美国食品药品监督管理局罕见病证据原则（RDEP）

Insight Guide FDA’s Rare Disease Use real world evidence in ultra-rare drug development DIEGO CORREA,MD, MSc, PhD. VP Medical, Global Head Cell and Gene Therapy Center of Excellence, IQVIAREID D’AMICO,PhD, Sr. Principal, Lead of Regulatory Science and Strategy, IQVIATIFFANY MERCADO,MS, Associate Principal, Regulatory Science and Strategy, IQVIA In September 2025, the United States (U.S.) Food andDrug Administration (FDA) announced the Rare Disease RDEP builds on existingFDA guidance Evidence Principles (RDEP),1a new review processdesigned to provide greater clarity and predictabilityfor therapies targeting ultra-rare, genetically defineddiseases. For sponsors who are developing therapiesfor conditions where patient populations number in RDEP builds on the precedent established in FDA’s2023 draft guidance onDemonstrating Substantial Evidence of Effectiveness with One Adequateand Well-Controlled Clinical Investigation and In recent publications, FDA has placed emphasis on theimportance of mechanistic rationale in ultra-rare diseasesettings. Specifically, in November 2025, the Agencyannounced the “plausible mechanism pathway”for personalized therapies. Under this pathway, This Insight Guide explores how the RDEP processcompares to existing pathways, in what situationsit should be considered, and how sponsors can therapies may be approved once sponsors show RDEP explicitly recognizes a broadrange of high-quality evidencesources… offering sponsors RDEP explicitly recognizes a broad range of high-qualityevidence sources, including mechanistic and biomarkerdata, relevant non-clinical studies, pharmacodynamic evidence, natural history data, expanded accessdata, and case reports, offering sponsors assurancethat regulators will consider these diverse forms of Itvisma demonstrated substantial evidence ofeffectiveness based on primary evidence froman adequate and well-controlled Phase III study, When is RDEP the right path? RDEP is intended for sponsors developing therapies supplemented by confirmatory evidence characterizingthe product’s mechanism of action as well as •The disease is caused by aknown in-born •Fewer than 1,000 patientsare affected in •The condition is life-threatening, rapidlyprogressive, and has no available therapy that •The sponsor can reasonably demonstrate thatone adequate and well-controlled study,supported by robust confirmatory evidence, RDEP therefore complements existing mechanisms, suchas Accelerated Approval, Orphan Drug Designation, andthe Rare Disease Endpoint Advancement (RDEA) pilot, by For sponsors targeting ultra-rare conditions, RDEPenhances predictability by formalizing evidentiaryexpectations already articulated in FDA guidance andreflected in emerging policy, such as the emphasis ona plausible mechanistic rationale and early, iterative Where RWE creates advantage— from patient finding to engagement with review divisions. The program alsoprovides context for FDA’s September 2025 draft Before sponsors can qualify for the RDEP process, theymust demonstrate that the disease meets the ultra-rareprevalence threshold. Just as RWE has long supportedprevalence estimates in orphan drug applications, it can AI-enabled analytics can further refine these estimates.Natural language processing (NLP) models can surfacephenotypic patterns, genetic variants, and diagnostic Relatedly, sponsors must anticipate payer evidenceneeds early, as limited pre-approval data may increasereliance on post-market studies for coverage decisions. Central role for RWE in RDEP •External comparator armsderived fromhigh-quality RWD can strengthen causal inference Once a program enters RDEP, RWE continues to •Natural history studiesestablish baseline •Patient registriesprovide longitudinal outcomes,support endpoint selection, and enable Sponsors must anticipate payer evidence needs early, as limited pre-approvaldata may challenge establishing the added value of the therapy and increase Patient advocacy organizationsalso play a critical role inidentifying undiagnosed or Especially in ultra-rare disease, RWE can play a criticalrole in developing and validating novel endpoints, aswell as in supporting innovative or adaptive trial designsthat streamline development. Hybrid study designs The challenge is to ensure, to the extent possible,that these diverse, often fragmented data sourcesare fit-for-purpose for regulatory decision-making. By Embedding patient-focuseddrug development and Ultra-rare diseases are often poorly characterized, withclinical expertise concentrated in only a few centersworldwide. This makes patient-focused drug developmentessential, requiring endpoints that are both clinically Especially in ultra-rare disease,RWE can play a critical role indeveloping and validating novel Patient advocacy organizations also play a critical rolein identifying undiagnosed or misdiagnosed individuals,raising clinician awareness through targeted education,and supporting recruitment