Recommendations for informed consent forms for critical care clinical trials*

Informed consent forms (ICFs) for clinical trials are often written above the recommended eighth-grade level. We aimed to compare the readability of original ICFs used for National Institutes of Health-funded stroke-related clinical trials with ICFs edited for readability using artificial intelligence. Publicly available ICFs associated with National Institutes of Health-funded stroke-related clinical trials were accessed through ClinicalTrials.gov (search period: inception to August 12, 2025). Using ChatGPT-4o, we created a customized Generative Pre-Trained Transformer (GPT) designed to lower the reading level to eighth grade or below while maintaining ICF content. We processed each ICF using this GPT to create edited ICFs. Standard readability metrics, including the Flesch-Kincaid grade level (primary outcome), were compared between original and edited ICFs using paired t tests or the McNemar test (cross-sectional design). We also assessed semantic similarity using the MPNet language model, which produced continuous scores from 0 (no similarity) to 1 (perfect similarity). ICFs were available for 46 stroke trials, including behavioral (n=21), device (n=15), drug (n=5), and other (n=5) intervention types. Mean reading levels were 11.52 for the original and 9.47 for the GPT-edited ICFs using the Flesch-Kincaid grade level (P<0.001). Only 1 (2%) of the original ICFs and 18 (39%) of the GPT-edited ICFs had a Flesch-Kincaid reading level at or below eighth grade (P<0.001). Both the Simple Measure of Gobbledygook and Gunning Fog Index favored the GPT-edited ICFs by 1 to 2 grade levels. The Flesch Reading Ease score favored the GPT-edited ICFs by about 8 points. The mean similarity score was 0.85 (SD=0.04). GPT-edited ICFs achieved a readability reduction of approximately 2 grade levels compared with the original ICFs while preserving high semantic similarity. Customized GPTs may be a useful tool to improve the readability of clinical trial ICFs.

Obtaining informed consent is part of the expression of the principle of participant autonomy during clinical trials. It is critical that participants understand the content of informed consent forms and remain in a position to seek independent advice on its content. We conducted a survey among past participants of a clinical trial in the Kassena-Nankana Districts of rural northern Ghana about the usefulness of informed consent forms that are written in the local dialects. The written forms of local dialects are largely undeveloped. We contacted a randomly selected sample of caregivers whose children were enrolled in a completed clinical trial and interviewed them using a structured questionnaire. Analysis sought to determine participants' preference and whether or not they were likely to find confidants who will be able to read, understand and give advice on the content of the informed consent form to them when they take the informed consent forms home. We interviewed 394 caregivers, 88.6% of whom were women. About half (54%) of the respondents wanted the informed consent forms to be in the English language. Caregivers with higher than primary level education were more likely to prefer the informed consent form to be in English than those with no formal education (74% versus 26%, p = 0.04). The majority (85%) indicated that they would be able to find close confidants who would be able to read and explain it to them if it is in English. In contrast, only 8% thought they would be able to do the same if the informed consent form was written in the local language. Respondents were more likely to find close confidants to read and explain the informed consent form if it were written in English than if it were written in the local language (94% versus 19%, p value < 0.01). The practice of translating informed consent forms into undeveloped local dialects and giving such copies to trial participants to send home needs to be re-evaluated. In populations where the written forms of local dialects are undeveloped and literacy is low, the use of local dialect versions of informed consent forms could ironically enhance the vulnerability of trial participants.

BackgroundCritical care is a complex field of medicine, especially because of its diversity and unpredictability. Mortality rates of the diseases are usually high and patients are critically ill, admitted in emergency, and often have several overlapping diseases. This makes research in critical care also complex because of patients’ conditions and because of the numerous ethical and regulatory requirements and increasing global competition. Many clinical trials in critical care have thus failed and almost no drug has yet been developed to treat intensive care unit (ICU) patients. Learning from the failures, clinical trials must now be optimized.Main bodySeveral aspects can be improved, beginning with the design of studies that should take into account patients’ diversity in the ICU. At the site level, selection should reflect more accurately the potential of recruitment. Management of all players that can be involved in the research at a site level should be a priority. Moreover, training should be offered to all staff members, including the youngest. National and international networks are also part of the future as they create a collective synergy potentially improving the efficacy of sites. Finally, computerization is another area that must be further developed with the appropriate tools.ConclusionClinical research in the ICU is thus a discipline in its own right that still requires tailored approaches. Changes have to be initiated by the investigators themselves as they know all the specificities of the field.

PurposeThis study aimed to evaluate the applicability of the principles and informed consent form (ICF) template proposed by the Strategic Initiative for Developing Capacity in Ethical Review (SIDCER) in a clinical pharmacokinetic study by comparing the volunteers’ understanding of the enhanced ICF (developed based on the SIDCER methodology) and the conventional ICF (which was previously approved by local Ethics Committee and used in the clinical study).MethodsA total of 550 volunteers were randomly assigned to read either the enhanced ICF or the conventional ICF (1:1) in a mock informed consent approach and subsequently performed the post-test questionnaire. The primary endpoint was the proportion of the participants who had the post-test score of ≥80 %; the secondary endpoints were the total score of the post-test, the score of the categorized ICF elements, and time spent for participation.ResultsThe proportion of the participants in the enhanced ICF group who achieved the primary endpoint was significantly higher than the conventional ICF group (82.2 % vs. 60.4 %, p < 0.001). The participants in the enhanced ICF group obtained higher scores and spent less time in reading the given ICF and answering the post-test than those in the conventional ICF group (total score 19/21 vs. 18/21, p < 0.001; time spent 20 min vs. 25 min, p < 0.001).ConclusionThe enhanced ICF improved the understanding of the participants in this study. This demonstrates the applicability of the SIDCER ICF principles and its template in the development of an enhanced ICF for improving the quality of ICFs and subjects’ understanding in clinical research.Trial registration: TCTR20140727001

6544 Background: Informed consent forms (ICF) play an integral role in the consent process for clinical trials (CT) by serving as a guide for discussion between the research team and study subjects. Our aims were to compare the quality of ICF among different 1) trial phases, 2) funding sources, 3) oncology subspecialties, 4) disease settings and 5) intervention modalities. Methods: ICF for prospectively conducted CT approved at the Princess Margaret Hospital from 2005–2007 were examined for their content on benefits and risks, alternatives, voluntary participation and confidentiality. Readability was assessed with the Flesch Reading Ease (FRE) score (range 0 to 100 with higher scores denoting greater reading ease) and Reading Grade Level (RGL). Results: Of the 262 evaluable CT, ICF contained an average of 3,982 words, 379 sentences and 10.5 pages. The mean FRE score and RGL were 61.2 and 7.4, respectively. All ICF explicitly stated that the CT was investigational. Only 2 (1%) promised direct personal benefits, 16 (6%) suggested the chance of cure or prolonged survival and 89 (34%) indicated a potential for tumor response. Conversely, 239 (91%) mentioned the risk of serious harms, 217 (83%) admitted that some side effects could be unknown or unpredictable and 126 (48%) reported hospitalization or death as a possibility. Alternatives to participation, right to withdraw from study and data confidentiality were addressed in 242 (92%), 254 (97%) and 260 (99%) ICF, respectively. Multivariate comparisons of benefit and risk descriptions and readability were tabulated (see table). ICF for hematology CT were most likely to highlight major risks (p=0.02), while readability was better in phase I CT and in those which were conducted by medical oncology, sponsored by governmental agencies and involved systemic therapy (all p<0.05). Conclusions: ICF provided a realistic overview of the benefits and risks of CT, although the risk of hospitalization or fatality was underreported. While readability was acceptable in most ICF, these documents remained lengthy. Parameter N Description of Benefits and Risks Readability % of CFs Stating CA May Improve p-value % of CFs Stating Risk of Death p-value Mean FRE p-value Mean RGL p-value Phase I I/II II III 57 25 90 90 26.3 24.0 33.3 42.2 0.12 43.9 44.0 48.9 51.1 0.28 62.9 58.5 61.2 60.8 0.002 7.1 7.8 7.3 7.5 0.001 Funding Academic Gov't Industry Unknown 36 39 158 29 38.9 41.0 29.1 42.9 0.27 27.8 51.3 56.3 25.0 0.16 60.4 64.1 60.8 60.8 0.003 7.5 6.9 7.5 7.4 <0.001 Specialty MedOnc Heme RadOnc Surgery 101 60 52 49 38.6 26.7 42.3 24.5 0.14 51.5 70.0 28.9 34.7 0.02 62.4 61.2 60.2 59.8 0.003 7.2 7.4 7.5 7.6 0.002 Setting Diagnostic Curative Metastatic 28 73 161 32.1 34.3 34.2 0.95 17.9 38.4 57.8 0.23 59.8 60.3 61.8 0.47 7.6 7.5 7.3 0.56 Modality SystemicTx Other 193 69 34.2 33.3 0.20 87.3 12.7 0.06 61.8 59.6 0.02 7.3 7.7 0.001 %: percentage; CFs: consent forms; CA: cancer; FRE: Flesch Reading Ease score; RGL: Reading Grade Level; Gov't: government; MedOnc: medical oncology; Heme: hematology; RadOnc: radiation oncology; SystemicTx: systemic therapy; p-values listed are based on multivariate analyses. No significant financial relationships to disclose.

Patient recruitment is a critical factor in running successful and timely clinical trials in the critical care field where the timing of presentation of patients is difficult to predict and the study interventions are often time sensitive. The goal of this study was to analyze the timing of patient enrollments from previous clinical trials to identify patterns and assess the impact of providing extended-hours coverage on patient enrollment. This was a retrospective cohort study at a tertiary academic hospital in the United States between 2016 and 2024 on patients who were enrolled in five recent critical care clinical trials. We reviewed the patient enrollment data. We quantified the number of enrollments during business hours (9 am-5 pm) compared with outside of business hours and analyzed the frequency of enrollment by day of the week and time of day. There were 352 patients enrolled between 2016 and 2024 across five clinical trials. A total of 242 patients (68.8%) were enrolled outside of business hours. 72.4% of patients were enrolled during weekdays and 27.6% during weekends. The enrollment pattern did not differ significantly across days of the week, ranging from 45 (12.8%) on Friday to 56 (15.9%) on Thursday. Enrollment from 2 pm to 10 pm accounted for more than 50% of the total enrollments. Recruiting only during business hours would have resulted in an additional 15 years to complete one of the trials. A review of our five recent critical care trials showed that nearly 70% of enrollment occurred outside of business hours. Limiting recruitment to only business hours would have resulted in a prohibitively longer time to complete the trials. This analysis provides a strong motivation and rationale for extending research staffing coverage beyond business hours.

BackgroundImmune checkpoint inhibitor (ICI)-induced hepatitis is a relatively common immune-related adverse event (irAE).1–3 Understanding the underlying genetic factors contributing to the development of irAEs is crucial for identifying individuals at...

Preclinical Alzheimer's disease (AD) clinical trials may require participants to learn if they meet biomarker enrollment criteria. To examine whether this requirement will impact trial recruitment, we presented 132 older community volunteers who self-reported normal cognition with 1 of 2 hypothetical informed consent forms (ICFs) describing an AD prevention clinical trial. Both ICFs described amyloid Positron Emission Tomography scans. One ICF stated that scan results would not be shared with the participants (blinded enrollment); the other stated that only persons with elevated amyloid would be eligible (transparent enrollment). Participants rated their likelihood of enrollment and completed an interview with a research assistant. We found no difference between the groups in willingness to participate. Study risks and the requirement of a study partner were reported as the most important factors in the decision whether to enroll. The requirement of biomarker disclosure may not slow recruitment to preclinical AD trials.

Alice K. Jacobs, MD, FACC, FAHA, Chair Jeffrey L. Anderson, MD, FACC, FAHA, Chair-Elect Nancy Albert, PhD, CCNS, CCRN, FAHA Mark A. Creager, MD, FACC, FAHA Steven M. Ettinger, MD, FACC Robert A. Guyton, MD, FACC Jonathan L. Halperin, MD, FACC, FAHA Judith S. Hochman, MD, FACC, FAHA

Introduction: Racial and ethnic minority enrollment in clinical trials is still a challenge and current recruitment planning has failed to improve diverse representation in clinical trials. The following literature review identified common barriers to diverse trial enrollment resulting in suggested tactics to address these barriers for breast cancer clinical trials. Methods: A literature review was conducted to identify barriers to oncology clinical trial enrollment for African American, Hispanic, Asian American, and Native American populations. A targeted review of barriers for patients in the lower socioeconomic status (SES) bracket was also performed. An advisory board of study coordinators was consulted to assess site–level awareness, barriers, and resources needed from the pharmaceutical industry. Additionally, ongoing initiatives were assessed including use of a Latino toolkit, patient navigators, and community outreach strategies. Results: The number of evidence based recruitment strategies targeting ethnic minorities was found to be lacking. There are four key aspects that influence diverse patients' decisions to participate in trials: family/friends, finances, faith, and physicians/staff. Barriers identified affected a majority of the analyzed patient populations. These included: protocol inclusion/exclusion criteria; logistical concerns; few incentives for participating; and cultural factors. The informed consent form and process were cumbersome and not patient-centric; costs related to travel and co-pays, and mistrust of medical research and the pharmaceutical industry were also identified as common barriers. The primary barriers were lack of invitations and lack of awareness at multiple levels within medical institutions, health care professionals, communities, and the pharmaceutical industry. Suggestions to address enrollment barriers include education to increase awareness, a patient-centric approach to consent and trial discussions, and tailoring site selection strategies. Other suggestions are immersion into communities, patient reimbursement, cultural competency training, pro-active translations, early recruitment planning, and identifying processes for approaching non-English speaking patients. Epidemiology data should also be incorporated in planning to establish baseline and enrollment goals. Conclusion: Although each of the analyzed populations is unique, common themes emerged. A patient-centric approach to increasing diversity in clinical trials should include considering a patient's key influences, addressing common concerns, conducting a properly informed consent process, and empowering a patient's decision making process. Gaps in current recruitment practices do still exist and further research on evidence based diverse recruitment strategies is also needed. Citation Format: Kelly R. Kirsch, Gebra C. Carter, Jacqueline M. Cole, Allicia C. Girvan, Coleman K. Obasaju. Recommendations to address common barriers to diversity in oncology clinical trials: An industry perspective. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A66. doi:10.1158/1538-7755.DISP13-A66

BackgroundBayesian adaptive designs can improve the efficiency of trials, and lead to trials that can produce high quality evidence more quickly, with fewer patients and lower costs than traditional methods. The aim of this work was to determine how Bayesian adaptive designs can be constructed for phase III clinical trials in critical care, and to assess the influence that Bayesian designs would have on trial efficiency and study results.MethodsWe re-designed the High Frequency OSCillation in Acute Respiratory distress syndrome (OSCAR) trial using Bayesian adaptive design methods, to allow for the possibility of early stopping for success or futility. We constructed several alternative designs and studied their operating characteristics via simulation. We then performed virtual re-executions by applying the Bayesian adaptive designs using the OSCAR data to demonstrate the practical applicability of the designs.ResultsWe constructed five alternative Bayesian adaptive designs and identified a preferred design based on the simulated operating characteristics, which had similar power to the original design but recruited fewer patients on average. The virtual re-executions showed the Bayesian sequential approach and original OSCAR trial yielded similar trial conclusions. However, using a Bayesian sequential design could have led to a reduced sample size and earlier completion of the trial.ConclusionsUsing the OSCAR trial as an example, this case study found that Bayesian adaptive designs can be constructed for phase III critical care trials. If the OSCAR trial had been run using one of the proposed Bayesian adaptive designs, it would have terminated at a smaller sample size with fewer deaths in the trial, whilst reaching the same conclusions. We recommend the wider use of Bayesian adaptive approaches in phase III clinical trials.Trial registrationOSCAR Trial registration ISRCTN, ISRCTN10416500. Retrospectively registered 13 June 2007.

Objective: This study aimed to evaluate the effect of a detailed pre-operative informed consent form on pre-operative anxiety. Methods: The research was designed as a quasi-experimental study. The participants were 66 patients, aged 18-70, who were randomly selected based on their order of registration from those admitted to the General Surgery Service of Atatürk University Faculty of Medicine between March and June 2013. The same method was applied to patients staying in the same room: odd-numbered room numbers were assigned to Group 1, and even-numbered room numbers to Group 2. The standard informed consent form was read to Group 1 using a face-to-face interview technique, while the Beck Anxiety Scale was applied to Group 2 after they received a detailed informed consent form that included photographs of the surgical technique, procedures, and potential complications. Statistical significance was determined with Student’s t-test, Mann-Whitney U test, and Pearson’s chi-square test. Results: The mean age of participants was 45.5±14.66 years, with 31 (47%) female and 35 (53%) male participants. It was found that 31.8% of the participants did not experience anxiety (n=24), 36.4% had mild anxiety (n=13), 19.7% had moderate anxiety (n=8), and 12.1% had severe anxiety. In Group 1, 15.2% (n=5) did not have anxiety, 36.4% (n=12) had mild anxiety, 36.4% (n=12) had moderate anxiety, and 12.1% (n=4) had severe anxiety. In Group 2, 48.5% (n=16) did not have anxiety, 36.4% (n=12) had mild anxiety, 3% (n=1) had moderate anxiety, and 12.1% (n=4) had severe anxiety. The difference between the two groups regarding the presence of anxiety was statistically significant (P = .04). Group 2 showed a lower anxiety level compared to Group 1. Furthermore, a positive correlation was found between lower education levels, presence of chronic disease, smoking, and higher anxiety levels. Conclusion: The study results emphasize that providing a detailed informed consent form, which includes images of the surgical procedure, significantly reduced pre-operative anxiety levels in patients. Moreover, factors such as male gender, marital status, smoking, and the presence of chronic diseases were associated with higher anxiety levels prior to surgery.

Informed consent consists a process that is able to inform, the research participant, of the planned medical interventions to be apply during the course of the study, and actively participate in the decision-making process. The Informed Consent Form (ICF) characterized by being an explanatory document, in written form, in which information about the research project is addressed, with the purpose of guaranteeing the individual's willingness. The quality of ICF in clinical research determined by the degree of understanding that participants develop during the informed consent process. The objective of this study is to evaluate the consent process of clinical research participants. It is a hybrid study, with prospective collection. For its development, it divided into the following phases: Elaboration and validation of the form, Training of the Team of Interviewers, Pilot Study, Data Collection and Evaluation of the Readability of ICF. A descriptive analysis of the data and a comparison between the variables performed using univariate analyses. Of the 70 participants, 83% were women, mean age was 46,7 years (S 13.99 years), 55,7% were white, 45,75% married, 52,9% illiterate or basic education, 49,3% economically active and average income of 1496,2 Reais. Of the participants, 35,7% didn't know the type of study they participated in, 38,6% didn't know about the research they participated, 64,7% didn't receive information regarding other types of treatment, 62,7% didn't have information about compensation, 66,2% didn't read the entire ICF before signing, 86,8% reported that the document was easy to read, 62,2% found the document long. After the ILFK calculation of the 12 ICF analysed, 100% presented values from 0 to 30, considered as very difficult reading. It is extremely important to encourage the development of national studies that evaluate the perception of research participants regarding their rights and the creation of instruments that enable such verification in the Brazilian population.

Introduction:People with visual impairment (VI) have loss of vision that causes impact on their daily living activities. Synonymous of VI are blindness, low vision, subnormal vision, visual incapacity, although there are peculiarities among them. The autonomic nervous system (ANS) provides the body with dynamic adaptation, moment by moment, according to changes in the internal and/or external body environment. As VI is an adverse condition, it is expected to be associated with changes in systemic autonomic activity, such as heart rate (HR) variability.Objective:To analyze the blindness stress by monitoring the activity of the ANS in the heart in subjects submitted acutely to low vision and also in subjects with chronic visual deficiency.Method:This is a randomized trial experimental study. In this clinical trial, initially, patients will undergo an ophthalmologic medical evaluation, along with monitoring of HR and systolic blood pressure /diastolic blood pressure. Volunteers with normal vision (Group i); and people with VI (Group ii) will be evaluated, all of them inhabitants of Rio Branco City, capital of Acre State, Brazilian Amazon. The intervention will consist of simulating blindness by sealing both eyes of each participant with good eyesight, using a sleep mask and allowing maximum occlusion for 45 minutes, split into 3 periods of 15 minutes each. Still blindfolded, participants will be requested to perform different tasks as walking, serve themselves water and/or cookies, and engaging in playful-pedagogical activity. Identical procedure will be done with the group with VI. The HR will be recorded by the Polar RS800 HR monitor. All findings with a value of P < .05 will be considered statistically significant. As a risk measure the odds ratio will be calculated, adjusted, and not adjusted with their respective 95% confidence intervals. The odds ratio = 1 of lowest risk for the outcome of interest will be considered as the base category for each independent variable.Ethics and dissemination:This study will be carried out in accordance with the guidelines that regulate human research in Resolution No. 466/12 of the National Health Council. We obtained the approval of the Research Ethics Committee of the ABC Medical School/Faculdade de Medicina do ABC, with CAAE: 73945017.0.0000.0082, and Opinion No. 2,275,101. All individuals who agreed to participate in the study will sign the free and informed consent form (FICF). The FICF is also available in audio and Braille versions. The results will be disseminated through peer-reviewed journal articles and conferences. This study is registered in the Brazilian Registry of Clinical Trials under the number RBR-9sm9dp.

Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease of the bile ducts that is surrounded by much uncertainty. First of all, it is a rare disease, with reported prevalence between 0 and 31.7 per 100,000 individuals,1Boonstra K. Beuers U. Ponsioen C.Y. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review.J Hepatol. 2012; 56: 1181-1188Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar,2Barner-Rasmussen N. Pukkala E. Jussila A. et al.Epidemiology, risk of malignancy and patient survival in primary sclerosing cholangitis: a population-based study in Finland.Scand J Gastroenterol. 2020; 55: 74-81Crossref PubMed Scopus (31) Google Scholar and establishing a diagnosis can be difficult. The primary pathology is hidden deep in the liver, and there is no specific and easy noninvasive diagnostic test for PSC. Histologic features of fibrosing cholangiopathy are present in <20% of liver biopsy specimens obtained from patients with PSC and can also be seen in cases of secondary sclerosing cholangitis. Current US and European guidelines do not recommend liver biopsy for making a diagnosis of PSC except for suspected cases of small duct PSC and pediatric cases.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar In addition, biliary tract abnormalities can be found on magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiography (ERC) in a wide array of conditions (see Supplementary Table 1). Furthermore, the course of PSC can be variable. Liver transplant–free survival ranges between 14.5 and 21.3 years in large cohorts.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (460) Google Scholar An important risk factor affecting survival is the development of cholangiocarcinoma (CCA). This has a cumulative incidence of approximately 20% at 20 years after diagnosis, but one third of CCA cases become manifest within 1 year after the diagnosis of PSC.5Weismüller T.J. Trivedi P.J. Bergquist A. et al.Patient age, sex, and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.Gastroenterology. 2017; 152: 1975-1984Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar,6Boonstra K. Weersma R.K. van Erpecum K.J. et al.Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.Hepatology. 2013; 58: 2045-2055Crossref PubMed Scopus (460) Google Scholar Last but not least, the cause of PSC is still enigmatic, and consequently, there is no therapy that has been proven to modify disease progression. In recent years, there has been an upsurge of pilot studies and phase 2 clinical trials. Phase 2 and 3 trials are hampered by the lack of established surrogate endpoints for clinical outcome, the heterogeneity of the disease course, and the lack of clear definitions for many key clinical disease characteristics.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (124) Google Scholar While the available national and international clinical practice guidelines predominantly focus on clinical management, the International PSC Study Group (IPSCSG) has recognized that there is a vital need for clinical trials to use uniform definitions for the diagnosis of PSC and for assessing disease severity and outcomes.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar,8Chapman M.H. Thorburn D. Hirschfield G.M. et al.British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.Gut. 2019; 68: 1356-1378Crossref PubMed Scopus (135) Google Scholar Therefore, the IPSCSG has commissioned a consensus process among its experts to issue a set of definitions to aid clinical trialists designing much needed clinical trials. To this end, an extensive consensus process was initiated, applying a hybrid between a Delphi process and a nominal group process, as was previously used by the IPSCSG and the European Crohn's and Colitis Organization.7Ponsioen C.Y. Chapman R.W. Chazouillères O. et al.Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.Hepatology. 2016; 63: 1357-1367Crossref PubMed Scopus (124) Google Scholar,9Dignass A. Eliakim R. Magro F. et al.Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis.J Crohns Colitis. 2012; 6: 965-990Abstract Full Text Full Text PDF PubMed Scopus (675) Google Scholar Where necessary, an additional survey was conducted among all IPSCSG members (see the Supplementary Methods for details). Results are presented as a comprehensive set of consensus statements (CSs) and diagnostic criteria for PSC. Although patients with PSC are increasingly diagnosed at earlier stages of disease based on asymptomatic serum liver enzyme abnormalities, at least 45% of patients PSC present with symptoms on either a constant or intermittent basis, which significantly reduces quality of life.10Broome U. Olsson R. Lööf L. et al.Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.Gut. 1996; 38: 610-615Crossref PubMed Google Scholar Furthermore, more than 22% of asymptomatic patients may develop symptoms within 5 years. The most common clinical symptoms associated with PSC are fatigue; pruritus; right upper quadrant (RUQ) abdominal pain; and emotional distress, which may include anxiety and depression symptoms. Pruritus and abdominal pain can fluctuate dramatically, and this may be suddenly worsened because of the development of a biliary obstruction or acute bacterial cholangitis. Therefore, clinical evaluation with laboratory testing and imaging may be necessary in the event of the sudden appearance or worsening of symptoms. Emotional distress for many patients is attributable to chronic anxiety about the uncertain etiology of the disease, the lack of effective therapy, and the risk of malignancy, among others.11Ranieri V. Kennedy E. Walmsley M. et al.The Primary Sclerosing Cholangitis (PSC) Wellbeing study: understanding psychological distress in those living with PSC and those who support them.PLoS One. 2020; 15e0234624Crossref PubMed Scopus (10) Google Scholar The incorporation of clearly defined patient-reported symptoms into the design of clinical trials is both desirable from a patient-centered perspective and highly encouraged by regulatory agencies12Ponsioen C.Y. Lindor K.D. Mehta R. et al.Design and endpoints for clinical trials in primary sclerosing cholangitis.Hepatology. 2018; 68: 1174-1188Crossref PubMed Scopus (43) Google Scholar (Box 1, CS 1.1). Recently, 2 such tools have emerged. One patient-reported outcome (PRO) dedicated to PSC showed excellent reliability and was able to discern patients with cirrhosis and those with a history of depression.13Younossi Z.M. Afendy A. Stepanova M. et al.Development and validation of a primary sclerosing cholangitis-specific patient-reported outcomes instrument: the PSC PRO.Hepatology. 2018; 68: 155-165Crossref PubMed Scopus (21) Google Scholar A more recently developed tool to assess patient-reported symptoms, the Simple Cholestatic Complaints Score, was developed through digital surveys of patients and showed good criterion and construct validity and a very high test-retest reproducibility.14Munster K.N. Dijkgraaf M.G.W. Gennep S. et al.The Simple Cholestatic Complaints Score is a valid and quick patient-reported outcome measure in primary sclerosing cholangitis.Liver Int. 2020; 40: 2758-2766Crossref PubMed Scopus (0) Google Scholar Further validation of these tools in larger and more diverse cohorts is needed.Box 1Consensus StatementsTabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn's and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab Tabled 11.Clinical symptoms1.1.Assessment of symptoms in patients with PSC for clinical trial purposes should be performed through disease-specific and validated quantitative tools.1.2.Assessment of symptoms in patients with PSC should take into consideration and be distinguished from symptoms attributable to active inflammatory bowel disease and other coexistent conditions.2.Laboratory markers2.1.The presence of significant elevations of serum aminotransferase activity (>5 × ULN) and/or IgG (>2 × ULN) can be indicative of features of coexisting autoimmune hepatitis and should trigger consideration of liver biopsy for diagnostic and stratification purposes when considering enrolling a subject in a clinical trial.2.2.Serum IgG4 concentrations can be elevated in patients with PSC, in the absence of classical features of IgG4-related disease, but IgG4 elevations are not validated markers of disease diagnosis, severity, prognosis, or treatment.3.Imaging3.1.The pattern of PSC can be defined according to the appearances of cholangiography using high-quality magnetic resonance cholangiography (MRC) (at least 1.5 T):3.1.1.Small duct when a recent cholangiogram (not older than 1 year) is normal3.1.2.Intrahepatic when there are intrahepatic changes but the common ducts and first-order ducts are normal3.1.3.Extrahepatic disease when the common ducts and/or the first-order ducts are involved4.Histology4.1.Histologic findings in a liver biopsy sample from patient suspected to have PSC can be defined (classified) as follows:4.1.1.Typical of PSC: features of fibrosing cholangiopathy present (periductal fibrosis, fibro-obliterative duct lesions)4.1.2.Compatible with PSC: features of chronic biliary disease present (see text for further details) without typical bile duct lesions4.1.3.Atypical for PSC: features atypical for PSC present. Examples include•unusually prominent inflammatory activity suggesting the possibility of PSC-AIH overlap syndrome•features suggesting an alternative diagnosis, such as fatty liver disease, or IgG4-associated cholangitis.4.2.A liver biopsy specimen showing typical or compatible histologic features is required to establish a diagnosis of small duct PSC.4.3.In a person with PSC, a liver biopsy specimen showing at least moderate interface hepatitis in addition to features compatible with or diagnostic of PSC is required to establish a diagnosis of PSC with features of AIH or PSC-AIH overlap syndrome.4.4.The histologic features that indicate disease progression (staging) in PSC include fibrosis, bile duct loss, and evidence of chronic cholestasis (demonstrated by deposition of copper-associated protein in periportal hepatocytes).5.Concurrent IBD5.1.The definition and description of IBD in PSC should follow the European Crohn's and Colitis Organization (ECCO) guidelines and Montreal classification. Any patient with established PSC should undergo a full ileocolonoscopy with histology before concurrent IBD may be excluded.5.2.When assessing the existence of backwash ileitis, it is recommended that the ECCO definition be followed. This defines backwash ileitis as continuous extension of macroscopic or histologic inflammation from the cecum into the most distal ileum.6.Staging6.1.Disease staging of PSC is defined as the histologic progression from initial disease onset to cirrhosis.6.2.A clinically significant change in disease stage is defined by a 1-point change in the Ludwig or Nakanuma system or a 2-point change in the Ishak system.6.3.Histologic cirrhosis is a clinically significant endpoint.6.4.Cirrhosis (stage 5–6 by Ishak) in PSC can be defined by an LS of >14.4 kPa measured by VCTE.6.5.Cirrhosis (stage 5–6 or greater by Ishak) in PSC can be defined by an ELF score of >9.8 or FibroTest of >7.3.7.Clinical endpoints7.1.Liver transplant:Liver transplant is an appropriate endpoint in PSC clinical trials. However, divergent indications for transplant listing (end-stage disease, dysplasia, CCA, symptoms, intractable cholangitis) and method of transplantation (deceased vs living donation) should not be grouped into a single endpoint because of the wide heterogeneity of clinical practice.7.2.Liver-related death:Liver-related death in the setting of PSC is defined as death from clinically significant portal hypertension, synthetic liver dysfunction, or specific complications from biliary disease such as hepatobiliary infections.8.Cancer development8.1.Cholangiocarcinoma:8.1.1.CCA in PSC requires pathologic confirmation and is classified according to CCA in general.8.1.2.Dysplastic changes considered precursors to CCA in PSC are defined by standard criteria.8.2.Colorectal carcinoma:8.2.1.CRC in the setting of PSC is defined according to standard criteria.9.Pediatric PSC9.1.Pediatric PSC is not a specific disease phenotype. PSC in children should be described in terms of small vs large duct involvement, whether features of overlap with AIH are present or absent, and whether IBD is present or absent, as in adult patients.9.2.Terms such as juvenile sclerosing cholangitis and autoimmune sclerosing cholangitis should be avoided.9.3.When gGT is substituted for ALP, the consensus definitions in this document are applicable to children.10.Recurrent PSC10.1.The diagnosis of rPSC is based on the presence of compatible radiologic changes (using high-quality MR) with/or without histologic findings, along with the exclusion of other causes of similar findings. Open table in a new tab A particular challenge in assessing clinical symptoms in patients with PSC is the frequent concurrence of inflammatory bowel disease (IBD), which itself can influence the clinical course of PSC and may also account for a significant proportion of symptoms, especially during periods of IBD exacerbations.15Cheung A.C. Patel H. Meza-Cardona J. et al.Factors that influence health-related quality of life in patients with primary sclerosing cholangitis.Dig Dis Sci. 2016; 61: 1692-1699Crossref PubMed Scopus (1) Google Scholar Existing tools, including the PSC PRO, do not specifically account for symptoms attributable to IBD. Although the Simple Cholestatic Complaints Score did not show a difference in PSC patient symptoms according to the presence or absence of IBD, a systematic evaluation of IBD symptoms in patients with PSC has not been performed, which can result in confounding findings. Therefore, assessment of PSC symptoms should be performed alongside specifically designed tools to detect symptoms from IBD in those with PSC-IBD or other relevant coexistent conditions (Box 1, CS 1.2) This is critically important for clinical trials that aim to use PRO measures as endpoints in PSC. Cholestatic serum liver tests are a characteristic, but nonspecific, feature of biliary disease irrespective of the nature of biliary involvement. Alkaline phosphatase (ALP) as the hallmark of cholestasis is elevated in the vast majority of patients with PSC.16Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation.Hepatology. 2015; 61: 2080-2090Crossref PubMed Scopus (75) Google Scholar Previously, it was thought that to make a diagnosis of PSC, elevation of ALP, or gamma-glutamyl transpeptidase (gGT) in children (see the "Pediatric Primary Sclerosing Cholangitis" section) was a prerequisite. Recent studies have shown that elevated cholestatic serum parameters need not always be present. For more background, see the Supplementary Material. Aminotransferases are often moderately elevated, whereas at diagnosis, serum bilirubin and albumin levels are usually normal.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar Aminotransferase activity of more than 5 times the upper limit of normal (ULN) and a serum IgG of >2 × ULN should raise the suspicion of coexisting autoimmune hepatitis (AIH) and should trigger consideration of liver biopsy to identify histologic features that would support a diagnosis of AIH or PSC/AIH overlap, also called variant syndrome (Box 1, CS 2.1). This has management consequences, because patients with PSC/AIH commonly respond favorably to immunosuppressive medication such as corticoids and thiopurines, although not as well as patients with isolated AIH.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In contrast to primary biliary cholangitis (PBC) and AIH, there is no pattern of autoantibody reactivity in patients with PSC of relevance to diagnosis or treatment. Positive titers of autoantibodies are common in PSC, including antinuclear antibody (8%–77%), smooth muscle antibody (0%–83%), and atypical perinuclear antibody (26%–94%).18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (139) Google Scholar,19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar However, these are also frequently present in AIH, and perinuclear antineutrophil cytoplasmic antibodies can be found in ulcerative colitis (UC) in 41%–73% and in Crohn's disease in 6%–38%.17Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatology. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 18Prideaux L. De Cruz P. Ng S.C. et al.Serological antibodies in inflammatory bowel disease: a systematic review.Inflamm Bowel Dis. 2012; 18: 1340-1355Crossref PubMed Scopus (139) Google Scholar, 19Moiseev S. Cohen Tervaert J.W. Arimura Y. et al.2020 International consensus on ANCA testing beyond systemic vasculitis.Autoimmun Rev. 2020; 19: 102618Crossref PubMed Scopus (18) Google Scholar Serum IgG4 levels can be elevated in patients with PSC, but this has no validated bearing on diagnosis or disease severity (Box 1, CS 2.2). For distinction from IgG4-sclerosing cholangitis, see the Supplementary Material. Biliary imaging is integral to the diagnosis and classification of PSC. MRCP has been established as the noninvasive imaging of choice.3Lindor K.D. Kowdley K.V. Harrison M.E. ACG clinical guideline: primary sclerosing cholangitis.Am J Gastroenterol. 2015; 110: 646-659Crossref PubMed Scopus (358) Google Scholar,4European Association for the Study of the LiverEASL clinical practice guidelines: management of cholestatic liver diseases.J Hepatol. 2009; 51: 237-267Abstract Full Text Full Text PDF PubMed Scopus (1433) Google Scholar Regarding the utility of magnetic resonance imaging (MRI) in PSC, the reader is referred to a recent publication from the IPSCSG Working Group on MRI in PSC.20Schramm C. Eaton J. Ringe K.I. et al.Recommendations on the use of magnetic resonance imaging in PSC-A position statement from the International PSC Study Group.Hepatology. 2017; 66: 1675-1688Crossref PubMed Scopus Google Scholar A of features are described in large duct PSC, including or within the and/or biliary of the intrahepatic ducts with of the biliary of the and changes not of PSC, and from causes of secondary sclerosing cholangitis in the absence of can be difficult. in the bile ducts on cholangiography are thought to be highly specific for PSC. in the common and common bile the are usually seen in disease and are reported in of cases in a large of C.Y. et al.Natural history of primary sclerosing cholangitis and prognostic of cholangiography in a 51: PubMed Scopus (0) Google Scholar small duct PSC cholangiography is normal is an in PSC. recent have reported on the history of small cohorts of small duct PSC patients to large duct PSC was described in and after a of years of in K. Eaton et resonance imaging features of primary sclerosing 2020; PubMed Scopus Google K.I. Bergquist A. H. et features and MRI progression of small duct primary sclerosing cholangitis J 2020; Full Text Full Text PDF PubMed Scopus (0) Google Scholar (Box 1, CS was no with MRI findings and progression to large duct PSC in either in the bile ducts are a common and clinically relevant of the chronic inflammatory process that in the biliary in PSC. a of large duct PSC patients with the incidence of the development of can be to to approximately in patients with large duct A. P. et al.Development of bile duct in patients with primary sclerosing cholangitis with outcome after endoscopic Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar extensive in the Supplementary the a of criteria that into the definition of a as in of is called a when it the criteria before MRCP or with of in or first-order intrahepatic not and worsening of cholestatic symptoms within 2 biliary or and/or of × ULN and recent for × P. et of in primary sclerosing cholangitis: outcome after Full Text Full Text PDF PubMed Scopus Google and/or within for × or of >2 × ULN no within is