Management of hemophilia B requires replacement therapy with factor IX (FIX) coagulation products. Extended half-life (EHL) recombinant FIX products are now available along with existing standard half-life (SHL) FIX products. The aim is to examine factor dispensation and expenditure for Japanese patients who switched from SHL to EHL product in a real world setting. Japanese real world data provided by Medical Data Vision Co., Ltd (MDV) were used to compute number of IUs dispensed, direct product and total health care expenditure (¥)among individuals with data for ≥3 months before and after switching from an SHL (nonacog alfa, nonacog gamma, freeze-dried human blood-coagulation factor IX) to EHL (eftrenonacog alfa) product (April 2010–November 2017). MDV is a commercially available large scale real-world hospital medical administrative and claims database in Japan, that includes claims data from hospitals, regardless of insurance types, from >10 million inpatients and outpatients. We report medians for IUs and expenditures to accommodate for skewness of data distribution. Seventeen patients switched from an SHL to EHL product and had ≥3 months of data pre and post switch. Median quarterly IUs dispensed increased from 29,600 IUs on SHL to 36,750 IUs on EHL when considering available data on the 4 quarters pre and post switch. Median FIX expenditures increased 398% from ¥1,522,368 to ¥7,589,255. FIX replacement expenditures represented 96% of total expenditures pre and 99% post switch. Similar patterns held when analyses were limited to 7 individuals who switched from nonacog alfa (Medians= 18,000 IUs; ¥1,896,510) to eftrenonacog alfa (Medians=36,000 IUs; ¥7,480,296) (294% increase in expenditures). This analysis shows that switching from an SHL to EHL product increased FIX replacement IUs dispensed. Expenditures on FIX replacement products increased post switch by 294% - 398%. Further analyses in larger patient populations should be explored.

Management of Hemophilia B requires intravenous factor IX (FIX) infusions to replenish missing coagulation factor. The introduction of extended half-life (EHL) replacement products in the US, with longer half-lives compared to standard half-life (SHL) product enabled comparison of expenditures and dispensation of clotting factor concentrates for the treatment of Hemophilia B with two EHL products versus an SHL product. De-identified claims from a large national specialty pharmacy claims database were used to identify male patients with severe or moderate hemophilia B who received FIX replacement from Apr 2015 (month first EHL FIX dispensed) to Sep 2017 and had data for at least 1 month of dispensation. SHL vs EHL groups were compared. Key outcome measures were direct expenditures and factor IUs dispensed. Expenditures and IUs dispensed were measured over monthly increments. Descriptive statistics were used to analyze results. Medians for expenditures and IUs were used to accommodate for the skewness of data distribution. 386 Hemophilia B patients met the inclusion criteria and were included in the analysis. The SHL group comprised of 293 nonacog alfa patients and the EHL group included 107 eftrenonacog alfa patients and 45 albutrepenonacog alfa patients. The albutrepenonacog group had a proportionately higher number of pediatric patients. The median FIX product dispensation per patient per calendar month was 16,134 IU (IQR, 26,903 IU) (nonacog) versus 16,380 IU (IQR, 17,287 IU) (eftrenonacog) and 10,039 IU (IQR, 10,620 IU) (albutrepenonacog). Median expenditures per patient per calendar month were higher for EHLs (eftrenonacog $48,336; IQR, $49,970; and albutrepenonacog $42,664; IQR, $45,135) than for SHL ($21,849; IQR, $36,102). This real-world data analysis, unadjusted for treatment regimen, showed higher expenditure among U.S. moderate/severe hemophilia B patients who used EHL, compared to SHL FIX. Further analyses, incorporating essential clinical characteristics and drug regimen, should be explored.

To quantitatively evaluate the factors driving subject preferences for recombinant human growth hormone (r-hGH) injection and injection device features among patients with growth hormone deficiency (GHD). A cross-sectional, observational Web-based study involving adult and pediatric patients (and their caregivers) receiving daily r-hGH injections for GHD was conducted. Patients/caregivers were screened by physicians at eight clinical locations in the United States and emailed unique URLs. Consented participants completed a discrete choice exercise (DCE) to indicate their preferred option from a choice of two across 20 tasks, trading off the following six attributes: Storage (Refrigerated vs. Room Temperature); Preparation (Mix vs. Mix, then Room Temperature vs. Ready to Use); Injection Device (Continuous Push Needle Device vs. Autoinjector vs. Needle Free Device); Maintenance (Single Use, Disposable Pen vs. Multiple Use, Disposable Pen vs. Multiple Use, Reusable Pen); Dose Setting (Set the Dose vs. Dose Memory vs. Pre-set Dose), and Injection Schedule (Once Daily vs. Once Weekly vs. Once Every Two Weeks vs. Once a Month). The conjoint analysis used a part-worth model and Hierarchical Bayesian (HB) analysis to evaluate relative importance of the attributes as choice drivers. Aggregate relative importance (ARI) across all attributes sums to 100%. In total, 224 patients (n=70 children/caregiver dyads, n=79 adolescents/caregiver dyads, n=75 adults) completed the DCE. Injection Schedule emerged as the strongest predictor (ARI: 48%), with greater preference for less frequent administration. Preparation was the next strongest predictor (ARI: 22%), as a “Ready to Use” device was more desired than one that involves reconstitution. The remaining four attributes had <10% ARI. Patients prefer a weekly (or less frequent) r-hGH injection regimen to a daily regimen and a ready to use device to one that requires reconstitution. Addressing patient preferences for treatment delivery may improve compliance, adherence, and, ultimately, clinical outcomes.

Recombinant human growth hormone (r-hGH) replacement therapy has been safely and effectively used for over 30 years in thousands of patients worldwide with growth hormone deficiency (GHD). Most commonly, r-hGH therapy is long-term and relies upon daily subcutaneous injections to achieve the goals of GHD treatment in children and adults. While caregivers commonly give or assist with injections, research documenting the burden experienced by caregivers is limited. This research explores this burden. As part of a study to establish the content validity of new questionnaires that assess injection regimen burden, semi-structured interviews were conducted with dyads (pediatric patients from the United States taking daily r-hGH injections for GHD [n=11 children ages 4 to 11, n=4 adolescents ages 13-14], and their caregivers). During the interviews, caregivers were asked to describe their experiences relating to their child’s r-hGH injections. Caregivers discussed a variety of burdens, including the need to keep medication cold (particularly when away from home), negative reactions from their children (e.g., crying, resisting injections), and impacts on travel (e.g., difficulties at airport security screening and travel limitations), emotions (e.g., being anxious about or bothered by giving injections to their children), and daily activities (an extra chore to do at night, changes to work schedule, unable to be away from home without child, ensuring that medicine and supplies are delivered and available). Daily r-hGH injection treatments impose emotional and practical burdens upon caregivers of pediatric patients. Caregivers of younger children are more constrained by the need to administer the injections daily, deal with greater resistance and hesitation from their children, and experience greater emotional effects from administering an uncomfortable or painful treatment every day to their very young children. Further research may help determine whether these burdens might be lessened with a less frequent injection regimen.

Management of hemophilia A includes replacement of factor VIII (FVIII) by intravenous infusion. The recent introduction of extended half-life (EHL) FVIII products has enabled comparison of health care expenditure and volumes of factor dispensed for hemophilia A patients switching from a standard half-life (SHL) to EHL FVIII product. The Truven Health MarketScan® Research US claims databases (Aug 1, 2014 to Jan 31, 2017) were used to identify direct expenditures and international units (IUs) dispensed for all patients who used SHL (SHL group) and/or EHL (EHL group). Data on patients who switched from an SHL to an EHL FVIII product were captured up to one year before and after the switch. Patients with at least 1 pre and post-calendar quarter of claims available were included in the switching analysis. Cross-sectional analysis: In the SHL group (N=415), Six distinct SHL FVIII products were dispensed, with two EHL FVIII products dispensed in the EHL group (N=91). Median FVIII product dispensation per calendar quarter was 46,409 IU (IQR, 12,760-87,670 IU) (SHL) versus 67,375 IU (IQR, 50,524-98,264 IU) (EHL). Median expenditures per calendar quarter were higher for EHL ($135,519; IQR, $100,320-186,557) than for SHL ($61,152; IQR, $18,593-115,845). Switching analysis: In the EHL group, 29 patients switched from one of three SHL FVIII products to one of two EHL FVIII products during the study period. Total median IU dispensation per calendar quarter increased following the switch from 58,598 IU (pre-switch, SHL) to 68,036 IU (post-switch, EHL; 16% increase). Factor-related expenditure also increased 84% ($76,553, SHL, versus $141,101, EHL). This analysis suggests that switching from an SHL to an EHL product is associated with increased IU dispensation, expenditures and variability, including more EHL IU dispensed post-switch than SHL in quarters pre-switch. Further real world analyses incorporating larger numbers of patients should be explored.

The objective of this study was to develop and validate a decision algorithm that replicates expert opinion regarding the level of disease activity in patients with acromegaly. A panel of key experts in endocrinology and outcomes research provided input as to what parameters are critical to assess disease activity. The top five parameters where then subsequently defined at three levels of severity. A final set of 243 unique health states were developed. A group of 21 expert endocrinologists from 5 European countries and Canada was recruited to participate in a discrete choice experiment. Each participant was presented with 10 common scenarios and 42 additional scenarios selected at random and asked to indicate whether the hypothetical patient was stable, having mild disease activity needing further evaluation, or having significant disease activity requiring clinical action. Concordance in decisions based on the 10 common scenarios was tested using Fleiss Kappa and a set of linear prediction models tested to predict outcome. The five parameters included: 1) IGF-I level (SDS score); 2) tumor status (change on MRI); 3) comorbidities (number and severity); 4) signs and symptoms (Patient Acromegaly Symptom Questionnaire score); and 5) health-related quality of life (scored on a disease specific measure). The Inter-rater reliability was adequate (Kappa = 0.52). Based on a CART analysis, the decision model of best fit was disjunctive with IGF-1 and Tumor status primarily predicting the health status. The remaining three parameters were instructive but not deterministic. Biochemical and tumor status are the primary predictors of disease activity, with the patient’s perceived disease state playing a secondary role. This may highlight the need for a more patient-centered approach to acromegaly disease management. To enable clinical use of the model, a disease specific tool named ACRODAT (ACROmegaly Disease Activity Tool) is currently in further development.

To test the reliability of the Patient Reported Scar Evaluation Questionnaire (PR-SEQ) in a general scar population at two time points and in two formats (pen/paper and electronic). The PR-SEQ, a 30-item 4-domain measure of scar experience, was administered to a total of 512 clinic- and self-recruited subjects with qualifying scars. The 101 clinic-recruited subjects were administered the PR-SEQ in a pen/paper format at Baseline and at Timepoint 1 (T1) and Timepoint 2 (T2) about 7 +/- 2 days apart using a computer-based version on the internet. The 413 self-recruited subjects were administered only the internet version at T1 and T2. Internal consistency reliability was assessed using Cronbach’s alpha for the total T1 cohort (n=512); test-retest reliability was assessed using the intraclass correlation coefficient (ICC) based on an ANOVA model for the T1-T2 retest cohort (n=359); and between forms reliability was assessed using the ICC for the clinic cohort data from baseline and T1 (n=100). Cronbach’s alpha was 0.96 for the PR-SEQ total score and 0.86 for Appearance (5 items), 0.68 for Symptoms (3 items), 0.92 for Bother (8 items), and 0.95 for Impact (14 items) domains. The ICC for the test-retest cohort was 0.85 for the total score and 0.76, 0.78, 0.80, and 0.81 for the domains of Appearance, Symptoms, Bother, and Impact, respectively. Between forms reliability was similarly acceptable with scores of 0.84, 0.90, 0.92, and 0.95 for the domains, and 0.94 for the total score. Overall, the two versions of the PR-SEQ demonstrated acceptable levels of reliability across the domains and total score, with the possible exception of the internal consistency of the 3-item Symptom domain. Further item reduction may be possible without significant risk to the reliability of the instrument.

To investigate the clinical significance of change in QoL-AGHDA score after 1 year of growth hormone (GH) replacement. Observational data were obtained from KIMS (Pfizer International Metabolic Database). Minimal important differences (MID) for the QoL-AGHDA score and its five domains (memory and concentration, tenseness, tiredness, self-confidence, and social isolation) were calculated using an anchor-based approach with a rating of patient-perceived treatment benefit and patient-reported change in need for assistance. Perception of treatment benefit was measured using the KIMS Patient Life Situation Form (PLSF), a 5-point ordinal assessment of change (much improved, a little improved, no change, a little worse, much worse). The effect of baseline (BL) scores on MID was analysed using the QoL-AGHDA thresholds included in the New Zealand (≥16) and England (≥11) reimbursement criteria. Data from 1404 patients (52% female, 96% Caucasian, mean age [SD] of 45 [14] years) were included in the analysis. Mean GH dose [SD]was 0.20 [0.14] mg/day at BL and 0.32 [0.16] mg/day during Year 1. The Spearman correlation between change in QoL-AGHDA score and perception of treatment benefit was moderately positive (0.45; p < 0.01). The correlation was stronger for females and for patients with more impaired (higher) BL QoL-AGHDA scores. Using the anchor-based approach with patient-perceived treatment benefit, the MID for the QoL-AGHDA score was -4.61 at Year 1. Self-confidence was most sensitive and tenseness least sensitive of the domains in predicting patient-perceived treatment benefit. Patients requiring assistance at BL and not at Year 1 experienced the largest mean improvement in QoL-AGHDA score. Several national reimbursement authorities currently include the QoL-AGHDA score in eligibility criteria for access to reimbursed GH replacement. This is the first study to calculate the MID for the QoL-AGHDA score. Findings indicate that change in QoL-AGHDA score is positively correlated with patient-perceived treatment benefit.

Photo-based questionnaires have been used to evaluate aesthetic treatment outcomes such as wrinkle reduction and eyelash growth. The objective of this study was to develop a photonumeric guide of scar severity intended for use by both clinicians and patients to measure scar treatment outcomes. Nine clinicians and 43 patients with linear surgical scars participated in a photograph sorting exercise. Patients sorted approximately 50 scar photographs consistent with their own skin type (light, medium or dark skin), while clinicians sorted all three sets of photographs (n=151 photographs). All participants arranged the photographs into 5 categories of perceived scar severity (least to most severe) and 5 photographs were considered for inclusion in the photonumeric guide based on analysis of inter-rater reliability, response consistency, redundancy, and variability. When photographs yielded similar results, clinical judgment was used to select the best photo. Instruction and response anchors were developed for the 5 scar photographs and the final guide was cognitively debriefed for relevance, comprehensibility, and acceptability in 24 additional scar patients. Based on the pre-specified criteria for inclusion and exclusion, 5 light skin and 5 dark skin photographs were included in the final photonumeric guide. A “medium” guide was not developed because of significant overlap between it and the light skin guide rendering it superfluous. Inter-rater reliability of the 52 subject cohort was strong (0.95-0.96) across all skin types. The 5 photographs included in the photonumeric guide demonstrated goodness-of-fit (infit mean-square < 1.4 and > 0.6), low variance in severity ratings (SD < one category change), and strong agreement between patients and clinicians. The Patient and Clinician Reported Scar Severity Scales were systematically developed to easily assess scar severity outcomes in clinical trials. Continued psychometric evaluation of the guide is planned to ensure the scales meet regulatory standards for labeling purposes.

Photoguides are used as measures of treatment effect. To interpret the results, an understanding of what change is “enough” is required. The purpose of this study was to determine the Patient Detectable Difference (PDD) and Patient Relevant Difference (PRD) in scar severity using a discrete choice experiment with paired comparisons of scar photos via the internet. Patients were asked to select the scar most like their own from a 5-photo photoguide as the referent. Each patient was then presented with a randomly selected scar from a scar library previously scored on severity by clinicians. For the PDD, patients were asked if the random scar was better, worse, or about the same. For the PRD, patients were asked if they would undergo treatment to “get” the random scar as opposed to keeping the referent scar. Each exercise was repeated five times. Optimal cutoff scores for PDD and PRD were based on a random intercept logistic model (RILM). Using a series of RILM estimations across 514 participants, the PDD was calculated as 15.4 points on a 100-point scale (area under curve = 0.85, sensitivity = 0.83, specificity = 0.73). In subgroup analyses by gender and scar source, the PDD ranged from 9.5 to 22.0 points. The replicate analysis adjusting for directionality of preference (improvement only) showed a PRD of 26.9 points (area under curve = 0.97, sensitivity = 0.90, specificity = 0.93), which ranged from 19.5 to 32.0 in the subgroups. Results show that, as expected, scar patients report detectable differences in scar severity that are smaller than what they report as relevant differences necessary to choose treatment. The Internet-based approach using a discrete choice experiment is a novel method to quantify the threshold of detectable and relevant differences in scar severity using a photoguide.

To examine the reliability and validity of the Injection Pen Assessment Questionnaire (IPAQ) in a European population. The IPAQ is a 29-item measure of objective and comparative ease of use and preference for recombinant human growth hormone (rhGH) injection devices based on content elicited from focus groups and one-on-one interviews of device users. The IPAQ was included in a Phase 3, open-label, multicenter trial in 136 experienced rhGH subjects (parent-child dyads) in the United States to test the ease of use and preference for a new Genotropin® disposable pen (NCT00965484). IPAQ content was adapted for use in adults and translated into seven languages. Data from a Phase 3, open-label, multicenter, crossover study (NCT01112865; N=120) was used to evaluate the psychometric properties of the IPAQ in a mixed sample of dyadic pairs, adult subjects and caregivers of pediatric subjects. Analyses were conducted by group and total sample. Confirmatory factor analysis provided evidence for a second order factor solution for four subscales and a total IPAQ score; and supported the conceptual framework developed from previous qualitative and quantitative research. Although IPAQ subscales did not consistently meet acceptable internal consistency reliability for some group level comparisons, the total IPAQ score showed high internal consistency for both pens (Cronbach's alpha = 0.77 – 0.86). In general, the construct validation (predictive validity) findings were consistent across pens and across subject groups and generally consistent with those from the US trial. The IPAQ total score for ease of use demonstrated good internal consistency reliability and good construct validity in measuring ease of use with injection pens to administer rhGH. Findings from this research are consistent with those from the US-based study, supporting the usefulness of the IPAQ total score in evaluating ease of use and preference for injection pens in clinical trials and in practice.

Currently available scar assessment tools focus on the appearance and symptoms of scars but avoid the complete scar experience. Additionally, existing instruments lack evidence or documentation (or both) of their development (e.g., content validity) and performance (e.g., reliability, construct-related validity, and responsiveness), and it is unlikely they would meet current regulatory requirements for labeling. The objective of the present work was to conduct qualitative research with patients to better understand scar appearance, symptoms, and impacts, and to use those results to inform the development of a content-valid PRO instrument for use in clinical trials. Eight physicians (3 dermatologists and 5 plastic surgeons) recruited subjects to participate in the CE research activities. Each subject (aged 18 to 65) was required to have a linear surgical (cosmetic or non-cosmetic) scar below the neck. Subjects with burn scars were excluded as were subjects with significant medical comorbidities. The interviews were conducted in multiple cities in the United States, transcribed, and used to derive the scar questionnaire items. A total of 43 interviews across five surgery types were conducted to elicit information regarding their experiences with their disfiguring scar. During the CE interviews, the most important and relevant concepts patients used to describe scar appearance were color, size (height, width, thickness), and texture. The most important and relevant scar symptom concepts reported were itchiness and pain. The most important, relevant, and bothersome scar impact concepts were limitations of wearing certain clothing and feeling self-conscious, sad, and less attractive because of the scar. The CE interviews provided rich information about how patients perceive and experience their scars which extends beyond the typical appearance dimensions. This work is fundamental in providing the basis for the conceptual framework of the scar experience and the first steps in the development of the PR-SEQ.

We used multi-attribute theory to develop a utility elicitation instrument for people with glaucoma based on the National Eye Institute-Visual Functioning Questionnaire (NEI-VFQ), a vision specific quality of life instrument frequently used in clinical trials. NEI-VFQ responses for 1677 people enrolled in glaucoma prevention trials were analyzed to identify items responsive to differences in vision status. We then constructed a conjoint interview administered to 48 people with glaucoma and identified the 6 items of greatest importance to people with glaucoma. Using these results, we constructed a web-based interview using standard gamble (SG) and visual analog scales(VAS) administered to a community sample of 404 people. The five attributes most important to people with glaucoma (and responsive to change in disease status) were: ability to read, driving at night, ability to leave home, needing help with activities and ability to accomplish tasks. We added a sixth attribute, peripheral vision, even though it was not rated highly by the participants as this is an important function lost early in the disease process. Final utility estimates were made using a method similar to that employed in the Health Utility Index. The results had excellent face validity and we note the range of utility loss from mild loss of function to severe difficulty: 1) Ability to read (0.011-0.039); 2) Driving at night (0.011-0.037); 3) Leaving home (0.014-0.056); 4) Needing help with activities (0.027-0.063); 5) Ability to accomplish tasks (0.016-0.046); and 6) Peripheral vision (0.008-0.032). We have developed an instrument that can be used to estimate the utility loss in people with glaucoma based upon the NEI-VFQ. When used in clinical trials, the instrument will provide an estimate of the utility loss associated with the progression of glaucoma. Further work will be required to refine and validate these estimates.

The aim of this study was to develop an instrument to assess patient-reported outcomes (PRO) in children / adolescents with short stature. This instrument is intended to focus on quality of life from children/ adolescents as well as from parent perspectives, and to be applicable to clinical studies ranging from RCTs to surveillance designs, with a major focus on the impact of Idiopathic Short Stature (ISS) and Growth Hormone Deficiency (GHD) and its treatment. Based on international guidelines of PRO-Instrument development the QOLISSY tool was designed simultaneously in five countries using focus groups, cognitive debriefing and pilot testing in 196 children and adolescents as well as 239 parents. This procedure yielded a psychometrically pretested version of the instrument.

Les troubles de croissance influencent la qualité de vie des patients. Le projet QoLISSY développe simultanément en cinq langues un instrument d’évaluation de l’impact de la petite taille sur les enfants (ISS/GHD, 3 groupes 4-7, 8-12, 13-16 ans) et leurs parents. Conformément aux recommandations internationales, des focus groups, des entretiens cognitifs, une étude pilote et de terrain sont réalisés. Vingt-quatre enfants (taille < -2DS) par pays et leurs parents ont été recrutés lors des focus groups selon l’âge, le sexe, le diagnostic (ISS/GHD) et le traitement par GH (oui/non). Cent sept enfants (8-16 ans) et 124 parents (enfants de 4-16 ans) ont participé aux focus groups. Le contenu en a été transcrit puis réduit en expressions-clé et enfin en items. L’instrument de mesure émanant de ces items a été présenté à 24 enfants et leurs parents par pays (débriefing cognitif). Les résultats préliminaires ont mis en évidence des différences interindividuelles et transculturelles, suggérant un modèle complexe de compréhension du fonctionnement global des patients. Ceci encourage les recherches sur la façon dont le traitement influence la qualité de vie des enfants de petite taille et de leurs familles.