Table of Contents
- Key Points
- Background: Why Trial Eligibility Rules Matter
- How the Study Was Conducted
- Why Patients Failed Screening: The Full Picture
- Potentially Modifiable Exclusions: The 69 Patients Who Might Have Qualified
- Detailed Examples of Modifiable Exclusions
- What This Means for Patients
- Limitations: What the Study Could Not Prove
- Recommendations and Next Steps
- Frequently Asked Questions
- Source Information
Key Points
- In a review of 509 patients with pancreatic or biliary tract cancer, 69 (13.6%) had exclusions that might have been safely relaxed.
- Most potentially modifiable exclusions involved borderline laboratory values, such as mildly abnormal liver or kidney tests or blood counts just below cutoff limits.
- Organ function and blood count rules accounted for 43% and 25% of potentially modifiable exclusions, respectively.
- The authors suggest that loosening rigid eligibility rules could let more real-world patients access experimental treatments without greater risk.
- Any relaxation of criteria must still preserve patient safety and scientific integrity, and prospective research is needed to evaluate broadened eligibility.
Background: Why Trial Eligibility Rules Matter
Clinical trials are the foundation of every new cancer treatment. The rules that decide who can join — called eligibility criteria — define the study population. These rules exist to keep patients safe and to keep the research clean and trustworthy.
But there is a growing problem. Rules that are too strict can shut out a large share of real-world patients who might actually benefit from a new treatment. The consequences reach far beyond a single patient. Most studies fail to recruit enough people within their planned timelines, and the results may not reflect how a drug performs in everyday practice.
The scale of the problem is striking: only 7.1% of patients with cancer in the United States currently take part in a clinical trial. That means fewer than 1 in 14 patients ever joins one.
Cancer treatment has changed dramatically. It has moved from traditional cytotoxic chemotherapy (drugs that kill fast-dividing cells) toward targeted molecular agents (drugs aimed at specific cancer mutations) and immune therapeutics (treatments that help the immune system attack cancer). Yet many eligibility rules were written decades ago, during the chemotherapy era, and were carried forward without being updated. Studies show these criteria have grown both more numerous over time and less representative of the typical patient with cancer.
This mismatch matters most for two hard-to-treat diseases: biliary tract cancer (BTC), which arises in the bile ducts or gallbladder, and pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer. Both are becoming more common and both carry a poor prognosis. For patients with advanced disease, median overall survival (the point at which half of patients are still alive) is only about 12 months. New options are urgently needed, which makes trial access especially important.
Despite recent calls to modernize eligibility criteria, few studies have examined how these rules play out specifically in pancreatic and biliary cancers. This research fills that gap.
How the Study Was Conducted
This was a retrospective study — meaning researchers looked backward at records already collected rather than enrolling new patients. It took place at The University of Texas MD Anderson Cancer Center in Houston.
The team reviewed all adults with confirmed biliary tract cancer or pancreatic ductal adenocarcinoma who were found ineligible for cancer clinical trials between August 2019 and November 2024. Patients were identified by systematically reviewing the screening logs of every trial during that period that included people with BTC and/or PDAC, so that no potential candidate was missed.
The researchers focused on screen-failed patients. This term covers anyone who was referred for screening and gave informed consent (formal permission after learning the risks and details) but then did not join the trial for any reason. That includes not meeting eligibility criteria, withdrawing consent, or failing other protocol-specific requirements.
Patients with insufficient documentation in their medical records were excluded to protect data quality. Clinical information came from electronic health records and was cross-checked against screening logs kept by research coordinators.
The heart of the study was identifying potentially modifiable exclusions (PMEs). A PME is any factor that caused screening failure but could possibly have been changed or waived — allowing the patient to join the trial without threatening safety or study integrity.
Critically, PMEs were not predetermined. They were identified only after a full review of each patient's record, weighing:
- Other medical conditions (comorbidities)
- Laboratory results
- How stable the patient's clinical condition was
- How the investigational drug works (its mechanism of action)
- Documented safety data from similar drugs
- How the patient later tolerated standard therapy
Two experienced medical oncologists independently applied a structured framework. They classified an exclusion as potentially modifiable when the patient's value was within 10%–15% of the eligibility threshold and was unlikely to significantly affect patient safety or study integrity. All co-investigators agreed on this approach.
The researchers also tracked what happened to each patient with a PME afterward, to see how they fared. Finally, they used descriptive statistics (simple summaries of the data) to report how common screen failures were and what caused them.
Why Patients Failed Screening: The Full Picture
Across 18 clinical trials, 585 patients failed screening. Of these, 76 were excluded because of incomplete information, leaving 509 patients for analysis: 367 with pancreatic cancer and 142 with biliary tract cancer.
The 18 trials included 10 for biliary tract cancer and 8 for pancreatic cancer. By phase:
- 4 phase 1 trials (early safety and dosing studies)
- 7 phase 1/2 trials
- 6 phase 2 trials (testing effectiveness)
- 1 phase 3 trial (large, definitive comparison)
All trials enrolled patients with advanced cancer. Eight trials tested targeted therapy, seven tested combinations of chemotherapy plus targeted therapy, two tested cellular therapy or cancer vaccines, and one tested a targeted therapy combined with an immune checkpoint inhibitor (a drug that releases brakes on the immune system).
The three most common reasons for screening failure were:
- Patient declined or withdrew consent — 99 patients (19%)
- Coexisting severe comorbidities — 59 patients (12%)
- Suboptimal organ function (kidney or liver) — 56 patients (11%)
Other reasons, in order of frequency, were:
- Absence of a required biomarker — 49 patients (10%)
- Screening error — 44 patients (9%)
- Research team logistics — 43 patients (8%)
- Lack of a biospecimen (tissue or blood sample) — 36 patients (7%)
- Previous therapy exceeding inclusion criteria limits — 28 patients (6%)
- Physician's decision or discretion — 25 patients (5%)
- Suboptimal performance status (overall fitness level) — 21 patients (4%)
- Concurrent or previous malignancy (another cancer) — 21 patients (4%)
- Cohort closed for enrollment — 12 patients (2%)
- Concomitant therapy that may interact with the study drug — 11 patients (2%)
- Lack of measurable disease — 5 patients (1%)
Within the group who declined to participate, the reasons break down as follows:
- Preference for standard care — 23 patients (4%)
- Travel constraints — 22 patients (4%)
- Competing trial availability — 5 patients (1%)
- Concerns about adverse events (side effects) — 4 patients (1%)
- Financial limitations — 3 patients (1%)
- Unknown reasons — 42 patients (8%)
That last figure stands out. Nearly half of the patients who withdrew consent gave no documented reason. This is a meaningful gap in understanding, and it points to opportunities both to improve trial design and to better educate patients.
Potentially Modifiable Exclusions: The 69 Patients Who Might Have Qualified
Among the 509 patients analyzed, 69 patients (13.6%) — roughly 1 in 7 — had exclusions that the expert reviewers judged potentially modifiable. These PMEs were spread evenly across trials, meaning no single study was the culprit.
The two largest categories were:
- Organ function abnormalities — 30 patients (43% of PMEs)
- Hematologic (blood) abnormalities — 17 patients (25% of PMEs)
Within organ function, the specific issues were strict cutoffs for liver function (16 patients, 23%) and kidney function (14 patients, 20%).
Within blood abnormalities, the breakdown was:
- Hemoglobin (oxygen-carrying protein in red blood cells) — 5 patients (7%), with values in the grade 1–2 range (from below 10 down to 8 g/dL)
- Absolute neutrophil count (a type of white blood cell that fights infection) — 4 patients (6%), in the grade 1–2 range (from below 1500 down to 1000/mm³)
- Platelet count (cells that help blood clot) — 8 patients (12%). Five had grade 1 low platelets (from below the lower limit of normal down to 75,000/mm³), and three had grade 1–2 low platelets (from below 75,000 down to 50,000/mm³)
Additional organ function details were equally mild. Fourteen patients had grade 2 creatinine clearance (a measure of kidney filtering) between 60 and 30 mL per minute. For bilirubin (a liver pigment), three patients had grade 1 elevation (above the upper limit of normal up to 1.5 times that limit) and ten had grade 2 elevation (from 1.5 to 3.0 times the limit). Three patients had grade 2 elevation of liver enzymes (from 3.9 to 5 times the upper limit of normal).
Beyond lab values, other PMEs included:
- Previous or concurrent malignancy — 6 patients (9%)
- Tumor-specific criteria — 6 patients (9%)
- Hepatitis B or C viral infection — 3 patients (4%)
- Recent chemotherapy or radiotherapy — 3 patients (5%)
- History of alcohol or substance use — 2 patients (3%)
- History of gastrointestinal bleeding — 1 patient (1%)
- Ongoing medication conflicts — 1 patient (1%)
The researchers plotted how far each patient's values deviated from the required thresholds. This visualization, shown as a boxplot, revealed that most deviations were small rather than extreme.
Detailed Examples of Modifiable Exclusions
The individual stories behind these numbers help explain why the authors see room for flexibility.
Among the six patients excluded because of another cancer, two had early-stage non–small cell lung cancer (stage IA and stage IB), and one had a localized basal cell carcinoma (a common, highly treatable skin cancer). All three were diagnosed within 5 years of screening and were treated with curative intent. The other three had chronic lymphocytic leukemia (a slow-growing blood cancer) under surveillance, breast cancer treated 19 years earlier, and cervical cancer treated 25 years earlier. Importantly, none of these six patients experienced progression of their earlier cancer during screening or during subsequent therapy.
Three patients were excluded because of hepatitis B or C infection. All three had viral DNA levels within normal limits and normal alanine transaminase levels (a liver enzyme marker). In other words, their infections were well controlled.
Two patients were excluded for a history of alcohol or substance use. One had been abstinent for 5 months when the trial required 6 months. The other had been abstinent for 17 years.
One patient was excluded for gastrointestinal bleeding. On endoscopy, he had duodenitis (inflammation of the first part of the small intestine) without varices (enlarged veins) or peptic ulcers. He never had a drop in hemoglobin or unstable vital signs, and he never needed a red blood cell transfusion.
Three patients were excluded for recent chemotherapy or radiotherapy when the protocol required a 6-month washout period (a waiting period after treatment). One had completed concurrent chemoradiotherapy 5 months before screening, another at 5.5 months, and one had received adjuvant chemotherapy 5 months before screening. Each fell just short of the required window.
One patient was excluded for ongoing treatment with leuprolide, a gonadotropin-releasing hormone agonist (a drug that suppresses certain hormones). Leuprolide has no known interaction with the study drug and no significant immune-suppressing or bone-marrow-suppressing effects.
Finally, six patients were excluded based on interpretations of criteria that were not explicitly defined in the protocol itself — such as KRAS mutation status (a specific cancer gene change), liver metastases (cancer spread to the liver), or tumor marker levels.
Notably, most of these patients went on to receive standard-of-care therapies afterward. Their subsequent treatments included chemotherapy alone, targeted therapy alone, combinations of chemotherapy with targeted therapy, chemotherapy with immune checkpoint inhibitors, and targeted therapy with immune checkpoint inhibitors.
What This Means for Patients
The central message is direct: rigid eligibility criteria exclude stable patients who might benefit from investigational treatments.
Because roughly 1 in 7 screen failures were potentially modifiable, a substantial number of additional patients could have joined these trials if the criteria had been thoughtfully adjusted. Organ function and blood count rules accounted for 43% and 25% of those modifiable exclusions, respectively.
Why do these rules exist? Largely for historical reasons. They were built for traditional cytotoxic chemotherapy, which is far harder on the body than many modern targeted drugs. Those old standards may simply not fit the safety profiles of today's treatments.
Evidence from other cancers supports this view. Patients excluded under strict eligibility rules have gone on to tolerate standard-of-care treatments well, even when their blood counts and organ function values sat near threshold limits. Trial access has already been broadened successfully in other areas — including for patients with brain metastases, human immunodeficiency virus (HIV) infection, and prior or concurrent cancers. That success sets a precedent.
The stakes are high for pancreatic and biliary cancers specifically. These patients often have borderline liver dysfunction, and their median overall survival is only about 12 months. For them, trial participation and completion are crucial to advancing treatment options and improving outcomes.
Any changes to eligibility criteria must still carefully balance wider access against patient safety and scientific validity. The goal is not to remove safeguards — it is to make sure safeguards actually match the risks.
Limitations: What the Study Could Not Prove
The authors are candid about the study's weaknesses.
- Retrospective design. Looking backward at records limits how firmly cause and effect can be established.
- Single institution. All patients came from one cancer center, so findings may not fully apply elsewhere.
- Subjective judgment. Even with two independent oncologists and agreement from co-investigators, deciding whether an exclusion was "potentially modifiable" involves interpretation and is prone to bias.
- Incomplete records. The review may have missed some possible modifications to eligibility criteria.
- Limited follow-up. Data after screening failure were incomplete, including how well patients tolerated subsequent standard treatments and what side effects they experienced.
To address these gaps, the authors call for future research that prospectively evaluates the impact of broadened eligibility criteria — that is, studying patients forward in time rather than looking back — with attention to both trial outcomes and patient safety in pancreaticobiliary cancers.
Recommendations and Next Steps
Based on their findings, the researchers offer several concrete recommendations.
- Re-examine rigid organ function criteria, especially for pancreaticobiliary cancers, where borderline liver dysfunction is common.
- Consider a flexible, data-driven strategy. Instead of fixed cutoffs, criteria could be adjusted based on real-time feedback from ongoing study data.
- Modernize trial design. Decentralized protocols, hybrid visit models (combining in-person and remote check-ins), and risk-adaptive approaches could address the logistical and safety concerns that deter participation.
- Improve patient education. Better communication about what trials involve could correct misconceptions, and researchers should capture detailed reasons whenever a patient declines.
- Strengthen biomarker testing strategies. Early molecular profiling could streamline patient selection and cut down on unnecessary screening procedures.
- Fix operational bottlenecks. Screening errors (9%) and research team logistics (8%) point to coordination gaps between clinical research teams and treating physicians.
These recommendations align with a broader movement in oncology. The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research launched initiatives beginning in 2017 to modernize trial eligibility, addressing barriers such as brain metastases, organ function requirements, concurrent malignancies, HIV status, and age restrictions. In 2021, those guidelines expanded to cover washout periods, concomitant medications (other medicines taken at the same time), prior therapies, laboratory parameters, and performance status.
One caution is repeated throughout: any relaxation of criteria must preserve both patient safety and scientific integrity. Broader access should never come at the cost of trustworthy results.
Frequently Asked Questions
What are potentially modifiable exclusions in cancer trials?
Potentially modifiable exclusions are reasons a patient failed screening that might have been safely changed or waived. In a review of 509 patients with pancreatic or biliary tract cancer, 69 (13.6%) had such exclusions. Most involved borderline laboratory values, like mildly abnormal liver or kidney tests or blood counts just below cutoff limits, rather than true safety threats.
How common are potentially modifiable exclusions in pancreatic and biliary cancer trials?
In a review of 509 patients with pancreatic or biliary tract cancer who consented but could not join trials, about 1 in 7 (13.6%, or 69 patients) had exclusions that might have been safely relaxed. These were spread evenly across 18 trials, so no single study was responsible. Most involved borderline organ function or blood count values.
What were the most common reasons patients failed screening?
Among 509 patients, the three most common reasons for screening failure were: patient declined or withdrew consent (99 patients, 19%), coexisting severe comorbidities (59 patients, 12%), and suboptimal organ function (56 patients, 11%). Other reasons included absence of a required biomarker, screening error, research team logistics, and lack of a biospecimen.
What happened to patients who were excluded from trials due to modifiable reasons?
Most patients with potentially modifiable exclusions went on to receive standard-of-care therapies afterward. Their subsequent treatments included chemotherapy alone, targeted therapy alone, combinations of chemotherapy with targeted therapy, chemotherapy with immune checkpoint inhibitors, and targeted therapy with immune checkpoint inhibitors. The review did not fully capture how well they tolerated these later treatments.
What are the risks of relaxing eligibility criteria for cancer trials?
Any changes to eligibility criteria must still carefully balance wider access against patient safety and scientific validity. The goal is not to remove safeguards but to make sure safeguards actually match the risks. The authors emphasize that broader access should never come at the cost of trustworthy results, and they call for prospective research to evaluate broadened criteria.
If I have pancreatic or biliary tract cancer and was told I failed clinical trial screening because of borderline liver, kidney, or blood test results, should I get a second opinion?
Roughly 1 in 7 screen failures in pancreatic and biliary tract cancer involved exclusions that expert reviewers judged potentially modifiable, mostly borderline liver or kidney values and blood counts just below cutoff limits rather than true safety threats. Two experienced oncologists classified an exclusion as potentially modifiable when values sat within 10%–15% of the threshold and were unlikely to affect safety or study integrity. A second opinion can help determine whether rigid criteria, many inherited from the chemotherapy era, actually apply to your situation. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Broadening the gates - Analysis of potentially modifiable study entry criteria in cancer trials
Authors: Fen Saj, MD, DM; Felicity K. Namayanja, MBChB, MPH; Lianchun Xiao, MS; Mitesh J. Borad, MD; Robin Kate Kelley, MD; Lipika Goyal, MD, MPhil; Nilofer S. Azad, MD; Melinda Bachini; Stacie Lindsey, BA; Shubham Pant, MD; Juan W. Valle, MBChB, MSc, FRCP; Lola A. Fashoyin-Aje, MD, MPH; Milind Javle, MD
Institutions: The University of Texas MD Anderson Cancer Center (Houston, Texas); Mayo Clinic (Scottsdale, Arizona); Helen Diller Family Comprehensive Cancer Center, University of California–San Francisco; Stanford Cancer Center (Palo Alto, California); Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine (Baltimore, Maryland); The Cholangiocarcinoma Foundation (Herriman, Utah); University of Manchester (Manchester, UK); and the Oncology Center of Excellence, US Food and Drug Administration (Silver Spring, Maryland)
Journal: Cancer (published by Wiley Periodicals LLC on behalf of the American Cancer Society)
Publication details: Received 24 March 2025; Revised 18 August 2025; Accepted 4 November 2025; published 2026; DOI: 10.1002/cncr.70227
This patient-friendly article is based on peer-reviewed research.
