SUBMISSION ON THE FUNDING OF EXTENDED HALF LIFE FACTOR VIII CONCENTRATES

Transcription

1 SUBMISSION ON THE FUNDING OF EXTENDED HALF LIFE FACTOR VIII CONCENTRATES WHO WE ARE In 1953, a small group of hemophiliacs, their families and physicians in Montreal founded the Canadian Hemophilia Society (CHS). Their dream at the time was to improve the quality of life and find a cure for hemophilia. The close collaboration among patients, health care providers and researchers was unique then and provides a model for the health care field today. Through their tireless efforts, the CHS quickly developed from a small, Montreal based support group to a national volunteer organization. Today, the Canadian Hemophilia Society is a national not for profit health charity, governed by a volunteer Board of Directors. Our national headquarters are in Montreal, and we have 10 provincial chapters. There are regional offices in three provinces: Quebec, Ontario and Manitoba. The CHS and its chapters have approximately 300 active volunteers and 20 staff across the country. The CHS is affiliated with the World Federation of Hemophilia, which is officially recognized by the World Health Organization. The CHS provides programs and services to people with hemophilia A and B, von Willebrand disease, rare factor deficiencies and inherited platelet disorders, and to the health care providers who care for them. OUR STRATEGIC PRIORITIES Care and Treatment We work in close collaboration with medical professionals physicians, nurses, physiotherapists, social workers, and other related specialists in the 26 bleeding disorder treatment centres across the country. Our common goal is to ensure optimal inter disciplinary care and treatment. We define this as comprehensive care. Research We provide clinical and research fellowships and we fund leading Canadian researchers working in the field of bleeding disorders in an effort to improve care and treatment and ultimately find a cure. The CHS invests $500,000 annually in peer reviewed research. Awareness, Support and Education We are the primary source of educational materials designed for people with bleeding disorders, their families, health care professionals and the general public. Our goal is to ensure access to up to date information adapted to each individual s needs. Safe, Secure Blood Supply In the 1990s we played key roles in the Royal Commission of Inquiry on the Blood System in Canada and in building a safer blood system for Canadians, leading to the creation of Canadian Blood Services and Héma Québec, and we continue to be the leading patient organization to independently monitor the safety and supply of blood, blood products and their recombinant alternatives within the Canadian Blood System. The CHS is committed to doing its part to make sure there is never another tainted blood tragedy. Its Blood Safety and Supply Committee is made up of physicians, CHS SUBMISSION ON THE FUNDING OF EXTENDED HALF LIFE FACTOR VIII CONCENTRATES page 1

2 nurses, public health experts and regular recipients of blood products and their alternatives. Collectively, they have over 200 years of experience in blood safety and supply issues. International Development The Canadian Hemophilia Society and its dedicated teams of volunteers and health care professionals undertake leadership roles in supporting developing countries to improve care and treatment. Currently we have twinning partnerships in four developing countries. FUNDING The CHS receives program funding from all the companies in the Canadian clotting factor concentrate market. Our relationship with them is carefully regulated by our Policy on Relationships with Companies in the Pharmaceutical Industry, which is guided by best ethical practices. The CHS also receives significant donations and bequests from members of the general public and is one of 16 members of Healthpartners, a federal government workplace giving program. While the national organization receives no government funding, two of our chapters, Quebec and Ontario, receive provincial supporting grants. CARE AND TREATMENT Since the 1950s, treatment for hemophilia A and B has gone through four distinct phases: 1950s to 1965 Treatment with fresh frozen plasma, which required frequent and long hospitalization 1965 to 1985 Treatment with cryoprecipitate (for hemophilia A only), which permitted out patient and Emergency Department administration of factor replacement therapy, and reduced hospitalization significantly 1970 to 1988 Treatment with large pool preparations of plasma derived factor VIII and IX concentrates, which facilitated home infusion, but which were not virally inactivated and led to widespread infection with HIV and hepatitis B and C 1988 to today Treatment with virally safe plasma derived and recombinant factor concentrates, which led to the introduction of preventative treatment, called prophylaxis, for almost all children and many adults with the severe forms of hemophilia A and B. ON DEMAND THERAPY Since the inception of hemophilia care in the 1950s, the standard care has been to infuse factor FVIII or IX as soon as possible after the onset of bleeding. The interval before effective hemostasis, however, allowed accumulation of blood in joint spaces and inevitably led to serious joint damage. PROPHYLAXIS Prophylactic treatment for hemophilia was initiated in Sweden in the 1960s and became widespread in Canada in the 1990s after the introduction of virally attenuated factor concentrates. Research published in 2007 by Manco Johnson et al i showed that CHS SUBMISSION ON THE FUNDING OF EXTENDED HALF LIFE FACTOR VIII CONCENTRATES page 2

3 prophylaxis with factor VIII prevents joint damage and decreases the frequency of joint and other hemorrhages in young boys with severe hemophilia A compared to on demand therapy. A second randomized controlled trial, the 2011 ESPRIT study, by Gringeri et al ii confirmed the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life. Similar RCTs have yet to be conducted in adults or with hemophilia B; however, observational studies clearly show that prophylaxis results in a reduction in the frequency of joint bleeding and, over time, a reduction in the severity of joint disease. A 2012 survey of the outcome of prophylaxis, on demand treatment or combined treatment in year old men with severe hemophilia in six countries iii, in which Canadians participated, found that people with severe hemophilia who have been on prophylaxis for their entire lives to date are reporting a quality of life much closer to their peers without hemophilia. This finding is supported by another Manco Johnson study iv in males aged years that concluded that the median number of total bleeding episodes and total bleeding episodes per year were significantly lower with prophylaxis than with on demand treatment (total, 0 vs. 54.5; total per year, 0 vs. 27.9; both P < ) Routine prophylaxis with rfviii FS leads to a significant reduction in bleeding as compared with on demand treatment. Prophylaxis is, nevertheless, a challenging therapy, especially in children, in whom it is ideally started before the age of two years or earlier. Factor VIII concentrates are infused intravenously two, three or more times a week and for some patients, daily. Factor IX concentrates, given the extended half life of the molecule, are usually infused every 3 or 4 days. Venous access can be difficult. Central venous access devices (e.g. port a caths) are sometimes needed in younger children. Traditionally, the goal of prophylaxis has been to raise the FVIII or IX level to 25 to 50% of normal and then re infuse when the level falls to 1%. While this has constituted a huge advance over on demand therapy, as demonstrated by Manco Johnson and Gringeri, factor levels as low as 1% do not prevent all bleeds. Even in young boys who report no episodes of bleeding, MRI, x ray and ultrasound examination of the joints often show radiological changes, likely due to subclinical bleeding. Manco Johnson s study suggests that 11% of normal factor VIII levels are required to completely prevent joint bleeding in hemophilia A patients. THE BENEFITS OF EXTENDED HALF LIFE FACTOR CONCENTRATES Excluding viral attenuation and recombinant preparation, the extended half life factor of concentrates constitutes the first significant change in factor replacement therapy since their introduction four decades ago. In the case of the first extended half life factor VIII concentrate to be approved, the half life is increased by half v ; in the case of the first factor IX, by two to three times vi. This advance has the potential to offer two different treatment improvements to patients with hemophilia A and B. 1. By virtue of their extended half life, prophylactic infusions can be less frequent. In factor VIII, instead of two or three infusions or more per week, the frequency can be reduced to one or two infusions. For those accessing veins peripherally with butterfly needles, this will mean less long term damage to veins. Some young children will be able to discard the central venous access device and its attendant infectious and CHS SUBMISSION ON THE FUNDING OF EXTENDED HALF LIFE FACTOR VIII CONCENTRATES page 3

4 thrombotic risks. Compliance with prescribed treatment protocols will be less hindered by the burden of frequent venous access. 2. For many patients, the chief drawback of hemophilia care is not the frequency of infusions or the difficulty in venous access, it is the breakthrough bleeding, both observable and sub clinical, that still occurs with prophylactic protocols that target a trough level of 1% of normal. The stated goal of gene therapy trials is to maintain a constant factor level in excess of 5% in order to transform severe hemophilia into a mild form of the disease. The advent of extended half life factor concentrates offers the possibility of maintaining current prophylactic frequency and significantly increasing trough levels, thereby achieving greater protection from bleeding. There are good reasons why individuals would choose different options. The benefits of fewer infusions are: - easier venous access (the best veins cannot be used too often) - less pain and suffering - better compliance on the part of very young children - less recourse to central venous access devices with their risks of infection and thrombosis - less burden on families if infusions do not have to be scheduled as often - the possibility of weekly infusions scheduled at a fixed time of the week when families have fewer vocational and educational obligations. The benefits of higher factor trough levels are: - better protection from bleeds - fewer sub clinical bleeds - less long term joint damage - the ability to be more active and maintain better fitness without causing bleeding - the ability to lead a more normal lifestyle - the ability to change severe disease into mild disease. It is not, of course, an either/or decision between higher troughs and less frequent infusions. The extended half life products offer not only the possibility of choosing which benefit is most important based on personalized medicine, but also offer the option of combining the benefits. For example, patients with factor VIII deficiency, by infusing the same dose as previously, could reduce the frequency of infusions from three times a week to twice a week and increase the trough level to close to 3%. Others could infuse a larger dose once a week. This would be a significant advance for children with difficult venous access. Moreover, a once weekly dosing schedule is considered ideal for adherence. For some patients, the combined benefits of less frequent infusions and better protection from hemorrhages will also be accompanied by lower doses, thus decreasing the overall annual consumption in IUs. CHS SUBMISSION ON THE FUNDING OF EXTENDED HALF LIFE FACTOR VIII CONCENTRATES page 4

5 PATIENT AND CAREGIVER ATTITUDES In 2012, the CHS conducted an online survey of adults with severe and moderate hemophilia A and B and the caregivers of children with severe and moderate hemophilia A and B. Close to 100 people responded. The objective was to discover which of the potential benefits patients and their caregivers thought most important. The options were presented in different ways. I would rather reduce the frequency of my infusions than get greater protection against bleeds. Strongly agree Agree Neutral Disagree Strongly disagree 5% 12% 14% 30% 38% Only 17% of respondents agreed or strongly agreed with the option of reducing frequency of infusions compared with a higher factor level and greater protection from bleeds. Almost 70% disagreed. This was somewhat surprising given that all the discussion by physicians over the last five years as these products moved from animal studies to the clinic, as well as public communications by the companies studying the products in human trials, focused solely on the benefit of fewer infusions. I would rather have higher factor levels than reduce my frequency of infusions. Strongly agree Agree Neutral Disagree Strongly disagree 20% 38% 32% 11% 0% Attitudes were similar even when the question was posed differently. Almost 60% agreed or strongly agreed that they would prefer higher factor levels to less frequent infusions. Only 11% disagreed. PATIENT AND CAREGIVER COMMENTS Our son is 6 years old and sometimes likes to argue with us or try to negotiate why he doesn't need to get his needle yet again. This can emotionally wear us all down (although we do not give in). His veins are still small and sometimes hard to get. Fewer needles, but still able to keep trough levels up would be an ideal situation! Mother of a boy with severe hemophilia If longer half life factor were available, it would make work and travel and other activities easier for our family. Yes, the ease of factor these days is wonderful, however, I worry about the vein damage to our son's only vein he lets us access. Longer half life factor would avoid the scar tissue building up and the risk of losing that vein. - Mother of a boy with severe hemophilia I have target joints that frequently bleed spontaneously without trauma. The low CHS SUBMISSION ON THE FUNDING OF EXTENDED HALF LIFE FACTOR VIII CONCENTRATES page 5

6 level of protection with today s concentrates has caused me bleeds that have damaged my joints, needed the use of additional factor product and required hospitalization and surgery. An extended half life product would save on product use and health care consumption. A young man with severe hemophilia As a late convert to prophylaxis I am so relieved to be bleeding only a couple of times a year now instead of a couple of times a month. A significant barrier to my ability to follow my doctor s recommendation of every other day infusions is the great increase in the number of needles. This is no small barrier. If I were able to go from 3 infusions a week to 1 or even 2 that would be a great help in maintaining what has become a great improvement of health and quality of life. A middle aged man with severe hemophilia CONCLUSIONS AND RECOMMENDATIONS ON THE INTRODUCTION OF ELOCTATE Eloctate received its Notice of Compliance from Health Canada in August 2014 following one of the most extensive clinical trials ever conducted in hemophilia, including research sites in Canada. 1. Eloctate s 1.5 fold extended half life (19.0 hours vs hours for Advate ) represents the first advance in efficacy in clotting factor concentrates in four decades. It has the potential to - reduce the frequency of infusions - increase the protection against hemorrhages by raising the trough level - procure both of these benefits at the same time. The extended half life is of special benefit to certain categories of patients, including those who - demonstrate short half lives and high clearance rates with current FVIII products - have difficulty accessing peripheral veins, especially young children - have advanced joint damage and, as a result, bleed more easily - bleed more frequently, for reasons unknown, despite their current prophylactic protocol. Given its potential to improve patient outcomes over current products, Eloctate should be listed for reimbursement through the CBS budget immediately. 2. It is not yet clear how physicians and patients will best take advantage of this innovative therapy. Given the quality and efficacy of the standard half life concentrates, uptake is expected to be gradual. Based on individual pharmacokinetics, bleeding susceptibility, the condition of joints, lifestyle and treatment challenges, treatment protocols will vary, some favouring less frequent infusions, some favouring higher trough levels, some both at the same time. It will be critical to closely monitor utilization and patient outcomes. In addition, rare adverse reactions, including the development of inhibitors, less likely to be detected during pre marketing clinical trials, must be monitored. CHS SUBMISSION ON THE FUNDING OF EXTENDED HALF LIFE FACTOR VIII CONCENTRATES page 6

7 Rigourous and systematic Phase IV post marketing surveillance and research should be conducted to measure patient outcomes, determine how best to utilize these products and to detect rare adverse reactions. 3. Other extended half life factor VIII products are expected to be approved and marketed in Canada within the next one to three years. The factor VIII marketplace will become increasingly competitive. Physicians and patients will have more options and the cost of therapies is likely to decrease. Contracts with the manufacturer of Eloctate should be short in duration to allow purchasing flexibility as more factor VIII products are approved for use in Canada. Prepared by the Canadian Hemophilia Society Blood Safety and Supply Committee Michael King, MD, chair (Alberta) Martin Kulczyk, vice chair (Quebec) Tom Alloway, PhD (Ontario) Sarah Crymble (Ontario) Bill Featherstone (Manitoba) Julia Hews Girard, RN (Alberta) Mohammad Qadura, MD (Ontario) Bruce Ritchie, MD (Alberta) Craig Upshaw (Alberta) Rick Waines (British Columbia) Paul Wilton (Ontario) David Page (Staff support, CHS national office) September 30, 2014 i ii iii iv v vi Prophylaxis versus Episodic Treatment to Prevent Joint Disease in Boys with Severe Hemophilia; Marilyn J. Manco Johnson et al; N Engl J Med 2007;357: Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM and The ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9: A survey of the outcome of prophylaxis, on demand treatment or combined treatment in year old men with severe haemophilia in six countries, D. Noone et al, Haemophilia (2012). DOI: /j x Randomized, controlled, parallel group trial of routine prophylaxis vs. on demand treatment with sucrose formulated recombinant factor VIII in adults with severe hemophilia A (SPINART), M.J. Manco Johnson et al, Journal of Thrombosis and Haemostasis, 11: , DOI: /jth Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Johnny Mahlangu et al. Pre published online November 13, 2013; Haemophilia doi: /blood Phase 3 Study of Recombinant Factor IX Fc Fusion Protein in Hemophilia B, Jerry S. Powell et al, N Engl J Med. DOI: /NEJMoa CHS SUBMISSION ON THE FUNDING OF EXTENDED HALF LIFE FACTOR VIII CONCENTRATES page 7