As leaders in clinical research, we often focus on enrolment challenges without examining the underlying structural forces that shape patient access to trials. Recent large-scale analyses of ClinicalTrials.gov data provide compelling insights into how eligibility criteria have evolved—and why this matters for the future of clinical development.
The Two-Thirds Rule: Exclusions Dominate Trial Design
A comprehensive Natural Language Processing study analyzing over 350,000 ClinicalTrials.gov records from the Clinical Trial Knowledge Base (CTKB) revealed a striking pattern: approximately two-thirds of all eligibility criteria are exclusions, while only one-third are inclusions. This fundamental imbalance reflects how we conceptualize trial participation—we define who we want by extensively cataloging who we don't want.
When examined at the protocol level, the typical trial structure emerges: 8-12 inclusion criteria paired with 15-20 exclusion criteria. However, these averages mask significant variation across therapeutic areas and development phases that deserves our attention.
Therapeutic Area Variations Tell a Story
The data reveals distinct patterns that reflect the inherent complexities of different research domains:
Oncology and rare disease trials consistently demonstrate the most restrictive profiles, often exceeding 25 exclusion criteria. This reflects the complex safety considerations, disease heterogeneity, and regulatory requirements inherent in these challenging therapeutic areas.
Device and behavioral intervention studies operate at the opposite end of the spectrum, frequently maintaining fewer than 10 total criteria. This difference highlights how intervention type fundamentally shapes trial accessibility.
Later-phase drug trials (Phase III/IV) typically settle into the mid-teens for inclusions and low-20s for exclusions, representing the mature understanding of target populations that comes with advanced development.
The Gradual Drift Toward Complexity
Perhaps most concerning for patient access is the temporal trend identified in industry-funded Phase III trials: a gradual increase of approximately 0.4 total criteria per year since the mid-2000s. This seemingly modest annual increase compounds over time, driven primarily by the addition of new exclusion criteria.
This trend raises important questions about whether we're inadvertently creating increasingly narrow patient populations that may not reflect real-world treatment contexts. As an industry, we must consider whether this drift toward complexity serves patient needs or primarily serves regulatory and liability concerns.
Strategic Implications for Clinical Development
These patterns have profound implications for how we approach clinical development strategy:
For Patient Access: The predominance of exclusion criteria may be systematically limiting the diversity and representativeness of trial populations, potentially reducing the generalizability of our findings.
For Enrollment Strategy: Understanding the typical criteria ranges by therapeutic area and phase can inform more realistic enrollment projections and site selection decisions.
For Protocol Design: The data suggests we should critically examine each exclusion criterion's necessity and consider whether some restrictions reflect outdated thinking rather than current scientific understanding.
Moving Forward: Balancing Rigor with Accessibility
As we design the next generation of clinical trials, these insights challenge us to be more intentional about eligibility criteria. Each exclusion criterion should be justified not just by safety or regulatory precedent, but by its contribution to answering the research question while maintaining reasonable patient access.
The goal is not to eliminate necessary exclusions, but to ensure that every criterion serves a clear scientific or safety purpose. In an era where patient centricity is increasingly recognized as essential to successful clinical development, understanding and optimizing the architecture of trial eligibility represents both an operational imperative and an ethical obligation.
Streamlining Protocol Communication
Given that trials average 8-12 inclusion and 15-20 exclusion criteria, Clinials can generate plain-language clinical trial materials, multilingual summaries, patient information sheets, landing pages, prescreening, and more in minutes. This directly addresses the complexity barrier that comes with increasingly restrictive eligibility criteria.
Operational Efficiency Gains
The platform delivers measurable improvements that directly impact the challenges of complexity and stringent inclusions and exclusions:
Improving feasibility by 70% and halving site startup time
Responding to RFPs 70% faster
Automated workflows that streamline communication
Addressing the "Two-Thirds Exclusion Rule" Challenge
When two-thirds of criteria are exclusions. Clinials' content generation can help by:
1. Making Complex Criteria Accessible: Creating both scientific and plain language materials in different languages, making complex trial information accessible and clear for all audiences
2. Reducing Interpretation Barriers: When criteria are numerous and complex (especially in oncology trials with 20-30+ exclusions), automated generation of clear, consistent explanations reduces the cognitive load on both sites and patients
3. Standardizing Communication: As criteria complexity increases (~0.4 per year), having automated, consistent communication becomes more critical to prevent enrolment delays
Strategic Impact on Your Key Concerns
This data emphasized the need to balance rigor with accessibility. Clinials helps by:
Democratizing Understanding: Complex protocols become more accessible when automatically translated into multiple formats and languages
Reducing Human Error: Automated generation reduces inconsistencies in how complex criteria are communicated across sites
Accelerating Decision-Making: Freeing up clinicians and research teams to focus on strategic decisions rather than documentation
Supporting Evidence-Based Protocol Design
During feasibility or site startup he platform's ability to rapidly generate multiple communication variants could support A/B testing of different criterion explanations, helping determine which formulations lead to better patient understanding and appropriate self-selection.
Bottom Line: While the analysis shows the industry is trending toward more complex eligibility criteria, Clinials' content generation platform provides the operational infrastructure to manage the communication of this complexity without sacrificing patient access or site efficiency. It transforms the challenge of communicating increasingly complex protocols into a scalable, automated solution.
