Posts Tagged HealthCore-NERI

Closing Gaps in Real-World Evidence through Data Linkage

Interview with Dr. Kevin Haynes, Principal Scientist, HealthCore-NERI.

Dr. Patti Peeples, CEO of HealthEconomics.Com, sat down with Dr. Kevin Haynes, Principal Scientist at HealthCore-NERI, to discuss closing gaps in real-world evidence through data linkage. The mission of HealthCore-NERI is to provide clarity that empowers decision makers to act with precision to improve quality, safety, and affordability in health care. HealthCore-NERI works with life science companies, payers and providers, and government and academic organizations to provide real-world evidence in support of a wide variety of health care decisions.

Dr. Peeples: Why is fragmentation in health care so important to health care researchers, and specifically real-world evidence?

Dr. Haynes: The fact that patients can seek care across health care systems, may move across geographies over time, and may change health plans fragments the patient journey within the health system. This fragmentation within the US health care system creates fragmentation of health care data and this data fragmentation inhibits our ability to generate high-quality evidence. In my opinion, the biggest gap to close is a gap in data. When we close the data gap, then we can begin to close the gaps in evidence. The same gaps in data that prevent us from generating high-quality evidence also create gaps in care. These gaps are closing as Health Information Exchanges, all-payer claims databases, and data integration with prescription dispensing records feed back into electronic medical record systems. As these data gaps close, our ability to generate high-quality evidence will improve. One area of data fragmentation is in the patient journey across health care systems creating a long-term fragmentation. As people traverse a lifetime of follow up periods, we traverse periods of our lives moving from childhood to college and early careers. This creates a fluid space of data moving across health plans as jobs, spouse, and life circumstances change our insurance coverage and access to health care systems. Today we need to be developing the infrastructure to be able to address these research issues moving forward. This is a long-term game as fragmentation of health care delivery currently has an impact on our ability to conduct observational comparative effectiveness research over a lifetime. Another area of fragmentation is cross-sectional data fragmentation which occurs as we seek care across health systems. For example in cancer we invariably fragment care as we instruct patients to seek a second opinion. As such tests and work up may be contained within one health system’s electronic records and treatment and longitudinal follow-up may be contained in a second health system’s electronic record.

Dr. Peeples: What are some of the biggest issues among stakeholders (providers, payers, patients, researchers, policy makers)?

Dr. Haynes: The biggest issue for stakeholders is data privacy and the governance required to manage the use of data for various purposes. There is clear governance with regards to HIPPA and other privacy considerations that govern the research aspects of data. Often the use of observational data at the institutional level notes loss of confidentiality as the only risk to the patient, and ensures that all data will be stored on secure servers with limited access. However, we are in an era now where we need to link to other data sources to close gaps in data fragmentation. This creates a need to utilize protected health information or personal identifiable information which may increase the risk to study participants in observational research. Therefore, we need to implement the technology to improve data privacy.

Dr. Peeples: With the fragmentation of health care across health systems, what do you see as the opportunities to overcome these data fragmentation challenges to enhance real-world evidence?

Dr. Haynes: There is tremendous opportunity as there is a lot going on in the data linkage space as people develop relationships with patients. For example, researchers involved in PCORnet’s Patient or People Powered Research Networks (PPRNs), the NIH’s All of Us, and other commercial ventures – are developing relationships with patients. They are able to get and seek, not only the consent, but also the authorization to link data across resources to develop the evidence that is needed. When researchers have access to patients, it is important to obtain sufficient patient authorization to conduct these linkage activities. Other opportunities exist in the space of protecting patient privacy in observational research, such as creating privacy protection record linkage.

Dr. Peeples: How do we do the data linkage? Are there specific use cases that have been successful?   

Dr. Haynes: One must either obtain patient consent through a relationship with the patient or utilize privacy-preserving record linkage strategies. For example, patients participating in PCORnet’s ADAPTABLE study, which seeks to identify the most appropriate dose of aspirin for secondary prevention of cardiovascular morbidity – have consented to participate. The study is therefore able to outreach and obtain authorization from participants to allow their health plan to share limited longitudinal information to help address one of the data gaps with regards to this study. Among PCORnet’s demonstration studies is a large obesity observational study looking at the effect of pediatric antibiotic exposure on the microbiome and the effect of weight gain at 5 and 10 years. This study is involving hundreds of thousands of patients. Considering the impossibility of obtaining the consent of or relationship with all patients, researchers are employing privacy-preserving record linkage to facilitate linkage of health plan pharmacy claims with clinical data.

Dr. Peeples: Patient privacy is of vital importance in the conduct of data linkage. How do you conduct the research and ensure patients their privacy is not being breached? What changes have occurred over time? What do you do that is a higher bar than is necessary, if anything?

Dr. Haynes: We as researchers need to develop the trust with our patients, especially patients who are recruited and enrolled in clinical trials where we have a relationship with the patient, to seek the necessary authorizations to do these linkages. We must also ensure that these linkages are used only for that intended purpose. As such, there is a need for governance around data use. When we have a relationship with the patient, we have an obligation to educate and inform patients in things like the ADAPTABLE study, the All of Us study, potential patient registries, and others, to inform patients of the importance of the linkage and that the linkage activities will be governed in such a way as to protect patient privacy. We also have a societal obligation to ensure that any linkage activities utilizing privacy-preserving record linkage modalities protect patients and their privacy.

Dr. Peeples: Expanding on the concept of data linkage, are there disease or therapeutic areas that are particularly challenging? Or areas where this data linkage has shown success?  

Dr. Haynes: There are tremendous opportunities and areas that are particularly challenging in this space of linkage. These challenges focus on both linking longitudinally and on linking over defined time periods to get deep clinical data. One example is in the opioids space where many states have prescription drug monitoring programs (PDMP). These programs are designed to capture all of the opioid prescriptions such that providers can access this resource and ensure that they have a complete picture of exposure to opioids across health systems. Pharmacists have an opportunity to assess this system to evaluate opioid utilizations beyond their pharmacy. These systems are designed to close a gap in care. However, one challenge is that these systems are not able to be utilized by health plans to potentially close gaps in evidence. The high-quality exposure information from state PDMP and the high quality outcome data from health plans would provide an opportunity to address evidence in the opioid epidemic.

Dr. Peeples: What are the ultimate rewards of linked data resources for RWE?  

Dr. Haynes: The most important thing from an epidemiologic standpoint to linked data is to reduce what we call information bias. There are several forms of information bias, including misclassification. Therefore, capturing outcomes or exposures of interest and knowing that you have complete capture is vital to the conduct of real-world data analysis.


Dr. Kevin Haynes, PharmD, MSCE, is a Principal Scientist at HealthCore-NERI. He is the Principal Investigator on two Patient Centered Outcomes Research Institute (PCORI) awards and the site Principal Investigator for HealthCore within the FDA Sentinel Initiative as well as a Data Core Co-Lead on Sentinel. At HealthCore-NERI, Dr. Haynes is currently responsible for developing responses to proposals and providing clinical pharmacoepidemiology expertise to various projects. Dr. Haynes has more than 14 years of experience in clinical pharmacy, clinical research, epidemiology, pharmacoepidemiology, surveillance, medical informatics, and project management. In addition, he has extensive experience collaborating with the Food and Drug Administration as well as multiple investigators on pharmacoepidemiology projects.

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Changing the Clinical Trial Paradigm for Rare and Orphan (R&O) Diseases using Real-World Evidence

Interview with Flora Sandra Siami, MPH. Vice President of Clinical Research, Regulatory Affairs, and Quality Assurance at HealthCore-NERI.

Dr. Patti Peeples, CEO of HealthEconomics.Com, sat down with Flora Sandra Siami, MPH, Vice President of Clinical Research, Regulatory Affairs, and Quality Assurance at HealthCore-NERI, to discuss changing the clinical trial paradigm for rare and orphan diseases using real-world evidence. The mission of HealthCore-NERI is to provide clarity that empowers decision makers to act with precision to improve quality, safety, and affordability in healthcare. HealthCore-NERI works with life science companies, payers and providers, and government and academic organizations to provide real-world evidence in support of a wide variety of healthcare decisions.  

Dr. Peeples: Millions of people are affected by rare diseases worldwide, yet few treatments are available to address these diseases. What are some of the unique challenges that researchers face when designing a clinical trial for rare and orphan diseases?

Sandi Siami: There are many challenges unique to developing and testing treatments for rare and orphan diseases. First and foremost is understanding the natural history of the disease. Because there are a limited number of people with the disease/condition, physicians may not be aware of the most appropriate way to diagnose the condition. Even if the disease/condition is diagnosed, there may be limited clinical information available to understand the disease/condition outside of published case studies.

Once sufficient information is available about the natural history, then products can be developed to treat the disease/condition because there is some level of understanding of the disease, its mechanism of action, how it progresses, and the population it may affect, but the population is also heterogenous. However, this information is needed to design the clinical trial to define eligibility (i.e. inclusion/exclusion criteria), evaluation measures (i.e. study procedures), identify endpoints (i.e. outcomes), and lend to the statistical assumptions for the trial design/methodology.

At HealthCore-NERI, we’ve grappled with a number of these rare/orphan disease trials, and have gained substantial insight into challenges and solutions. One approach we’ve used is to arrange and execute state-of-the-science Consensus Conferences. We’ve held several of these for our clients. These are usually 1-2 day conferences with CME accreditation as put forth by the ACCME that focus on major topic areas, such as pathophysiology and diagnostic criteria, unmet need and available treatment, clinical management, and quality of life and health outcomes that related to internationally available treatment and management of the disease. These conferences present current evidence and discuss how the disease is currently treated and managed either in primary care or a specialty, as well as quality of life and potential psycho-social impact of the disease or its associated symptoms and provide guidance for appropriateness of establishing disease-specific treatment guideline and strategies. A white paper-style report from the conference is generated and submitted to a peer-reviewed publication in a relevant top-line journal. This would serve as the basis of evidence to overcome the above challenges.

Dr. Peeples: The Orphan Drug Act was able to put a spotlight on rare and orphan diseases, encouraging more research to address the unmet need of patients impacted by these diseases. However, traditional clinical trials remain challenged in addressing this need. How do you see the growth in large data sets and real-world evidence impacting the ability to improve the volume and efficiency of research studies focused on rare and orphan diseases?

Sandi Siami: Identifying investigators that treat a rare disease is a major challenge, in addition to identifying the patients themselves. Therefore, having access to large integrated data sets and the use of real-world evidence is essential, but also represents a major clinical trial paradigm shift. In the past we have used disease registries that collected information about rare/orphan/underserved/neglected diseases/conditions. These registries are designed to learn more about the natural history, diagnostic patterns, medical interventions, and outcomes in order to determine the types of treatments/interventions that will be suitable for that particular patient population. Our registries have included as few as 40 patients to as many as 19,000 patients in diseases from sickle cell anemia and thalassemia to pediatric cardiomyopathy and congenital heart disease.

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But in addition to registries and datasets, the HealthCore Integrated Research Database (HIRD®), for example, is a large administrative healthcare database maintained by HealthCore for use in health outcomes and pharmacoepidemiologic research. The HIRD is a broad, clinically rich, and geographically diverse spectrum of longitudinal medical and pharmacy claims data from health plan members across the U.S. Member enrollment, medical care (professional and facility claims), outpatient prescription drug use, outpatient laboratory test result data, and health care utilization may be tracked for health plan members in the database dating back to January 2006, and with diagnoses recorded in International Classification of Disease, Version 10 (ICD-10) since October 2015. The HealthCore Integrated Research Environment (HIRE) has the ability to link the claims data in the HIRD to complementary data sources, including inpatient and outpatient medical records, national vital statistics records, cancer and vaccine registries (state-by-state), disease and device registries, member and provider surveys, and point of care clinical data, which is especially critical for rare, orphan, and underserved diseases/conditions. Using these resources, HealthCore conducts real-world research designed to meet various client needs, including retrospective database studies, medical record review studies, cross-sectional and longitudinal patient and PRO surveys, electronic data linkage studies (including linkage of patient survey data with electronic claims), randomized controlled trials (RCTs), pragmatic clinical trials (PCTs), and site-based enrollment for prospective observational studies using electronic data capture.

Dr. Peeples: There has been substantial growth in interest and research around genetics and genomics. In many cases, genetic diseases are being described alongside rare and orphan diseases. Do you see genomics research as a way to further accelerate research for other rare and orphan diseases?

Sandi Siami: Genomics is an integral part of rare/orphan disease research and has been for over a decade. There are different approaches to genomic studies such as genome wide association, copy number variation, pathway analysis, and next generation studies, all of which have been used to identify genetic variants in the pediatric population. A great example is the Bench to Bassinet Program (B2B) funded by the National Heart, Lung, and Blood Institute, for which HealthCore-NERI served as the initial Coordinating Center. One of the studies, referred to as CHD GENES, collected phenotype and biospecimens from children, their biological parents, and siblings to determine the primary and secondary aims which include genome-wide association studies, whole exome sequencing, and whole genome sequencing to discover genes responsible for congenital heart disease. Secondary aims included identification of mutations responsible for CHD in large numbers of participants, and genotype/phenotype correlation including long-term clinical follow-up of enrolled participants to determine how genetics influences the clinical outcome in CHD.

Another example, for which HealthCore-NERI was a Coordinating Center is the Cooperative Study of Sickle Cell Disease that identified genetic variants associated to the severity of sickle cell disease and fetal hemoglobin expression. Results of these genomic studies can then be used to guide prospective clinical trials to sub-divide patient populations (by genotype/phenotype) to predict those that are responsive to some active drug substances or to use genetic variants as surrogates for diagnosis or outcomes. This is especially important as we are moving toward patient-centric personalized medicine.

Dr. Peeples: Similar to genomics research, special populations such as pediatrics are singled out as areas of importance in the R&O research world. Do you see this as a benefit in that it provides visibility for a broader class of research into R&O, or does this disadvantage other R&O diseases that may not be ‘trending’? On the other hand, how do you see R&O research benefiting such special populations?

Sandi Siami: Most rare diseases are also life-threatening or aggressively progressive in nature, and many also affect the pediatric population. Thus, once a potential therapy is targeted, identifying potential participants for clinical trials becomes challenging not only because of the rare nature of the disease and the limited number of physicians/investigators that may treat the disease but the special ethical considerations that must be given to children who are considered part of the vulnerable population.

More than half of the rare/orphan diseases/conditions affect the pediatric population, and as you know, research in this vulnerable population also has its own challenges. Certainly there are the standard regulatory pathways such as the Humanitarian Device Exemption, Accelerated Approval, Breakthrough Designation, or Regenerative Medicine Advanced Therapy Designation to reduce the regulatory, economic, legal, technical, and logistical burdens associated with development of interventions. And the additional regulations encouraging interventions in pediatric populations under the Best Pharmaceutical for Children Act (BPCA) and Pediatric Research Equity Act (PREA) may account for concentration in pediatric research over other populations. Section 529 of the Food, Drug, and Cosmetic Act (FDCA) specifically encourages development of new interventions for the prevention and treatment of certain rare pediatric diseases.

But the reality is that 50-75% of rare diseases begin in childhood1, and thus it would be expected that there would be more research centered around pediatric rare diseases. According to Children’s Wish Foundation International there are 7,000 different types of rare diseases, 80% are genetic in origin, 50% are children, and 30% of the children don’t live past the age of 5 years of age. Organizations such as this, as well as Global Genes and National Organization for Rare Disorders provide resources to patients, families, researchers, and clinicians on rare diseases. HealthCore-NERI has over 30 years of experience in conducting research in this challenging population engaging more than 490 sites globally and close to 25,000 pediatric subjects in diseases ranging from sickle cell disease, thalassemia, Marfan syndrome, pulmonary hypertension, and spinal muscular atrophy to name a few. Given the unique nuances in conducting pediatric research, on top of the challenges of rare/orphan diseases, our digital strategies have produced award-winning products to aid in educating children, their parents, and pediatricians on clinical trials and participating in clinical trials from websites, to DVDs/posters, YouTube videos, Facebook, video games, and national broadcast film.

Works Cited

  1. 1-Bavisetty S, Grody WW, Yazandi S. Emergence of pediatric rare diseases: review of present policies and opportunities for improvement. Rare Dis. 2013;1:e23579.

Flora Sandra Siami, MPH, is Vice President of Clinical Research, Regulatory Affairs, and Quality Assurance at HealthCore-NERI with close to 25 years of industry experience. She oversees the Clinical Research business unit that includes early and late phase trials, including pragmatic clinical trials, across all therapeutic areas with specific interest and passion in rare, orphan, and underserved diseases as well as pediatric and minority populations. As part of her clinical research oversight, she directs the pharmacovigilance/medical device safety activities including management of Data and Safety Monitoring Boards and Clinical Events/Endpoints Committees. She leads all domestic and international regulatory affairs activities in over 37 countries worldwide. She oversee the quality assurance team overseeing SOPs, internal/external and client/regulatory agency audits, and quality systems.

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