Abstract
Background:
According to the new AASLD Practice Guidance, all patients with primary sclerosing cholangitis (PSC) should be considered for participation in clinical trials. However, PSC’s rarity has posed challenges to characterizing patient interest in trial participation and identifying predictors of patient willingness to participate in drug trials.
Methods:
PSC Partners Seeking a Cure developed the “Our Voices” survey to inform the development of the Externally-Led Patient-Focused Drug Development Forum, an FDA initiative to capture patient experiences and perspectives on drug development.
Results:
Of 797 survey respondents from over 30 countries, 536 (67%) identified slowing disease progression as the most important outcome. Eighty-nine percent identified their hepatologist/gastroenterologist as someone they would approach for advice about trials. Although 61% reported being willing to participate in drug trials, only 26% had ever been asked to participate. Notable barriers to trial involvement included unknown long-term risks (71%), long travel times to the study center (32%), and a liver biopsy requirement (27%). On multivariable logistic regression, pruritus (OR 1.62, 95% CI: 1.09–2.40, p = 0.017) was positively associated with willingness to participate in disease-modifying therapy trials, while jaundice (OR 0.34, 95% CI: 0.19–0.61, p < 0.001) and inflammatory bowel disease (OR 0.64, 95% CI: 0.42–0.98, p = 0.038) were negatively associated. Pruritus (OR 2.25, 95% CI: 1.50–3.39, p < 0.001) was also independently associated with willingness to participate in symptom treatment trials.
Conclusions:
Most patients with PSC report interest in participating in clinical trials, but few have been asked to participate. Referral of patients with PSC by their hepatologist/gastroenterologist to clinical trials and patient education on trial participation are vital to closing the gap between trial interest and participation. Pruritus may serve as a key indicator of patient interest in trial participation.
INTRODUCTION
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease that causes bile duct strictures and leads to life-threatening complications, including bacterial cholangitis, cholangiocarcinoma, and cirrhosis. Currently, there are no disease-modifying treatments proven to alter the natural history of PSC except for liver transplantation. Furthermore, ~25% of patients will develop PSC recurrence within 5 years of transplantation.5–7 The treatments for most clinical symptoms other than cholestatic pruritus are not effective. While patient-reported outcome measures (PROMs) for pruritus that are PSC-specific8 and disease-agnostic9 have been developed. However, there is an absence of validated PSC-specific PROMs for nonpruritus symptoms.
Recently, new PSC practice guidance documents have been released by the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL). Given the absence of proven disease-modifying therapies, AASLD recommends that all patients with PSC be considered for participation in clinical trials.10 Similarly, EASL recognizes that clinical trials for PSC are usually concentrated in experienced centers and suggests that patients should be offered the chance to enter into such trials.11 However, little is known regarding predictors of and barriers to clinical trial involvement from the patient's perspective. The Externally-Led Patient-Focused Drug Development (EL-PFDD) program is an FDA initiative to ensure that patient experiences, needs, and priorities are captured and meaningfully incorporated into drug development and evaluation.12,13 Quantitative and qualitative data from EL-PFDD initiatives across numerous disciplines and diseases have been used to highlight the patient's voice, identify unmet clinical needs based on patient concerns, and develop PROMs.14–16 An EL-PFDD Forum for patients with PSC was conducted in October 2020 and generated data through a patient survey to better characterize the patients with PSC experience and therapeutic priorities.17 Using these data, we sought to characterize interest in clinical trial participation, identify barriers to trial involvement, and discover factors associated with willingness to participate in trials.
METHODS
PSC Partners developed the 40-question “Our Voices” survey as part of the PSC EL-PFDD Forum, which was distributed to patients enrolled in the PSC Partners Patient Registry starting in July 2020. The Registry was established by PSC Partners in collaboration with the National Institutes of Health Office of Rare Disease Research and currently has over 2500 patients. The primary goal of the registry is to facilitate and accelerate clinical research in PSC through direct patient-reported data collection. The registry is patient-driven, web-based, and de-identified in accordance with the NIH standards for privacy and confidentiality.18 It is reviewed and approved annually by a central institutional review board. The survey was also made available through an external website to patients not enrolled in the Registry. The survey included demographics, disease status, concurrent diagnoses, medications, clinical trial enrollment, and quality-of-life measures. Adult patients 18 years or older who completed the survey before the EL-PFDD Forum were included in this study. Institutional review board approval was obtained from the UCSF Human Research Protection Program.
Outcomes and covariates
Identifying patient willingness to participate in clinical trials for disease-modifying therapy was the primary outcome of this study, while patient willingness to participate in clinical trials targeting PSC symptoms was the secondary outcome. Other patient attributes and opinions related to clinical trials, including important trial outcomes, barriers to clinical trial involvement, past/current trial participation, and the proportion of patients who reported ever being approached about a clinical trial, were also characterized. All answers to survey questions used for data analyses in this study were closed-ended, with options predominantly being binary yes/no. The exceptions were the question asking for the most important clinical outcome to participants (3 possible options), the questions on barriers to clinical trial participation (rank top 5 choices), and preferred sources for advice about clinical trials (rank top three choices).
Statistical analysis
Baseline patient demographics and covariates are reported as frequencies and percentages. Univariable analyses were performed using chi-squared or Fisher exact tests. Multivariable logistic regression was employed to adjust for potential confounders. Patients who reported having undergone liver transplantation and patients who reported receiving treatment for decompensated liver disease (eg, paracentesis, lactulose/rifaximin treatment, variceal bleeding) were excluded from the logistic regression models evaluating interest in clinical trial participation, as posttransplant patients and patients with decompensated liver disease would typically not be considered candidates for clinical trials. Covariates included in logistic regression models were those that were either identified a priori as potentially being related to the primary or secondary outcomes or those that were associated with the outcomes on univariable analysis. Covariates deemed to be on the causal pathway between another variable and the outcomes being studied were excluded from multivariable logistic regression; in all cases, these excluded covariates were therapies (eg, pruritus medications, antidepressants) for symptoms that were included in the models (eg, pruritus, depression). The sample sizes for the multivariable models exceeded the 10:1 events (the number of the less frequent outcomes) per variable rule of thumb commonly used to avoid overfitting.19,20 Statistical significance was defined as p < 0.05 for all analyses. Statistical analyses were performed using SAS version 9.4 (Cary, NC, USA) and R version 4.3 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
A total of 797 adults completed the Our Voices survey before the Patient-Focused Drug Development Meeting on October 23, 2020. Patients from over 30 countries completed the survey. Most patients lived in the United States (76%), with Canada (11%), the United Kingdom (3%), Australia (2%), and Norway (1%) being the next most represented countries of origin. Demographics and clinical characteristics are shown in Table 1. Most patients were between 26 and 59 years of age, with 45.5% of patients self-identifying as male and 85.7% as non-Latino White. Most patients (59%) had ulcerative colitis and 15.7% had Crohn’s disease. Autoimmune hepatitis overlap was present in 9.9% of patients, and 17.8% reported being diagnosed with cirrhosis. In terms of liver transplantation status, 16.3% of patients received a deceased-donor liver transplant, 6.9% received a living-donor liver transplant, and 4.3% were listed for transplantation. Almost all patients reported receiving a magnetic resonance cholangiopancreatography (95.5%); most patients also underwent a liver biopsy (70.9%). Most patients reported having at least 1 endoscopic retrograde cholangiopancreatography (61.0%), with 32.5% undergoing stenting during endoscopic retrograde cholangiopancreatography and 42.4% reporting ever receiving antibiotics for treatment of bacterial cholangitis. Interventions for complications of cirrhosis (variceal banding, treatment with lactulose and/or rifaximin, paracentesis, and TIPS placement) occurred in 13% or fewer of respondents. The most common PSC-related therapy in the study population was ursodiol (52.9%). Vancomycin treatment (7.2%) was relatively uncommon. Patients reported taking medications for various PSC-related symptoms, including pruritus (18.8%), nausea (15.2%), depression (14.9%), and pain (13.9%).
TABLE 1.
Clinical characteristics
| Characteristics | Study participants (n=797) |
|---|---|
| Age, n (%) | |
| 18–25 y | 81 (10.2) |
| 26–39 y | 243 (30.5) |
| 40–59 y | 313 (39.3) |
| 60 and older | 160 (20.1) |
| Gender, male | 361 (45.5) |
| Race, n (%) | |
| White, non-Latino | 683 (85.7) |
| White, Latino | 58 (7.3) |
| Asian | 15 (1.9) |
| Black | 13 (1.7) |
| Mixed | 10 (1.3) |
| Indigenous | 1 (0.1) |
| Prefer not to answer or leave blank | 17 (2.1) |
| Comorbidities, n (%) | |
| Autoimmune hepatitis overlap | 79 (9.9) |
| Ulcerative colitis | 470 (59.0) |
| Crohn’s | 125 (15.7) |
| Cirrhosis | 142 (17.8) |
| Cholangiocarcinoma | 19 (2.4) |
| Transplant status, n (%) | |
| Listed for transplantation | 34 (4.3) |
| Transplanted, deceased donor | 130 (16.3) |
| Transplanted, living donor | 55 (6.9) |
| Tests/interventions at or since diagnosis, n (%) | |
| MRI/MRCP | 761 (95.5) |
| MR elastography | 190 (23.8) |
| Fibroscan | 423 (53.1) |
| Liver biopsy | 565 (70.9) |
| ERCP | 486 (61.0) |
| ERCP with stenting | 259 (32.5) |
| Antibiotics for cholangitis | 338 (42.4) |
| Lactulose or rifaximin treatment | 102 (12.8) |
| Paracentesis | 84 (10.5) |
| Variceal banding | 108 (13.6) |
| TIPS | 26 (3.3) |
| Current PSC-related therapies, n (%) | |
| Ursodiol | 422 (52.9) |
| Chronic antibiotics | 56 (7.0) |
| Vancomycin | 57 (7.2) |
| Pain medications | 111 (13.9) |
| Pruritus medications | 150 (18.8) |
| Nausea medications | 121 (15.2) |
| Antidepressants | 119 (14.9) |
| AIH overlap medications | 57 (7.2) |
| Posttransplant medications | 155 (19.4) |
| Encephalopathy medications | 33 (4.1) |
| Current IBD therapies, n (%) | |
| 5-ASA | 234 (29.4) |
| Steroids | 54 (6.8) |
| Immunosuppressants | 89 (11.2) |
| Biologics | 116 (14.6) |
Note: Data are n (%).
Abbreviations: AIH, autoimmune hepatitis; ASA, aminosalicylic acid; ERCP, endoscopic retrograde cholangiopancreatography; IBD, inflammatory bowel disease; MRCP, magnetic resonance cholangiopancreatography; PSC, primary sclerosing cholangitis.
Patient responses regarding clinical trial characteristics are displayed in Table 2. Overall, 67.3% of patients identified slowing progression of PSC as the single most important outcome for drug development. Most patients (59.5%) reported that they would be willing to participate in drug clinical trials; 57.3% indicated the willingness to participate in a trial for disease-modifying therapy, and 44.2% indicated the willingness to participate in a trial for symptom treatment. However, only a minority of patients (27.0%) reported ever being asked to participate in a clinical trial, and 88.1% of patients had never been involved in a trial. When asked to identify the top 5 factors that might prevent them from joining a trial, uncertainty about side-effects/long-term risks (71.1%) and fear of jeopardizing current quality of life (49.1%) were highlighted. Other common responses were long travel times (31.5%), the possibility that the drug might affect the treatment of their other diseases (27.6%), liver biopsy requirement (26.7%), and potentially affecting transplantation chances (24.0%). When asked to identify the top 3 sources they would approach for advice or with questions about joining a trial, patients overwhelmingly identified their hepatologist or gastroenterologist (89.1%), followed by the clinical trial team (52.1%), family members (50.1%), their primary care doctor (28.2%), the internet (17.9%), and patient organizations (17.8%).
TABLE 2.
Clinical trial characteristics
| Characteristics | Study participants (n=797) |
|---|---|
| Most important outcome for patients, n (%) | |
| Slowing progression of PSC | 536 (67.3) |
| Reducing risk of CCA | 144 (18.1) |
| Reducing symptoms | 78 (9.8) |
| Trial participation, n (%) | |
| Ever asked to be in the clinical trial | 215 (27.0) |
| Current clinical trial participant | 26 (3.3) |
| Past clinical trial participant | 74 (9.3) |
| Never participated in trial | 702 (88.1) |
| Willing to participate in drug trial | 474 (59.5) |
| Willing to participate in the trial of disease-modifying therapy | 457 (57.3) |
| Willing to participate in trial for symptom treatment | 352 (44.2) |
| Top 5 factors that might prevent patients from joining a trial, n (%) | |
| Unknown side-effects or long-term risks | 567 (71.1) |
| Fear of jeopardizing current quality of life | 391 (49.1) |
| Long travel time to the study center | 251 (31.5) |
| Possibility that drug may affect the treatment of their other diseases | 220 (27.6) |
| A liver biopsy | 213 (26.7) |
| Participation might affect the chance for transplantation | 191 (24.0) |
| Too much time off work | 178 (22.3) |
| Worried about receiving placebo | 170 (21.3) |
| General fear of the unknown | 143 (17.9) |
| Frequent/long study visits | 137 (17.2) |
| Other invasive procedures such as endoscopy | 128 (16.1) |
| Too much disruption to family life | 116 (14.6) |
| Lack of access to study results | 112 (14.1) |
| Difficulty communicating with the trial team | 104 (13.0) |
| Not understanding or trusting the consent | 66 (8.3) |
| Don’t understand role in trial | 56 (7.0) |
| Too many blood draws | 43 (5.4) |
| Concerns about future access to trial medication | 36 (4.5) |
| Total study duration is too long | 26 (3.3) |
| Top 3 sources who patients would approach for advice or with questions about joining a clinical trial, n (%) | |
| Hepatologist/gastroenterologist | 710 (89.1) |
| Clinical trial team | 415 (52.1) |
| Family | 399 (50.1) |
| Primary care doctor | 225 (28.2) |
| Internet | 143 (17.9) |
| Patient organization | 142 (17.8) |
| Other provider | 49 (6.1) |
Notes: Data are n (%).
Abbreviation: CCA, cholangiocarcinoma; PSC, primary sclerosing cholangitis.
Factors associated with willingness to participate in drug trials
Table 3 details clinical characteristics and patient-reported symptoms stratified by willingness to participate in trials for disease-modifying therapy after excluding patients who underwent liver transplantation and patients with decompensated liver disease; these patients were significantly less likely to be willing to participate in disease-modifying trials (RR 0.37, 95% CI: 0.28–0.49, p < 0.001 and RR 0.64, 95% CI: 0.49–0.82, p < 0.001, respectively) and as discussed in the Methods section would not be typical clinical trial candidates. Among patients with compensated liver disease without a history of liver transplantation, pruritus was positively associated with willingness to participate in disease-modifying drug trials (RR 1.26, 95% CI: 1.00–1.59, p = 0.050). Factors negatively associated with willingness to participate in disease-modifying drug trials were inflammatory bowel disease (IBD) (RR 0.89, 95% CI: 0.80–0.99, p = 0.034) and jaundice (RR 0.47, 95% CI: 0.29–0.76, p = 0.002).
TABLE 3.
Clinical characteristics and symptoms, stratified by willingness to participate in trial for disease-modifying therapy
| Characteristics | Not willing to participate (n = 191) | Willing to participate (n = 354) | p |
|---|---|---|---|
| Age | — | — | 0.670 |
| 18–25 y | 25 (13.1) | 40 (11.3) | — |
| 26–39 y | 62 (32.5) | 109 (30.8) | — |
| 40–59 y | 65 (34.0) | 139 (39.3) | — |
| 60 and older | 39 (20.4) | 66 (18.6) | — |
| Male gender | 82 (42.9) | 157 (44.6) | 0.750 |
| White, non-Latino | 175 (95.6) | 330 (94.8) | 0.495 |
| Autoimmune hepatitis overlap | 16 (8.4) | 33 (9.3) | 0.713 |
| Inflammatory bowel disease | 147 (77.0) | 242 (68.4) | 0.034 |
| Cirrhosis | 18 (9.4) | 44 (12.4) | 0.292 |
| History of receiving ERCP | 103 (53.9) | 178 (50.3) | 0.417 |
| History of antibiotics treatment for cholangitis | 55 (28.8) | 125 (35.3) | 0.123 |
| Current PSC-related therapies | |||
| Ursodiol | 96 (50.3) | 203 (57.3) | 0.113 |
| Chronic antibiotics | 6 (3.1) | 22 (6.2) | 0.121 |
| Vancomycin | 19 (9.9) | 25 (7.1) | 0.238 |
| Pruritus medications | 30 (15.7) | 78 (22.0) | 0.077 |
| Number of symptoms experienced | 4 (1–9) | 5 (2–8) | 0.452 |
| Symptoms | |||
| Fatigue | 129 (67.5) | 242 (68.4) | 0.844 |
| Insomnia | 105 (55.0) | 176 (49.7) | 0.241 |
| Anxiety | 92 (48.2) | 157 (44.4) | 0.393 |
| Joint pain | 73 (38.2) | 145 (41.0) | 0.533 |
| Depression | 79 (41.4) | 140 (39.5) | 0.680 |
| Weakness | 64 (33.5) | 134 (37.9) | 0.314 |
| Abdominal pain | 69 (36.1) | 127 (35.9) | 0.954 |
| Pruritus | 64 (33.5) | 149 (42.1) | 0.050 |
| Liver pain | 65 (34.0) | 132 (37.3) | 0.450 |
| Brain fog | 61 (31.9) | 131 (37.0) | 0.237 |
| Other pain | 49 (25.7) | 98 (27.7) | 0.611 |
| Nausea/vomiting | 55 (28.8) | 94 (26.6) | 0.575 |
| Anorexia | 51 (26.7) | 98 (27.7) | 0.806 |
| Night sweats | 59 (30.9) | 87 (24.6) | 0.112 |
| Jaundice | 31 (16.2) | 27 (7.6) | 0.002 |
Note: Data are n (%).
Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; PSC, primary sclerosing cholangitis.
Table 4 details clinical characteristics and patient-reported symptoms stratified by the willingness to participate in trials for symptom treatment, also after excluding patients who underwent liver transplantation and patients with decompensated liver disease. Patients willing to participate in symptom treatment trials experienced more symptoms (median 63-9 vs. 4,1-7 p < 0.001) than those not willing to participate, and almost all patient-reported symptoms were associated with the willingness to participate, as were treatment with pain medications (RR 2.52, 95% CI: 1.56–4.08, p < 0.001), pruritus medications (RR 1.77, 95% CI: 1.24–2.51, p = 0.001), nausea medications (RR 1.80, 95% CI: 1.15–2.81, p=0.009), and antidepressants (RR 1.51, 95% CI: 0.99–2.28, p = 0.051). History of antibiotic treatment for bacterial cholangitis was a non–symptom-related factor positively associated with willingness to participate in symptom treatment trials (RR 1.29, 95% CI: 1.02–1.64, p = 0.037), while there was a trend towards IBD being negatively associated with willingness to participate in symptom treatment trials (RR 0.91, 95% CI: 0.82–1.01, p = 0.088).
TABLE 4.
Clinical characteristics and symptoms, stratified by the willingness to participate in the trial for symptom treatment
| Characteristic | Not willing to participate (n=283) | Willing to participate (n=262) | p |
|---|---|---|---|
| Age | — | — | 0.505 |
| 18–25 y | 35 (12.4) | 30 (11.5) | — |
| 26–39 y | 85 (30.0) | 86 (32.8) | — |
| 40–59 y | 102 (36.0) | 102 (38.9) | — |
| 60 and older | 61 (21.6) | 44 (16.8) | — |
| Male gender | 129 (45.7) | 110 (42.1) | 0.398 |
| White, non-Latino | 260 (94.5) | 245 (95.7) | 0.464 |
| Autoimmune hepatitis overlap | 23 (8.1) | 26 (9.9) | 0.464 |
| Inflammatory bowel disease | 211 (74.6) | 178 (67.9) | 0.088 |
| Cirrhosis | 31 (11.0) | 31 (11.8) | 0.747 |
| History of receiving ERCP | 145 (51.2) | 136 (51.9) | 0.875 |
| History of antibiotic treatment for cholangitis | 82 (29.0) | 98 (37.4) | 0.037 |
| Current PSC-related therapies | |||
| Ursodiol | 147 (51.9) | 152 (58.0) | 0.155 |
| Vancomycin | 26 (9.2) | 18 (6.9) | 0.321 |
| Pain medications | 21 (7.4) | 49 (18.7) | <0.001 |
| Pruritus medications | 41 (14.5) | 67 (25.6) | 0.001 |
| Nausea medications | 27 (9.5) | 45 (17.2) | 0.009 |
| Antidepressants | 33 (11.7) | 46 (17.6) | 0.051 |
| Number of symptoms experienced | 4 (1–7) | 6 (3–9) | <0.001 |
| Symptoms | |||
| Fatigue | 175 (61.8) | 196 (74.8) | 0.001 |
| Insomnia | 141 (49.8) | 140 (53.4) | 0.399 |
| Anxiety | 117 (41.3) | 132 (50.4) | 0.034 |
| Joint pain | 98 (34.6) | 120 (45.8) | 0.008 |
| Depression | 107 (37.8) | 112 (42.7) | 0.240 |
| Weakness | 84 (29.7) | 114 (43.5) | 0.001 |
| Abdominal pain | 89 (31.4) | 107 (40.8) | 0.022 |
| Pruritus | 79 (27.9) | 134 (51.1) | <0.001 |
| Liver pain | 82 (29.0) | 115 (43.9) | <0.001 |
| Brain fog | 83 (29.3) | 109 (41.6) | 0.003 |
| Other pain | 60 (21.2) | 87 (33.2) | 0.002 |
| Nausea/vomiting | 65 (23.0) | 84 (32.1) | 0.017 |
| Anorexia | 58 (20.5) | 91 (34.7) | <0.001 |
| Night sweats | 67 (23.7) | 79 (30.2) | 0.088 |
| Jaundice | 35 (12.4) | 23 (8.8) | 0.175 |
Data are n (%).
Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; PSC, primary sclerosing cholangitis.
Two multivariable logistic regression models are displayed in Table 5. After adjusting for age, gender, and ursodiol treatment, pruritus (OR 1.62, 95% CI: 1.09–2.40, p = 0.017), jaundice (OR 0.34, 95% CI: 0.19–0.61, p < 0.001), and IBD (OR 0.64, 95% CI: 0.42–0.98, p = 0.038) were significantly associated with the primary outcome of the study, willingness to participate in disease-modifying drug trials.
TABLE 5.
Logistic regression models
| Covariate | OR | 95% CI | p-value |
|---|---|---|---|
| A: Willingness to participate in disease-modifying therapy trial | |||
| Agea | 1.00 | 0.82–1.22 | 0.962 |
| Male gender | 1.15 | 0.80–1.66 | 0.464 |
| IBD | 0.64 | 0.42–0.98 | 0.038 |
| Ursodiol treatment | 1.22 | 0.84–1.75 | 0.293 |
| Pruritus | 1.62 | 1.09–2.40 | 0.017 |
| Jaundice | 0.34 | 0.19–0.61 | <0.001 |
| B: Willingness to participate in trial for symptom treatment | |||
| IBD | 0.81 | 0.54–1.20 | 0.290 |
| History of antibiotic treatment for cholangitis | 1.26 | 0.86–1.84 | 0.243 |
| Ursodiol treatment | 1.16 | 0.80–1.66 | 0.436 |
| Fatigue | 1.22 | 0.78–1.91 | 0.388 |
| Anxiety | 1.02 | 0.69–1.53 | 0.913 |
| Joint pain | 0.97 | 0.61–1.54 | 0.886 |
| Weakness | 1.14 | 0.69–1.88 | 0.615 |
| Abdominal pain | 0.76 | 0.46–1.26 | 0.290 |
| Pruritus | 2.14 | 1.44–3.20 | <0.001 |
| Liver pain | 1.49 | 0.93–2.37 | 0.097 |
| Brain fog | 1.16 | 0.74–1.83 | 0.512 |
| Other pain | 1.38 | 0.80–2.36 | 0.247 |
| Nausea/vomiting | 0.71 | 0.41–1.22 | 0.215 |
| Anorexia | 1.47 | 0.86–2.50 | 0.158 |
| Night sweats | 0.81 | 0.52–1.28 | 0.369 |
Ordinal variable: 18–25 y, 26–39 y, 40–59 y, >60 y.
Abbreviation: IBD, inflammatory bowel disease.
Regarding the secondary outcome, pruritus (OR 2.14, 95% CI: 1.44–3.20, p < 0.001) was positively associated with willingness to participate in symptom treatment trials after adjusting for other PSC-related symptoms, IBD, history of antibiotic treatment for cholangitis, and ursodiol treatment. There was a trend towards liver pain being positively associated with willingness to participate in symptom treatment trials (OR 1.49, 95% CI: 0.93–2.37, p = 0.097).
DISCUSSION
Patient advocacy organizations play a crucial role in patient-focused drug development through efforts to define unmet patient needs, advocate for patients in policy development and clinical services, and shape and co-produce PSC research.11 The PSC Partners EL-PFDD Forum and the “Our Voices” survey brought together the voices of 797 patients from over 30 countries in the largest-ever patient survey for this rare disease. The results of this survey are particularly timely given recent AASLD and EASL guidance recommending that all patients with PSC be considered for clinical trials. Despite this recommendation, only 27% of participants reported ever being asked to consider enrolling in a trial. Notably, most patients (60%) expressed that they were willing to participate in a trial. As patients overwhelmingly identified their hepatologist/gastroenterologist as whom they would approach with questions about joining a clinical trial (89%), addressing the substantial gap between interest in clinical trial participation and actual clinical trial enrollment falls first and foremost upon PSC specialists.
Our data also identified several covariates associated with interest in drug trial participation following multivariable adjustment. Pruritus was the only patient-reported symptom positively associated with willingness to participate in both disease-modifying and symptom treatment trials, with robust ORs for both outcomes. This suggests that pruritus is a highly impactful symptom, and its presence could be used to flag patients who are particularly interested in participating in trials. This is consistent with evidence associating pruritus with substantial impairments in quality of life in patients with PSC.21 Jaundice was negatively associated with the willingness to participate in disease-modifying therapy trials. We speculate that the presence of jaundice is a sign of more advanced liver disease or other medical complications, which may decrease the patient's ability or willingness to participate in trials. Concurrent IBD was also negatively associated with willingness to participate in disease-modifying therapy trials. This may reflect a population of patients with IBD with active disease who have greater nonhepatic symptom burden, which may also decrease motivation to participate in PSC trials. Additionally, patients with jaundice and active IBD often meet trial exclusionary criteria, influencing how they are approached about potential trials. The impact of jaundice and IBD was somewhat unexpected and warrants further investigation.
Almost all patient-reported PSC symptoms were positively associated with the willingness to participate in symptom treatment trials, suggesting the need for drug development to address the PSC symptom burden. No validated PSC-specific PROMs currently exist and are urgently needed for use in clinical trials. PSC Partners is leading efforts to develop validated PROMs that can measure meaningful changes in symptom frequency and severity of key symptoms.
Patients identified multiple potential barriers to clinical trial involvement. While liver biopsy is not required for diagnosis, liver histology continues to be a primary end point in clinical trials as there are currently no established noninvasive surrogate end points for PSC.22,23 This highlights the unmet clinical need to identify and validate noninvasive surrogate biomarkers of PSC disease activity. Other barriers revolving around time constraints (eg, long travel time to the study center, too much time off work, frequent/long study visits) are starting to be addressed through the adoption of telehealth or at-home study visits. Addressing these logistical factors may also facilitate enrollment of disadvantaged patients and/or those of lower socioeconomic status, as this group is often underrepresented among clinical trial participants.24
Strengths of this study include the international patient enrollment, which was done through direct patient outreach by PSC Partners, which enabled a large sample size for this rare disease and avoided center-specific or provider-specific biases. A limitation of this study is sampling bias, as only 45% of responders identified as male, while ~two-thirds of patients with PSC are male.25 The respondents of the “Our Voices” survey may therefore differ from the general PSC population, including the possibility that they may have more positive attitudes towards clinical trial involvement or may be more likely to experience a greater number of PSC-related symptoms. However, rates of PSC-related comorbidities in our study, including autoimmune hepatitis overlap and IBD, were consistent with the reported literature,10 supporting population validity. Furthermore, though there was a high percentage of non-Latino White patients, this proportion was consistent with a large cohort of adults with PSC,26 suggesting that the diversity initiative undertaken by PSC Partners for enrollment was reasonably successful. Recall and nonresponse biases are always possible in survey-based studies, though our analyses focused on active symptoms at the time of survey completion, and there were minimal (<1%) missing data for any given survey question, suggesting that these biases were limited in our study.
In summary, there is a substantial gap that exists between patient interest in clinical trial involvement and trial referral by providers. Given the almost universal trust by patients in their hepatologist or gastroenterologist, PSC specialists must be responsible for closing this gap. Pruritus appears to be a highly influential PSC symptom, and its presence may predict patient willingness to enroll in clinical trials. Key potentially modifiable barriers to trial involvement include invasive procedures, time constraints, and patient communication and education.
ACKNOWLEDGMENTS
The authors thank Dr Stephen Rossi for his support in the development of the “Our Voices” survey. They also thank Dr Bettina Hansen and Dr Anilga Tabibian for their review of the “Our Voices” survey.
Footnotes
Abbreviations: AASLD, American Association for the Study of Liver Disease; AIH, autoimmune hepatitis; ASA, aminosalicylic acid; CCA, cholangiocarcinoma; EASL, European Association for the Study of the Liver; EL-PFDD, Externally-Led Patient-Focused Drug Development; ERCP, endoscopic retrograde cholangiopancreatography; IBD, inflammatory bowel disease; MRCP, magnetic resonance cholangiopancreatography; PROMs, patient-reported outcome measures; PSC, primary sclerosing cholangitis.
Contributor Information
Michael Li, Email: michael.li@ucsf.edu.
Ruth-Anne Pai, Email: ruthannepai@gmail.com.
Rachel Gomel, Email: rachel@pscpartners.org.
Mary Vyas, Email: mary@pscpartners.ca.
Sarah Curup Callif, Email: sarah@pscpartners.org.
Joanne Hatchett, Email: joanne@pscpartners.org.
Christopher L. Bowlus, Email: cbowlus@ucdavis.edu.
Jennifer C. Lai, Email: jennifer.lai@ucsf.edu.
AUTHOR CONTRIBUTIONS
Michael Li: conceptualization, data curation, formal analysis, methodology, writing (original draft). Ruth-Anne Pai, Joanne Hatchett, Sarah Curup Callif: conceptualization, data curation, methodology, writing (review and editing). Rachel Gomel and Mary Vyas: conceptualization, data curation, writing (review and editing). Christopher L. Bowlus: conceptualization, writing (review and editing). Jennifer C. Lai: conceptualization, methodology, supervision, writing (review and editing).
Michael Li and Ruth-Anne Pai are co-first authors.
FUNDING INFORMATION
This study was supported by the UCSF Liver Center P30DK026743 (Jennifer C. Lai), R01AG059183 (Jennifer C. Lai), K24AG080021 (Jennifer C. Lai), PSC Partners Young Investigator Award (Michael Li), Bill Falik UCSF PSC Research Program (Michael Li and Jennifer C. Lai).
CONFLICTS OF INTEREST
Christopher L. Bowlus received grants from Gilead, Bristol Myers Squibb, BiomX, Boston Scientific, COUR, CymaBay, GENFIT, GlaxoSmithKline, Mirum, Genkyotex, Intercept, Novartis, Pliant, and Target. Jennifer C. Lai consults for GENFIT. She advises Novo Nordisk. She received grants from Axcella and Pliant. The remaining authors have no conflicts to report.
REFERENCES
- 1.Tischendorf JJW, Hecker H, Krüger M, Manns MP, Meier PN. Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: A single center study. Am J Gastroenterol. 2007;102:107–114. [DOI] [PubMed] [Google Scholar]
- 2.Broome U, Olsson R, Loof L, Bodemar G, Hultcrantz R, Danielsson A, et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut. 1996;38:610–615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Kuo A, Gomel R, Safer R, Lindor KD, Everson GT, Bowlus CL. Characteristics and outcomes reported by patients with primary sclerosing cholangitis through an online registry. Clin Gastroenterol Hepatol. 2019;17:1372–1378. [DOI] [PubMed] [Google Scholar]
- 4.Tabibian JH, Bowlus CL. Primary sclerosing cholangitis: A review and update. Liver Res. 2017;1:221–230. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis - A comprehensive review. J Hepatol. 2017;67:1298–1323. [DOI] [PubMed] [Google Scholar]
- 6.Visseren T, Erler NS, Polak WG, Adam R, Karam V, Vondran FWR, et al. Recurrence of primary sclerosing cholangitis after liver transplantation - Analysing the European Liver Transplant Registry and beyond. Transpl Int. 2021;34:1455–1467. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Visseren T, Erler NS, Heimbach JK, Eaton JE, Selzner N, Gulamhusein A, et al. Inflammatory conditions play a role in recurrence of PSC after liver transplantation: An international multicentre study. JHEP Rep. 2022;4:100599. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Younossi ZM, Afendy A, Stepanova M, Racila A, Nader F, Gomel R, et al. Development and validation of a primary sclerosing cholangitis-specific patient-reported outcomes instrument: The PSC PRO. Hepatology. 2018;68:155–165. [DOI] [PubMed] [Google Scholar]
- 9.Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: A new measure of pruritus. Br J Dermatol. 2010;162:587–593. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology. 2023;77:659–702. [DOI] [PubMed] [Google Scholar]
- 11.easloffice@easloffice.eu EAftSotLEa, Liver EAftSot . EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol. 2022;77:761–806. [DOI] [PubMed] [Google Scholar]
- 12.Perfetto EM, Burke L, Oehrlein EM, Epstein RS. Patient-focused drug development: A new direction for collaboration. Med Care. 2015;53:9–17. [DOI] [PubMed] [Google Scholar]
- 13.Crossnohere NL, Fischer R, Crossley E, Vroom E, Bridges JF. The evolution of patient-focused drug development and Duchenne muscular dystrophy. Expert Rev Pharmacoecon Outcomes Res. 2020;20:57–68. [DOI] [PubMed] [Google Scholar]
- 14.Ettenger R, Albrecht R, Alloway R, Belen O, Cavaillé-Coll MW, Chisholm-Burns MA, et al. Meeting report: FDA public meeting on patient-focused drug development and medication adherence in solid organ transplant patients. Am J Transplant. 2018;18:564–573. [DOI] [PubMed] [Google Scholar]
- 15.Ashline J, McKay K. content analysis of patient voices at the FDA’s “female Sexual dysfunction patient-focused drug development public meeting”. Sex Cult. 2017;21:569–592. [Google Scholar]
- 16.Seo J, Smith BD, Estey E, Voyard E, O’ Donoghue B, Bridges JFP. Developing an instrument to assess patient preferences for benefits and risks of treating acute myeloid leukemia to promote patient-focused drug development. Curr Med Res Opin. 2018;34:2031–2039. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.https://pscpartners.org/about/the-disease/voice-of-the-patient-report-pfdd-forum.html Report of the PSC Partners Externally-Led Patient-Focused Drug Development (PFDD) Meeting. Accessed May 4, 2023.
- 18.https://pscpartners.org/about/participate/patient-registry.html PSC Partners Patient Registry. PSC Partners. Accessed May 4, 2023.
- 19.Harrell FE, Lee KL, Califf RM, Pryor DB, Rosati RA. Regression modelling strategies for improved prognostic prediction. Stat Med. 1984;3:143–152. [DOI] [PubMed] [Google Scholar]
- 20.Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996;49:1373–1379. [DOI] [PubMed] [Google Scholar]
- 21.Gotthardt DN, Rupp C, Bruhin M, Schellberg D, Weiss KH, Stefan R, et al. Pruritus is associated with severely impaired quality of life in patients with primary sclerosing cholangitis. Eur J Gastroenterol Hepatol. 2014;26:1374–1379. [DOI] [PubMed] [Google Scholar]
- 22.Ponsioen CY, Lindor KD, Mehta R, Dimick‐Santos L. Design and endpoints for clinical trials in primary sclerosing cholangitis. Hepatology. 2018;68:1174–1188. [DOI] [PubMed] [Google Scholar]
- 23.Ponsioen CY, Chapman RW, Chazouillères O, Hirschfield GM, Karlsen TH, Lohse AW, et al. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process. Hepatology. 2016;63:1357–1367. [DOI] [PubMed] [Google Scholar]
- 24.Ford JG, Howerton MW, Lai GY, Gary TL, Bolen S, Gibbons MC, et al. Barriers to recruiting underrepresented populations to cancer clinical trials: A systematic review. Cancer. 2008;112:228–242. [DOI] [PubMed] [Google Scholar]
- 25.Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BWM, Poen AC, et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology. 2013;58:2045–2055. [DOI] [PubMed] [Google Scholar]
- 26.Bayable A, Ohabughiro M, Cheung R, Wong RJ. Ethnicity-specific differences in liver transplant outcomes among adults with primary sclerosing cholangitis: 2005-2017 United Network for Organ Sharing/Organ Procurement and Transplantation Network. J Clin Exp Hepatol. 2021;11:30–36. [DOI] [PMC free article] [PubMed] [Google Scholar]