To support a transition towards a precision medicine approach to treatments, the NHLBI in partnership with the Cardiovascular Medical Research and Education Fund (CMREF) organized a workshop to address the barriers, gaps and opportunities to applying precision medicine to PVD including pulmonary hypertension. The workshop generated recommendations to the NHLBI for future research priorities in this area in line with NHLBI Strategic Vision Goals.
This workshop was timely to leverage the anticipated scientific output from the recently launched “Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics” (PVDOMICS) program with the Precision Medicine Initiative. PVDOMICS is supporting collaborative, protocol driven, comprehensive, deep phenotyping across all groups of PH patient populations in order to define novel pulmonary vascular disease (PVD) phenotypes. As such, new cohorts will emerge for testing: a) currently available drugs in those predicted by molecular phenotype to be the most responsive and b) novel therapies derived from our increasing mechanistic understanding of disease. Stakeholders in PVD need to be brought together (scientists, clinicians, patient advocacy organizations, regulatory agency representatives, and pharmaceutical industries) to discuss the current needs, challenges, and new opportunities in applying precision medicine to PVD clinical research and treatments. Critical protocol elements including diagnostic tests, biomarkers, and meaningful outcomes need discussion to develop PH interventional trials using a more granular, phenotype-based disease classification.
The workshop addressed multiple topics that are central to the development of true personalized medicine in PVD, including inputs from all the stakeholders, from basic science, to drug development to clinical trials to master protocol. Each expert addressed the needs in their area of expertise to advance the field. The overall goal was to identify needs, and make recommendations for future progress.
Key areas addressed
- Applying precision medicine to PVD: The NHLBI perspective.
- Current gaps and needs in applying precision medicine for PVD: clinical trials issues.
- Current needs for a precision medicine approach to PVD: patient perspective.
- Current challenges and barriers in clinical trials in PVD: The FDA perspective.
- Current pharmaceutical industry interest, capacity and constraints in PVD.
- Novel biomarkers for clinical diagnosis and treatment of PVD; gaps and opportunities.
- Genetic phenotypes of PVD, how to develop for personalized medicine.
- Novel imaging of the lung and heart: gaps and opportunities for phenotyping.
- Redefining endpoints and outcomes that are needed for PVD clinical trials.
- The biostatistical challenges facing a precision medicine approach in PVD clinical trials.
- The application of big data analytics and deep clinical phenotyping for PVD management.
- Learning from existing registration trials to better define phenotypes.
- Applying novel systems biology approach to the clinical care of PH.
- The Master Protocol in Oncology: Lessons learned from Oncology.
- A national effort should seek to co-ordinate bio-samples and bio-data from all funded programs to a web based repository so that information can be shared and correlated with other and all research projects. This is an effort that will pay off for decades.
- Example programs include PVDOMICS, Pulmonary Hypertension Breakthrough Initiative (PHBI), the National Biological Sample and Data Repository for PAH and other projects where bio-samples are collected and biological data are stored.
- This effort is especially true for genomic data which should be coordinated with the National Precision Medicine Initiative so that large genetic databases can be used to detect genotype-phenotype relationships.
- A taskforce of stakeholders to develop a master clinical trials protocol for PVD that will apply precision medicine principles to future interventional clinical trials should be created with development of a template for phase II and phase III clinical trials as the goal. It is anticipated that PVDOMICs project data will be a source of precision approaches.
- Outcome measures that incorporate patient needs and preferences should be identified in PVD, and included, in future clinical trials along with traditional medical outcomes measures such has hemodynamic changes and 6 min walk.
- The development of precision medicine initiatives will alter the size and composition of clinical trials, requiring the adoption of adaptive and innovative statistical design. For agents seeking regulatory approval, FDA will need to provide guidance on acceptable trial designs.
- Development and testing of newer meaningful endpoints, both primary and secondary. Current endpoints are unsatisfactory to all stakeholders, because they are currently designed for a statistical significance that may not reflect important patient responses. There is a need for new endpoints that represent well-defined and clinically meaningful changes which accurately reflect whether a drug is working in a given patient. Future trials should incorporate secondary endpoints that inform not only if a drug is effective but where it is working and how it is working.
- Continued development of imaging, hemodynamic, cellular, genomic and metabolic variables that will identify patients for their individual features. Such development should be hypothesis based where possible to reveal differences that can lead to trials development and personalized medicine whose effects can be objectively measured.
Future clinical trials to evaluate therapies for PVD with a precision medicines approach will need a common platform that satisfy the needs and concerns of regulatory authorities, industry, patients, and clinicians. This master protocol would target a patient population that will be defined by novel phenotyping based on validated studies over a broad range of biomarkers including clinical features, proteomics, metabolomics, and genomics. It will incorporate advances in trial design science to allow for a precision approach that includes adaptive and enrichment strategies and should address important concerns of academia by selecting appropriate endpoints which reflect meaningful treatment effects, inform the mechanism of drug effect, and reveal any disease modifying effects.
- Stuart Rich, M.D., Northwestern University
- John H. Newman, M.D., Vanderbilt University
- Adrian F. Hernandez, M.D., Duke University
- Anna Hemnes, M.D., Vanderbilt University
- Declan Doogan, M.D., Independent Consultant
- Evangelos D. Michelakis, M.D., University of Alberta
- Evelyn M. Horn, M.D., Cornell University
- Franz Rischard, M.D., University of Arizona
- Gerald J. Beck, Ph.D., Cleveland Clinic
- Greg D. Lewis, M.D., Massachusetts General Hospital
- Grier Page, Ph.D., RTI International
- Hunter Gillies, M.D., Independent Consultant Pharmaceutical Physician
- Hyung J. Chun, M.D., Yale University
- Jane A. Leopold, M.D., Brigham and Women's Hospital
- Jocelyn Dupuis, M.D., Ph.D., University of Montreal
- John H. Alexander, M.D., Duke University
- John Barnard, Ph.D., Cleveland Clinic
- Jonathan Rich, M.D., Northwestern University
- Kendall Hunter, Ph.D., University of Colorado
- Mark Geraci, M.D., Indiana University
- Mark Gladwin, M.D., University of Pittsburgh
- Marlene Rabinovitch, M.D., Stanford University
- Michael P. Gray, MPH, Pulmonary Hypertension Association
- Nicholas S. Hill, M.D., Tufts University
- Raymond L. Benza, M.D., Allegheny Health Network
- Robert P. Frantz, M.D., Mayo Clinic
- Roger Johns, M.D., Ph.D., Johns Hopkins University
- Roy S. Herbst, M.D., Ph.D., Yale University
- Sanjay Kaul, M.D., Cedars-Sinai Medical Center
- Sanjiv J. Shah, M.D., Northwestern University
- Scott S. Emerson, M.D., Ph.D., University of Washington
- Serpil C. Erzurum, M.D., Cleveland Clinic
- Sharon Rounds, M.D., Brown University
- Stephen Y. Chan, M.D., Ph.D., University of Pittsburgh
- Stephen C. Mathai, M.D., MHS, Johns Hopkins University
- Steven H. Abman, M.D., University of Colorado
- Steven Kawut, M.D., University of Pennsylvania
- Steven D. Nathan, M.D., Inova Fairfax Hospital
- Tim Lahm, M.D. Indiana University
- Todd M. Bull, M.D., University of Colorado
- Vallerie V. McLaughlin, M.D., University of Michigan
- Victor F. Tapson, M.D., Cedars-Sinai Medical Center
- William Nichols, Ph.D., Cincinnati Children’s Hospital
- Zhi-Cheng Jing, M.D., FuWai Hospital, PUMC & CAMS
- James Kiley, Ph.D., Division of Lung Diseases
- Gail Weinmann, M.D., Division of Lung Diseases
- Lei Xiao, M.D. Ph.D., Division of Lung Diseases
- Naomi Lowy, M.D.
- Norman Stockbridge, M.D., Ph.D.