Cost Effectiveness of Fremanezumab in Episodic and Chronic Migraine Patients from a Japanese Healthcare Perspective.

BACKGROUND AND OBJECTIVES: Fremanezumab is an effective treatment for episodic (EM) and chronic migraine (CM) patients in Japan, but its cost effectiveness remains unknown. The objective of this study was to determine the cost effectiveness of fremanezumab compared with standard of care (SOC) in previously treated EM and CM patients from a Japanese healthcare perspective. METHODS: Estimated regression models were implemented in a probabilistic Markov model to inform effectiveness and health-related quality-of-life data for fremanezumab and SOC. The model was further populated with data from the literature. The adjusted Japanese healthcare perspective included productivity losses. The main model outcomes were quality-adjusted life-years (QALYs), costs (2022 Japanese Yen [¥]), and incremental outcomes including the incremental cost-effectiveness ratio (ICER). Analyses were performed separately for the EM and CM patients and combined. Costs and effects were discounted at an annual rate of 2.0%. RESULTS: The mean QALYs over a 25-year time horizon for the EM and CM populations combined were 13.03 for SOC and 13.15 for fremanezumab. The associated costs were ¥27,550,292 for SOC and ¥28,371,048 for fremanezumab. QALYs were higher and costs lower for EM patients compared with CM patients for both fremanezumab and SOC. The deterministic ICERs of fremanezumab versus SOC were ¥6,334,861 for EM, ¥7,393,824 for CM, and ¥6,530,398 for EM and CM combined. Indirect costs and choice of mean migraine days model distribution had a substantial impact on the ICER. CONCLUSION: Using fremanezumab in a heterogeneous mixture of Japanese EM and CM patients resulted in a reduction of monthly migraine days and thus more QALYs compared with SOC. The cost effectiveness of fremanezumab versus SOC in EM and CM patients resulted in an ICER of ¥6,530,398, from an adjusted Japanese public healthcare perspective.

Fremanezumab is an effective treatment for episodic and chronic migraine patients in Japan, but it is unknown how the costs relate to the health benefits. The current research determined the relation between costs and effects of fremanezumab compared with the current standard of care in Japanese clinical practice, to see if the costs are justified by the health benefits. A model was used to inform the treatment effect of fremanezumab and standard of care. Data on costs, the frequency in which health care was used, and impairment of work due to migraine were also included in the model and obtained from the literature. The main outcomes were the number of years that patients were alive while taking their quality of life into account, costs, and the difference in these outcomes between patients who were treated with fremanezumab and those receiving standard of care. Subsequently, it was estimated how costs and effects related to one another and whether the costs were justified by the health benefits. The outcomes showed that patients treated with fremanezumab had a better quality of life compared with those receiving standard of care, while the costs associated with fremanezumab were higher. Compared with standard of care, the health benefits of treating patients with fremanezumab were justified by the costs within an acceptable range. Taking the absence from work due to illness into account had a substantial impact on the model outcomes.

Sensitivity analyses in longitudinal clinical trials via distributional imputation.

Missing data is inevitable in longitudinal clinical trials. Conventionally, the missing at random assumption is assumed to handle missingness, which however is unverifiable empirically. Thus, sensitivity analyses are critically important to assess the robustness of the study conclusions against untestable assumptions. Toward this end, regulatory agencies and the pharmaceutical industry use sensitivity models such as return-to-baseline, control-based, and washout imputation, following the ICH E9(R1) guidance. Multiple imputation is popular in sensitivity analyses; however, it may be inefficient and result in an unsatisfying interval estimation by Rubin's combining rule. We propose distributional imputation in sensitivity analysis, which imputes each missing value by samples from its target imputation model given the observed data. Drawn on the idea of Monte Carlo integration, the distributional imputation estimator solves the mean estimating equations of the imputed dataset. It is fully efficient with theoretical guarantees. Moreover, we propose weighted bootstrap to obtain a consistent variance estimator, taking into account the variabilities due to model parameter estimation and target parameter estimation. The superiority of the distributional imputation framework is validated in the simulation study and an antidepressant longitudinal clinical trial.

Assessment of the Minimum Clinically Important Difference in Symptoms and Functions of Patients With Acute Schizophrenia: A Post hoc Analysis of an Open-Label, Single-Arm Multicenter Study.

The purpose of this study was to evaluate the application of the minimum clinically important difference (MCID) concept to clinical results in Chinese patients with acutely exacerbated schizophrenia. The original study was an 8-week, open-label, single-arm, multicenter study of flexible doses of paliperidone-extended release (pali-ER) in Chinese patients with acutely exacerbated schizophrenia. This is a post hoc analysis to determine the MCID value of PANSS, PSP and evaluate the responsiveness of each outcome measurements in the acute phase of schizophrenia. The responsiveness of the four measurements (PANSS, PANSS reduction rate, PSP, CGI-S) was analyzed. Four hundred ninety nine patients completed the 8-week follow-up and were finally used for this post hoc analysis. The MCID calculated by different approaches varied from 14.02 to 31.50 for PANSS, 15.14 to 42.79% for PANSS reduction rate, and 7.62 to 13.13% for PSP. In addition, the improvement of the CGI-S owned the highest responsiveness of the four outcome measurements. The threshold value of MCID for schizophrenia patients was determined by choice of the assessment method to an extent. In addition, the CGI-S score appeared to be the most valid and responsive measure of effectiveness for the acute phase of schizophrenia when take the treatment satisfaction of patients as anchor.

Assessment of pharmacokinetic interaction between rilotumumab and epirubicin, cisplatin and capecitabine (ECX) in a Phase 3 study in gastric cancer.

AIMS: Rilotumumab is a fully human monoclonal antibody investigated for the treatment of MET-positive gastric cancer. The aim of this study was to evaluate the potential pharmacokinetic (PK)-based drug-drug interaction (DDI) between rilotumumab and epirubicin (E), cisplatin(C) and capecitabine (X). METHODS: This was a Phase 3 double-blind, placebo-controlled study, in which rilotumumab, epirubicin and cisplatin were administered intravenously at 15 mg kg-1 , 50 mg m-2 , and 60 mg m-2 Q3W, respectively, while capecitabine was given orally at 625 mg m-2 twice daily. Rilotumumab PK samples were taken at pre-dose and at the end-of-infusion from all patients in cycles 1, 3, 5 and 7. ECX PK samples were taken in cycle 3 from patients who participated in the intensive PK assessment. ECX PK was assessed by non-compartmental (NCA) analyses and PK parameters were compared between two arms. Rilotumumab PK was assessed by comparing the observed rilotumumab serum concentrations with model-predicted concentrations using a population PK model developed from previous Phase 1 and Phase 2 studies. RESULTS: The study enrolled 609 patients. ECX plasma concentrations in the presence and absence of rilotumumab were similar, as demonstrated by the geometric mean ratios for Cmax and AUC, which were close to 1.0, suggesting ECX PK was not affected by co-administration of rilotumumab. The observed rilotumumab serum concentrations were similar to the values predicted by population PK modelling on the basis of a prediction-corrected visual predictive check, indicating rilotumumab exposure was not affected by co-administration of ECX. CONCLUSIONS: The results suggest lack of PK-based DDI between rilotumumab and ECX.

Assessment of the minimum clinically important difference in neurological function and quality of life after surgery in cervical spondylotic myelopathy patients: a prospective cohort study.

PURPOSE: The purpose of this study was to evaluate the application of the minimum clinically important difference (MCID) concept to postoperative clinical results by using a prospective cohort study in Chinese patients with cervical spondylotic myelopathy (CSM). METHODS: The sample consisted of 113 patients who underwent surgical treatment for CSM in our hospital between February 2008 and November 2012. The preoperative and 1-year postoperative modified Japanese Orthopaedic Association (mJOA) scores, mJOA score recovery rate, physical component summary (PCS) and mental component summary (MCS) of the Short Form 36 were collected. The MCID of each outcome measurement was calculated by four approaches including average change, minimum detectable change, change difference and receiver operating characteristic curve. The responsiveness of each measurement was then analyzed. RESULTS: The patients presented a statistically significant improvement (p < 0.01) postoperatively in mJOA, PCS, and MCS. The MCID calculated by four approaches varied from 4.09 to 9.62 for the PCS, 3.11 to 7.41 for the MCS, 1.25 to 3.07 for mJOA score, and 31.37 to 44.02% for mJOA recovery rate. In addition, the improvement of the mJOA score owned the highest responsiveness of the four outcome measurements. CONCLUSIONS: The threshold value of the MCID was determined by the choice of the assessment approach. In addition, the recovery rate of the mJOA score appeared to be the most valid and responsive measure of effectiveness of surgery in CSM patients.

Assessment of health-related quality of life using the SF-36 in Chinese cervical spondylotic myelopathy patients after surgery and its consistency with neurological function assessment: a cohort study.

BACKGROUND: We aimed to calculate the responsiveness and statistically prove the reliability of the Medical Outcomes Study Short Form Health Survey (SF-36) in a prospective cohort study. We investigated the profile of mid-term health-related quality of life (QOL) outcome assessments after surgery for cervical spondylotic myelopathy (CSM) and determined the consistency of the SF-36 assessments of neurological function. METHODS: A total of 142 consecutive patients with CSM who underwent surgery were enrolled in the study. QOL and neurological assessments were evaluated before and at 3 months, 1 year, and more than 2 years postoperatively. We subsequently analyzed the reliability and responsiveness of the SF-36 and the QOL profile for its consistency regarding the neurological function assessment. RESULTS: (1) Cronbach's α ranged from 0.73 (for role-emotional) to 0.85 (for physical function). The effect size ranged from 0.57 to 0.93 for SF-36's eight scales. Minimum clinically important differences (MCIDs) in the physical scores (PCS) and mental scores (MCS) were 5.52 and 3.43, respectively. (2) The scores for all SF-36 scale sections indicated that patients with CSM were significantly impaired compared with healthy adults. SF-36 PCS and MCS peaked at 17.7 and 18.9 months after surgery, respectively. (3) At 3 months after surgery, improvements in the modified Japanese Orthopaedic Association (mJOA) scores significantly correlated only with patients' physical function and bodily pain scores. At 1 year after surgery, improvements in the mJOA scores significantly correlated with physical function, general health, social function, and role-emotional. At the final follow-up, improvements in the mJOA scores significantly correlated with physical function, vitality, and role-emotional. CONCLUSIONS: SF-36 is reliable and has moderate responsiveness for evaluating patients with CSM, with MCID at 5.52 for the PCS and at 3.43 for the MCS. The preoperative QOL of the CSM patients was severely impaired compared with that of the normal population. Postoperatively, each SF-36 domain improved to a variable degree. During the early stage of recovery the mJOA score improvements correlated with SF-36's physical component domains, whereas during the later stages the improvements were associated with the mental component domains.

Human health risk assessment of groundwater in Hetao Plain (Inner Mongolia Autonomous Region, China).

Groundwater quality significantly affects public health. In order to better understand groundwater suitability, a total of 887 shallow groundwater samples were collected from the Hetao Plain (HP), Inner Mongolia, China; the maximum and minimum health guideline values of each element were established in this work. Subsequently, the desirability functions (DFs) theory was employed to evaluate the human health risk of groundwater. The results indicate that 780 of the samples were unsuitable for drinking purposes due to the iron, total dissolved solids (TDS), arsenic, strontium, fluoride, and manganese concentrations present, all of which exceeded their maximum guideline value (MaGV). Only 107 samples were suitable for drinking use; however, these samples also have adverse effects on human health to some extent, due to the extremely lower concentrations of nutrient elements and existence of non-nutrient elements. Based on the observed results, groundwater that is unsuitable for drinking use must undergo bacteriological treatment prior to consumption. It was necessary for residents in the western, central, and northeastern parts of the study area are required to be supplied with certain nutrient elements, such as iron, iodine, molybdenum, manganese, and lithium. According to the human health risk assessment of groundwater, the general public can safely and reasonably consume the groundwater for drinking, agriculture irrigation, and industrial purposes.

Assessment of competency in electrocardiogram interpretation of graduating physician assistant students.

PURPOSE: This study assessed the competency in electrocardiogram (ECG) interpretation of the 2011 physician assistant (PA) class at George Washington University School of Medicine and Health Sciences. METHODS: A survey and 22-item ECG examination were completed by 51 students prior to graduation. Six strips were critical ECGs. RESULTS: The students scored 50.7% on the 22 ECGs and 68.0% on the six critical ECGs. Students who were more confident regarding their ability to accurately interpret ECGs and those who took a cardiology elective performed statistically significantly better on the 22 ECG examination (P = .005 and P = .032 respectively) but not on the six critical ECGs (P = .130 and P = .132 respectively). There were no significant associations between scores on either the 22 ECGs or six critical ECGs and students' perceived sufficiency of ECG training and desire for more ECG training. CONCLUSION: The students' overall scores indicate the need for improved training in ECG interpretation skills.