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Albert Farrugia,1,2 Declan Noone,3 Uwe Schlenkrich,4 Steffen Schlenkrich,5 Brian O'Mahony,3 Josephine Cassar6 1School of Surgery, QEII Medical Centre, The University of Western Australia (M509), Crawley, WA, Australia; 2College of Medicine, Medicine and Environment, Australian National University, Canberra, WA, Australia; 3Irish Haemophilia Society, Dublin, Ireland; 4Deutsche Hämophiliegesellschaft (DHG), Hamburg, Germany; 5Am Holzbiel, Erfurt-Töttleben, Germany; 6Faculty of Health, University of Canberra, Canberra, WA, Australia Abstract: Following the obviation of the pathogen safety threats posed by previous generations of clotting factor concentrates for the treatment of hemophilia, the principal issue facing the patient community is timely access to adequate supplies of continuously improving therapies. The application of evidence-based medicine has enhanced the basis of hemophilia therapy, while resulting in some challenges to patient care. Increasingly, the criteria used for the approval and payment of treatment products by regulatory and reimbursement agencies, respectively, are becoming inflexible and unrealistic. This is occurring particularly in the requirements for demonstrating product efficacy. Concurrently, emerging evidence of the interpatient variability in the clinical response to therapy has led to the proposed personalization of therapeutic regimens. Possible impediments to optimal care include competitive tensions among suppliers who seek to gain label claims for reimbursement purposes, which result in clinical trial designs of, arguably, unethical design, carried out in poor countries. We synthesize these converging developments to suggest some changes to the current hemophilia treatment paradigm, which should make it more patient-centric and enable speedier access to new therapies. Keywords: hemophilia, treatment products, clinical trials, standards, reimbursement

Aim: To establish any differences between patients with and without a diagnosis of personality disorders, being treated in a secure inpatient service for offenders with intellectual disability (ID) in the UK. Method: A cohort study involving a selected population of people with ID and offending behaviours. Results: The study included a total of 138 patients, treated over a 6 year period--77 with a dissocial or emotionally unstable personality disorder and 61 without. Women were more likely to be in the personality disorder group. Both groups had high prevalence of abuse with no significant differences. Depressive disorders and substance abuse were more common in the personality disorder group, while epilepsy and autistic spectrum disorders were more common in the non-personality disorder group. Rather than differences, what was more striking was the rate and range of these comorbidities across both groups. Although past histories of violence and institutional aggression were no different, compulsory detention under criminal sections and restriction orders were more common in the personality disorder group. There were no differences in treatment outcomes. Conclusions: Although about half of patients detained in secure units for offenders with ID have a personality disorder, there were more similarities than differences between this group and the rest. While good treatment outcomes supported the case for specialised secure treatment units for people with ID, the case for establishing a more specialised ID-personality disorder unit was less convincing. There is also a need to explore whether there are alternative diagnostic models that can delineate better the group with personality difficulties in this population.

Gene therapy presents a potentially transformational approach to haemophilia management. The patient journey for gene therapy is unlike that for other haemophilia treatments, and its one-time, irreversible nature has led to broad agreement that informed shared decision-making is essential. Understanding the educational and support needs of people with haemophilia (PwH) who may consider or undergo gene therapy in the future is key to enabling this. A one-day patient advisory board was conducted with the aim of gaining insights on what education and support would enable PwH to have appropriate conversations with health care practitioners (HCPs) about gene therapy and participate in informed shared decision-making. The participants were 11 age-diverse men with severe haemophilia A or B, including six who had received gene therapy in phase 1-3 clinical trials. Two were members of a national patient organisation or a patient organisation leader. Participants agreed that informed shared decision-making was essential for gene therapy, but most felt the choice to have gene therapy would be limited by healthcare budgets and access arrangements. They identified key education needed by PwH to enable true informed decision-making, best delivered through a collaborative approach by patient organisations and HCPs. Eligibility criteria should be more widely shared within the community as part of general education around gene therapy. Gene therapy should be presented as one of a range of treatment options; understanding its risks, uncertainties and benefits is key to managing expectations and minimising treatment remorse. Awareness of how different factor levels impact bleeding tendency and frequency would be helpful, as success of gene therapy cannot be determined by factor activity alone. Other key educational needs included follow-up commitments, the role and potential side effects of corticosteroids or other immunosuppressants, impact on sense of identity, mental health, family planning, and managing bleeds after gene therapy. Teach-back could help ensure appropriate levels of understanding; psychological support could aid managing expectations. Peer-to-peer learning delivered across a variety of platforms, to share experiences of gene therapy and contextualise more ‘formal’ gene therapy education, was considered invaluable.

As gene therapy for haemophilia is now licensed in Europe, and the hub and spoke approach is widely promoted for its delivery and follow-up, it is essential that people with haemophilia (PwH) who are eligible and opt to have this treatment are enabled to obtain the maximum benefit. Ensuring the pathway that makes up the patient gene therapy journey is effective is key to achieving this. EAHAD and the EHC have recommended that gene therapy is delivered through a hub and spoke model of care to ensure that the right expertise is available throughout the various stages of the haemophilia gene therapy journey. Effective communication between hub and spoke centres is essential, and the processes that make up the journey must be understood clearly by both PwH and the multidisciplinary teams delivering their care. The starting point for this is to take each step of the gene therapy journey in turn – through initial engagement, eligibility, detailed patient education, informed decision-making, dosing, and follow up in year 1, year 2 and beyond – and to consider and identify the roles and responsibilities of the patient, the hub centre and the spoke centre. It is important that the expectations of both health care practitioners (HCPs) and patients are aligned with the key challenges and goals associated with each step. Understanding these from the patient point of view will help to ensure that the individual PwH treading this path receive the information, guidance and support they need from hub and spoke HCPs throughout their journey, and that they, as the patient, remain the focus of care. Visualising the journey may help to explain the gene therapy clinical pathway to PwH and could provide a useful tool for HCPs in spoke centres. Visualisation may also serve as a tool for facilitating discussion, not only in terms of initial engagement and education, but throughout the haemophilia gene therapy journey.

Introduction: Growing budgetary demands have led to increased scrutiny of healthcare spending for rare diseases, leading to a unified goal within the haemophilia community to define objectively patient‐centred value in haemophilia care. Aim: To develop a patient‐centred outcomes framework with global applicability for assessing value in haemophilia healthcare. Methods: An international, multidisciplinary panel of experts convened to identify the range of patient impacts of haemophilia health care and organize these into a three‐tiered, patient‐centred outcomes framework based on Porter's model for assessing value. Results: In addition to measures common to other chronic diseases (eg survival and quality of life), Tier 1, health status achieved or retained, includes haemophilia‐specific outcomes of bleeding frequency, musculoskeletal complications and life‐threatening bleeds, as well as measures of function or activity. Tier 2, process of recovery, includes such outcomes as time to initial treatment, time to recovery and time missed at education/work; also included are disutility of care, measured by inhibitor development, pathogen transmission/infections, orthopaedic intervention and difficult venous access. Tier 3, sustainability of health, is measured by bleed avoidance, maintenance of productive lives and good health over time; potential long‐term negative consequences include insufficient or inappropriate therapy and age‐related complications. The applicability of the outcomes framework for different types of haemophilia healthcare interventions is described. Conclusion: Haemophilia health care can affect multiple patient‐centred outcomes across diverse patient types and healthcare systems. This framework organizes those outcomes for informing value‐based decision making by multiple stakeholders and provides the basis for further refinement and development of a standardized outcomes set. [ABSTRACT FROM AUTHOR]

The current standard of care for treating people with haemophilia (PWH) in the developed world is prophylaxis with regular infusions of clotting factor concentrates. Gene therapy is being investigated as a new treatment paradigm for haemophilia and if approved would potentially eliminate the need for chronic, burdensome infusions. In recent years, shared decision making (SDM) has become increasingly common in patient care settings. SDM is a stepwise process that relies on reciprocal information sharing between the practitioner and patient, resulting in health care decisions stemming from the informed preferences of both parties. SDM represents a departure from the traditional, paternalistic clinical model where the practitioner drives the treatment decision and the patient passively defers to this decision. As the potential introduction of gene therapy in haemophilia may transform the current standard of care, and impact disease management and goals in unique ways, both practitioners and PWH may find their knowledge tested when considering the appropriate use of a novel technology. Therefore, it is incumbent upon haemophilia practitioners to foster an open, trusting, and supportive relationship with their patients, while PWH and their caregivers must be knowledgeable and feel empowered to participate in the decision making process to achieve truly shared treatment decisions.

Haemophilia is an inherited bleeding disorder characterised by spontaneous bleeding, often leading to impaired health-related quality of life (HRQoL). Commonly used treatments include episodic and prophylactic treatment regimens. Gene therapies could soon become available, potentially creating a paradigm shift in patient management.

Introduction Prior to the introduction of viral inactivation of factor concentrates and screening of blood, 225 people with haemophilia became infected with hepatitis C ( HCV) in Ireland. Aim Our aim was to assess liver disease progression and mortality in this population after 30 years of infection. Methods Demographic and clinical data were collected from medical records in five hepatology units and one infectious disease unit retrospectively in 2005, and on four subsequent occasions. Results The participation rate was 73% (165/225). Eighty three percent of patients, who had been tested for RNA ( n = 106/128), developed chronic HCV infection. Thirty four percent were co-infected with HIV. All-cause mortality, after approximately 30 years of infection with chronic HCV, was 44% in HIV positive patients and 29% in HIV negative patients. Liver-related mortality was 12.5% and did not vary significantly by HIV status. Thirty seven percent of patients had developed advanced liver disease, including 20% with cirrhosis and 9% with hepatocellular carcinoma. In the pre-interferon-free direct acting antivirals era, 57% ( n = 60/106) of patients were treated for HCV, 65% of whom achieved a sustained virological response. Successfully treated patients had few adverse liver outcomes. Conclusion After 30 years of infection, 40% of the patients who had evidence of chronic HCV had developed advanced liver disease, such as cirrhosis and HCC, or had died from liver-related causes. This proportion is high relative to similar international cohorts despite good anti- HCV treatment uptake and responses. [ABSTRACT FROM AUTHOR]

Introduction This report summarizes recommendations relating to haemophilia therapy arising from discussions among experts from 36 European countries during the 'Kreuth IV' meeting in May 2016. Aim The objective of the meeting was for experts in the field of haemophilia from across Europe to draft resolutions regarding current issues relating to the treatment of haemophilia. Results Hospitals providing clinical care for people with haemophilia and related disorders are strongly recommended to seek formal designation as either European Haemophilia Treatment Centres ( EHTC) or European Haemophilia Comprehensive Care Centres ( EHCCC). There should be agreed national protocols or guidelines on management of the ageing patient with haemophilia. The minimum consumption of factor VIII and IX concentrate in any country should be 4 IU and 0.5 IU per capita of general population respectively. Treatment for hepatitis C with direct-acting antiviral agents should be provided to all people with haemophilia on a priority basis. Genotype analysis should be offered to all patients with severe haemophilia. Genetic counselling, when given, should encompass the recommendation that genetic relatives of the affected person be advised to seek genetic counselling. People with inhibitors should have access to bypassing agents, immune tolerance and elective surgery. National or regional tenders for factor concentrates are encouraged. Outcome data including health related quality of life should be collected. Treatment with extended half-life factors should be individualized and protection against bleeding should be improved by increasing trough levels. Steps should be taken to understand and minimize the risk of inhibitor development. Conclusion It is hoped that these recommendations will help to foster equity of haemophilia care throughout Europe. [ABSTRACT FROM AUTHOR]

Introduction Procurement of coagulation factor concentrates ( CFCs) for the treatment of haemophilia is a vital process that determines the quantity and quality of factor replacement therapy. Aim The aim of this study was to examine the different tender and procurement systems used in Europe for the procurement of CFCs and the outcomes produced by the various systems. Methods The survey questionnaire consisted of 30 items and explored various aspects of the procurement process including the prices of CFCs. In 2014, the survey was sent out by the European Haemophilia Consortium ( EHC) to 45 national haemophilia patient organizations affiliated to the EHC in all European countries as well as to a designated clinician familiar with the procurement process. Results The survey was completed by 38 European countries. Nineteen countries use a tender process, 17 an alternative procurement process and 2 use a combination of methods. A wide variety of agencies and individuals are involved in the process. Factors associated with optimum outcome and lower prices include a tender process with a specific legal framework and a tender board including haemophilia clinicians and patient organization representatives. Safety was reported as the most important selection criterion but given the safety profile of almost all currently licensed products, price was the main criterion used in many countries. Conclusion The involvement of both clinicians and patient organizations greatly improves the outcome of a tender or procurement process, as does the presence of a legal framework that governs the process. [ABSTRACT FROM AUTHOR]

A questionnaire was circulated in 2012 to national haemophilia patient organizations in Europe affiliated to the European Haemophilia Consortium ( EHC) and the World Federation of Hemophilia ( WFH) to seek information about the organization of haemophilia care and treatment available at a national level. The 35 responses received highlighted major differences in the availability of treatment and care. There was a wide range in factor VIII consumption with usage ranging from 0.20 IU per capita in Armenia to 8.56 IU per capita in Sweden (median: IU per capita). The decrease in health budgets in many countries was not matched by decreases in use of FVIII per capita. In the 19 countries that responded to the previous survey, there was a significant improvement in access to prophylaxis and home treatment. [ABSTRACT FROM AUTHOR]

Prophylaxis has been established as the treatment of choice in children with haemophilia and its continuation into the adult years has been shown to decrease morbidity throughout life. The cost of factor therapy has made the option questionable in cost-effectiveness studies. The role of prophylaxis in pharmacokinetic dosage and tolerization against inhibitor formation were used to model the cost utility of prophylaxis vs. on-demand ( OD) therapy over a lifetime horizon in severe haemophilia A. The model was applied to a single provider national health system exemplified by the United Kingdom's National Health Service and a third party provider in the United States. The incremental cost-effectiveness ratio ( ICER) was estimated and compared to threshold values used by payer agencies to guide reimbursement decisions. A cost per quality-adjusted life year ( QALY) was also estimated for Sweden. Prophylaxis was dominant over OD treatment in the UK. The model resulted in an ICER - $68 000 - within the range of treatments reimbursed in the USA. In Sweden, a cost/ QALY of SEK 1.1 million was also within the range of reimbursed treatments in that country. Dosage- and treatment-induced inhibitor incidence were the most important variables in the model. Subject to continuing clinical evidence of the effectiveness of pharmacokinetic dosage and the role of prophylaxis in decreasing inhibitor incidence, treatment for life with prophylaxis is a cost-effective therapy, using current criteria for the reimbursement of health care technologies in a number of countries. [ABSTRACT FROM AUTHOR]

A number of studies have been published on the benefits of prophylactic treatment in adults with haemophilia. However, in many countries, it is considered as optional due to financial constraints. This survey was carried out to examine the long-term effects of prophylaxis and the continuing benefit of the treatment into adulthood. Self-assessed health-related data and the EQ-5D questionnaire measuring health utility were collected from 124 men (26.9 ± 4.6 years) from Canada ( N = 40), France ( N = 14), Ireland ( N = 17), the Netherlands ( N = 16), Poland ( N = 24) and the UK ( N = 13). The respondents were split into four groups: On-Demand, <50% life on prophylaxis, ≥50% life on prophylaxis, Prophylaxis. Overall, long-term prophylaxis results in lower presence of target joints ( P ≤ 0.001), occurrence of serious bleeding episodes ( P ≤ 0.05), recurring bleeding episodes ( P ≤ 0.01) and requirement for surgical procedures ( P ≤ 0.05). Furthermore, health utility ( P ≤ 0.01) in the On-demand group was significantly lower ( P ≤ 0.01) compared to the ≥50% life on prophylaxis and the Prophylaxis group. No significant differences between countries were found except between the Netherlands and Poland, with Poland showing the lowest health utility ( P ≤ 0.01) and the most problems with mobility ( P ≤ 0.05) and pain/discomfort ( P ≤ 0.001). The Netherlands showed the highest health utility (0.915) followed by Canada (0.791), Ireland (0.786), UK (0.768), France (0.687) and Poland (0.629). The results demonstrate consistently higher quality of life of individuals who are on long-term prophylactic treatment when compared to on-demand treatment or intermittent prophylaxis and on -demand treatment. [ABSTRACT FROM AUTHOR]

The article focuses on the Dublin Consensus Statement 2011 in Dublin, Ireland regarding blood components provision, principles of collection, and plasma-derived medicinal products (PDMPs). It says that the patient must be the center of the plasma industry and blood establishments. It mentions that the people involved in the plasma and blood donation process must be respected. Furthermore, the cooperation and the utilization of donated plasma and blood worldwide is discussed.

In 2009, a questionnaire was circulated to 19 national haemophilia patient organizations in Europe affiliated to the European Haemophilia Consortium (EHC) and the World Federation of Hemophilia (WFH) to seek information about the organization of haemophilia care and treatment available at a national level. The responses received highlighted differences in the level of care despite the recent promulgation of consensus guidelines designed to standardize the care of haemophilia throughout the continent of Europe. There was a wide range in factor VIII consumption with usage ranging from 0.38 IU per capita in Romania to 8.7 IU per capita in Sweden (median: 3.6 IU per capita). Despite the specific inclusion of coagulation factor concentrate in the WHO list of essential medications, cryoprecipitate is still used in some eastern European countries. [ABSTRACT FROM AUTHOR]

This paper describes an innovative, multi-modular group therapy programme based on cognitive-behavioural principles and psycho-education. It introduces participants to strategies and skills to assist with deficits such as poor social skills, low self-esteem, poor emotional regulation and problematic inter-personal relationships. The manual-based format of this programme enables members to be introduced to working in a group, and enables facilitators to obtain qualitative information about group members to promote existing skills in future treatment programmes. The core deficit areas targeted by the programme are not by any means exclusive to individuals in in-patient forensic learning disability settings, so the programme can be useful for clients with learning disability and offending behaviours who are resident in the community. [ABSTRACT FROM AUTHOR]

This paper outlines the history of the World Federation of Hemophilia (WFH) and its work. The WFH produces a number of publications each year, and conducts regular surveys and data collection. Two of its most important roles are in the provisions of programmes to developing countries, and in promoting the views of the haemophilia community on issues that impact on the lives of people with haemophilia. Further initiatives are planned in the future to increase the length and quality of life for those living with haemophilia. [ABSTRACT FROM AUTHOR]

Doctors who use handheld, or palmtop, computers say they'd be lost without them--not just for the time saved but--also for the increased efficiency in caring for patients, running a practice, and handling their daily information needs. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about the importance and benefit of patient reported outcomes (PRO) incorporating health related quality of life (HRQoL) measures within the issue.

Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study.Methods: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results.Results: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants.Conclusions: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.). [ABSTRACT FROM AUTHOR]