Sheri Fehnel - Academia.edu (original) (raw)

Papers by Sheri Fehnel

Advances in therapy, 2017

To improve understanding of the diabetic gastroparesis (DGP) patient experience and inform the pa... more To improve understanding of the diabetic gastroparesis (DGP) patient experience and inform the patient-reported outcome measurement strategy for future trials in DGP, qualitative interviews were conducted with participants in a phase 2 clinical trial of a novel DGP treatment. Trial participants were invited to participate in interviews at both the pretreatment visit (PTV) and the end-of-treatment visit (EOTV). The interviews were conducted by experienced qualitative researchers and followed a semistructured interview guide. The PTV interviews focused on patients' DGP symptoms and the impact of DGP on their lives, and the EOTV interviews focused on any symptom changes patients experienced during the trial. Of 90 enrolled trial participants, 78 (86.7%) opted to participate in the interview study. Bloating, stomach fullness, upper abdominal pain, vomiting, constipation, and heartburn or reflux were each reported spontaneously by a majority of the 73 PTV interview participants with ...

Value in Health, 2003

shown to be significantly lower in ED patients than in non-ED subjects (84.4 vs. 89.4, respective... more shown to be significantly lower in ED patients than in non-ED subjects (84.4 vs. 89.4, respectively; p = 0.0109), suggesting an association between self-confidence and erectile dysfunction. CONCLUSION: Assessment of selfconfidence through this Spanish version of the Johnson and McCoy's questionnaire is reliable and valid and provides a new instrument to measure the psychological impact of erectile dysfunction.

PharmacoEconomics, 2003

The Diabetic Foot Ulcer Scale (DFS) provides comprehensive measurement of the impact of diabetic ... more The Diabetic Foot Ulcer Scale (DFS) provides comprehensive measurement of the impact of diabetic foot ulcers on patients' QOL through self-administration of 64 items comprising 15 subscales. To develop and evaluate a short form of the DFS (DFS-SF) to reduce patient burden and the number of outcome measures, and to improve sensitivity to change in clinical condition. The DFS-SF was created through the analysis of data from a double-blind, placebo-controlled, randomised trial of the efficacy and safety of becaplermin (recombinant human platelet-derived growth factor BB) in the treatment of chronic, full-thickness, neuropathic, diabetic foot ulcers. Using these data, items demonstrating poor psychometric properties were eliminated. Exploratory factor analyses were then conducted to develop a new, more parsimonious scaling algorithm that optimised the internal consistency of the new subscales. Finally, data from two additional clinical trials were used to assess replicability of the...

To identify candidate items for deletion from the questionnaire, three steps were taken, utilizin... more To identify candidate items for deletion from the questionnaire, three steps were taken, utilizing data from the two aforementioned clinical trials. ■Pairwise t-tests were conducted, comparing changes on each MEI item for responders and nonresponders, with the goal of identifying items that were not optimally sensitive to differences between these two groups. Responders were subjects whose Hamilton Rating Scale for

The American Journal of Gastroenterology, 2006

Clinical and Experimental Gastroenterology, 2014

While chronic constipation (CC) clinical trials have focused primarily on bowel symptoms (symptom... more While chronic constipation (CC) clinical trials have focused primarily on bowel symptoms (symptoms directly related to bowel movements), abdominal symptoms are also prevalent among patients. The United States Food and Drug Administration's (FDA's) guidance on the use of patient-reported outcome measures to support product approvals or labeling claims recommends that endpoints be developed with direct patient input and include all symptoms important to patients. To identify a comprehensive set of CC symptoms that are important to patients for measurement in clinical trials. Following a targeted literature review to identify CC symptoms previously reported by patients, 28 patient interviews were conducted consistent with the FDA's guidance on patient-reported outcomes. Subsequent to open-ended questions eliciting descriptions of all symptoms, rating and ranking methods were used to identify those of greatest importance to patients. All 67 studies reviewed included bowel symptoms; more than half also addressed at least one abdominal symptom. Interview participants reported 62 potentially distinct concepts: 12 bowel symptoms; 21 abdominal symptoms; and 29 additional symptoms/impacts. Patients' descriptions revealed that many symptom terms were highly related and/or could be considered secondary to CC. The rating and ranking task results suggest that both bowel (for example, stool frequency and consistency) and abdominal symptoms (for example, bloating, abdominal pain) comprise patients' most important symptoms. Further, improvements in both bowel and abdominal symptoms would constitute an improvement in patients' CC overall. Abdominal symptoms in CC patients are equal in relevance to bowel symptoms and should also be addressed in clinical trials to fully evaluate treatment benefit.

Value in Health, 2012

Objectives: Previous analyses of patient-reported outcome (PRO) label claims concentrated only on... more Objectives: Previous analyses of patient-reported outcome (PRO) label claims concentrated only on successful label claims. The goal of this research was to explore the reasons why PRO label claims were denied and to compile regulatory feedback regarding the use of PROs in clinical trials. Methods: By using the Food and Drug Administration's Drug Approval Report Web page, all new molecular entities and biologic license applications approved between January 2006 and December 2010 were identified. For identified drug products, medical review sections from publicly available drug approval packages were reviewed to identify PRO end-point status and any Study Endpoints and Label Development team comments. Results: Of the 116 new molecular entities and biologic license applications with accompanying drug approval packages identified and reviewed, 44.8% of the products included PROs as part of the pivotal studies; however, only 24.1% received PRO label claims. Primary reasons for denial included issues of fit for purpose, issues of study design, data quality or interpretation, statistical issues, administrative issues, and lack of demonstrated treatment benefit. Conclusions: Based on drug approval packages, nearly half (45%) of new molecular entitity/biologic license application products in the years 2006 to 2010 included PROs in the clinical trials supporting their approval, yet this rate is not reflected by claims granted. Understanding the nature of PRO claims granted under the current regulatory guidance is important. In addition, a clear understanding of denied claims yields valuable insight into where sponsors may improve implementation of PROs in clinical trials and submission of PRO evidence to increase the likelihood of obtaining PRO label claims.

Quality of Life Research, 2002

The Acne-Specific Quality of Life Questionnaire (Acne-QoL) was developed to measure the impact of... more The Acne-Specific Quality of Life Questionnaire (Acne-QoL) was developed to measure the impact of facial acne across four dimensions of patient quality of life. The main objective of the current study was to evaluate the responsiveness of this instrument. Secondarily, this study provided an opportunity to extend the developer's psychometric validation. The Acne-QoL was utilized in two randomized, double-blind, placebo-controlled studies of the efficacy of Estrostep Ò (norethindrone acetate/ethinyl estradiol) in the treatment of facial acne; a total of 296 Estrostep Ò and 295 placebo patients were evaluated. The Acne-QoL was completed at the beginning, middle (cycle 3), and end (cycle 6) of the 6-month treatment period. The responsiveness of the Acne-QoL was demonstrated through its ability to detect both small (baseline to midstudy) and moderate (baseline to study end) treatment advantages for Estrostep Ò patients. Confirmatory factor analysis supported the subscale structure, and internal consistency estimates were excellent. Convergent and discriminant validity were supported by correlations between Acne-QoL scores and clinical measures that were both in the direction and relative magnitude hypothesized. Finally, item response theory analyses confirmed that each item is highly related to its subscale's latent construct and that each subscale is sensitive across a broad range of the underlying continuum. The results of this evaluation confirm that the Acne-QoL is responsive, internally consistent, and valid.

PharmacoEconomics, 2003

The Acne-Specific Quality of Life Questionnaire (Acne-QoL) is a responsive, reliable and valid in... more The Acne-Specific Quality of Life Questionnaire (Acne-QoL) is a responsive, reliable and valid instrument developed to measure the impact of facial acne across four dimensions of patient QOL. Score changes on this instrument have been used to report statistically significant treatment advantages for a low-dose oral contraceptive (Estrostep, containing norethisterone (norethindrone) acetate (NA) 1mg and ethinylestradiol (EE) [20, 30, 35 mg] as compared with placebo in women with moderate acne vulgaris. However, the question remained if these statistically significant results were also clinically meaningful. To evaluate the statistically significant Acne-QoL benefits observed with NA/EE in terms of their clinical significance, and to compare the three different approaches for defining a minimal clinically important difference (MCID) for the Acne-QoL instrument. Since the optimum method for estimating MCIDs has yet to be established, three different published approaches for determining MCIDs were applied and compared using data from two randomised, double-blind, placebo- controlled studies of the efficacy of NA/EE in the treatment of facial acne. Although the approaches differed substantially, the resulting MCID estimates were comparable. Specifically, the MCID estimates ranged from 0.50-10.3 mean change per item, depending on the domain. The results showed that the statistically significant treatment advantages for NA/EE were also clinically significant. When applied to the change scores present, the results showed that the statistically significant treatment advantages for NA/EE were also clinically significant.

Clinical and Experimental Gastroenterology, 2014

Measures assessing treatment outcomes in previous CC clinical trials have not met the requirement... more Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration's guidance on patient-reported outcomes. Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures. Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed. The CC Symptom Severity Measures demonstrated satisfactory test-retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change. In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.

Value in Health, 2012

In 2004, Willke and colleagues reviewed the efficacy endpoints reported in the labels of new drug... more In 2004, Willke and colleagues reviewed the efficacy endpoints reported in the labels of new drugs approved in the United States from 1997 through 2002 to evaluate the use of patient-reported outcome (PRO) endpoints. Of the labels reviewed, 30% included PROs. Our study aimed to build on this work by describing the current state of PRO label claims granted for new molecular entities (and biologic license applications since February 2006 after the release of the US Food and Drug Administration (FDA) draft PRO guidance. All new molecular entities and biologic license applications approved by the FDA from January 2006 through December 2010 were identified by using the Web page of the FDA Drug Approval Reports. For all identified products, drug approval packages and approved product labels were reviewed to identify PRO endpoint status and to determine the number and type of PRO claims. Of the 116 products identified, 28 (24%) were granted PRO claims; 24 (86%) were for symptoms, and, of these, 9 (38%) claims were pain related. Of the 28 products with PRO claims, a PRO was a primary endpoint for 20 (71%), all symptom related. The FDA continues to approve PRO claims, with 24% of new molecular entities and biologic license applications being granted. Successful PRO label claims over the past 5 years have generally supported treatment benefit for symptoms specified as primary endpoints.

The Patient: Patient-Centered Outcomes Research, 2008

Restless legs syndrome (RLS) affects approximately 10-15% of the general population and has delet... more Restless legs syndrome (RLS) affects approximately 10-15% of the general population and has deleterious effects on sleep and subsequent daytime performance. The disorder may also give rise to long-term complications such as psychological distress and diminished quality of life. The condition is often unrecognized or misdiagnosed, and the magnitude of the effects of RLS on the sizeable proportion of undiagnosed (and therefore untreated) individuals has not previously been evaluated. This study examined the impact of RLS on overall health status, sleep, psychological functioning, work productivity, and daily activities in individuals with diagnosed and in those with undiagnosed (self-reported) RLS. An internet-based survey was conducted on a multimillion-member panel of US adults. Eligible participants were currently experiencing RLS symptoms as determined using established diagnostic criteria. Participants provided information related to self-reported RLS diagnosis, treatment, symptom frequency and severity, and responses to validated instruments (Medical Outcomes study [MOS] Short Form 12, version 2 [SF-12v2], MOS Sleep Scale, Center for Epidemiological Studies Depression Scale [CES-D], Work Productivity and Activity Impairment - General Health Questionnaire [WPAI-GH] and Work Limitations Questionnaire [WLQ]). Analysis of co-variance (ANCOVA) models were developed to evaluate the relationships among symptom severity, diagnosis status, age, and sex, and the impact of RLS. Participants included 702 adults with RLS symptoms. Means for the SF-12v2 scores (physical component score = 35.6, mental component score = 42.6) were at least 1 standard deviation lower than sex- and age-adjusted general population norms. Participants reported poorer sleep quality scores across each MOS Sleep Scale domain, with differences from published norms of >16 points on 100-point scales, as well as approximately 1 hour less sleep per night on average. A majority (64%) met the cut-off score for depression. Compared with population norms, the sample reported greater limitations in time management, physical demands, mental/interpersonal demands, general work output, and usual activities. Symptom intensity and frequency were shown to be the primary predictors of RLS impact on the various outcomes. These results support previous reports that RLS often goes undiagnosed or misdiagnosed. The results of this survey also suggest that regardless of whether RLS is recognized, the burden of the disorder is substantial, implying a need for improved diagnosis and management of RLS.

Quality of Life Research, 2012

Understand the choice of recall period for PRO measures based on intended use, characteristics of... more Understand the choice of recall period for PRO measures based on intended use, characteristics of the disease, treatment, and attributes of studies. Current practice and considerations were reviewed within several disease areas (overactive bladder, menopausal hot flashes, niacin-induced flushing, osteoarthritis pain, irritable bowel symptoms, benign prostatic hyperplasia, and alopecia). Rationales were identified for using different recall periods, including event-driven (immediate), daily, up to weekly, and longer than weekly. This work demonstrates that (1) recall depends on what the PRO measure captures, its intended use, and attributes of the disease and study; (2) within the same disease area, recall can vary depending on the concept or phenomenon of interest; (3) recall must consider patient burden and their ability to easily and accurately recall the information requested; and (4) recall must be consistent with the duration of the trial and the scheduled clinic visits. Shorter recall periods may underestimate symptom burden when symptoms have diurnal or day-to-day fluctuation and may place undue burden on patients. On the other hand, recall intervals that are too long may either over- or underestimate the health state. Therefore, appropriate criteria should be considered given attributes of the disease when selecting an adequate recall period.

Psychology and Aging, 2001

Menopause, 2007

The Menopause Symptoms Treatment Satisfaction Questionnaire, an eight-item questionnaire with a 4... more The Menopause Symptoms Treatment Satisfaction Questionnaire, an eight-item questionnaire with a 4-week recall period, was developed to assess women's satisfaction with treatment for symptoms associated with menopause. We describe the development and initial testing of the scale. Following standard instrument-development procedures, focus groups were conducted with menopausal women experiencing hot flushes to generate potential constructs. Multiple items were drafted to address each construct. An iterative process of cognitive testing, item revision, and item reduction was followed to identify the most appropriate items and optimal response scales. The psychometric validation of the questionnaire used data collected through a multicenter, randomized, double-blind, placebo-controlled study including 543 postmenopausal women. Psychometric analyses were conducted to explore potential item reduction and to address questionnaire scaling and scoring. Internal consistency reliability, construct validity, and discriminant validity of the new scale were also examined. The questionnaire includes items addressing the control of daytime and nighttime hot flushes; effects of treatment on sleep, mood, libido, and cognition; medication tolerability; and overall satisfaction. Correlation analyses indicated that the items are related to each other without being overly redundant and that the item set is best described using a one-factor model. The subsequent scale score demonstrated sound internal consistency reliability, strong construct validity, and good discriminant validity. The results of the development and initial validation are favorable. It is expected that the questionnaire will prove to be a worthwhile tool for assessing women's satisfaction with treatment for menopausal symptoms.

Maturitas, 2007

A population-based study was used to describe healthcare seeking behavior for menopausal symptoms... more A population-based study was used to describe healthcare seeking behavior for menopausal symptoms and treatment among women 40-65 years old in the United States. Participants were recruited into the Menopause Epidemiology Study from the KnowledgePanel(SM), which is selected by random digit dialing and probability sampling from the US population. From this source, 6201 women 40-65 years old were contacted and 4402 women participated. From the 3135 peri- and postmenopausal women, detailed information was obtained on menopausal symptoms, healthcare seeking, medication usage, and symptom relief from the medication. Many women (60%) reported seeking health care for their menopausal symptoms. More than half of these women sought health care in the past 12 months. Vasomotor symptoms were the most frequently reported menopause symptoms across all races/ethnicities, and the most common symptoms discussed with a health care professional. One-third of the women (34%) used only hormone therapies, 12% used complementary and/or alternative medicines, and 16% used both for treatment of menopausal symptoms. This study has shown that a large number of women consult healthcare providers for menopausal symptoms, indicating these symptoms are bothersome. Yet, in the United States, there is considerable variation in the symptomatology, healthcare seeking, and use of therapies for menopausal symptoms across cultures. To alleviate these symptoms women have tried alternative treatments as well as hormone therapies, yet many women did not get complete relief of specific symptoms.

Journal of Psychiatric Research, 2008

Fast-acting anxiolytics are important to patients and society. Measuring early onset, however, re... more Fast-acting anxiolytics are important to patients and society. Measuring early onset, however, requires a sensitive and clinically responsive measure. This study develops and evaluates the psychometric properties of a new patient-reported instrument, the Daily Assessment of Symptoms - Anxiety (DAS-A), designed to detect reduction of anxiety symptoms in patients with Generalized Anxiety Disorder (GAD) during the first week of treatment. Clinician interviews and patient focus groups were conducted to identify relevant constructs; discussions focused on early symptom improvement and meaningful changes in GAD symptoms. The draft questionnaire underwent iterative sets of cognitive interviews to inform item reduction and revision. A double-blind, randomized, placebo-controlled study of paroxetine and lorazepam assessed the performance of the new instrument in GAD patients. Analyses evaluated the structure, reliability, validity, and utility of the instrument. There was consistency across focus groups and clinicians in the description of symptoms that improve first. The final item set was easily understood by interview participants. Factor analyses indicated that a unidimensional structure best described the data. Item-level descriptive statistics, Cronbach's alphas, effect sizes, and validity correlations with other scales were favorable. Most importantly, the DAS-A demonstrated separation of lorazepam from placebo within 24h of first dose and correlated with other anxiety measures. This study resulted in the development of a reliable and valid instrument addressing the DSM-IV dimensions of GAD. The DAS-A is capable of detecting reduction in anxiety symptoms within 24h, making it a desirable measure to include in future trials of fast-acting anxiety medications.

Journal of psychopharmacology (Oxford, England), 2010

Sexual dysfunction is a common but often unrecognized side effect of many antidepressants. Buildi... more Sexual dysfunction is a common but often unrecognized side effect of many antidepressants. Building upon the results of a previous investigation, this study aimed to assess the prevalence and impact of antidepressant-associated sexual dysfunction (AASD) in three European countries. A cross-sectional survey of 704 adults in Germany, Spain, and The Netherlands was used in the study. All participants had recently started taking a selective serotonin reuptake inhibitor or serotonin- noradrenaline reuptake inhibitor. Information about other medications and conditions known to impair sexual functioning was gathered, and changes in sexual functioning and the impact of such changes were assessed. The SF-12 and Arizona Sexual Experience Scale (ASEX) were administered to measure health status and sexual functioning. AASD was defined using ASEX scores and information regarding changes in sexual functioning. ASEX scores generally exceeded the threshold defining sexual dysfunction: 67.2% in the ...

Advances in therapy, 2017

To improve understanding of the diabetic gastroparesis (DGP) patient experience and inform the pa... more To improve understanding of the diabetic gastroparesis (DGP) patient experience and inform the patient-reported outcome measurement strategy for future trials in DGP, qualitative interviews were conducted with participants in a phase 2 clinical trial of a novel DGP treatment. Trial participants were invited to participate in interviews at both the pretreatment visit (PTV) and the end-of-treatment visit (EOTV). The interviews were conducted by experienced qualitative researchers and followed a semistructured interview guide. The PTV interviews focused on patients' DGP symptoms and the impact of DGP on their lives, and the EOTV interviews focused on any symptom changes patients experienced during the trial. Of 90 enrolled trial participants, 78 (86.7%) opted to participate in the interview study. Bloating, stomach fullness, upper abdominal pain, vomiting, constipation, and heartburn or reflux were each reported spontaneously by a majority of the 73 PTV interview participants with ...

Value in Health, 2003

shown to be significantly lower in ED patients than in non-ED subjects (84.4 vs. 89.4, respective... more shown to be significantly lower in ED patients than in non-ED subjects (84.4 vs. 89.4, respectively; p = 0.0109), suggesting an association between self-confidence and erectile dysfunction. CONCLUSION: Assessment of selfconfidence through this Spanish version of the Johnson and McCoy's questionnaire is reliable and valid and provides a new instrument to measure the psychological impact of erectile dysfunction.

PharmacoEconomics, 2003

The Diabetic Foot Ulcer Scale (DFS) provides comprehensive measurement of the impact of diabetic ... more The Diabetic Foot Ulcer Scale (DFS) provides comprehensive measurement of the impact of diabetic foot ulcers on patients' QOL through self-administration of 64 items comprising 15 subscales. To develop and evaluate a short form of the DFS (DFS-SF) to reduce patient burden and the number of outcome measures, and to improve sensitivity to change in clinical condition. The DFS-SF was created through the analysis of data from a double-blind, placebo-controlled, randomised trial of the efficacy and safety of becaplermin (recombinant human platelet-derived growth factor BB) in the treatment of chronic, full-thickness, neuropathic, diabetic foot ulcers. Using these data, items demonstrating poor psychometric properties were eliminated. Exploratory factor analyses were then conducted to develop a new, more parsimonious scaling algorithm that optimised the internal consistency of the new subscales. Finally, data from two additional clinical trials were used to assess replicability of the...

To identify candidate items for deletion from the questionnaire, three steps were taken, utilizin... more To identify candidate items for deletion from the questionnaire, three steps were taken, utilizing data from the two aforementioned clinical trials. ■Pairwise t-tests were conducted, comparing changes on each MEI item for responders and nonresponders, with the goal of identifying items that were not optimally sensitive to differences between these two groups. Responders were subjects whose Hamilton Rating Scale for

The American Journal of Gastroenterology, 2006

Clinical and Experimental Gastroenterology, 2014

While chronic constipation (CC) clinical trials have focused primarily on bowel symptoms (symptom... more While chronic constipation (CC) clinical trials have focused primarily on bowel symptoms (symptoms directly related to bowel movements), abdominal symptoms are also prevalent among patients. The United States Food and Drug Administration's (FDA's) guidance on the use of patient-reported outcome measures to support product approvals or labeling claims recommends that endpoints be developed with direct patient input and include all symptoms important to patients. To identify a comprehensive set of CC symptoms that are important to patients for measurement in clinical trials. Following a targeted literature review to identify CC symptoms previously reported by patients, 28 patient interviews were conducted consistent with the FDA's guidance on patient-reported outcomes. Subsequent to open-ended questions eliciting descriptions of all symptoms, rating and ranking methods were used to identify those of greatest importance to patients. All 67 studies reviewed included bowel symptoms; more than half also addressed at least one abdominal symptom. Interview participants reported 62 potentially distinct concepts: 12 bowel symptoms; 21 abdominal symptoms; and 29 additional symptoms/impacts. Patients' descriptions revealed that many symptom terms were highly related and/or could be considered secondary to CC. The rating and ranking task results suggest that both bowel (for example, stool frequency and consistency) and abdominal symptoms (for example, bloating, abdominal pain) comprise patients' most important symptoms. Further, improvements in both bowel and abdominal symptoms would constitute an improvement in patients' CC overall. Abdominal symptoms in CC patients are equal in relevance to bowel symptoms and should also be addressed in clinical trials to fully evaluate treatment benefit.

Value in Health, 2012

Objectives: Previous analyses of patient-reported outcome (PRO) label claims concentrated only on... more Objectives: Previous analyses of patient-reported outcome (PRO) label claims concentrated only on successful label claims. The goal of this research was to explore the reasons why PRO label claims were denied and to compile regulatory feedback regarding the use of PROs in clinical trials. Methods: By using the Food and Drug Administration's Drug Approval Report Web page, all new molecular entities and biologic license applications approved between January 2006 and December 2010 were identified. For identified drug products, medical review sections from publicly available drug approval packages were reviewed to identify PRO end-point status and any Study Endpoints and Label Development team comments. Results: Of the 116 new molecular entities and biologic license applications with accompanying drug approval packages identified and reviewed, 44.8% of the products included PROs as part of the pivotal studies; however, only 24.1% received PRO label claims. Primary reasons for denial included issues of fit for purpose, issues of study design, data quality or interpretation, statistical issues, administrative issues, and lack of demonstrated treatment benefit. Conclusions: Based on drug approval packages, nearly half (45%) of new molecular entitity/biologic license application products in the years 2006 to 2010 included PROs in the clinical trials supporting their approval, yet this rate is not reflected by claims granted. Understanding the nature of PRO claims granted under the current regulatory guidance is important. In addition, a clear understanding of denied claims yields valuable insight into where sponsors may improve implementation of PROs in clinical trials and submission of PRO evidence to increase the likelihood of obtaining PRO label claims.

Quality of Life Research, 2002

The Acne-Specific Quality of Life Questionnaire (Acne-QoL) was developed to measure the impact of... more The Acne-Specific Quality of Life Questionnaire (Acne-QoL) was developed to measure the impact of facial acne across four dimensions of patient quality of life. The main objective of the current study was to evaluate the responsiveness of this instrument. Secondarily, this study provided an opportunity to extend the developer's psychometric validation. The Acne-QoL was utilized in two randomized, double-blind, placebo-controlled studies of the efficacy of Estrostep Ò (norethindrone acetate/ethinyl estradiol) in the treatment of facial acne; a total of 296 Estrostep Ò and 295 placebo patients were evaluated. The Acne-QoL was completed at the beginning, middle (cycle 3), and end (cycle 6) of the 6-month treatment period. The responsiveness of the Acne-QoL was demonstrated through its ability to detect both small (baseline to midstudy) and moderate (baseline to study end) treatment advantages for Estrostep Ò patients. Confirmatory factor analysis supported the subscale structure, and internal consistency estimates were excellent. Convergent and discriminant validity were supported by correlations between Acne-QoL scores and clinical measures that were both in the direction and relative magnitude hypothesized. Finally, item response theory analyses confirmed that each item is highly related to its subscale's latent construct and that each subscale is sensitive across a broad range of the underlying continuum. The results of this evaluation confirm that the Acne-QoL is responsive, internally consistent, and valid.

PharmacoEconomics, 2003

The Acne-Specific Quality of Life Questionnaire (Acne-QoL) is a responsive, reliable and valid in... more The Acne-Specific Quality of Life Questionnaire (Acne-QoL) is a responsive, reliable and valid instrument developed to measure the impact of facial acne across four dimensions of patient QOL. Score changes on this instrument have been used to report statistically significant treatment advantages for a low-dose oral contraceptive (Estrostep, containing norethisterone (norethindrone) acetate (NA) 1mg and ethinylestradiol (EE) [20, 30, 35 mg] as compared with placebo in women with moderate acne vulgaris. However, the question remained if these statistically significant results were also clinically meaningful. To evaluate the statistically significant Acne-QoL benefits observed with NA/EE in terms of their clinical significance, and to compare the three different approaches for defining a minimal clinically important difference (MCID) for the Acne-QoL instrument. Since the optimum method for estimating MCIDs has yet to be established, three different published approaches for determining MCIDs were applied and compared using data from two randomised, double-blind, placebo- controlled studies of the efficacy of NA/EE in the treatment of facial acne. Although the approaches differed substantially, the resulting MCID estimates were comparable. Specifically, the MCID estimates ranged from 0.50-10.3 mean change per item, depending on the domain. The results showed that the statistically significant treatment advantages for NA/EE were also clinically significant. When applied to the change scores present, the results showed that the statistically significant treatment advantages for NA/EE were also clinically significant.

Clinical and Experimental Gastroenterology, 2014

Measures assessing treatment outcomes in previous CC clinical trials have not met the requirement... more Measures assessing treatment outcomes in previous CC clinical trials have not met the requirements described in the US Food and Drug Administration's guidance on patient-reported outcomes. Psychometric analyses using data from one Phase IIb study and two Phase III trials of linaclotide for the treatment of chronic constipation (CC) were conducted to document the measurement properties of patient-reported CC Symptom Severity Measures. Each study had a multicenter, randomized, double-blind, placebo-controlled, parallel-group design, comparing placebo to four doses of oral linaclotide taken once daily for 4 weeks in the Phase IIb dose-ranging study (n=307) and to two doses of linaclotide taken once daily for 12 weeks in the Phase III trials (n=1,272). The CC Symptom Severity Measures addressing bowel function (Bowel Movement Frequency, Stool Consistency, Straining) and abdominal symptoms (Bloating, Abdominal Discomfort, Abdominal Pain) were administered daily using interactive voice-response system technology. Intraclass correlations, Pearson correlations, factor analyses, F-tests, and effect sizes were computed. The CC Symptom Severity Measures demonstrated satisfactory test-retest reliability and construct validity. Factor analyses indicated one factor for abdominal symptoms and another for bowel symptoms. Known-groups F-tests substantiated the discriminating ability of the CC Symptom Severity Measures. Responsiveness statistics were moderate to strong, indicating that these measures are capable of detecting change. In large studies of CC patients, linaclotide significantly improved abdominal and bowel symptoms. These psychometric analyses support the reliability, validity, discriminating ability, and responsiveness of the CC Symptom Severity Measures for evaluating treatment outcomes in the linaclotide clinical studies.

Value in Health, 2012

In 2004, Willke and colleagues reviewed the efficacy endpoints reported in the labels of new drug... more In 2004, Willke and colleagues reviewed the efficacy endpoints reported in the labels of new drugs approved in the United States from 1997 through 2002 to evaluate the use of patient-reported outcome (PRO) endpoints. Of the labels reviewed, 30% included PROs. Our study aimed to build on this work by describing the current state of PRO label claims granted for new molecular entities (and biologic license applications since February 2006 after the release of the US Food and Drug Administration (FDA) draft PRO guidance. All new molecular entities and biologic license applications approved by the FDA from January 2006 through December 2010 were identified by using the Web page of the FDA Drug Approval Reports. For all identified products, drug approval packages and approved product labels were reviewed to identify PRO endpoint status and to determine the number and type of PRO claims. Of the 116 products identified, 28 (24%) were granted PRO claims; 24 (86%) were for symptoms, and, of these, 9 (38%) claims were pain related. Of the 28 products with PRO claims, a PRO was a primary endpoint for 20 (71%), all symptom related. The FDA continues to approve PRO claims, with 24% of new molecular entities and biologic license applications being granted. Successful PRO label claims over the past 5 years have generally supported treatment benefit for symptoms specified as primary endpoints.

The Patient: Patient-Centered Outcomes Research, 2008

Restless legs syndrome (RLS) affects approximately 10-15% of the general population and has delet... more Restless legs syndrome (RLS) affects approximately 10-15% of the general population and has deleterious effects on sleep and subsequent daytime performance. The disorder may also give rise to long-term complications such as psychological distress and diminished quality of life. The condition is often unrecognized or misdiagnosed, and the magnitude of the effects of RLS on the sizeable proportion of undiagnosed (and therefore untreated) individuals has not previously been evaluated. This study examined the impact of RLS on overall health status, sleep, psychological functioning, work productivity, and daily activities in individuals with diagnosed and in those with undiagnosed (self-reported) RLS. An internet-based survey was conducted on a multimillion-member panel of US adults. Eligible participants were currently experiencing RLS symptoms as determined using established diagnostic criteria. Participants provided information related to self-reported RLS diagnosis, treatment, symptom frequency and severity, and responses to validated instruments (Medical Outcomes study [MOS] Short Form 12, version 2 [SF-12v2], MOS Sleep Scale, Center for Epidemiological Studies Depression Scale [CES-D], Work Productivity and Activity Impairment - General Health Questionnaire [WPAI-GH] and Work Limitations Questionnaire [WLQ]). Analysis of co-variance (ANCOVA) models were developed to evaluate the relationships among symptom severity, diagnosis status, age, and sex, and the impact of RLS. Participants included 702 adults with RLS symptoms. Means for the SF-12v2 scores (physical component score = 35.6, mental component score = 42.6) were at least 1 standard deviation lower than sex- and age-adjusted general population norms. Participants reported poorer sleep quality scores across each MOS Sleep Scale domain, with differences from published norms of >16 points on 100-point scales, as well as approximately 1 hour less sleep per night on average. A majority (64%) met the cut-off score for depression. Compared with population norms, the sample reported greater limitations in time management, physical demands, mental/interpersonal demands, general work output, and usual activities. Symptom intensity and frequency were shown to be the primary predictors of RLS impact on the various outcomes. These results support previous reports that RLS often goes undiagnosed or misdiagnosed. The results of this survey also suggest that regardless of whether RLS is recognized, the burden of the disorder is substantial, implying a need for improved diagnosis and management of RLS.

Quality of Life Research, 2012

Understand the choice of recall period for PRO measures based on intended use, characteristics of... more Understand the choice of recall period for PRO measures based on intended use, characteristics of the disease, treatment, and attributes of studies. Current practice and considerations were reviewed within several disease areas (overactive bladder, menopausal hot flashes, niacin-induced flushing, osteoarthritis pain, irritable bowel symptoms, benign prostatic hyperplasia, and alopecia). Rationales were identified for using different recall periods, including event-driven (immediate), daily, up to weekly, and longer than weekly. This work demonstrates that (1) recall depends on what the PRO measure captures, its intended use, and attributes of the disease and study; (2) within the same disease area, recall can vary depending on the concept or phenomenon of interest; (3) recall must consider patient burden and their ability to easily and accurately recall the information requested; and (4) recall must be consistent with the duration of the trial and the scheduled clinic visits. Shorter recall periods may underestimate symptom burden when symptoms have diurnal or day-to-day fluctuation and may place undue burden on patients. On the other hand, recall intervals that are too long may either over- or underestimate the health state. Therefore, appropriate criteria should be considered given attributes of the disease when selecting an adequate recall period.

Psychology and Aging, 2001

Menopause, 2007

The Menopause Symptoms Treatment Satisfaction Questionnaire, an eight-item questionnaire with a 4... more The Menopause Symptoms Treatment Satisfaction Questionnaire, an eight-item questionnaire with a 4-week recall period, was developed to assess women's satisfaction with treatment for symptoms associated with menopause. We describe the development and initial testing of the scale. Following standard instrument-development procedures, focus groups were conducted with menopausal women experiencing hot flushes to generate potential constructs. Multiple items were drafted to address each construct. An iterative process of cognitive testing, item revision, and item reduction was followed to identify the most appropriate items and optimal response scales. The psychometric validation of the questionnaire used data collected through a multicenter, randomized, double-blind, placebo-controlled study including 543 postmenopausal women. Psychometric analyses were conducted to explore potential item reduction and to address questionnaire scaling and scoring. Internal consistency reliability, construct validity, and discriminant validity of the new scale were also examined. The questionnaire includes items addressing the control of daytime and nighttime hot flushes; effects of treatment on sleep, mood, libido, and cognition; medication tolerability; and overall satisfaction. Correlation analyses indicated that the items are related to each other without being overly redundant and that the item set is best described using a one-factor model. The subsequent scale score demonstrated sound internal consistency reliability, strong construct validity, and good discriminant validity. The results of the development and initial validation are favorable. It is expected that the questionnaire will prove to be a worthwhile tool for assessing women's satisfaction with treatment for menopausal symptoms.

Maturitas, 2007

A population-based study was used to describe healthcare seeking behavior for menopausal symptoms... more A population-based study was used to describe healthcare seeking behavior for menopausal symptoms and treatment among women 40-65 years old in the United States. Participants were recruited into the Menopause Epidemiology Study from the KnowledgePanel(SM), which is selected by random digit dialing and probability sampling from the US population. From this source, 6201 women 40-65 years old were contacted and 4402 women participated. From the 3135 peri- and postmenopausal women, detailed information was obtained on menopausal symptoms, healthcare seeking, medication usage, and symptom relief from the medication. Many women (60%) reported seeking health care for their menopausal symptoms. More than half of these women sought health care in the past 12 months. Vasomotor symptoms were the most frequently reported menopause symptoms across all races/ethnicities, and the most common symptoms discussed with a health care professional. One-third of the women (34%) used only hormone therapies, 12% used complementary and/or alternative medicines, and 16% used both for treatment of menopausal symptoms. This study has shown that a large number of women consult healthcare providers for menopausal symptoms, indicating these symptoms are bothersome. Yet, in the United States, there is considerable variation in the symptomatology, healthcare seeking, and use of therapies for menopausal symptoms across cultures. To alleviate these symptoms women have tried alternative treatments as well as hormone therapies, yet many women did not get complete relief of specific symptoms.

Journal of Psychiatric Research, 2008

Fast-acting anxiolytics are important to patients and society. Measuring early onset, however, re... more Fast-acting anxiolytics are important to patients and society. Measuring early onset, however, requires a sensitive and clinically responsive measure. This study develops and evaluates the psychometric properties of a new patient-reported instrument, the Daily Assessment of Symptoms - Anxiety (DAS-A), designed to detect reduction of anxiety symptoms in patients with Generalized Anxiety Disorder (GAD) during the first week of treatment. Clinician interviews and patient focus groups were conducted to identify relevant constructs; discussions focused on early symptom improvement and meaningful changes in GAD symptoms. The draft questionnaire underwent iterative sets of cognitive interviews to inform item reduction and revision. A double-blind, randomized, placebo-controlled study of paroxetine and lorazepam assessed the performance of the new instrument in GAD patients. Analyses evaluated the structure, reliability, validity, and utility of the instrument. There was consistency across focus groups and clinicians in the description of symptoms that improve first. The final item set was easily understood by interview participants. Factor analyses indicated that a unidimensional structure best described the data. Item-level descriptive statistics, Cronbach's alphas, effect sizes, and validity correlations with other scales were favorable. Most importantly, the DAS-A demonstrated separation of lorazepam from placebo within 24h of first dose and correlated with other anxiety measures. This study resulted in the development of a reliable and valid instrument addressing the DSM-IV dimensions of GAD. The DAS-A is capable of detecting reduction in anxiety symptoms within 24h, making it a desirable measure to include in future trials of fast-acting anxiety medications.

Journal of psychopharmacology (Oxford, England), 2010

Sexual dysfunction is a common but often unrecognized side effect of many antidepressants. Buildi... more Sexual dysfunction is a common but often unrecognized side effect of many antidepressants. Building upon the results of a previous investigation, this study aimed to assess the prevalence and impact of antidepressant-associated sexual dysfunction (AASD) in three European countries. A cross-sectional survey of 704 adults in Germany, Spain, and The Netherlands was used in the study. All participants had recently started taking a selective serotonin reuptake inhibitor or serotonin- noradrenaline reuptake inhibitor. Information about other medications and conditions known to impair sexual functioning was gathered, and changes in sexual functioning and the impact of such changes were assessed. The SF-12 and Arizona Sexual Experience Scale (ASEX) were administered to measure health status and sexual functioning. AASD was defined using ASEX scores and information regarding changes in sexual functioning. ASEX scores generally exceeded the threshold defining sexual dysfunction: 67.2% in the ...