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Introduction There is a need to understand how patients assess perceived benefits and risks of treatments. Objectives The study aimed to (i) elucidate how patients evaluate treatment experiences and (ii) develop a brief patient-reported outcome (PRO) instrument for use across disease areas for perceived benefit–risk evaluation of a new medicine in a clinical trial setting. Methods Concepts relating to patient-perceived benefit–risk were identified from literature reviews and qualitative concept elicitation interviews with patients across a variety of primary medical conditions. Draft instrument items were developed from identified concepts and evaluated for clarity, relevance and appropriateness of response options in cognitive interviews. Items were iteratively revised to address patient feedback. Results Qualitative interviews were conducted with 47 patients (primary condition: 20 oncological, 12 respiratory, 10 metabolic, 5 cardiovascular), of whom 32 contributed to concept elicitation and 42 to cognitive debriefing. Elicited concepts could be grouped into four medication-related categories: effectiveness of treatment, burden of side effects, convenience of use and overall acceptance/satisfaction. Cost, trial experience and altruism were additional concept categories unrelated to medication. The final instrument contained one item each on the medication’s effectiveness, side effects and convenience, and an overall item capturing patient benefit–risk assessment. An upfront question was included to separate out non-medication aspects of patients’ experiences. Conclusion We developed a brief PRO instrument, the Patient Global Impression of Benefit–Risk (PGI-BR), which can be applied across disease areas to assess patient views of benefit–risk of a new medicine in the clinical trial setting.

Patients experience a wide range of signs, symptoms, and impacts related to coronavirus disease 2019 (COVID-19). A patient-reported outcome (PRO) item bank that measures the most relevant patient experiences is needed to fully evaluate treatment benefit in COVID-19 clinical trials.A review of the literature and social media informed a novel PRO item bank of COVID-19 signs, symptoms, and impacts and general pandemic impacts. Twenty 1:1 concept elicitation and cognitive debriefing interviews were conducted with adults in the US who had symptomatic COVID-19. A conceptual model was developed and the PRO item bank refined following interviews.A heterogenous set of signs, symptoms, and impacts of COVID-19, as well as impacts associated with the pandemic overall, was identified. Fifty-five short-term and long-term signs and symptom items, 26 items assessing disease-related impacts, and seven items evaluating pandemic-related impacts are included in the item bank.The novel and preliminarily content-valid IQVIA COVID-19 Daily Diary Item Bank

Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.

Background Desmoid tumors (or aggressive fibromatosis) are locally infiltrative connective-tissue tumors that can arise in any anatomic location; they can be asymptomatic, or they can result in pain, deformity, swelling, and loss of mobility and/or threaten visceral organs with bowel perforation, hydronephrosis, neurovascular damage, and other complications. Existing clinical trial endpoints such as the Response Evaluation Criteria in Solid Tumors (version 1.1) and progression-free survival are inadequate in capturing treatment efficacy. This study was designed to develop a novel clinical trial endpoint by capturing patient-reported outcomes (PROs). Methods Following best practices in qualitative methodology, this study used concept elicitation (CE) interviews to explore desmoid patients' perspectives on key disease-related symptoms and impacts. Qualitative analysis was performed to determine the relative frequency and disturbance of symptoms and impacts as well as other characteristics of these concepts. A draft PRO scale was then developed and tested with cognitive interviewing. Information from the interviews was subsequently incorporated into the refined PRO scale. Results CE interviews with desmoid patients (n = 31) helped to identify salient concepts and led to a draft scale that included symptom and impact scales. Cognitive interviews were completed with additional patients (n = 15) across 3 phases. Patient input was used to refine instructions, revise and/or remove items, and modify the response scale. This resulted in an 11-item symptom scale and a 17-item impact scale. Conclusions This is the first disease-specific PRO instrument developed for desmoid tumors. The instrument is available as an exploratory endpoint in clinical trials. This study highlights the feasibility and challenges of developing PRO instruments for rare diseases.

Supplemental digital content is available in the text., Atopic dermatitis (AD) is a pruritic or painful dermatologic disease characterized by xerosis and eczema lesions. The symptoms/signs of AD can significantly impact patients' health-related quality of life (HRQoL). This study aimed to qualitatively explore the adult and adolescent experience of AD. A targeted literature review and qualitative concept elicitation interviews with clinicians (n = 5), adult AD patients (n = 28), and adolescent AD patients (n = 20) were conducted to elicit AD signs/symptoms and HRQoL impacts experienced. Verbatim transcripts were analyzed using thematic analysis. Twenty-nine symptoms/signs of AD were reported, including pruritus, pain, erythema, and xerosis. Atopic dermatitis symptoms/signs were reported to substantially impact HRQoL. Scratching was reported to influence the experience of symptoms and HRQoL impacts. Four proximal impacts (including discomfort and sleep disturbance) were reported. Ten domains of distal impact were reported, including impacts on psychological and social functioning and activities of daily living. A conceptual model was developed to summarize these findings. This study highlights the range of symptoms and HRQoL impacts experienced by adults and adolescents with AD. To our knowledge, this study was first to explore the lived experience of AD in both adult and adolescent patients, providing valuable insight into the relatively unexplored adolescent experience of AD.

Background Endometriosis is a common gynecological disorder that causes inflammation and pelvic pain. Endometriosis-related pain is best captured with patient-reported outcome (PRO) measures, however, assessment of endometriosis-related pain in clinical trials has been difficult in the absence of a reliable and valid PRO instrument. We describe the development of the Endometriosis Pain Daily Diary (EPDD), an electronic PRO developed as a survey instrument to assess endometriosis-related pain and its impact on patients’ lives. Methods The EPDD was initially developed on the basis of an existing Endometriosis Pain and Bleeding Diary, a targeted review of relevant literature, clinical expert interviews, and open-ended (concept elicitation) patient interviews in the United States (US) and Japan which captured patients’ experience with endometriosis. Cognitive interviews of patients with endometriosis were conducted to evaluate patient comprehension of the EPDD items. A conceptual model of endometriosis was developed, and meetings with US and European regulatory authorities provided feedback for validating the EPDD in the context of clinical trials. Translatability assessments of the EPDD were conducted to confirm its appropriate interpretation and ease of completion across 17 languages. Results The iterative development progressed through three versions of the instrument. The EPDDv1 included 18 items relating to dysmenorrhea/pelvic pain, dyspareunia and sexual activity, bleeding, hot flashes, daily activities, and use of rescue medication. The EPDDv2 was a larger 43-item survey tested in cognitive interviews and subsequently revised to yield the current 11-item EPDDv3, consisting of five core items relating to dysmenorrhea, non-menstrual pelvic pain, and dyspareunia, and six extension items relating to sexual activity, daily activities, and use of rescue medication. Conclusions The EPDD is a PRO for the evaluation of endometriosis-related pain and its associated impacts on patients’ lives. The EPDD represents an important step in providing a PRO that is relevant to patients with endometriosis-related pain in the context of a clinical study setting (ie, fit-for-purpose), designed to evaluate pain associated with endometriosis, including regulatory agency support for its further exploration in clinical trials.

Objectives: In this unprecedented era of conducting clinical research during a global pandemic a Patient-Reported Outcomes (PRO) tool is required to (1) provide a comprehensive epidemiological understanding of SARS-COV-2 (COVID-19) symptoms, clustering and resolution;(2) provide data on the impact of both infection and the pandemic on people’s lives;and (3) offer a full understanding of treatment benefit in studies designed to treat or vaccinate against COVID-19 Methods: A review of the literature (March 2020) used COVID-19 and signs, symptoms and impacts search terms A preliminary conceptual model was developed and novel PRO items were drafted A review of social media (June 2020) informed an updated conceptual model and PRO items Joint concept elicitation-cognitive interviews were completed with people who had experienced COVID-19 (June-July 2020) Results: The literature (25 articles), social media (>200 million mentions) and interviews (n=10) highlighted a heterogenous list of signs, symptoms and impacts of COVID-19 infections, and a broad list of impacts of the pandemic in general Novel PROs are intended to be comprehensive, so the incidence and severity of 42 signs and symptoms are measured Fifteen additional items ask about the impact of infection (physical, emotional and social) and 18 about the impact of the pandemic The PRO is adaptive (modular) to allow administration to people with and without COVID-19 infection Weekly- and daily-recall versions were tested in cognitive interviews resulting in adjustments to ensure understandability Conclusions: Novel content-valid PROs have been developed to measure the signs, symptoms and impacts of COVID-19 pandemic and infection These are currently being employed in a large longitudinal study to evaluate their psychometric measurement properties

Along with reducing spleen size, relieving symptom severity is a key objective of the treatment of myelofibrosis (MF). Several questionnaires have been developed for patient self-report of MF symptoms in clinical trials and each includes unique instructions, items, and/or response scales. This variability in questionnaire content increases uncertainty; it is unclear which questionnaire is the most appropriate for assessing MF symptoms and it makes comparisons across trials difficult. The Patient-Reported Outcome (PRO) Consortium's MF Working Group (WG) was established to review existing MF symptom questionnaires and to develop a harmonized, consensus-based PRO questionnaire for use in future MF trials. The WG focused on the seven core symptoms of MF: fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety, and bone pain. The resulting Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) asks respondents to report symptom severity at its worst for each of the seven items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale. The MFSAF v4.0, for which there are 24-h and 7-day recall formats, will be maintained and licensed by the Critical Path Institute and made publicly available for use in future clinical trials.

Introduction Acute myeloid leukemia (AML) imposes significant burden on patients, their families, and the healthcare system. Published literature has reported many AML signs and symptoms, as well as their impact on patients. However, there are no publications on the experience of living with AML from the patient's perspective. In this study, we performed qualitative interviews with patients with AML to understand their experience. Methods Participants were recruited from the US and Japan. All patients were screened to assess eligibility, and were divided into four subgroups (i.e., newly-diagnosed, high-intensity chemotherapy; newly-diagnosed, low-intensity chemotherapy; relapse/refractory; and post-transplant). Patients were interviewed over the phone by a trained researcher and asked about their day-to-day experience with AML. Signs/symptoms and impacts were coded, analyzed using Atlas.ti software, and reported as frequencies, with the medians of patient-reported disturbance levels (0–10) computed for each symptom and impact. Results The most commonly reported sign/symptom in the US was fatigue (95.7%), followed by bruising and weakness (both 78.3%), and in Japan, nausea (94.4%), followed by fatigue and headache (both 88.9%). The most commonly reported impact in the US was a decreased ability to maintain social/familial roles (91.3%), followed by anxiety and a decreased ability to function (both 87.0%), and most commonly reported in Japan was anxiety, a decreased ability to function, and remission uncertainty (94.4%). Conclusion Although the frequency of signs/symptoms and their level of disturbance varied between the US and Japan, there was remarkable consistency in the types of signs/symptoms and impacts reported across all patients. The consistency in the experience of the disease across patients suggests that measurement of AML experience can be achieved by using the same tool for most, if not all, of these patients. Funding Astellas Pharma Inc., Northbrook, IL, USA. Electronic supplementary material The online version of this article (doi:10.1007/s40487-016-0029-8) contains supplementary material, which is available to authorized users.

In the ongoing phase 3, CheckMate 214 trial, nivolumab plus ipilimumab improved overall survival compared with sunitinib in patients with intermediate or poor risk, previously untreated, advanced renal cell carcinoma. We aimed to assess whether health-related quality of life (HRQoL) could be used to further describe the benefit-risk profile of nivolumab plus ipilimumab versus sunitinib.In the phase 3, randomised, controlled, CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced or metastatic renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by risk status into favourable, intermediate, and poor risk subgroups and randomly assigned (1:1) to open-label nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg/day for 4 weeks of each 6-week cycle. Randomisation was done with a block size of four and stratified by risk status and geographical region. Patient-reported outcomes (PROs) were assessed using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 (FKSI-19), Functional Assessment of Cancer Therapy-General (FACT-G), and EuroQol five dimensional three level (EQ-5D-3L) instruments. The coprimary endpoints of the trial, reported previously, were overall survival, progression-free survival, and the proportion of patients who had an objective response in those categorised as at intermediate or poor risk. PROs in all randomised participants were assessed as an exploratory endpoint; here we report this exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but is now closed to recruitment.Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) were randomly assigned to treatment, of whom 847 (77%) were at intermediate or poor risk and randomly assigned to nivolumab plus ipilimumab (n=425) or sunitinib (n=422). Median follow-up was 25·2 months (IQR 23·0-27·4). PROs were more favourable with nivolumab plus ipilimumab than sunitinib throughout the first 103 weeks after baseline, with mean change from baseline at week 103 for FKSI-19 total score being 4·00 (95% CI 1·91 to 6·09) for nivolumab plus ipilimumab versus -3·14 (-6·03 to -0·25) for sunitinib (p0·0001), and for FACT-G total score being 4·77 (1·73 to 7·82) for nivolumab plus ipilimumab versus -4·32 (-8·54 to -0·11) for sunitinib (p=0·0005). Significant differences were also seen for four of five FKSI-19 domains (disease-related symptoms, physical disease-related symptoms, treatment side-effects, and functional wellbeing) and FACT-G physical and functional wellbeing domains. However, there was no significant difference between the treatment groups at week 103 in EQ-5D-3L visual analogue rating scale (VAS) scores, with mean change from baseline to week 103 of 10·07 (95% CI 4·35 to 15·80) for nivolumab plus ipilimumab and 6·40 (-1·36 to 14·16) for sunitinib (p=0·45). Compared with sunitinib, nivolumab plus ipilimumab reduced risk of deterioration in FKSI-19 total score (hazard ratio [HR] 0·54; 95% CI 0·46-0·63), FACT-G total score (0·63, 0·52-0·75), and EQ-5D-3L VAS score (HR 0·75, 95% CI 0·63-0·89) and UK utility scores (0·67, 0·57-0·80).Nivolumab plus ipilimumab leads to fewer symptoms and better HRQoL than sunitinib in patients at intermediate or poor risk with advanced renal cell carcinoma. These results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib comes with the additional benefit of improved HRQoL.Bristol-Myers Squibb and ONO Pharmaceutical.

Aims This observational study compared data values, reliability, consistency and compliance collected by electronic and paper diaries of differing durations. Methods Subjects ≥18 years with overactive bladder (OAB) on stable antimuscarinic treatment for ≥12 weeks were assigned to one of five, 15-week diary schedules in this randomized, parallel-group observational study. Sample size was sufficient to assess reliability and consistency of diary data with adequate precision. Reliability was assessed via intraclass correlation coefficients, variability with ANCOVAs, and consistency using Cronbach's alpha. Results Demographic characteristics of randomized subjects were representative of OAB trial populations. For mean volume voided, reliability was comparable across diary groups. For incontinence, reliability improved with increasing diary duration. For micturition frequency, electronic 7-day diary results had highest reliability and lowest variability. Lowest overall reliability was observed in the 3-day paper diary. Consistency was highest in the electronic continuous groups; Cont A (daily measurements throughout the study period [fully Continuous]) and Cont B (daily measurements for some but not all endpoints of interest [Partially Continuous]). Compliance was generally high; across groups ≥90% of diaries had at least one entry per day. There was no significant change in average micturition frequency with diary duration, suggesting no diary fatigue. One-third of subjects in the electronic Cont B group also reported micturitions as incontinence when they only needed to report incontinence; they also reported lowest satisfaction with the study. The electronic 7-day and electronic Cont A schedules (who reported incontinence and micturitions throughout the study) had lowest residual errors. Conclusions For future OAB trials, 7-day or continuous electronic diaries may improve accuracy and reliability of micturition and incontinence frequency data compared with shorter collection periods and paper diaries. Neurourol. Urodynam. © 2015 Wiley Periodicals, Inc.

Patients’ experience of symptoms and associated treatment is an increasingly important consideration in both regulatory and health technology assessments, and can inform treatment decisions. This study aimed to gain insight directly from patients with advanced breast cancer about which symptoms and treatment side effects are important to them. Women with locally advanced or metastatic breast cancer were interviewed individually by trained interviewers, using a semi-structured interview guide. Verbatim transcripts were analyzed qualitatively, including whether symptoms were mentioned spontaneously (indicating their importance to patients) or only when questioned directly. Sixteen women (aged 38–74 years) participated. The most commonly reported symptom aspects were: pain (16/16 [all reported spontaneously]); feeling tired/fatigued (15/16 [12 spontaneously]); changes in weight (15/16 [2 spontaneously]); hair loss (15/16 [5 spontaneously]); changes in appetite (11/16 [8 spontaneously]); nausea (9/16 [all spontaneously]). Pain was attributed mostly to the disease or to its treatment. Tiredness, changes in weight/appetite, and hair loss were attributed mostly to the treatment. All women (14 spontaneously) reported that the cancer affected their emotional well-being and their ability to perform daily activities. Further qualitative research is needed to understand how patients distinguish cancer-related symptoms from treatment-related side effects, to gain insight into which patient experiences should be measured and how best to measure them.

The objective of this report was to address the use and mixing of data collection modes within and between trials in which patient-reported outcome (PRO) end points are intended to be used to support medical product labeling. The report first addresses the factors that should be considered when selecting a mode or modes of PRO data collection in a clinical trial, which is often when mixing is first considered. Next, a summary of how to "faithfully" migrate instruments is presented followed by a section on qualitative and quantitative study designs used to evaluate measurement equivalence of the new and original modes of data collection. Finally, the report discusses a number of issues that must be taken into account when mixing modes is deemed necessary or unavoidable within or between trials, including considerations of the risk of mixing at different levels within a clinical trial program and mixing between different types of platforms. In the absence of documented evidence of measurement equivalence, it is strongly recommended that a quantitative equivalence study be conducted before mixing modes in a trial to ensure that sufficient equivalence can be demonstrated to have confidence in pooling PRO data collected by the different modes. However, we also strongly discourage the mixing of paper and electronic field-based instruments and suggest that mixing of electronic modes be considered for clinical trials and only after equivalence has been established. If proceeding with mixing modes, it is important to implement data collection carefully in the trial itself in a planned manner at the country level or higher and minimize ad hoc mixing by sites or individual subjects. Finally, when mixing occurs, it must be addressed in the statistical analysis plan for the trial and the ability to pool the data must be evaluated to then evaluate treatment effects with mixed modes data. A successful mixed modes trial requires a "faithful migration," measurement equivalence established between modes, and carefully planned implementation to minimize the risk of increased measurement error impacting the power of the trial to detect a treatment effect.

3073Background: In CheckMate 214, overall survival (OS) with nivolumab + ipilimumab (N+I) was superior to sunitinib (S; HR, 0.63; P

Background: Naltrexone (NTX) has proven to be effective with alcoholics in treatment, with most controlled clinical trials showing beneficial effects on heavy drinking rates. However, little is known about the behavioral mechanisms underlying the effects of NTX on drinking, or about patient characteristics that may moderate NTX's effects on drinking. In this study, ecological momentary assessment (EMA) techniques were used to investigate some of the putative mechanisms of naltrexone's effects on drinking in heavy drinkers who were not seeking treatment for alcohol problems. Polymorphisms in the D4 dopamine receptor (DRD4) gene and the μ-opiate receptor (OPRM1) gene, family history of alcohol problems, age of onset of alcoholism and gender were explored as potential moderators of NTX's effects. Methods: After a one-week placebo lead-in period, heavy drinkers (n = 180), 63% of whom were alcohol-dependent, were randomized to 3 weeks of daily naltrexone (50 mg) or placebo. Throughout the study, participants used EMA on palm-pilot computers to enter, in real time, drink data, urge levels, and subjective effects of alcohol consumption. Results: NTX reduced percentage drinking days in all participants and reduced percent heavy drinking days in DRD4-L individuals; NTX decreased urge levels in participants with younger age of alcoholism onset; NTX increased time between drinks in participants who had more relatives with alcohol problems; and NTX reduced the stimulating effects of alcohol in women. OPRM1 status did not moderate any of NTX's effects. Conclusions: These results confirm earlier findings of NTX's effects on drinking and related subjective effects, and extend them by describing individual difference variables that moderate these effects in the natural environment, using data collected in real time.

Introduction No existing patient-reported outcome instrument focuses solely on assessment of varicose veins symptoms that are bothersome to patients. Methods The VVSymQ® instrument is a five-item patient-reported outcome that assesses symptoms most important to patients with varicose veins (heaviness, achiness, swelling, throbbing and itching). This paper describes how the VVSymQ® instrument was incorporated into an electronic daily diary to monitor key outcomes over time and capture treatment benefit in two randomized, controlled, phase 3 clinical trials. Results Patients were highly compliant in completing the electronic daily diary, and the VVSymQ® instrument demonstrated ability to detect overall change and ability to detect change that is meaningful to patients. Conclusion The VVSymQ® instrument is a reliable, valid instrument responsive to measuring change in the patient experience of varicose vein symptoms pre- and post-intervention, and is uniquely focused on patient-reported symptoms compared with other widely used questionnaires completed by clinicians.

This observational study compared data values, reliability, consistency and compliance collected by electronic and paper diaries of differing durations.Subjects ≥18 years with overactive bladder (OAB) on stable antimuscarinic treatment for ≥12 weeks were assigned to one of five, 15-week diary schedules in this randomized, parallel-group observational study. Sample size was sufficient to assess reliability and consistency of diary data with adequate precision. Reliability was assessed via intraclass correlation coefficients, variability with ANCOVAs, and consistency using Cronbach's alpha.Demographic characteristics of randomized subjects were representative of OAB trial populations. For mean volume voided, reliability was comparable across diary groups. For incontinence, reliability improved with increasing diary duration. For micturition frequency, electronic 7-day diary results had highest reliability and lowest variability. Lowest overall reliability was observed in the 3-day paper diary. Consistency was highest in the electronic continuous groups; Cont A (daily measurements throughout the study period [fully Continuous]) and Cont B (daily measurements for some but not all endpoints of interest [Partially Continuous]). Compliance was generally high; across groups ≥90% of diaries had at least one entry per day. There was no significant change in average micturition frequency with diary duration, suggesting no diary fatigue. One-third of subjects in the electronic Cont B group also reported micturitions as incontinence when they only needed to report incontinence; they also reported lowest satisfaction with the study. The electronic 7-day and electronic Cont A schedules (who reported incontinence and micturitions throughout the study) had lowest residual errors.For future OAB trials, 7-day or continuous electronic diaries may improve accuracy and reliability of micturition and incontinence frequency data compared with shorter collection periods and paper diaries. Neurourol. Urodynam. 35:743-749, 2016. © 2015 Wiley Periodicals, Inc.

Aims To examine the natural history of nicotine withdrawal and individual differences associated with withdrawal duration and severity. Design and Setting Prospective study of withdrawal symptoms among smokers who quit for at least 24 hours. Participants used Ecological Momentary Assessment to monitor symptoms in their natural environment using an Electronic Diary (ED). Participants A total of 214 cigarette smokers (59% female, 92% Caucasian). Intervention All participants received a clinic-based, behavioral, group cessation intervention. Severity and duration of withdrawal was not addressed explicitly in treatment. Measurements Participants were ‘beeped’ by the ED approximately five times/day to complete affect assessments (negative affect, arousal, attention disturbance, restlessness), and daily assessments of sleep disturbance (at waking) and of cognitive performance (each evening) for a week prior to quitting and for up to 21 days after quitting. Withdrawal was considered resolved when withdrawal scores returned to baseline levels for at least 2 consecutive days. Findings All symptoms returned to baseline levels within 10 days of quitting. All variables except arousal and sleep disturbance showed change over time. No robust predictors of individual differences in withdrawal responses emerged. Conclusions The time-course of withdrawal may be shorter than previously reported. The natural history of nicotine withdrawal may have implications for theories of withdrawal and smoking relapse and for smoking cessation treatment.

Adult social drinkers used handheld computers to monitor alcohol intake as well as the precursors and consequences of drinking over a 2-week period. The within-person relationship between mood and amount of alcohol consumed was examined, as well as the role of individual differences. When individuals made internal attributions for their greater than average consumption, they were in a more negative mood after drinking. Individuals who experienced a negative mood after drinking consumed more subsequently. This dysregulatory process may help explain the progression from social drinking to more problematic drinking; indeed, the relationship between mood and alcohol intake was stronger for heavier drinkers. Likewise, gender and trait temptation and restriction moderated this process. The results are consistent with the Limit Violation Effect model (R. L. Collins, 1993) of mood and regulation of alcohol intake.

Theory suggests that cigarette smoking is under stimulus control and that affect is a key trigger for smoking. A previous study (S. Shiftman et al., 2002) showed little relationship between affect and smoking, but this relationship could have been suppressed by the impact of smoking restrictions. The study evaluated these associations in a 1988 sample that was subject to few smoking restrictions. Smokers (N = 28) not seeking treatment used palmtop computers to record context and affect prior to smoking (n = 2217 observations) and also at random times when not smoking (n = 2,380). Comparisons showed little relationship between smoking and affect. Smoking was associated with particular activities and locations. Urge to smoke was the strongest predictor of smoking. The results replicated the findings of S. Shiffman et al. (2002).

Most attempts to quit smoking end in failure, with many quitters relapsing in the first few days. Responses to smoking-related cues may precipitate relapse. A modified emotional Stroop task-which measures the extent to which smoking-related words disrupt performance on a reaction time (RT) task-was used to index the distracting effects of smoking-related cues. Smokers (N = 158) randomized to a high-dose nicotine patch (35 mg) or placebo patch completed the Stroop task on the 1st day of a quit attempt. Smokers using an active patch exhibited less attentional bias, making fewer errors on smoking-related words. Smokers who showed greater attentional bias (slowed RT on the first block of smoking words) were significantly more likely to lapse in the short-term, even when controlling for self-reported urges at the test session. Attentional bias measures may tap an important component of dependence.

A. A. Stone and S. Shiffman (1994) defined ecological momentary assessment (EMA) as monitoring or sampling strategies that assess phenomena at the moment they occur in natural settings, thus maximizing ecological validity while avoiding retrospective recall. To address the extent to which EMA affects the behaviors and cognitions under observation, the authors examined behavioral and motivational reactivity to EMA among male and female undergraduate problem drinkers (n = 33). Participants completed a 2-week monitoring protocol using palmtop computers as well as pre- and postmonitoring measures of their drinking behavior and motivation for change. The findings suggest that the magnitude of reactivity to EMA is small. Suggestions for future research are presented.

11022 Background: Desmoid tumors (DT) are locally aggressive and cause significant morbidity. Clinical trials in DT typically utilize response rates and progression free survival as primary endpoints. However, these endpoints do not capture improvements in clinical symptoms. To date, there are no validated PRO tools in DT to capture the patient experience and efficacy of a drug. Methods: A review of the published literature and interviews with sarcoma clinicians were used to formulate a list of signs and symptoms and impact on patients (pts). These were collected to build a conceptual model. DT pts (n = 31) with a range of anatomical locations and presentations were interviewed, initially in an open-ended fashion, followed by interrogating the conceptual model. For the concepts that pts reported, they were asked to rate how disturbing each was on a 0-10 scale (0 being not at all, and 10 being as bad as they can imagine). The pts interview data was then used to refine the conceptual model and generate two new PRO instruments Results: Pt interviews demonstrated that across tumor locations, the most frequent and disturbing symptoms were: ‘muscle’ pain (65% pts, median disturbance (MD) of 6.8), ‘nerve’ pain (73%, MD 6.0), and fatigue (65%, MD 5.0). Some symptoms were specific to tumor locations, especially abdominal tumors. Restricted range of motion (68%, MD 4.0), fear (84%, MD 6.5), sleep disturbance (77%, MD 7.5) , disfigurement (81%, MD 6.8), and impact on daily activities (65%, MD 6.8) were the most frequent and disturbing impact on pts lives. These concepts were then used to develop two new PRO instruments: the sign and symptom PRO includes 11 items; the impact on pts lives instrument includes 17 items. The instruments vary in asking pts about the last 24 hours, or the last week. Conclusions: This is the first validated PRO tool in DT. This tool adequately captures symptoms central to the DT pts experience and its impacts on their lives. The instruments are ready for implementation in a DT clinical trial for further evaluation of their measurement properties.

The collection of real-time, real-world patient experience data that are reliable, valid, and sensitive to drug effects presents many challenges to clinical trial sponsors and investigators. Recent developments in electronic patient experience diary (PED) systems highlight the importance of building a robust, subject-friendly system that can enhance subjects' protocol compliance and is regulatory compliant. To succeed in a clinical trial, an electronic PED system must simultaneously meet two related standards: clinical integrity and system integrity. Clinical integrity includes the elements of protocol compliance, measurement reliability, data validity, and auditable subject quality. An electronic PED system with clinical integrity produces compliance metadata that can be used to better understand and evaluate the efficacy data. System integrity includes the elements of management control, system reliability, data integrity, and auditable system quality for computerized data handling. An electronic PED system with system integrity collects data that have been authenticated by built-in logic and security checks and can be attributed to the subject. The challenges and promises of such a system are presented.

According to self-efficacy and relapse theories. abstinence self-efficacy (ASE) ratings should be context-specific: they should vary across situations. This variability may be important, as it could signal high-risk for relapse situations. In this study, confirmatory factor analysis was used to identify situational variability in a novel ASE assessment (Relapse Situation Efficacy Questionnaire. or RSEQ). Results supported a hierarchical structure, where both context-specific and unidimensional measures of ASE exist within the assessment. Context-specific factors included Negative Affect, Positive Affect, Restrictive Situations (to smoking). Idle Time, Social-Food Situations, Low Arousal, and Craving. Multiple context-specific factors and the aggregate factor predicted cessation outcome, even after controlling for concurrent smoking rate. However, the context rated with the least confidence proved to be the best outcome predictor, suggesting the existence of "Achilles' heel" situations. These data indicate the internal and predictive validity of the RSEQ.

Aims. To compare a transdermal nicotine patch designed for 24-hour wear with one designed for 16-hour wear for relief of craving and withdrawal, particularly in the morning hours. Design. Smokers were randomly assigned to use one of two common patch regimens: NicoDerm/NiQuitin (24-hour wear, 21 mg nicotine) or Nicotrol/Nicorette (16-hour wear, 15 mg). In a double-dummy design, participants wore two patches during the day, one active, one placebo and one patch while sleeping. Setting. A smoking cessation research clinic. Participants. Two hundred and forty-four smokers who suffered morning cravings. Intervention. Two patch formulations approved and marketed for over-the-counter use in the US- NicoDerm CQ (labeled as 21 mg over 24 hours) and Nicotrol (labeled as 15 mg over 16 hours)-were each used according to its instructions. Smokers also received behavioral counseling. Measurements. For a week of baseline and 2 weeks after quitting, smokers used palm-top computers to assess craving and withdrawal symptoms several times each day. Findings. The 21 mg/24-hour patch yielded consistently better control of craving, not only during the morning hours, but throughout the day, and over the 2-week period of abstinence. Additionally, the 21 mg/24-hour patch yielded greater reductions in anxiety, irritability and restlessness. Smokers using the 21 mg/24-hour dosing regimen also experienced longer abstinence than those using the 15 mg/16-hour patch. Conclusions. These findings demonstrate that 24-hour dosing with a 21 mg patch affords superior relief of craving and withdrawal during the first 2 weeks of abstinence, when symptoms are at their peak, and when relapse is most likely. They confirm the importance of dosing parameters in nicotine replacement products.

Ambulatory blood pressure (ABP) may be an independent predictor of cardiovascular endpoints, but little is known about its psychosocial determinants. The acute effects of psychosocial processes on cardiovascular activity during daily life were examined by random-effects regression. Healthy adults (N = 120) were monitored over a 6-day period with ABP monitors and computer-assisted self-report assessments. Task strain, social conflict, and emotional activation were rated following each ABP measurement, as were activity, posture, and other covariates. Results show that blood pressure (BP) and heart rate (HR) were elevated during periods of emotional activation (high negative affect or high arousal). Diastolic BP was lower during periods involving high decisional control, and HR was lower during high-control, low-demand activities. There were substantial individual differences in the effects of psychosocial influences on ambulatory cardiovascular activity. Psychological factors are reliable determinants of ABP, which may account in part for the unique predictive value of ABP.

Research on relapse has often focused either on the momentary context of lapses or on stable traits that predict who will relapse. We examine the relation between the two, analyzing how individual differences relate to characteristics of initial lapses, which were recorded nearly in real time by 105 smokers using hand-held computers. More nicotine-dependent smokers lapsed under more negative affect and more intense urges, but they did not smoke more in the initial lapse. Questionnaire measures of negative affect smoking did not predict negative affect lapses. Smokers who lapsed when drinking were less nicotine dependent, but they had a history of smoking while drinking, as assessed by computer monitoring. Smokers who attempted coping but lapsed nevertheless reported less active coping styles on the Ways of Coping questionnaire. The results demonstrate the interplay between individual traits and contextual influences in smoking relapse, and they particularly highlight the role of nicotine dependence in relation to contextual factors.

We evaluated abstinence violation effects (AVEs) (a constellation of negative reactions to a lapse) following an initial lapse to smoking in 105 recent lapsers, and in temptation episodes from these lapsers and from 35 maintainers. Participants used palm-top computers to record AVE data within minutes of the episode, thus avoiding retrospective bias. Lapses resulted in increased negative affect and decreased self-efficacy; participants also felt guilty and discouraged. Lapsers who attributed their lapse to more controllable causes felt worse and more guilty; attributions did not otherwise moderate affective or efficacy reactions. AVE intensity was unrelated to amount smoked, length of abstinence, or performance of immediate or restorative coping. Temptations neither provoked an AVE nor enhanced self-efficacy in either lapsers or maintainers. Maintainers' reactions to temptations were nearly identical to lapsers', except that maintainers felt worse. The data demonstrate the reality of AVE reactions, but do not support hypotheses about their structure or determinants.

Research and treatment assessments often rely on retrospective recall of events. The accuracy of recall was tested using accounts of smoking lapse episodes from 127 participants who had quit smoking, and lapses and temptations were recorded in near-real time using a hand-held computer. These computer records were compared with retrospective accounts elicited 12 weeks later, with a focus on recall of lapses in 4 content domains: mood, activity, episode Triggers, and abstinence violation effects. Recall of lapses was quite poor: Average kappas for items ranged from 0.18 to 0.27. Mean profile rs assessing recall for the overall pattern of behavior were .36, .30, .33, and .44 for these domains, respectively. In recall, participants overestimated their negative affect and the number of cigarettes they had smoked during the lapse, and their recall was influenced by current smoking status. The findings suggest caution in the use of recall in research and intervention.

OBJECTIVES: We aimed to develop and validate the Reflux Symptom Questionnaire electronic Diary (RESQ-eD) for use in clinical trials in patients with a partial response to proton pump inhibitor (PPI) therapy, using methods that meet US Food & Drug Administration (FDA) regulatory standards. METHODS: Patient interviews were performed to elicit new items and evaluate existing items from the Reflux Disease Questionnaire. The instrument's measurement properties were evaluated, based on data from two clinical trials of patients with gastroesophageal reflux disease (GERD) with a partial response to PPIs who received lesogaberan or placebo as an add-on to PPI therapy. RESULTS: The content validity phase resulted in 13 RESQ-eD items. Principal component analysis supported a four-domain structure. All domains had a high inter-item correlation (Cronbach's alpha lower 95% confidence limit: 0.87–0.95). Test-retest reliability was good to excellent (intraclass correlation coefficient: 0.65–0.85). Convergent and discriminant validity was confirmed by correlation assessments referencing the Gastrointestinal Symptom Rating Scale. The RESQ-eD demonstrated a good ability to capture change in mean intensity and proportion of symptom-free days. Confirmatory psychometric evaluation verified internal consistency reliability, test-retest reliability, and ability to capture change. CONCLUSIONS: The RESQ-eD demonstrated good content validity and psychometric properties in the clinical trial setting in patients with GERD who have a partial response to PPI therapy. To our knowledge, the RESQ-eD is the first electronic symptom diary for use in partial responders to PPI that has been developed in line with the FDA guidance on patient-reported outcomes.