Improvement of assessment in surrogate endpoint and safety outcome of single-arm trials for anticancer drugs

ABSTRACT

Introduction

Single-arm trials (SATs) and surrogate endpoints were adopted as pivotal evidence for accelerated approval of anticancer drugs for more than 30 years. However, concerns regarding clinical evidence quality in trials, particularly in the SATs of anticancer drugs have increasingly been raised. SAT may not always provide strong evidence due to the lack of control and endpoint of overall survival that is typically present in randomized controlled trials.

Areas covered

Clinical trial endpoint adjudication is a crucial factor in surrogate outcome measurement to ensure the data quality of the clinical trial of anticancer drugs. In this review, we systematically discuss the characteristics of adjudications in assessments in surrogate endpoint and safety outcome respectively, which are essential for ensuring reliable and transparent outcomes. Endpoint adjudication effectively reduces potential bias and mitigates variance that may be introduced by investigators when analyzing the medical records for the surrogate endpoints. We analyze the advantages and disadvantages of each type of adjudicator and provide a summary of the roles of adjudicators.

Expert opinion

By suggestion of improving data reliability and transparency in pivotal trials, this review aims to supply a strategy for better clinical investigation for anticancer drugs, ultimately leading to better patient outcomes.

KEYWORDS:

• Oncological clinical trial
• surrogate endpoint
• endpoint adjudication
• single-arm trials
• safety outcome
• anticancer activity

Article highlights

• The practice of utilizing single-arm trials and surrogate endpoints to support accelerated approval (AA) of anticancer drugs has raised the increasing reconsideration of the clinical evidence quality in evaluation of anticancer activity and safety.

• Endpoint adjudication plays an important role in ensuring the data quality of a clinical trial of anticancer drugs. It supports that the data assessment for the study endpoints is accurate, complete, and consistent.

• Endpoint adjudication reduces the potential bias such as information bias and selection bias. It also helps to mitigate variances such as intra- and inter-reader variances. Depending on the trial circumstance, three typical models are utilized for endpoint adjudication, namely the ‘central review committee (CRC),’ ‘independent review committee (IRC)’ and ‘blinded independent review committee (BIRC).’

• Adverse event adjudication typically relied on ‘safety assessment committee (SAC)’ as the FDA requisite before 2021, which was reformed into a more flexible ‘safety assessment entity’ according to the new FDA guidance 2021. ‘safety assessment entity’ presents advantages in terms of low cost, organizational flexibility, and effective performance.

• This review systematically discussed the approach to meet the FDA’s demand for higher quality evidence to support anticancer drugs. Appropriate endpoint adjudication was suggested to promote assessment in anticancer activity and safety.

• By improving data reliability and transparency in pivotal trials, this strategy aims to provide a better landscape for clinical development of anticancer drugs, ultimately leading to better patient outcomes.

Abbreviations

AA	=	Accelerated Approval
AE	=	Adverse Event
ASCO	=	American Society of Clinical Oncology
BA	=	Bioavailability
BE	=	Bioequivalence
BIRC	=	Blinded Independent Review Committee
CRC	=	Central Review Committee
DLT	=	Dose-Limiting Toxicity
DMC	=	Data Monitoring Committee
FDA	=	The US Food and Drug Administration
FIH	=	First-In-Human
IND	=	Investigational New Drug
IRC	=	Independent Review Committee
NSCLC	=	Non-Small Cell Lung Cancer
ODAC	=	Oncologic Drugs Advisory Committee
ORR	=	Objective Response Rate
OS	=	Overall Survival
PFS	=	Progression-Free Survival
RCT	=	Randomized Controlled Trial
RECIST	=	Response Evaluation Criteria in Solid Tumors
REMS	=	Risk Evaluation and Mitigation Strategies
RP2D	=	Recommended Phase 2 Dose
RR	=	Response Rate
SA	=	Safety Assessment
SAC	=	Safety Assessment Committee
SAE	=	Serious Adverse Events
SAT	=	Single-Arm Trial
SMP	=	Safety Monitor Plan
SRC	=	Safety Review Committee

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

YH drafted the manuscript. JY revised the manuscript. All authors approved the submitted version.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [82104133].