Mifamurtide for high-grade, resectable, nonmetastatic osteosarcoma following surgical resection: a cost-effectiveness analysis.

OBJECTIVES: Mifamurtide is an immune macrophage stimulant that when added to standard chemotherapy has demonstrated survival benefit for newly diagnosed osteosarcoma. The objectives of this study were to investigate the cost-effectiveness of adding mifamurtide to standard three- or four-agent chemotherapy for high-grade, resectable, nonmetastatic osteosarcoma following surgical resection and the issues of obtaining robust cost-effectiveness estimates for ultra-orphan drugs, given the shortage of data. METHODS: An economic evaluation was conducted from the perspective of the UK's National Health Service as part of the manufacturer's submission to the National Institute for Health and Care Excellence. The disease process was simplified to a transition through a series of health states, modeled by using a Markov approach. Data to inform the model were derived from patient-level data of Study INT-0133, published literature, and expert opinion. The final efficacy measure was life-years gained (LYG), and utilities were used to obtain quality-adjusted life-years (QALYs). RESULTS: For a 60-year time frame and a discount rate of 3.5% for outcomes, patients receiving mifamurtide benefited from an average additional 1.57 years of life and 1.34 QALYs, compared with patients receiving chemotherapy alone, giving an incremental cost-effectiveness ratio (ICER) of £58,737 per LYG and £68,734 per QALY. Because treatment effects were both substantial in restoring health and sustained over a very long period, the National Institute for Health and Care Excellence changed its guidance to allow a discount of 1.5% for outcomes to be applied in these special circumstances. By using this discount factor, it was found that patients receiving mifamurtide had an average additional 2.58 years of life and 2.20 QALYs compared with patients receiving chemotherapy alone, resulting in an ICER of £35,765 per LYG and £41,933 per QALY. CONCLUSION: Mifamurtide's ICER is cost-effective compared with that of other orphan and ultra-orphan drugs, for which prices and corresponding cost-effectiveness estimates are high.

Cost Offsets in the Treatment Journeys of Patients With Relapsed/Refractory Multiple Myeloma.

PURPOSE: Multiple new regimens are available for the treatment of relapsed/refractory multiple myeloma (RRMM). In this context, it is increasingly important to understand the differential costs of regimens used to treat RRMM. METHODS: A treatment journey for RRMM during a 12-month period of therapy was developed to reflect real-world clinical practice based on current treatment guidelines and input from hematologists/oncologists. The journey incorporated prescreening visits, laboratory tests, regimen-specific premedication, treatment-related costs, medical costs, and indirect costs. A cost model was constructed from the standard RRMM treatment pathway to compare overall, direct, and indirect costs across therapies over a 12-month period from initiation of second-line therapy and to determine cost offsets (incremental costs) associated with use of ixazomib-based therapy versus comparator regimens. According to the clinical input, the standard pathway was modified for patients with high unmet need to determine specific cost offsets in these subgroups. FINDINGS: Total costs ranged from $93,683 for bortezomib-cyclophosphamide-dexamethasone to $315,296 for daratumumab-bortezomib-dexamethasone. Drug cost comprised the highest proportion (83%-98%) of total costs of second-line therapy across regimens, which were generally highest for regimens based on recently approved agents. Indirect costs were higher for regimens that required more frequent or longer durations of drug administration, and lower for all-oral regimens. Costs were reduced among frail patients because of the use of adjusted dosing, whereas indirect costs were increased for regimens that required a greater number of clinic visits among patients with barriers to physician access. IMPLICATIONS: Cost model analyses highlight the differential direct and indirect costs associated with multiple regimens for the treatment of RRMM, including many recent new regimens. The results indicate the lower treatment burden and indirect costs associated with administering all-oral regimens compared with regimens that require frequent and/or lengthy subcutaneous or intravenous infusions. Understanding comparative costs associated with the treatment journeys of different patients with RRMM may help inform payer and patient therapeutic choices.

Systematic reviews of economic burden and health-related quality of life in patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a rare hematologic malignancy largely affecting older adults. Comorbidities may compromise fitness and eligibility for high-intensity chemotherapy (HIC). This study presents the results of two systematic reviews (SRs) assessing (1) the impact of AML and current treatments on health-related quality of life (HRQoL), and (2) the economic burden and cost drivers of AML in patients who are ineligible for HIC. METHODS: Electronic searches (MEDLINE, EMBASE, EconLit, Cochrane library) were supplemented with manual searching of conference, utility, and HTA databases. All studies reporting HRQoL or economic data for patients with AML who were ineligible for HIC were included. RESULTS: The HRQoL SR included ten studies. Patients with AML have lower baseline HRQoL than other cancer patients or the general population, and those receiving lower intensity treatment have lower HRQoL than those eligible for HIC. Low baseline HRQoL predicts poor outcomes, and treatment had variable effects on HRQoL. The economic burden SR included nine studies. Medical costs varied widely, reflecting the heterogeneity of AML. Hospitalization is a key cost driver in AML treatment but was largely not considered in cost studies. Medical resource utilization comprised drug acquisition, drug administration, disease monitoring tests, transfusions, adverse event management, supportive care/monitoring costs and terminal care. CONCLUSION: As new drugs emerge that extend survival, assessment of HRQoL will be important to evaluate the quality of that survival. Cost data, driven by transfusions and hospitalization, will be important to evaluate the economic value of new treatments.

Review and comparison of clinical evidence submitted to support European Medicines Agency market authorization of orphan-designated oncological treatments.

BACKGROUND: Clinical trials for treatments indicated for orphan diseases may be limited due to the low prevalence of such diseases; this can result in implications for both regulatory and health economic perspectives. This study assessed the pivotal clinical evidence packages submitted to support applications for European Medicines Agency (EMA) marketing authorizations for treatments for orphan conditions, in relation to the size of the eligible patient population. METHODS: Approved treatments for EMA-designated orphan conditions (defined as life-threatening or chronically debilitating conditions that affect ≤5/10,000 people) were identified from the EMA web site. All treatments reviewed were included in anatomical therapeutic chemical (ATC) category L (antineoplastic and immunomodulating drugs): this category was selected because it is the largest ATC category, containing almost 50% of all approved orphan-designated products. Treatments were reviewed if they had been approved within the past 7 years and had been evaluated in a controlled trial using at least one survival-based clinical endpoint. Treatments were compared in terms of patient-years (accumulated duration of follow-up), the number of patients in the pivotal trials and disease prevalence. RESULTS: As of 1 February 2014, 68 treatments had been approved for orphan-designated conditions, of which 30 belonged to ATC category L and 14 met all inclusion criteria. The number of patients in the pivotal trials ranged from 162 to 846 (median 485). In terms of patient-years, the longest duration of follow-up was seen in the pivotal trial of mifamurtide in osteosarcoma, which had 4068 patient-years; excluding this trial, follow-up ranged from 308 to 2906 patient-years (median 1796 years). Osteosarcoma had the second smallest eligible patient population (0.5/10,000 persons) of the reviewed treatments. CONCLUSIONS: Clinical trials of orphan treatments are often limited by low patient numbers and inadequate follow-up. Pooling of expertise in single centres and the establishment of rare disease reference networks and patient registries may facilitate appropriate trial design for orphan-designated treatments. This analysis found that the pivotal clinical trial for mifamurtide in osteosarcoma had the largest number of patient-years of follow-up, despite a small eligible patient population, showing that it is possible to conduct studies with an adequate patient population size and duration of follow-up in patient-years, and a comparative design with clinical, survival-based, endpoints.

Influence of gender on attention-deficit/hyperactivity disorder in Europe--ADORE.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) in girls in Europe is poorly understood; it is not known whether they exhibit similar symptom patterns or co-existing problems and receive the same type of treatment as boys. OBJECTIVE: To examine gender differences for referral patterns, social demographic factors, ADHD core symptomatology, co-existing health problems, psychosocial functioning and treatment. METHODS: Baseline data from the ADHD Observational Research in Europe (ADORE) study, a 24-month, naturalistic, longitudinal observational study in 10 European countries of children (aged 6-18 years) with hyperactive/inattentive/impulsive symptoms but no previous diagnosis of ADHD, were analysed by gender. RESULTS: Data from 1,478 children were analysed: 231 girls (15.7%) and 1,222 boys (84.3%) (gender data missing for 25 patients). Gender ratios (girl:boy) varied by country, ranging from 1:3 to 1:16. Comparisons showed few gender effects in core ADHD symptomatology and clinical correlates of ADHD. Compared with boys, girls had significantly more parent-rated emotional symptoms and prosocial behaviour and were more likely to be the victim of bullying and less likely to be the bully. Girls and boys had similar levels of co-existing psychiatric and physical health problems, and received the same type of treatment. CONCLUSIONS: Fewer girls than boys are referred for ADHD treatment, but they have a similar pattern of impairment and receive similar treatment.

Which factors impact on clinician-rated impairment in children with ADHD?

OBJECTIVES: To describe the associations between a range of demographic, family and clinical factors and clinician-rated measures of global impairment in children with ADHD symptoms obtained at the baseline assessment in the ADHD Observational Research in Europe (ADORE) study. METHODS: Global impairment was measured by clinicians using the Clinical Global Impression-Severity (CGI-S) scale and the Children's Global Assessment Scale (CGAS). Associations with independent variables were investigated using forward-stepwise regression models. RESULTS: For the CGI-S and CGAS analyses, complete data sets were available for 1,265 and 985 children, respectively. The baseline mean CGI-S score in this population was 4.4 (SD 0.9) and the mean CGAS score was 55.0 (SD 10.6). Factors significantly associated with increased impairment on both outcome measures were: increased severity of ADHD symptoms, increased peer relationship problems and presence of oppositional defiant disorder and/or conduct disorder. Also, the presence of anxiety and/or depression and the presence of somatic symptoms were associated with increased impairment on CGI-S,while family health problems and premature birth were associated with increased impairment on CGAS. CONCLUSIONS: The severity of clinician-rated impairment in the ADORE sample is increased by the presence of disruptive behaviour problems and emotional problems, somatic symptoms, peer relationship difficulties, family health problems and premature birth.

Cross-cultural reliability and validity of ADHD assessed by the ADHD Rating Scale in a pan-European study.

OBJECTIVES: To provide psychometric information on the Attention-Deficit/Hyperactivity Disorder (ADHD) Rating Scale-IV (ADHD-RS-IV) in a large population of children with ADHD. METHODS: Patients aged 6-18 years (n=1,478 in baseline analysis) were rated by 244 physicians on the ADHD-RS-IV based on a semi-structured interview with the patient's parent. Physicians additionally rated functional impairment (CGAS) and health status (CGI-S), and parents rated their child's behavioural and emotional problems (SDQ) and quality of life (CHIP-CE). RESULTS: Inattention and hyperactivity-impulsivity as dimensions of ADHD were replicated. 3-factor solutions reflecting the ICD-10 definition, with hyperactivity, impulsivity and inattention as separate dimensions were extracted in some national sub-samples and in separate analyses for boys and younger children.Good internal consistencies, strong country effects and small effects of age were found. Based on ADHD-RS-IV, 88.5% of patients met the criteria for any ADHD diagnosis. Correlations between ADHD-RS-IV and measures of functional impairment were low but statistically significant. The correlations with SDQ and CHIP-CE scales confirm the convergent and divergent validity of ADHD-RS-IV. CONCLUSIONS: Impressive evidence for the cross-cultural factorial validity, internal consistency as well as convergent and divergent validity of ADHD-RS-IV was found. ADHD can be assessed reliably and validly in routine care across Europe. The ICD-10 3-factor model seems to be less robust than the DSM-IV 2-factor model, but may be a good description for special populations (boys, younger children).

Validity of the health-related quality of life assessment in the ADORE study: Parent Report Form of the CHIP-Child Edition.

OBJECTIVES: To examine the cross-sectional reliability and validity of the Parent Report Form of the Child Health and Illness Profile-Child Edition (CHIP-CE), a generic measure of health-related quality of life (HRQoL), in children with ADHD in the pan-European ADHD Observational Research in Europe (ADORE) study. METHODS: Parents of children with ADHD (aged 6-18 years) in 10 European countries completed the CHIP-CE at the baseline visit (n=1,477; data missing for one patient). Analyses included determination of internal consistency reliability, ceiling and floor effects, factor analysis, and Pearson's correlations between CHIP-CE and other scales used to measure ADHD severity, problems and family strain. RESULTS: Internal consistency reliability was good-to-excellent (Chronbach's alpha>0.70) for all CHIP-CE domains and subdomains, and almost no ceiling and floor effects were observed. Factor analysis of the subdomains yielded a 12-factor solution. The domainlevel factor analysis identified six factors, the four domains of Satisfaction, Comfort, Resilience and Risk Avoidance. The two subdomains of Achievement domain, Peer Relations and Academic Performance, were separate factors in this sample. There were moderate-to-high correlations between the CHIP-CE scales and measures of ADHD and family factors. The HRQoL of children in ADORE was dramatically lower than that of community youth,with mean CHIP-CE scores almost 2 standard deviations below community norms. CONCLUSIONS: The validity and reliability of CHIP-CE to measure HRQoL in children with ADHD across Europe was confirmed.

The Family Strain Index (FSI). Reliability, validity, and factor structure of a brief questionnaire for families of children with ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) in children affects every member of the family. Practical tools are needed to assess the effects of ADHD on families to better understand and address the level of stress, strain and burden that families experience. OBJECTIVE: To provide the preliminary reliability, validity and factor structure of the Family Strain Index (FSI), a 6-item parent-report questionnaire. METHODS: The FSI was completed by 1,477 parents of children with ADHD (aged 6-18 years) at the baseline visit of the ADORE study in 10 European countries (data missing for one patient). RESULTS: The FSI taps into an overall experience of worry and interruptions of activities in families of children with ADHD, as a single factor was identified with excellent internal consistency (alpha=0.87). Despite its brevity, almost no ceiling (worst score) or floor (best score) effects were observed for families of these highly symptomatic children. This score distribution and the 5-point response options suggest that the FSI will be responsive to changes in the experience of family strain associated with children's ADHD treatment. CONCLUSION: The ease of completion and coherence of the underlying construct indicates that the FSI may be a practical clinical tool for monitoring changes in family strain associated with children's ADHD treatment.

Factors related to health-related quality of life (HRQoL) among children with ADHD in Europe at entry into treatment.

OBJECTIVE: To describe the associations between a range of baseline factors (demographic, family and clinical) and parent-reported health-related quality of life (HRQoL) of children with ADHD taking part in the ADORE study. METHODS: HRQoL was rated using the Parent Report Form of the Child Health and Illness Profile-Child Edition (CHIP-CE). Forward-stepwise linear regression models were used to investigate associations with 26 independent variables. Separate models were fitted for each of the five CHIP-CE domains (Satisfaction, Comfort, Resilience, Risk Avoidance and Achievement) and two subdomains of Achievement (Academic Performance and Peer Relations). RESULTS: CHIP-CE domain mean scores were lower than community norms, especially for Risk Avoidance and Achievement, indicating a low level of HRQoL. Clinical factors significantly associated with a poorer HRQoL included ADHD symptoms (inattention, hyperactivity-impulsivity), conduct problems, peer relationship problems, having asthma, multiple other somatic symptoms and co-ordination problems. Family factors, such as having a parent with a health or mental health problem possibly caused by the child's illness, child not living with both parents and maternal smoking during pregnancy were also associated with a worse HRQoL in some CHIP-CE domains/subdomains. CONCLUSIONS: Numerous factors independently impact on the HRQoL of children with ADHD.

Study design, baseline patient characteristics and intervention in a cross-cultural framework: results from the ADORE study.

OBJECTIVE: To describe the methodology and to present the baseline findings of the Attention-deficit/hyperactivity Disorder Observational Research in Europe (ADORE) study, the primary objective of which is to describe the relationship between treatment regimen prescribed and quality of life of children with ADHD in actual practice. METHODS: In this 2-year prospective observational study, data on diagnosis, prescribed treatment and outcomes of ADHD were collected at seven time points by paediatricians and child psychiatrists on 1,573 children recruited in 10 European countries. The data presented here from the 1,478 patients included in the analyses describe the baseline condition, initial treatment regimen prescribed and quality of life of families with children with ADHD. RESULTS: Patients had a mean age of 9.0 years (SD 2.5) and 84% were male. Physicians diagnoses were made using DSM-IV (43%), ICD-10 (32%) and both DSM-IV and ICD-10 (12%). Mean age of awareness of a problem was 5.1 years, suggesting an average delay of approximately 4 years between awareness and diagnosis of ADHD. Baseline ADHD rating scale scores (physician-rated) indicated moderate to severe ADHD. Parent-rated SDQ scores were in agreement and suggested significant levels of co-existing problems. CGI-S, CGAS and CHIP-CE scores also indicated significant impairment. Patients were offered the following treatments after the initial assessment: pharmacotherapy (25%), psychotherapy (19%), combination of pharmacotherapy and psychotherapy (25%), other therapy (10%) and no treatment (21%). CONCLUSION: The ADORE study shows that ADHD is similarly recognised across 10 European countries and that the children are significantly impaired across a wide range of domains. In this respect, they resemble children described in previous ADHD samples.

Psychopathological screening of children with ADHD: Strengths and Difficulties Questionnaire in a pan-European study.

OBJECTIVE: To examine the psychometric properties of the Strengths and Difficulties Questionnaire (SDQ) parent version and to determine the effects of age, gender, country and investigator type (paediatrician, child psychiatrist, other physician) on the SDQ scores in the prospective, non-interventional ADORE study. METHODS: The SDQ was completed for 1,459 children with ADHD (aged 6-18 years) in 10 European countries. RESULTS: Factor analysis provided an exact replication of the original 5-factor SDQ subscale structure. All subscales were sufficiently homogeneous. The mean total difficulties and SDQ subscale scores of the ADORE sample clearly differed from UK normative data. Younger children were more impaired on different SDQ scales than older children, and girls were more emotionally affected than boys. Differences between countries were found for each SDQ scale, but the investigator type had no significant effect. Correlation coefficients between SDQ scales and other scales used in ADORE ranged from low (r<0.30) to high (r>0.50). CONCLUSIONS: The present study confirmed the validity and reliability of the parent-reported SDQ scale structure and showed that the scale scores are dependent on age and gender. In contrast to investigator type, different cultures had a significant effect on SDQ scores. Correlations with other scales used in the ADORE study underline both separate domains and meaningful associations.

Co-existing psychiatric problems in ADHD in the ADORE cohort.

OBJECTIVE: To study the impact of co-existing psychiatric problems with ADHD on behavioural features, psychosocial functioning and quality of life in subjects of the ADORE cohort (N=1,478). METHODS: The following six groups of associated psychiatric problems with ADHD were compared: oppositional-defiant disorder or conduct disorder only (ODD/CD); anxiety or depressive disorder only (ANX/DEP); tic/Tourette's disorder only (TIC/Tourette's); developmental co-ordination disorder only (DCD); two or more associated conditions; and none. Dependent variables included the ADHD Rating Scale-IV, the Strengths and Difficulties Questionnaire, the Clinical Global Impression-Severity scale, the Children's Global Assessment Scale and the Child Health Illness Profile-Child Edition. RESULTS: Having multiple co-existing psychiatric problems increased the severity of ADHD in all domains, be it behavioural features, psychosocial impairment or deterioration of quality of life. A similar though less consistent pattern applied to subjects with co-existing ODD/CD. CONCLUSIONS: The ADORE study provides impressive evidence for the far-reaching consequences of co-existing psychiatric problems in children with ADHD that warrant intensive consideration in clinical assessment and treatment.

ADORE -- Attention-Deficit Hyperactivity Disorder Observational Research in Europe.

BACKGROUND: Since there is little information about the naturalistic way of treatment in daily European practice, the Attention-Deficit Hyperactivity Disorder Observational Research in Europe (ADORE) project was designed as a prospective, non-interventional study of approximately 1,500 patients observed by approximately 300 investigators in various European regions. OBJECTIVE: The primary objective is the description of the relationship between treatment regimen prescribed and quality of life in ADHD patients over a two-year period. METHOD: The naturalistic care provided and the outcomes (psychopathology, quality of life) are recorded at 7 data collection points. RESULTS: The present preliminary report provides data on the first 315 patients who were included in the study by the beginning of January 2004. The data provide an impression of the sample characteristics, the clinical diversity, and the effects of ADHD on school careers and social activities. Furthermore, treatment information dealing with the time both before and at baseline is given. CONCLUSION: Even with this limited sample the negative effects on psychosocial development and quality of life in ADHD children are apparent.