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What is FDA Acceptable Real World Evidence?
(Thursday, August 8, 2024) There is a significant misunderstanding about what is acceptable Real World Evidence (RWE) to support market approval applications for regulated products by the FDA. Is published literature acceptable, or is it clinical experience with marketed products, what is the weight of patient-reported outcomes, or is it only data from medical records, and so on? Apparently, this misunderstanding exists within the FDA as well. RWE comes from diverse sources hence there are multiple opinions about the weight/importance of each for supporting safety and effectiveness claims. In its multiple guidance documents and numerous presentations, the FDA advises that sponsors treat RWE as another type of clinical evidence that must be robust, complete, unambiguous, and accurate. From a regulatory point of view, sponsors should not expect the FDA to be lax in accepting RWE. FDA has listed the acceptable sources of RWE. At the top of the list are the medical records, electronic or otherwise. The medical records contain a wealth of data about the patient’s condition through a given treatment. If collected properly, this is the most important and trustworthy data for the FDA reviewers. The key difference between clinical trial data and RWE lies in how the data is collected. Clinical trials typically follow strict protocols and data is generated based on a prospective plan. RWE, on the other hand, is based on data from routine clinical practice collected based on a retrospective protocol. The clinical protocol and the RWE protocol should follow similar quality standards. The biggest confusion is about the use of data from publications. Most publications lack line-wise raw data and hence do not meet the FDA acceptance criteria for RWE. Also, publications on clinical trials that usually include selected data, do not meet the FDA acceptance criteria. However, meta-analyses based on published medical data demonstrating trends in patient experience might be acceptable. Analysis of accumulated data from published individual case reports might be acceptable, as well. These include data gathered from normal medical practice and published as a study or case series. Conditions for which clinical trials are not feasible such as short-term life-threatening indications might instead rely on trends from data collected for individual case reports. In all such situations, the RWE does not mean just giving the FDA a list of publications but a thorough analysis of the information in the publications to support the claims made by the sponsor. The RWE data must be relevant and reliable just like that from controlled clinical trials. Usually, RWE is evaluated in the context of clinical trial data (CTD) to fill gaps in one set of data, with that from the other. Together the two kinds of data, RWE and CTD must establish substantial evidence of safety and effectiveness for marketing authorization; the FDA is agnostic whether that evidence comes from clinical trials, RWE, or a combination of the two. The 21st Century Cures Act of 2016 requires the FDA to create specific requirements for RWE in support of regulatory decisions, so the FDA is committed to considering RWE, but that does not mean that there are lax requirements for RWE. Trends in the FDA’s recent decisions show it carefully assesses all types of clinical evidence, including RWE, and considers factors like bias and uncertainty when making decisions. RWE acceptance is not automatic; it must be relevant, reliable, and properly evaluated just like any other clinical data. 
AUTHOR
Dr. Mukesh Kumar Founder & CEO, FDAMap Email: [email protected] Linkedin: Mukesh Kumar, PhD, RAC Instagram: mukeshkumarrac Twitter: @FDA_MAP Youtube: MukeshKumarFDAMap |
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