Examining the Impact of Real-World Evidence on Medical Product Development Proceedings of a Workshop Series (2019) / Chapter Skim
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5 Getting Unstuck: Mythbusting the Current System
5 Getting Unstuck: Mythbusting the Current System
Pages 51-70
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From page 51... ...
could address multiple challenges along the drug development pathway; possible uses for RWE throughout the development cycle include the development of clinical pathways, the optimization of trial design and price, the study of comparative effectiveness, and the study of com pliance and adherence patterns. (Graham)
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From page 52... ...
, and identifying the challenges that need to be addressed, this final session instead focused on dissecting the current system of evidence generation. Evidence for decision making, particularly regulatory decision making, is traditionally generated through randomized controlled trials (RCTs)
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From page 53... ...
As computing advanced faster in non-medical sectors than in the practice of medicine, research experts developed parallel systems to record clinical findings entirely separately from clinical practice; the perpetuation of this "parallel universe" of data and antiquated systems led to some "bizarre" inefficiencies. For example, said Califf, as electronic health records (EHRs)
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From page 54... ...
In addition, the lessons learned would return to the point of care and be used to improve care. Califf observed that this capability is being developed by public–private partnerships and integrated health systems, and noted that "if these various systems can work together in a federated way, I think we are getting close to having a national system that can be reused at a very low cost for different kinds of questions." This vision of a new national system would collect data during routine care, would use active surveillance to protect patients, would leverage RWE to support regulatory decisions, and could be used to inform decisions by all stakeholders in the ecosystem, said Califf.
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developing infrastructure to share the results with practitioners to support a constantly learning system. Califf noted that automated analysis of data could help fill in the evidence gaps on endpoints that are less well understood, at a considerably lower cost.
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Real-World Evidence to Address Challenges Along the Drug Development Pathway John Graham, head of value, evidence, and outcomes at GlaxoSmithKline (GSK) , echoed other speakers in his opening remarks: "We need to have the right answers to the right questions at the right time." In getting these answers, said Graham, RWE is a must-have, but it is not a replacement for traditional research.
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RWE can be used during discovery to estimate unmet needs, or to characterize patient heterogeneity. RWE can be used during development to form clinical pathways, optimize trial design, and optimize price.
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58 FIGURE 5-2 Broad sources of real-world data and broad uses of real-world evidence. NOTE: EHR = electronic health record; EMR = electronic medical record; FDA = U.S.
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From page 59... ...
Randomization also allows use of a blinded control group, which can help ensure events are ascertained similarly in the randomized treatment groups, yielding unbiased treatment comparisons. The current challenges with RCTs, said Collins, are in large part due to the widespread misapplication of the GCP guidelines for clinical trials issued by the International Conference on Harmonisation (ICH)
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From page 60... ...
As a consequence, he contended, it has led some researchers to pursue the alternative of using non-randomized observational studies -- what he called the misuse of RWE -- to assess treatments, despite their potential for biases. Noting that the ICH-GCP guidelines require specific qualifications for investors, source data verification, and regulatory documentation, Collins argued there is an urgent need to improve RCT methodology through the development of comprehensive new RCT guidelines based on key scientific principles required to generate evidence about the safety and efficacy of treatments that can be trusted.
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. The study found an observed association between antidepressants and preeclampsia, and found that the association was stronger for selective serotonin reuptake inhibitors (SSRIs)
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62 FIGURE 5-3 Effect estimates from published observational studies on anti epressants and the risk of preeclampsia. d NOTE: CI = confidence interval.
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From page 63... ...
This exercise, said Ryan, demonstrates that "we can't necessarily trust the process that we are using to generate evidence as a community." Our current process, Ryan said, is to conduct one observational study at a time, with one hypothesis, one dataset, and one method. Each of these studies is viewed individually, but given the pattern on the funnel plot, "it can't possibly be the case that all of these studies are totally correct." The process of generating evidence in RCTs, said Ryan, is not much better.
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64 FIGURE 5-4 Effect estimates from published observational studies on all disease states, all treatments, and all causal effects. NOTE: CI = confidence interval.
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FIGURE 5-5 Systematically generated evidence from observational data, comparing all depression treatments on all outcomes of interest. NOTE: CI = confidence interval.
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From page 66... ...
The device guidance, titled "Use of Real-World Evidence to Support Regulatory Decision-Making,"4 discusses the challenges with current device evidence development, and proposes potential uses of RWE for device regulation. These uses include using RWE to examine outcomes, but also as historical or concurrent controls, to expand the label for an approved device, or for safety surveillance.
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Woodcock gave several examples of ways in which FDA has used or is considering using RWE for drug approval. Drugs for rare diseases have been approved using data from registry-like case series, she said.
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From page 68... ...
One design approach that is particularly promising, said Woodcock, is the use of master protocols. Master protocols are continuous, ongoing trials that can study multiple interventions and outcomes, with the goal of having "continuous improvement in the disease outcome." The use of master protocols, said Woodcock, saves time, offers an opportunity to include community practitioners and integrate research and practice, can answer multiple questions, is patient-centric, and can use adaptive designs creatively.
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From page 69... ...
GETTING UNSTUCK: MYTHBUSTING THE CURRENT SYSTEM 69 individual experience." The research community could instead focus on making evidence generation easier and more efficient, while still emphasizing reliability, in order to get the answers that patients, providers, and regulators need to make decisions.
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