Michael Pollock

	Real-world evidence (RWE) research is an increasingly important component of biopharmaceutical product development and commercialization. The growing industry need for broader information on real-world effectiveness and safety-both of which will impact the eventual reimbursement and utilization of new products-is driven by regulators, public and private payers, and prescribers, all of whom seek to better understand the impact of a new product in a real-world setting. The result is that real-world evidence is now included earlier in the research and development phase.

	Today, a regulatory authority may require post-approval research or monitoring to determine real-world safety, due to concerns about a product's safety when it becomes widely prescribed, while payers may require validation of a product's real-world clinical value and cost-effectiveness to determine optimal formulary placement.

	Data about real-world patient experience also has the potential to improve the quality and delivery of medical care, reduce overall costs and improve outcomes by accelerating the understanding of how best to incorporate new therapies and technologies into everyday clinical practice. Essentially, these data help fill the knowledge gap between clinical trials and actual clinical practice.

	While clinical trials remain the gold standard for drug approval, more information is needed on how specific drugs perform within different age groups, such as the elderly, and different genders, races and ethnicities, as well as differences in disease severity and unstudied co-morbid conditions for use of products in the real world, as reflected in Figure 1.

	Figure 1. Patients Exposed to Inadequately Assessed Health Care Technologies

	Biopharmaceutical sponsors, providers, payers and regulators are eager to investigate real-world data for insights that can increase quality, drive down costs and improve patient safety. For example, several years ago, Anthem, Inc. asked HealthCore, its outcomes research subsidiary, to conduct a study comparing the effectiveness of oral asthma controller medications to that of inhaled corticosteroids. HealthCore found that when members took their medication as directed, those taking inhaled corticosteroids had fewer inpatient and emergency room visits and lower total health care costs. But among members who were not taking their medication properly, those taking oral asthma controllers were less likely to have inpatient and emergency room visits.

	The insurer’s pharmacy and therapeutics committee used this real-world evidence, in addition to the overall evidence supporting these therapies, to keep the oral controller medication on a less-expensive, preferred tier and remove the prior authorization requirement for its use so its members could continue to use the product that worked best for them. This research was conducted when the products were far along in their life cycles, raising the question about what a difference this information could have made on this product’s reimbursement if it had been conducted, shared and acted on earlier.

	Health economics and outcomes research (HEOR) generates evidence of the economic value of new and existing products and helps decision-makers and payers determine reimbursement policies and insurance coverage for new and existing therapies. HEOR has become a more integral part of traditional R&D, impacting clinical trial design and the management of economic endpoints within these trials. With major global shifts in health care systems to control costs, a growing number of Phase III trials now include economic endpoints and analyses, alongside the clinical outcome measures, to demonstrate the cost-efficacy of new products.

	A meaningful real-world research study design for a new product begins with a deeper understanding of its real-world environment. Access to robust real-world health data, including administrative claims data and other clinical data sources, together with the technology and analytics capability to effectively analyze that data is essential. Other prerequisites are scientific excellence, the scope and scale of operations to efficiently execute studies, expertise in clinical trial design and HEOR, and knowledge of related regulatory requirements.

	Real-world research is an area of methodological innovation. Compared to clinical trial data, RWE data more closely describes how the product will perform in a broader, more representative population over a longer timeframe, and provides information on comparators and outcomes that are not part of the clinical trial protocol.

 There is a wide range of study types and complexities for a typical RWE research program.

	RWE can be divided into two types: primary data, collected specifically for research purposes; and secondary data, collected for other purposes. Primary data are generally obtained from study-specific case report forms, electronic medical and health records, and/or clinical outcomes assessments. These data are collected in interventional Phase IV studies and in non-interventional prospective observational studies, patient registries and health surveys. Secondary data are often obtained from clinical chart reviews, registries and/or insurance claims databases, and are used in retrospective database studies or as an input to prospective study design or hybrid studies.

	Trials of health care interventions often are described as either pragmatic or explanatory. Explanatory trials generally measure efficacy, the benefit a treatment produces under ideal conditions, often using carefully defined subjects in a research clinic. These specialized studies recruit as homogeneous a population as possible and aim primarily to further scientific knowledge.

	By contrast, pragmatic randomized clinical trials measure effectiveness, the benefit the treatment produces in routine clinical practice, and are carried out after product approval. A pragmatic trial reflects variations between patients that occur in real clinical practice and aims to inform choices between treatments, as portrayed in Figure 2. These trials should represent patients to whom the treatment will be applied, and test whether an intervention works in real-world circumstances. Pragmatic trials offer a scientific method of research for policymakers and clinicians, and serve as real-world evidence sources for decisions, such as for funding, regulations, policy and organizational changes.

	Figure 2. Schematic of the relationship between explanatory and pragmatic trials. The wide based of the pyramid depicts the relatively higher proportion of explanatory trials.

 with the permission of the publisher (Les Laboratoires Servier, Suresnes, France). ©Les Laboratoires Servier.

	An example of a pragmatic RWE study is a new Sanofi Aventis trial to determine the efficacy and health outcomes of Toujeo, a long-acting basal insulin to improve glycemic control in adults with type 2 diabetes. Currently recruiting patients, the objective of the study is to demonstrate the clinical benefit of the drug in achieving specific therapeutic targets in patients initiating basal insulin therapy in a real-world setting. The secondary objective is to compare the drug to commercially available basal insulins after initiating insulin therapy in a real world setting, in terms of patient persistence with the assigned therapy, differences in patient- and provider-reported outcomes, and health care resource utilization, including hospitalizations and emergency department or other provider visits, and health care costs.

	In a cluster randomized trial (CRT), groups of subjects, rather than individual subjects, are randomized to receive one of the interventions being studied. Clusters may include provider practices, families, schools, clinics, health plans, towns and others. An example of the application of a CRT is in the assessment of health promotion programs, where it is problematic to design a study in which one member of a cluster (e.g., a town, a community or a patient in a group practice) can be exposed to the full impact of a program while another member would have no exposure. A CRT can provide a way to better approximate the real-world setting for drug/program combinations. With the increased interest in pragmatic clinical trials, comparative effectiveness research and community health promotional activities, the use of CRTs has been growing.

	Several organizations have been formed to help the life sciences industry supply practical information about its products. The Patient-Centered Outcomes Research Institute (PCORI) was established to help patients and clinicians improve key health outcomes. The group identifies critical research questions, funds patient-centered comparative clinical effectiveness research and disseminates evidence-based results.

	The Institute for Clinical and Economic Review (ICER) is an independent source for evaluating the value of new drugs and providing a transparent, objective basis for price negotiations and coverage decisions. Over the next two years, ICER will produce 15-20 public reports on new high-impact drugs near the time of FDA approval, and calculate a benchmark price for each new drug anchored to the real benefits of the drug.

	Another organization, the American Society of Clinical Oncology (ASCO), is the world's leading professional organization representing physicians who care for cancer patients. Recently ASCO published a conceptual framework to assess the value of new cancer treatment options based on clinical benefit, side effects and costs. The framework is intended as a user-friendly, standardized tool doctors can use to discuss with patients the relative value of new cancer therapies compared with established treatments.

	To meet the increasing demand for RWE studies, sponsors and clinical research organizations (CRO) are ramping up their capabilities in this growing area of interest. Many are forming partnerships and building capabilities to leverage the opportunities offered by RWE. As an example, PPD and HealthCore recently established a collaboration to further expand their services to help biopharmaceutical clients demonstrate more quickly and cost-effectively how their products will perform and benefit patients in the real world.

	Through this collaboration, PPD and HealthCore have all the capabilities needed to plan, execute and deliver all types of RWE studies, in particular, pragmatic Phase IV trials. This alliance combines extensive experience and expertise in clinical trial design, HEOR, medical affairs research, epidemiology, access to large databases of integrated medical and pharmacy claims and lab results, innovative real-world research designs, analytics, and qualitative research. Together, their RWE capabilities include: observational research, post-approval safety studies, pragmatic Phase IV trials, patient, product, and disease registries, patient-reported outcomes, and economic evaluation.

	RWE studies serve many purposes and are creating new opportunities for evidence generation in drug development. The EMA guidance

 requires the collection of risk-benefit data in post-authorization safety studies. Pharmaceutical companies now must take a more granular approach, examining different subpopulations to determine their respective risk-benefit balance. There is also an increasing demand from payers to conduct observational studies on a new product's effectiveness, and payers and clinicians are eager for more detailed health outcomes data to inform prescribing and reimbursement decisions.

	The outlook for RWE generation-stand-alone or in conjunction with clinical trials-is promising, with the potential to improve health outcomes and cost-effectiveness of new health technologies. The demand for RWE is growing and is unlikely to subside as health care decision-makers become increasingly aware of what it offers. Biopharmaceutical companies and CROs need to stay at the forefront of developments in RWE, data sources, analytic techniques and study methodologies to ensure they are able to optimize patient access and formulary placement of new products.

 is Vice President of Research at HealthCore; and 

 is Vice President, Real World Outcomes for PPD.

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Articles

Real-world evidence (RWE) research is an increasingly important component of biopharmaceutical product development and commercialization. The growing industry need for broader information on real-world effectiveness and safety-both of which will impact the eventual reimbursement and utilization of new products-is driven by regulators, public and private payers, and prescribers, all of whom seek to better understand the impact of a new product in a real-world setting. The result is that real-world evidence is now included earlier in the research and development phase.

Michael Pollock

Articles

Real-World Evidence Studies