Optimizing the NHLBI Clinical Trials Enterprise
Working Group on Designing Trials for Uncommon Diseases and Therapeutics
Investigators seeking to develop and conduct Phase IIB/III clinical trials in heart, lung, blood and sleep diseases are often faced with challenges that arise from issues such as the rarity of the disease, access to the target population, and sufficient clinical trial design support necessary for development of robust and competitive investigator initiated clinical trial applications to NHLBI.
The National Heart, Lung, and Blood Institute (NHLBI) convened a workgroup of multidisciplinary researchers on May 2 and 3 2016, in Bethesda, MD. The goal was to identify and provide recommendations to address the barriers to the design and implementation of Phase IIB/III clinical trials for challenging populations and indications facing heart, lung, blood and sleep investigators. Challenges include but are not limited to trials for uncommon diseases, and non-centralized patient management. The main goals of the workgroup were as follows:
- Identify key barriers to investigator and trial success
- Link barriers to gaps in training and clinical trial resources
- Make recommendations for the National Heart, Lung, and Blood Institute (NHLBI) to consider to close gaps and support both trainees and established investigators
Discussion and Recommendations
Workshop participants recommended that the following actions be explored. The participants recognized four focus areas to be addressed. Priority recommendations for each focus area are presented here:
- Develop new strategies to provide clinical trial leadership experience and mentorship to the junior investigators.
- NHLBI should consider encouraging senior investigators to incorporate junior investigators in the trials they run as part of "succession planning." One way to accomplish this goal is to encourage applicants to designate co-principal investigators for trials. To successfully implement this recommendation, grant reviewers need to accept junior investigators in key positions of clinical trial management.
- Develop a formal workforce development strategy that will result in exposure and mentorship of junior investigators during the course of the clinical trial design and trial operations. One approach is to give the junior investigator recognition of their experience in peer review of subsequent applications. Establishment of small grants to pair junior investigators with senior investigators may serve to encourage the commitment of senior investigators to mentorship and help maintain protected time.
- Develop a list of core competencies for clinical research, and set up formal training opportunities through master’s degree programs and American Society of Hematology (ASH) training.
- For large, multicenter NHLBI funded Phase IIb or Phase III clinical trial awards, a clinical research apprenticeship for training junior investigators could be included in applications along with clear descriptions of the trainee’s role in the trial.
- Small grants (R03, R21, R34) can enable recently completed K recipients to maintain clinical research activities and avoid getting "pulled" into the clinic. These grants could be used for the beginning of the investigator’s independent work and pave the way to the first R01, or R01 equivalent, funded clinical trial.
- Develop new strategies to address the needs of mid-level investigators lacking Phase II or III multi-site clinical trial leadership experience and expertise.
- Develop intense but brief training for mid-career investigators to help develop expert clinical trialists.
- Identify a way to give mid-level academicians recognition for their efforts as site PIs in multi-site trials or other trial experience. The acknowledgement of these contributions in publications may be part of the means to accomplish this objective.
- More flexible mid-career apprenticeship-type opportunities are needed. Exposing investigators who are running small trials to large clinical trial project management, through their inclusion on management team teleconferences may be one element to improve mid-level investigators knowledge base. Another is to provide ongoing and interactive institutional and national resources to mid-career people to expand and improve their clinical trial management skills.
- Improve infrastructure and resources for clinical trial development and management.
- Consider providing a resource, modeled on the Clinical Trials Development Resource for Hematologic Disorders (U24), but with a broader scope that encompasses the scientific interests of NHLBI.
- Investigate new models to provide infrastructure to academic medical institutions with less Phase IIb/III trial experience. Institutions that have expertise in traditional and/or innovative clinical trial design, statistical analysis and trial implementation, may be interested.
- Develop a network of clinical trial mentors. The best clinical trialists have expertise that applies to trials in any field.
- Build learning communities—an organic research infrastructure—to support interaction and accountability in our research community.
- Find pathways to leverage other NIH clinical trial initiatives such as the NCATS’ Trial Innovation Network.
- Electronic health records should be leveraged to determine where the patients are and what studies are feasible at which institutions. Natural history and epidemiologic studies can also identify places where patients are available. For trainees and early career investigators, support could be provided (e.g., by CTSAs) to utilize such available resources for development of their clinical research programs.
- Implement metrics and develop quality improvement processes for investigators, institutions, programs, and trials.
- The NHLBI may consider involving more experts in specific clinical disorders and innovative trial designs, especially for rare diseases, to be part of the institute clinical trial review process to address perceived barrier to the review of smaller trials requiring alternative design or analysis strategies.
- Master’s degree programs and small-group approaches (e.g., retreats, workshops) for ongoing training and skills development in clinical research may be helpful.
- A trial does not end with a publication; it is important to ensure the T4 translational step occurs.
The co-chair, Dr. Ellenberg said that visionary leaders can be catalysts for trials. She recounted the story of Dr. Bernie Fisher in the 1970s who inspired many surgeons around the country to randomize their breast cancer patients to simple mastectomy or radical surgery. He inspired women to participate in trials and allow researchers to select their treatment by flipping a coin. Dr. Ellenberg posed the question "How can we develop more clinical trialists to be like Bernie Fisher and move the fields of HLBS research forward through innovation and perseverance?"
To summarize, the overall vision expressed by the work group was for a future in which the NHLBI transforms trial conduct by supporting an interactive learning community around clinical trials of blood disorders, in contrast to the current approach that is centered on supporting individual studies. Various means were discussed to achieve the NHLBI’s goals. It is hoped that this discussion will prove helpful to the NHLBI in re-designing its approach to trials of uncommon diseases and therapeutics.
Susan S. Ellenberg, Ph.D., University of Pennsylvania Perelman School of Medicine
Suresh Vedantham, M.D., Washington University School of Medicine
Eugene Blackstone, M.D., Case Western Reserve University
Diane Catellier, Ph.D., RTI International
Marianne S. Clancy, R.D.H., M.P.A.; HHT Foundation International
Ed Connor, M.D., M.B.E., Clinical Research Alliance, LLC
Susan Geyer, Ph.D., University of South Florida
Michael B. Jordan, M.D., Cincinnati Children's Hospital
Fedor Lurie, M.D., Ph.D., University of Michigan and President, American Venous Forum
Sarah O’Brien, M.D., M.Sc., Nationwide Children’s Hospital
Jeff Sestokas, M.S., Children’s National Health System
Mark Walters, M.D., Children's Hospital and Research Center
Deepika Darbari, M.D., Children’s Research Institute
Alice Kuaban, M.S., American Society of Hematology
Amanda Kasper, MPH, Children’s National Health System
Amy Patterson, M.D., NHLBI Director of the Scientific Research Program, Policy, and Strategic Initiatives
W. Keith Hoots, M.D., Director, Division of Blood Diseases and Resources
Donna DiMichele, M.D., Deputy Director, Division of Blood Diseases and Resources
Jacqueline Corrigan-Curay, M.D., Office of the Director
Pablo Cure, M.D., M.P.H., Division of Blood Diseases and Resources
Nancy DiFronzo, Ph.D., Division of Blood Diseases and Resources
Simone Glynn, M.D., Division of Blood Diseases and Resources
Malgorzata Klauzinska, Ph.D., Division of Blood Diseases and Resources
Andrei Kindzelski, M.D., Division of Blood Diseases and Resources
Traci Mondoro, Ph.D., Division of Blood Diseases and Resources
Lisbeth Welniak, Ph.D., Division of Blood Diseases and Resources