DOI: 10.25934/pr00009128
title: A comparison between the assessments of overall response rate carried out by local assessors and a blinded independent central review in oncology trials. Analysis of differences in the assessment conducted at single-patient level.

description: Project background:
Cancer is one of the major causes of death across the world, leading to a significant reduction of life expectancy in several countries. The burden of cancer is steadily increasing worldwide; in 2020, there were 19.29 million new cancer cases, 9.96 million cancer deaths, and a total of 50.55 million people living with cancer within 5 years of diagnosis. The rising incidence of cancer coupled with the high mortality rates highlights the need for new and more effective treatments in oncology. Currently, an increasing number of cancer drugs have been approved through the evaluation of clinical endpoints that are based on the tumor assessment through radiological imaging (where internal images or pictures are taken of the affected part of the body). These endpoints include the objective response rate (ORR) and progression-free survival (PFS). ORR measures the response to a pharmacological (drug) treatment via the assessment of changes in the overall tumor mass during treatment in comparison to pre-treatment values, whereas PFS is defined as the time from randomization or treatment initiation until first evidence of tumor progression or death from any cause. However, the evaluation of outcomes based on radiological imaging may be influenced by subjective factors, including differences in how tumors are measured, differences in the selection of target lesions (areas of abnormal tissue), failure to diagnose new lesions, and differences in the analysis of non-target lesions. This may be particularly relevant when the evaluations are performed by local investigators, e.g., the treating physician and local radiologist, considering that blinding of treatment (where the physician doesn't know what treatment the patient is being given) is not always possible in modern oncology trials, e.g., drugs administered orally compared to old anti-cancer drugs given intravenously. The investigator expectation is indeed considered an important confounding factor in the interpretation of these clinical outcomes, thus the main regulatory bodies recommend the adoption of Blinded Independent Central Review (BICR) for all clinical outcomes based on radiological tumor assessment except for truly blinded trials.

Necessity of the research 
In our previous research, we have shown that there is strong correlation between local investigators and BICR for the evaluation of PFS both in phase-2 and phase-3 randomized clinical trials. In contrast, we found significant ORR over-estimation by local investigators both in phase-2 and phase-3 trials. The local investigator is on average more optimistic than the central reviewer. These trials usually lack a comparator group (control group where the patient receives a different treatment or placebo) and are used in the early phase of clinical drug development. Notably, many novel oncology drugs are currently approved with fast-track procedures based on preliminary phase-2 trials. Therefore, the discrepancy between local investigators and BICR in the assessment of ORR in phase-2 trials can significantly impact the estimate of drug efficacy, with a relevant impact on drug approval and future programs of drug development. 

How the research will be conducted 
Our analyses were conducted on aggregate data from reports published in the literature (Dello Russo and Navarra, doi: 10.3389/fphar.2022.858354). The present research is set to analyze the source of variability between local investigators and BICR in the evaluation of the ORR. This can be performed only by comparing the local investigators’ and BICR assessment at the single patient level. Several elements that are used for the evaluation of ORR will be compared.
We will evaluate the discrepancies related to patients’ categorization, such as number of patients with complete response, partial response, stable disease and progression in order to highlight possible causes of discrepancy. The outcome of our research can potentially influence the development of novel anti-cancer drugs and help the regulatory bodies as well as the pharmaceutical companies to devise appropriate strategies to reduce variability between the two evaluations and properly evaluate drug efficacy in the early phase of clinical development.