FDA Acceptance of Surrogate End Points for Cancer Drug Approval: 1992-2019

Chen, Emerson Y.; Haslam, Alyson; Prasad, Vinay

doi:10.1001/jamainternmed.2020.1097

Cited by 66 publications

(53 citation statements)

References 6 publications

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“…This is possibly due to the surrogate endpoints, overall response rate (ORR) and progression-free survival (PFS), used in earlier trials that are not sufficient to predict the overall survival (OS). In concordance with this, several analyses [ 16 , 17 , 18 , 19 , 20 , 21 ] highlight that improved ORR or longer PFS do not always correlate to survival benefit, and there are often little or unknown correlations between surrogate endpoints and OS. Undoubtedly, targeted cancer therapies have impacted the treatment outcome profoundly, although effective only in a small cancer subpopulation with specific biomarkers, while chemotherapy has made a modest difference across all the stages of disease in all population [ 22 ].…”

Section: Introductionmentioning

confidence: 78%

Trends in Phase II Trials for Cancer Therapies

Azam

Vázquez

2021

Cancers

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Background: Drug combinations are the standard of care in cancer treatment. Identifying effective cancer drug combinations has become more challenging because of the increasing number of drugs. However, a substantial number of cancer drugs stumble at Phase III clinical trials despite exhibiting favourable efficacy in the earlier Phase. Methods: We analysed recent Phase II cancer trials comprising 2165 response rates to uncover trends in cancer therapies and used a null model of non-interacting agents to infer synergistic and antagonistic drug combinations. We compared our latest efficacy dataset with a previous dataset to assess the progress of cancer therapy. Results: Targeted therapies reach higher response rates when used in combination with cytotoxic drugs. We identify four synergistic and 10 antagonistic combinations based on the observed and expected response rates. We demonstrate that recent targeted agents have not significantly increased the response rates. Conclusions: We conclude that either we are not making progress or response rate measured by tumour shrinkage is not a reliable surrogate endpoint for the targeted agents.

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Section: Introductionmentioning

confidence: 78%

Trends in Phase II Trials for Cancer Therapies

Azam

Vázquez

2021

Cancers

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“…In oncology clinical trials, improvements in overall survival are a key measure of an intervention’s efficacy, and one of the gold standards used in regulatory approvals [ 4 ]. However, therapeutic effects either known or reasonably likely to predict clinical benefit, and measurable earlier than survival improvements, such as increases in progression-free survival (PFS) time or in durable response rates (RR), have also supported approvals [ 5 , 6 ]. In traditional trials, the use of standardized criteria, such as the Response Evaluation Criteria in Solid Tumors (RECIST), helps ensure the objectivity, validity, and reliability of these outcome measurements and associated endpoints [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Real-World Response Variable and Comparison with RECIST-Based Response Rates from Clinical Trials in Advanced NSCLC

Bellomo

Magee

et al. 2021

Adv Ther

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Introduction Effectiveness metrics for real-word research, analogous to clinical trial ones, are needed. This study aimed to develop a real-world response (rwR) variable applicable to solid tumors and to evaluate its clinical relevance and meaningfulness. Methods This retrospective study used patient cohorts with advanced non-small cell lung cancer from a nationwide, de-identified electronic health record (EHR)-derived database. Disease burden information abstracted manually was classified into response categories anchored to discrete therapy lines (per patient-line). In part 1, we quantified the feasibility and reliability of data capture, and estimated the association between rwR status and real-world progression-free survival (rwPFS) and real-world overall survival (rwOS). In part 2, we investigated the correlation between published clinical trial overall response rates (ORRs) and real-world response rates (rwRRs) from corresponding real-world patient cohorts. Results In part 1, 85.4% of patients ( N = 3248) had at least one radiographic assessment documented. Median abstraction time per patient-line was 15.0 min (IQR 7.8–28.1). Inter-abstractor agreement on presence/absence of at least one assessment was 0.94 (95% CI 0.92–0.96; n = 503 patient-lines abstracted in duplicate); inter-abstractor agreement on best confirmed response category was 0.82 (95% CI 0.78–0.86; n = 384 with at least one captured assessment). Confirmed responders at a 3-month landmark showed significantly lower risk of death and progression in rwOS and rwPFS analyses across all line settings. In part 2, rwRRs (from 12 rw cohorts) showed a high correlation with trial ORRs (Spearman’s ρ = 0.99). Conclusions We developed a rwR variable generated from clinician assessments documented in EHRs following radiographic evaluations. This variable provides clinically meaningful information and may provide a real-world measure of treatment effectiveness. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01659-0.

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“…This is possibly due to the surrogate endpoints, overall response rate (ORR) and progression-free survival (PFS), used in earlier trials that are not sufficient to predict the overall survival (OS). In concordance with this, several analyses [16][17][18][19][20][21] highlight that improved ORR or longer PFS do not always correlate to survival benefit, and there are often little or unknown correlations between surrogate endpoints and OS. Undoubtedly, targeted cancer therapies have impacted the treatment outcome profoundly, although effective only in a small cancer subpopulation with specific biomarkers, while chemotherapy has made a modest difference across all the stages of disease in all population.…”

Section: Introductionmentioning

confidence: 78%

Trends in Phase II trials for cancer therapies

Azam

Vázquez

2020

Preprint

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BackgroundDrug combinations are the standard of care in cancer treatment. Identifying effective cancer drug combinations has become more challenging because of the increasing number of drugs. However, a substantial number of cancer drugs stumble at Phase III clinical trials despite exhibiting favourable efficacy in the earlier Phase.MethodsWe analysed recent Phase II cancer trials comprising 2,165 response rates to uncover trends in cancer therapies and used a null model of non-interacting agents to infer synergistic and antagonistic drug combinations. We compared our latest efficacy dataset with a previous dataset to assess the progress of cancer therapy.ResultsWe demonstrate that targeted therapies should be used in combination with cytotoxic drugs to reach high response rates. We identify 4 synergistic and 10 antagonistic combinations based on the observed and expected response rates. We also demonstrate that recent targeted agents have not significantly increased the response rates.ConclusionsWe conclude either we are not making progress or response rate measured by tumour shrinkage is not a reliable surrogate endpoint for the targeted agents.

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FDA Acceptance of Surrogate End Points for Cancer Drug Approval: 1992-2019

Cited by 66 publications

References 6 publications

Trends in Phase II Trials for Cancer Therapies

Trends in Phase II Trials for Cancer Therapies

Characterization of a Real-World Response Variable and Comparison with RECIST-Based Response Rates from Clinical Trials in Advanced NSCLC

Trends in Phase II trials for cancer therapies

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