The U.S. Food and Drug Administration (FDA) has released a draft guidance document on the use of real-world evidence (RWE) in regulatory decision-making. In the posted guidance, the FDA discusses regulatory considerations for observational studies involving the use of RWD, including RWD access, study monitoring, safety reporting, and other sponsor responsibilities.
Kensington, MD – The Medical Technology and Practice Patterns Institute (MTPPI) has submitted comments to the publication of FDA-2021-D-1214-0001: Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making for Drug and Biological Products; Draft Guidance for Industry; Availability. This draft guidance was posted in response to certain mandates issued under the 21st Century Cures Act. MTPPI’s comments are published below:
Before terms such as “real-world data” and “real-world evidence” were in use, the Medical Technology and Practice Patterns Institute (MTPPI) – a not for profit health services research organization located in Kensington, MD – conducted an analysis of Medicare claims data for EPOGEN® (EPO), a human erythropoietin used to treat dialysis-related anemia. In the early 1990s, EPO was a “revolutionary” drug – the first ‘blockbuster’ biologic of its kind. It was expensive and highly effective in increasing hematocrit levels and most notably, replacing the frequent use of blood transfusions that dialysis patients had previously endured. However, long term effectiveness and potential adverse outcomes associated with EPO use were not known at the time of FDA approval.
MTPPI was one of the first organizations to apply observational study designs to empirically examine the use of EPO in the “real-world”. The research team recruited a Technical Advisory Committee (TAC) made up of renal community stakeholders to oversee the project. The TAC met quarterly to review the findings and to ensure (1) there was transparency in data collection and analysis methods (2) that researchers were granted the needed access to data (3) proper study monitoring and safety reporting (5) centralized governance of the research team’s interactions with the sponsor [in this case, Ortho Biotech (n.k.a Janssen) sponsored the project at the direction of the judge handling the arbitration stated below]. The study developed over 44 “Issue Profiles” related to data validity/quality, the analytic approach, and the interpretation of results that were meant to account for the amount of EPO administered to the Medicare dialysis patient population. The claims data emanated from routine billing for EPO services. This billing process produced a continuous record of EPO resource consumption as well as actively collecting healthcare data to support the billing.
The early Issue Profiles addressed the compliance of providers with Medicare EPO documentation and billing rules, with a focus on the identification of and removal of dose and hematocrit outliers. The product of this 7-year study was an accounting of the amount of EPO administered to dialysis patients between 1989 and 1998 that was used in an on-going arbitration proceeding between Amgen and Ortho Biotech to settle an EPO licensure dispute.
A secondary use of the study supported a large number a peer-reviewed practice pattern and outcome studies which served as the underpinnings for both the FDA and CMS presentations and petitions regarding EPO policy and for Congressional oversight interests. The early papers focused on disparities in access to EPO therapy and provider practice patterns. Because the FDA defines an observational study as a “type of study in which patients received the marketed drug of interest during routine medical practice and are not assigned to an intervention according to a protocol” we focused on the effects of large dialysis chain EPO protocols on patient outcomes. The next wave of analyses focused on dose-response, risk, outcomes, and policies governing appropriate use. The final set of analyses focused on causal inference studies modeling EPO therapy and outcomes among high-risk subgroups. These research efforts led to (1) the removal of Medicare’s perverse reimbursement incentives that rewarded EPO overuse and (2) changes to the FDA approved EPO drug labeling. The analytic process used for this decades long research program and the lessons and experiences learned by MTPPI researchers could be useful to the FDA in formulating how to use real-world data in other important applications.
MTPPI thanks the FDA for the opportunity to provide these comments. We appreciate the hard work of the FDA scientists and staff seeking to advance a real-world evidence framework and stand ready to offer our insights and experience. If you have any questions or need further clarification, please do not hesitate to reach out to our team. Thank you for your consideration of our comments as you work toward finalizing this important guidance.
The Research Scientists of MTPPI
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