Abstract
Background
Eligibility criteria for clinical trials are crucial for maintaining safety and study integrity. However, overly restrictive criteria can result in unrepresentative trial populations, leading to gaps in understanding real‐world treatment efficacy. Addressing potentially modifiable exclusions (PMEs) could enhance trial accessibility and participation without compromising safety.
Methods
The authors retrospectively analyzed screen‐failed patients with biliary tract cancer or pancreatic cancer between August 2019 and November 2024 at The University of Texas MD Anderson Cancer Center. Screen‐failed patients were those who provided informed consent but did not participate for any reason. Clinical data were obtained from screening logs and electronic health records. PMEs were identified and validated by two independent medical oncologists.
Results
Of 585 screen‐failed patients from 18 trials, 509 were analyzed (367 with pancreatic cancer and 142 with biliary tract cancer) after excluding 76 because of incomplete data. Leading causes of screen failure were declined participation (19%), comorbidities (12%), suboptimal organ function (11%), absence of a biomarker (10%), and insufficient biospecimens (7%). Reasons for declining included preference for standard care (23%), travel (22%), and competing trials (5%). The authors identified 69 patients (13.6%) who had PMEs (primarily borderline laboratory abnormalities), including liver function (23%), kidney function (20%), platelet count (12%), hemoglobin (7%), and white blood cell count (6%) abnormalities. Other PMEs included previous or concurrent malignancies (9%) and viral hepatitis (4%). PMEs were evenly distributed across trials.
Conclusions
Rigid eligibility criteria exclude stable patients who might benefit from investigational treatments. Easing criteria related to incidental or asymptomatic laboratory abnormalities could broaden trial accessibility and improve enrollment in populations that are more representative of real‐world use.
Keywords: biliary tract cancer, clinical trials, eligibility criteria, pancreatic cancer, screen failure
Short abstract
Restrictive study entry criteria in pancreatic and biliary tract cancer trials led to exclusion of stable patients who might benefit from investigational treatments. Easing specific criteria could broaden trial access and representation.
INTRODUCTION
Clinical trials are the cornerstone of cancer therapy development, with their success hinging on carefully designed eligibility criteria that define the study population. 1 , 2 Although these criteria aim to identify patients most likely to benefit from experimental treatments and minimize safety risks, an emerging challenge has become apparent: overly restrictive requirements may exclude a significant proportion of real‐world patients who could potentially benefit from trial participation. 3 , 4 , 5 The consequences of such stringent eligibility criteria are far‐reaching. They not only limit trial accrual—with most studies failing to meet recruitment targets within planned timelines—but they also potentially compromise the generalizability of results to routine clinical practice. 6 , 7 This disconnect is particularly concerning because only 7.1% of patients with cancer in the United States currently participate in clinical trials. 8
The evolution of cancer therapeutics from cytotoxic chemotherapy to targeted molecular agents and immune therapeutics has further highlighted this challenge. Many traditional eligibility criteria, carried forward from the chemotherapy era, may be unnecessarily restrictive for modern targeted therapies. 9 , 10 Studies have shown that these criteria have not only increased in number over time but have become progressively less representative of the typical population of patients with cancer. 5 , 11
This is particularly relevant for biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC), in which the rising incidence and poor prognosis create an urgent need for new therapeutic options. 12 , 13 Despite recent recommendations to modernize the eligibility criteria, 14 , 15 their implementation and impact specifically in BTC and PDAC clinical trials remain underexplored. Our research addresses this gap by analyzing screen failures and potentially modifiable exclusions (PMEs) in BTC and PDAC trials, with the objective of identifying opportunities to enhance trial participation.
MATERIALS AND METHODS
This retrospective study was conducted at The University of Texas MD Anderson Cancer Center and focused on adult patients with histologically confirmed BTC or PDAC who were deemed ineligible for participation in cancer clinical trials between August 2019 and November 2024. Patients were systematically identified through an extensive review of the screening logs from all trials conducted during this period that included patients who had BTC and/or PDAC, ensuring that every potential candidate was considered.
Screen‐failed patients were broadly defined as those who were referred for screening and had provided informed consent but subsequently did not participate in the trial for any reason, including not meeting eligibility criteria, withdrawal of consent, or other protocol‐specific requirements. To maintain the integrity of the data, individuals with insufficient documentation in their medical records were excluded from the analysis. A key aspect of the study was identifying PMEs, which refers to factors causing screen failure that could have potentially been modified or eliminated, enabling the patient to join a clinical trial without jeopardizing safety or the overall integrity of the study. The PMEs were not predetermined and were identified after a comprehensive review of each patient's medical record, including assessments of comorbidities, laboratory results, clinical stability, mechanism of action of the investigational agent, documented safety data from similar agents, and subsequent tolerance to standard therapy. Two experienced medical oncologists (M.J. and S.P.) independently applied a structured evaluation framework that classified exclusions as potentially modifiable when they were within 10%–15% of eligibility thresholds and unlikely to significantly affect patient safety or study integrity. This classification framework was agreed upon by all co‐investigators.
Detailed clinical information was extracted from electronic health records and cross‐referenced with screening log data provided by research coordinators to ensure accuracy and completeness. Moreover, the clinical course of all patients with identified PMEs was carefully followed to assess outcomes and implications for future trial eligibility criteria. Finally, descriptive statistics were used to summarize the findings, providing valuable insights into the frequency and nature of screen failures and highlighting opportunities for modifying exclusion criteria in future clinical trials.
RESULTS
In total, 585 patients who failed screening were identified across 18 clinical trials. Seventy‐six patients were excluded due to incomplete information. Of the 509 patients analyzed, 142 had BTC and 367 had PDAC. Among the 18 included trials, 10 were for BTC and 8 for PDAC (see Table S1). The trials included four phase 1 studies, seven phase 1/2 studies, six phase 2 studies, and one phase 3 study. All trials enrolled participants with advanced cancer. Eight trials investigated targeted therapy, seven investigated combinations of chemotherapy and targeted therapy, two investigated cellular therapy or cancer vaccines, and one studied a combination of targeted therapy with an immune checkpoint inhibitor.
The three most common reasons for screen failure were patient withdrawal of consent (n = 99; 19%), coexisting severe comorbidities (n = 59; 12%), and suboptimal organ function (renal or liver function; n = 56; 11%). The main reasons patients declined participation included preference for standard care (n = 23; 4%), travel constraints (n = 22; 4%), competing trial availability (n = 5; 1%), concerns about adverse events (n = 4; 1%), financial limitations (n = 3; 1%), and unknown reasons (n = 42; 8%). A detailed list of the reasons for screen failure is provided in Table 1.
TABLE 1.
Reasons for screen failure, n = 509.
| Category | No. of patients (%) |
|---|---|
| Patient declined or withdrew consent | 99 (19.0) |
| Preference for standard care | 23 (4.0) |
| Travel | 22 (4.0) |
| Competing trials | 5 (1.0) |
| Adverse event concerns | 4 (1.0) |
| Financial issues | 3 (1.0) |
| Unknown reasons | 42 (8.0) |
| Coexisting severe comorbidities | 59 (12.0) |
| Organ function status suboptimal | 56 (11.0) |
| Absence of biomarkers | 49 (10.0) |
| Screen error | 44 (9.0) |
| Research team logistics | 43 (8.0) |
| Lack of biospecimen | 36 (7.0) |
| Previous therapy exceeding inclusion criteria limits | 28 (6.0) |
| Physician’s decision or discretion | 25 (5.0) |
| Performance status suboptimal | 21 (4.0) |
| Concurrent or previous malignancy | 21 (4.0) |
| Cohort closed for enrollment | 12 (2.0) |
| Concomitant therapy that may interact with the study drug | 11 (2.0) |
| Lack of measurable disease | 5 (1.0) |
We identified 69 patients (13.6%) who had PMEs (Table 2). The most common reasons were organ function abnormalities (n = 30; 43%) and hematologic abnormalities (n = 17; 25%). Organ function abnormalities included strict eligibility criteria for liver function (n = 16; 23%) and kidney function (n = 14; 20%). Five patients had hemoglobin in the grade 1–2 range (from <10 to 8 g/dL), four had absolute neutrophil counts in the grade 1–2 range (from <1500 to 1000/mm3), five had platelets grade 1 (from less than the lower limit of normal to 75,000/mm3), and three had platelets in the grade 1–2 range (from <75,000 to 50,000/mm3). Fourteen patients had grade 2 creatinine clearance levels (60–30 mL per minute). Three patients had grade 1 bilirubin elevation (from greater than the upper limit of normal [>ULN] to 1.5 times the ULN), 10 had grade 2 elevation (from >1.5 to 3.0 times the ULN), and three had grade 2 elevation of liver enzymes (from >3.9 to 5 times the ULN). 16 We have plotted the reduction factor for hematologic and organ function parameters in Figure 1, illustrating the extent of deviation from the eligibility requirements.
TABLE 2.
Potentially modifiable exclusions, n = 69.
| Category | No. of patients (%) |
|---|---|
| Hematologic abnormalities | |
| Hemoglobin level | 5 (7.0) |
| Absolute neutrophil count | 4 (6.0) |
| Platelet count | 8 (12.0) |
| Organ function abnormalities | |
| Liver function test | 16 (23.0) |
| Kidney function test | 14 (20.0) |
| Personal/past medical history | |
| Hepatitis B or C viral infection | 3 (4.0) |
| Previous or concurrent malignancy | 6 (9.0) |
| History of alcohol/substance use | 2 (3.0) |
| History of gastrointestinal bleeding | 1 (1.0) |
| Recent chemotherapy/radiotherapy | 3 (5.0) |
| Ongoing medication conflicts | 1 (1.0) |
| Tumor‐specific criteria | 6 (9.0) |
FIGURE 1.
Box plot depicting the reduction factor for hematologic and organ function parameters. The reduction factor represents the extent to which individual values deviate from eligibility requirements. Each box represents the interquartile range (IQR), with the horizontal line inside indicating the median. Whiskers extend to the minimum and maximum values within 1.5 times the IQR, whereas outliers are displayed as individual points. Parameters include hemoglobin (Hb), absolute neutrophil count (ANC), platelet count, creatinine clearance, total bilirubin, and serum aspartate and alanine transaminase levels (AST/ALT). PMEs indicates potentially modifiable exclusions.
Among the six patients who failed screening because of previous or concurrent malignancy, two had early stage nonsmall cell lung cancer (stage IA and IB), and one had localized basal cell carcinoma; all diagnosed within 5 years of screening and were treated curatively. The remaining three patients had chronic lymphocytic leukemia on surveillance, breast cancer treated 19 years ago, and cervical cancer treated 25 years ago, respectively. None of these patients experienced progression of their previous malignancy during screening or subsequent therapy.
The three patients who were excluded because of hepatitis B or C viral infection had viral DNA within normal limits and normal alanine transaminase levels. Two patients who were excluded because of a history of alcohol or substance use had been abstinent for a significant period—one for 5 months when the trial criteria mandated 6 months of abstinence and the other for 17 years.
The patient who was excluded because of gastrointestinal bleeding had duodenitis on endoscopy without varices or peptic ulcers. He did not experience hemoglobin drop or hemodynamic instability and did not require red blood cell transfusion.
Among the three patients who failed screening because of previous chemotherapy or radiotherapy, one had completed concurrent chemoradiotherapy 5 months before screening, another had completed concurrent chemoradiotherapy 5.5 months before screening, and one had received adjuvant chemotherapy 5 months before screening, with the protocol requiring a 6‐month washout period. In addition, one patient was excluded because of ongoing treatment with leuprolide (a gonadotropin‐releasing hormone agonist), although the drug has no known interaction with the study drug or significant immunosuppressive or myelosuppressive effect. 17 Six patients were excluded based on interpretations of criteria not explicitly defined in the protocol, such as KRAS mutation status, liver metastases, or tumor marker levels. The list of PMEs is provided in Table 2. Notably, a majority of these patients received subsequent standard‐of‐care therapies. The details are provided in Figure 2 and Table S2.
FIGURE 2.
Subsequent therapy received by patients with potentially modifiable exclusions (n = 69) from a phase 1 drug trial. CCRT indicates concurrent chemoradiotherapy; CT, chemotherapy alone; CT, IO, chemotherapy and immune checkpoint inhibitors; CT, TT, chemotherapy and targeted therapy; TT, targeted therapy alone; TT, IO, targeted therapy and immune checkpoint inhibitors.
DISCUSSION
This study provides important insights into the patterns of screen failures in clinical trials for biliary tract and pancreatic cancers, with particular emphasis on potentially modifiable exclusions. Our findings highlight several key areas in which clinical trial eligibility criteria could be reconsidered to improve patient participation while maintaining trial integrity and patient safety.
Our analysis revealed that 13.6% of screen failures were potentially modifiable, indicating that, with thoughtfully adjusted eligibility criteria, a substantial number of additional patients could have participated in clinical trials. It is particularly significant that organ function abnormalities and hematologic parameters accounted for 43% and 25% of these potentially modifiable exclusions, respectively. These restrictive criteria often stem from historical standards developed for traditional cytotoxic chemotherapy—standards that may not reflect the distinct safety profiles of modern, targeted therapies. 14 , 18 Evidence from studies involving other cancers has demonstrated that patients who were excluded because of stringent eligibility criteria successfully tolerated standard‐of‐care treatments, even when their hematologic and organ function values were near threshold limits. 19 , 20 , 21 , 22 Recent progress in broadening trial access, such as the successful inclusion of patients with brain metastases, human immunodeficiency virus infection, and prior and/or concurrent malignancies. sets an important precedent. 23 , 24 , 25 Drawing on these recent data, we recommend re‐examining the rigid organ function criteria currently applied in clinical trials—especially those for pancreaticobiliary cancers, in which patients often exhibit borderline liver dysfunction. An alternative approach would be to implement a flexible strategy that allows for adjustments to these criteria based on real‐time feedback from study data.
Patient withdrawal of consent represented the largest category of screen failures (19%), with travel considerations, preference for standard care, and concerns about adverse events as key factors. Although these findings align with previous studies on logistical barriers to trial participation, 26 , 27 the finding that nearly one half of consent withdrawals had undocumented reasons represents a critical gap in our understanding. This pattern suggests two clear opportunities for improvement. First, modern trial design innovations—including decentralized protocols, hybrid visit models, and risk‐adaptive approaches—could directly address the logistical and safety concerns that deter participation. 28 , 29 Second is the opportunity to improve patient education by addressing misconceptions about clinical trials while capturing more detailed insights when patients decline participation. 30 , 31
The presence of biomarker‐related screen failures (10%) reflects the increasing complexity of precision medicine trials but also highlights the need for more efficient biomarker testing strategies. 32 This finding suggests that early molecular profiling could help streamline patient selection and reduce unnecessary screening procedures. 33 , 34 In addition, screen failures related to screen error (9%) and research team logistics (8%) suggest opportunities for operational improvements. Enhanced coordination between clinical research teams and treating physicians, along with streamlined screening processes, could potentially reduce these administrative barriers to trial participation. 35 , 36
Our results support the broader movement toward more inclusive eligibility criteria in oncology trials, as advocated by major professional organizations. 15 , 37 , 38 Recognizing these challenges, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research launched initiatives to modernize trial eligibility. Their 2017 recommendations addressed key barriers, including brain metastases, organ function requirements, concurrent malignancies, human immunodeficiency virus status, and age restrictions. 14 In 2021, they expanded these guidelines to encompass washout periods, concomitant medications, prior therapies, laboratory parameters, and performance status. 15 Subsequent research in solid tumors has validated this approach, demonstrating that many traditionally excluded patients can safely receive standard therapies without increased complications. 19 , 26 , 39 The implications of these findings are particularly significant for patients with advanced stages of BTC and PDAC who face a grim prognosis, with median overall survival of only approximately 12 months. 12 , 13 For these patients, clinical trial participation and completion is crucial to advance treatment options and improve outcomes. The identification of specific PMEs provides actionable insights for future trial design. However, any modifications to eligibility criteria must carefully balance increased access with patient safety and scientific validity. 40
Limitations of our study include its retrospective nature and single‐institution setting, which may limit generalizability. The assessment of PMEs was based on a retrospective review of medical records and may not have captured all potential modifications to eligibility criteria. Although the assessment of PMEs was conducted by two independent oncologists and confirmed by the co‐investigators, it remains inherently subjective and prone to bias. Limited follow‐up time and incomplete data after screen failure (e.g., with respect to tolerability/treatment‐related adverse events on standard subsequent therapy) further restrict our analysis. Future research should prospectively evaluate the impact of broadened eligibility criteria on trial outcomes and patient safety in pancreaticobiliary cancers.
Conclusion
Our current study highlights the effect of restrictive eligibility criteria on patient accrual in biliary tract and pancreatic cancer clinical trials. By addressing potentially modifiable exclusions and implementing novel trial designs, we can broaden the gates of clinical trial participation and accelerate the development of novel therapies that are generalizable to real‐world populations.
AUTHOR CONTRIBUTIONS
Fen Saj: Investigation, writing–original draft, and writing–review and editing. Felicity K. Namayanja: Data curation and investigation. Lianchun Xiao: Formal analysis. Mitesh J. Borad: Validation. Robin Kate Kelley: Validation. Lipika Goyal: Validation. Nilofer S. Azad: Validation. Melinda Bachini: Validation. Stacie Lindsey: Validation. Shubham Pant: Validation, investigation, and supervision. Juan W. Valle: Validation. Lola A. Fashoyin‐Aje: Validation. Milind Javle: Conceptualization, investigation, writing–review and editing, and supervision.
CONFLICT OF INTEREST STATEMENT
Mitesh J. Borad reports institutional grants/contracts from Agios, Alentis Therapeutics, Arvinas, AstraZeneca, Basilea, Biond, Cogent, Compass Therapeutics, Elevar, Elevation, H3 Biomedicines, Incyte, Medinlink, Nuvectis, Pfizer, RayzeBio, Relay Therapeutics, Revolution Medicines, Sanofi, SeaGen, and Tango Therapeutics; personal/consulting fees from Amplia, George Clinical, Guardant, Imugene, Revolution Medicines, and Servier; service on a Data Safety Monitoring Board or Advisory Board for Accession Therapeutics, Breakthru Bio, Cardinal Health, Cedilla, Cogent, Compass Therapeutics, Diffusion Pharmaceuticals, Eisai, Elevar, Exelixis, IMVAX, Jazz Pharmaceuticals, Kalivir Immunotherapeutics, Karkinos, Khora, Kriya Therapeutics, Merck, Moderna, Orum Therapeutics, Processa, RayzeBio, Reignite Therapeutics, Revolution Medicines, Senti Biosciences, Servier, Sirtex, Tempus, Vionix, Zielbio, and ZymeWorks; and owns stock or stock options in Abeona, ADC Therapeutics, Assertio, and Homology outside the submitted work. Robin Kate Kelley reports grants/contracts from Agios Pharmaceuticals, Inc., AstraZeneca, Bayer, Bristol Myers Squibb Company, Compass Therapeutics, Exelixis Inc., Genentech Inc., Merck, Partner Therapeutics Inc., Roche, Servier Pharmaceuticals LLC, Taiho Pharmaceutical, and Tyra Biosciences; and personal/consulting fees from Moderna and Jazz Pharmaceuticals Inc. outside the submitted work. Lipika Goyal reports institutional research funding from Alyssum Therapeutics, AstraZeneca, Boehringer Ingelheim, Cogent, Genentech, and Tyra Biosciences; personal/consulting fees from AbbVie, Agenus, AstraZeneca, Boehringer Ingelheim, Civela, Compass Therapeutics, Exelixis, Jazz Pharmaceuticals, Kinnate Biopharma, Merck, Relay Therapeutics, Revolution Medicine, Revolution Medicines, Servier, Surface Oncology, Taiho, TransThera Biosciences, and Tyra Biosciences; and service on a Data Safety Monitoring Board or Advisory Board for AstraZeneca outside the submitted work. Nilofer S. Azad reports grants/contracts from Agios Pharmaceuticals Inc., Array Biopharma Inc, Bayer HealthCare Pharmaceuticals Inc., Celgene, EMD Serono, Incyte Corporation, Merck, and Taiho Pharmaceutical; personal/consulting fees from AstraZeneca, Bristol Myers Squibb Company, Revolution Medicines, and Verastem Inc.; and owns stock options in Tempus outside the submitted work. Melinda Bachini reports support for professional activities from AstraZeneca outside the submitted work. Stacie Lindsey reports a fiduciary role at the Cholangiocarcinoma Foundation outside the submitted work. Shubham Pant reports grants/contracts from Arcus, Janssen, Novartis, Immuneering, ImmunoMET, Amal Therapeutics, Elicio, Biontech, Bristol Myers Squibb Company, Boehringer Ingelheim, and Pfizer; and personal/consulting fees from Alligator Bioscience, AskGene Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo Company, EMD Serono, Ipsen, Janssen Biotech, Jazz Pharmaceuticals, Merck, Nihon Medi‐Physics Company Ltd., Novartis, and Theriva Biosciences outside the submitted work. Juan W. Valle reports personal/consulting fees from AstraZeneca, Incyte, Jazz Pharmaceuticals, Servier Affaires Medicales, and Taiho Oncology Inc. outside the submitted work. Lola A. Fashoyin‐Aje reports personal/consulting fees from PAREXEL International outside the submitted work. Milind Javle reports grants/contracts from AstraZeneca, EMD Serono, Inc., Genentech, Helsinn, Incyte Corporation, and Merck; and support for other professional activities from Novartis outside the submitted work. The remaining authors disclosed no conflicts of interest.
Supporting information
Supplementary Material
Saj F, Namayanja FK, Xiao L, et al. Broadening the gates: analysis of potentially modifiable study entry criteria in pancreatic and biliary tract cancer trials. Cancer. 2026;e70227. doi: 10.1002/cncr.70227
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.