Randomized Controlled Trials (RCTs) Are the Gold Standard: Are They Always Used?
Author(s)
Elena Chaiter, MSc, Valeria Viola, Second-level Master's degree, Federico Tartarelli, MSc.
Pharma Value srl, Rome, Italy.
Pharma Value srl, Rome, Italy.
OBJECTIVES: RCTs are the cornerstone of medical research, providing strong validity through randomization and control of confounding factors1. However, they may be impractical in contexts with ethical constraints, high costs and lengthy timelines. This study analyses RCT use among approved orphan and oncology drugs between 2022 and 20242.
METHODS: This analysis included 124 new active substances approved by the European Medicines Agency. Four were excluded due to their non-therapeutic nature or lack of clinical trials. Among the 120 drugs analysed, 123 pivotal studies were identified, as three products had two distinct trials. Each study was classified by phase, randomization, and control (placebo, standard of care, or uncontrolled). Subgroup analysis was performed on orphan drugs (n = 42) and non-orphan oncology drugs (n = 27) including onco-haematological ones.
RESULTS: RCTs accounted for 79.7% of all studies (98/123). The proportion was lower among orphan drug studies (69.0%, 29/42) and non-orphan oncology studies (63.0%, 17/27). Conversely, the proportion of uncontrolled and non-randomized studies was higher in these subgroups: 31.0% (13/42) in orphan drug studies and 37.0% (10/27) in non-orphan oncology studies, compared to 19.5% (24/123) in the dataset. Notably, among these, 7 of the 13 orphan drugs and 9 of the 10 oncology drugs received conditional marketing authorisation, while 3 of the orphan drugs were authorised under exceptional circumstances. Considering study phases, Phase III trials were predominantly represented (82.9%, 102/123), although their frequency was lower in orphan drug studies (76.2%, 32/42) and non-orphan oncology studies (63.0%, 17/27).
CONCLUSIONS: RCTs remain the gold standard for evidence generation, the results show that they are not always conducted. This reflects flexibility in study design when RCTs are not feasible, particularly in orphan and oncology areas. However, rigor is maintained as 53.8% of orphan drugs and 90% of oncology drugs without RCT support must still provide additional evidence under conditional approval.
METHODS: This analysis included 124 new active substances approved by the European Medicines Agency. Four were excluded due to their non-therapeutic nature or lack of clinical trials. Among the 120 drugs analysed, 123 pivotal studies were identified, as three products had two distinct trials. Each study was classified by phase, randomization, and control (placebo, standard of care, or uncontrolled). Subgroup analysis was performed on orphan drugs (n = 42) and non-orphan oncology drugs (n = 27) including onco-haematological ones.
RESULTS: RCTs accounted for 79.7% of all studies (98/123). The proportion was lower among orphan drug studies (69.0%, 29/42) and non-orphan oncology studies (63.0%, 17/27). Conversely, the proportion of uncontrolled and non-randomized studies was higher in these subgroups: 31.0% (13/42) in orphan drug studies and 37.0% (10/27) in non-orphan oncology studies, compared to 19.5% (24/123) in the dataset. Notably, among these, 7 of the 13 orphan drugs and 9 of the 10 oncology drugs received conditional marketing authorisation, while 3 of the orphan drugs were authorised under exceptional circumstances. Considering study phases, Phase III trials were predominantly represented (82.9%, 102/123), although their frequency was lower in orphan drug studies (76.2%, 32/42) and non-orphan oncology studies (63.0%, 17/27).
CONCLUSIONS: RCTs remain the gold standard for evidence generation, the results show that they are not always conducted. This reflects flexibility in study design when RCTs are not feasible, particularly in orphan and oncology areas. However, rigor is maintained as 53.8% of orphan drugs and 90% of oncology drugs without RCT support must still provide additional evidence under conditional approval.
Conference/Value in Health Info
2025-11, ISPOR Europe 2025, Glasgow, Scotland
Value in Health, Volume 28, Issue S2
Code
HPR169
Topic
Clinical Outcomes, Health Policy & Regulatory
Topic Subcategory
Reimbursement & Access Policy
Disease
Oncology, Rare & Orphan Diseases