FDA Issues Guidance on Cancer Clinical Trial Eligibility: Performance Status
The U.S. Food and Drug Administration (FDA), through its Oncology Center of Excellence (OCE), Center for Drug Evaluation and Research (CDER), and Center for Biologics Evaluation and Research (CBER), has published final guidance titled "Cancer Clinical Trial Eligibility Criteria: Performance Status".
The guidance provides clinical trial sponsors, institutional review boards (IRBs), and clinical investigators with recommendations on expanding performance status (PS) eligibility criteria in adult oncology clinical trials to improve patient representativeness and trial generalizability.
Purpose and Limitations of Traditional Performance Status Criteria
Performance status—primarily assessed using the Eastern Cooperative Oncology Group (ECOG) scale or the Karnofsky Performance Status (KPS) scale—is one of the most common eligibility criteria in oncology studies. Historically, clinical trial protocols have restricted enrollment to high-functioning patients (ECOG PS 0–1 or KPS 80–100), excluding those with lower functional capacity.
The FDA points out several key limitations of traditional PS eligibility criteria:
Subjectivity and Rater Bias: PS scoring is inherently subjective. Clinical studies show that healthcare providers frequently assign higher numeric ECOG PS scores (indicating poorer function) to patients aged 65 and older compared to younger patients, even when objectively measured physical activity levels are identical.
Failure to Identify Etiology: Current PS scales do not differentiate whether poor performance status is driven by underlying cancer burden or by non-cancer comorbidities. When low PS is caused by tumor burden, effective anticancer therapy often leads to functional recovery and symptom relief.
Unnecessary Exclusions: Blanket exclusions based on PS slow patient accrual, restrict access to promising therapies, and yield clinical trial data that fail to reflect the real-world population that will receive the therapy post-approval.
Expanding Inclusion: Recommendations for ECOG PS2 / KPS 60–70
The FDA recommends that sponsors default to including patients with ECOG PS2 or KPS 60–70 in oncology trials unless established safety concerns provide a clear scientific or clinical rationale for exclusion.
Key guidance recommendations include:
Evidence-Based Protocol Design: Protocol inclusion criteria should mirror the patient population expected to receive the drug in clinical practice. Any exclusion based on PS must be explicitly justified in the protocol with supporting safety data.
Development Lifecycle Progression: PS eligibility should evolve as clinical safety data accumulates. While early phase studies may initially limit enrollment to evaluate baseline safety, pivotal Phase 2 and Phase 3 trials should routinely include ECOG PS2 patients unless earlier data demonstrated prohibitive toxicity.
Stratification: When enrolling a broad range of functional capabilities, sponsors should utilize baseline PS as a randomization stratification factor to balance treatment arms and prevent safety or efficacy confounding.
Alternative Trial Designs for Low Performance Status Cohorts
To manage potential risks while capturing valuable safety and efficacy data, the FDA outlines flexible trial design options for sponsors:
Exploratory Low-PS Cohorts: Protocols may incorporate pre-specified, exploratory cohorts for patients with lower performance status (ECOG PS $\ge$ 2) that are evaluated independently of the primary efficacy analysis.
Incremental Enrollment & Safety Stopping Rules: Low-PS cohorts can utilize staged enrollment alongside predefined safety stopping rules, allowing sponsors to gather early safety signals without jeopardizing the main trial objectives.
Decentralized Trial Elements: To improve retention and reduce travel burden for patients with reduced functional status, sponsors are encouraged to leverage decentralized study components, such as local lab collections and home health visits.
Functional Assessments: PROs, Digital Health, and Geriatric Tools
To complement clinician-assessed ECOG or KPS scores, the FDA emphasizes the integration of modern functional assessment tools:
Patient-Reported Outcomes (PROs): Capturing longitudinal patient-reported physical function provides a more comprehensive understanding of functional trajectory before and during treatment.
Digital Health Technologies (DHTs): Wearable sensors and continuous activity trackers offer objective, real-world physical activity data to supplement periodic clinician ratings.
Geriatric Assessment Tools: For older adults (aged $\ge$ 65), traditional PS scales are often suboptimal. The FDA recommends incorporating streamlined Comprehensive Geriatric Assessment (CGA) tools to evaluate baseline health, functional reserve, and toxicity risk more accurately.
Impact on Clinical Trial Sponsors and Drug Developers
For biotechnology companies, pharmaceutical sponsors, and contract research organizations (CROs), this guidance requires a proactive re-evaluation of standard oncology protocol templates.
Sponsors should prioritize:
Re-evaluating standard template exclusions to incorporate ECOG PS2 (KPS 60–70) candidates by default;
Documenting scientific safety rationales in trial protocols whenever lower PS populations are excluded;
Implementing stratification by baseline PS in Phase 2/3 randomized trials;
Designing exploratory low-PS sub-cohorts with early safety monitoring where appropriate;
Integrating PROs, wearable DHTs, and geriatric assessment tools into clinical study workflows.
By adopting these recommendations, sponsors can accelerate trial recruitment, enhance the external validity of trial findings, and generate robust safety and efficacy data representative of real-world cancer patients.
