RWE FOR SINGLE AND WELL-CONTROLLED STUDIES: AN EVALUATION OF FDA SUBMISSIONS FOR EFFECTIVENESS
Author(s)
Shivani Aggarwal, PhD, MS1, David Goldfarb, PhD, MPH2.
1Landmark Science, Inc, Los Angeles, CA, USA, 2Landmark Science, Inc, New York, NY, USA.
1Landmark Science, Inc, Los Angeles, CA, USA, 2Landmark Science, Inc, New York, NY, USA.
OBJECTIVES: Per 21 CFR 314.126, substantial evidence of effectiveness is generally met by two adequate and well-controlled studies. In certain circumstances, a single adequate and well-controlled clinical investigation together with confirmatory evidence can be sufficient. Real-world evidence (RWE) has been used to support regulatory decision-making for effectiveness—increasingly in absence of two well-controlled studies. However, its use and acceptance as a single and well-controlled study versus confirmatory evidence has not been well characterized.
METHODS: We conducted a targeted review of marketing authorization applications (MAAs) containing RWE accepted by the FDA between January 2020-December 2025 for effectiveness. Single adequate well-controlled studies with confirmatory evidence were evaluated. Publicly available reports including DEPI and OBE reviews from CDER and CBER were reviewed. Two reviewers independently extracted the RWE, evaluated trial and RW study designs, and characterized the regulatory positioning of RWE (adequate well-controlled study vs confirmatory evidence). Regulatory feedback on the RWE was examined.
RESULTS: Among RWE submitted for effectiveness in single adequate well-controlled studies with confirmatory evidence, the majority were used as confirmatory evidence. Examples of medicines where regulators categorized RWE as a single well-controlled study included palovarotene and tacrolimus while RWE as confirmatory included omaveloxolone, alpelisib, and pneumococcal 20-valent conjugate vaccine. All medicines where RWE contributed to a single and well controlled study were for orphan or ultra-orphan drugs, oncology/hematology, or rare diseases. Common RW study designs for single well-controlled studies included external control arms (ECAs) compared to a trial arm, and retrospective cohort with historical controls. ECAs paired with trial data also served as confirmatory evidence, depending on the totality of evidence. Few MAAs solely relied on RWE for effectiveness alone.
CONCLUSIONS: While RWE use in MAAs has increased substantially, regulatory acceptability of RWE—particularly for effectiveness—has varied based on totality of evidence. Sponsors should consider the totality of evidence when incorporating RWE into MAAs.
METHODS: We conducted a targeted review of marketing authorization applications (MAAs) containing RWE accepted by the FDA between January 2020-December 2025 for effectiveness. Single adequate well-controlled studies with confirmatory evidence were evaluated. Publicly available reports including DEPI and OBE reviews from CDER and CBER were reviewed. Two reviewers independently extracted the RWE, evaluated trial and RW study designs, and characterized the regulatory positioning of RWE (adequate well-controlled study vs confirmatory evidence). Regulatory feedback on the RWE was examined.
RESULTS: Among RWE submitted for effectiveness in single adequate well-controlled studies with confirmatory evidence, the majority were used as confirmatory evidence. Examples of medicines where regulators categorized RWE as a single well-controlled study included palovarotene and tacrolimus while RWE as confirmatory included omaveloxolone, alpelisib, and pneumococcal 20-valent conjugate vaccine. All medicines where RWE contributed to a single and well controlled study were for orphan or ultra-orphan drugs, oncology/hematology, or rare diseases. Common RW study designs for single well-controlled studies included external control arms (ECAs) compared to a trial arm, and retrospective cohort with historical controls. ECAs paired with trial data also served as confirmatory evidence, depending on the totality of evidence. Few MAAs solely relied on RWE for effectiveness alone.
CONCLUSIONS: While RWE use in MAAs has increased substantially, regulatory acceptability of RWE—particularly for effectiveness—has varied based on totality of evidence. Sponsors should consider the totality of evidence when incorporating RWE into MAAs.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
HPR52
Topic
Health Policy & Regulatory
Topic Subcategory
Approval & Labeling
Disease
SDC: Oncology, SDC: Rare & Orphan Diseases, STA: Multiple/Other Specialized Treatments