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From Discovery to Practice and Survivorship: Building a National Real‐World Data Learning Healthcare Framework for Military and Veteran Cancer Patients

2019; Wiley; Volume: 106; Issue: 1 Linguagem: Inglês

10.1002/cpt.1425

1532-6535

Jerry Lee, Kathleen M. Darcy, Hai Hu, Yovanni Casablanca, Thomas P. Conrads, Clifton L. Dalgard, John Freymann, Sean E. Hanlon, Grant D. Huang, Leonid Kvecher, G. Larry Maxwell, Frank Meng, Joel T. Moncur, Clesson Turner, J. Mitchell Wells, Matthew D. Wilkerson, Kangmin Zhu, Rachel Ramoni, Craig D. Shriver,

Frailty in Older Adults

The Applied Proteogenomics OrganizationaL Learning and Outcomes (APOLLO) network is implementing a prospective curation and translation of real-world data (RWD) into real-world evidence (RWE) within the learning healthcare environment of the Department of Defense and Department of Veterans Affairs. To support basic, translational, clinical, and epidemiological sciences, APOLLO will release data to public repositories for secondary analysis to assist others in assessing whether similar molecular-driven clinical practice guidelines will improve health outcomes for their relevant cancer populations. In the United States, > 80% of patients with cancer are initially diagnosed and treated in a community hospital setting rather than an academic hospital setting. Despite the increased adoption of electronic health records (EHRs), the lack of interoperable health information systems makes it challenging to aggregate RWD generated from a cancer patient's journey before diagnosis, during treatment, and throughout survivorship. RWD might include data collected as part of routine health and cancer care delivery or for research (translational, implementation science, and/or epidemiological) efforts. Longitudinal collection of RWD is essential to generating RWE and is often absent when elucidating long-term consequences of care strategies. Recent studies have demonstrated the success of individualized cancer care strategies enabled by molecular profiling and targeted therapies. In the past 2 years, the US Food and Drug Administration (FDA) has approved tumor site–agnostic, biomarker-driven cancer treatments and next-generation sequencing in vitro diagnostic devices.1 A parallel review process by the Center for Medicare & Medicaid Services led to a national coverage determination next-generation sequencing-based in vitro diagnostics. The rapid development and approval of such technologies underscored this widening gap in capturing real-world use of molecular-driven cancer care to generate RWE to help inform regulatory and clinical decisions.2 Conducting valid real-world studies requires data quality assurance through auditable data abstraction methods and incentives to drive electronic capture of data during delivery of care.2 The Department of Veterans Affairs (VA) has the nation's largest integrated healthcare system with over 9 million veterans enrolled and is a high-volume provider of cancer care with nearly 50,000 incident cancer cases reported in 2010.3 The VA Office of Research and Development has as its three major priorities to: (i) enhance veteran access to multisite clinical trials, (ii) make VA data a national resource, and (iii) increase the real-world impact of research findings. The VA Office of Research and Development's national Cooperative Studies Program4 and data resources enable researchers to access and identify initial cohorts for further studies to advance RWD analysis have been leveraged through partnerships with federal collaborators to further a learning health care system within the VA. The Department of Defense (DoD) Military Health System (MHS) is responsible for maintaining the health and readiness of 1.7 million active-duty and reserve service members (SMs) and caring for 9.4 million beneficiaries in TRICARE health benefit plans. The John P. Murtha Cancer Center at Uniformed Services University and Walter Reed National Military Medical Center offers a comprehensive cancer care operational view in 64 capability areas to proactively mitigate and close gaps in cancer care and research in the MHS. The John P. Murtha Cancer Center utilizes agreements with other federal agencies and extramural collaborators to provide return on investment by deploying the most robust and modern molecular technologies under various programs. The administrative and medical care data from both direct and indirect care are stored in the military data repository, which includes detailed information on demographics, diagnoses, diagnostic procedures, prescriptions, ancillary and radiology services, treatments, cost of care, and vital status. The DoD also has a cancer registry that collects detailed data on cancer diagnosis and features, including some cancer biomarkers. These RWD have been widely used for cancer research among DoD beneficiaries.5, 6 Leveraging the two largest nationwide connected healthcare systems, the APOLLO network was launched in 2016 with the intent of curating longitudinal RWD and health outcome data to create and assess adoption of new molecular-driven clinical practice guidelines. By developing, defining, and aligning RWD elements of MHS, patients with cancer from prediagnosis through survivorship among the federal and civilian partners, the APOLLO network is implementing an integrated multifederal network for prospective curation and translation of RWD into RWE in a learning healthcare environment that will assist other payers in assessing whether similar clinical practice guidelines will improve health outcomes for their relevant populations. Previous large-scale tumor characterization projects, such as The Cancer Genome Atlas and the ongoing Clinical Proteomics Tumor Analysis Consortium, focused on analyzing the genomics and proteomics profile of tumors at a single time point.7 The lack of focus on longitudinal RWD collection limits the clinical utilization of these programs' data.8 APOLLO is distinct from The Cancer Genome Atlas and other previous tumor characterization projects as it was focused on integrated proteogenomic analyses, the collection of longitudinal RWD, and development of a sustainable collection pipeline from its inception. The foundation of the approach is a network of biospecimen collection sites throughout the DoD and VA plus select civilian sites. APOLLO tissue collection is infused into pathology departments to preserve patient care, optimize collections, and control for preanalytic variables while involving the local organizations as true partners. This culture of collaboration also promotes the capture of longitudinal clinical, radiology imaging, and patient data throughout patients' disease cycles that can otherwise be difficult to obtain. This culture expands to Clinical Laboratory Improvement Amendment (CLIA) laboratories, biobanking, imaging characterization, and proteogenomic analysis centers to form a robust APOLLO ecosystem that will be leveraged to enable additional longitudinal oncology studies of both established and new patients. To maximize longitudinal clinical data collection, APOLLO uniquely designed a combination of disease-specific pilot retrospective studies of hundreds of cases (APOLLOs 1–4) and prospective studies of ~ 8,000 cases (APOLLO 5). Successes and lessons learned during the implementation of these pilot projects, as well as those from past large-scale molecular and clinical studies, are being leveraged to successfully forge the APOLLO ecosystem. Central to generating RWE from RWD in combination with molecular data is the challenge of balancing effective biospecimen matching and integration of data from multiple modalities from the same patient while maintaining accuracy and privacy over time. One way the network tackled this issue was bringing together early stakeholders to develop and adopt a prospectively generated unique APOLLO participant and aliquot identifiers (APOLLO ID; Figure 1). APOLLO ID will also be linked to a 128-byte global unique participant and aliquot identifiers with an "AP-" prefix when data are uploaded to public repositories for secondary analysis. The APOLLO system is electronically supported by an enterprise informatics infrastructure, which includes a Data Tracking System (DTS-APOLLO) for transactional activities, a Data Warehouse for Translational Research for (DW4TR-APOLLO),9 and a network of connected public data repositories to support capturing, management, and delivery of RWD to the study team and the public to enable discovery of RWE. Initial pilot datasets have been successfully uploaded to the National Cancer Institute's Genomic Data Commons and The Cancer Imaging Archive (TCIA) from both VA and DoD studies. The length of patient follow-up time within APOLLO will be pre-estimated for each cancer type using prior literature rather than by duration of a funding cycle, so advanced planning will enable continued capturing of such data from both the regulatory and technical perspectives. The APOLLO program aspires to accelerate the application of next-generation proteogenomic profiling with deep baseline and longitudinal RWD from DoD and VA EHRs and research records into RWE for FDA-approved tests and treatments for development and deployment of tools and strategies used in the prevention, diagnosis, and treatment of cancer. These activities support readiness and health by empowering patients and providers to optimize their care and health through customized and enterprise solutions. The program will deploy both retrospective and prospective observational designs with provisions for clinical trial participation. Select civilian cohorts with aggressive or rare cancers will be incorporated with SMs and veterans to contribute diversity, events, experiences, and outcomes to the disease-oriented and pan-cancer cohorts to learn about, treat, and prevent cancers that develop in warfighters. Types of clinical and research RWD that will be collected by the APOLLO network are listed in Table 1. This program will require and utilize operationalized processes and procedures tracked via a user-friendly APOLLO Dashboard. Integrated analyses will incorporate a deep complement of RWD from medical and research records. Sequencing and proteomic data generated by CLIA facilities and analytical core facilities will not only be analyzed using current clinical databases but will be available for iterative reanalysis over time applying new clinical databases and trusted sources to advance reinterpretation of the patients' molecular profiling data to determine future access to new FDA-approved drugs and/or clinical trial opportunities. This program will provide data in support studies of basic science, translational medicine, epidemiology, comparative effectiveness, cost-effectiveness, and health disparities. Various data-release provisions were incorporated into the APOLLO framework, including release to repositories for future research, clinical trials, indications and guidelines, dissemination to scientists, healthcare professionals, and the public, release to study doctors when research results meet guidelines for medical consideration for follow-up and clinical assessments, and return to patients when the research results qualifies for release without clinical certification, as recommended recently by the National Academies of Sciences, Engineering, and Medicine.10 Translation of RWD into RWE is a key component of APOLLO with integrated systems for enhancing capabilities across the cancer care continuum, driving efficiencies, and enhancing quality, thereby improving health outcomes and the readiness of warfighters and the operational medical force. The full potential of APOLLO will be realized when interoperable EHRs are readily and securely exchangeable across the DoD and VA with enterprise solutions and clinical decision tools for molecular pathology, clinical imaging, patient-reported outcomes, clinical trials, serious adverse events reporting, prevention clinics, rehabilitative and other supportive services, pain management, survivorship, palliative care, end-of-life care, research, and education. Improvements in readiness, health care, and outcomes for SMs, veterans, health beneficiaries, and civilians will be achieved not only from deliverables generated by the APOLLO network but also from release of RWD and RWE to the public for secondary research. APOLLO patients may also benefit from release of research data that qualify either for clinical certification or direct release based on criteria, such as level and quality of the evidence. Federal agencies may also benefit from the generated agreements, established working groups, and taskforces with representation from the stakeholders and invited nonfederal experts, aligned resources and assets, integrated and expanded infrastructure and workforces, and the capabilities developed for APOLLO and operationalized across the DoD and VA for implementing precision oncology solutions to acquire and translate RWD from APOLLO into RWE for SMs, veterans, and the global cancer ecosystem. The authors would like to thank Joseph Shaw, Sara Sakura, Autumn Beemer Phillips, Gregory Samuel, Olga Castellanos, Jillian Infusino, and Mayada Aljehani for their critical review of the figure and paper. Funding for these efforts was provided from Uniformed Services University of the Health Sciences (USUHS) awards from the Defense Health Program to the Murtha Cancer Center Research Program (HU0001-16-2-0014, C.D. Shriver and J.S.H. Lee), the Gynecologic Cancer Center of Excellence (HU0001-16-2-0006, Y. Casablanca and G. Larry Maxwell), and HU0001-16-2-004 (L. Kvecher and H. Hu) administered by the Henry M. Jackson Foundation for the Advancement of Military Medicine. This project has also been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (J.B. Freymann). The authors declared no competing interests for this work. The contents of this publication are the sole responsibility of the authors and do not necessarily reflect the views, opinions, or policies of the USUHS, the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force, Department of Health and Human Services, or Department of Veterans Affairs. Mention of trade names, commercial products, or organization does not imply endorsement by the U.S. Government.