Missing repeated measures data in clinical trials

2021 ◽  
Author(s):  
Stephanie L Pugh ◽  
Paul D Brown ◽  
Danielle Enserro
Keyword(s):  
Clinical Trials ◽  
Missing Data ◽  
Repeated Measures ◽  
Drop Out ◽  
Sensitivity Analyses ◽  
Analysis Methods ◽  
Patient Reported ◽  
The Impact ◽  
Proper Interpretation

Abstract Clinical trials typically collect longitudinal data, data that is collected repeated over time, such as labs, scans, or patient-reported outcomes. Due to a variety of reasons, this data can be missing, whether a patient stops attending clinical visits (i.e., drop-out), or misses assessments intermittently. Understanding the reasons for missing data as well as predictors of missing data can aid in determination of the missing data mechanism. The analysis methods employed are dependent on the missing data mechanism and may make certain assumptions about the missing data itself. Methods for non-ignorable missing data, which assumes that the missing data depends on the missing data itself, make stronger assumptions and include pattern mixture-models and shared parameter models. Missing data that is ignorable after adjusting for other covariates, can be analyzed using methods that adjust for covariates, such as mixed effects models or multiple imputation. Missing data that is ignorable can be analyzed using standard approaches that require complete case data, such as change from baseline or proportion of patients who declined at a specified time point. In clinical trials, truly ignorable data is rare, resulting in additional analysis methods required for proper interpretation of the results. Conducting several analyses under different assumptions, called sensitivity analyses, can determine the extent of the impact of the missing data.

Effect of abiraterone acetate (AA) on patient-reported pain in metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel: Results of longitudinal sensitivity analyses.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9618-9618 ◽  
Author(s):  
Yanni Hao ◽  
Charles S. Cleeland ◽  
Dennis Gagnon ◽  
Derek Espindle ◽  
Arturo Molina ◽  
...  
Keyword(s):  
Missing Data ◽  
Pain Intensity ◽  
Short Form ◽  
Mixed Effects ◽  
Pain Interference ◽  
Sensitivity Analyses ◽  
Repeated Measure ◽  
Patient Reported ◽  
Pain Outcomes ◽  
The Impact

9618 Background: The COU-AA-301 phase 3 trial showed that AA + prednisone (P) improved overall survival in mCRPC patients (pts) post-docetaxel. Compared with P alone, AA + P also had significant benefits on patient-reported pain. Here we describe post hoc sensitivity analyses of pain data from that trial, using different methods to compensate for the potential impact of missing data. Methods: Pts with mCRPC progressing after docetaxel-based chemotherapy were randomized 2:1 to AA + P or placebo + P. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form (BPI-SF) questionnaire at baseline, Day 15 of Cycle 1, and Day 1 of each 28-day treatment cycle thereafter until treatment discontinuation. The effect of treatment on BPI-SF scores was analyzed using repeated measure mixed-effects (RMM) models, piecewise linear mixed-effects (PWLME) models, and joint mixed-effects and log time-to-dropout (JMEL) models. RMM and PWMLE models assumed missing data (due to death, study dropout, or administrative issues) to be missing at random, the JMEL model to be missing not at random. Model results were compared between treatment arms. Results: 797 pts were randomized to AA + P, and 398 to P only. RMM model estimates suggested statistically significant (p < 0.05) differences in change from baseline for pain intensity and pain interference scores in favor of AA + P at the majority of study visits through cycle 11. PWLME models yielded significantly smaller areas under the curve (AUCs) for AA + P vs P for pain intensity (p = 0.0031) and pain interference (p = 0.0006); smaller AUCs reflect better pain outcomes. Results using JMEL models were nearly identical to those with PWLME models, with AUCs for AA + P significantly smaller than for P alone for pain intensity (p = 0.0031) and pain interference (p = 0.0007). Conclusions: Using various modeling methods that assess the impact of missing data, AA + P showed superior patterns of pain outcomes over time compared with P only in mCRPC pts refractory to docetaxel. These results support the previously reported pain benefits of AA + P over P alone from the same trial. Clinical trial information: NCT00638690.

scholarly journals Estimating and reporting treatment effects in clinical trials for weight management: using estimands to interpret effects of intercurrent events and missing data

2021 ◽  
Author(s):  
Sean Wharton ◽  
Arne Astrup ◽  
Lars Endahl ◽  
Michael E. J. Lean ◽  
Altynai Satylganova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Missing Data ◽  
Weight Management ◽  
Treatment Effect ◽  
Repeated Measures ◽  
Treatment Effects ◽  
Randomized Clinical Trials ◽  
Weight Losses ◽  
The Difference ◽  
Treatment Of Obesity

AbstractIn the approval process for new weight management therapies, regulators typically require estimates of effect size. Usually, as with other drug evaluations, the placebo-adjusted treatment effect (i.e., the difference between weight losses with pharmacotherapy and placebo, when given as an adjunct to lifestyle intervention) is provided from data in randomized clinical trials (RCTs). At first glance, this may seem appropriate and straightforward. However, weight loss is not a simple direct drug effect, but is also mediated by other factors such as changes in diet and physical activity. Interpreting observed differences between treatment arms in weight management RCTs can be challenging; intercurrent events that occur after treatment initiation may affect the interpretation of results at the end of treatment. Utilizing estimands helps to address these uncertainties and improve transparency in clinical trial reporting by better matching the treatment-effect estimates to the scientific and/or clinical questions of interest. Estimands aim to provide an indication of trial outcomes that might be expected in the same patients under different conditions. This article reviews how intercurrent events during weight management trials can influence placebo-adjusted treatment effects, depending on how they are accounted for and how missing data are handled. The most appropriate method for statistical analysis is also discussed, including assessment of the last observation carried forward approach, and more recent methods, such as multiple imputation and mixed models for repeated measures. The use of each of these approaches, and that of estimands, is discussed in the context of the SCALE phase 3a and 3b RCTs evaluating the effect of liraglutide 3.0 mg for the treatment of obesity.

Overview of the Patient Perspective at OMERACT 10 — Conceptualizing Methods for Developing Patient-Reported Outcomes

2011 ◽  
Vol 38 (8) ◽  
pp. 1699-1701 ◽  
Author(s):  
JOHN R. KIRWAN ◽  
PETER S. TUGWELL
Keyword(s):  
Clinical Trials ◽  
Experimental Work ◽  
Patient Reported Outcomes ◽  
Patient Perspective ◽  
Methodological Issues ◽  
Instrument Selection ◽  
Patient Reported ◽  
The Impact ◽  
Choice Of Instruments ◽  
The Way

This overview draws out the main conclusions from the 4 workshops focused on incorporating the patient perspective into outcome assessment at the 10th Outcome Measures in Rheumatology (OMERACT 10) conference. They raised methodological issues about the choice of outcome domains to include in clinical trials, the development or choice of instruments to measure these domains, and the way these instruments might capture the impact of a disease and its treatment. The need to develop a more rigorous conceptual model of quantifying the way conditions affect health, and the need to ensure patients are directly involved in the decisions about domains and instruments, emerged clearly. The OMERACT participants voted to develop guidelines for domain and instrument selection, and conceptual and experimental work will be brought forward to revise and upgrade the OMERACT Filter.

Dare voce ai pazienti nella ricerca sulle malattie rare e sui famaci orfani / Giving patients a voice in the rare diseases and orphan drugs research

2018 ◽  
Vol 67 (1) ◽  
pp. 25-40
Author(s):  
Elena Mancini ◽  
Roberta Martina Zagarella
Keyword(s):  
Clinical Trials ◽  
Rare Diseases ◽  
Patient Reported Outcomes ◽  
Narrative Medicine ◽  
Orphan Drugs ◽  
New Drugs ◽  
Patient Centered ◽  
Patient Reported ◽  
Critical Issues ◽  
The Impact

L’articolo ha l’obiettivo di mettere in luce potenzialità e criticità dell’inclusione della prospettiva dei pazienti nella ricerca sulle malattie rare e sui farmaci orfani. A tal fine, nella prima parte, si propone un’analisi epistemologica dell’utilizzo dei racconti dell’esperienza individuale della malattia nella ricerca scientifica e nei trial clinici, facendo emergere, anche attraverso gli strumenti della medicina narrativa, le sfide teoriche e operative poste dall’inclusione della soggettività del paziente e del vissuto di malattia nonché l’importanza della valorizzazione della prospettiva del paziente, sia in generale sia nella ricerca sulle malattie rare e sui farmaci orfani. Nella seconda parte, il testo analizza in particolare il ruolo degli esiti riportati dai pazienti o Patient Reported Outcomes (PROs), misure per la valutazione complessiva della salute basate sulla prospettiva dei pazienti stessi, incentrandosi sulla sperimentazione clinica nel campo delle malattie rare. In questo contesto, infatti, i racconti di malattia, raccolti e valorizzati da fonti istituzionali e associazioni di pazienti, hanno contribuito a far emergere importanti questioni critiche e difficoltà nell’impiego di outcome centrati sul paziente nello sviluppo di nuovi farmaci e trattamenti, generando una serie di documenti e raccomandazioni relative al loro utilizzo per il benessere della comunità dei malati rari. ---------- This paper aims to highlight the potentiality and criticality of including patients’ perspective in rare diseases and orphan drugs research. In the first part, we propose an epistemological analysis of individual narrations of disease experience as they are used in scientific research and clinical trials. With the help of narrative medicine approach, this analysis points out theoretical and operational challenges of a perspective that includes patient’s subjectivity and illness experience. Furthermore, it reveals the significance of patients’ standpoints in general and in rare diseases as well as in the orphan drugs research. The second part of our article focuses on the role of the Patient reported Outcomes (PROs) – which are measures for the health’s overall assessment based on patient’s perspective – by investigating the impact on clinical trials for rare diseases. In this context, illness stories, which are collected and promoted by institutional sources and patients’ associations, contribute to underline important critical issues at stake in the employment of patient-centered outcomes both in new drugs and in the treatments development. Moreover, these stories are crucial to elaborate documents and recommendations concerning the use of PROs for the rare patients’ community welfare.

scholarly journals Managing Clinical Trials for Alzheimer’s Disease During the COVID-19 Crisis: Experience at Fundació ACE in Barcelona, Spain

2020 ◽  
Vol 77 (4) ◽  
pp. 1805-1813
Author(s):  
Carla Abdelnour ◽  
Ester Esteban de Antonio ◽  
Alba Pérez-Cordón ◽  
Asunción Lafuente ◽  
Mar Buendía ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ad Hoc ◽  
Strategic Plan ◽  
Lessons Learned ◽  
Drop Out ◽  
Rt Pcr ◽  
Serological Tests ◽  
Clinical Trial Research ◽  
Research Activities ◽  
The Impact

Background: The COVID-19 pandemic has brought great disruption to health systems worldwide. This affected ongoing clinical research, particularly among those most vulnerable to the pandemic, like dementia patients. Fundació ACE is a research center and memory clinic based in Barcelona, Spain, one of the hardest-hit countries. Objective: To describe the ad-hoc strategic plan developed to cope with this crisis and to share its outcomes. Methods: We describe participants’ clinical and demographic features. Additionally, we explain our strategic plan aimed at minimizing the impact on clinical trial research activities, which included SARS-CoV-2 RT-PCR and IgG serological tests to all participants and personnel. The outcomes of the plan are described in terms of observed safety events and drop-outs during the study period. Results: A total of 130 patients were participating in 16 active clinical trials in Fundació ACE when the lockdown was established. During the confinement, we performed 1018 calls to the participants, which led to identify adverse events in 26 and COVID-19 symptoms in 6. A total of 83 patients (64%) could restart on-site visits as early as May 11, 2020. All SARS-CoV-2 RT-PCR diagnostic tests performed before on-site visits were negative and only three IgG serological tests were positive. Throughout the study period, we only observed one drop-out, due to an adverse event unrelated to COVID-19. Discussion: The plan implemented by Fundació ACE was able to preserve safety and integrity of ongoing clinical trials. We must use the lessons learned from the pandemic and design crisis-proof protocols for clinical trials.

scholarly journals Impact of Medium Cut-Off Dialyzers on Patient-Reported Outcomes: COREXH Registry

2020 ◽  
pp. 1-9
Author(s):  
Juan Carlos Alarcon ◽  
Alfonso Bunch ◽  
Freddy Ardila ◽  
Eduardo Zuñiga ◽  
Jasmin I. Vesga ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Kidney Disease ◽  
Repeated Measures ◽  
Patient Reported Outcomes ◽  
Short Form ◽  
High Flux ◽  
Middle Molecules ◽  
Patient Reported ◽  
The Impact

<b><i>Introduction:</i></b> A new generation of hemodialysis (HD) membranes called medium cut-off (MCO) membranes possesses enhanced capacities for middle molecule clearance, which have been associated with adverse outcomes in this population. These improvements could potentially positively impact patient-reported outcomes (PROs). <b><i>Objective:</i></b> The objective of this study was to evaluate the impact of MCO membranes on PROs in a cohort of HD patients in Colombia. <b><i>Methods:</i></b> This was a prospective, multicenter, observational cohort study of 992 patients from 12 renal clinics in Colombia who were switched from high-flux HD to MCO therapy and observed for 12 months. Changes in Kidney Disease Quality of Life 36-Item Short Form Survey (KDQoL-SF36) domains, Dialysis Symptom Index (DSI), and restless legs syndrome (RLS) 12 months after switching to MCO membranes were compared with time on high-flux membranes. Repeated measures of ANOVA were used to evaluate changes in KDQoL-SF36 scores; severity scoring was used to assess DSI changes over time; Cochran’s Q test was used to evaluate changes in frequency of diagnostic criteria of RLS. <b><i>Results:</i></b> During 12 months of follow-up, 3 of 5 KDQoL-SF36 domains improved compared with baseline: symptoms (<i>p</i> &#x3c; 0.0001), effects of kidney disease (<i>p</i> &#x3c; 0.0001), and burden of kidney disease (<i>p</i> &#x3c; 0.001). The proportion of patients diagnosed with RLS significantly decreased from 22.1% at baseline to 10% at 12 months (<i>p</i> &#x3c; 0.0001). No significant differences in the number of symptoms (DSI, <i>p =</i> 0.1) were observed, although their severity decreased (<i>p</i> = 0.009). <b><i>Conclusions:</i></b> In conventional HD patients, the expanded clearance of large middle molecules with MCO-HD membranes was associated with higher health-related quality of life scores and a decrease in the prevalence of RLS.

scholarly journals The impact of patient-reported outcome (PRO) data from clinical trials: a systematic review and critical analysis

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Samantha Cruz Rivera ◽  
Derek G. Kyte ◽  
Olalekan Lee Aiyegbusi ◽  
Anita L. Slade ◽  
Christel McMullan ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Case Studies ◽  
Real World ◽  
Clinical Trial Data ◽  
Research Impact ◽  
Trial Data ◽  
Patient Reported ◽  
The Impact

Abstract Background Patient-reported outcomes (PROs) are commonly collected in clinical trials and should provide impactful evidence on the effect of interventions on patient symptoms and quality of life. However, it is unclear how PRO impact is currently realised in practice. In addition, the different types of impact associated with PRO trial results, their barriers and facilitators, and appropriate impact metrics are not well defined. Therefore, our objectives were: i) to determine the range of potential impacts from PRO clinical trial data, ii) identify potential PRO impact metrics and iii) identify barriers/facilitators to maximising PRO impact; and iv) to examine real-world evidence of PRO trial data impact based on Research Excellence Framework (REF) impact case studies. Methods Two independent investigators searched MEDLINE, EMBASE, CINAHL+, HMIC databases from inception until December 2018. Articles were eligible if they discussed research impact in the context of PRO clinical trial data. In addition, the REF 2014 database was systematically searched. REF impact case studies were included if they incorporated PRO data in a clinical trial. Results Thirty-nine publications of eleven thousand four hundred eighty screened met the inclusion criteria. Nine types of PRO trial impact were identified; the most frequent of which centred around PRO data informing clinical decision-making. The included publications identified several barriers and facilitators around PRO trial design, conduct, analysis and report that can hinder or promote the impact of PRO trial data. Sixty-nine out of two hundred nine screened REF 2014 case studies were included. 12 (17%) REF case studies led to demonstrable impact including changes to international guidelines; national guidelines; influencing cost-effectiveness analysis; and influencing drug approvals. Conclusions PRO trial data may potentially lead to a range of benefits for patients and society, which can be measured through appropriate impact metrics. However, in practice there is relatively limited evidence demonstrating directly attributable and indirect real world PRO-related research impact. In part, this is due to the wider challenges of measuring the impact of research and PRO-specific issues around design, conduct, analysis and reporting. Adherence to guidelines and multi-stakeholder collaboration is essential to maximise the use of PRO trial data, facilitate impact and minimise research waste. Trial registration Systematic Review registration PROSPERO CRD42017067799.

Emerging trends and utilization of patient-reported outcomes (PROs) in clinical trials of chimeric antigen receptor (CAR) T-cell therapies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19142-e19142
Author(s):  
Anthony John Messina ◽  
Vasily Andrianov ◽  
Daniel Mazzolenis ◽  
Liat Vidal-Fisher
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Phase I ◽  
Patient Reported Outcomes ◽  
Utilization Rate ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Patient Reported ◽  
Car T ◽  
The Impact

e19142 Background: Patient-reported outcomes (PROs) are an important tool to assess the impact of new therapies on health-related quality of life (HRQoL). This study aimed to describe if and what PRO instruments are currently being utilized in CAR-T cell therapy studies in solid and hematological malignancies while assessing the patterns of inclusion and trends of HRQoL data reporting. Methods: We used Citeline to search for clinical trials between Jan 2008 - Jan 2020, excluding planned or terminated studies, non-oncology, non-treatment, and duplicates. Reviewers extracted various parameters for included trials, then cross-matched data with EU Clinical Trials Register, Clinical trials.gov, trial protocols (when available), and Google. The reporting of PRO data was then assessed for those Closed/Completed trials that included a PRO via PubMed/MEDLINE, Sponsor, and Google. Results: A sample of 664 CAR-T trials was identified. PROs were included in only 6.17% (41/664) studies. Of the 41 trials that included a PRO, 63.41% (26/41) utilized more than one PRO, with the generic EORTC QLQ-C30 and the EQ-5D being used predominately. Median HRQoL follow-up was 5-years on most trials. No studies used PROs as primary endpoints. The majority of PROs were observed to be utilized in early phase trials (phase I, 12; Phase I/II, 17). PROs were first incorporated in CAR-T trials beginning in 2014, and the utilization rate has increased steadily, except for 2019. PROs were included in 3 first line trials, 22 second line, 5 third line, and 11 fourth line or greater. PRO utilization between solid tumor trials and hematologic malignancies was comparable (6.04% [9/149], and 6.26% [32/511]). Of the completed/closed trials, 28.57% (3/14) published PRO data and met at least eight of the CONSORT-PRO quality indicators. Conclusions: The utilization of PROs in CAR-T trials (6.17%) is under the industry average of 27%, despite the growing importance of HRQoL and its impact on value-based care. The findings from this review reflect the overall increased attention to CAR-T as a new therapeutic entity and the continued deficiency of including and reporting of PROs in trial designs.

Current Status of Patient-Reported Outcomes in Industry-Sponsored Oncology Clinical Trials and Product Labels

2007 ◽  
Vol 25 (32) ◽  
pp. 5087-5093 ◽  
Author(s):  
Kathleen Gondek ◽  
Pierre-Philippe Sagnier ◽  
Kim Gilchrist ◽  
J. Michael Woolley
Keyword(s):  
Clinical Trials ◽  
Patient Reported Outcomes ◽  
Symptom Assessment ◽  
Current Status ◽  
Cancer Therapies ◽  
Package Inserts ◽  
Patient Reported ◽  
Oncology Clinical Trials ◽  
Related Quality ◽  
The Impact

Assessing patient-reported outcomes (PROs) in clinical trials is of interest to clinicians, patients, regulators, and industry. The use and impact of PROs is a growing area of methodologic research, particularly as they relate to tumor types, biomarkers, and various patient populations and cultures. Both the US Food and Drug Administration (FDA) and European Agency for the Evaluation of Medicinal Products in recent guidance have acknowledged the need to account for treatment-related impact on patient symptoms and/or health-related quality of life (HRQOL). Clinical research likely reflects the informative value of PROs. A search of www.clinicaltrials.gov , the FDA Web site, and product package inserts was conducted to assess the inclusion of symptom assessment and HRQOL within industry-sponsored clinical trials in cancer and approved cancer therapies and their respective product labels. Overall, there were 2,704 industry-sponsored oncology trials, of which 322 (12%) included a PRO measure. Of the 70 FDA new or revised labels, only six package inserts include PRO data. Symptoms were assessed uniformly across the phases of clinical trials, whereas HRQOL assessment increased in the later phases of clinical trials. Collecting PRO data can enhance our understanding of cancer burden and the impact of interventions on patients' lives.

scholarly journals Tackling Diversity in Prostate Cancer Clinical Trials: A Report From the Diversity Working Group of the IRONMAN Registry

2021 ◽  
pp. 495-505
Author(s):  
Rana R. McKay ◽  
Theresa Gold ◽  
Jelani C. Zarif ◽  
Ilkania M. Chowdhury-Paulino ◽  
Adam Friedant ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Race And Ethnicity ◽  
Working Group ◽  
Advanced Prostate Cancer ◽  
Unmet Need ◽  
Minority Populations ◽  
Eligibility Criteria ◽  
Patient Reported ◽  
The Impact

Prostate cancer disproportionately affects racial and ethnic minority populations. Reasons for disparate outcomes among minority patients are multifaceted and complex, involving factors at the patient, provider, and system levels. Although advancements in our understanding of disease biology have led to novel therapeutics for men with advanced prostate cancer, including the introduction of biomarker-driven therapeutics, pivotal translational studies and clinical trials are underrepresented by minority populations. Despite attempts to bridge the disparities gap, there remains an unmet need to expand minority engagement and participation in clinical trials to better define the impact of therapy on efficacy outcomes, quality of life, and role of biomarkers in diverse patient populations. The IRONMAN registry (ClinicalTrials.gov identifier: NCT03151629 ), a global, prospective, population-based study, was borne from this unmet medical need to address persistent gaps in our knowledge of advanced prostate cancer. Through integrated collection of clinical outcomes, patient-reported outcomes, epidemiologic data, and biospecimens, IRONMAN has the goal of expanding our understanding of how and why prostate cancer outcomes differ by race and ethnicity. To this end, the Diversity Working Group of the IRONMAN registry has developed informed strategies for site selection, recruitment, engagement and retention, and trial design and eligibility criteria to ensure broad inclusion and needs awareness of minority participants. In concert with systematic strategies to tackle the complex levels of disparate care, our ultimate goal is to expand minority engagement in clinical research and bridge the disparities gap in prostate cancer care.

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