Assessing the efficacy‐effectiveness gap for cancer therapies: A comparison of overall survival and toxicity between clinical trial and population‐based, real‐world data for contemporary parenteral cancer therapeutics

Abstract

Background Although increasing evidence has suggested that an efficacy‐effectiveness gap exists between clinical trial (CT) and real‐world evidence (RWE), to the authors' knowledge, the magnitude of this difference remains undercharacterized. The objective of the current study was to quantify the magnitude of survival and toxicity differences between CT and RWE for contemporary cancer systemic therapies. Methods Patients receiving cancer therapies funded under Cancer Care Ontario's New Drug Funding Program (NDFP) were identified. Landmark CTs with data regarding survival and adverse events (AEs) for each drug indication were identified. RWE for survival and hospitalization rates during treatment were ascertained through Canadian population‐based databases. The efficacy‐effectiveness gap for each drug indication was calculated as the difference between RWE and CT data for median overall survival (OS), 1‐year OS, and generated hazard ratios (HRs) with 95% CIs from Kaplan‐Meier OS curves. Toxicity differences were calculated as the difference between RWE of hospitalization rates and CT serious AE rates. Results Twenty‐nine indications from 20 systemic therapies were included. Twenty‐eight of 29 indications (97%) demonstrated worse survival in RWE, with a median OS difference of 5.2 months (interquartile range, 3.0‐12.1 months). Lower effectiveness in RWE also was demonstrated through a meta‐analysis of an OS hazard ratio of 1.58 (95% CI, 1.39‐1.80). The median difference between RWE for hospitalization rates and CT serious AEs was 14% (95% CI, 9%‐22%). Conclusions An efficacy‐effectiveness gap exists for contemporary cancer systemic therapies, with a 5.2‐month lower median OS observed in RWE compared with CT data. These data supports the use of RWE to better inform real‐world decision making regarding the use of cancer systemic therapies.

Real-World Association of HER2/ ERBB2 Concordance with Trastuzumab Clinical Benefit in Advanced Esophagogastric Cancer

“…This pattern is consistent with the difference in OS that we observed for patients who were HER2/ERBB2 concordant (13.02 months) versus HER2/ERBB2 discordant (7.52 months). Although these real-world OS estimates are lower than what has been reported from clinical trials [46], this difference is expected given the known gap in efficacy as measured in clinical trials compared with real-world effectiveness for cancer therapies. Clinical trial eligibility criteria typically limit participation for patients with significant comorbidities, and most trial populations are younger and healthier than real-world patients.…”

Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations

“…The performance of drugs in clinical trials generally exceeds results seen in real‐world practice. Studies have demonstrated an efficacy‐effectiveness gap for hepatocellular carincoma, 23 lung cancer, 24,25 prostate cancer, 26 breast and hematological malignancies 27 . The efficacy‐effectiveness gap is often attributed to the differences that exist between patients in trials and in routine practice including clinically relevant differences in age, performance status, co‐morbidities and prior and subsequent lines of therapy.…”

“…Studies have demonstrated an efficacy‐effectiveness gap for hepatocellular carincoma, 23 lung cancer, 24 , 25 prostate cancer, 26 breast and hematological malignancies. 27 The efficacy‐effectiveness gap is often attributed to the differences that exist between patients in trials and in routine practice including clinically relevant differences in age, performance status, co‐morbidities and prior and subsequent lines of therapy. These differences can result in variability in toxicity and drug tolerability as well as long‐term outcomes.…”

Considerations for Developing a Reassessment Process: Report from the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration’s Reassessment and Uptake Working Group

“…Real-world evidence (RWE), derived from real-world data [4], has been suggested by stakeholders as being potentially valuable for facilitating systematic evidence-based reassessment to enable lifecycle HTA and improve reimbursement decision making [5][6][7][8][9]. An inherent strength of RWE is the unselected patient population that may be more relevant to routine practice, as randomized clinical trials (RCTs) often have selective inclusion criteria, which contributes to the variation between efficacy observed in trials and effectiveness observed in the real world [4,[10][11][12][13][14][15]. Since initial drug funding decisions are based on clinical benefit observed from RCTs and the value of a drug is estimated using economic models, a large efficacy-effectiveness gap is particularly important to decision makers [16].…”