Facets of physical function assessed by patient-reported outcome measures in oncology research.

PURPOSE: The U.S. Food & Drug Administration has identified physical functioning (PF) as a core patient-reported outcome (PRO) in cancer clinical trials. The purpose of this study was to identify PF PRO measures (PROMs) in adult cancer populations and classify the PROMs by content covered (facets of PF) in each measure. METHODS: As part of the Patient Reports of Physical Functioning Study (PROPS) research program, we conducted a targeted literature review to identify PROMs that could be used in clinical trials to evaluate PF from the patient perspective. Next, we convened an advisory panel to conduct a modified, reactive, Delphi study to reach consensus on which PF facets are assessed by PROMs identified in the review. The panel engaged in a "card sort" activity to classify PROM items by PF facets. Consensus was reached when 80% of panel members agreed that at least one facet was being measured by each PROM item. RESULTS: The literature review identified 13 PROMs that met inclusion criteria. Eight facets of PF were identified for classification in the Delphi study: ability, completion, difficulty, limitation, quality, frequency, bother, and satisfaction. Through two rounds, the panel documented and classified conceptual approaches for each PRO item presented. The most prevalent PF facets were ability, difficulty, and limitation. CONCLUSION: Classifying PF PROMs by PF facets will promote more consistent communication regarding the aspects of PF represented in each PROM, helping researchers prioritize measures for inclusion in cancer clinical trials.

What facets of physical function are most important to adults diagnosed with cancer?

PURPOSE: Successful patient-focused drug development involves selecting and measuring outcomes in clinical trials that are important to patients. The U.S. Food & Drug Administration's definition of clinical benefit includes how patients feel, function, or survive. Patients are considered the experts in describing how they feel and function. In cancer trials, patient-reported measures of physical function provide insight into how patients function at baseline, benefit from the interventions being studied, and the impact of treatment side effects. We conducted a qualitative study with adults diagnosed with cancer to describe facets of physical function from their perspective and to identify which facets are most important to this patient population. METHODS: Using concept elicitation and cognitive interviewing techniques, we conducted semi-structured interviews with 72 adults ≥ 22 years of age with cancer who received treatment with an anticancer drug or biologic within six months of the interview. We selected participants using purposive sampling with the aim to elicit diverse experiences regarding how they may interpret and respond to questions related to physical function. Participants were presented with patient-reported outcome (PRO) items representative of PRO measures used in cancer and general populations. RESULTS: Five facets of how physical function relates to activities were defined from the patient perspective: ability, difficulty, limitation, satisfaction, and completion. More than half of the participants indicated that ability was the most important facet of physical function. The next most important were satisfaction (18.3%), limitation (14.1%), difficulty (5.6%), and completion (2.8%). CONCLUSION: This study demonstrates that we must be more specific about the facets of physical function that we set out to assess when we use PRO measures to describe the patient experience. These results have implications for the specificity of physical function facets when measured in cancer clinical trials.

Measuring Frailty Using Patient-Reported Outcomes (PRO) Data: A Feasibility Study in Patients with Multiple Myeloma.

PURPOSE: The objective of this retrospective study was to determine the feasibility of measuring frailty using patient responses to relevant EORTC QLQ-C30 items as proxy criteria for the Fried Frailty Phenotype, in a cohort of patients with Relapsed/Refractory Multiple Myeloma (RRMM). METHODS: Data were pooled from nine Phase III randomized clinical trials submitted to the FDA for regulatory review between 2010 and 2021, for the treatment of RRMM. Baseline EORTC QLQ-C30 responses were used to derive a patient-reported frailty phenotype (PRFP), based on the Fried definition of frailty. PRFP was assessed for internal consistency reliability, structural validity, and known groups validity. RESULTS: This study demonstrated the feasibility of adapting patient responses to relevant EORTC QLQ-C30 items to serve as proxy Fried frailty criteria. Selected items were well correlated with one another and PRFP as a whole demonstrated adequate internal consistency reliability and structural validity. Known groups analysis demonstrated that PRFP could be used to detect distinct comorbidity levels and distinguish between different functional profiles, with frail patients reporting more difficulty in walking about, washing/dressing, and doing usual activities, as compared to their pre-frail and fit counterparts. Among the 4928 patients included in this study, PRFP classified 2729 (55.4%) patients as fit, 1209 (24.5%) as pre-frail, and 990 (20.1%) as frail. CONCLUSION: Constructing a frailty scale from existing PRO items commonly collected in cancer trials may be a patient-centric and practical approach to measuring frailty. Additional psychometric evaluation and research is warranted to further explore the utility of such an approach.

US Food and Drug Administration Analysis of Patient-Reported Diarrhea and Its Impact on Function and Quality of Life in Patients Receiving Treatment for Breast Cancer.

OBJECTIVES: Many trials conclude "no clinically meaningful detriment" to health-related quality of life (HRQL) or function between arms, even when notable differential toxicity is observed. Mean change from baseline analyses of function or HRQL can possibly obscure important change in subgroups experiencing symptomatic toxicity. We evaluate the impact of diarrhea, a key treatment arm toxicity, on patient-reported HRQL and functioning in clinical trials submitted to US Food and Drug Administration. METHODS: This study used 4 randomized, breast cancer trials (adjuvant to late-line metastatic) as case examples. Diarrhea, physical functioning (PF), and global health status and quality of life (GHS/QoL) from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were analyzed at baseline and approximately 3 and 6 months. RESULTS: Generally, patients reporting very much diarrhea at months 3 and 6 had worse PF (9-19 points lower) and GHS/QoL (16-19 points lower) than patients reporting no diarrhea regardless of treatment arm. In the change from baseline analysis, patients reporting very much diarrhea also experienced a greater decrease in PF (6-13 points) and GHS/QoL (6-16 points) versus patients reporting no diarrhea in both arms. CONCLUSIONS: In trials with moderate to large differences in symptomatic toxicity by arm, reporting "no meaningful difference in functioning and HRQL between arms" based on mean change from baseline analysis is insufficient and may obscure important impacts on subgroups experiencing symptomatic adverse events. Additional exploratory analyses with simple data visualizations evaluating functioning or HRQL in patient subgroups experiencing expected symptomatic toxicities can further inform the safety and tolerability of an investigational agent.

Timing is everything: The importance of patient-reported outcome assessment frequency when characterizing symptomatic adverse events.

OBJECTIVE: Although patient-reported symptoms and side effects are increasingly measured in cancer clinical trials, an appropriate assessment frequency has not yet been established. To determine whether differences in assessment frequency affect the apparent incidence and severity of patient-reported symptoms using two well-established patient-reported outcome measures used within the same clinical trial. METHODS: We examined patient-reported outcome results from AURA3 (NCT02151981), a randomized open-label study comparing Tagrisso (osimertinib) with platinum-based chemotherapy in patients with previously treated estimated glomerular filtration rate/T790M mutation-positive metastatic non-small cell lung cancer. The outcome of interest was the proportion of patients in each arm that reported worsening of nausea, vomiting, fatigue, diarrhea, constipation, and appetite loss from baseline measured using the patient-reported outcome-common terminology criteria for adverse event (weekly) or European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (every 6 weeks). RESULTS: Similar trends were observed for all six symptoms investigated. Using nausea in the chemotherapy arm as an example, 76% of patients reported any worsening from baseline based on weekly patient-reported outcome-common terminology criteria for adverse event assessments. When using an every 6-week assessment of Quality of Life Questionnaire Core 30 nausea and restricting analysis to an every 6-week assessment for patient-reported outcome-common terminology criteria for adverse event nausea, the proportion of chemotherapy arm patients reporting any worsening of nausea was 40% for both measures. Across the six patient-reported symptomatic adverse events, we observed differential proportions when comparing frequent versus sparse assessment. CONCLUSION: This analysis demonstrates that more frequent assessment of patient-reported symptomatic adverse events will lead to improved detection, and therefore a more complete understanding of the tolerability of experimental anti-cancer therapies.

Qualitative modification and development of patient- and caregiver-reported outcome measures for iron chelation therapy.

BACKGROUND: Compliance, palatability, gastrointestinal (GI) symptom, and treatment satisfaction patient- and observer-reported outcome (PRO, ObsRO) measures were developed/modified for patients with transfusion-dependent anemias or myelodysplastic syndrome (MDS) requiring iron chelation therapy (ICT). METHODS: This qualitative cross-sectional observational study used grounded theory data collection and analysis methods and followed PRO/ObsRO development industry guidance. Patients and caregivers of patients with transfusion-dependent anemias or MDS were individually interviewed face-to-face to cognitively debrief the Compliance, Palatability, GI Symptom Diary, and Modified Satisfaction with Iron Chelation Therapy (SICT) instruments presented electronically. Interviews were conducted in sets. Interviews began open-endedly to spontaneously elicit ICT experiences. Item modifications were debriefed during the later interviews. Interviews were audio recorded, transcribed, and coded. Data was analyzed using ATLAS.ti qualitative research software. RESULTS: Twenty-one interviews were completed (Set 1: 5 patients, 6 caregivers; Set 2: 6 patients, 4 caregivers) in 6 US cities. Mean age was 43 years for patients and 9 years for children of caregivers. Conditions requiring ICT use across groups included transfusion-dependent anemias (85.7%) and MDS (14.3%). Concepts spontaneously reported were consistent with instruments debriefed. Interview analysis resulted in PRO and ObsRO versions of each instrument: Compliance (2 items), Palatability (4 items), GI Symptom Diary (6 items), and Modified SICT (PRO = 13, ObsRO = 17 items). CONCLUSION: Qualitative research data from cognitive interviews supports the content validity and relevance of the instruments developed/modified. Quantitative validation of these PRO and ObsRO measures is needed testing for validity, reliability, and responsiveness for future research use with new formulations of oral ICT.

Economic Burden of Atopic Dermatitis in High-Risk Infants Receiving Cow's Milk or Partially Hydrolyzed 100% Whey-Based Formula.

OBJECTIVE: To estimate the health and economic impact of feeding partially hydrolyzed formula-whey (PHF-W) instead of standard cow's milk formula (CMF) for the first 4 months of life among US infants at high risk for developing atopic dermatitis (AD). STUDY DESIGN: A Markov model was developed integrating published data, a survey of US pediatricians, costing sources and market data, and expert opinion. Key modeled outcomes included reduction in AD risk, time spent post AD diagnosis, days without AD flare, and AD-related costs. Costs and clinical consequences were discounted at 3% annually. RESULTS: An estimated absolute 14-percentage point reduction in AD risk was calculated with the use of PHF-W compared with CMF (95% CI for difference, 3%-22%). Relative to CMF, PHF-W decreased the time spent post-AD diagnosis by 8.3 months (95% CI, 2.78-13.31) per child and increased days without AD flare by 39 days (95% CI, 13-63) per child. The AD-related, 6-year total cost estimate was $495 less (95% CI, -$813 to -$157) per child with PHF-W ($724 per child; 95% CI, $385-$1269) compared with CMF ($1219 per child; 95% CI, $741-$1824). CONCLUSION: Utilization of PHF-W in place of CMF as the initial infant formula administered to high-risk US infants not exclusively breastfed during the first 4 months of life may reduce the incidence and economic burden of AD. Broad implementation of this strategy could result in a minimum savings of $355 million per year to society.

Patient-reported frailty phenotype (PRFP) vs. International Myeloma Working Group frailty index (IMWG FI) proxy: A comparison between two approaches to measuring frailty.

INTRODUCTION: Frailty assessments may help to identify patients at highest risk for treatment-related toxicity, early treatment discontinuation due to toxicity, and death in Multiple Myeloma. We aimed to compare the patient-reported frailty phenotype (PRFP) and a modified version of the International Myeloma Working Group frailty index (IMWG FI) in terms of their strengths, limitations, and classification of frailty in a cohort of patients with relapsed/refractory multiple myeloma (RRMM). MATERIALS AND METHODS: Data were pooled from six RRMM Phase 3 randomized clinical trials submitted to the Food and Drug Administration for regulatory review between 2010 and 2021. Patients were classified as fit, intermediate fit/pre-frail, or frail using both PRFP and the IMWG FI proxy. Agreement between the two approaches in classification of patient frailty was assessed using weighted Cohen's kappa. A contingency table and Venn diagram were generated to analyze overlap in categorization of patient frailty across the different severity groups. Descriptive statistics were used to summarize and compare the clinical and demographic characteristics of patients categorized as frail by PRFP vs. IMWG FI proxy. RESULTS: Of the 2,750 patients included in this analysis, IMWG FI proxy classified 16.4% (452) patients as frail, 28.1% (772) as intermediate fit/pre-frail, and 55.5% (1,526) as fit. Meanwhile, PRFP classified 21.7% (597) of patients as frail, 24.5% (675) as intermediate fit/pre-frail, and 53.8% (1478) as fit. Fair agreement was observed between PRFP and IMWG FI proxy (weighted Cohen's Kappa = 0.34 [0.31-0.37]). On average, patients who were categorized as frail by IMWG FI proxy were older and had higher Charlson Comorbidity Index scores than patients classified as frail by PRFP. In contrast, patients who were classified as frail by PRFP had worse EORTC QLQ-C30 Physical Functioning subscale summary scores as compared to patients in the IMWG FI proxy frail group (median score of 40 vs. 47 out of 100). DISCUSSION: Our analysis found fair concordance between IMWG FI proxy and PRFP. This demonstrates that while both frailty models measure the same underlying construct, the variables that constitute each approach may result in differing frailty categorizations for the same patient. Further prospective studies are needed to establish and compare the predictive and prognostic abilities of the different frailty indices in MM.

Patterns of clinical management of atopic dermatitis in infants and toddlers: a survey of three physician specialties in the United States.

OBJECTIVE: To describe atopic dermatitis (AD) management patterns in children ≤36 months old as reported by pediatricians, dermatologists, and allergists in the US. STUDY DESIGN: A nationally-representative survey was administered to pediatricians (n = 101), dermatologists (n = 26), and allergists (n = 26). Main outcomes included referrals to health care professionals, suggested/ordered laboratory tests, management approach (dietary, pharmacologic, or combination of both) by age, AD location, and severity. RESULTS: Significant differences were observed in referrals to healthcare professionals (P < .001). Pediatricians more frequently referred to dermatologists than allergists in mild (52.4% vs 32.0%) and moderate/severe (60.6% vs 38.1%) cases. Dermatologists referred to allergists less frequently for mild (9.1%) than moderate/severe (40.7%) AD cases. Pediatricians (59%), allergists (61.5%), and dermatologists (26.9%) reported treating at least some of their patients with AD with dietary management (infant formula change) alone (with or without emollients). Soy-based formulas were often used. For mild AD, the most commonly reported first-line pharmacologic treatments included topical emollients, topical corticosteroids, and barrier repair topical therapy/medical devices. Over 80% of physicians used a dietary and pharmacologic combination approach. Dermatologists were most likely to manage AD symptoms with a pharmacologic-only approach. AD lesion location influenced pharmacologic treatment in >80% of physicians. CONCLUSIONS: Significant and distinct differences in AD treatment approach exist among physicians surveyed. Most pediatricians and allergists use formula change as a management strategy in some patients, whereas dermatologists favor a pharmacologic approach. This diversity may result from inadequate evidence for a standard approach. Consistent methods for managing AD are needed.

Patient-Reported Outcomes in Pediatric Cancer Registration Trials: A US Food and Drug Administration Perspective.

Pediatric patient-reported outcome (PRO) data can help inform the US Food and Drug Administration's (FDA's) benefit-risk assessment of cancer therapeutics by quantifying symptom and functional outcomes from the patient's perspective.This study assessed use of PROs in commercial pediatric oncology trials submitted to the FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (ie, sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded in addition to whether any PRO endpoints were included in product labeling.We reviewed 17 pediatric oncology applications, 4 of which included PRO data: denosumab, tisagenlecleucel, larotrectinib, and selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials that collected PRO data were phase II or phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic adverse events (AEs) were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report.PROs were infrequently used in pediatric cancer registration trials. When PROs were used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries, such as the National Cancer Institute's Pediatric PRO-CTCAE, may provide an opportunity to better evaluate the occurrence and impact of symptomatic AEs, from the patient's perspective, in pediatric oncology trials.

Economic value of using partially hydrolysed infant formula for risk reduction of atopic dermatitis in high-risk, not exclusively breastfed infants in Singapore.

INTRODUCTION: Previous trials have demonstrated reductions in atopic dermatitis (AD) incidence when healthy, high-risk, non-exclusively breastfed infants were fed until four months of age with 100% whey-based partially hydrolysed formula (PHF-W) versus standard cow's milk formula (CMF). We assessed the cost-effectiveness of this intervention in Singapore. METHODS: Modelling techniques were used to simulate, from birth to Month 30, the incidence and clinical/economic burden of AD in high-risk, non-exclusively breastfed infants fed with PHF-W or CMF for up to four months. Epidemiologic and clinical data were from a local comparative trial. Expert opinion informed AD treatment patterns and outcomes. Outcomes included reduction in AD risk, time spent with AD, days without AD flare, quality-adjusted life years (QALYs) and direct/indirect costs. Multivariate probabilistic sensitivity analysis was used to assess model parameter uncertainty. RESULTS: Over 30 months, with the use of PHF-W instead of CMF, the proportion of children who developed AD and the time spent with AD decreased by 16.0% (28.3% vs. 44.3%) and 6.4 months, respectively, while time without AD flare and QALYs increased by 14.9 days and 0.021 QALYs per patient, respectively. Estimated AD-related discounted costs per child for PHF-W and CMF were SGD 771 and SGD 1,309, respectively (net savings: SGD 538). PHF-W was less expensive and more effective than CMF for 73%, and cost less than SGD 50,000 per QALY for 87% of all multivariate simulations. CONCLUSION: Early short-term nutritional intervention with PHF-W instead of CMF may reduce AD incidence and costs for healthy, high-risk, non-exclusively breastfed infants in Singapore.

Economic value of atopic dermatitis prevention via infant formula use in high-risk Malaysian infants.

BACKGROUND: Breastfeeding is best for infants and the World Health Organization recommends exclusive breastfeeding for at least the first 6 months of life. For those who are unable to be breastfed, previous studies demonstrate that feeding high-risk infants with hydrolyzed formulas instead of cow's milk formula (CMF) may decrease the risk of atopic dermatitis (AD). OBJECTIVE: To estimate the economic impact of feeding high-risk, not exclusively breastfed, urban Malaysian infants with partiallyhydrolyzed whey-based formula (PHF-W) instead of CMF for the first 17 weeks of life as an AD risk reduction strategy. METHODS: A cohort Markov model simulated the AD incidence and burden from birth to age 6 years in the target population fed with PHF-W vs. CMF. The model integrated published clinical and epidemiologic data, local cost data, and expert opinion. Modeled outcomes included AD-risk reduction, time spent post AD diagnosis, days without AD flare, quality-adjusted life years (QALYs), and costs (direct and indirect). Outcomes were discounted at 3% per year. Costs are expressed in Malaysian Ringgit (MYR; MYR 1,000 = United States dollar [US $]316.50). RESULTS: Feeding a high-risk infant PHF-W vs. CMF resulted in a 14% point reduction in AD risk (95% confidence interval [CI], 3%-23%), a 0.69-year (95% CI, 0.25-1.10) reduction in time spent post-AD diagnosis, additional 38 (95% CI, 2-94) days without AD flare, and an undiscounted gain of 0.041 (95% CI, 0.007-0.103) QALYs. The discounted AD-related 6-year cost estimates when feeding a high-risk infant with PHF-W were MYR 1,758 (US $556) (95% CI, MYR 917-3,033) and with CMF MYR 2,871 (US $909) (95% CI, MYR 1,697-4,278), resulting in a per-child net saving of MYR 1,113 (US $352) (95% CI, MYR 317-1,884) favoring PHF-W. CONCLUSION: Using PHF-W instead of CMF in this population is expected to result in AD-related costs savings.

Cost-Effectiveness of Partially Hydrolyzed Whey Protein Formula in the Primary Prevention of Atopic Dermatitis in At-Risk Urban Filipino Infants.

OBJECTIVE: To estimate, from a Filipino societal perspective, the cost-effectiveness of preventing atopic dermatitis (AD) via early nutritional intervention with 100% whey-based partially hydrolyzed formula (PHF-W) versus standard cow's milk formula (SF) in healthy, urban infants with atopic heredity who are not exclusively breast-fed. METHODS: A Markov model was used to simulate over 6 years the incidence of AD, days with AD symptoms, quality-adjusted life-years (QALYs), and AD-related direct and indirect (i.e., parents'/caregivers' productivity loss) costs incurred by hypothetical cohorts of healthy, at-risk infants fed with either PHF-W or SF as AD prevention for ≤ 17 weeks. Efficacy estimates of PHF-W versus SF in preventing AD were literature-based. The resources used to manage AD (by severity, age, and treatment modality) were estimated using clinical pathways derived from clinical expert opinion. Local costs were applied to resource use. Results were presented as point estimates and as 95 percent credible intervals (CIs, i.e., range of values around the point estimate that include 95% of model simulations) generated via multivariate probabilistic sensitivity analysis using Monte-Carlo simulation techniques. All costs are reported in Philippines pesos (₱, where ₱1000 = US $22.24). All reported outcomes were discounted at a rate of 3.5% per year. RESULTS: Based on the 6-year simulation, compared with SF, PHF-W was predicted to result in a 14-percentage point reduction (i.e., 39% vs. 25%) (95% CI 0.09-0.19) in the incidence of AD and a gain of 0.03 (i.e., 5.46 vs. 5.43) (95% CI 0.01-0.07) QALYs/patient. PHF-W's higher feeding formula cost (+₱1,304/patient) (95% CI -₱3,090 to ₱5,779) were offset by reductions in AD-related costs (-₱11,959/patient; i.e., ₱27,228 vs. ₱15,269) (95% CI -₱14,685 to -₱7,284), including, in particular, the costs of pharmacotherapy, formula used as treatment, and visits to physicians. As a result, PHF-W became a net cost-saving strategy within 38 weeks. Overall, PHF-W resulted in net savings of -₱10,654 (-US $237) (CI -₱4,240 [-US $94] to -₱14,544 [-US $323]) (i.e., ₱27,228 [US $606] vs. ₱16,574 [US $369]). Sensitivity analysis confirmed the robustness of results; the most influential variable was the first-year risk reduction in AD. CONCLUSIONS: Based on the present modeling exercise, compared with SF, PHF-W appears to substantially reduce the risk of AD and its associated direct and indirect medical costs in healthy, at-risk urban Filipino infants over a 6-year period.