Can we use social media to support content validity of patient-reported outcome instruments in medical product development?

We report a panel designed to open a dialog between pharmaceutical sponsors, regulatory reviewers, and other stakeholders regarding the use of social media to collect data to support the content validity of patient-reported outcome instruments in the context of medical product labeling. Multiple stakeholder perspectives were brought together to better understand the issues encountered in pursuing social media as a form of data collection to support content validity. Presenters represented a pharmaceutical sponsor of clinical trials, a regulatory reviewer from the Food and Drug Administration, and an online data platform provider. Each presenter shared its perspective on the advantages and disadvantages of using social media to collect this type of information. There was consensus that there is great potential for using social media for this purpose. There remain, however, unanswered questions that need to be addressed such as identifying which type of social media is most appropriate for data collection and ensuring that participants are representative of the target population while maintaining the advantages of anonymity provided by online platforms. The use of social media to collect evidence of content validity holds much promise. Clarification of issues that need to be addressed and accumulation of empirical evidence to address these questions are essential to moving forward.

Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease. METHODS: We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036. FINDINGS: We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). INTERPRETATION: Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. FUNDING: Janssen Research & Development.

Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial.

BACKGROUND: Bone metastases are a major cause of morbidity in metastatic castration-resistant prostate cancer. Abiraterone acetate potently disrupts intracrine androgen receptor signalling pathways implicated in the progression of the disease, including bone metastases. We assessed data for pain control and skeletal-related events prospectively collected as part of the randomised, phase 3 COU-AA-301 trial of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with metastatic castration-resistant prostate cancer after docetaxel chemotherapy. METHODS: The COU-AA-301 trial enrolled patients with metastatic castration-resistant prostate cancer in whom one or two lines of chemotherapy (one docetaxel based) had been unsuccessful and who had Eastern Cooperative Oncology Group performance statuses of 2 or less. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form questionnaire at baseline, day 15 of cycle 1, and day 1 of each treatment cycle thereafter until discontinuation. We assessed, with prospectively defined response criteria that incorporated analgesic use, clinically meaningful changes in pain intensity and interference with daily living. We measured time to first occurrence of skeletal-related events, which we defined as pathological fracture, spinal cord compression, palliative radiation to bone, or bone surgery, and regularly assessed them throughout the study. Pain palliation was assessed in patients who had clinically significant baseline pain, whereas all other analyses were done in the overall intention-to-treat population. COU-AA-301 is registered with ClinicalTrials.gov, number NCT00638690. FINDINGS: Median follow-up was 20·2 months (IQR 18·4-22·1). In patients with clinically significant pain at baseline, abiraterone acetate and prednisone resulted in significantly more palliation (157 of 349 [45·0%] patients vs 47 of 163 [28·8%]; p=0·0005) and faster palliation (median time to palliation 5·6 months [95% CI 3·7-9·2] vs 13·7 months [5·4-not estimable]; p=0·0018) of pain intensity than did prednisone only. Palliation of pain interference (134 of 223 [60·1%] vs 38 of 100 [38·0%], p=0·0002; median time to palliation of pain interference 1·0 months [95% CI 0·9-1·9] vs 3·7 months [2·7-not estimable], p=0·0004) and median duration of palliation of pain intensity (4·2 months [95% CI 3·0-4·9] vs 2·1 months [1·4-3·7]; p=0·0056) were significantly better with abiraterone acetate and prednisone than with prednisone only. In the overall population, median time to occurrence of first skeletal-related event was significantly longer with abiraterone acetate and prednisone than with prednisone only (25·0 months [95% CI 25·0-not estimable] vs 20·3 months [16·9-not estimable]; p=0·0001). INTERPRETATION: In patients with metastatic castration-resistant prostate cancer previously treated with docetaxel, abiraterone acetate and prednisone offer significant benefits compared with prednisone alone in terms of pain relief, delayed pain progression, and prevention of skeletal-related events. FUNDING: Janssen Research & Development and Janssen Global Services.

Validation of a bowel function diary for assessing opioid-induced constipation.

OBJECTIVES: Validated tools to assess opioid-induced constipation (OIC) are needed. The aim of this study was to validate a Bowel Function Diary (BF-Diary) that includes patient-reported outcomes (PROs) associated with OIC. METHODS: In a multicenter, observational study, opioid-naive or recently untreated (≥ 14 days) adults with nonmalignant, chronic pain who were prescribed oral opioid and usual care completed an electronic diary daily for 2 weeks. Test-retest reliability was assessed. Validity was evaluated for two composite end points--number of spontaneous bowel movements (SBM) and complete SBMs (SCBM)--and for other relevant PROs. RESULTS: Of 238 patients (mean age 54 years, 58% women), 63% reported constipation. The intraclass correlation coefficient for numbers of SBM and SCBM, and other BF-Diary PROs was ≥ 0.71 for all items except stool consistency. Mean (s.d.) number of SBM per week was significantly less in each week for patients with vs. without constipation (5.6 ± 4.3 and 7.3 ± 3.6, respectively over week 1, P=0.0012; similarly, P=0.0096 over week 2). Validity of individual items in the BF-Diary was supported (P<0.05, stool consistency; P<0.0001, all others). CONCLUSIONS: BF-Diary items are generally reliable and valid assessments for OIC research. Specifically, number of SBM is a valid measure for differentiating opioid-treated patients with and without constipation.

Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials.

INTRODUCTION: Dapoxetine has been evaluated for the on-demand treatment of premature ejaculation (PE) in five phase 3 studies in various populations worldwide and has recently been approved in several countries. AIM: To present integrated efficacy and safety data from phase 3 trials of dapoxetine. METHODS: Data were from five randomized, multicenter, double-blind, placebo-controlled studies conducted in over 25 countries. Men (N=6,081)≥18 years who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE; four studies required a baseline intravaginal ejaculatory latency time (IELT) of ≤2 minutes. Dapoxetine 30 and 60 mg on demand (prn; 1-3 hours before intercourse) were evaluated for either 12 or 24 weeks in four studies; one study evaluated dapoxetine 60 mg daily (qd; included in safety assessments only) or prn for 9 weeks. MAIN OUTCOME MEASURES: End points included stopwatch-measured IELT, Premature Ejaculation Profile (PEP) items, clinical global impression of change (CGIC) in PE, and adverse events (AEs). RESULTS: Average IELT (mean [standard deviation], geometric mean [standard error]) increased from baseline (across groups, 0.9 [0.49] minutes, 0.8 [1.01] minutes) to a significantly greater extent with dapoxetine 30 (3.1 [3.91] minutes, 2.0 [1.03] minutes) and 60 mg (3.6 [3.85] minutes, 2.3 [1.03] minutes) vs. placebo (1.9 [2.43] minutes, 1.3 [1.02] minutes; P<0.001 for all) at week 12 (geometric mean fold increase, 2.5, 3.0, and 1.6, respectively). All PEP items and CGIC improved significantly with both doses of dapoxetine vs. placebo (P<0.001 for all). The most common AEs included nausea, dizziness, and headache, and evaluation of validated instruments demonstrated no anxiety, akathisia, suicidality, or changes in mood with dapoxetine use and no discontinuation syndrome following abrupt withdrawal. CONCLUSIONS: In this diverse population, dapoxetine significantly improved all aspects of PE and was generally well tolerated.

Treatment of premature ejaculation in the Asia-Pacific region: results from a phase III double-blind, parallel-group study of dapoxetine.

INTRODUCTION: Dapoxetine is a short-acting selective serotonin reuptake inhibitor that was recently approved for the on-demand treatment of premature ejaculation (PE). AIM: To evaluate the efficacy and safety of dapoxetine 30 mg and 60 mg on demand (prn) in men with PE from the Asia-Pacific region. METHODS: This randomized, double-blind, parallel-group, placebo-controlled trial enrolled men who were 18 years or older; in a monogamous, heterosexual relationship for at least 6 months; met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision, criteria for PE for at least 6 months; and had an intravaginal ejaculatory latency time (IELT) of 2 minutes or less in at least 75% of sexual intercourse episodes. Subjects received placebo, dapoxetine 30 mg, or dapoxetine 60 mg prn (1-3 hours before intercourse) for 12 weeks. MAIN OUTCOME MEASURES: Stopwatch-measured Average IELT, the Premature Ejaculation Profile (PEP), Clinical Global Impression (CGI) of change in PE, treatment-emergent adverse events (TEAEs). RESULTS: Of the 1,067 subjects randomized, 858 completed the study. Mean Average IELT increased from approximately 1.1 minutes at baseline (across groups) to 2.4, 3.9, and 4.2 minutes with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively, and geometric mean Average IELT increased from approximately 0.9 minutes at baseline (across groups) to 1.8, 2.7, and 3.1 minutes, respectively (fold-increases of 2.0, 2.8, and 3.3, respectively). All PEP measures and the CGI of change were significantly improved with dapoxetine vs. placebo at study endpoint (P < or = 0.005 for all). The most common TEAEs with dapoxetine included nausea, dizziness, somnolence, headache, vomiting, diarrhea, and nasopharyngitis; TEAEs led to discontinuation in 0.3%, 1.7%, and 5.1% of subjects with placebo, dapoxetine 30 mg, and dapoxetine 60 mg, respectively. CONCLUSIONS: Dapoxetine treatment significantly prolonged IELT and improved PEP measures and was generally well tolerated in men with PE in the Asia-Pacific region.

Validity of the patient-reported Clinical Global Impression of Change as a measure of treatment response in men with premature ejaculation.

INTRODUCTION: The Clinical Global Impression of Change (CGIC) measures have high utility in clinical practice. However, it is unknown whether the CGIC is valued for assessing premature ejaculation (PE) symptoms and/or the relationship between CGIC and other validated PE patient-reported measures. AIM: The study aims to assess the validity of the patient-reported CGIC measure in men with PE and to examine the relationship between CGIC ratings and assessments of control, satisfaction, personal distress, and interpersonal difficulty. METHODS: Data from a randomized, double-blind, 24-week phase 3 trial in 1,162 men with PE who received dapoxetine (30 mg or 60 mg) or placebo on demand provided the basis for the analysis. Patients were ≥18 years, in a stable monogamous relationship for ≥6 months, met the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision criteria for PE for ≥6 months, and had an intravaginal ejaculatory latency time (IELT) ≤2 minutes in ≥75% of intercourse episodes. MAIN OUTCOME MEASURES: The CGIC asked patients to rate improvement or worsening of their PE compared with the start of the study using a 7-point response scale; other patient-reported measures were control over ejaculation, satisfaction with sexual intercourse, interpersonal difficulty, and personal distress related to ejaculation. Stopwatch-measured IELT was recorded. Associations between CGIC and change in other measures at study end point were assessed. RESULTS: The magnitude of IELT increased for each category of improvement on the CGIC: 1.63, 4.03, and 7.15 minutes for slightly better, better, and much better, respectively. Higher CGIC ratings were correlated with greater improvement in control (r = 0.73), satisfaction (r = 0.62), greater reduction in distress (r = -0.52), and interpersonal difficulty (r = -0.39). Total variance accounted for was 57.4%: control (48.7%), satisfaction (4.5%), IELT (2.8%), and distress (1.15%). CONCLUSIONS: The analyses support the validity of the CGIC measure in men with PE. The CGIC can provide clinicians in practice with a valid and brief outcome assessment of their patient's condition.

The Premature Ejaculation Profile: validation of self-reported outcome measures for research and practice.

OBJECTIVE: To evaluate the reliability and validity of the Premature Ejaculation Profile (PEP), a self-reported outcome instrument for evaluating domains of PE and its treatment, comprised of four single-item measures, a profile, and an index score. SUBJECTS AND METHODS: Data were from men participating in observational studies in the USA (PE, 207 men; non-PE, 1380) and Europe (PE, 201; non-PE, 914) and from men with PE (1238) participating in a phase III randomized, placebo-controlled clinical trial of dapoxetine. The PEP contains four measures: perceived control over ejaculation, personal distress related to ejaculation, satisfaction with sexual intercourse, and interpersonal difficulty related to ejaculation, each assessed on five-point response scales. Test-retest reliability, known-groups validity, and ability to detect a patient-reported global impression of change (PGI) in condition were evaluated for the individual PEP measures and a PEP index score (the mean of all four measures). Profile analysis was conducted using multivariate analysis of variance. RESULTS: All PEP measures showed acceptable reliability (intraclass correlation coefficients ranged from 0.66 to 0.83) and mean scores for all measures differed significantly between PE and non-PE groups (P < 0.001). Men who reported a reduction in PE with treatment in the phase III trial had significantly greater scores on each of the four measures. The PEP profiles of men with and without PE differed significantly (P < 0.001) in both observational studies; higher levels of PGI were associated with higher PEP profiles (P < 0.001). The PEP index score also showed acceptable reliability and was significantly different between the PE and non-PE groups (P < 0.001). Men who reported an improvement in PE with treatment in the phase III trial had significantly greater PEP index scores. In the phase III trial, nausea was the most common adverse event with dapoxetine. CONCLUSION: The PEP provides a reliable, valid, and interpretable measure for use in monitoring outcomes of men with PE.

Use of existing patient-reported outcome (PRO) instruments and their modification: the ISPOR Good Research Practices for Evaluating and Documenting Content Validity for the Use of Existing Instruments and Their Modification PRO Task Force Report.

BACKGROUND: Patient-reported outcome (PRO) instruments are used to evaluate the effect of medical products on how patients feel or function. This article presents the results of an ISPOR task force convened to address good clinical research practices for the use of existing or modified PRO instruments to support medical product labeling claims. The focus of the article is on content validity, with specific reference to existing or modified PRO instruments, because of the importance of content validity in selecting or modifying an existing PRO instrument and the lack of consensus in the research community regarding best practices for establishing and documenting this measurement property. METHODS: Topics addressed in the article include: definition and general description of content validity; PRO concept identification as the important first step in establishing content validity; instrument identification and the initial review process; key issues in qualitative methodology; and potential threats to content validity, with three case examples used to illustrate types of threats and how they might be resolved. A table of steps used to identify and evaluate an existing PRO instrument is provided, and figures are used to illustrate the meaning of content validity in relationship to instrument development and evaluation. RESULTS & RECOMMENDATIONS: Four important threats to content validity are identified: unclear conceptual match between the PRO instrument and the intended claim, lack of direct patient input into PRO item content from the target population in which the claim is desired, no evidence that the most relevant and important item content is contained in the instrument, and lack of documentation to support modifications to the PRO instrument. In some cases, careful review of the threats to content validity in a specific application may be reduced through additional well documented qualitative studies that specifically address the issue of concern. CONCLUSION: Published evidence of the content validity of a PRO instrument for an intended application is often limited. Such evidence is, however, important to evaluating the adequacy of a PRO instrument for the intended application. This article provides an overview of key issues involved in assessing and documenting content validity as it relates to using existing instruments in the drug approval process.

Perceived control over ejaculation is central to treatment benefit in men with premature ejaculation: results from phase III trials with dapoxetine.

OBJECTIVES: To assess the utility of perceived control over ejaculation ('control') in the evaluation of treatment benefit in men with premature ejaculation (PE), and to compare effects associated with a two-category or greater increase in this variable between men receiving dapoxetine and placebo. PATIENTS AND METHODS: This subanalysis used combined data from all treatment groups in an integrated analysis of two identically designed, 12-week, double-blind, randomized, placebo-controlled trials of dapoxetine. Men (2614) met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision) criteria for PE, had a stopwatch-measured intravaginal ejaculatory latency time (IELT) of < or =2 min in > or =75% of events in a 2-week baseline period, and self-reported moderate or severe PE. Men received placebo or dapoxetine 30 or 60 mg, 1-3 h before intercourse. The stopwatch-measured IELT was recorded for each episode; the patient-reported global impression of change (PGI; 7-point scale, 'much worse' to 'much better'), control and satisfaction with sexual intercourse (5-point scales, 'very poor' to 'very good') were assessed monthly. The utility of a two-category or greater increase in control was evaluated by examining the relationship of this variable with IELT and satisfaction with sexual intercourse. RESULTS: Of 2341 men with baseline and endpoint assessments, 96.8% reported 'very poor' or 'poor' control at baseline, and 748 (32%) reported a two-category or greater increase in control after treatment. More than 95% of those men rated their PE as 'slightly better', 'better', or 'much better' on the PGI; 67.1% gave ratings of 'better' or 'much better.' They also had greater improvements in IELT than men with less than a two-category increase in control, with a mean (sd) change from baseline of 3.7 (4.3) vs 0.77 (1.8) min, respectively, and a greater percentage reported good or very good satisfaction with sexual intercourse than men with less than a two-category increase in control (74% vs 19%, respectively). Nausea, headache and upper respiratory tract infection were the most common adverse events reported by men with a two-category or greater increase in control (15.8%, 7.4% and 6.6%, respectively) and those without (8.5%, 5.5% and 6.5%, respectively). The proportions of men with a two-category or greater increase in control with dapoxetine 30 and 60 mg were 36.3% and 44.5%, respectively (vs 15% with placebo). CONCLUSIONS: A two-category or greater increase in control (5-point scale) is useful for assessing the treatment benefit in men with PE; it corresponds with improvements in the man's perception of his condition, substantially greater prolongation of IELT, and higher levels of satisfaction with sexual intercourse.

Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.

UNLABELLED: A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed. PERSPECTIVE: Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.

Characterizing the burden of premature ejaculation from a patient and partner perspective: a multi-country qualitative analysis.

BACKGROUND: Premature ejaculation (PE) is a common sexual dysfunction among men which affects men and their partners. Little qualitative data are available to characterize the impact of PE on men and their partners about ejaculatory control, sexual satisfaction, emotional distress and relationships. The objective of this study was to assess the impact of PE from the perspective of men with PE and the female partners of men with PE on their sexual experience, distress and relationships. METHODS: Qualitative data were collected through 14 focus groups in the US and through one-on-one interviews in the US, UK, Italy, France, Germany, and Poland. Study participants included heterosexual men with PE and female partners of males with PE. All participants were asked about how PE affects their daily life, including emotional impacts. One-on-one interviews also included obtaining feedback on the male and female versions of 4-single item measures of PE focusing on ejaculatory control, satisfaction with intercourse, interpersonal distress, and relationship difficulty. RESULTS: Participants included 172 males with PE and 67 female partners of men with PE. Lack of control over ejaculation and dissatisfaction with intercourse emerged as central themes of PE. Lack of ejaculatory control resulted in greater dissatisfaction and greater emotional distress, including feelings of inadequacy, disappointment, and anxiety. Continued PE ultimately leads to greater problems with partners and often disrupts partner relationships. Participants indicated that PE was keeping them from attaining complete intimacy in their relationships even when their partners were generally satisfied with sexual intercourse. Impacts of PE on sexual satisfaction, emotional distress and partner relationships were consistent across countries. Feedback on the single-item PE measures confirmed relevance of the item content and further confirmed major themes identified from the qualitative data. CONCLUSION: This qualitative study provides valuable insights on the substantial psychosocial burden of PE in the US and the Europe. Lack of control over ejaculation resulted in dissatisfaction with intercourse and increased emotional distress, and wide-ranging impact for both men with PE and their partners of men with PE. Data collected in this study may help inform the content of new patient reported measures for use in PE research.

Patient-reported outcomes: conceptual issues.

There is a broad agreement that patient-reported outcome (PRO) assessment in health care should proceed from a strong conceptual basis, with rationales clearly articulated in advance concerning what is to be measured and how this is to be accomplished. The representation of the patient's perspective has been part of clinical trials for some time; but the formalization of, and broader emphasis on PROs has become increasingly important with the release of the draft guidance for industry on patient-reported outcomes. In response, we address the challenges in constructing the conceptual foundations for PRO assessment to support drug product labeling claims submitted to regulatory agencies worldwide. After discussing what constitutes a PRO concept and an adequate basis for framing a PRO assessment, we examine the consequences of choosing PRO instruments without reference to a well-established conceptual framework for measurement. Then we illustrate through a hypothetical example the important interplay between the sponsor's proposed product claim, the corresponding conceptual model that depicts hypotheses involving the PRO concept(s) in the claim, and the resulting conceptual framework(s) for measurement to guide instrument selection and psychometric analyses. We discuss how these conceptual issues may vary or evolve over time depending on the phase of product development. As the science of PRO measurement continues to develop and experience accumulates, a consensus may emerge on how best to articulate the conceptual basis of PRO measurement for purposes of product labeling and regulation. In the meantime, one point is imminently clear: in regulatory decisions expected to affect not only the quantity but the quality of life, it is imperative to incorporate the patient's own perspective on the illness experience and the effects of therapy.

The Mayo Clinic manuscript series relative to the discussion, dissemination, and operationalization of the Food and Drug Administration guidance on patient-reported outcomes.

Patient-reported outcomes (PROs) have become increasingly prevalent in clinical research and practice. On February 2, 2006, the Food and Drug Administration (FDA) released a draft guidance document with respect to incorporating PROs into clinical research endeavors which include FDA involvement. Researchers at the Mayo Clinic worked with FDA personnel and experts from academia, industry, clinical research, and clinical practice to facilitate discussion, dissemination, and operationalization of the FDA guidance document. This article introduces a manuscript series that resulted from this collective effort. Basic terms are defined and a précis of each article in the manuscript series is given. The ultimate conclusion to be drawn from this series is that, while the goals of assessing and analyzing PRO elements of clinical practice and research are challenging, there now exists a scientific foundation that makes achieving these goals feasible and the results credible. This is vitally important because after all, at the heart of all healthcare endeavors is the patient.

A Phase III study to assess the clinical utility of low-dose fentanyl transdermal system in patients with chronic nonmalignant pain.

BACKGROUND: The transdermal fentanyl delivery system (fentanyl TTS; Duragesic) is currently widely available in patch strengths of 25, 50, 75, and 100 microg/h. However, a lower dose of 12 microg/h would allow optimal titration and fine tuning of the analgesic effect, and may be beneficial in certain patient populations such as the elderly or opioid-naïve. A 12 microg/h fentanyl TTS patch has been developed, and the clinical efficacy and safety tested in this single-arm, non-randomized, open-label, multicenter, 28-day trial in opioid-exposed and -naïve patients with moderate to severe pain for at least 6 months. PATIENTS: Patients were treated with fentanyl TTS for 28 days in an intent-to-treat manner starting at 12 microg/h (one patch), titrated upwards in increments of 12 mug/h to a maximum dose of 36 microg/h (three patches). RESULTS: A total of 227 patients were enrolled. The majority of patients with a "global assessment of therapy" of fair/poor at baseline (63.4%) improved to good/very good, while 28.9% of patients with an assessment of good/very good at baseline worsened to fair/poor at endpoint. The average pain intensity levels for the efficacy evaluable population steadily decreased over the course of the trial. The adverse event (AE) profile of fentanyl TTS in this trial was generally similar to that identified in previous fentanyl TTS trials, and no unexpected safety issues or AEs were noted. Furthermore, the drop-out rate in this trial was lower than has been noted in previous trials. CONCLUSION: This trial demonstrated that the lower 12 microg/h dose of fentanyl TTS provided a therapeutic benefit in non-malignant chronic pain, with a similar AE rate but a lower drop-out rate than that seen in trials at higher doses. This lower dose may, therefore, be of particular benefit to elderly or opioid-naïve patients.

Patient-reported Outcomes for Multicentric Castleman's Disease in a Randomized, Placebo-controlled Study of Siltuximab.

BACKGROUND: Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder driven by dysregulated interleukin-6 production. MCD has a poor prognosis, and treatment is generally noncurative and aimed at symptom relief. Siltuximab is a novel, monoclonal interleukin-6 antibody recently shown to be effective in a registration clinical trial. MCD symptoms, such as fatigue, pain, and weakness, are most appropriately quantified using patient-reported outcome (PRO) measures. We assessed the effect of siltuximab on patient perception of symptoms, functional status, and wellbeing using PRO instruments. METHODS: We analyzed results of a randomized, double-blind trial comparing siltuximab 11 mg/kg every 3 weeks with placebo to treat MCD. Subjects (N = 79) completed the recently developed MCD-Symptom Scale (MCD-SS), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale, and the Short Form (SF)-36 at predetermined time points throughout the treatment period. Scores were compared at baseline and over time between the treatment arms and PRO instruments. RESULTS: At baseline, the mean number of symptoms reported was 9.2 (standard deviation 3.76) out of 16 total, as measured by the MCD-SS. Fatigue was a key symptom across all PRO instruments. Siltuximab-treated subjects reported early improvements in symptoms compared with subjects in the placebo arm on both the MCD-SS and FACIT-Fatigue scale. Statistically significant improvements in five SF-36 domains were observed in siltuximab-treated patients, namely role physical, role emotional, vitality, bodily pain, and mental health. CONCLUSIONS: Patients with MCD commonly report impairments in functioning, wellbeing, and fatigue at baseline. Siltuximab-treated patients reported significant improvements in these outcomes after treatment.

Time and economic cost of constipation care in nursing homes.

OBJECTIVE: Chronic constipation is a common disorder among residents in long-term care; yet the cost to the nursing home of constipation-related care is not known. The objective of this study was to quantify the nursing staff and supply-related cost of constipation care to nursing homes from the perspective of the nursing home. DESIGN: Prospective, observational time-and-motion design. SETTING: Two United States nursing homes. PARTICIPANTS: A total of 59 nursing home residents with chronic constipation and nursing staff providing constipation care to them. MEASUREMENTS: Actual time to complete constipation care-related tasks was measured via stopwatch by trained observers, and the number and professional level (eg, staff nurse, CNA) of staff performing each task was recorded. Frequency of constipation care task data was obtained through 60-day retrospective medical chart review for each subject. Nurse wage rate data was obtained from the Nursing Home Salary and Benefits Report, a US-based national source. Resident and nursing home descriptive information was also collected. RESULTS: The average cost per task occurrence ranged from 0.72 US dollars for enema administration to 1.74 US dollars for oral medication administration. Average nursing staff costs per subject per year were 1577 US dollars for oral medication administration, 215 US dollars for dietary supplement administration, 39 US dollars for constipation assessment, 17 US dollars for suppository administration, and 6 US dollars for enema administration. Based on estimates of frequency of occurrence, the total annual labor and supply cost per long-term care resident with constipation was 2253 US dollars. CONCLUSION: Nursing staff performance of constipation care-related tasks is time consuming and costly in the long-term care setting.