WFH: Closing the global gap achieving optimal care

Transcription

1 DOI: /j x ORIGINAL ARTICLE WFH: Closing the global gap achieving optimal care MARK W. SKINNER World Federation of Hemophilia, Washington, DC, USA Summary. For 50 years, the World Federation of Hemophilia (WFH) has been working globally to close the gap in care and to achieve Treatment for All patients, men and women, with haemophilia and other inherited bleeding disorders, regardless of where they might live. The WFH estimates that more than one in 1000 men and women has a bleeding disorder equating to 6,900,000 worldwide. To close the gap in care between developed and developing nations a continued focus on the successful strategies deployed heretofore will be required. However, in response to the rapid advances in treatment and emerging therapeutic advances on the horizon it will also require fresh approaches and renewed strategic thinking. It is difficult to predict what each therapeutic advance on the horizon will mean for the future, but there is no doubt that we are in a golden age of research and development, which has the prospect of revolutionizing treatment once again. An improved understanding of optimal treatment is fundamental to the continued evolution of global care. The challenges of answering government and payer demands for evidence-based medicine, and cost justification for the introduction and enhancement of treatment, are ever-present and growing. To sustain and improve care it is critical to build the body of outcome data for individual patients, within haemophilia treatment centers (HTCs), nationally, regionally and globally. Emerging therapeutic advances (longer half-life therapies and gene transfer) should not be justified or brought to market based only on the notion that they will be economically more affordable, although that may be the case, but rather more importantly that they will be therapeutically more advantageous. Improvements in treatment adherence, reductions in bleeding frequency (including microhemorrhages), better management of trough levels, and improved health outcomes (including quality of life) should be the foremost considerations. As part of a new WFH strategic plan ( ) the WFH has identified several key initiatives for particular emphasis continuation of the Global Alliance for Progress (GAP) program, a new initiative to address underserved countries and regions (The Cornerstone Initiative), enhancing health outcomes research and analysis, and a new research mentorship program. Despite our progress to date in closing the global gap in care, our work is not complete. Too many patients remain undiagnosed and too few receive adequate treatment. This paper will also discuss historical, present and future challenges and opportunities to close the gap in care and achieve Treatment for All. Keywords: global alliance for progress, health outcomes analysis, optimal care, WFH development model, WFH global survey, World federation of hemophilia The WFH is the cornerstone of global development. For 50 years, the WFH has been working globally to close the gap in care and to achieve Treatment for All patients, men and women, with haemophilia and other inherited bleeding disorders, regardless of where they might live. As WFH marks its 50th anniversary, it is appropriate to reflect on the many accomplishments, milestones and Correspondence: Mark W. Skinner, JD, President, World Federation of Hemophilia, rd St NW #3A, Washington, DC , USA. Tel.: ; fax: ; mskinner@wfh.org Accepted after revision 21 May 2012 lessons learned. To close the gap in care between developed and developing nations a continued focus on the successful strategies deployed heretofore will be required. However, in response to the rapid advances in treatment and emerging therapeutic advances on the horizon it will also require fresh approaches and renewed strategic thinking. Each year we have moved one step closer to achieving our collective vision of Treatment for All. Over the past five decades of the WFH s history, there has been tremendous progress in our understanding of bleeding disorders, improvement of treatment, and enhancement of access bringing hope to patients and their families throughout the world. Nonetheless, despite our progress to date in closing the global gap in care, our work Ó 2012 Blackwell Publishing Ltd 1

2 2 M. W. SKINNER is not complete. Too many patients remain undiagnosed and too few receive adequate treatment. The WFH remains committed to its vision of achieving Treatment for All. This paper will discuss some the historical, present and future challenges and opportunities to close the gap in care and achieve Treatment for All. Discussion Historical context Over the past 50 years, we have seen enormous advances in treatment and therapies for bleeding disorders. Although access and availability vary widely around the world, our understanding of coagulation mechanisms, prevention and treatment of bleeding disorders is far different than in 1963, the year the WFH was founded. It is now well established that, with proper treatment, people with haemophilia 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. The journey to improve treatment globally began in June 1963 when Frank Schnabel, our founder and a man with severe hemophilia, convened a global meeting to establish an international haemophilia organization. There were many others involved in the early and formative years of the WFH who served either as the interim (1963) or first (1964) officers or led the medical advisory board including: Sir Weldon Balrymple- Champneys (UK), Prof. Kenneth Brinkhous (US), Henri Chaigneau (France), Dr. Cecil Harris (Canada), Dr. E. Neumark (UK), Dr. Knut-Eric Sjolin (Denmark), Prof. J.P. Soulier (France), John Walsh (US), Dr. S. Van Creveld (The Netherlands). Mr. Schnabel s opening words to those assembled still ring true. The threat to the life of just one haemophiliac would be sufficient reason for us to travel to this meeting. We are here however to help the hundreds of thousands of haemophiliacs by adding another organization which can be instrumental, in liaison with national societies [1]. What began with a meeting of representatives from 12 countries (Argentina, Australia, Belgium, Canada, Denmark, France, Germany, Japan, Netherlands, Sweden, United Kingdom and the United States) [2] has grown to become a truly global organization. During the WFH General Assembly 2012, the WFH membership is expected to expand further with the addition of Afghanistan, Mauritius, Montenegro, Uganda, and United Arab Emirates reaching 122 member countries [3]. The WFH member countries will then represent 95% of the world s population (Fig. 1). Soon after our founding, in 1969, the WFH received official recognition and entered into relations with the World Health Organization (WHO). In the early 1960s, fresh frozen plasma (FFP) was the principal therapy available for the treatment of haemophilia. At the time, the U.S. National Hemophilia Foundation (NHF) commented in its brochures, The hemophiliac cannot live unless his blood is induced to clot by the addition of normal blood (or blood plasma) and now there is fresh frozen blood plasma which can be stored to provide a constant life-saving supply [4]. Poignantly, the brochure also included a call to sponsor needed research which will some day bring a cure or a control, by solving the mystery of blood coagulation [5]. These words are certainly as relevant today as they were in the early 1960s. Although many mysteries have been solved, many still remain. Fig. 1. Map indicating the twelve countries represented in the inaugural WFH meeting in 1963 and total membership of the WFH now 122 countries in Total membership reflects countries accredited as WFH National Member Organizations (NMOs) as of the 2010 WFH General Assembly and the five proposed new NMOs presented for accreditation during the 2012 WFH General Assembly. Ó 2012 Blackwell Publishing Ltd

3 WFH: CLOSING THE GLOBAL GAP 3 In 1964, Dr. Judith Graham Pool was responsible for the next major advance. She published a method of preparing concentrated factor VIII from thawing FFP, giving rise to what we know today as cryoprecipitate. In announcing Dr. Pool s discovery, the NHF Medical Bulletin stated, Over the past several years there has been increasing recognition that concentrates of anti-hemophilic globulin have a distinct role in the treatment of hemophilia The expense involved in the production has hampered the development of such concentrate It is difficult to predict the exact role that the concentrate developed by Dr. Pool will finally play in the treatment of hemophilia [6]. Since the 1960s, we have experienced an amazing revolution in treatment. Dr. Pool s discovery changed the course of care and launched a new beginning for those living with a bleeding disorder. The later development and availability of lyophilized plasma-derived clotting factor concentrates (CFCs) (early 1970s), bypassing agents (late 1970s) and more recently the development of their recombinant analogues (FVIII 1989, FVIIa 1996, FIX 1997), brought an improved quality of life for many. Care has steadily improved around the world, with more governments taking responsibility to ensure the availability of treatment including the provision of CFCs. However, this progress did not come without a cost. The toll of HIV and hepatitis transmitted by cryoprecipitate and the early generations of plasma-derived factor CFCs, manufactured in the 1980s and early 1990s, is still being felt. Although current generations of treatment products have a robust safety profile (plasmaderived and recombinant), over 40% of the countries reporting treatment product usage data to the WFH in 2010 indicate FFP and cryoprecipitate are still used for the treatment of haemophilia [7]. The risk of viral transmission from FFP and cryoprecipitate remains a significant concern. Moreover, greater than 75% of CFCs are consumed by those living in regions representing just over 15% of the world s population [8]. Thus, it is important to think not only about how to improve the current state-of-the-art products, but also about ways in which existing therapies, important to an even larger percentage of the world s population, can advance as well. The WFH estimates that more than one in 1000 men and women has a bleeding disorder equating to conservatively 6,900,000 worldwide (Table 1). This global estimate includes haemophilia [9] and women with hemophilia (symptomatic carriers) [10 13], von Willebrand disease (VWD) [14], rarer factor deficiencies [15], Glanzmann thrombasthenia and Bernard Soulier Syndrome [7], and is based on established prevalence rates, where known, published or developed by the WFH. The prevalence of VWD is based on those presenting with bleeding symptoms to primary care physicians and is now thought to be approximately 1 per 1000 [14]. Some incidence estimates for the rarer factor deficiencies may only reflect the severe phenotypes. Additionally, geographical distribution for some of these deficiencies may vary due to consanguineous marriages. Where global prevalence data are not available the actual number of known individuals has been utilized [7]. Although available data, as reflected in the Table 1 indicate a more precise number of one (1) in 880 men Table 1. WFH global estimate of the prevalence of bleeding disorders. More than 1 in 1000 people is estimated to have a bleeding disorder. Bleeding disorder WFH published estimates WFH prevalence estimates based on a world population of 6,927,000,000 [16] Haemophilia A 105 in 1 million* (more commonly cited as 1 in 10,000 ) 363,668 Haemophilia B 28 in 1 million* (more commonly cited as 1 in 50,000 ) 96,978 Women with haemophilia 1.56 per person with haemophilia; 50% at risk of bleeding 359,303 (symptomatic carriers) Von Willebrand Disease 1,000 in 1 million* (1 per thousand with bleeding symptoms) 6,927,000 Factor I (Afibrinogenemia) 0.5 in 1 million 3,464 Factor I (Dysfibrinogenemia) 1 in 1 million 6,927 Factor II 0.5 in 1 million 3,464 Factor V 1 in 1 million 6,927 Factor V+VIII 1 in 1 million 6,927 Factor VII 2 in 1 million 13,854 Factor X 1 in 1 million 6,927 Factor XI 10 in 1 million 69,270 Factor XII Not known Factor XIII 0.33 in 1 million 2,309 Glanzmann thrombasthenia WFH identified number 1,584 Bernard-Soulier syndrome WFH identified number 323 TOTAL 7,868,924 Equals 1 person with a bleeding disorder per 880 Conservatively estimated by the WFH to be 1 person with a bleeding disorder per 1000 equating to approximately 6,900,000 worldwide. * Prevalence estimate. Incidence estimate. Ó 2012 Blackwell Publishing Ltd

4 4 M. W. SKINNER and women has a bleeding disorder, given the imprecise nature of many of the estimates, the WFH has adopted a more conservative global prevalence estimate of one (1) in 1000 men and women has a bleeding disorder. More research into the incidence and prevalence of VWD and other inherited platelet disorders is needed. We expect this global estimate to be refined over time. We seek to establish this new global estimate to better reflect the totality of all bleeding disorders, as well as to facilitate monitoring progress on patients identified over time as the world population grows and care expands globally. To date, 257,182 individuals with bleeding disorders have been identified worldwide including: 162,781 haemophilia, 65,100 VWD, and 29,301 other bleeding disorders (rarer factor deficiencies and inherited platelet disorders) [7]. Looking just at people with haemophilia, we estimate only about 25% worldwide receive at least minimally adequate treatment. The percentage is far lower for those with VWD and the other bleeding disorders. Adequate treatment means minimum access to episodic therapy with CFCs. The WFH has established that one international unit (IU) of factor (F) VIII CFC per capita should be the target minimum for countries to achieve optimal survival for the haemophilia population [17]. The consensus recommendations of an expert panel assembled by the European Directorate for the Quality of Medicines and HealthCare (EDQM) has concluded that the minimum acceptable national level of CFC use should be 2 IU per capita [18]. However, even higher levels are required to achieve a quality of life equivalent to those who do not have haemophilia. The WFH Programs Department was formally established in1996, although some WFH programs (e.g. the International Hemophilia Training Center fellowship program 1972 and Twinning program 1994) were established earlier. Through many years of country program experience, the WFH identified the essential elements for a systemic integrated model to introduce and develop sustainable national care (WFH Development Model) [19]. Currently, the five essential elements of the WFH Development Model, which are integrated and interdependent, comprise (1) ensuring accurate laboratory diagnosis; (2) achieving government support for a national program; (3) improving the care delivery system; (4) increasing the availability of treatment products; and (5) building a strong national patient organization [19]. Recently, a sixth element, the ability to track and report patient health outcomes, has emerged and going forward will be separately recognized in the Model as critical to achieving sustainable care (discussed below). Treatment for all. In the spirit of our founder Frank Schnabel s vision, the WFH has always worked to achieve Treatment for All patients with haemophilia and other inherited bleeding disorders (VWD, inherited platelet disorders and the rarer factor deficiencies), regardless of where they live. However, Treatment for All was not formalized as the WFH vision until 2006 [20]. Today, Treatment for All is the foundation upon which the overall WFH global development strategy is built [20]. Although access to safe viral-inactivated CFCs is fundamentally important, it alone is not sufficient to optimize care. It is important to note that Treatment for All means more than simply access to treatment products. It means: Proper diagnosis, management, and care by a multidisciplinary team of trained specialists; Safe, effective treatment products are available for all people with inherited bleeding disorders; Expansion of services beyond haemophilia, to those with VWD, rare factor deficiencies, and inherited platelet disorders. Introduction of multidisciplinary comprehensive care. Like the discovery of cryoprecipitate, the recognition of the importance of the provision of treatment and care in a comprehensive multidisciplinary care setting brought equally remarkable improvements in patient outcomes. The concept was first pioneered in the United Kingdom in the 1950s [21]. The WHO and WFH recommend that treatment for patients with bleeding disorders be provided in a specialized HTC where hematologists, nurses, orthopedists, physical therapists, psychologists, social workers, dentists, and others come together as a specialized multidisciplinary care team to comprehensively look after each patient s unique care needs [22 24]. The comprehensive care model has been one of the most successful public health programs in many developed countries, resulting in significantly improved health for patients with haemophilia as well as producing a reduction in healthcare utilization [25]. It is an essential feature of national health systems desiring to achieve the best health outcomes for their patients. The improved outcomes in morbidity and mortality when comprehensive care occurs within an HTC setting are well established [26]. As care expands within a country, national networks of HTCs are typically established to ensure coordinated, localized, and rapid treatment access across a country. Because care for those living with a bleeding disorder is complex, specialized, and affects many other areas of the patient s physical and mental health, the needs of the patient are best met through a multidisciplinary team approach. Comprehensive care ensures the unique treatment needs of a patient are met to maintain health, including physical, emo- Ó 2012 Blackwell Publishing Ltd

5 WFH: CLOSING THE GLOBAL GAP 5 tional, psychological, social, and educational aspects [25]. Health-related quality of life is also influenced by both psychosocial and clinical variables. Thus, managing the psychological and social aspects of living with a bleeding disorder become important and deserve increased recognition in clinical care. The full value of the treatment product advances will remain unknown or intangible without a comprehensive care framework. This holistic approach to treatment reflects the importance of addressing quality of life (QOL) issues as well. Over the past 50 years, the field of QOL measurement for the person living with haemophilia has emerged in parallel with the increasing ability to treat their haemophilia. Starting with the World Health Organization s (WHO) definition of health in 1946, in which health was defined as a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity [27], there has been an increasing focus on including endpoints in haemophilia evaluation that capture these concepts in addition to clinical endpoints focusing on morbidity and mortality and surrogate endpoints, such as laboratory values, e.g. factor VIII/IX levels [28]. Collecting patient outcome data that includes QOL measurement has become ever more important to support arguments to funders and to sustain the high cost of treatment and care. This information is critical in identifying the changing needs of the patients, identifying particular problems that need to be addressed, or assessing and documenting the effect that changes in healthcare delivery have made for both the individual and population overall [29,30]. Such a surveillance system allows for assessments to be made on data, with regards to optimizing resources and care for the patients. Going forward, surveillance and analysis of health outcomes and QOL must be integrated into the comprehensive care model, through both observational and translational research initiatives. In the coming decade, the WFH will expand initiatives and training programs to build global capacity to address this critical need (discussed below). In low resourced countries, where treatment is typically not immediately and consistently available, patients are at increased risk of suffering severe and permanent disability and early death [31]. WFH data demonstrate that as the economic capacity of a country decreases so do the ratio of adults to children [7]. However, importantly, WFH data also suggest that the organization of care, training of a multidisciplinary healthcare team, and education of patients and their families lead to improved mortality independent of economic capacity or increased CFC availability [13]. The progressive benefits achieved through the introduction of comprehensive care in low resourced countries may also be further demonstrated with the aid of appropriately constructed data collection and analysis. Present day Global alliance for progress (GAP) a decade of growth and achievement. This year, 2012, marks the tenth anniversary of GAP, the flagship development program of the WFH. GAP was launched in 2003 to introduce or improve national programs for patients with bleeding disorders in 20-targeted countries over 10 years and to identify 50,000 additional individuals with haemophilia worldwide. The twenty countries include: Algeria, Armenia, Azerbaijan, Belarus, China, Ecuador, Egypt, Georgia, Jordan, Lebanon, Mexico, Moldova, Morocco, Peru, Philippines, Syria, Thailand, Tunisia Russia, and South Africa. To date, government agreements to establish national care programs (NCP) have been signed with the WFH in 13 of these countries. As part of GAP, three key indicators were identified to track progress in achieving Treatment for All and to monitor progress in closing the gap in treatment between developed and developing nations globally. They are the differences between (1) the estimated and actual number of people known with bleeding disorders; (2) the need for versus the availability of treatment products; and (3) the number of people born with haemophilia and those who reach adulthood [32]. Although vast unmet needs remain, the gaps are closing. Using data from the WFH Global Survey and outcomes achieved through utilization of the WFH Development Model improvements in each of these key indicators can be demonstrated across economic groupings. (1) Closing the gap in diagnosis All Bleeding Disorders In 2003, 164,077 people were known worldwide living with a bleeding disorder [33]. As of year-end 2010 the number has reached 257,182 [7]. Haemophilia In relation to the 2003 GAP goal to identify 50,000 new patients in 10 years with haemophilia, in just eight years the number diagnosed with haemophilia has increased from 105,971 in 2003 [33] to 162,751 in 2010 [7]. We have achieved over 100% of our end goal with two years of progress remaining to include. GAP Countries Looking just to GAP countries, data from the first nine years indicate a cumulative increase of 23,324 [34] newly identified people with haemophilia was achieved during their program participation. This equates to a 126% cumulative increase in the total number diagnosed from the baseline levels during the year a country enrolled in GAP. Subsequent to a country s participation in GAP, the gains in each of these countries have continued demonstrating the sustainability of the program achievements. Ó 2012 Blackwell Publishing Ltd

6 6 M. W. SKINNER (2) Closing the gap in treatment product access Since the WFH began collecting global data on the use of treatment products in 2001 the availability of treatment products globally (measured by FVIII CFC IU per capita) has increased by >225%. In 2001, the mean global per capital usage for FVIII was 0.89 IU; in 2009 it rose to 2.02 IU [31]. (3) Closing the gap in mortality Over six years ( ) in countries with a GDP <10,000 USD there has been a 5% increase in the number of children with bleeding disorders surviving to adulthood [31]. This reflects the change over time in the number of children (ages <13 years) and the rise in the number of adults (ages >18) for 39 countries for which comparable longitudinal data was available. Recent data collection enhancements to the WFH Global Survey will allow more refined analysis in the future. The next decade of global development As part of a new WFH strategic plan ( ) [35] the WFH has identified several key initiatives for particular emphasis over the next decade continuation of GAP ( ), a new initiative to address underserved countries and regions (The Cornerstone Initiative), health outcomes research and analysis, and research mentorship. GAP The next decade. As illustrated above, GAP has brought demonstrable change in the targeted countries and led to significant and measurable improvements worldwide in the management of haemophilia and other bleeding disorders. The track record and the achievements to date show the value and potential in continuing GAP. As part of the WFH s 50th anniversary in 2013, a new phase of GAP will be initiated. In addition to continuing to track the three key indicators (diagnosis, treatment product access and mortality) an additional global metric to measure quality of life is also being considered. Historically, these metrics have primarily measured gaps in haemophilia care, due to the absence of adequate complimentary data for all bleeding disorders. They will continue to serve, for the time being, as a proxy measurement of the overall development of care within a country and globally. However, in the future we will be striving to develop metrics to expand our analysis of the trends and gaps for other bleeding disorders as well. The overarching goals for the next decade ( ) will be to: Increase the worldwide number of people with all bleeding disorders identified/diagnosed by 50,000. This goal reflects the expanded WFH mission to increase diagnosis for all bleeding disorders, not only haemophilia as was the goal in the initial phase of GAP. Ensure that 50% of those newly diagnosed are from the world s most impoverished countries. In order to reach these goals, the WFH will restructure GAP into three tiers of activity: I. Target new countries to initiate NCPs similar to the first GAP phase; II. Promote continuous improvement in NCPs established in countries that were part of the initial GAP phase, and; III. Provide support to other targeted mid-tier developed countries that need assistance in moving to the next level of care. In particular for Tiers II and III, the next phase of GAP will also allow a more concerted effort to enhance diagnosis and access to treatment for underrecognized populations (including people with inhibitors, VWD, rarer factor deficiencies, and inherited platelet disorders, particularly women with these disorders and carriers). GAP will continue to utilize the WFH Development Model with a new sixth essential element to improve data collection and outcomes-based research. As with the initial phase of GAP the development of educational tools and training guides will be applied to benefit and improve the level and effectiveness of care and treatment in all countries worldwide. Although the elements and methodology of the WFH Development Model are relatively straightforward and proven, it should be recognized that there are challenging and difficult decisions to be made when ordering their implementation, particularly when moving beyond the provision of basic care for haemophilia and in those countries where care is already well established. While it is easy to agree on the major goals (achieving a sustainable NCP, maximizing the impact for the greatest number of patients, levelling the quality of treatment across the country, and universal access to virally safe treatment) as care evolves in a country the complexity of prioritization increases. This includes decisions such as when to introduce the following: prophylaxis (to whom and for how long); home-based care; high-purity or recombinant products; outreach to identify women with bleeding disorders; care for patients with inhibitors, von Willebrand disease, platelet or rarer factor deficiencies; and immune tolerance induction. Tendering and purchasing decisions will become increasingly more price competitive and payers will demand greater justification for each therapeutic advance. However, the lowest price or newest product should not be the primary consideration. Safety should always be the first consideration. Treatment continuity and the sustainability of selection and purchasing decisions are also important considerations. Access today and no treatment tomorrow will negatively impact patient outcomes and decrease the long-term Ó 2012 Blackwell Publishing Ltd

7 WFH: CLOSING THE GLOBAL GAP 7 value that could otherwise be achieved through consistent levels of treatment that would incrementally increase over time. The WFH will continue to play a role in educating patients, clinicians and governments on tenders, product selection and purchasing decisions. The arrival of longer-lasting therapies and gene transfer will further add to the complexity of the development model. Longer lasting products will require the WFH Development Model to be retooled particularly as it relates to selection and acquisition of products (tenders), building laboratory capacity, data collection, modification of national treatment protocols, as well as patient and clinician education. The cornerstone initiative The Cornerstone Initiative (Cornerstone) is specifically aimed at supporting treatment and care for those countries which have heretofore been underserved by WFH development programs and where the gap in care is the greatest. Many countries in underserved and impoverished regions have not been able to fully take advantage of the WFH Development Model due to their less developed infrastructure. Through training the WFH will work to lay the cornerstone to provide a solid foundation upon which future building and development may occur. WFH support to improve care will not be limited by geography, economic wealth of a nation, or the existing healthcare infrastructure. However we recognize achieving Treatment for All is in fact limited by these very variables. Today, only 9% of the total number of patients identified with a bleeding disorder worldwide are from countries with a GNI per capita of <$1 500 USD [7]. This group of countries represents one third of the world s population. While the WFH has a range of development programs applicable to all countries, Cornerstone specifically targets those countries and regions of the world where even diagnosis may be considered futile given the complete lack of accessibility to care. The WFH will work with targeted Cornerstone countries over two to four years to improve very basic aspects of care development, scaled to their skills and resource capacity: Developing or improving diagnosis capacity Providing basic training in the management of bleeding disorders Strengthening patient organizations With the addition of Cornerstone, WFH will now have a continuum of development programs that may be deployed and targeted to address the unique needs of countries, regardless of economic capacity (Fig. 2). Future research challenges Over 50 years, we have witnessed treatment progress from fresh frozen plasma and cryoprecipitate to advanced plasma-derived and recombinant CFCs. Limited or No Care The Cornerstone Initiative Country Programs Global Alliance for Progress (GAP) Sustainable National Care Program Fig. 2. Illustration of the continuum of WFH development programs from limited or no care to achieving a sustainable National Care Program. Today, we are on the cusp of another revolution in treatment, potentially as big as that brought on by the discovery of cryoprecipitate in the early 1960s. Over the next few years, we will see treatment product advances on all fronts. These will range from viral inactivated (solvent detergent) cryoprecipitate, biosimilars ( generic versions) of current therapies (which will expand availability and improve price competition), and treatment products with substantially enhanced efficacy that will last two to three times or even longer in preventing bleeding, to the increasingly real prospect that through gene transfer a cure may become a reality. The development of gene therapy and more efficacious products with longer half-lives would provide significant therapeutic advances, dramatically ease the burden of treatment and improve a patient s quality of life. We should not presume these therapeutic advances would be unaffordable in the future, even where they cannot be purchased presently. Over time, they will have an equally significant global impact. There will be no single pathway to improving access and affordability around the world. However, it is entirely feasible that each of these advances will have implications for the development of care, whether a country is resourcepoor or -rich. If you consider the telecommunications industry, there are countries in the world today that have skipped over landlines from limited or no telecommunications infrastructure to cellphone technology. Decisions on the most appropriate therapy will remain a local decision based on local circumstances and individual preferences [36]. Certainly, the challenges and expense of research, development and production facing our community in the 1960s are equally present today. Likewise, the expense of treatment has challenged us since the very beginning. Therapies once thought to be expensive to produce are now relatively affordable when compared with the latest generations of these therapies. Optimal treatment. An improved understanding of optimal treatment is fundamental to the continued evolution of global care. In current treatment regimens, patient compliance and costs have become significant issues to achieving optimal outcomes. We have advanced into an era where treating the individual patient and not simply an individual s disease Ó 2012 Blackwell Publishing Ltd

8 8 M. W. SKINNER will be the reality. Individualizing treatment strategies for individual patients will potentially help to mitigate cost, be more cost-effective overall, and yield more therapeutic benefit [37]. Targeting prophylactic regiments based on individual pharmacokinetics will increasingly become the norm. This will include adjusting frequency and dose of treatment (e.g. low dose prophylaxis), as well as personalizing the desired trough level to be sustained. New outcome measures will be needed to support this advance (discussed below). Given the aim of treatment is to reduce the frequency of joint bleeds and their crippling effect, the concept of prophylactic treatment to maintain FVIII/FIX levels >1% was pioneered in Sweden in the 1960 [38]. Twenty-five years of Swedish prophylaxis experience [39], was later confirmed in a large cohort study clearly establishing the concept of prophylaxis to prevent bleeds [40]. Today, patients and clinicians have been conditioned to accept converting a patient s phenotype from severe to a moderate state as the desired end-point. This has been interpreted to be maintaining a baseline factor level >1%. Given impending product advances and taking note that normal FVIII/FIX activity is 50% 150%, it may be time to consider whether a 1% target is sufficient to prevent bleeding or if it is simply conveniently based on existing economics and treatment protocol burdens (frequency of dosing and venous access). Although it may seem impossible to imagine, based on currently available therapies, the paradigm may shift to a point were treatment goals could more closely mimic a normal state. Recognition of the significance and benefit of preventing sub-clinical bleeds (microhemorrhages) may be an important factor in optimizing long-term outcomes [40]. Until recently, there has been little evidence to suggest a baseline FVIII/FIX level >1% might be preferred for some patients. A recent analysis of low frequency bleeding data demonstrated the association between joint bleeds and baseline FVIII activity levels. Clinical data on bleeding according to baseline FVIII levels suggest that absence of joint bleeding may only be reached when approaching FVII levels of 15% [41,42]. Patients with low baseline factor levels (<5%) had the highest risk for joint bleeds, and patients with clotting factor activity levels of 10% and higher had a very low risk, which approximated no expected joint bleeds in patients with baseline factor activity of 15% and higher. The analysis also demonstrated an 18% reduction in joint bleed frequency with every percent increase in residual clotting factor activity in moderate and mild patients treated on demand [42]. With FVIII/FIX activity levels of 1% significant care is still required in daily living thus limiting the ability for full social integration equivalent to someone without a bleeding disorder. It is wholly insufficient to accommodate major or accidental trauma causing bleeding. The fear of traumatic injury remains a constant. Although advances over the past 50 years have brought us closer to the opportunity of having a near normal life expectancy, over time, future generations of patients should aspire to achieve full integration opportunities in all aspects of life. Improving patient quality of life should drive treatment decisions, not economics. Although theoretically a trough level of 15% may be ideal to achieve the absence of joint bleeding, it is, in the near term, unattainable given economic constraints on demand. However, we should aspire to an absence of joint bleeds. Moving forward incrementally from 1% to higher baseline factor levels (e.g. 3% or 5%) would be a step in the right direction. Prophylaxis, even as currently practiced in countries where there are no significant resource constraints, is an expensive treatment and is only possible if significant resources are allocated to haemophilia care. The high cost is a barrier to widespread acceptance of prophylaxis globally [40]. Of note, others have demonstrated that the higher costs of prophylaxis compared with episodic therapy are balanced by a better orthopaedic outcome and hence a better quality of life [43]. Sufficient and consistent supply of CFCs and appropriate financing of haemophilia care will allow the clinical benefits of more aggressive treatment regimens such as prophylaxis to be realized [44]. Unconstrained demand assumes unlimited supply or availability of CFCs. It is important for manufactures to understand demand to adequately plan production and for national health care policy makers to better allocate financial and other resources [44]. Current treatment paradigms are often dictated by the scarcity of treatment products. Treatment levels have been minimized in many environments because of the cost of CFCs. In the era before recombinant CFCs supply levels were constrained due to the availability of plasma and thus there would have been inadequate supplies to sustain higher trough levels prophylactically. Today, conceptually, recombinant technology and new advanced therapies on the horizon eliminate the supply constraint. The remaining obstacle is affordability. Patients, governments and industry need to work together to change the paradigm. The new paradigm needs to include the consideration that much more product is needed globally, and that if it were to be made available demand would go up as more and more patients were treated. Thus, rather than managing scarcity, industry would be faced with an expanding market and increased global demand leading to benefits for manufactures, patients and payers alike. Accelerating innovation of treatment products should, in parallel, accelerate global access to Treatment for All. Given a growing global demand for treatment products, present day global economic constraints, and the competitive market pressures that are coming with the arrival of biosimilars and other new Ó 2012 Blackwell Publishing Ltd

9 WFH: CLOSING THE GLOBAL GAP 9 therapies (longer half-life therapies and gene transfer), a newer 21st century business model will be required. Alternative models based on high-volume, low margins should be considered. Industry must continue to evolve their business development, marketing and pricing strategies to adapt to a changing and new global reality. Likewise, it is reasonable for payers to expect that continuing optimization and efficiencies achieved in the manufacturing process over the life cycle of a product would be passed on in final product pricing. For some, in the foreseeable future, the definition of optimal treatment may vary based on the economic capacity of a country, or be only incrementally achievable over time. Although, the emerging therapies will afford the opportunity to revisit the current treatment paradigm from purely an economic perspective, no one should lose sight that the overriding goal is to improve care and health outcomes. The production, pricing and marketing strategy of companies bringing newer products to market will, if they breakout of the current business model, significantly and favorably impact the cost benefit equation and the pace at which we are able to achieve Treatment for All. The technology, knowledge and capacity exist to dramatically improve global access to CFCs, it is now a moral imperative for governments, payers and industry to rise to the challenge by improving market accessibility, reducing reimbursement barriers, and adopting market-based business solutions to achieve it. Recent experience with a Health Technology Assessment (HTA) in Sweden and advancement of HTAs and similar tools such as Comparative Effectiveness Research in other countries underscores the importance of outcomes analysis to support the high cost of present day treatment practices. There is an on-going need for additional research, outcomes analysis and evidence. The Swedish HTA concluded, in part, that the scientific evidence is insufficient to determine if there are any differences in effects between different dosing strategies or to determine which dosing strategy, i.e., on-demand or prophylaxis, is the most cost-effective in treating haemophilia [45,46]. Readers should not interpret this to mean prophylaxis is not the appropriate clinical decision; rather it means that the level of graded evidence to assess cost-effectiveness is not always of the highest level and, perhaps out of necessity, is often based on best clinical practice. Given the well-documented outcomes of current clinical practice, randomized controlled studies to obtain additional evidence would be considered unethical in many countries today. Thus, fresh approaches to confront such assessments and to advance care beyond current levels are required. Assessment of treatment interventions for rare diseases such as haemophilia should not be confined to traditional analysis. Ranking haemophilia related interventions with standard interventions of therapeutics and public health in Cost Utility Analysis comparisons is inappropriate. They should be assessed with new methodologies specific to the disease and take into consideration societal willingness to support people with rare diseases [47]. Given bleeding frequency is one of the most important outcome measures, greater emphasis and understanding of concepts such as the cost savings for a bleed prevented need to be integrated into our analysis. Following from this and the Swedish HTA, a novel cost-utility model for the assessment of the costeffectiveness of prophylaxis to treat haemophilia has been proposed taking into account other variables in the equation such as reductions in the incidence of inhibitors, co-morbidities other than joint bleeds, and quality of life [48]. Emerging therapeutic advances should not be justified or brought to market based only on the notion that they will be economically more affordable, although that may be the case, but rather more importantly that they will be therapeutically more advantageous. Improvements in treatment adherence, reductions in bleeding frequency (including microhemorrhages), better management of trough levels, and improved health outcomes (including quality of life) should be the foremost considerations. Although not discussed in this paper, there are other significant research challenges to be addressed if we are to optimize and advance Treatment for All particularly for those living with inhibitors or a rarer factor deficiency. Notably these include: Improving treatment options for patients with rarer factor deficiencies, such as factor II, factor V, factor VII, factor V+VIII, factor X, factor XI and factor XIII. Understanding individual risk factors for the development of inhibitors, the immunogenicity of different treatment products and optimizing treatment strategies to overcome them. Health outcomes research analysis, surveillance and data collection. Over the past 50 years we have witnessed major improvements to the safety and efficacy of treatment for inherited bleeding disorders, and a greater understanding of their management. The challenge of answering government and payer demands for evidence-based medicine and cost justification for the advances, or for the introduction and further enhancement of treatment are ever-present and growing. As a global community we must recognize the challenge and build capacity to produce the necessary outcomes-based data to defend and support continued treatment advances. The need to have a surveillance system becomes more and more important as ministries of health want to know the expected outcomes of investing resources into haemophilia [30]. Even with the improvements of recent decades, further enhancement of the therapeutic options are Ó 2012 Blackwell Publishing Ltd

10 10 M. W. SKINNER needed to improve access to treatments, enhance convenience, elevate quality of life and mitigate treatment complications such as inhibitor development. In order to achieve these goals, detailed and objective clinical outcomes data must be available from large patient populations to serve as the critical comparator for evaluating the influence of new interventions. Beginning in 2013, the WFH Development Model will be expanded to include a sixth element the ability to track and report patient health outcomes through surveillance, enhanced data collection and outcomes analysis. In doing so, the WFH will build on its current data collection and analysis expertise from the WFH Global Survey [7]. Today, the WFH Global Survey, begun in 1998, reports national, regional, global and longitudinal trend data from over 100 countries collected through an annual survey of patient registries for a set of targeted demographic and treatment metrics. Quantifiable data contained in national registries and the WFH Global Survey facilitates the measurement of the effectiveness of healthcare programs. The WFH will continue to promote the establishment of national registries through collaboration between national patient organizations, healthcare professionals, HTCs and ministries of health [29,49]. This new WFH Development Model element will also support a new WFH research initiative to provide access and support of clinical outcomes collation and analysis infrastructures. In this area, special training projects could support observational or outcomes-based research projects in areas such as quality of life, psychosocial aspects, economics and treatment outcomes using data driven approaches [50]. Additionally, experiential or self-reported data collected through patient surveys or by NMOs through utilization of a simple standardized instrument for measuring health outcomes such as EQ-5D (Euro-Qol) [51] could provide important baseline and comparator data for measuring quality of life between patient groups, countries or treatment regimens over time [52]. As indicated above, through continuing research, clinical tools and knowledge are evolving to allow treatment delivery tailored and personalized to the individual patient rather than generally treating the disease. Concepts such as personalized prophylaxis, the identification of individuals at risk of developing an inhibitor, and health indicators unique to women with bleeding disorders are moving into clinical care. Accurate and comprehensive data will accelerate these advances and optimize their utility in clinical care. Research mentorship. We are living in a robust era for research. However, advancing the necessary research to achieve Treatment for All is a challenge that cannot be met by the efforts of one individual, organization, company, or country. To ensure the continued advance towards Treatment for All, it is vital that international collaboration occur on the research front as well. Many clinical studies require large multicenter multinational participation to achieve the level of outcome data needed for adequate analysis and/or regulatory approval. In the decade ahead, the WFH will be seeking to enhance the global capacity to conduct clinical research. Too often studies languish due to the lack of patient recruitment by HTCs, lack of patients consenting to enroll in the trial, lack of HTCs equipped to participate as study sites and lack of HTC resources including dedicated staff time to devote to research. It is not simply training and equipping hematologists to conduct clinical research. Clinical research should also form a core component of the role of HTC nurse specialist and others within the multidisciplinary care team. One of the identified elements to supporting the integration of research into clinical nursing practice includes undertaking small-scale multi-site collaborative research supported by more experienced research colleagues [53]. We therefore are proposing to initiate a global WFH Research Mentorship program as a complimentary approach to achieve our vision of achieving Treatment for All. The WFH will work to develop a focused and distinct research program that builds on the existing strengths of the organization and fills a niche that is currently missing in the global bleeding disorder community. It is also recognized that this program must not detract from the existing areas of excellence of the WFH or compete with others research initiatives [50]. It is the intent of the program that a research twinning framework be developed between a trainee, who will usually come from a developing country, and a mentor, who will usually be located in a developed country. The program will focus on initiatives in the areas of clinical and translational investigation. As patients, we also play an important role in this research framework. Without our collaboration and participation, research will not advance. An additional purpose of the WFH Research Program will be to develop a research training and education curriculum focused on enhancing patient and HTC participation within research studies worldwide in an ethical manner, including the benefits, roles, responsibilities and importance of research to advance care. When recruiting patients globally, investigators must be ever mindful that the patient population is a precious resource that must be treated with respect and care. Thoughtful attention must be given to a number of interrelated issues, including ethical considerations in patient recruitment, informed consent, and the geographical variables of global clinical trials. The global inequalities in healthcare mean that the ethics of international medical research, especially when it includes countries where people do not usually receive quality care, Ó 2012 Blackwell Publishing Ltd