discussion to expand and enhance the clinical trials research enterprise.  Dr. Moen thanked everyone and adjourned the meeting at 2:42 p.m.