Archive for category RWE

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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Advancing Real-World Evidence with Pragmatic Clinical Trials: Interview with Dr. Joseph Singer, Chief Medical Officer of HealthCore-NERI

Dr. Patti Peeples, CEO of HealthEconomics.Com, sat down with Dr. Joseph Singer, CMO of HealthCore-NERI, to discuss how pragmatic clinical trials are advancing real-world evidence (RWE). 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: What is the shift we are seeing in the industry from typical Randomized Controlled Trials (RCTs) design to Pragmatic Clinical Trials (PCTs) design?

Dr. Singer: For the past fifty years, healthcare has been relying on randomized controlled trials (RCTs) to establish safety and efficacy of medical and surgical treatments. RCTs have been integral in establishing the potential efficacy and the beginning of understanding the risk profiles of new treatments and interventions.  While RCTs have been the standard for evaluating early phase therapies, they are limited in evaluating treatment options in a real-world, post-approval setting.  Real-world evidence using pragmatic clinical trials (PCTs) is increasingly being used for decision making by payers, life science companies, health systems, and practicing physicians. There is a need for devices and interventions, both biopharmaceutical and surgical, in a value-based system to demonstrate the actual benefit and risks occurring in a real-world patient setting, as opposed to the tightly controlled populations of a traditional RCT. Pragmatic studies allow for observation of a more generalizable and diverse population, and are designed to include many different kinds of patients – with various comorbidities, ages, and demographics. We have seen a strong industry shift toward these new types of studies with the PDUFA VI Regulations and the 21st Century Cures Act, requiring the FDA to explore the use of real-world evidence in support of new indications for approved drugs or fulfill post-approval requirements. There is significant potential gain by integrating results of both efficacy from RCTs and effectiveness from PCTs to personalize most appropriate placement of an intervention in the treatment plan of individuals by their treating physicians.

Dr. Peeples: How are Pragmatic Clinical Trials advancing Real World Evidence?

Dr. Singer: Currently, as little as 15 percent of clinical guidelines are based on solid evidence.  For instance, if we zero in on cardiovascular guidelines, there are 16 high impact cardiovascular guidelines used to power healthcare decisions by payers, healthcare providers and consumers – with 2,722 recommendations within these guidelines. However, only 11 percent are actually based on enough evidence to warrant the recommendation, with most only relying on a single trial or expert opinion.[1] Expert opinion is essential to fill gaps in evidence when strong scientific evidence has not been generated, but it is not optimal for personalizing care for any given patient.

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One way to get at generating real-world evidence is through retrospective research looking at utilization and costs, but another important way to study real-world evidence is through prospective study designs that randomize patients to various treatment options to determine the appropriate treatment for patients in the real world.  PCTs enable the healthcare industry to more nimbly and efficiently answer questions related to how a treatment option performs in a real-world setting, contributing important evidence to establish future clinical guidelines that are applicable to a broad array of patients.

Dr. Peeples: What are the benefits to Pragmatic Clinical Trial design?

Dr. Singer: While retrospective research can answer important questions about trends and utilization of certain treatment options, prospective study designs allow us to more accurately observe treatment effects because of randomization.  However, traditional prospective study designs, such as RCTs, offer challenges in terms of implementation and often don’t include a representative patient population.We know that over90 percent of patients do not participate in traditional RCT research.  An important contributing factor is the overall burden, time and resources required of participating physicians and patients in these complex and highly structured studies. Because pragmatic clinical trials are rooted in real-world practice, they require significantly less time and resources. Physicians do not need to take hours on a daily basis to document findings, to hire additional staff and disrupt their typical practice operational flow. Often times, patients’ participation in the trial only requires informed consent, randomization and responding to a few surveys. Therefore, it opens the door to include many more physicians for participation and offers opportunities for their patients, which ultimately improves our understanding of how treatments perform in routine practice.

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PCTs are designed to be minimally burdensome to both participating physicians and patients, are structured to allow existing office staff to do much of the work, and minimize the bureaucracy and paperwork associated with performing research.

Dr. Peeples: What are some of the challenges with implementing PCTs?

Dr. Singer: Moving from high-touch research interventions to real-world pragmatic studies requires a complete shift in mindset among the FDA, the industry, trial sponsors and trial participants. What works in RCT implementation may not work in PCT implementation. Rather than targeting the same traditional physician groups, who offer a limited number of patients, there is an opportunity to work with more research limited or research naïve sites.  Working with these sites does pose some challenges, such as provider and patient unfamiliarity with research and limited staff support and resources. However, the lean resource approach PCTs can take allows seamless integration with community clinics who may lack experience with research but who have the ideal patient population for implementation.

Dr. Peeples: How can we overcome barriers to physician and patient recruitment?

Dr. Singer: We recognize that85 percent of RCTs fail to meet recruitment targets, with 15 to 20 percent of trial sites never enrolling a single patient.[2,3] To meet and exceed targets and timelines, a new set of tools is needed to address physician and patient recruitment into PCTs. First, it is essential to know the ideal physicians and sites to target and approach. Secondly, sites need the appropriate tools and resources to identify and enroll patients, and conduct the research. Through the use of site intelligence (physician and patient population demographics), targeted physician and patient communications, and technology automation, PCTs can improve efficiency, meet enrollment targets and exceed timelines.

Dr. Peeples: What is the best way to get started on designing and implementing a PCT?

Dr. Singer: Success for PCTs involves an understanding of the unique challenges of pragmatic studies, and having the right tools to overcome those barriers. At HealthCore-NERI, through the Integrated Research Network (IRN), a connected network of physicians, integrated delivery systems, patients and payers, we are building the ecosystem to support real-world evidence, pragmatic clinical trials. The IRN uses a unique identification and automation processor to leverage existing relationships and intelligence collected on sites to accelerate time to first patient in. Through targeted communications, we equip sites with the tools they need to be successful in patient recruitment. We’ve created a community where physicians and patients become the direct recipients of the research we conduct to improve quality and satisfaction and to foster long-term engagement.

Dr. Peeples: Thank you, Joe. For more information on the Integrated Research Network (IRN), pragmatic clinical trials, and other HealthCore-NERI research solutions, contact IRN@HealthCore.com.


[1] Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC Jr. Scientific evidence underlying the ACC/AHA clinical practice guidelines. JAMA. 2009; 301:831–41. Available here: https://jamanetwork.com/journals/jama/fullarticle/183453

[2] Carlisle B, Kimmelman J, Ramsay T, MacKinnon N. Unsuccessful trial accrual and human subjects protections: an empirical analysis of recently closed trials. Clin Trials 2015; 12:77-83. Available here: https://journals.sagepub.com/doi/abs/10.1177/1740774514558307?journalCode=ctja

[3] Budgeting at the Investigative Site, University of North Carolina at Chapel Hill, Office of Clinical Trials Newsletter. July/August 2006.

Dr. Joseph Singer is responsible for guiding HealthCore-NERI’s project teams to optimize the clinical, coding, and insurance industry perspectives embedded within their analytic projects. He also supports development of clinical aspects of HealthCore-NERI’s research environment and manages HealthCore-NERI’s Integrated Research Network (IRN). As an Initiative Owner, he is leading the development of a research environment to optimize the efficiency and effectiveness of studies performed by HealthCore-NERI. He serves as clinical lead for several Payment Innovation activities within Anthem, Inc. (i.e. building the bundled payment methodologies), as well as provides leadership in numerous enterprise steering committees

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