From the voices of people with haemophilia A and their caregivers: Challenges with current treatment, their impact on quality of life and desired improvements in future therapies.

INTRODUCTION: Haemophilia A is a chronic disease requiring frequent intravenous infusions of recombinant factor VIII. Previous studies have shown that challenges associated with current treatments may have significant impacts on quality of life (QoL) that are as important as the health outcomes conferred by the therapy. Emerging therapeutic innovations offer the potential to mitigate treatment-related challenges, and it is therefore important to develop a better understanding of patient and caregiver experiences with existing haemophilia A treatments in order to characterize the full value of new treatments. AIM: To gather firsthand perspectives from people with haemophilia A (PWHA) and caregivers on the challenges with current treatment, their impact on QoL and desired improvements in future therapies. METHODS: Qualitative insights were gathered from 20 non-inhibitor PWHA or caregivers of PWHA across Canada through one-on-one interviews; insights were further explored through focus group sessions to uncover overarching themes and prioritize issues with current treatments. RESULTS: PWHA and caregivers identified several challenges, including administration of intravenous infusions, coordination of treatment schedules and ensuring adequate medication and supplies. Participants described how these challenges impact psychosocial well-being, physical health, personal/social life and work. Alternate modes of administration and longer-lasting treatment effects were identified as desired improvements over current treatments. CONCLUSION: This study emphasizes the impact that existing haemophilia A treatments have on psychological well-being, employment opportunities and adherence to treatment regimens. These considerations may help to inform decision-making for policymakers and health systems around the true value of new therapies entering the haemophilia market.

Supply and demand for hemophilia treatments-Systems-based approaches to mitigate the risk.

Treatment of hemophilia consists of replacement of the missing coagulation factor, either prophylactically or at the time of injury or bleeding. Because of the high cost of these products, which can present a barrier to care, different procurement strategies have been developed at national and regional levels. The emergence of novel therapeutic agents adds complexity to these strategies. This paper examines the benefits and challenges of these strategies, with primary reference to the Canadian context and a consideration of the concepts of value-based care.

Joint health scores in a haemophilia A cohort from Pakistan with minimal or no access to factor VIII concentrate: correlation with thrombin generation and underlying mutation.

Haemophilia A is associated with recurrent joint bleeding which leads to synovitis and debilitating arthropathy. Coagulation factor VIII level is an important determinant of bleed number and development of arthropathy . The aim of this study was to compare the haemophilia joint health score (HJHS) and Gilbert score with severity, age, thrombin generation (TG) and underlying mutation in a haemophilia A cohort which had minimal access to haemostatic replacement therapy. Ninety-two haemophilia A individuals were recruited from Pakistan. Age, age at first bleed, target joints, haemophilic arthropathy joints, HJHS and Gilbert score were recorded. A strong correlation was found between HJHS and Gilbert score (r = 0.98), both were significantly higher in severe (n = 59) compared with non-severe (n = 29) individuals before the age of 12 years (P ≤ 0.01) but not thereafter. When individuals were divided according to developmental age (<12 years, 12-16 years and >16 years), both HJHS and Gilbert score were significantly lower in the youngest group (P ≤ 0.001), there was no difference between 12-16 years and >16 years. In severe individuals there was no correlation between in vitro TG and joint score, whereas in non-severe individuals there was a weak negative correlation. In the severe group, no significant difference was observed for either joint score according to the underlying mutation type (inversion, missense, nonsense, frameshift). In this cohort of haemophilia A individuals with minimal access to haemostatic treatment, haemophilic arthropathy correlated with severity and age; among severe individuals, joint health scores did not relate to either the underlying mutation or in vitro TG.

Public expenditure for plasma-derived and recombinant medicinal products in Italy.

BACKGROUND: In Italy, the supply of plasma-derived medicinal products funded by the National Health Service can be through public healthcare facilities, accredited pharmacies or toll fractionation agreements between Regions and the manufacturer. Pharmaceutical public expenditure includes the supply related to the first two channels and costs can significantly vary because of channel-specific price reductions. This paper describes 2011 public expenditure for plasma-derived medicinal products purchased on the market, as well as the cost analysis per active substance. MATERIALS AND METHODS: Analysis of the usage of plasma-derived medicinal products and of the related expenditure in public facilities has been carried out using medicinal product traceability data. The analysis related to the accredited pharmacies channel has been carried out using quantities for every medicinal package recorded by Pharmacy Associations and applying reference prices in force on March 1(st), 2012 as well as discounts for the accredited pharmaceutical expenditure imposed by law. RESULTS: At national and regional level, total and total per capita expenditures on plasma-derived medicinal products by market channel and funded by the National Health Service are shown. Analysis was conducted considering the active substances in three groups: substances included in toll fractionation agreements, recombinant coagulation factors, and other substances not included in toll fractionation agreements. In 2011, the national expenditure estimate for plasma-derived and recombinant medicinal product acquisition on the market was about € 535 million. DISCUSSION: The purchased volumes and mean purchased prices per unit of each substance have a significant influence on the observed regional variability of the pharmaceutical public expenditure. A strategy of regional comparison aimed at both sharing a national range of reference for purchase prices and evaluating modalities for centralised purchasing is desirable.

Benefits associated with a broad selection of dosage strengths for recombinant factor VIII products.

Factor VIII (FVIII) concentrates for haemophilia A patients are dosed according to body weight. This results in a continuous range of prescribed doses, which challenges pharmacies to find dosage strengths closest to the prescribed dose while utilizing the least number of vials. This study was conducted to determine whether a broader selection of FVIII dosage strengths results in improved dispensing accuracy and an increased number of single-vial users. This research retrospectively analyzed a US pharmacy database of prescriptions filled in 2008. Recombinant FVIII (rFVIII) therapies were classified by the range of dosage strengths offered in 2008: Group 1 had three dosage strengths; Group 2 had four dosage strengths; and Group 3 had six dosage strengths. A total of 76,584 dispensed doses of rFVIII for 1,244 patients were included in this analysis. Dispensing accuracy (calculated as both the absolute and relative difference between dispensed and prescribed dose) was significantly better for Group 3 (23.2 IU, 1.2%) than Groups 1 (33.5 IU, 1.6%) and 2 (50.2 IU, 2.4%) (both P < 0.01). In addition, the average number of unique actual rFVIII potencies dispensed per month was highly correlated (-0.977) with dispensing accuracy for each dosage strength group. Among Groups 1, 2 and 3, 23.0%, 44.9% and 73.4% of patients, respectively, had at least one single vial option dispensed (P < 0.0001). A broader selection of rFVIII dosage strengths and more actual rFVIII potencies were associated with improved dispensing accuracy and more single-vial users. This may translate into less waste, cost savings, increased convenience and improved adherence to physician-prescribed regimens.

Haemophilia: provision of factors and novel therapies: World Federation of Hemophilia goals and achievements.

For nearly 50 years, the goal of the World Federation of Hemophilia (WFH) has been to achieve 'Treatment for All' patients with inherited bleeding disorders, regardless of where they live. With proper diagnosis, management and care, people with bleeding disorders can live perfectly healthy lives. Without treatment, the reality is that many will die young or, if they survive, suffer joint damage that leaves them with permanent disabilities. Only about 25% of the estimated 400 000 people with haemophilia worldwide receive adequate treatment. The percentage is far lower for those with von Willebrand Disease (VWD) and the rarer bleeding disorders. The achievements of the WFH to close the gap in care for people with bleeding disorders are measureable over time by using three key indicators; the difference in the estimated and actual number of people known with bleeding disorders, the amount of treatment products needed versus that available, and the number of people born with bleeding disorders and the number who reach adulthood. There are five essential elements to achieve a sustainable national care programme: ensuring accurate laboratory diagnosis, achieving government support, improving the care delivery system, increasing the availability of treatment products, and building a strong national patient organization.

Primary prophylaxis in children with haemophilia.

Starting from the clinical observations that moderate haemophiliacs experienced only few bleeding episodes and rarely developed significant joint deterioration (haemophilic arthropathy), and the pioneer experience in Sweden, prophylaxis (i.e. the regular and long-term administration of clotting factor concentrate in order to prevent bleeding) has been practiced for more than forty years in severe haemophilia and is currently recommended as the first choice of treatment by the World Health Organisation and World Federation of Hemophilia and by many national medical/scientific organizations. Observational studies clearly established the superiority of prophylaxis over on-demand treatment in reducing the risk of arthropathy, also showing that starting prophylaxis earlier in life and after very few joint bleeds was associated with better joint outcomes, and led to the current definitions of primary (started before the age of 2 yrs and after no more than one joint bleed) and secondary prophylaxis. More recently, evidences from randomized trials, which were previously lacking in this setting, were also provided. This review summarizes available data from which current clinical practice of primary (and early secondary) prophylaxis in children with severe haemophilia was drawn. Open issues concerning optimal regimens and barriers to the implementation of prophylaxis are also discussed.

Modelling haemophilia epidemiology and treatment modalities to estimate the unconstrained factor VIII demand.

The article presents a new method for estimating the unconstrained factor VIII (FVIII) demand based on the principles of decision analysis. Epidemiology and treatment modalities were integrated into a model for unconstrained FVIII demand. Assumptions for each variable with impact on the unconstrained FVIII demand were defined and probability estimates for these variables were obtained from the literature and medical experts. The sensitivity of the unconstrained FVIII demand to each of the variables was determined, and the variables with the greatest impact were modelled probabilistically. The probability-weighted average for the unconstrained FVIII demand model was 6.9 units per capita with a 90% uncertainty interval of 2.7-13.6 units per capita. When compared with FVIII usage in countries, only Luxembourg's use of FVIII (7.7 units per capita) exceeded the probability-weighted average for the modelled unconstrained FVIII demand. As better information becomes available, revision of model variables is easily accomplished allowing for a more accurate and dynamic forecast of demand over time. More accurate modelling of the 'true' demand longitudinally should help prevent shortages of FVIII concentrates such as those that have occurred in the past. In addition, a more accurate forecast of FVIII demand will allow national health care policy makers to better allocate financial and other resources. Sufficient and consistent supply of FVIII concentrates and appropriate financing of haemophilia care will allow the clinical benefits of more aggressive treatment regimens such as prophylaxis to be realized.

Factor replacement therapy in haemophilia--are there models for developing countries?

Successful models for factor replacement in severe haemophilia involves prophylactic or on-demand administration of large quantities (1500-9000 IU kg-1 year-1) of very high purity factor concentrates starting early in life. The prohibitive cost of these protocols make them completely impractical in developing countries where the quantity of factor used for replacement therapy is much lower and varies considerably (25-500 IU kg-1 year-1). At this level of treatment, as some joint damage is inevitable, the aim of therapy shifts to preventing disability and preserving reasonable joint function rather than perfect architecture. There are no carefully recorded data on long-term outcome of musculo-skeletal function on these doses. Appropriate studies are needed to document such data. With regard to products for factor replacement, economic compulsions lead to the use a variety of factor concentrates and blood-bank products for replacement therapy. Most patients in the developing world do not have access to adequate replacement therapy. Among the rest, some get limited quantities of plasma-derived concentrates while others use cryoprecipitate, fresh frozen plasma or even whole blood. Since the superiority of virus-inactivated purified factor concentrates in achieving the aims of replacement therapy is well established, the aim should be to provide this for all people with haemophilia. This can be achieved by production of such concentrates locally or by importing them. Different models are possible depending on the circumstances in each country.