The overall response rate (ORR) is a largely adopted outcome measure in early-phase oncology trials. ORR is highly relevant in cancer drug development at the time of deciding whether to move to confirmatory phase 3 trials; moreover, ORR is gaining increasing relevance in fast-track registration procedures. No systematic analysis has been conducted so far to investigate whether a discrepancy exists between ORR assessed by local investigators and those assessed by blinded reviewers in phase 2 oncology trials. In this study, we carried out a search in the clinicaltrials.gov and EudraCT databases, looking at the trials reporting the results of both investigator-assessed and independently-assessed ORR. A discrepancy index was obtained by calculating the ratio of each investigator-assessed ORR on the corresponding independently assessed ORR, so that a discrepancy index >1 indicates that the investigator was “more optimistic,” whereas a discrepancy index <1 indicates the opposite. We also analyzed different subgroups (by tumor type, by drug type, by year). Twenty trials met the search criteria; in some cases, >1 comparison was conducted in the trial, so that the total number of comparisons analyzed was 33. The estimated mean discrepancy index was 1.175 (95% confidence interval, 1.083-1.264; n = 33). In conclusion, local investigators significantly overestimate ORR compared to paired blinded reviewers in phase 2 oncology trials. This may represent a risk in drug development, when deciding whether to move to confirmatory, more expensive phase 3 trials. Blinded independent central review should be used in ORR assessment if a more conservative estimate of treatment efficacy is required, as in the case of fast-track drug developments leading to accelerated approvals of cancer therapies.

Dello Russo, C., Cappoli, N., Pilunni, D., Navarra, P., Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials, <<THE JOURNAL OF CLINICAL PHARMACOLOGY>>, 2021; 61 (6): 810-819. [doi:10.1002/jcph.1790] [https://hdl.handle.net/10807/168236]

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials

Dello Russo, Cinzia;Cappoli, Natalia;Navarra, Pierluigi
2021

Abstract

The overall response rate (ORR) is a largely adopted outcome measure in early-phase oncology trials. ORR is highly relevant in cancer drug development at the time of deciding whether to move to confirmatory phase 3 trials; moreover, ORR is gaining increasing relevance in fast-track registration procedures. No systematic analysis has been conducted so far to investigate whether a discrepancy exists between ORR assessed by local investigators and those assessed by blinded reviewers in phase 2 oncology trials. In this study, we carried out a search in the clinicaltrials.gov and EudraCT databases, looking at the trials reporting the results of both investigator-assessed and independently-assessed ORR. A discrepancy index was obtained by calculating the ratio of each investigator-assessed ORR on the corresponding independently assessed ORR, so that a discrepancy index >1 indicates that the investigator was “more optimistic,” whereas a discrepancy index <1 indicates the opposite. We also analyzed different subgroups (by tumor type, by drug type, by year). Twenty trials met the search criteria; in some cases, >1 comparison was conducted in the trial, so that the total number of comparisons analyzed was 33. The estimated mean discrepancy index was 1.175 (95% confidence interval, 1.083-1.264; n = 33). In conclusion, local investigators significantly overestimate ORR compared to paired blinded reviewers in phase 2 oncology trials. This may represent a risk in drug development, when deciding whether to move to confirmatory, more expensive phase 3 trials. Blinded independent central review should be used in ORR assessment if a more conservative estimate of treatment efficacy is required, as in the case of fast-track drug developments leading to accelerated approvals of cancer therapies.
2021
Inglese
Dello Russo, C., Cappoli, N., Pilunni, D., Navarra, P., Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials, <<THE JOURNAL OF CLINICAL PHARMACOLOGY>>, 2021; 61 (6): 810-819. [doi:10.1002/jcph.1790] [https://hdl.handle.net/10807/168236]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/168236
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