A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials

Barbara K. Burton; Anne Skalicky; Christoph Baerwald; Deborah A. Bilder; Cary O. Harding; Aaron B. Ilan; Elaina Jurecki; Nicola Longo; David T. Madden; H. Serap Sivri; Gisela Wilcox; Janet Thomas; Kathleen Delaney

doi:10.1016/j.ymgmr.2021.100810

A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials

Barbara K. Burton^*, Anne Skalicky, Christoph Baerwald, Deborah A. Bilder, Cary O. Harding, Aaron B. Ilan, Elaina Jurecki, Nicola Longo, David T. Madden, H. Serap Sivri, Gisela Wilcox, Janet Thomas, Kathleen Delaney

^*Corresponding author for this work

Pediatrics

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

5 Scopus citations

Abstract

Introduction: Current clinical outcome assessments (COAs) are not effectively capturing the complex array of symptoms of adults with phenylketonuria (PKU). This study aimed to identify concepts of interest relevant to adults with PKU. Based on these concepts, COAs for patient-reported outcomes (PROs), observer-reported outcomes (ObsROs), and clinician-reported outcomes (ClinROs) were selected or developed and content validity was assessed. Materials and methods: Concept-elicitation interviews were conducted with an international cohort of adults with PKU (n = 30), family member observers (n = 14), and clinical experts (n = 8). Observers and clinical experts were included to overcome the risk of lack of self-awareness among adults with PKU. The concepts of interests endorsed by ≥30% of patients, observers, and/or clinical experts were selected, mapped to items in existing COAs, and used to develop global impression items for patients, observers, and clinicians. Next, the content validity of the COAs and global impression items was evaluated by cognitive interviews with patients (n = 22), observers (n = 11), and clinical experts (n = 8). All patients were categorized according to blood phenylalanine (Phe) levels (i.e., <600 μmol/L, 600–1200 μmol/L, and >1200 μmol/L). Results: Concepts of interests were identified across four domains: emotional, cognitive, physical, and behavioral. After mapping, eight existing COAs were selected based on the concept coverage (six PROs, one ObsRO, and one ClinRO). The six PRO measures were considered as potentially fit-for-purpose. The ObsRO measure was not deemed relevant for use in observers of adults with PKU and only a subscale of the ClinRO measure was considered valid for assessing adults with PKU by clinicians. Due to the lack of existing COAs covering all concepts of interests, global impression items for symptom severity and change in symptoms were developed, which were limited to one question covering in total 14 concepts. Upon validation, some of the patient and observer global impression items were excluded as they were subject to lack of insight or could not be reported by observers. Due to the limited interaction time between clinician and patient, use of the clinician global impression items was not supported. Conclusion: Existing COAs relevant to adults with PKU were selected and PKU-specific global impression items were developed by mapping the most frequently identified concepts of interests from internationally-conducted in-depth interviews. Future studies should address the appropriateness of the selected COAs and global impression items to assess if these can be used as efficacy endpoints in PKU clinical trials.

Original language	English (US)
Article number	100810
Journal	Molecular Genetics and Metabolism Reports
Volume	29
DOIs	https://doi.org/10.1016/j.ymgmr.2021.100810
State	Published - Dec 2021

Funding

All clinical experts were financially compensated by BioMarin for their participation to the study. Additional disclosures: AS is an employee of Evidera. CB has received consulting fees from Genzyme and Shire and was a speaker for BioMarin, Genzyme, Nutricia, Shire, and Vitaflo. BKB has received personal fees from BioMarin , Homology Medicines , Takeda , Horizon , Denali , JCR Pharma , Ultragenyx , and Moderna outside the submitted work. DB has received grants and personal fees from BioMarin outside the submitted work. COH has received personal fees from BioMarin , grants from StrideBio , grants and personal fees from Synlogic , and personal fees from Sanofi-Genzyme outside the submitted work. JT has received support from BioMarin outside of the submitted work. GW has received travel grants from Sanofi-Genzyme , BioMarin , Shire/Takeda , and Amicus , received speaker honoraria from Sanofi-Genzyme , BioMarin , Shire/Takeda , and Nutricia , was awarded research grants from the MPS society (UK) , received advisory board membership with BioMarin and Meta Healthcare, received Medical Advisory Panel membership for the National Society for PKU (NSPKU), and performed consultancies for Dimension Therapeutics/Ultragenyx. KD, ABI, EJ, and DTM are employees of BioMarin Pharmaceutical Inc. This study and support in the process of manuscript development were funded by BioMarin Pharmaceutical Inc., Novato, CA, USA.All clinical experts were financially compensated by BioMarin for their participation to the study. Additional disclosures: AS is an employee of Evidera. CB has received consulting fees from Genzyme and Shire and was a speaker for BioMarin, Genzyme, Nutricia, Shire, and Vitaflo. BKB has received personal fees from BioMarin, Homology Medicines, Takeda, Horizon, Denali, JCR Pharma, Ultragenyx, and Moderna outside the submitted work. DB has received grants and personal fees from BioMarin outside the submitted work. COH has received personal fees from BioMarin, grants from StrideBio, grants and personal fees from Synlogic, and personal fees from Sanofi-Genzyme outside the submitted work. JT has received support from BioMarin outside of the submitted work. GW has received travel grants from Sanofi-Genzyme, BioMarin, Shire/Takeda, and Amicus, received speaker honoraria from Sanofi-Genzyme, BioMarin, Shire/Takeda, and Nutricia, was awarded research grants from the MPS society (UK), received advisory board membership with BioMarin and Meta Healthcare, received Medical Advisory Panel membership for the National Society for PKU (NSPKU), and performed consultancies for Dimension Therapeutics/Ultragenyx. KD, ABI, EJ, and DTM are employees of BioMarin Pharmaceutical Inc.

Keywords

Adults
Clinical outcome assessments
Clinician-reported outcomes
Observer-reported outcomes
PKU
Patient-reported outcomes
Phenylketonuria

ASJC Scopus subject areas

Molecular Biology
Genetics
Endocrinology

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10.1016/j.ymgmr.2021.100810

Cite this

Burton, B. K., Skalicky, A., Baerwald, C., Bilder, D. A., Harding, C. O., Ilan, A. B., Jurecki, E., Longo, N., Madden, D. T., Sivri, H. S., Wilcox, G., Thomas, J., & Delaney, K. (2021). A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials. Molecular Genetics and Metabolism Reports, 29, Article 100810. https://doi.org/10.1016/j.ymgmr.2021.100810

@article{4de4bead00514637a13f1d6bd4db8278,

title = "A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials",

abstract = "Introduction: Current clinical outcome assessments (COAs) are not effectively capturing the complex array of symptoms of adults with phenylketonuria (PKU). This study aimed to identify concepts of interest relevant to adults with PKU. Based on these concepts, COAs for patient-reported outcomes (PROs), observer-reported outcomes (ObsROs), and clinician-reported outcomes (ClinROs) were selected or developed and content validity was assessed. Materials and methods: Concept-elicitation interviews were conducted with an international cohort of adults with PKU (n = 30), family member observers (n = 14), and clinical experts (n = 8). Observers and clinical experts were included to overcome the risk of lack of self-awareness among adults with PKU. The concepts of interests endorsed by ≥30% of patients, observers, and/or clinical experts were selected, mapped to items in existing COAs, and used to develop global impression items for patients, observers, and clinicians. Next, the content validity of the COAs and global impression items was evaluated by cognitive interviews with patients (n = 22), observers (n = 11), and clinical experts (n = 8). All patients were categorized according to blood phenylalanine (Phe) levels (i.e., <600 μmol/L, 600–1200 μmol/L, and >1200 μmol/L). Results: Concepts of interests were identified across four domains: emotional, cognitive, physical, and behavioral. After mapping, eight existing COAs were selected based on the concept coverage (six PROs, one ObsRO, and one ClinRO). The six PRO measures were considered as potentially fit-for-purpose. The ObsRO measure was not deemed relevant for use in observers of adults with PKU and only a subscale of the ClinRO measure was considered valid for assessing adults with PKU by clinicians. Due to the lack of existing COAs covering all concepts of interests, global impression items for symptom severity and change in symptoms were developed, which were limited to one question covering in total 14 concepts. Upon validation, some of the patient and observer global impression items were excluded as they were subject to lack of insight or could not be reported by observers. Due to the limited interaction time between clinician and patient, use of the clinician global impression items was not supported. Conclusion: Existing COAs relevant to adults with PKU were selected and PKU-specific global impression items were developed by mapping the most frequently identified concepts of interests from internationally-conducted in-depth interviews. Future studies should address the appropriateness of the selected COAs and global impression items to assess if these can be used as efficacy endpoints in PKU clinical trials.",

keywords = "Adults, Clinical outcome assessments, Clinician-reported outcomes, Observer-reported outcomes, PKU, Patient-reported outcomes, Phenylketonuria",

author = "Burton, {Barbara K.} and Anne Skalicky and Christoph Baerwald and Bilder, {Deborah A.} and Harding, {Cary O.} and Ilan, {Aaron B.} and Elaina Jurecki and Nicola Longo and Madden, {David T.} and Sivri, {H. Serap} and Gisela Wilcox and Janet Thomas and Kathleen Delaney",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = dec,

doi = "10.1016/j.ymgmr.2021.100810",

language = "English (US)",

volume = "29",

journal = "Molecular Genetics and Metabolism Reports",

issn = "2214-4269",

publisher = "Elsevier Inc.",

}

Burton, BK, Skalicky, A, Baerwald, C, Bilder, DA, Harding, CO, Ilan, AB, Jurecki, E, Longo, N, Madden, DT, Sivri, HS, Wilcox, G, Thomas, J & Delaney, K 2021, 'A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials', Molecular Genetics and Metabolism Reports, vol. 29, 100810. https://doi.org/10.1016/j.ymgmr.2021.100810

TY - JOUR

T1 - A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials

AU - Burton, Barbara K.

AU - Skalicky, Anne

AU - Baerwald, Christoph

AU - Bilder, Deborah A.

AU - Harding, Cary O.

AU - Ilan, Aaron B.

AU - Jurecki, Elaina

AU - Longo, Nicola

AU - Madden, David T.

AU - Sivri, H. Serap

AU - Wilcox, Gisela

AU - Thomas, Janet

AU - Delaney, Kathleen

PY - 2021/12

Y1 - 2021/12

N2 - Introduction: Current clinical outcome assessments (COAs) are not effectively capturing the complex array of symptoms of adults with phenylketonuria (PKU). This study aimed to identify concepts of interest relevant to adults with PKU. Based on these concepts, COAs for patient-reported outcomes (PROs), observer-reported outcomes (ObsROs), and clinician-reported outcomes (ClinROs) were selected or developed and content validity was assessed. Materials and methods: Concept-elicitation interviews were conducted with an international cohort of adults with PKU (n = 30), family member observers (n = 14), and clinical experts (n = 8). Observers and clinical experts were included to overcome the risk of lack of self-awareness among adults with PKU. The concepts of interests endorsed by ≥30% of patients, observers, and/or clinical experts were selected, mapped to items in existing COAs, and used to develop global impression items for patients, observers, and clinicians. Next, the content validity of the COAs and global impression items was evaluated by cognitive interviews with patients (n = 22), observers (n = 11), and clinical experts (n = 8). All patients were categorized according to blood phenylalanine (Phe) levels (i.e., <600 μmol/L, 600–1200 μmol/L, and >1200 μmol/L). Results: Concepts of interests were identified across four domains: emotional, cognitive, physical, and behavioral. After mapping, eight existing COAs were selected based on the concept coverage (six PROs, one ObsRO, and one ClinRO). The six PRO measures were considered as potentially fit-for-purpose. The ObsRO measure was not deemed relevant for use in observers of adults with PKU and only a subscale of the ClinRO measure was considered valid for assessing adults with PKU by clinicians. Due to the lack of existing COAs covering all concepts of interests, global impression items for symptom severity and change in symptoms were developed, which were limited to one question covering in total 14 concepts. Upon validation, some of the patient and observer global impression items were excluded as they were subject to lack of insight or could not be reported by observers. Due to the limited interaction time between clinician and patient, use of the clinician global impression items was not supported. Conclusion: Existing COAs relevant to adults with PKU were selected and PKU-specific global impression items were developed by mapping the most frequently identified concepts of interests from internationally-conducted in-depth interviews. Future studies should address the appropriateness of the selected COAs and global impression items to assess if these can be used as efficacy endpoints in PKU clinical trials.

AB - Introduction: Current clinical outcome assessments (COAs) are not effectively capturing the complex array of symptoms of adults with phenylketonuria (PKU). This study aimed to identify concepts of interest relevant to adults with PKU. Based on these concepts, COAs for patient-reported outcomes (PROs), observer-reported outcomes (ObsROs), and clinician-reported outcomes (ClinROs) were selected or developed and content validity was assessed. Materials and methods: Concept-elicitation interviews were conducted with an international cohort of adults with PKU (n = 30), family member observers (n = 14), and clinical experts (n = 8). Observers and clinical experts were included to overcome the risk of lack of self-awareness among adults with PKU. The concepts of interests endorsed by ≥30% of patients, observers, and/or clinical experts were selected, mapped to items in existing COAs, and used to develop global impression items for patients, observers, and clinicians. Next, the content validity of the COAs and global impression items was evaluated by cognitive interviews with patients (n = 22), observers (n = 11), and clinical experts (n = 8). All patients were categorized according to blood phenylalanine (Phe) levels (i.e., <600 μmol/L, 600–1200 μmol/L, and >1200 μmol/L). Results: Concepts of interests were identified across four domains: emotional, cognitive, physical, and behavioral. After mapping, eight existing COAs were selected based on the concept coverage (six PROs, one ObsRO, and one ClinRO). The six PRO measures were considered as potentially fit-for-purpose. The ObsRO measure was not deemed relevant for use in observers of adults with PKU and only a subscale of the ClinRO measure was considered valid for assessing adults with PKU by clinicians. Due to the lack of existing COAs covering all concepts of interests, global impression items for symptom severity and change in symptoms were developed, which were limited to one question covering in total 14 concepts. Upon validation, some of the patient and observer global impression items were excluded as they were subject to lack of insight or could not be reported by observers. Due to the limited interaction time between clinician and patient, use of the clinician global impression items was not supported. Conclusion: Existing COAs relevant to adults with PKU were selected and PKU-specific global impression items were developed by mapping the most frequently identified concepts of interests from internationally-conducted in-depth interviews. Future studies should address the appropriateness of the selected COAs and global impression items to assess if these can be used as efficacy endpoints in PKU clinical trials.

KW - Adults

KW - Clinical outcome assessments

KW - Clinician-reported outcomes

KW - Observer-reported outcomes

KW - PKU

KW - Patient-reported outcomes

KW - Phenylketonuria

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U2 - 10.1016/j.ymgmr.2021.100810

DO - 10.1016/j.ymgmr.2021.100810

M3 - Article

C2 - 34815941

AN - SCOPUS:85118833980

SN - 2214-4269

VL - 29

JO - Molecular Genetics and Metabolism Reports

JF - Molecular Genetics and Metabolism Reports

M1 - 100810

ER -

A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials

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