Time to deterioration of symptoms or function using patient-reported outcomes in cancer trials.

Time-to-event endpoints for patient-reported outcomes, such as time to deterioration of symptoms or function, are frequently used in cancer clinical trials. Although time-to-deterioration endpoints might seem familiar to cancer researchers for being similar to survival or disease-progression endpoints, there are unique considerations associated with their use. The complexity of time-to-deterioration endpoints should be weighed against the information that they add to the tumour, survival, and safety data used to inform the risks and benefits of an investigational drug. Here we use the estimand framework to show how analytical decisions answer different clinical questions of interest, some of which might be uninformative. Challenges including the consideration of intercurrent events, the difficulty in maintaining adequate completion rates, and considerable patient and trial burden from long-term, serial, patient-reported outcome measurements render time to deterioration a problematic approach for widespread use. For trials in which a comparative benefit in symptoms or function is an objective, an analysis at pre-specified relevant timepoints could be a better approach.

The use of proxies and proxy-reported measures: a report of the international society for quality of life research (ISOQOL) proxy task force.

AIMS: Proxy reports are often used when patients are unable to self-report. It is unclear how proxy measures are currently in use in adult health care and research settings. We aimed to describe how proxy reports are used in these settings, including the use of measures developed specifically for proxy reporting in adult health populations. METHODS: We systematically searched Medline, PsycINFO, PsycTESTS, CINAHL and EMBASE from database inception to February 2018. Search terms included a combination of terms for quality of life and health outcomes, proxy-reporters, and health condition terms. The data extracted included clinical context, the name of the proxy measure(s) used and other descriptive data. We determined whether the measures were developed specifically for proxy use or were existing measures adapted for proxy use. RESULTS: The database search identified 17,677 possible articles, from which 14,098 abstracts were reviewed. Of these, 11,763 were excluded and 2335 articles were reviewed in full, with 880 included for data extraction. The most common clinical settings were dementia (30%), geriatrics (15%) and cancer (13%). A majority of articles (51%) were paired studies with proxy and patient responses for the same person on the same measure. Most paired studies (77%) were concordance studies comparing patient and proxy responses on these measures. DISCUSSION: Most published research using proxies has focused on proxy-patient concordance. Relatively few measures used in research with proxies were specifically developed for proxy use. Future work is needed to examine the performance of measures specifically developed for proxies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO No. CRD42018103179.

Does Knowledge of Treatment Assignment Affect Patient Report of Symptoms, Function, and Health Status? An Evaluation Using Multiple Myeloma Trials.

OBJECTIVES: Unblinded trials are common in oncology, but patient knowledge of treatment assignment may bias response to questionnaires. We sought to ascertain the extent of possible bias arising from patient knowledge of treatment assignment. METHODS: This is a retrospective analysis of data from 2 randomized trials in multiple myeloma, 1 double-blind and 1 open label. We compared changes in patient reports of symptoms, function, and health status from prerandomization (screening) to baseline (pretreatment but postrandomization) across control and investigational arms in the 2 trials. Changes from prerandomization scores at ~2 and 6 months on treatment were evaluated only across control arms to avoid comparisons between 2 different experimental drugs. All scores were on 0- to 100-point scales. Inverse probability weighting, entropy balancing, and multiple imputation using propensity score splines were used to compare score changes across similar groups of patients. RESULTS: Minimal changes from screening were seen at baseline in all arms. In the control arm, mean changes of <7 points were seen for all domains at 2 and 6 months. The effect of unblinding at 6 months in social function was a decline of less than 6 points (weighting: -3.09; 95% confidence interval -8.41 to 2.23; balancing: -4.55; 95% confidence interval -9.86 to 0.76; imputation: -5.34; 95% confidence interval -10.64 to -0.04). CONCLUSION: In this analysis, we did not find evidence to suggest that there was a meaningful differential effect on how patients reported their symptoms, function or health status after knowing their treatment assignment.

The estimand framework and its application in substance use disorder clinical trials: a case study.

Relapse rates among individuals with substance use disorder (SUD) remain high and new treatment approaches are needed, which require evaluation in randomized controlled trials (RCTs). Measurement and interpretation challenges for SUD RCT data are often ignored or presented only in statistical analysis plans. Since different analytic approaches may result in different estimates and thus interpretations of the treatment effect, it is important to present this clearly throughout the trial. Inconsistencies between study analyses and objectives present further challenges for interpretation and cross-study comparisons. The recent International Council for Harmonization (ICH) addendum provides standardized language and a common framework for aligning trial objectives, design, conduct, and analysis. The framework focuses on estimands, which describe the treatment effect and link the trial objective with the scientific question and the analytic approach. The use of estimands offers SUD researchers and clinicians the opportunity to explicitly address events that affect measurement and interpretation at the outset of the trial. Furthermore, the use of standard terminology can lead to clearer interpretations of SUD trials and the treatments evaluated in SUD trials. Resources for understanding and applying estimands are needed to optimize the use of this new, helpful framework. This Perspective provides this resource for SUD researchers. Specifically, it highlights the relevance of estimands for SUD trials. Furthermore, it demonstrates how estimands can be used to develop clinically relevant analyses to address challenges in SUD trials. It also shows how a standardized framework can be employed to improve the interpretation and presentation of SUD study findings.

Patient and proxy reports regarding the experience of treatment decision-making in cancer care.

OBJECTIVE: Shared decision-making, including the elicitation of patient preferences regarding treatment decisions, is considered part of high-quality cancer care. However, patients may not be able to self-report due to illness, and therefore proxy reports may be used. We sought to determine the difference between proxy and patient reports about patient decisions and preferences among patients who received or were scheduled for chemotherapy using data from a large, population-based survey of patients with incident lung or colorectal cancer. METHODS: Of 3573 patients who received or were scheduled for chemotherapy, 3108 self-reported and 465 had proxies reporting on their behalf about preferred and actual decision roles regarding this treatment. Preferred and actual decision roles were assessed using the Control Preferences Scale, and categorized as shared, patient-controlled, or doctor-controlled. Multivariable logistic regression models were used to assess the association between patient and proxy responses and whether preferences were met. The models adjusted for sociodemographic and clinical variables and patient/proxy-reported health status. RESULTS: Sixty-three percent of all respondents reported actual roles in decisions that matched their preferred roles (role attainment). Proxies and patients were similarly likely to report role attainment (65% vs 63%). In adjusted analyses, proxies were more likely report role attainment (OR = 1.27, 95%CI = 1.02-1.59), but this difference was smaller if health variables were excluded from the model (OR = 1.14, 95%CI = 0.92-1.41). CONCLUSION: Most patients' preferences for treatment participation were met. Surveys from proxies appear to yield small differences on the reports of attainment of preferred treatment decision-making roles in cancer care vs surveys from patients.

Exploration of baseline patient-reported side effect bother from cancer therapy.

BACKGROUND: Patient reports of expected treatment side effects are increasingly collected as part of the assessment of patient experience in clinical trials. A global side effect item that is patient-reported has the potential to inform overall tolerability. Therefore, the aim of this study was to examine the completion and distribution of such a global single-item measure of side effect burden in five cancer clinical trials. METHODS: Data from five trials from internal Food and Drug Administration databases that included the Functional Assessment of Cancer Therapy-General single-item measure of overall side effect burden (i.e. impact on degree of bother) were analyzed. Completion rates for the side effect bother item, items adjacent to this item, and two non-adjacent items on the Functional Assessment of Cancer Therapy-General that are related to health-related quality of life were calculated at the baseline assessment and at the 3-month assessment. To evaluate the distribution, the percentage of patients reporting high levels (quite a bit or very much bother) of side effect bother at baseline and 3 months was assessed. RESULTS: Completion rates for all items were at least 80% regardless of time point or trial population. However, in three of the five trials, completion rates for the side effect bother item were lower at baseline compared to adjacent and non-adjacent items. This difference was not observed at 3 months. Up to 9.4% of patients reported high levels of side effect bother at baseline. CONCLUSION: Patients may enter trials already reporting some bother from side effects. This can make interpretation of results with respect to the investigational agent under study challenging. Patients may skip an item evaluating side effect bother at baseline, suggesting some difficulty with interpretation of what is being asked. Further study of the wording and utility of a baseline side effect bother assessment is warranted.

US Food and Drug Administration review of statistical analysis of patient-reported outcomes in lung cancer clinical trials approved between January, 2008, and December, 2017.

With the advent of patient-focused drug development, the US Food and Drug Administration (FDA) has redoubled its efforts to review patient-reported outcome (PRO) data in cancer trials submitted as part of a drug's marketing application. This Review aims to characterise the statistical analysis of PRO data from pivotal lung cancer trials submitted to support FDA drug approval between January, 2008, and December, 2017. For each trial and PRO instrument identified, we evaluated prespecified PRO concepts, statistical analysis, missing data and sensitivity analysis, instrument completion, and clinical relevance. Of the 37 pivotal lung cancer trials used to support FDA drug approval, 25 (68%) trials included PRO measures. The most common prespecified PRO concepts were cough, dyspnoea, and chest pain. At the trial level, the most common statistical analyses were descriptive (24 trials [96%]), followed by time-to-event analyses (19 trials [76%]), longitudinal analyses (12 trials [48%]), and basic inferential tests or general linear models (10 trials [40%]). Our findings indicate a wide variation in the analytic techniques and data presentation methods used, with very few trials reporting clear PRO research objectives and sensitivity analyses for PRO results. Our work further supports the need for focused research objectives to justify and to guide the analytic strategy of PROs to facilitate the interpretation of patient experience.

Analyzing patient-reported outcome data when completion differs between arms in open-label trials: an application of principal stratification.

PURPOSE: Cancer trials are often open-label and include patient-reported outcomes (PROs). Previous work has demonstrated that patients may complete PRO assessments less frequently in the control arm compared with the experimental arm in open-label trials. Such differential completion may affect PRO results. This paper sought to explore principal stratification methodology to address potential bias caused by the posttreatment intermediate variable of questionnaire completion. METHODS: We evaluated six randomized trials (five open-label and one double-blind) of anticancer therapies with varying levels of PRO completion submitted to the Food and Drug Administration (FDA). We applied complete case analysis (CCA), multiple imputation (MI), and principal stratification to evaluate PRO results for quality of life (QOL) and the domains of physical, role, and emotional function (PF, RF, and EF). Assignment to potential principal strata was by the expectation maximization algorithm using patient baseline characteristics. RESULTS: Completion rates in the experimental arm ranged from 66% to 94% and 51% to 95% in the control arm. Four trials had negligible completion differences between arms (1%-2%), and two had large differences favoring the experimental arm (15%-17%). For trials with negligible completion differences, principal stratification results were similar to CCA and MI results for all domains. Notable differences in point estimates may be observed in trials with large differences in completion rates. However, in the examined trials, the confidence intervals for the principal stratification estimates overlapped with the ones obtained using CCA. CONCLUSIONS: The principal stratification estimand may be a useful additional analysis, especially if PRO completion differs between arms.

Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions.

BACKGROUND: Patient-reported outcome measures can be used to capture the patient's experience with disease and treatment. Immunotherapy agents including the anti-programmed death receptor-1/programmed death-ligand-1 inhibitor therapies have unique symptomatic side effects and patient-reported outcome data can help to characterize the benefits and burdens associated with therapy. METHODS: We reviewed registration trials in the Food and Drug Administration database for five anti-programmed death receptor-1/programmed death-ligand-1 inhibitor therapies to characterize trial design and patient-reported outcome assessment strategy (cutoff 31 December 2017). We evaluated the patient-reported outcome measurement coverage of eight key symptoms related to adverse events reported in immunotherapy agent product labels (fatigue, diarrhea, cough, shortness of breath, musculoskeletal pain, rash, pruritus, and fever). RESULTS: There were a total of 28 trials across seven disease types and one tumor agnostic indication reviewed, of which 17 were randomized and 25 were open label. Of the 28 trials, 21 contained patient-reported outcome measures and all 21 used >1 instrument. The most common instruments were the EuroQol five dimension (N = 19), and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (N = 17). Disease-specific patient-reported outcome tools were included in nine trials (six lung, one head and neck, one melanoma and one renal cell). No trial used a patient-reported outcome strategy assessing all eight selected adverse events. CONCLUSION: Collection of patient-reported outcome data in anti-programmed death receptor-1/programmed death-ligand-1 inhibitor trials were variable and did not consistently assess important symptomatic adverse events. Use of a patient-reported outcome instrument with well-defined functional scales supplemented by item libraries to incorporate relevant symptomatic adverse events may allow for improved understanding of the patient experience while receiving therapy. These data, along with other clinical data such as hospitalizations and supportive care medication use can help inform the benefit-risk assessment for regulatory purposes.

The Effect of a "Class Smoke Free Pledge" on Breath Carbon Monoxide in Arabic Male Adolescents.

Introduction: Arabic male adolescents have a high smoking prevalence. Introduction of "Class smoke-free" pledges have been successful amongst European adolescents but have not been evaluated using objective valid measures. We tested the impact of adding a smoke free pledge strategy to a proven peer-led asthma and smoking prevention program on breath carbon monoxide level (BCO) in male high-school students in Jordan. Methods: We enrolled male students from four high-schools in Irbid, Jordan. Schools were randomly assigned to receive either TAJ (Triple A in Jordan, n = 218) or TAJ-Plus (with added class smoke-free pledge, n = 215). We hypothesized that students receiving TAJ-Plus would have greater reduction in BCO levels than those only receiving the TAJ intervention. Asthma and smoking status were assessed by self-administered questionnaires. Smoking outcomes were collected using a BCO Monitor. Results: Both groups had significant reductions in BCO levels post-intervention (p < .0001), however, decreases were greater in TAJ-Plus group (3.9 ± 0.2 vs. 4.8 ± 0.2, p < .0001). Intervention effects on BCO over time did not vary by smoking status (p = .085), asthma status (p = .602), or a combination of the two (p = .702). Conclusions: An added smoke-free pledge strategy to a proven peer-led asthma education program appears to be a promising approach to motivate adolescents to abstain from smoking in Jordan. Future research is required to determine if these results can be extended to Jordanian adolescent females. Implications: A commitment by students via a "class smoke-free" pledge can be an added incentive to motivate adolescents in Arabic-speaking countries to abstain from smoking. Social influence approaches in schools can be useful in countering the aggressive tobacco marketing campaigns targeting Jordanian and other Arabic-speaking youth. The combination of "class smoke-free" pledges and an evidence-based peer-led asthma and smoking education can be implemented in schools to influence adolescents with asthma to abstain from smoking.