Cheryl D. Coon

Interpreting patient-reported outcome results: US FDA guidance and emerging methods.

In recent years, the US FDA has become more critical of instruments used to measure patient-reported outcomes (PROs) in clinical trials. To facilitate decisions related to the approval of drugs, labels and promotional claims based on PROs, the FDA created the Study Endpoints and Label Development (SEALD) group. SEALD has developed a PRO guidance related to the use of PRO measures used to support drug approvals and label claims, including recommendations for establishing thresholds for meaningful change at the individual level (i.e., defining a responder). This article examines in detail the FDA-recommended methodology for defining a responder and analyzing responder-based PRO measure results. We also present other responder analysis approaches for consideration in furthering the precision and interpretation of this methodology.

Using Classical Test Theory, Item Response Theory, and Rasch Measurement Theory to Evaluate Patient-Reported Outcome Measures: A Comparison of Worked Examples

OBJECTIVE To provide comparisons and a worked example of item- and scale-level evaluations based on three psychometric methods used in patient-reported outcome development-classical test theory (CTT), item response theory (IRT), and Rasch measurement theory (RMT)-in an analysis of the National Eye Institute Visual Functioning Questionnaire (VFQ-25). METHODS Baseline VFQ-25 data from 240 participants with diabetic macular edema from a randomized, double-masked, multicenter clinical trial were used to evaluate the VFQ at the total score level. CTT, RMT, and IRT evaluations were conducted, and results were assessed in a head-to-head comparison. RESULTS Results were similar across the three methods, with IRT and RMT providing more detailed diagnostic information on how to improve the scale. CTT led to the identification of two problematic items that threaten the validity of the overall scale score, sets of redundant items, and skewed response categories. IRT and RMT additionally identified poor fit for one item, many locally dependent items, poor targeting, and disordering of over half the response categories. CONCLUSIONS Selection of a psychometric approach depends on many factors. Researchers should justify their evaluation method and consider the intended audience. If the instrument is being developed for descriptive purposes and on a restricted budget, a cursory examination of the CTT-based psychometric properties may be all that is possible. In a high-stakes situation, such as the development of a patient-reported outcome instrument for consideration in pharmaceutical labeling, however, a thorough psychometric evaluation including IRT or RMT should be considered, with final item-level decisions made on the basis of both quantitative and qualitative results.

US FDA patient-reported outcome guidance: great expectations and unintended consequences

Release of the US FDA patient-reported outcome (PRO) guidance raised expectations within the pharmaceutical industry for the use of PRO measures in support of labeling claims. The FDA developed the guidance with admirable intent, and the recommendations within this document are based on sound scientific principles. However, implementation of the guidance has been somewhat inconsistent within the Study Endpoints and Label Development (SEALD) and across the various FDA-reviewing divisions. Industry and regulatory bodies need to work toward gaining common ground to best support registration of treatments that could extend patients’ lives, reduce symptoms, and/or improve health-related quality of life. PROs are valuable tools in communicating these messages, and realistic implementation of the FDA PRO Guidance may truly facilitate this process.

Validation of a 4-item Negative Symptom Assessment (NSA-4): a short, practical clinical tool for the assessment of negative symptoms in schizophrenia

The 16‐item Negative Symptom Assessment (NSA‐16) scale is a validated tool for evaluating negative symptoms of schizophrenia. The psychometric properties and predictive power of a four‐item version (NSA‐4) were compared with the NSA‐16. Baseline data from 561 patients with predominant negative symptoms of schizophrenia who participated in two identically designed clinical trials were evaluated. Ordered logistic regression analysis of ratings using NSA‐4 and NSA‐16 were compared with ratings using several other standard tools to determine predictive validity and construct validity. Internal consistency and test–retest reliability were also analyzed. NSA‐16 and NSA‐4 scores were both predictive of scores on the NSA global rating (odds ratio = 0.83–0.86) and the Clinical Global Impressions–Severity scale (odds ratio = 0.91–0.93). NSA‐16 and NSA‐4 showed high correlation with each other (Pearson r = 0.85), similar high correlation with other measures of negative symptoms (demonstrating convergent validity), and lesser correlations with measures of other forms of psychopathology (demonstrating divergent validity). NSA‐16 and NSA‐4 both showed acceptable internal consistency (Cronbach α, 0.85 and 0.64, respectively) and test–retest reliability (intraclass correlation coefficient, 0.87 and 0.82). This study demonstrates that NSA‐4 offers accuracy comparable to the NSA‐16 in rating negative symptoms in patients with schizophrenia. Copyright

Development, Reliability, and Validity of a New Preference and Satisfaction Questionnaire

OBJECTIVES Existing questionnaires that assess preference and/or satisfaction with postmenopausal bone loss treatments were reviewed and determined to be inadequate for the assessment of an oral pill versus a subcutaneous injection. The Preference and Satisfaction Questionnaire (PSQ) was developed to assess preference, satisfaction, and bother with a weekly oral tablet versus a once every 6 months subcutaneous injection for treatment of postmenopausal bone loss. METHODS Questions were developed based on literature review and expert input. Content validity of the PSQ in this patient population was assessed among current or previous bisphosphonate users in group interviews, and item comprehension and readability were also evaluated. Reliability, validity, and structure of the questionnaire were assessed in two phase 3 randomized clinical trials. RESULTS Twenty-four women participated in cognitive interviews and found the PSQ understandable and acceptable. Subsequently, 1583 trial participants took the PSQ. Interitem correlations, ranging from 0.50 to 0.97 for preference items, 0.85 to 0.94 for pill-satisfaction items, and 0.84 to 0.92 for injection-satisfaction items, and a well-fitting confirmatory factor analysis (root mean square error of approximation 0.04, nonnormed fit index 0.99, and root mean square residual 0.08) supported the structure of the instrument. Cronbachs alpha reliability values for pill satisfaction, injection satisfaction, pill bother, and injection bother were 0.93, 0.89, 0.82, and 0.61, respectively. Discriminative validity was indicated with better satisfaction and bother scores being related to adherence and the absence of adverse events. CONCLUSIONS The PSQ is a valid and reliable measure and may be a valuable tool to assess patient preference and satisfaction with a weekly oral tablet and 6-month subcutaneous injection for postmenopausal bone loss.

Evaluation of the fibromyalgia diagnostic screen in clinical practice

RATIONALE, AIMS AND OBJECTIVES Fibromyalgia (FM) is challenging to diagnose, especially in primary care settings. The Fibromyalgia Diagnostic Screen was developed to facilitate the diagnosis of FM in clinical practice. The objectives of this study were to assess the performance of the Fibromyalgia Diagnostic Screen in primary care and specialty clinics, using the 1990 American College of Rheumatology (ACR) diagnostic criteria as the gold standard, and comparing the Fibromyalgia Diagnostic Screen with the London Fibromyalgia Epidemiology Study Screening Questionnaire (LFESSQ) and the modified 2010 ACR Fibromyalgia Diagnostic Criteria (ACR-FDC). METHODS This multicenter, cross-sectional study included 150 adult chronic pain patients who underwent a physician-administered structured history and physical exam and completed the Fibromyalgia Diagnostic Screen, the LFESSQ and the modified ACR-FDC. The analyses determined the predictive ability of the Fibromyalgia Diagnostic Screen for FM. RESULTS Item-level analyses provided support for the response categories and predictive ability of most of the Fibromyalgia Diagnostic Screen items. Additionally, the evaluation of the Fibromyalgia Diagnostic Screen scoring models demonstrated the greatest accuracy in predicting an FM diagnosis with a combination of patient items and clinician items that included an abbreviated tender point exam (sensitivity 0.68, specificity, 0.82). Sensitivity of the modified ACR-FDC and the LFESSQ was 0.87 and 0.86, respectively, with specificity 0.62 and 0.49, respectively. CONCLUSIONS The Fibromyalgia Diagnostic Screen is a useful new clinical tool to aid in the evaluation of FM in clinical practice.

Psychometric evaluation of the Sheehan Disability Scale in adult patients with attention-deficit/hyperactivity disorder

Inattention and impulsivity symptoms are common among adults with attention-deficit/hyperactivity disorder (ADHD), which can lead to difficulty concentrating, restlessness, difficulty completing tasks, disorganization, impatience, and impulsiveness. Many adults with ADHD find it difficult to focus and prioritize. Resulting outcomes, such as missed deadlines and forgotten engagements, may ultimately impact the ability to function at work, school, home, or in a social environment. The European Medicines Agency guidelines for evaluating medicinal products for ADHD recommend inclusion of both functional outcomes, such as school, social, or work functioning, and outcomes related to symptoms of ADHD in clinical studies of novel medication primary efficacy endpoints. Due to its performance in other disease areas and the relevance of its items as evidenced by content validity analyses, the Sheehan Disability Scale (SDS) was chosen to assess functional impairment in ADHD. The aim of this study was to investigate the psychometric properties of the SDS, used as a brief measure of functional impairment in a number of psychiatric disorders, in adult patients with ADHD. To the authors’ knowledge, this is the first study to evaluate the reliability of the SDS (based on Cronbach’s coefficient alpha and test-retest reliability), its validity (construct and known-groups validity), and its ability to detect change in this patient population. This study also established a preliminary responder definition for the SDS in this study population to determine when change can be considered clinically beneficial in a clinical trial setting. The psychometric results support the use of the SDS subscales (items 1–3) and total score (sum of items 1–3) in an ADHD population. In addition, the evaluation provides evidence for a three-point preliminary responder definition for the SDS and further evidence of its responsiveness in adults with ADHD. Altogether, the results indicate that the SDS is a simple and easy-to-score scale that would have great utility in future clinical trials for monitoring functional impairment in adults with ADHD.

Three-year patient-reported visual function outcomes in diabetic macular edema managed with ranibizumab: the RESTORE extension study

Abstract Objective: To determine the impact of ranibizumab 0.5 mg on patient-reported visual function over 36 months in individuals with visual impairment from diabetic macular edema. Methods: RESTORE comprises a phase 3, randomized, multicenter, 12 month core study and a 24 month open-label extension study. Eyes assigned to ranibizumab in the core study received ranibizumab for 36 months; eyes assigned to laser monotherapy in the core study received ranibizumab during the extension. The primary outcome was least-squares mean change in National Eye Institute 25-item Visual Functioning Questionnaire (NEI VFQ-25) overall composite and subscale scores. Results: Of 303 core study participants, 240 (79%) entered the extension, comprising 83 (35%) participants initially assigned to ranibizumab, 83 (35%) assigned to ranibizumab plus laser combination therapy, and 74 (31%) assigned to laser monotherapy. Least-squares mean (standard error) change in NEI VFQ-25 composite score from baseline to month 12 (+5.9 [1.5]; +5.0 [1.5], for the ranibizumab and combination therapy groups, respectively) decreased by month 36 (+4.1 [1.7]; +4.0 [1.7], respectively, from baseline to month 36) following reduced injection frequency relative to the core study. At 36 months, the least-squares mean (standard error) change in the laser monotherapy group was similar to that in the ranibizumab groups (+4.1 [1.8]). Most subscale scores showed outcomes similar to that for the composite score. The greatest NEI VFQ-25 gains were consistently observed in participants for whom the study eye was the better-seeing eye. Limitations: Patients entering the extension were not randomized, and 21% of the core study participants did not enter the extension, which may have affected the results. Conclusions: Gains in patient-reported visual function at month 12 among eyes receiving ranibizumab in the core study decreased slightly by 36 months. Eyes originally receiving laser monotherapy for 12 months then ranibizumab for 24 months achieved similar gains by 36 months to eyes receiving ranibizumab for 36 months. Trial Registration: ClinicalTrials.gov: NCT00687804 and NCT00906464.

Patient-Reported Outcomes: Current Perspectives and Future Directions

t H p a S i a P F e s t t a The patient perspective or “patient voice” is critical for the optimization of decisions regarding treatment, as well as the accurate assessment of burden of illness and quality of care. For decades, patient-reported outcome (PRO) measures have facilitated comprehensive assessment and description of how patients feel and function. Within the context of drug development, PRO cores often supplement clinical indices that are inadquate for assessing the signs, symptoms, and effects mportant to patients. In some therapeutic areas, PRO easures are of even greater importance, assessing key ndices of efficacy known only to the patient, such as hanges in the severity of pain or frequency of gastrontestinal symptoms. Within the pharmaceutical industry, interest in ROs increased greatly after the US Food and Drug dministration (FDA) released their draft and then fial guidance documents describing review criteria for ROs used in labeling claims within the United States. The PRO Guidance was developed with input from the FDA’s Study Endpoints and Label Development (SEALD) team, and SEALD serves as a consultant to the various reviewing divisions to facilitate and help inform decisions related to PROs in product labeling. In addition to the PRO Guidance, the FDA also has described a qualification process for PRO end points as part of the Drug Development Tools Qualification Guidance, which outlines the process for preapproval of measures before inclusion in a specific clinical trial program. The latter guidance was issued, in part, to ncourage the collaborative development of clinical asessment measures in a precompetitive space. Most often, sponsors work independently to idenify or develop the most appropriate PRO measure for heir product and its particular profile. However, there re a number of collaborative efforts with the potential o streamline this process. For example, the Patienteported Outcomes Measurement Information Sys-

Sphygmomanometry-evoked allodynia in chronic pain patients with and without fibromyalgia

Background:Fibromyalgia is a chronic pain syndrome that affects about 2% of the U.S. general population, with greater prevalence among women (3.5%) than men (0.5%). Previous research results suggest that the experience of pain (allodynia) upon sphygmomanometry may indicate the presence of fibromyalgia. Objective:The aim of this study was to confirm these findings in patients with fibromyalgia and other chronic pain conditions and evaluate the use of sphygmomanometry as a potential screening tool for the identification of patients with fibromyalgia. Methods:A total of 150 people participated in this multicenter, cross-sectional observational study. The study included a physician-conducted evaluation to determine if the participant met the American College of Rheumatology (ACR) 1990 diagnostic criteria for fibromyalgia. The presence of sphygmomanometry-evoked allodynia was assessed during a seated cuff pressure inflation that was repeated three times on each arm. Each site was provided a sphygmomanometer to ensure standardization, and the pressure of the cuff at the moment of pain initiation was recorded. If the patient did not indicate pain prior to 180 mmHg, then the inflation was stopped, a notation of no pain was made, and a cuff pressure of 180 mmHg was recorded. The mean of the six cuff pressure measurements was used for the analyses. Logistic regression was performed to analyze the relationship between sphygmomanometry-evoked allodynia and fibromyalgia. Results:The evaluable sample was 148 (one participant had too large an arm circumference for the sphygmomanometer and another did not receive the clinician evaluation of ACR-determined fibromyalgia diagnosis). Over half of the participants were determined to have an ACR diagnosis of fibromyalgia. Of these, 71 (91%) were women and had an average age of 54 years. Of the 70 participants with no fibromyalgia diagnosis, 42 (60%) were women and also had an average age of 54 years. Sixty-one (78%) of the fibromyalgia participants, compared with 25 (36%) of those with no fibromyalgia diagnosis, reported sphygmomanometry-evoked allodynia. The participants with fibromyalgia reported pain ata lower cuff pressure compared with those without fibromyalgia (132 mmHg vs. 166 mmHg, p < .01). The logistic regression showed that sphygmomanometry-evoked allodynia predicted an ACR-determined FM diagnosis (&khgr;2 = 19.4, p < .01). Discussion:These findings support previous research suggesting that patients who report pain upon sphygmomanometry may warrant further evaluation for the presence of fibromyalgia.