Examining the Impact of Real-World Evidence on Medical Product Development Proceedings of a Workshop Series (2019) / Chapter Skim
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10 Looking Ahead
10 Looking Ahead
Pages 153-176
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(Stem) • Newer clinical trial designs, such as adaptive designs, platform trials, or incorporating RWE, have the potential to significantly reduce cost and time investments required for medical product development.
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Food and Drug Administration (FDA) input -- RWE can inform regulatory decisions for biologics, drugs, and devices in the United States and abroad.
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Comparators in RCTs sometimes do not reflect the local practice or clinical practice, which makes it difficult to assess real-life comparative effectiveness of a product, he said. Of course, he added, using RWE also has challenges, including limited availability of data at time of assessment, potential for bias, poor quality or missing data, and data sources that are not established for research purposes.
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Jonsson provided three examples of how the GetReal initiative has affected the work of NICE in the past several years. Jonsson noted that NICE is a unique stakeholder in that it is not a regulator or a payer, but sits "somewhere in between" and provides guidance to a broad range of stakeholders, including health care, public health, and social care organizations.
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Finally, NICE's Science Policy and Research team is prioritizing areas for methods development, said Jonsson. The team is engaging in research projects with partners in order to develop best practices for applying adjustment methods for confounding, explore the use of big data in health care decision making, and consider the use of advanced analytics and artificial intelligence for RWE analysis.
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There are data from wearables, social media, smartphones, and electronic health records (EHRs) , and these data are complex and variable.
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To capitalize on these trends and to involve patients as partners, said Stem, monARC Bionetworks has developed an integrated RWD learning platform. monARC worked directly with patients to generate virtual research networks where patients can share data, and be engaged and recruited for research (see Figure 10-2)
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. Levy said this rate suggests that despite a growing understanding of human biology, the research community's "ability to identify targets outstrips our ability to validate and confirm their importance." The data requirements for new products are increasing, with a growing demand for active comparator data, patient-reported outcomes, and long-term safety follow-up data.
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In essence, adaptive designs allow researchers to "fail efficiently and succeed efficiently," Levy said. He shared a hypothetical example of a traditional design compared to a Bayesian adaptive design (see Figure 10-3)
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162 FIGURE 10-3 Hypothetical example of traditional design versus Bayesian adaptive design. SOURCE: Levy presentation, July 17, 2018.
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NOTE: BLA = biologics license application; CSR = clinical study report; SOC = standard of care. 163 SOURCE: Levy presentation, July 17, 2018.
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TABLE 10-1 Hypothetical Examples of Cost Savings Example Savings Risk-based monitoring ~5 percent of total clinical trial spend Average saving of ~20 percent study subjects and up to 25 Adaptive trials designs percent reduction in trial timeline ~20–40 percent saving of trial costs and reduction of timeline Platform trials by ~25 percent Highly simplified trials ~50 percent reduction in per-site and per-patient costs Real-world evidence (in lieu of randomized Up to ~90 percent reduction in total trial cost and ~75 percent controlled trial) reduction in trial timeline SOURCE: Levy presentation, July 17, 2018.
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The workshop also explored definitions, and defined RWD as a "subset of big data relating to patient health status, delivery of routine health care, collected from a variety of sources [including] electronic health records, claims, product and disease registries, and social media." RWE, said Breckenridge, was considered to be evidence drawn from RWD through the application of research methods.
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The program shifts the burden of evidence from the pre- to postmarket space, and emphasizes postauthorization efficacy and safety studies. MAPP uses the existing European Union legal framework, he said, and requires the ongoing involvement of the company, regulators, health technology assessment experts, payers, and patients.
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. Drug Indication Status Data Open label clinical trial Lutathera GEP-NET Approved Analysis of 360 patients in an investigator sponsored, (lutetium 177 Gastropanc.
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In 2013, FDA released guidance on the best practices for conducting and reporting pharmacoepidemiologic safety studies using EHR data.2 These practices can likely inform best practices in other areas of RWD analysis and RWE use, said Corrigan-Curay. For example, one goal of this guidance is to ensure that patients whose electronic health care data have been used in an outcomes analysis have actually experienced the event; it suggests practical steps such as ensuring that the code or algorithm has either been validated previously or that its predictive value was calculated, and describing the sensitivity of the outcome.
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The second goal is to automate adverse event reporting by using methods such as machine learning and natural language processing in order to mine adverse events related to biologics from EHRs and automatically submit them to FDA. The BEST program, said Anderson, will help CBER to better meet its regulatory needs by building "better,
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CBER is also working with the entinel S staff to develop a mobile app to collect patient input, said Anderson. There are several challenges in using RWD for regulatory decision making, said Anderson, including bias, quality of data, missing data, and how well a patient's exposure and outcome can be captured.
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MDEpiNet has also worked to develop active surveillance methodologies, conducted studies exploring the utility of claims and EHR data, and worked on evidence synthesis through in silico model ing and other approaches. Several dozen projects are in the MDEpiNet pipeline, Shuren said, including developing tools to move clinical data from EHRs into the Women's Health Coordinated Registry Network4; implementing the Delta System for active surveillance in the transcatheter valve therapy registry and the cardioverter–defibrillator registry; and testing the capabilities of state-based claims.
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This cost savings, he said, does not consider that a quicker time to market results in lives saved and improved quality of life for patients, as well as additional economic benefits to the companies. The use of RWE for making regulatory decisions about devices is not a thing that is "nice to have," it is a "need to have," said Shuren.
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He said that companies should engage in conversation with FDA early and often in order to improve the likelihood that their studies will produce this type of "regulatory-grade evidence." Shuren broadened this issue slightly, noting that evidence should be produced that is fit for purpose, whether that purpose is regulatory decision making or some other purpose such as clinical decision making. He added that FDA and other regulators do not look at RWE in a vacuum, but rather as part of the totality of the evidence from a variety of sources.
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Anderson noted that these types of studies are costly and take years to conduct, and that CBER would likely continue to "be the referee rather than [primarily generating] the data." Shuren responded that CDRH both generates data and has built infrastructure and partnerships that enable CDRH to use RWE for regulatory decisions.
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Important questions could potentially be answered "cheaper and faster" with a systematic, validated framework for generating RWE, he said. The key to creating this framework will be clarity and specificity about when using RWE is BOX 10-1 Key Messages Identified by Individual Speakers • Lists of questions, such as those laid out in the decision aids discussed at the third workshop, are useful, particularly as a framework to add details for specific stakeholders or applications.
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Jennifer Graff suggested that the word "patient" be incorporated into the decision aids, because while FDA and other stakeholders use evidence to make decisions, so do patients and caregivers. McClellan closed by saying that tools such as the decision aids are "intended to help us move from case by case to more systematic and predictable opportunities." He noted that there is growing infrastructure for RWE, from Sentinel to registries to NEST, and that FDA and other regulators were open to engaging with RWE and building the systems necessary to use RWE for decision making.
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