The U.S. Food and Drug Administration (FDA), in collaboration with the LUNGevity Foundation and the National Cancer Institute (NCI), is working to standardize eligibility criteria for advanced non-small cell lung cancer (NSCLC) clinical trials. This initiative aims to address the challenges posed by complex and often restrictive inclusion and exclusion criteria that limit patient access to novel therapies, hinder trial recruitment, and complicate the comparison of results across different trials. The effort is particularly focused on first-line therapeutic clinical trials intended to support marketing applications. This standardization effort is intended to broaden trial access and improve the efficiency of clinical research in NSCLC. The work may serve as a prototype for similar efforts in other cancers.
Addressing Challenges in Clinical Trial Eligibility
Clinical trial sponsors use eligibility criteria to manage patient characteristics, ensure participant safety, and optimize the interpretation of results. However, the increasing complexity and stringency of these criteria have created significant barriers. LUNGevity, a patient advocacy organization, initiated a Scientific and Clinical Research Roundtable to streamline lung cancer clinical trials, addressing issues such as difficulties in navigating trial protocols, the exclusion of a growing proportion of patients due to stringent criteria, and the heterogeneity of study populations that complicates cross-trial comparisons.
Development of Standardized Criteria
Beginning in 2019, experts from the NCI, FDA, LUNGevity, and trial sponsors (Genentech, Janssen, AstraZeneca) developed a baseline eligibility criteria framework for lung cancer clinical trials. This framework includes a prioritized library of terms designed to provide sponsors with a consistent approach to developing study protocols. The goal is to standardize the wording and order of eligibility criteria, thereby assisting patients and clinicians in evaluating trial enrollment opportunities, supporting regulatory officials, and encouraging a more consistent approach to eligibility considerations.
The forthcoming FDA draft Guidance document contains 13 eligibility categories in a recommended order, covering aspects such as disease stage and histology, biomarkers, performance status, organ function, brain metastases, and comorbidities. These recommendations are intended to serve as a starting point for investigators and sponsors drafting study protocols.
Key Eligibility Categories and Considerations
Disease Stage and Histology: The recommendations focus on advanced (stage 4) NSCLC, including specific classifications according to the American Joint Committee on Cancer (AJCC) 8th edition.
Biomarkers: The working group discussed the need for biomarker testing and the processes required to ensure adequate rigor. While some clinicians supported allowing locally performed testing to save time and money, industry representatives emphasized the importance of detailed biomarker measurements. The recommendations suggest that the use of approved companion diagnostics for patient screening, followed by central lab confirmation, may be sufficient for established biomarkers.
Performance Status: Clinicians advocated for more frequent inclusion of patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, given the development of cancer treatments with limited toxicity profiles. The group agreed on a baseline recommendation of including ECOG performance status 0-2, with justification required for excluding performance status 2.
Organ Function: For liver and kidney function, the working group acknowledged that eligibility criteria based on isolated AST/ALT elevations may result in the exclusion of patients with adequate organ function. They suggested specific thresholds for bilirubin and AST/ALT levels, while the FDA draft guidance recommends basing eligibility on available data related to the agent(s) under investigation.
Brain Metastases: The working group considered language from earlier FDA guidance documents, encouraging modeling criteria on widespread clinical practice, such as not requiring pre-trial treatment of small and/or asymptomatic brain metastases and adjusting washout periods according to the tolerability and toxicity of brain metastasis treatment.
Impact and Future Directions
The standardized eligibility criteria are expected to facilitate the development of more inclusive and efficient clinical trials for NSCLC. By harmonizing trial populations, the initiative aims to support inter-trial comparisons of treatment effects and improve patient access to novel therapies. The open comment period following the issuance of the draft guidance will provide an opportunity for the public to provide feedback on these recommendations, further refining the approach to clinical trial eligibility in lung cancer.
