Health-related quality of life of patients with resistant/intolerant chronic phase chronic myeloid leukemia treated with asciminib or bosutinib in the phase 3 ASCEMBL trial.

In ASCEMBL, an open-label, randomized Phase 3 study, asciminib demonstrated superior efficacy and better safety profile compared with bosutinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors. Health-related quality of life (HRQOL) reported by patients is key to understanding the benefit and impact of treatment on patients' lives, and is becoming increasingly important as the life expectancy of CML-CP patients increases and patients require long-term treatment. In ASCEMBL, patients completed questionnaires to assess CML symptoms and interference with daily life (M.D. Anderson Symptom Inventory - CML [MDASI-CML]), general HRQOL (five-level EQ-5D [EQ-5D-5L], Patient Global Impression of Change - CML [PGIC-CML]), and impact of CML on working life and activity (Work Productivity and Activity Impairment questionnaire - CML [WPAI-CML]). Patients' CML symptoms and HRQOL remained stable during 48 weeks of treatment with asciminib, with a general trend for decreased CML symptom severity, particularly for fatigue, and improvement in HRQOL. A clinically meaningful increase in diarrhea severity was observed in patients treated with bosutinib compared to asciminib. These data provide better understanding of the patient perspective and treatment impact on HRQOL in a later-line setting, where little information has been published to date.

Qualitative research with patients and caregivers of patients with PIK3CA related overgrowth spectrum: content validity of clinical outcome assessments.

BACKGROUND: PIK3CA-Related Overgrowth Spectrum (PROS) are rare syndromes caused by a mutation in the PIK3CA gene, including fibroadipose hyperplasia or overgrowth; congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal (CLOVES); megalencephaly-capillary malformation (MCAP or M-CM); fibro-adipose vascular anomaly (FAVA); Klippel-Trenaunay syndrome (KT; also known as, Klippel-Trenaunay-Weber syndrome); capillary, lymphatic, and venous malformations (CLVM); and lymphatic malformation (LM). Characterized by malformations and tissue overgrowth, PROS manifests at birth or in early childhood. Pain and functional limitations associated with these conditions may greatly impact the health-related quality of life (HRQoL) of persons with PROS including physical functioning, work/school, social functioning, and emotional well-being. RESULTS: Selected clinical outcome assessments (COAs), identified during a literature review, were tested with adults with PROS, and children with PROS and their caregivers to determine comprehensibility, relevance, and appropriateness for measuring symptom severity and HRQoL. Tested were the Patient Global Impression of Symptom Severity (PGI-S), Brief Pain Inventory (BPI), Wong-Baker FACES, Patient-Reported Outcomes Measurement Information System (PROMIS) Profile, PROMIS Pediatric Short Form Sleep Disturbance, and PROMIS Dyspnea Severity. Qualitative interviews tested the self-report adult, self-report pediatric, and observer-report COAs with adults with PROS, and children with PROS and their caregivers. Ten adults (≥ 18 years old) with PROS, and 20 children (6-17 years old) with PROS and their caregivers, participated. All reported positive feedback on item relevance. Adults and children over the age of 12 comprehended and responded to self-reported items. Secondary objectives examined the age children could self-report their conditions using pediatric versions and assessed available observer-report versions of the COAs with caregivers. Some participants under the age of 12 had trouble understanding some terminology. Further, adults and children with cognitive impairment associated with MCAP/M-CM sometimes had difficulty with self-report. Caregivers were able to report their child's symptoms and impacts using observer-report COAs. Participant feedback prompted further consideration of the measurement of pain in this population, including variability of pain over time, location of pain, and type. CONCLUSIONS: This study provided valuable information from patients about PROS, supporting the content validity of the COAs, with recommended revisions. COAs are easily understood by persons with PROS and caregivers and are appropriate for measuring symptoms and disease-related impacts across diverse PROS syndromes in clinical trials.

Patient experiences with patient-reported outcome measures in metastatic breast cancer trials: qualitative interviews.

BACKGROUND: Patient-reported outcome (PRO) measures are critical for assessing treatment benefit of anticancer treatments. Although PRO measures have been developed with the intention of capturing patient-centric concepts, a gap exists in understanding the patient experience with these tools. We characterized the experience of patients with metastatic breast cancer (mBC) with PRO measures in an oncology clinical trial setting to determine the importance, relevance, barriers, and facilitators for PRO completion. METHODS: The multicenter, qualitative design included semistructured interviews with 18 women with mBC who completed PRO measures in a clinical trial setting within 1 year of screening. Interviews began with concept elicitation to understand symptom characterization, decision to participate in a clinical trial, pre-trial expectations, and thoughts on study-related questionnaires. Cognitive debriefing was conducted to determine if items in a commonly used PRO instrument were relevant to the patient experience. Qualitative data were analyzed using a constant comparative approach. RESULTS: Participants described the need for detailed explanation of PRO measures at study start, including information about how the PRO data will likely be used to support drug development. Respondents who felt connected to clinical trial research were more likely to feel as if the measures adequately captured their experiences. Items that were deemed irrelevant or out of date to the patient experience may cause a respondent to feel marginalized and adds to the overall burden of PRO measure completion. Mode of PRO measure administration (electronic/paper) was important to some, but placement of the instrument completion within a study visit appeared to influence respondent willingness to fully engage with the measures. A lack of any type of feedback loop to allow respondents to learn from the captured PRO data was noted as important but missing from the patient experience. CONCLUSIONS: PRO measures need to include content that is relevant to the patient experience over the course of the clinical trial period to be considered meaningful to respondents, and administration techniques also impact engagement. Robust communication strategies that socialize the intent, use, and results of PRO data may enrich the patient experience and support greater adherence to PRO completion in future studies.

Content validation of observer-reported sickle cell pain diaries (SCPD-CS and SCPD-CN): results from interviews with caregivers.

BACKGROUND: Patients with sickle cell disease (SCD) experience daily pain and acute episodes known as sickle cell pain crises (SCPCs). The Sickle Cell Pain Diary-Caregiver Report (SCPD-C) is an observer-reported diary for use by caregivers of children ages < 12 years with SCD. This study reports on the content validity of the SCPD-C. METHODS: The SCPD-C was developed based on a literature review, measurement expert input, and a patient advisory board including clinicians. Three rounds of interviews (including both concept elicitation and cognitive debriefing methodologies) were conducted with caregivers of children with SCD aged < 12 to evaluate the content validity of the SCPD-C. RESULTS: Across three rounds of interviews, caregivers confirmed concepts in the SCPD-C and described observed impacts that were important and were added. Overall, caregivers evaluated the SCPD-C as easy to understand, with some minor adaptations for clarity. Additionally, the diary was split into two versions based on the child's age and school enrollment status (SCPD-CS for school-aged and SCPD-CN for non-school age children). CONCLUSIONS: Caregivers provided valuable input that led to important additions and changes to the measures. The SCPD-CS and SCPD-CN are appropriate and fit-for-purpose observer-reported outcome measures of SCPC-related pain frequency and severity, and impacts on health-related quality of life.

Psychometric Evaluation of ITP Life Quality Index (ILQI) in a Global Survey of Patients with Immune Thrombocytopenia.

INTRODUCTION: Immune thrombocytopenia (ITP) is an autoimmune disorder caused by immunologic destruction of otherwise normal platelets. Patients and physicians differ in their views pertaining to the limitations imposed on patients' daily lives by ITP and its treatment. Poor understanding of ITP symptoms can result in misdiagnosis and complex treatment patterns, and affect patient health-related quality of life (HRQoL). The ITP Life Quality Index (ILQI) is a 10-item patient-reported outcome measure developed for clinical practice to aid discussions between patients and physicians. This research aimed to validate the psychometric properties of the ILQI using data collected in the ITP World Impact Survey (I-WISh). METHODS: I-WISh data containing responses to the ILQI from 1507 patients with ITP across 13 countries worldwide was subject to psychometric analysis to evaluate the structure, reliability and validity of the ILQI and assess scoring cut-offs. RESULTS: The ILQI has an overarching unidimensional structure, supporting a total score including all 10 items. Reliability was supported (Cronbach's alpha = 0.90). ILQI scores monotonically increased with ITP severity. ILQI scores correlated with measures of fatigue and emotional well-being, supporting construct validity. Differential item functioning (DIF) analyses showed that ILQI item responses were interpreted similarly between the USA and other Western countries. It was suggested that previous clinical cut-off score of 20 for "impaired HRQoL" was reduced to 17 and a cut-off of 23-25 (rather than 30) was suggested to assess "significantly impaired HRQoL". CONCLUSION: The validity and reliability of the ILQI to assess HRQoL of patients with ITP is supported. The revised cut-off scores for the ILQI will aid patient-centric decision-making.

Qualitative study to support the content validity of the immune thrombocytopenia (ITP) Life Quality Index (ILQI).

Immune thrombocytopenia (ITP) is an acquired immune-mediated disorder. Bleeding is the primary symptom that presents in varying severities. ITP has a negative impact on health-related quality of life (HRQoL). The ITP Life Quality Index (ILQI) was developed as a 10-item patient-reported outcome measure to assess impact on HRQoL in ITP. The objective of the present study was to confirm the content validity of the ILQI with a qualitative interview study in the UK involving 15 adult participants with ITP. Combined concept elicitation (CE) and cognitive debriefing (CD) interviews were conducted to explore the symptoms and impacts associated with ITP and confirm content validity of the draft ILQI. The CE phase elicited 14 ITP symptom concepts, including: bruising (all 15 patients, 100%), fatigue (14, 93·3%) and bleeding gums/blood blisters (13, 86·7%). Impacts included decreased ability to participate in sport (all 15 patients, 100%) and anxiety (12, 80%). The CD phase resulted in an adjustment to the ILQI recall period from 1 week to 'the past month'. Updates were made to improve relevance and response options. The qualitative interviews support the content validity of the ILQI and confirm that the concepts assessed are relevant and consistently understood and interpreted by adult patients with ITP.

Use of Patient and Investigator Global Impression Scales: A Review of Food and Drug Administration-Approved Labeling, 2009 to 2019.

OBJECTIVE: Identify disease categories in which single-item global impression (GI) scales were included in product labeling of new drugs approved by the US Food and Drug Administration (FDA) in January 2009-December 2019 and review the characteristics of GIs included in product labeling of new FDA-approved drugs (January 2017-December 2019). METHODS: FDA Clinical Outcome Assessment (COA) Compendium was reviewed for drug labels that included GIs for drugs approved in 2009-2016. The indication, year of approval, ICD-10 code, and GI respondent were noted. A manual review of labels of FDA-approved drugs (2017-2019) was undertaken to identify GIs included in the labels. Corresponding drug approval packages were reviewed to identify details of any regulatory reviewer comments related to GIs. GI characteristics were noted from the drug label or the review documents, including the respondent, type of measure (static or dynamic), item wording, concept assessed, and response options. RESULTS: Product labeling containing GIs was most common in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs were included in 30/77 (39.0%) drug labels in the four disease categories. CONCLUSION: In the past 10 years, GIs have been included as endpoint measures in confirmatory clinical trials and have generated evidence of treatment benefit in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs frequently provide important insights into the patient experience. Before GIs are included in clinical trials to assess treatment benefit, it is important to ensure that they are valid, reliable, and responsive.

Content validation of a self-report daily diary in patients with sickle cell disease.

BACKGROUND: Sickle Cell Disease (SCD) is a genetic progressive vascular disease that impacts patients overall health and quality of life. Sickle-cell pain crises (SCPCs) are a hallmark clinical presentation of SCD and have been associated with increased morbidity and mortality. The Sickle Cell Pain Diary- Self Report (SCPD-S) was developed as a daily patient-reported outcome (PRO) measure primarily intended to capture the frequency and severity of SCD-related pain during and outside of a SCPC. The SCPD-S also examines the impact of the pain associated with an SCPC on other health-related quality of life concepts. The objective of this study was to investigate the content validity of the SCPD-S. METHODS: The content validation testing included 18 in-depth hybrid concept elicitation and cognitive debriefing interviews conducted with SCD patients in the US aged 12 years and older. Interviewers used a semi-structured interview guide and a think-aloud approach for the cognitive debriefing portion. All interviews were recorded, transcribed, coded and analyzed. RESULTS: Eighteen interviews across two rounds were conducted. Round 1 hybrid interviews (n = 12) resulted in the expansion of the SCPD-S from 13 to 19 items. Items on the impact of an SCPC on social and recreational activities, sleep, and emotional well-being were added. Five items were significantly revised, as were three response choice sets. Round 2 hybrid interviews (n = 6) confirmed the comprehensiveness of the revised diary, understandability of the wording, and appropriateness of the recall period and response sets. Saturation analyses specific to concept elicitation revealed that no additional interviews were needed. CONCLUSIONS: This study provided evidence to support the content validity of the SCPD-S, a self-report daily diary. Data gathered during patient interviews indicated that the SCPD-S is a fit for purpose measure of SCD and SCPC-related pain frequency and severity and the impact of this pain on other health-related quality of life concepts including fatigue and emotional health. The numerous changes to the SCPD-S as a result of the study findings highlight the importance of the content validation process when developing a PRO measure.

What is an estimand & how does it relate to quantifying the effect of treatment on patient-reported quality of life outcomes in clinical trials?

BACKGROUND: Published in 2019, a new addendum to the ICH E9 guideline presents the estimand framework as a systematic approach to ensure alignment among clinical trial objectives, trial execution/conduct, statistical analyses, and interpretation of results. The use of the estimand framework for describing clinical trial objectives has yet to be extensively considered in the context of patient-reported outcomes (PROs). We discuss the application of the estimand framework to PRO objectives when designing clinical trials in the future, with a focus on PRO outcomes in oncology trial settings as our example. MAIN: We describe the components of an estimand and take a naïve PRO trial objective to illustrate how to apply attributes described in the estimand framework to inform construction of a detailed clinical trial objective and its related estimand. We discuss identifying potential post-randomization events that alter the interpretation of the endpoint or render its observation impossible (also defined as intercurrent events) in the context of PRO endpoints, and the implications of how to handle intercurrent events in the construction of the PRO objective. Using a simple objective statement, "What is the effect of treatment X on patient's quality of life?", we build up an example estimand statement and also use a previously published phase III oncology clinical trial to illustrate how an estimand for a PRO objective could have been written to align to the estimate framework. CONCLUSION: The use of the estimand framework, as described in the new ICH E9 (R1) addendum guideline will become a key common framework for developing clinical trial objectives for evaluating effects of treatment. In the context of considering PROs, the framework provides an opportunity to more precisely specify and build the rationale for patient-focused objectives. This will help to ensure that clinical trials used for registration are designed and analysed appropriately, enabling all stakeholders to accurately interpret conclusions about the treatment effects for patient-focused outcomes.

A Review of Patient-Reported Outcomes Labeling for Oncology Drugs Approved by the FDA and the EMA (2012-2016).

OBJECTIVES: To compare US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labeling for evidence based on patient-reported outcomes (PROs) of new oncology treatments approved by both agencies. METHODS: Oncology drugs and indications approved between 2012 and 2016 by both the FDA and the EMA were identified. PRO-related language and analysis reported in US product labels and drug approval packages and EMA summaries of product characteristics were compared for each indication. RESULTS: In total, 49 oncology drugs were approved for a total of 64 indications. Of the 64 indications, 45 (70.3%) included PRO data in either regulatory submission. No FDA PRO labeling was identified. PRO language was included in the summary of product characteristics for 21 (46.7%) of 45 indications. European Organisation for Research and Treatment of Cancer and Functional Assessment of Cancer Therapy measures were used frequently in submissions. FDA's comments suggest that aspects of study design (eg, open labels) or the validity of PRO measures was the primary reason for the lack of labeling based on PRO endpoints. Both agencies identified missing PRO data as problematic for interpretation. CONCLUSIONS: During this time period, the FDA and the EMA used different evidentiary standards to assess PRO data from oncology studies, with the EMA more likely to accept data from open-label studies and broad concepts such as health-related quality of life. An understanding of the key differences between the agencies may guide sponsor PRO strategy when pursuing labeling. Patient-focused proximal concepts are more likely than distal concepts to receive positive reviews.

Health-related quality of life predicted subsequent health care resource utilization in patients with active cancer.

PURPOSE: The objective of this study was to estimate the association between SF-12v2® Health Survey (SF-12v2) scores and subsequent health care resource utilization (HCRU) among patients with cancer. METHODS: We analyzed 18+ year participants in the Medical Expenditure Panel Survey, diagnosed with active cancer or malignancy (n = 647). HCRU was measured by total medical expenditures (MEs) and number of medical events (EVs) in the 6 months following the SF-12v2 assessment. The effect of SF-12v2 scores (physical (PCS) and mental (MCS) component summary scores and the SF-6D health-utility score) on HCRU was estimated using generalized linear models. Estimates were obtained for the entire sample and for the four cancer groups present in the sample: breast, prostate, skin, and lung. RESULTS: For PCS and MCS, a one-point better score was associated with 2% lower MEs (P < 0.001) and 2.5% lower MEs (P = 0.015), respectively. A 0.05-point better SF-6D score was associated with 7% lower MEs (P = 0.003). PCS and SF-6D were more strongly associated with MEs for prostate cancer patients (P = 0.009 and P = 0.003) and PCS was more strongly associated with MEs for skin cancer patients (P = 0.019), compared to other cancer groups. A 1-point better PCS predicted 1% lower EVs, while a 0.05 better SF-6D score predicted 4% lower EVs. CONCLUSIONS: The significant associations between SF-12v2 scores from oncology patients and subsequent HCRU can guide interpretations of SF-12v2 scores in evaluation of therapies and in health policy decisions.

Payer Perspectives on Patient-Reported Outcomes in Health Care Decision Making: Oncology Examples.

BACKGROUND: Health authorities and payers increasingly recognize the importance of patient perspectives and patient-reported outcomes (PROs) in health care decision making. However, given the broad variety of PRO endpoints included in clinical programs and variations in the timing of PRO data collection and country-specific needs, the role of PRO data in reimbursement decisions requires characterization. OBJECTIVES: To (a) determine the effect of PRO data on market access and reimbursement decisions for oncology products in multiple markets and (b) assess the effect of PRO data collected after clinical progression on payer decision making. METHODS: A 3-part assessment (targeted literature review, qualitative one-on-one interviews, and online survey) was undertaken. Published literature was identified through searches in PubMed/MEDLINE and Embase. In addition, a targeted search was conducted of health technology assessment (HTA) agency websites in the United States, the United Kingdom, France, and Germany. Qualitative one-on-one interviews were conducted with 16 payers from the RTI Health Solutions global advisory panel in 14 markets (Australia, Brazil, France, Germany, Italy, South Korea, Netherlands, Poland, Spain, Sweden, Taiwan, Turkey, the United Kingdom, and the United States [n = 3]). Of the 200 payers and payer advisors from the global advisory panel invited to participate in the online survey, 20 respondents (China, France, Germany, Spain [n = 2], Taiwan, the United Kingdom, and the United States [n = 13]) completed the survey, and 6 respondents (Australia, South Korea, and the United States [n = 4]) partially completed the survey. RESULTS: Reviews of the literature and publicly available HTAs and reimbursement decisions suggested that HTA bodies and payers have varying experience with and confidence in PRO data. Payers participating in the survey indicated that PRO data may be especially influential in oncology compared with other therapeutic areas. Payers surveyed offered little differentiation by cancer type in the importance of PRO data but felt that it was most important to collect PRO data in phase 3 and postmarketing studies. Payers surveyed also anticipated an increasing significance for PRO data over the next 5-10 years. Characteristics of PRO data that maximize influence on payer decision making were reported to be (a) quality, well-controlled, and transparent PRO evidence; (b) psychometric validation of the PRO measure in targeted populations; and (c) publication in peer-reviewed journals. In markets with decentralized health care decision making, PRO data currently have more influence at the local level. Inclusion of PRO data in cancer treatment guidelines is key for centralized markets. Payers surveyed generally considered collecting PRO data postprogression to be useful. Of the 16 interviewees, 11 indicated that it is worthwhile to collect PRO data postprogression and that positive PRO data may support continued therapy at the physician's discretion upon regulatory approval, even in progressive disease. CONCLUSIONS: PRO data may help to differentiate treatments, particularly after clinical progression in oncology. Payers worldwide recognize high-quality PRO data as a key component of their decision-making process and anticipate the growing importance of PRO data in the future. DISCLOSURES: This study and preparation of this article were funded by Novartis Pharmaceuticals. This research was performed under a research contract between RTI Health Solutions and Novartis Pharmaceuticals. Brogan, Hogue, Demuro, and Barrett are employees of RTI Health Solutions. D'Alessio and Bal are employees of Novartis Pharmaceuticals. Study concept and design were contributed by DeMuro, Barrett, Bal, and Hogue. Brogan and Hogue took the lead in data collection, assisted by DeMuro and Bal. Data interpretation was performed by Brogan and Hogue, assisted by the other authors. The manuscript was written by D'Alessio and Brogan, along with the other authors, and revised primarily by Brogan, along with Hogue and assisted by the other authors. The abstract for this article was presented as a research poster at the following meetings: Hogue SL, Brogan A P, De Muro C, D'Alessio D, Bal V. Patient-reported outcomes (PRO) in post-progression oncology: implications in health technology assessments and payer decision making. Poster presented at the ISPOR 18th Annual European Meeting; November 7-11, 2015. Milan, Italy. Hogue SL, Brogan AP, De Muro C, D'Alessio D, Bal V. Influence of patient-reported outcomes (PRO) on market access decisions in markets with centralized healthcare systems. Poster presented at the ISPOR 18th Annual European Meeting; November 7-11, 2015. Milan, Italy. Hogue SL, Brogan AP, De Muro C, Barrett A, D'Alessio D, Bal V. Influence of patient-reported outcomes on market access decisions in decentralized markets (Brazil, Italy, Spain and the United States). Poster presented at the ISPOR 20th Annual Meeting; May 16-20, 2015. Philadelphia PA. Hogue SL, Brogan A P, De Muro C, Barrett A, McLeod L, D'Alessio D, et al. Payer Perspectives of Patient-Reported Outcomes Data: An Online Assessment. Poster presented at the ISOQOL 22nd Annual Meeting; October 21-24, 2015. Vancouver, British Columbia, Canada.