A Systematic Review of Patient-Reported Outcomes in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Hannah P. Kim; Sarah R. Lieber; Michael E. Rogers; Andrew M. Moon; Marci Loiselle; Jennifer Walker; David N. Assis; Ricky Safer; Rachel Gomel; Donna M. Evon

doi:10.1002/hep4.1567

A Systematic Review of Patient-Reported Outcomes in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Hannah P. Kim, Sarah R. Lieber, Michael E. Rogers, Andrew M. Moon, Marci Loiselle, Jennifer Walker, David N. Assis, Ricky Safer, Rachel Gomel, Donna M. Evon

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with decreased health-related quality of life and debilitating symptoms. These experiences can be defined as patient-reported outcome (PRO) concepts and measured using PRO instruments. We identified all PRO concepts and instruments used in the PBC and PSC literature. This systematic review identified PBC and/or PSC studies from January 1, 1990, to May 6, 2019, that measured at least one PRO concept. Study population, design, PRO concept, PRO instrument, and validation data for PRO instruments were investigated. We provided descriptive statistics of PRO concepts and instruments used, stratified by population type. Use of PRO concepts and instruments were assessed over time. The search yielded 318 articles (69% in PBC, 18% in PSC, 13% in both, and 24% in drug trials). Forty-nine unique PRO concepts were identified. The five most common PRO concepts included pruritus (25%), fatigue (19%), broad health-related quality of life (16%), gastrointestinal adverse events (6%), and physical adverse events (6%). Only 60% of PRO concepts were measured with a PRO instrument, most of which were nonvalidated visual analogue or numeric rating scales. Only three of 83 PRO instruments were developed with feedback from the target populations (one for PBC, one for PSC, and one for both), and only six documented any psychometric testing in the target populations. Use of PRO instruments increased over time from 30% in the 1990s to 67% by 2019. Conclusion: The overwhelming majority of PRO instruments used in PBC/PSC were nonspecific and lacked patient validation or empirical justification. Significant opportunities exist to use qualitative methods to better understand patient experiences, and translate this knowledge into meaningful, patient-driven study outcomes.

Original language	English (US)
Pages (from-to)	1502-1515
Number of pages	14
Journal	Hepatology Communications
Volume	4
Issue number	10
DOIs	https://doi.org/10.1002/hep4.1567
State	Published - Oct 1 2020
Externally published	Yes

ASJC Scopus subject areas

Hepatology

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10.1002/hep4.1567

Cite this

@article{892c8d462b2949cf86cfde011e6a813c,

title = "A Systematic Review of Patient-Reported Outcomes in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis",

abstract = "Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with decreased health-related quality of life and debilitating symptoms. These experiences can be defined as patient-reported outcome (PRO) concepts and measured using PRO instruments. We identified all PRO concepts and instruments used in the PBC and PSC literature. This systematic review identified PBC and/or PSC studies from January 1, 1990, to May 6, 2019, that measured at least one PRO concept. Study population, design, PRO concept, PRO instrument, and validation data for PRO instruments were investigated. We provided descriptive statistics of PRO concepts and instruments used, stratified by population type. Use of PRO concepts and instruments were assessed over time. The search yielded 318 articles (69% in PBC, 18% in PSC, 13% in both, and 24% in drug trials). Forty-nine unique PRO concepts were identified. The five most common PRO concepts included pruritus (25%), fatigue (19%), broad health-related quality of life (16%), gastrointestinal adverse events (6%), and physical adverse events (6%). Only 60% of PRO concepts were measured with a PRO instrument, most of which were nonvalidated visual analogue or numeric rating scales. Only three of 83 PRO instruments were developed with feedback from the target populations (one for PBC, one for PSC, and one for both), and only six documented any psychometric testing in the target populations. Use of PRO instruments increased over time from 30% in the 1990s to 67% by 2019. Conclusion: The overwhelming majority of PRO instruments used in PBC/PSC were nonspecific and lacked patient validation or empirical justification. Significant opportunities exist to use qualitative methods to better understand patient experiences, and translate this knowledge into meaningful, patient-driven study outcomes.",

author = "Kim, {Hannah P.} and Lieber, {Sarah R.} and Rogers, {Michael E.} and Moon, {Andrew M.} and Marci Loiselle and Jennifer Walker and Assis, {David N.} and Ricky Safer and Rachel Gomel and Evon, {Donna M.}",

note = "Funding Information: This comprehensive systematic review identified PRO concepts and instruments described in PBC and PSC studies over the last 30 years. Despite many studies involving a PRO concept, PRO instruments were used to measure these concepts only 50%-60% of the time. We observed tremendous variation in the types of instruments being used to evaluate the most common PRO concepts of pruritus, fatigue, and broad HRQOL. Moreover, most instruments were not developed with qualitative input from patients living with PBC or PSC, raising the question of whether these items appropriately capture the experiences and perceptions of these patients. This uncertainty likely exists, in part, due to a woefully low number of qualitative studies (e.g., in-depth interviews, focus groups) with patients with PBC or PSC, which stymies our understanding of their subjective experiences and perspectives. These findings highlight significant opportunities to improve the ways we capture disease symptoms, treatment side effects, and patient preferences using validated PRO instruments for PBC and PSC. In the field of PBC, the PBC-40, published in 2005, is the only PRO instrument that included formative patient interviews to guide the development of the measure, and thus has strong content validity and sound psychometric properties.(18) Because the PBC-40 also includes fatigue and itch subscales with proven content validity, this instrument is an ideal patient-centered choice for studies of PBC HRQOL, fatigue, and itch. Importantly, the instrument has also been adapted into briefer versions (PBC-27, PBC-10).(23,26) In addition to the PBC-40, the Itch Diary was recently developed based on qualitative interviews with patients with PBC, and thus is another viable option to measure PBC-induced itch.(19) Finally, the psychometric properties of the Fatigue Impact Scale and the Fisk Fatigue Severity Scale were evaluated for use in PBC in 2000, with the Fatigue Impact Scale being used frequently thereafter; however, because both were originally developed in other patient populations, neither can claim to be truly representative of PBC-related fatigue until further qualitative studies are conducted.(20,21) In contrast with PBC, far fewer studies of PRO concepts and instruments have been published for PSC. This may, in part, be due to the fact that no validated PRO instruments were developed specifically for PSC until 2018. The PSC-PRO instrument has followed guidelines for PRO measure development; more specifically, cognitive interviews were conducted with patients with PSC to validate item content.(25) However, patients from advocacy groups have stated that the PSC-PRO does not provide an accurate representation of how patients with PSC function and feel, as patients did not partake in the initial stages of development of the tool. The qualitative findings, which would provide valuable information for all PSC stakeholders, have not been published. This tool requires future testing in larger diverse samples of patients with PSC, to determine whether the overall measure is sensitive to change from disease progression or treatment. The CLDQ is a disease-specific measure of HRQOL developed for patients with various types of chronic liver disease; however, only 30% of the study cohort had PSC or PBC.(22) Finally, there is a new PSC HRQOL instrument currently under development that includes substantive patient engagement in every stage of development of the tool and will undergo international validation.(27) Aside from the new PSC-PRO that contains one itch item and two fatigue items, we identified no optimal choice for fatigue and pruritus measurements in PSC. Future qualitative studies should investigate patient preferences regarding pre-existing instruments to evaluate PSC-associated fatigue and itch, including the PBC-40, Fatigue Impact Scale, Fisk Fatigue Severity Scale, 5-D Itch Scale, Itch Diary, and ItchRO (developed qualitatively in children with Alagilles). The 5-D Itch measure was developed in patients with itch, but not specifically PSC, and encompasses five dimensions: duration, degree, direction, disability, and distribution. Finally, studies need to better distinguish between symptoms attributable to inflammatory bowel disease, a comorbidity that occurs in over 70% of patients with PSC, and those attributed to PSC. This study revealed significant gaps in the extant literature and highlights implications for future research. For instance, most PRO studies used visual analog and numeric rating scales, yet we identified no published scientific justification for these scales based on patient preferences. Moreover, there was significant heterogeneity in the types of visual and numeric rating scales, making it difficult to compare results in this literature. Therefore, a reduced reliance on these types of instruments in future studies is recommended until more empirical support is demonstrated. More studies in special populations (e.g., pediatric, pregnant, liver transplantation) are needed to understand patients{\textquoteright} perspectives, needs, and priorities to inform study outcomes and measures. There may be opportunities to modify and validate the National Institutes of Health Patient-Reported Outcome Measurement System measures in PBC and PSC, as these measures underwent robust qualitative development and psychometric testing in diverse populations. Most clinical trials in PBC or PSC did not measure AEs from the patients{\textquoteright} point of view and did not use PRO instruments. As a result, important information regarding the harms of treatments may be undetected and underrecognized. We acknowledge that these results likely reflect that patient-centered reporting of AEs is not a part of the current culture of conducting clinical trials. However, it is precisely for this reason that we believe existing practices should adopt a more patient-centered approach. Evaluating AEs systematically using PRO instruments is another way to enhance patient-focused drug development. Recently, the National Cancer Institute spearheaded the development of a PRO version of the Common Terminology Criteria for Adverse Events, called the “PRO-CTCAE,” as a more accurate method of detecting AEs during oncology drug trials.(28) The items were identified and developed using cognitive interviews with patients receiving active cancer treatment; furthermore, they underwent validation and extensive psychometric testing.(29,30) The PRO-CTCAE contains 78 patient-reported AEs rated on presence, frequency, severity, and life interference. A recent study highlighted significant discordance between clinician-graded AEs and the PRO-CTCAE, demonstrating the complementary and added value of the patient instrument.(31) A high-yield contribution to the field could be to imbed qualitative studies into PBC or PSC drug trials to develop a modified version of the PRO-CTCAE for these patients. As a way to facilitate patient-centered reporting of AEs, electronic modalities (e.g., tablets, cellphones, websites) could be used for reporting of AEs; participants could use validated instruments to report symptoms or experiences they had during the clinical trial. It is imperative that more qualitative or mixed methods studies be conducted to move the field of PROs in PBC and PSC forward. We identified only three qualitative and three mixed-methods articles that described the experiences of patients with PBC(12,32-36); astonishingly, no qualitative studies have been published describing the experiences of patients with PSC. We acknowledge that there may be a bias against publishing qualitative studies, and researchers may not be incentivized to conduct these types of works. However, qualitative studies are absolutely essential to deepen our understanding of patient experiences, perspectives, needs, and priorities; this is especially true in the setting of studying different medical treatments.(37-39) Toward this end, clinical investigators are encouraged to familiarize themselves with the systematic, step-by-step approaches for conducting formative, qualitative work needed to develop or modify accompanying PRO instruments. In 2019, the FDA published a series of four guidance documents to facilitate patient-focused drug development.(40) The new guidance includes best practices for qualitative research to gain insight into patient experiences and needs. Additionally, the International Society for Pharmacoeconomics and Outcomes has also published two best practice papers for developing new, or modifying pre-existing, PRO instruments.(16,41) Collectively these guidances provide systematic approaches to conduct qualitative work that can move the field forward. In conclusion, this systematic review identified the most commonly reported PRO concepts and PRO instruments published in the PBC and PSC literature. PRO instruments were used to measure these concepts only half the time, and most instruments were not validated in the target populations. Given significant gaps in our current knowledge regarding patient experiences and preferences, more qualitative studies and systematic approaches for incorporating the patient voice are needed in current research endeavors, including clinical trials, among patients living with PBC and PSC. Publisher Copyright: {\textcopyright} 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.",

year = "2020",

month = oct,

day = "1",

doi = "10.1002/hep4.1567",

language = "English (US)",

volume = "4",

pages = "1502--1515",

journal = "Hepatology Communications",

issn = "2471-254X",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "10",

}

TY - JOUR

T1 - A Systematic Review of Patient-Reported Outcomes in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

AU - Kim, Hannah P.

AU - Lieber, Sarah R.

AU - Rogers, Michael E.

AU - Moon, Andrew M.

AU - Loiselle, Marci

AU - Walker, Jennifer

AU - Assis, David N.

AU - Safer, Ricky

AU - Gomel, Rachel

AU - Evon, Donna M.

N1 - Funding Information: This comprehensive systematic review identified PRO concepts and instruments described in PBC and PSC studies over the last 30 years. Despite many studies involving a PRO concept, PRO instruments were used to measure these concepts only 50%-60% of the time. We observed tremendous variation in the types of instruments being used to evaluate the most common PRO concepts of pruritus, fatigue, and broad HRQOL. Moreover, most instruments were not developed with qualitative input from patients living with PBC or PSC, raising the question of whether these items appropriately capture the experiences and perceptions of these patients. This uncertainty likely exists, in part, due to a woefully low number of qualitative studies (e.g., in-depth interviews, focus groups) with patients with PBC or PSC, which stymies our understanding of their subjective experiences and perspectives. These findings highlight significant opportunities to improve the ways we capture disease symptoms, treatment side effects, and patient preferences using validated PRO instruments for PBC and PSC. In the field of PBC, the PBC-40, published in 2005, is the only PRO instrument that included formative patient interviews to guide the development of the measure, and thus has strong content validity and sound psychometric properties.(18) Because the PBC-40 also includes fatigue and itch subscales with proven content validity, this instrument is an ideal patient-centered choice for studies of PBC HRQOL, fatigue, and itch. Importantly, the instrument has also been adapted into briefer versions (PBC-27, PBC-10).(23,26) In addition to the PBC-40, the Itch Diary was recently developed based on qualitative interviews with patients with PBC, and thus is another viable option to measure PBC-induced itch.(19) Finally, the psychometric properties of the Fatigue Impact Scale and the Fisk Fatigue Severity Scale were evaluated for use in PBC in 2000, with the Fatigue Impact Scale being used frequently thereafter; however, because both were originally developed in other patient populations, neither can claim to be truly representative of PBC-related fatigue until further qualitative studies are conducted.(20,21) In contrast with PBC, far fewer studies of PRO concepts and instruments have been published for PSC. This may, in part, be due to the fact that no validated PRO instruments were developed specifically for PSC until 2018. The PSC-PRO instrument has followed guidelines for PRO measure development; more specifically, cognitive interviews were conducted with patients with PSC to validate item content.(25) However, patients from advocacy groups have stated that the PSC-PRO does not provide an accurate representation of how patients with PSC function and feel, as patients did not partake in the initial stages of development of the tool. The qualitative findings, which would provide valuable information for all PSC stakeholders, have not been published. This tool requires future testing in larger diverse samples of patients with PSC, to determine whether the overall measure is sensitive to change from disease progression or treatment. The CLDQ is a disease-specific measure of HRQOL developed for patients with various types of chronic liver disease; however, only 30% of the study cohort had PSC or PBC.(22) Finally, there is a new PSC HRQOL instrument currently under development that includes substantive patient engagement in every stage of development of the tool and will undergo international validation.(27) Aside from the new PSC-PRO that contains one itch item and two fatigue items, we identified no optimal choice for fatigue and pruritus measurements in PSC. Future qualitative studies should investigate patient preferences regarding pre-existing instruments to evaluate PSC-associated fatigue and itch, including the PBC-40, Fatigue Impact Scale, Fisk Fatigue Severity Scale, 5-D Itch Scale, Itch Diary, and ItchRO (developed qualitatively in children with Alagilles). The 5-D Itch measure was developed in patients with itch, but not specifically PSC, and encompasses five dimensions: duration, degree, direction, disability, and distribution. Finally, studies need to better distinguish between symptoms attributable to inflammatory bowel disease, a comorbidity that occurs in over 70% of patients with PSC, and those attributed to PSC. This study revealed significant gaps in the extant literature and highlights implications for future research. For instance, most PRO studies used visual analog and numeric rating scales, yet we identified no published scientific justification for these scales based on patient preferences. Moreover, there was significant heterogeneity in the types of visual and numeric rating scales, making it difficult to compare results in this literature. Therefore, a reduced reliance on these types of instruments in future studies is recommended until more empirical support is demonstrated. More studies in special populations (e.g., pediatric, pregnant, liver transplantation) are needed to understand patients’ perspectives, needs, and priorities to inform study outcomes and measures. There may be opportunities to modify and validate the National Institutes of Health Patient-Reported Outcome Measurement System measures in PBC and PSC, as these measures underwent robust qualitative development and psychometric testing in diverse populations. Most clinical trials in PBC or PSC did not measure AEs from the patients’ point of view and did not use PRO instruments. As a result, important information regarding the harms of treatments may be undetected and underrecognized. We acknowledge that these results likely reflect that patient-centered reporting of AEs is not a part of the current culture of conducting clinical trials. However, it is precisely for this reason that we believe existing practices should adopt a more patient-centered approach. Evaluating AEs systematically using PRO instruments is another way to enhance patient-focused drug development. Recently, the National Cancer Institute spearheaded the development of a PRO version of the Common Terminology Criteria for Adverse Events, called the “PRO-CTCAE,” as a more accurate method of detecting AEs during oncology drug trials.(28) The items were identified and developed using cognitive interviews with patients receiving active cancer treatment; furthermore, they underwent validation and extensive psychometric testing.(29,30) The PRO-CTCAE contains 78 patient-reported AEs rated on presence, frequency, severity, and life interference. A recent study highlighted significant discordance between clinician-graded AEs and the PRO-CTCAE, demonstrating the complementary and added value of the patient instrument.(31) A high-yield contribution to the field could be to imbed qualitative studies into PBC or PSC drug trials to develop a modified version of the PRO-CTCAE for these patients. As a way to facilitate patient-centered reporting of AEs, electronic modalities (e.g., tablets, cellphones, websites) could be used for reporting of AEs; participants could use validated instruments to report symptoms or experiences they had during the clinical trial. It is imperative that more qualitative or mixed methods studies be conducted to move the field of PROs in PBC and PSC forward. We identified only three qualitative and three mixed-methods articles that described the experiences of patients with PBC(12,32-36); astonishingly, no qualitative studies have been published describing the experiences of patients with PSC. We acknowledge that there may be a bias against publishing qualitative studies, and researchers may not be incentivized to conduct these types of works. However, qualitative studies are absolutely essential to deepen our understanding of patient experiences, perspectives, needs, and priorities; this is especially true in the setting of studying different medical treatments.(37-39) Toward this end, clinical investigators are encouraged to familiarize themselves with the systematic, step-by-step approaches for conducting formative, qualitative work needed to develop or modify accompanying PRO instruments. In 2019, the FDA published a series of four guidance documents to facilitate patient-focused drug development.(40) The new guidance includes best practices for qualitative research to gain insight into patient experiences and needs. Additionally, the International Society for Pharmacoeconomics and Outcomes has also published two best practice papers for developing new, or modifying pre-existing, PRO instruments.(16,41) Collectively these guidances provide systematic approaches to conduct qualitative work that can move the field forward. In conclusion, this systematic review identified the most commonly reported PRO concepts and PRO instruments published in the PBC and PSC literature. PRO instruments were used to measure these concepts only half the time, and most instruments were not validated in the target populations. Given significant gaps in our current knowledge regarding patient experiences and preferences, more qualitative studies and systematic approaches for incorporating the patient voice are needed in current research endeavors, including clinical trials, among patients living with PBC and PSC. Publisher Copyright: © 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with decreased health-related quality of life and debilitating symptoms. These experiences can be defined as patient-reported outcome (PRO) concepts and measured using PRO instruments. We identified all PRO concepts and instruments used in the PBC and PSC literature. This systematic review identified PBC and/or PSC studies from January 1, 1990, to May 6, 2019, that measured at least one PRO concept. Study population, design, PRO concept, PRO instrument, and validation data for PRO instruments were investigated. We provided descriptive statistics of PRO concepts and instruments used, stratified by population type. Use of PRO concepts and instruments were assessed over time. The search yielded 318 articles (69% in PBC, 18% in PSC, 13% in both, and 24% in drug trials). Forty-nine unique PRO concepts were identified. The five most common PRO concepts included pruritus (25%), fatigue (19%), broad health-related quality of life (16%), gastrointestinal adverse events (6%), and physical adverse events (6%). Only 60% of PRO concepts were measured with a PRO instrument, most of which were nonvalidated visual analogue or numeric rating scales. Only three of 83 PRO instruments were developed with feedback from the target populations (one for PBC, one for PSC, and one for both), and only six documented any psychometric testing in the target populations. Use of PRO instruments increased over time from 30% in the 1990s to 67% by 2019. Conclusion: The overwhelming majority of PRO instruments used in PBC/PSC were nonspecific and lacked patient validation or empirical justification. Significant opportunities exist to use qualitative methods to better understand patient experiences, and translate this knowledge into meaningful, patient-driven study outcomes.

AB - Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with decreased health-related quality of life and debilitating symptoms. These experiences can be defined as patient-reported outcome (PRO) concepts and measured using PRO instruments. We identified all PRO concepts and instruments used in the PBC and PSC literature. This systematic review identified PBC and/or PSC studies from January 1, 1990, to May 6, 2019, that measured at least one PRO concept. Study population, design, PRO concept, PRO instrument, and validation data for PRO instruments were investigated. We provided descriptive statistics of PRO concepts and instruments used, stratified by population type. Use of PRO concepts and instruments were assessed over time. The search yielded 318 articles (69% in PBC, 18% in PSC, 13% in both, and 24% in drug trials). Forty-nine unique PRO concepts were identified. The five most common PRO concepts included pruritus (25%), fatigue (19%), broad health-related quality of life (16%), gastrointestinal adverse events (6%), and physical adverse events (6%). Only 60% of PRO concepts were measured with a PRO instrument, most of which were nonvalidated visual analogue or numeric rating scales. Only three of 83 PRO instruments were developed with feedback from the target populations (one for PBC, one for PSC, and one for both), and only six documented any psychometric testing in the target populations. Use of PRO instruments increased over time from 30% in the 1990s to 67% by 2019. Conclusion: The overwhelming majority of PRO instruments used in PBC/PSC were nonspecific and lacked patient validation or empirical justification. Significant opportunities exist to use qualitative methods to better understand patient experiences, and translate this knowledge into meaningful, patient-driven study outcomes.

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A Systematic Review of Patient-Reported Outcomes in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

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