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Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials
Author(s) -
Dello Russo Cinzia,
Cappoli Natalia,
Pilunni Daniela,
Navarra Pierluigi
Publication year - 2021
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1790
Subject(s) - medicine , clinical trial , confidence interval , oncology , phases of clinical research , index (typography) , drug development , drug , pharmacology , world wide web , computer science
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.