Faculty Bibliography

OBJECTIVES/OBJECTIVE:Numerous real-world evidence (RWE) guidance documents have been published by many regulatory agencies, health technology assessment agencies, and academic groups.These guidances are largely focused on generating unbiased treatment effect estimates from real-world data (RWD) for use in approval and coverage decisions. One of the most prominently cited documents, is a joint ISPOR/ISPE Task Force guidance on the use of RWD for Hypothsis Evaluating Treatment Effectiveness (HETE) Studies. However there are a variety of uses of RWD that existing guidance does not explicitly address. Our goal was to assess existing guidance for its relevance to a range of non-HETE analyses. METHODS:In this paper, we delineate categories of non-HETE applications of RWD. This range of applications includes various types of non-HETE RWD analyses as well as the use of RWD as inputs into other types of analyses such as health economic modeling or simulation studies that are not typically considered RWD studies. We then map existing guidance documents to the categories of non-HETE studies to help identify existing resources for analysts interested in conducting these types of analyses. RESULTS:We identified 13 published guidance documents for detailed review, including documents that outline best practices, provide checklists, or are structured templates. They were selected for their prominence, recency, specific reference to "fit-for-purpose" RWE generation, or their relevance to specific analysis categories. CONCLUSIONS:We conclude that existing guidance documents, even though they were largely developed for HETE studies, are highly useful for the broad range of non-HETE RWD analyses as well.

OBJECTIVES/OBJECTIVE:Advances in informatics research come from academic, nonprofit, and for-profit industry organizations, and from academic-industry partnerships. While scientific studies of commercial products may offer critical lessons for the field, manuscripts authored by industry scientists are sometimes categorically rejected. We review historical context, community perceptions, and guidelines on informatics authorship. PROCESS/METHODS:We convened an expert panel at the American Medical Informatics Association 2022 Annual Symposium to explore the role of industry in informatics research and authorship with community input. The panel summarized session themes and prepared recommendations. CONCLUSIONS:Authorship for informatics research, regardless of affiliation, should be determined by International Committee of Medical Journal Editors uniform requirements for authorship. All authors meeting criteria should be included, and categorical rejection based on author affiliation is unethical. Informatics research should be evaluated based on its scientific rigor; all sources of bias and conflicts of interest should be addressed through disclosure and, when possible, methodological mitigation.

OBJECTIVE:To evaluate whether synthetic data derived from a national COVID-19 data set could be used for geospatial and temporal epidemic analyses. MATERIALS AND METHODS/METHODS:Using an original data set (n = 1,854,968 SARS-CoV-2 tests) and its synthetic derivative, we compared key indicators of COVID-19 community spread through analysis of aggregate and zip-code level epidemic curves, patient characteristics and outcomes, distribution of tests by zip code, and indicator counts stratified by month and zip code. Similarity between the data was statistically and qualitatively evaluated. RESULTS:In general, synthetic data closely matched original data for epidemic curves, patient characteristics, and outcomes. Synthetic data suppressed labels of zip codes with few total tests (mean=2.9±2.4; max=16 tests; 66% reduction of unique zip codes). Epidemic curves and monthly indicator counts were similar between synthetic and original data in a random sample of the most tested (top 1%; n = 171) and for all unsuppressed zip codes (n = 5,819), respectively. In small sample sizes, synthetic data utility was notably decreased. DISCUSSION/CONCLUSIONS:Analyses on the population-level and of densely-tested zip codes (which contained most of the data) were similar between original and synthetically-derived data sets. Analyses of sparsely-tested populations were less similar and had more data suppression. CONCLUSION/CONCLUSIONS:In general, synthetic data were successfully used to analyze geospatial and temporal trends. Analyses using small sample sizes or populations were limited, in part due to purposeful data label suppression - an attribute disclosure countermeasure. Users should consider data fitness for use in these cases.

PURPOSE: We analyzed the effects of baseline symptom severity and placebo response magnitude on the decision to dose escalate in a 12-week, randomized, double-blind, flexible dose antimuscarinic trial of subjects with overactive bladder symptoms. MATERIALS AND METHODS: Data from the placebo arm of the trial were used for this post hoc analysis. Subjects could elect dose escalation at week 2. Those in the placebo arm received sham escalation. RESULTS: Most placebo treated subjects who continued to week 2 elected dose escalation (75% or 325 of 435). Overactive bladder symptoms at baseline were similar between placebo escalators and nonescalators. Nonescalators showed a significantly larger placebo response than escalators, as measured by improvements in bladder diary end points and patient reported outcomes, and by the incidence rate of adverse events before and after sham escalation. CONCLUSIONS: These findings suggest that the decision to dose escalate among placebo treated subjects is independent of baseline symptom severity but may be influenced by the placebo response magnitude for efficacy assessment and adverse events. Placebo nonescalators showed a rapid, large placebo response while placebo escalators showed a smaller placebo response even after sham escalation. These observations may have important implications for the design and interpretation of flexible dose trials using a placebo control.

AIMS: To assess the efficacy and tolerability of fesoterodine 8 mg versus tolterodine extended release (ER) 4 mg in subjects with overactive bladder (OAB) stratified by age (<65, 65-74, and >/=75 years). METHODS: This was a post hoc analysis of data from two double-blind trials. Subjects reporting >/=1 urgency urinary incontinence (UUI) episode and >/=8 micturitions/24 hr at baseline were randomized to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks), tolterodine ER 4 mg, or placebo. Subjects completed 3-day bladder diaries, Urgency Perception Scale (UPS), Patient Perception of Bladder Condition (PPBC), and OAB questionnaire (OAB-q) at baseline and week 12. The primary endpoint in both studies was change from baseline to week 12 in UUI episodes. RESULTS: Among subjects <65 years (n = 2,670), improvements in UUI episodes, micturitions, urgency episodes, severe urgency episodes, frequency-urgency sum, UPS, PPBC, and all OAB-q scales and domains were significantly greater with fesoterodine versus tolterodine ER, and diary-dry rates were significantly higher. Among subjects 65-74 years (n = 990), improvements in mean voided volume per void, PPBC, and OAB-q Symptom Bother and Coping were significantly greater with fesoterodine versus tolterodine ER. Among subjects aged >/=75 years (n = 448), improvements in urgency episodes, severe urgency episodes, frequency-urgency sum, UPS, and OAB-q Symptom Bother were significantly greater with fesoterodine versus tolterodine ER. Both active treatments produced significant improvements in most outcomes versus placebo across age groups. Adverse event rates were similar among age groups. CONCLUSIONS: Fesoterodine 8 mg consistently improved several OAB-related variables versus tolterodine ER 4 mg in subjects aged <65, 65-74, and >/=75 years, with some differences reaching statistical significance, and was generally well tolerated.

AIMS: To characterize the response to fesoterodine treatment for overactive bladder (OAB) in subjects who did or did not choose to dose escalate in a flexible-dose study. METHODS: Subjects were randomized to fesoterodine 4 mg or placebo. At week 2, subjects could remain on 4 mg (non-escalators) or choose to increase to 8 mg (escalators) for the remaining 10 weeks (sham escalation for placebo). Subjects completed 3-day bladder diaries at baseline, week 2 and week 12 noting micturitions, urgency episodes, and urgency urinary incontinence (UUI) episodes. RESULTS: Sixty-three per cent of 438 subjects randomized to fesoterodine and 73% of 445 randomized to placebo dose escalated. At baseline, fesoterodine escalators had significantly more micturitions and urgency episodes than fesoterodine non-escalators (P < 0.001); at week 2, before dose escalation, diary-dry rate and improvement in micturitions and urgency episodes were significantly greater among fesoterodine non-escalators versus escalators (P < 0.001); and by week 12, after dose escalation, diary-dry rate and improvements in micturitions and UUI episodes were similar between fesoterodine non-escalators and escalators (P > 0.05). The placebo escalator group did not demonstrate a similar response over placebo non-escalators following the dose escalation decision point. CONCLUSION: A rapid and robust response to fesoterodine 4 mg was demonstrated in non-escalators. Subjects who chose to dose escalate to fesoterodine 8 mg at week 2 showed significant improvement by week 12 versus baseline and week 2 (prior to escalation), as well as versus placebo. Dose escalation to 8 mg fesoterodine provided subjects with efficacy and tolerability similar to those who were satisfied with the 4-mg dose

OBJECTIVE: To assess the onset of efficacy of fesoterodine 4 mg once daily on overactive bladder (OAB) symptoms after 1 week of treatment. PATIENTS AND METHODS: This was a prespecified analysis of data collected during the first week of a 12-week, open-label, single-arm, flexible-dose study of fesoterodine. Eligible subjects were adult men and women (aged >/= 18 years) who reported urinary frequency (eight or more micturitions per 24 h) and urgency (three or more episodes per 24 h) in 5-day bladder diaries at baseline, and dissatisfaction with previous tolterodine or tolterodine extended-release treatment received within 2 years of screening. All subjects received fesoterodine 4 mg once daily during the first 4 weeks of treatment (with an optional dose increase to fesoterodine 8 mg after week 4). Early onset of efficacy of fesoterodine 4 mg was assessed based on changes from baseline to week 1 in variables recorded in 5-day bladder diaries, including total micturitions, urgency episodes, urgency urinary incontinence (UUI) episodes and nocturnal micturitions. Urgency and severe urgency episodes were defined as those rated >/= 3 and >/= 4, respectively, on the five-point Urinary Sensation Scale (USS) (1 = no urgency, 5 = UUI); frequency-urgency sum (a combined measure of micturition frequency and urgency) was defined as the sum of all USS ratings. RESULTS: All bladder diary variables, including total and nocturnal micturitions, UUI episodes, urgency episodes, severe urgency episodes and frequency-urgency sum per 24 h, were significantly improved (all P < 0.0001) after 1 week of treatment with fesoterodine 4 mg compared to baseline. The diary-dry rate at week 1 (i.e. subjects with at least one UUI episode at baseline who subsequently reported no UUI episodes on week 1 diary) was 38%. CONCLUSION: In this open-label study of subjects with OAB who had been previously treated and dissatisfied with tolterodine, fesoterodine 4 mg showed a rapid onset of efficacy at 1 week

OBJECTIVE: To assess changes in overactive bladder (OAB) symptoms and patient-reported outcomes in a post hoc analysis in which subjects from a 12-week, open-label, flexible-dose fesoterodine study were stratified according to whether they opted for dose escalation. PATIENTS AND METHODS: Subjects with OAB (eight or more micturitions and three or more urgency episodes per 24 h) who reported dissatisfaction with tolterodine within 2 years of screening received fesoterodine 4 mg once daily for 4 weeks, with an optional dose increase to 8 mg after week 4 based on discussion of efficacy and tolerability between the subject and investigator. Subjects completed 5-day diaries, the Patient Perception of Bladder Condition (PPBC) and Urgency Perception Scale (UPS) at baseline and weeks 4 and 12, and the Overactive Bladder Questionnaire (OAB-q) at baseline and week 12. Subjects rated treatment satisfaction at week 12. RESULTS: Dose escalation to 8 mg at week 4 was chosen by 255 (50%) of 513 subjects. At baseline, subjects who opted for dose escalation at week 4 (escalators) had significantly higher means for all diary variables except urgency urinary incontinence (UUI) episodes, significantly greater OAB-q Symptom Bother scores and significantly lower OAB-q health-related quality of life (HRQL) scores (all P < 0.05) compared to subjects who did not opt for dose escalation (non-escalators). There was no significant difference in the percentage of escalators (51%) and non-escalators (48%) who reported at least one UUI episode on baseline diary. At week 4 (before the decision to escalate was made), all outcomes were significantly improved vs baseline among both groups (all P < 0.0001), although non-escalators had significantly greater improvements in all diary variables and in PPBC and UPS scores than escalators (all P < 0.05), and the 5-day diary-dry rate (i.e. the percentage of subjects with at least one UUI episode on baseline diary and no UUI episodes on week 4 diary) was significantly higher (P = 0.0016) among non-escalators (62%) than among escalators (42%). At week 12, all outcomes were again significantly improved vs baseline among both groups (all P < 0.0001). There were no significant differences between non-escalators and escalators in week 12 improvements for most diary variables, UPS scores, OAB-q Symptom Bother scores, the diary-dry rate (68% vs 60%) or the percentage of subjects who reported treatment satisfaction (82% vs 78%). However, escalators still had significantly greater improvements from baseline in urgency episodes, PPBC scores and OAB-q total HRQL and Coping domains (P < 0.05). Adverse event rates were similar between non-escalators and escalators. Dry mouth was the most frequently reported adverse event; most cases were mild. CONCLUSION: Flexible-dose fesoterodine significantly improved OAB symptoms and patient-reported outcomes in subjects who chose to remain on the initial 4-mg dose, as well as in the 50% of subjects who escalated to the 8-mg dose after 4 weeks. Non-escalators had significantly fewer OAB symptoms at baseline and significantly greater improvements than escalators before dose escalation. Escalators showed increased symptom relief after dose escalation; improvements in most outcomes were similar among non-escalators and escalators by week 12. Flexible-dose fesoterodine was well tolerated, with similar adverse-event profiles observed in the escalator and non-escalator groups. These results may help clinicians to identify patients more likely to require fesoterodine 8 mg to achieve maximum relief of OAB symptoms and thus facilitate dose escalation in these patients

OBJECTIVES: To evaluate the efficacy and tolerability of flexible-dose fesoterodine vs placebo in subjects with overactive bladder (OAB). METHODS: In a 12-week double-blind trial, subjects were randomized to fesoterodine 4 mg or placebo once daily, taken within 4 hours of bedtime. At week 2, subjects could increase the fesoterodine dose to 8 mg (sham escalation for placebo). Subjects completed 3-day bladder diaries, Patient Perception of Bladder Condition, and Urgency Perception Scale at baseline and weeks 2, 6, and 12 as well as OAB Questionnaire at baseline and week 12. RESULTS: Of 883 subjects, 63% and 73% of the fesoterodine (n = 438) and placebo (n = 445) groups, respectively, opted for dose escalation. Week 12 improvements from baseline in total micturitions, urgency episodes, urgency urinary incontinence episodes, frequency-urgency sum, and all OAB Questionnaire scales and domains, but not nocturnal micturitions or nocturnal urgency episodes, were significantly greater with fesoterodine than placebo (all P <.05). Treatment differences in micturitions and frequency-urgency sum were significant by week 2 and in urgency urinary incontinence and urgency episodes by week 6. Significantly greater percentages of subjects taking fesoterodine had improved Patient Perception of Bladder Condition and Urgency Perception Scale scores at weeks 2, 6, and 12 (P <.05). Dry mouth (fesoterodine, 26%; placebo, 8%) and constipation (fesoterodine, 11%; placebo, 6%) were the most common adverse events. In both groups, 87% of the subjects completed the trial; 8% and 5% of the fesoterodine and placebo groups, respectively, discontinued because of an adverse event. CONCLUSIONS: Flexible-dose fesoterodine was efficacious and generally well tolerated for treatment of OAB symptoms