UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Published by United Kingdom Haemophilia Centre Doctors’ Organisation 2016

© UKHCDO 2016

Copyright of the United Kingdom Haemophilia Centre Doctors’ Organisation. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any other form by any means, electronic, mechanical, photocopying or otherwise without the prior permission in writing of the Chairman, c/o Secretariat, UKHCDO, City View House, Union Street, Ardwick, Manchester, M12 4JD.

ISBN: 978-1-901787-20-7 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Contents 1. Chairman’s Report 1 2. Bleeding Disorder Statistics for 2015 / 2016 Contents 4 2.0. Comments on the Bleeding Disorder Statistics for 2015 / 2016 7 2.1 Haemophilia A 10 2.2 Haemophilia B 39 2.3 Von Willebrand Disease 56 2.4 Inhibitors Congenital and Acquired 61 2.5 Rarer Bleeding Disorders 67 2.6 Adverse Events 71 2.7 Morbidity and Mortality 74 3. Data Management Working Party 81 4. Haemtrack Group Report 84 5. Genetics Working Party 86 6. Genetic Laboratory Network 87 7. Inhibitor Working Party 89 8. Musculoskeletal Working Party 91 9. Paediatric Working Party 92 10. von Willebrand Disease Working Party 94 11. Obstetric Task Force 95 12. Therapeutic Task Force on Enhanced Half-Life Products 96 13. UK Haemophilia Data Managers’ Forum Group 97 14. Haemophilia Nurses’ Association 98 15. Haemophilia Chartered Physiotherapists’ Association 99 16. BCSH Haemostasis and Thrombosis Task Force 100 17. Haemophilia Society 102 18. The Macfarlane Trust 110

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 1. Chairman’s Report

Welcome to the QEII centre in Central London and the 2016 Annual General Meeting of the UKHCDO. I hope you will find it a useful, informative and enjoyable meeting. We have made some alterations to the format of the meeting this year; on the Thursday we are concentrating on the progress made by the UKHCDO Working Parties and these sessions will be open to everybody to listen and feedback on findings and ideas for future work. Two of the working parties are due to re-form later this year and there will be opportunity for newer members to apply to participate. On the Thursday we will also hear about some other completed and on-going research studies including a presentation from the Dutch group on the OPTI-CLOT project, a collaborative UK/Dutch study looking at pharmacokinetic dosing in haemophilia B. On the Friday morning we will have two ‘hot topic’ lectures on monitoring enhanced half-life (EHL) products and a gene therapy update followed by the standard AGM business and presentation of the annual statistics. Please do feedback after this meeting as this will help planning of future meetings. As we all know we are living in difficult times within the NHS with enormous shortfalls in the funding required to pay for existing and innovative services and treatments. The National procurement exercises that we have undertaken over the last few years have enabled us to make considerable savings and we now have very favourable factor concentrate prices when compared to other prices globally. During the last year the UKHCDO has continued to be very closely involved with the Commercial Medicines Unit (CMU) in the latest factor concentrate procurement exercise. The previous tender was a collaborative project between the UKHCDO and the NHS England appointed Clinical Reference Group (CRG) for Haemophilia. The latter was disbanded in early 2016 and reformed some months later but despite this disruption we were able to provide clinical input and oversight of the procurement process. The frameworks are now in place and we are able to purchase the majority of these factor concentrates for our patients; details have been communicated with all Centres. I would like to extend our gratitude for the continued support we receive from Alison Greenwood and Wendy Roach from the CMU. The recent tender will enable us to treat some of our patients with the new extended half-life products. The UKHCDO guideline on the use of ‘extended half-life’ products, written by a Task Force set-up in 2015, was published earlier on this year and is an informative document to refer to when discussing the use of these products. In England there has been recent commissioning guidance on how we can use these concentrates in a cost-neutral or cost- saving way; again this was circulated to members recently. The NHSE CRG has not met since the last AGM due to its dissolution but it has now been reformed and we will have a CRG update session during the AGM. Despite the hiatus in CRG status we were pleased to hear in mid-2016 that the UKHCDO protocol for immune tolerance was adopted as an NHSE official policy. This means that ITI for children in England should only be done according to this protocol as this is the only ITI that is commissioned. We are planning detailed collection of outcome data using this protocol which will be co-ordinated by the Inhibitor Working Party. The UKHCDO has a good track record at peer review and audit but moving forward on this has been somewhat on the back burner over the last year or so. I am delighted to welcome John Hanley as the new Audit Lead for the UKHCDO and look forward to working with him and a multi-disciplinary ‘audit team’ (yet to be formed) to develop a new audit tool to use for 2017. It is likely that future audits will have more credibility with commissioners if they include

Page | 1 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 assessments of outcome measures and evidence of adherence to national protocols and guidelines. During the AGM we will as usual hear about the work and projects being done by the NHD and updates to HCIS and Haemtrack. Haemtrack usage uptake has continued to increase across the country and it has benefits that improve patient care. NHS England has adopted Haemtrack usage as a CQUIN for 2016/17; the development of this was time-consuming and it is a complicated CQUIN which has been adopted by the majority – but not all – of the English centres. It is being refined for 2017/18 and may well become mandatory for all Centres. My first year has Chairman (‘Chairperson’) has gone very quickly and required more hours of input than I envisaged; there are still a number of tasks I have not yet addressed but hope to be able to in the coming months. I am very grateful for the support of the rest of the Executive and particularly want to thank David Keeling who will be stepping down as Vice-Chair at the AGM and I am delighted that he will be replaced by Professor Peter Collins who we welcome onto the Executive Committee. I would like to encourage all members to come to me and the other Executive Committee members with queries, suggestions and feedback on any bleeding disorder issues. In the coming year the UKHCDO will continue to work closely with the newly formed NHSE Clinical Reference Group (and NHS Scotland, Wales and N.I) on moving forward with improving haemophilia care. Lastly I would like to thank all members of the NHD staff and their hard work in supporting the UKHCDO and the challenging times that we are working in.

Dr Ri Liesner UKHCDO Chair October 2016

Page | 2 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Bleeding Disorder Statistics for April 2015 to March 2016

A report from the National Haemophilia Database

November 2016

Page | 3 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 2. Bleeding Disorder Statistics for 2015 / 2016

Contents Appendix 1: Glossary ...... 7

2.0. Comments on the Bleeding Disorder Statistics for 2015 / 2016 ...... 9

2.1 Haemophilia A ...... 10

Table 1 Patients with congenital Haemophilia A registered and treated April 2015 ‐ March 2016 ...... 11 Figure 1 Carriers of Haemophilia A currently registered and newly registered, by baseline factor VIII level ...... 12 Table 2 New registrations of Haemophilia A between April 2015 & March 2016, by age at mid‐year and severity ...... 13 Table 3 New registrations of patients with Severe Haemophilia A aged over 5 years old, and subsequent treatment by year ...... 14 Figure 2 Trend in numbers of Severe Haemophilia A patients aged 60 years and above, 1975 – 2015/16 (including HIV +ve pts)...... 15 Figure 3 Trend in numbers of non‐Severe Haemophilia A patients aged 60 years and above, 1975 – 2015/16 (including HIV +ve pts)...... 15 Figure 4 Factor VIII units used by UK Haemophilia Centres 1992 ‐ 2015/16 all diagnoses ...... 17 Figure 5 Factor VIII units used by UK Haemophilia Centres to treat Severe Haemophilia A – 2010/11 ‐ 2015/16 ...... 18 Table 4 Treatment intensity of patients with Severe Haemophilia A – 2010/11 ‐ 2015/16 ...... 19 Figures 6a, b & c Patients with Severe / Moderate / Mild Haemophilia A treated with FVIII by UK Haemophilia Centres – 2007 ‐ 2015/16 ...... 20 Figure 7 Number of Severe Haemophilia A patients treated per million capita ...... 22 Figure 8 Factor VIII usage (including Inhibitor) divided per Severe Haemophilia A patients by commissioning region ...... 23 Table 5 Factor VIII usage by region for patients with Severe Haemophilia A (incl. treatment for inhibitors) ...... 24 Figure 9 Annual FVIII usage 2015/16 in Severe Haemophilia A patients aged under 18 years with no current inhibitor, by centre, ranked by median usage ...... 26 Figure 10 Annual FVIII usage 2015/16 in Severe Haemophilia A patients aged 18 years or more with no current inhibitor, by centre, ranked by median usage ...... 28 Figures 11a&b Median factor VIII units used per kilogram body weight per year in Severe Haemophilia A patients without inhibitors by age, 2015/16 ...... 30 Figure 12 Median factor VIII units used per kilogram body weight per year in Severe Haemophilia A patients without inhibitors aged 16 and over, by bodyweight 2015/16 ...... 32 Figure 13 Median usage of factor VIII: UK patients with severe Haemophilia A without inhibitors broken down by age, 2010/11 – 2015/16 ...... 33

Page | 4 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 14 Severe Haemophilia A patients with no current inhibitor between April 2015 & March 2016: median usage by inhibitor history ...... 34 Table 6 Products used to treat Haemophilia A (including inhibitors) between April 2015 & March 2016 ...... 35 Table 7 Factor VIII units used by UK Haemophilia Centres between April 2015 & March 2016, broken down by diagnosis ...... 37 Figure 15 Market Share of factor VIII concentrates issued by UK Haemophilia Centres during 2015/16 ...... 38

2.2 Haemophilia B ...... 39

Table 8 Patients with congenital Haemophilia B registered and treated April 2015 ‐ March 2016 ...... 40 Figure 16 Carriers of Haemophilia B currently registered and newly registered, by baseline factor IX level ...... 41 Table 9 New registrations of Haemophilia B between April 2015 & March 2016, by age at mid‐year and severity ...... 42 Figure 17 Trend in numbers of Severe Haemophilia B patients aged 60 years and above, 1975 – 2015/16 (including HIV +ve pts)...... 43 Figure 18 Trend in numbers of non‐Severe Haemophilia B patients aged 60 years and above, 1975 – 2015/16 (including HIV +ve pts)...... 43 Figure 19 Factor IX units used by UK Haemophilia Centres 1992‐ 2015/16 all diagnoses ...... 45 Figure 20 Number of Severe Haemophilia B patients treated per million capita ...... 46 Figure 21 Factor IX Usage (including inhibitor) divided by number of Severe Haemophilia B patients by commissioning region ...... 47 Table 10 Factor IX usage by region for patients with Severe Haemophilia B (incl. treatment for inhibitors) ...... 48 Figure 22 Annual FIX usage 2015/16 in Severe Haemophilia B patients aged under 18 years with no current inhibitor, by centre, ranked by median usage ...... 50 Figure 23 Annual FIX usage 2015/16 in Severe Haemophilia B patients aged 18 years or more with no current inhibitor, by centre, ranked by median usage ...... 52 Table 11 Products used to treat Haemophilia B (including inhibitors) between April 2015 & March 2016 ...... 53 Table 12 Factor IX units issued by UK Haemophilia Centres between April 2015 & March 2016, broken down by diagnosis ...... 54 Figure 24 Market Share of factor IX concentrates issued by UK Haemophilia Centres during 2015/16 ...... 55

2.3 Von Willebrand Disease ...... 56

Table 13 Patients with von Willebrand Disease registered and treated April 2015 ‐ March 2016 ...... 57 Table 14 New Registrations of von Willebrand Disease between April 2015 ‐ March 2016, by age at mid‐year, severity, and gender ...... 59

Page | 5 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 15 Concentrates used to treat von Willebrand Disease (including inhibitors) between April 2015 & March 2016 ...... 60

2.4 Inhibitors: Congenital and Acquired Haemophilia A, Haemophilia B and von Willebrand Disease ...... 61

Table 16 Inhibitors by Disease Severity – Haemophilia A, Haemophilia B & von Willebrand Disease ...... 62 Table 17 Annual concentrate usage by patients with congenital bleeding disorders who were inhibitor positive at any time within 2015/16 ...... 64 Table 18 Concentrates used to treat Acquired Inhibitors ...... 65 Table 19 FEIBA® usage: breakdown by diagnosis ...... 66 Table 20 NovoSeven® usage: breakdown by diagnosis ...... 66

2.5 Rarer Bleeding Disorders ...... 67

Table 21 Patients with rarer types of bleeding disorders registered and treated April 2015 & March 2016 ...... 67 Table 22 Patients with selected rarer bleeding disorders registered and treated April 2015 ‐ March 2016, by disease severity ...... 68 Table 23 New registrations of rarer bleeding disorders between April 2015 & March 2016 showing their coagulation defect and gender ...... 69 Table 24 Concentrates used to treat Rarer Bleeding Disorders between April 2015 & March 2016 ...... 70

2.6 Adverse Events ...... 71

Table 25 Adverse Events reported between April 2015 & March 2016 ...... 71 Table 26 Summary of patients ‘at risk’ of vCJD for public health purposes who received UK sourced plasma products as reported by Centres ...... 73

2.7 Morbidity and Mortality ...... 74

Table 27 Causes of death in patients with Haemophilia A, Haemophilia B and all Carriers of Haemophilia A & B between April 2015 & March 2016 ...... 74 Table 28 Causes of death in other coagulation defects ...... 75 Figure 25 Cumulative incidence chart of deaths from hepatocellular carcinoma or liver failure in UK patients with bleeding disorders 1969 ‐ 2015 ...... 77 Figure 26 Total number of patients with Haemophilia A, Haemophilia B or von Willebrand Disease treated by UK Haemophilia Centres ...... 79 Figure 27 Total number of patients with severe Haemophilia A and Haemophilia B treated by UK Haemophilia Centres ...... 79 Appendix 1 Quarterly Returns ‐ Participating Centres ...... 80

Page | 6 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Appendix 1: Glossary

APPG All-party parliamentary group An Open-Label, multicenter Evaluation of the Long-Term Safety and Efficacy of Recombinant Human Coagulation Factor VIII Fusion ASPIRE study Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding Episodes in Previously Treated Subjects with Haemophilia A BCSH British Committee for Standards in Haematology BMI Body mass index BSH British Society for Haematology CCC Comprehensive Care Centre Pharmacovigilance program to monitor the safety of treatments for CHESS study people with inherited bleeding disorders in Canada CMU Commercial Medicines Unit CPA Clinical Pathology Accreditation CPD Continuing Professional Development CPI Consumer price index CQUIN Commissioning for Quality and Innovation CRG Clinical Reference Group DH Department of Health DMWP Data Management Working Party EAHAD European Association for Haemophilia and Allied Disorders ECHO study Expanding Communications on Haemophilia-A Outcomes EHC European Haemophilia Consortium EHL Enhanced Half-life EQA External quality assessment GLN Genetic Laboratory Network HAART Highly active antiretroviral therapy HCC Hepatocellular carcinoma HCIS Haemophilia Clinical Information System HCPA Haemophilia Chartered Physiotherapists’ Association HCV Hepatitis C virus HNA Haemophilia Nursing Association HSCIC Health and Social Care Information Centre HT Haemtrack ICH Intracranial Haemorrhage IQR Interquartile range ISO International Organization for Standardization

Page | 7 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

ISTH International Society on Thrombosis and Haemostasis ITI Immune tolerance induction IU/dl International units per decilitre IU/kg International units per kilogram kg Kilogram MFET Macfarlane and Eileen Trust MFT The Macfarlane Trust MSK Musculoskeletal MTP Minimally treated patient NEQAS National External Quality Assessment Service NHD National Haemophilia Database NHSE NHS England NIBSC National Institute for Biological Standards and Control NICE The National Institute for Health and Care Excellence PUP Previously untreated patient PWH People with haemophilia RCOG Royal College of Obstetricians and Gynaecologists SHA Severe Haemophilia A SIPPET study Survey of Inhibitors in Plasma-Products Exposed Toddlers TDS 3 times a day (Latin: ter die sumendum) Treatment of Haemophilia, Unmet Need, and Disease Epidemiology THUNDER project in the Real world UKAS United Kingdom Accreditation Service UKHCDO GLN United Kingdom Genetic Laboratory Network UKGTN United Kingdom Genetic Testing Network UKHCDO United Kingdom Haemophilia Centre Doctors’ Organisation VWD Von Willebrand disease VWF Von Willebrand factor WFH World Federation of Hemophilia

Page | 8 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 2.0. Comments on the Bleeding Disorder Statistics for 2015 / 2016

The statistics on bleeding disorders for the financial year 2015/16 follow. Most of these speak for themselves or have some brief commentary next to them. Please note that we are using the ISTH classification for severity of haemophilia A and B. The report follows the same, easier to follow order that we used in last year’s report, with subsections including Haemophilia A, Haemophilia B, von Willebrand Disease and inhibitors. More detail is given in the inhibitor section, breaking down usage of products to treat inhibitors, and usage of bypassing products regardless of inhibitor status, by diagnosis and number of patients treated. The commissioners expressed a heightened interest in the impact of immigration on registrations and treatment cost. Since we have only just started to ask for country of origin, we have tried to estimate the proportion of patients born overseas from the number of severely affected Haemophilia patients registering after their fifth birthday. This will miss infant immigrants registered at a younger age. Nevertheless, it appears at least 25% of new registrations for severe haemophilia were born overseas and our data show that about 90% of these stay and continue to require treatment and are therefore not just visitors. Without this, the number of patients with severe haemophilia would probably be stable or falling and the consumption would probably now be stable. Although Centres vary considerably in their treatment intensity this seems largely stable, especially in the paediatric population. Most of the increase in factor VIII usage over the past five years can be attributed to an increase in the number of patients rather than a change in treatment intensity. It is also clear that greater treatment intensity is at least partly attributable to some centres attracting a higher proportion of inhibitor and ex-inhibitor patients who need more product e.g. GOSH, but in other cases more intensive treatment is attributable to the use of larger doses or more follow-on treatment. Treatment patterns and usage are explored in more depth in the attached Haemtrack report. We continue to experience difficulty obtaining mortality data from NHS Digital (formerly HSCIC and before that The Office of National Statistics). This difficulty relates to information governance issues and operational difficulties with NHS Digital which prevent them answering e-mails, the phone or letters. These difficulties have not been resolved by changing their title! We would remind members and centre staff that they are expected to report all deaths of patients with bleeding disorders to NHD. NHS Digital is supposed to provide a confirmatory service. We would like to thank all the Haemophilia Centres and their staff for sending in their data and for making enquiries on our behalf. We would also like to thank the NHD team for pulling this all together. It is a lot of work. Professor Charles RM Hay, Ben Palmer & Lynne Dewhurst On behalf of the UK National Haemophilia Database Manchester, November 2016

Page | 9 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

2.1 Haemophilia A

Page | 10

Table 1 Patients with congenital Haemophilia A registered and treated April 2015 - March 2016

Age Factor VIII level (iu/dl) Haemophilia A Range < 1 1 ‐ 5 >5 & <40 ≥ 40 Unknown Total

<18 years 665 (0) 219 (4) 690 (87) 136 (113) 9 (8) 1,719 (212) Total In Register (including low‐ ≥18 years 1,182 (2) 669 (2) 2,983 (559) 990 (840) 157 (155) 5,981 (1558) level carriers) Total 1,847 (2) 888 (6) 3,673 (646) 1,126 (953) 166 (163) 7,700 (1770) UKHCDO New <18 years 57 (0) 11 (0) 67 (15) 19 (18) 4 (3) 158 (36) Page |11 Registrations * ≥18 years 16 (0) 4 (0) 108 (43) 100 (91) 25 (24) 253 (158)

(including low‐ Annual level carriers) Total 73 (0) 15 (0) 175 (58) 119 (109) 29 (27) 411 (194)

Report Treated in <18 years 638 (0) 173 (3) 157 (7) 6 (2) 1 (0) 975 (12)

year** 2016

≥18 years 1,134 (0) 464 (2) 663 (48) 38 (17) 2 (1) 2,301 (68) &

(including low‐ B level carriers) Total 1,772 (0) 637 (5) 820 (55) 44 (19) 3 (1) 3,276 (80) leeding

* New registrations are a subset of the ‘In Register’ numbers ** Treated includes patients ‘In Register’ and ‘New Registratio Disorder

Table 1: This shows the total number of patients with haemophilia A registered in the UK during 2015/16 broken down by age and disease Statistics severity (mild, moderate and severe). Low level carriers (<40 iu/dl), but not carriers with normal levels, are included in this estimate, since they may require replacement therapy for surgery or trauma. The number of new registrations continues to rise and is now over three times

for

higher than a decade ago. Much of this increase is accounted for by net immigration. 201 ns’ 5 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 1 Carriers of Haemophilia A currently registered and newly registered, by baseline factor VIII level

593 600 Haemophilia A Carrier In Register (Excl. new registrations) 500 Haemophilia A Carrier New Registrations

400 349 320

300

195 200

95 100 66 42 34 38 12 3 0 12 1 3 7 0 <2 2‐9 10‐19 20‐29 30‐39 40‐49 50+ N/K

Factor VIII level (iu/dl) Diagnosis Grand <2 2‐9 10‐19 20‐29 30‐39 40‐49 50+ N/K Total Haemophilia A Carrier In Register 3 12 66 195 320 349 593 38 1576 (Excl. new registrations)

Haemophilia A Carrier 0 1 3 124234957194 New Registrations

Total 3 13 69 207 362 383 688 45 1770

Figure 1: This shows the number and distribution by baseline VIII of the carriers currently registered with NHD. This includes females registered by their centre as having factor VIII deficiency or haemophilia A. It is possible that centres may have misclassified one or two patients with von Willebrand disease Normandy. Low level carriers (<40 iu/dl) still predominate in the register, even though we know at least two thirds of carriers will have normal factor VIII levels. This is because registration of clinically unaffected carriers started only a year ago. New registrations of unaffected carriers continue but are not yet complete. Very low levels amongst carriers are, perhaps, not as rare as might have been expected. This is usually accounted for by extreme lyonisation. Two patients with levels <2 iu/dl are compound heterozygotes for mutations which cause severe haemophilia.

Page | 12 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 2 New registrations of Haemophilia A between April 2015 & March 2016, by age at mid-year and severity

Number of Patients (Factor VIII level (iu/dl)) Coagulation Age Defect (years) < 1 1 ‐ 5 >5 & <40 ≥ 40 Unknown Total

0 : 45210231 187 5 : 9 3 1 13 0 0 17 10 : 19 2 0 20 1 0 23 20 : 29 13 2 16 2 1 34 Haemophilia A 30 : 39 3 2 10 1 0 16 40 : 490092011 50 : 59007108 60 : 69008109 70 + 0 0 11 1 0 12

Total 73 15 117 10 2 217 Table 2: This shows the number of new registrations of haemophilia A and B broken down by reported severity and age at mid-year (30/09/2016). The underlying birth rate of patients with severe haemophilia A born in the UK runs at 40-45 patients per year. Nearly 30% of new registrations of severe haemophilia are now registered after the age of five and often in adulthood. All of these patients and some of those registered under the age of five are recent migrants to this country. Just under half of these patients come from the wider EU, some of whom stay for only a few months to a year or so. The remainder originate from the rest of the world. This appears to be a stable trend over recent years (see table 3).

Page | 13

Table 3 New registrations of patients with Severe Haemophilia A aged over 5 years old, and subsequent treatment by year

Registration year Total Haemophilia A 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 2014/15 2015/16 2008/2016

New registrations 12 10 11 15 11 17 19 23 118 per year

Treated in each year 2008/09 12 12

2009/10 11 6 17 UKHCDO Page |14 2010/11 10 8 10 28

2011/12 9 8 9 14 41 Annual 2012/13 8 8 7 14 10 53

2013/14 8 8 8 12 9 16 63 Report 2014/15 7 8 8 12 9 16 18 79

2015/16 7 8 6 10 8 15 19 20 93 2016

No treatment record 01101003 6 &

B leeding Table 3: This shows the number of patients over 5 years of age and newly registered (and therefore thought to be migrants) each year from

2008. It also shows the number treated in each year subsequent to their registration from 2008. This shows that potentially at least 118 Disorder patients with severe haemophilia A have migrated to the UK since 2008. This is likely to be an underestimate, since children under 5 years old are not included in this table. Although six patients in the table required no treatment, 93 of them were treated in 2015/16, suggesting that

Statistics most remain and require regular treatment.

Commissioners have recognised that net medical migration is a significant cost pressure and have requested far more data from us on this for

group of patients. We now request data on immigration status and so would expect this analysis to become more refined with the passage of 201

time. 5 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 2 Trend in numbers of Severe Haemophilia A patients aged 60 years and above, 1975 – 2015/16 (including HIV +ve pts)

100 80 60 40 Patients (n) 20 0 60-74 75+ 60-74 75+ 60-74 75+ 60-74 75+ 60-74 75+ 1975 1985 1995 2005 2015/16 Age group (years) by reporting year Graphs by Year

Figure 3 Trend in numbers of non-Severe Haemophilia A patients aged 60 years and above, 1975 – 2015/16 (including HIV +ve pts)

600 500 400 300 Patients (n) 200 100 0 60-74 75+ 60-74 75+ 60-74 75+ 60-74 75+ 60-74 75+ 1975 1985 1995 2005 2015/16 Age group (years) by reporting year Graphs by Year

Page | 15 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figures 2 & 3: Shows an almost threefold increase in the number of patients with severe haemophilia aged 60-74, and an almost fourfold increase in those aged 75 and above, over the past forty years. The number of elderly patients with severe haemophilia A actually declined during the 1990’s because older patients had a poorer prognosis than younger ones when infected with HIV. Pre-HIV patient numbers were not reached again until 2008. The effect of HIV is not seen markedly in non-severe haemophilia A (Figure 3) because proportionately far fewer of these patients were infected. The number of patients aged greater than 60 years increased thirteen-fold over the past 40 years. Some of this increase is probably attributable to better diagnosis rather than increasing lifespan, however. Both groups show evidence of an increase in elderly patients.

Page | 16

Figure 4 Factor VIII units used by UK Haemophilia Centres 1992 - 2015/16 all diagnoses

600 4,000 Plasma Recombinant Investigational 3,500 500

3,000

400 2,500

(millions) 300 2,000 UKHCDO Page |17 Patients (n) Units 1,500

Annual 200

1,000 Report

100 2016 500

& B leeding

0 0

Disorder

Time Period

Statistics N.B: Data for St Thomas’ were not submitted 1996-2006.

for

201 Figure 4 shows UK factor VIII usage for all diagnoses from 1992 to 2015/16. The number of patients reported to have been treated is shown 5 by the blue line. This shows steady continued growth throughout this period levelling off to some extent in recent years. /201 6

Figure 5 Factor VIII units used by UK Haemophilia Centres to treat Severe Haemophilia A – 2010/11 - 2015/16

500 1,750 Figure 5 shows a bar diagram of factor VIII usage for Investigational Recombinant Plasma severe haemophilia A in the UK from 2010/11 to 2015/16. 450 1,700 The blue line shows the number of patients treated in each 400 year. The numbers above the bars are the number of 350 1,650 patients treated in each year. This shows a 13% increase 300 in patient numbers over that period but a 22% increase in 1,600

product use. This has seen factor VIII consumption for (thousands) 250

severe haemophilia increase from 365 million units in 1,550 Patients (n) 200 2010/11 to 445 million units in 2015/16. This increase is Units largely, but not wholly attributable to increased numbers 150 1,500 UKHCDO Page |18 of patients. 100 1,450 At the same time, the use of investigational factor VIII has 50

Annual increased twelve-fold. 0 1,400

Report Time Period

2016 Recombinant

Plasma Investigational rFVIII Total Patients &

(excluding investigational) B leeding Year

IU % difference IU % difference IU % difference IU % difference % difference Disorder n (thousands) since 2010/11 (thousands) since 2010/11 (thousands) since 2010/11 (thousands) since 2010/11 since 2010/11

2010/11 37,185 100.00% 327,010 100.00% 1,123 100.00% 365,318 100.00% 1,511 100.00% Statistics 2011/12 33,846 91.02% 329,137 100.65% 6,645 591.49% 369,629 101.18% 1,550 102.58% 2012/13 33,358 89.71% 330,012 100.92% 8,116 722.50% 371,487 101.69% 1,562 103.38%

for

2013/14 30,189 81.19% 348,973 106.72% 18,484 1645.39% 397,646 108.85% 1,623 107.41% 201 2014/15 31,438 84.54% 377,822 115.54% 17,496 1557.45% 426,756 116.82% 1,663 110.06% 5 /201 2015/16 30,094 80.93% 400,601 122.50% 14,198 1263.90% 444,893 121.78% 1,710 113.17% 6

Table 4 Treatment intensity of patients with Severe Haemophilia A – 2010/11 - 2015/16

Change in treatment Patients Treatment Intensity FVIII Units intensity Treatment (n) (Units/Pt) since 2010/11 (%) Period <18 Years ≥18 years <18 Years ≥18 years <18 Years ≥18 years <18 Years ≥18 years

2010/11 131,141,658 234,176,810 607 904 216,049 259,045 100.0 100.0

2011/12 128,016,899 241,611,622 597 953 214,434 253,527 99.3 97.9

2012/13 125,289,759 246,197,158 605 957 207,091 257,259 95.9 99.3 UKHCDO

Page |19 2013/14 131,810,117 265,836,344 625 998 210,896 266,369 97.6 102.8

2014/15 140,999,503 285,756,508 622 1,041 226,687 274,502 104.9 106.0 Annual

2015/16 139,722,386 305,170,204 628 1,082 222,488 282,043 103.0 108.9

Report Treatment includes Plasma, Recombinant, Investigational factor

2016 Table 4: This shows that factor VIII treatment intensity (units/patient/year) has only increased by 3% in under 18 year-old patients with severe

&

haemophilia A in the last five years. The increase in the number of units used for this group, from 131 to 140 million units is almost entirely B leeding accounted for by the increase in the number of patients, from 607 to 628 patients.

The picture in adults with severe haemophilia A (>18 years old) is a little more complex in that treatment intensity has increased by almost 9% Disorder over five years; a modest increase over that timescale attributable to the wider use of prophylaxis. At the same time the numVIIIber and of patientsITI usage

has increased by almost 20%, much of which is probably caused by inward migration, from 904 to 1082 patients. The increase in the number Statistics of factor VIII units used, from 234 to 305 million units over those five years is attributable to a combination of greater treatment intensity and

a significant increase in the number of patients with severe haemophilia A treated. for

201 5 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figures 6a, b & c Patients with Severe / Moderate / Mild Haemophilia A treated with FVIII by UK Haemophilia Centres – 2007 - 2015/16

Figure 6a

1800 Haemophilia A 1600 <1 1400 1200 1000 800 Patients (n) 600 400 200 0

Year of treatment Figure 6b

610 Haemophilia A 1 ‐ 5 600

590

580 Patients (n) 570

560

550

Year of treatment Figure 6c

680 Haemophilia A 660 >5 & <40

640

620

600

580 Patients (n) 560

540

520

500

Year of treatment

Page | 20 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Data table for Figures 6a, 6b & 6c

Haemophilia A Haemophilia A Haemophilia A Haemophilia A <1 1 ‐ 5 >5 & <40 ≥ 40 Treatment % % % % Year n difference n difference n difference n difference since 2007 since 2007 since 2007 since 2007 2007 1405 100.0 587 100.0 583 100.0 26 100.0 2008/09 1454 103.5 587 100.0 561 96.2 22 84.6 2009/10 1475 105.0 569 96.9 617 105.8 26 100.0 2010/11 1511 107.5 578 98.5 641 109.9 26 100.0 2011/12 1550 110.3 594 101.2 650 111.5 20 76.9 2012/13 1562 111.2 572 97.4 647 111.0 19 73.1 2013/14 1623 115.5 603 102.7 652 111.8 19 73.1 2014/15 1663 118.4 603 102.7 648 111.1 21 80.8 2015/16 1710 121.7 605 103.1 668 114.6 21 80.8

Figures 6a, 6b & 6c data table: These show the numbers of patients with haemophilia A registered by severity between the years 2007 and 2015/16. These numbers declined as a result of HIV, stabilising after the introduction of HAART in the mid 1990’s. Pre-HIV patient numbers with severe haemophilia A were not achieved again until 2006/07, a decade later. However, a large proportion of the increase in the number of registrations in the past 5 years appears to be caused by net immigration.

Page | 21 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 7 Number of Severe Haemophilia A patients treated per million capita

Figure 7: This shows that the distribution of haemophilia is not merely a reflection of general population density. There is at least a more than threefold range in frequency per million of population between regions with a marked concentration in London.

Page | 22 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 8 Factor VIII usage (including Inhibitor) divided per Severe Haemophilia A patients by commissioning region

Figure 8: This map shows factor VIII treatment intensity for patients with severe haemophilia A, including patients with a current inhibitor, by commissioning region. This shows considerable regional variation.

Page | 23

Table 5 Factor VIII usage by region for patients with Severe Haemophilia A (incl. treatment for inhibitors)

Patients Total FVIII FVIII Units Mean Usage General treated (n) Units (IU) Per Capita Region Severe Population Severe Severe Severe Haemophilia A Haemophilia A Haemophilia A Haemophilia A London 491 158,483,666 322,777 South Yorkshire & Bassetlaw 118 35,383,750 299,862 Cumbria, Northumberland & Tyne and Wear 63 16,678,500 264,738 East Anglia 60 15,568,000 259,467 Surrey & Sussex 34 8,434,500 248,074 UKHCDO

Page |24 Wessex 232 53,075,594 228,774 Cheshire, Warrington & Wirral 146 30,905,250 211,680

Bristol, North Somerset & South Gloucestershire 77 16,087,750 208,932 Annual Source accreditation: Leicestershire & Lincolnshire 91 16,300,727 179,129

England, Northern Ireland & Wales: Mid-2015 Population estimate Report Scotland:Birmingham & Black Country Mid-2015 Population Estimates supplied by National Re 146 25,330,000 173,493

England 54,786,300 1,423 376,247,737 264,405 6.87 2016

&

Northern Ireland 1,851,600 69 15,524,750 224,996 8.38 B Scotland East 3,021,290 85 22,173,000 260,859 7.34 leeding

Scotland West 2,351,710 56 13,327,500 237,991 5.67 : Office for National Statistics licensed under the Open Gover Disorder Walescords 3,099,100 of Scotland under 83the Open Government 17,619,603 Licence v3.0 © 212,284 Crow 5.69

United Kingdom 65,110,000 1,711 444,892,590 260,019 6.83 Statistics

English regions ranked by mean usage

for

201 nment Licence v.3.0. 5 /201 n Copyright 2016 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 5: This shows factor VIII usage by country and commissioning region, ranked by the mean number of units used per patient with severe haemophilia. This suggests a wider range of clinical practice from region to region than observed last year. Usage per capita of population is not reported for the English regions as the administrative regions do not match specialist commissioning regions, therefore, population figures are not available. Usage per capita for Scotland (East and West combined) and England are fairly closely matched though per capita usage in Northern Ireland is noticeably higher, and in Wales it is noticeably lower. The English commissioning area teams have been mapped to the following geographical regions:

Area Team Name Geographical Region Name

Birmingham and the Black Country West Midlands Bristol, North Somerset and South Gloucestershire South West Cheshire, Warrington and Wirral North West Cumbria, Northumberland, Tyne and Wear North East & Cumbria East Anglia East of England Leicestershire and Lincolnshire East Midlands London London South Yorkshire and Bassetlaw Yorkshire & Humber Surrey and Sussex South East Coast Wessex Thames Valley & Wessex

Please note, that the figures are based on severe haemophilia A patients treated and not on the number of patients registered. Not all patients with severe haemophilia require regular treatment. The allocation of patients to regions is explained below.

N.B:

Patients resident in England are reported against all English commissioning areas in which they were treated, so may be counted more than once.

The total number of severe Haemophilia A patients treated in the UK in 2015/16 was 1711.

Patients resident in England and treated in Wales, Scotland or Northern Ireland are reported against the devolved administration in which they were treated.

Patients resident in Wales, Scotland or Northern Ireland are reported against their devolved administrations, regardless of where they were treated.

Patients resident in Scotland are reported against East/West Scotland according to their home postcode, rather than where they were treated.

Patients resident outside the UK are reported against the commissioning areas in which they were treated.

Page | 25 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 9 Annual FVIII usage 2015/16 in Severe Haemophilia A patients aged under 18 years with no current inhibitor, by centre, ranked by median

usage

Leeds Royal London Nottingham centres with <=4 patients meeting criteria Liverpool Birmingham Sheffield Belfast Coventry North Hampshire Manchester Cardiff Newcastle upon Tyne Oxford Cambridge centres with 5-9 patients meeting criteria Edinburgh Leicester Glasgow St Thomas' Bristol Great Ormond Street

0 2 4 6 8 10 12 14 16 18 >20 Median units (thousands) per kilogram per patient

N.B:

Patients treated at more than 1 centre during the year have all their usage reported against the centre where they received the most units

Indicated outside values show where a patient's usage is more than 1.5 times the interquartile range (IQR) from the nearest quartile at centre level

The vertical green line indicates the 95th percentile of units, regardless of centre (11,852 IU/kg)

The vertical red line indicates a break in the axis in order to illustrate extreme outliers Figure 9: This shows factor VIII usage per kilogram per patient by Haemophilia Centre (ranked by median usage) in patients with severe haemophilia A aged less than 18 years old with no current inhibitor. The boxes show the 25th and 75th percentiles and the whiskers show the arithmetic range of use excluding outliers. Indicated outside values show outliers from the normal practice of the centre rather than by reference to practice in the UK as a whole. Some outliers in some centres therefore use less than patients not deemed to be outliers in other centres. The vertical red line indicates a break in the axis so that the scale is not overly influenced by an extreme outlier who used 62.1 thousand units per kilogram. All patients represented in this figure were reportedly inhibitor free during the 2015/16 reporting year. This shows a twofold range in median treatment intensity between centres (excluding Leeds, for whom weight data was largely missing and for whom the data may therefore not be representative). This implies a wide range in the intensity of prophylaxis used. The range appears to be stable in recent years. Most centres have broadly similar treatment intensity

Page | 26 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

(IU/Kg/year), - as one would expect given that prophylaxis is the standard of care. The difference in practice at the extremes is not easily explained for some centres. However, those centres such as Great Ormond Street, who conduct a far greater number of Immune Tolerance Induction procedures than other paediatric centres, will be expected to have high median usage. Although this chart excludes patients with a current inhibitor, it is now well recognised that patients who fulfil the internationally recognised criteria for tolerance (half-life greater than eight hours), and who have traditionally been thought to be inhibitor free, continue to have low level inhibitor activity, which is too low to detect in the Bethesda assay but high enough to impair factor VIII pharmacokinetics and increase factor VIII consumption. Figure 14 shows that patients aged under 18 years with a past inhibitor history, but currently thought to be inhibitor- free, nevertheless use 20% more factor VIII than those with no past inhibitor history (p<0.005). Summary statistics for this chart are presented in the accompanying data table.

Data table for Figure 9

Patients Patients treated with Median Median Haemophilia Centre Total Units treated weight Units Units/Kg reported Belfast 18 18 2,827,750 155,375 4,049 Birmingham 39 28 5,244,750 130,000 3,844 Bristol 23 12 4,672,250 157,000 6,545 Cambridge 23 22 3,077,000 124,500 4,806 Cardiff 10 9 1,734,750 175,000 4,290 Coventry 10 10 1,679,750 140,750 4,112 Edinburgh 11 9 1,848,000 98,500 5,026 Glasgow 21 21 3,720,750 157,500 5,125 Great Ormond Street 77 76 19,965,240 245,000 7,462 Leeds 24 2 4,905,500 184,875 1,424 Leicester 10 8 958,200 96,375 5,056 Liverpool 22 22 2,984,750 100,500 3,708 Manchester 42 40 6,398,000 132,750 4,252 Newcastle upon Tyne 16 16 3,524,500 220,500 4,552 North Hampshire 19 19 3,102,250 165,000 4,171 Nottingham 19 5 1,999,500 87,500 3,609 Oxford 39 37 8,526,750 183,000 4,752 Royal London 13 7 2,234,500 168,000 3,607 Sheffield 15 10 2,855,250 111,500 3,856 St Thomas' 22 13 3,641,000 140,875 5,329 Centres with <=4 patients meeting criteria 16 11 2,955,250 167,500 3,683 Centres with 5‐9 patients meeting criteria 61 56 13,617,100 190,000 4,911

Page | 27 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 10 Annual FVIII usage 2015/16 in Severe Haemophilia A patients aged 18 years or more with no current inhibitor, by centre, ranked by

median usage

Bristol Cardiff Aberdeen Liverpool Birmingham centres with 5-9 patients meeting criteria Leicester Oxford Dundee Nottingham Belfast St George's centres with <=4 patients meeting criteria Manchester Canterbury North Hampshire Glasgow Sheffield Edinburgh Cambridge Newcastle upon Tyne Royal Free Southampton St Thomas' Royal London Hammersmith Leeds

0 2 4 6 8 10 12 14 16 18 >20 Median units (thousands) per kilogram per patient

N.B:

Patients treated at more than 1 centre during the year have all their usage reported against the centre where they received the most units

Indicated outside values show where a patient's usage is more than 1.5 times the IQR from the nearest quartile at centre level

The vertical green line indicates the 95th percentile of units, regardless of centre (6,980 IU/kg) The vertical red line indicates a break in the axis in order to illustrate extreme outliers Figure 10: This shows factor VIII usage per kilogram per patient by Haemophilia Centre (ranked by median usage) in patients with severe haemophilia A aged over 18 years with no current inhibitor. The boxes show the 25th and 75th percentiles and the whiskers show the arithmetic range of use excluding outliers. Outliers are identified by the statistical software by reference to the usage in that individual centre where the patient’s usage is greater than 1.5 times the IQR from the nearest quartile at centre level. They are outliers from the normal practice of the centre rather than by reference to practice in the UK as a whole. Some outliers in some centres therefore use less than patients not deemed to be outliers in other centres. The x-axis is broken using the red line so that it is not overly influenced by extreme outliers. All patients were reportedly inhibitor free during the reporting period. The 95th percentile of usage for the whole group, regardless of centre (at 7.0 thousand units per kilogram) is indicated by the green line.

Page | 28 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Note that the 95th percentile for adults is lower than for children. This is partly a reflection of the shorter half-life found in small children, who require larger doses /Kg bodyweight. The adult outliers also show that a small number of patients, use a great deal of factor VIII, despite having apparently no reported inhibitor in year. The extreme outlier uses in excess of 20 thousand units per kilogram and a further 40 use in excess of 7 thousand units per kilogram. This group will be the subject of separate study, to better understand the reasons for their factor usage. The median treatment intensity range is 2.7-fold (excluding Leeds and Bristol, for whom weight data was largely missing and for whom the data may therefore not be representative). This range is possibly less than in the past, but there is still a wide range in clinical practice from one centre to the next with a strong trend for the London centres to treat their patients more intensely than the rest of the UK.

Data table for Figure 10

Patients Patients treated with Median Median Haemophilia Centre Total Units treated weight Units Units/Kg reported Aberdeen 11 8 2,892,750 228,000 2,142 Belfast 40 39 9,500,500 217,000 2,707 Birmingham 70 40 12,838,000 165,750 2,276 Bristol 28 7 5,757,000 165,000 1,220 Cambridge 32 31 10,023,000 332,750 3,671 Canterbury 18 14 5,729,000 308,500 2,980 Cardiff 35 23 6,079,353 164,000 1,821 Dundee 12 12 3,142,000 268,000 2,552 Edinburgh 20 18 5,793,250 233,500 3,402 Glasgow 38 38 9,769,000 234,000 3,132 Hammersmith 25 22 8,234,500 350,500 4,931 Leeds 31 12 14,883,000 318,000 5,280 Leicester 18 15 4,089,027 241,000 2,440 Liverpool 29 29 6,153,000 173,000 2,166 Manchester 52 48 11,820,250 235,750 2,937 Newcastle upon Tyne 39 38 12,328,500 281,000 3,680 North Hampshire 53 45 14,129,344 249,000 3,066 Nottingham 26 6 6,251,000 231,750 2,647 Oxford 88 85 20,686,500 209,000 2,477 Royal Free 122 116 38,606,950 317,400 3,880 Royal London 43 27 12,883,410 285,000 4,515 Sheffield 17 16 4,410,000 242,000 3,163 Southampton 12 11 3,236,000 273,750 4,209 St George's 26 26 5,812,000 241,500 2,794 St Thomas' 102 48 38,770,000 348,000 4,259 Centres with <=4 patients meeting criteria 27 17 7,790,000 265,000 2,860 Centres with 5‐9 patients meeting criteria 45 26 10,957,750 180,000 2,392

Page | 29 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figures 11a&b Median factor VIII units used per kilogram body weight per year in Severe Haemophilia A patients without inhibitors by age, 2015/16

11a. Paediatrics

24 22 20 18 16 14 12 10 8 6 4 2

Median units (thousands) per kilogram per year 0

0 1 2 3 4 5 6-8 9-11 12-15 Age (years) excludes outside values

Weight data are missing for 84/481, including 14/34 aged <12m 11b. Adults

10 9 8 7 6 5 4 3 2 1 0 Median units (thousands) per kilogram per year

24 34 + - - 65 16 25 35-44 45-54 55-64 Age (years) excludes outside values

Weight data are missing for 257/1129

Page | 30 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figures 11a & 11b These show (overleaf) the median (central lines), IQR (box) and the arithmetic range (whiskers) of factor VIII usage per kilogram bodyweight per year in UK patients with severe haemophilia A without inhibitors, broken down by age. The most intensive general usage appears to be in young children (Figure 15a). Treatment intensity (iu/kg/year) declines after the fifth year of life. Vial size is an issue for small children since doses will often be rounded up because the range of available vial sizes does not make it possible to make small dose-adjustments in very small individuals. Amongst adults over 16 years of age, treatment intensity was greatest in young adults, declining from the 25-34 years age group. Most young adults are using prophylaxis. The median units used per kilogram is in the prophylactic range 3,000-6,000 iu/kg/year for this group. Older patients have a median usage below the prophylactic range and their IQRs suggest that some of these patients use prophylaxis and some are on modest treatment-on- demand regimens. Haemtrack provides a more detailed analysis of treatment regimens.

Page | 31 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 12 Median factor VIII units used per kilogram body weight per year in Severe Haemophilia A patients without inhibitors aged 16 and over,

by bodyweight 2015/16

12,000

n=9 10,000 n=336 n=405 8,000 n=122 6,000

4,000 Units per kilogram per year 2,000

0

0-50 50-75 75-100 100+ Bodyweight (kg) excludes outside values

Weight data are missing for 257/1129 SHA patients known to be aged 16+ Figure 12: This shows box and whisker plots (median, IQR and arithmetic range) of median units per kilogram per year used by all UK patients with severe haemophilia A aged 16 and over without inhibitors, broken down by bodyweight. The total number of patients in each group is indicated by the number over each box. Since factor VIII recovery increases progressively as Body Mass Index (BMI) increases, one would expect factor VIII consumption per kilogram bodyweight to decline as bodyweight increases. This seems to be the case Although BMI would be a better reflection of obesity than bodyweight we have no record of patient height and so could not calculate BMI. We presume that the `greater than 100 kg’ group will all be obese.

Page | 32 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 13 Median usage of factor VIII: UK patients with severe Haemophilia A without inhibitors broken down by age, 2010/11 – 2015/16

1,000 900 800 700 600 500 400 300 200 100

Median Units (thousands) per Patient 0 0-9 10-19 20-49 50-59 60+ Age (years) 2010/11 2011/12 2012/13 2013/14 2014/15 2015/16

excludes outside values

Figure 13: This shows median, IQR and arithmetic range of factor VIII usage by all UK patients with severe haemophilia A without inhibitors, broken down by age and year. This shows a general upward trend in the number of units issued per year in the under-10s, and a fluctuating trend in the 10-19 year’s age group in which patients appear to have reached adult treatment intensity. Since prophylaxis has been their standard of care since 1996, this implies greater intensity of prophylaxis in this group and probably reflects a general trend from 3- times a week to every second day prophylaxis. Treatment intensity appears to have stabilised in most age groups except the relatively elderly who may be starting prophylaxis or having more surgery.

Page | 33 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 14 Severe Haemophilia A patients with no current inhibitor between April 2015 & March 2016: median usage by inhibitor history

1,000 900 800 n=914 700 n=145 600 n=451 n=100 500 400 300 200 100 Median Units (thousands) per Patient 0 Under 18 18 and over Age (years) No inhibitor history Inhibitor history

excludes outside values

Mann-Whitney U test: Under 18 years: p<0.005 (significant); 18 years and over: p=0.33 (not significant) Figure 14: This shows median usage of factor VIII for UK patients with severe haemophilia without a current inhibitor. Usage is broken down by age (less than 18 years, and 18 years and older) and by past history or no past history of factor VIII inhibitors. The number of subjects in each group is indicated by the number over each box. This shows that children with a past history of factor VIII inhibitors use significantly more factor VIII than those without such a history. The small difference seen between non-inhibitor and ex- inhibitor adults fails to achieve statistical significance (Mann-Whitney U test p<0.005 for children, and p=0.33 for adults). Whilst there are a number of possible explanations for this, it raises the possibility that “tolerant” ex-inhibitor patients may still have a relatively reduced half- life and low-level circulating factor VIII inhibitors, below the limit of detection of the current Bethesda assay, which is very gradually abolished by ongoing factor VIII prophylaxis.

Page | 34 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 6 Products used to treat Haemophilia A (including inhibitors) between April 2015 & March 2016

Manufacturer Product Total Units

Advate 164,292,360 Baxalta FEIBA 36,176,573 Bayer Kogenate 21,489,750 Biotest Haemoctin 340,000 FVIII 8Y 256,620 BPL Optivate 4,715,460 Haemate P 202,000 CSL Behring Helixate Nexgen 27,913,250 Kybernin 6,500 Alphanate 142,000 Grifols Fanhdi 25,281,600 Novo Nordisk NovoSeven (mg) 23,124.00 Nuwiq 5,218,500 Octapharma Octanate 3,572,500 BeneFIX 1,000 Pfizer ReFacto AF 276,868,501 SOBI/Biogen Elocta 285,250.00 Various Manufacturers Investigational Factor VIII 16,147,178

Units in IU unless otherwise stated Table 6: This shows a breakdown of products, listed by supplier, used to treat UK patients with haemophilia A in 2015/16, including those with inhibitors but excluding acquired haemophilia. These figures have been cross-checked against sales figures supplied by the manufacturers for the same period. Whilst one would not expect a perfect match between NHD figures and the manufacturer’s sales figures, there is a very high level of correlation for all but the low usage products. Those sales figures are not reported at the request of the suppliers for reasons of commercial sensitivity. By and large, the plasma derived products listed were used for immune tolerance induction. The exception, Fanhdi, is used for a group of patients without inhibitors attending a single centre in the South of England. I note that the usage of Fanhdi has declined in the last two years.

Page | 35 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Note that the use of over 16 million units of investigational factor VIII was reported to us during the year, 4 million less than last year and nearly 5 million less than the year before. Several of these trials are coming to an end and so it is likely that the use of investigational factor VIII may decline further from its recent historic high. We have deliberately aggregated and anonymised these products to avoid any breach of individual centre’s confidentiality agreements and to take account of commercial sensitivities.

Potentially anomalous product use in Table 5 is accounted for as follows:  Alphanate: Patient choice  BeneFIX: given in error  FVIII 8Y: Inhibitor ITI  Haemate P: Inhibitor  Octanate: Inhibitor  Optivate: Inhibitor ITI

Table 7: This shows a breakdown of all factor VIII concentrate use by diagnosis including apparently anomalous use. Some products used to treat von Willebrand Disease will include VWF as well as FVIII.

* Potentially anomalous use of factor VIII in Table 7 is accounted for as follows: 8Y usage in four patients reported to have either miscellaneous bleeding disorder or platelet defect but who had thrombotic thrombocytopenia purpura (which we do not register). The patient with Haemophilia B treated with 500iu of rFVIII was treated in error.

Page | 36

Table 7 Factor VIII units used by UK Haemophilia Centres between April 2015 & March 2016, broken down by diagnosis

Patients Plasma Recombinant Investigational Total Coagulation Defect Treated FVIII (IU) FVIII (IU) FVIII (IU) FVIII (IU)

Haemophilia A 2,966 34,510,180 494,997,361 16,147,178 545,654,719 Haemophilia A Carrier 41 ‐ 1,070,250 ‐ 1,070,250 Acquired Haemophilia A 7 87,000 48,000 ‐ 135,000 Haemophilia B 1 ‐ 500 ‐ 500 von Willebrand disease 739 19,512,500 43,500 ‐ 19,556,000

Acquired von Willebrand Disease 35 919,800 ‐ ‐ 919,800 UKHCDO Page |37 Platelet‐type Pseudo von Willebrand D 2 4,500 ‐ ‐ 4,500

Probable von Willebrand disease 1 2,000 ‐ ‐ 2,000 Annual

Combined V+VIII Deficiency 6 ‐ 35,750 ‐ 35,750 Report Other combined diagnoses 20 343,500 1,370,000 ‐ 1,713,500

2016 Platelet defects* 1 40,000 ‐ ‐ 40,000

& B

Miscellaneous* 3 72,500 ‐ ‐ 72,500 leeding Unclassified* 1 1,000 ‐ 1,000

Disorder Total 3,823 55,492,980 497,565,361 16,147,178 569,205,519

Statistics N.B: Haemophilia A Carrier incl Products containing VWF as well

for

201 udes females with factor VIII de 5 /201 as FVIII are reported in FVIII 6

ficiency units

Figure 15 Market Share of factor VIII concentrates issued by UK Haemophilia Centres during 2015/16

Investigational Recombinant SOBI/Biogen ‐ Recombinant 2.84% 0.05%

Baxalta ‐Recombinant Pfizer ‐ Recombinant 28.99% 48.76% UKHCDO

Page |38 Bayer ‐ Recombinant 3.78%

Annual

Biotest ‐ Plasma Report 0.06%

2016 BPL ‐ Plasma

0.91% & B

CSL Behring ‐ Plasma leeding Grifols ‐Plasma 2.44% 4.61%

Octapharma ‐ Recombinant Octapharma ‐Plasma CSL Behring ‐ Recombinant Disorder 4.91% 0.93% 1.73%

Figure 15: This shows the market breakdown of factor VIII used for all diagnoses and inhibitor patients. Plasma-derived factor VIII is generally Statistics used for treatment of von Willebrand disease or for immune tolerance induction but one centre has a significant use of Fanhdi for non-inhibitor

patients with haemophilia A and one or two other, isolated patients in other centres, use plasma-derived products as their routine replacement for

therapy. 201 5 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

2.2 Haemophilia B

Page | 39

Table 8 Patients with congenital Haemophilia B registered and treated April 2015 - March 2016

Age Factor IX level (iu/dl) Haemophilia B Range < 1 1 ‐ 5 >5 & <40 ≥ 40 Unknown Total

<18 years 111 (0) 86 (0) 141 (44) 29 (24) 2 (2) 369 (70) Total In Register (including low‐ ≥18 years 230 (1) 278 (6) 593 (214) 214 (182) 23 (19) 1,338 (422) level carriers) Total 341 (1) 364 (6) 734 (258) 243 (206) 25 (21) 1,707 (492)

New <18 years 7 (0) 4 (0) 10 (6) 3 (3) 1 (1) 25 (10) UKHCDO Page |40 Registrations * ≥18 years 3 (0) 2 (0) 22 (9) 18 (16) 5 (4) 50 (29) (including low‐

level carriers)

Total 10 (0) 6 (0) 32 (15) 21 (19) 6 (5) 75 (39) Annual

<18 years 105 (0) 57 (0) 30 (1) 1 (1) ‐ (0) 193 (2)

Treated in Report year** ≥18 years 206 (0) 142 (1) 135 (37) 5 (3) 1 (0) 489 (41)

(including low‐ 2016

level carriers) Total 311 (0) 199 (1) 165 (38) 6 (4) 1 (0) 682 (43) & B leeding * New registrations are a subset of the ‘In Register’ numbers ** Treated includes patients ‘In Register’ and ‘New Registratio

Disorder

Table 8: This shows the number of patients with haemophilia B, including low level haemophilia B carriers, broken down by severity and age.

Statistics Patients newly registered are also shown, as are the numbers treated. The number of registered patients withThe haemophilia numbers in brackets B continues are females to rise, especially non-severe haemophilia B.

for

ns’ 201 5 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 16 Carriers of Haemophilia B currently registered and newly registered, by baseline factor IX level

120 Haemophilia B Carrier 114 In Register 106 (Excl. new registrations) Haemophilia B Carrier 100 91 New Registrations 83 80

60

40 40

17 20 12 10 4 5 6 1 00 1 2 0 <2 2‐9 10‐19 20‐29 30‐39 40‐49 50+ N/K

Factor VIII level (iu/dl) Diagnosis Grand <2 2‐9 10‐19 20‐29 30‐39 40‐49 50+ N/K Total Haemophilia B Carrier In Register 1 124083114911066453 (Excl. new registrations) Haemophilia B Carrier 001410517239 New Registrations

1 124187124961238492

N.B:

Haemophilia B Carrier includes: Females registered by their Haemophilia Centre as Females with FIX deficiency Females registered by their Haemophilia Centre as Haemophilia B FIX Leyden carriers

Figure 16: This shows the distribution of reported factor IX levels amongst registered carriers of haemophilia B in the UK. It is interesting that there is a relatively large number of very low level carriers. These mostly have an extreme degree of lyonisation but some are homozygous products of consanguineous unions. In some cases, the level is not known either because the patient is too young to be tested or because a test result has been inadvertently omitted. Carriers with normal factor IX levels are still under-represented in this chart, since we have only recently started to register all carriers and registration is understandably still incomplete at this time.

Page | 41 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 9 New registrations of Haemophilia B between April 2015 & March 2016, by age at mid-year and severity

Number of Patients (Factor IX level (iu/dl)) Coagulation Age Defect (years) < 1 1 ‐ 5 >5 & <40 ≥ 40 Unknown Total

0 : 46310010 5 : 9111003 10 : 19004004 20 : 29304119 Haemophilia B 30 : 39004004 40 : 49012003 50 : 59010102 60 : 69000000 70 +001001 Total 10 6 17 2 1 36 N.B: Haemophilia B includes patients with FIX Leyden Table 9: This shows new registrations of Haemophilia B broken down by their age at the time of registration. All 4 patients with severe disease registering after the age of five were born outside the UK. Less severe disease will often present at a later age and we have not investigated the proportion of that group which is native to the UK.

Page | 42 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 17 Trend in numbers of Severe Haemophilia B patients aged 60 years and above, 1975 – 2015/16 (including HIV +ve pts)

50 40 30 20 Patients (n) 10 0 60-74 75+ 60-74 75+ 60-74 75+ 60-74 75+ 60-74 75+ 1975 1985 1995 2005 2015/16 Age group (years) by reporting year Graphs by Year

Figure 18 Trend in numbers of non-Severe Haemophilia B patients aged 60 years and above, 1975 – 2015/16 (including HIV +ve pts)

120 110 100 90 80 70 60 50 Patients (n) 40 30 20 10 0 60-74 75+ 60-74 75+ 60-74 75+ 60-74 75+ 60-74 75+ 1975 1985 1995 2005 2015/16 Age group (years) by reporting year Graphs by Year

Page | 43 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 17 This shows the trend in numbers of patients aged over 60 years with severe Haemophilia B since 1975. This shows a fivefold increase over the past 40 years. The mid-2000s plateau in numbers for the 60-74 years’ age group is attributable to HIV, as in the similar graph of patients with Haemophilia A, but less marked. A smaller proportion of patients with haemophilia B were infected with HIV than haemophilia A because the UK was self-sufficient in factor IX concentrate during the period of risk and HIV spread into the UK donor population later than it did in the United States. Suffice it to say, there is ample evidence of a burgeoning population of older patients with severe Haemophilia B.

Figure 18 This shows a similar bar diagram of patients with non-severe haemophilia B showing an sevenfold increase in patients aged over 60 years with non-severe haemophilia B during the past 40 years. This will reflect a combination of better diagnosis, more complete registration and improved life expectancy.

Page | 44

Figure 19 Factor IX units used by UK Haemophilia Centres 1992- 2015/16 all diagnoses

100,000,000

Plasma Recombinant Investigational 90,000,000

80,000,000

70,000,000

60,000,000

50,000,000 UKHCDO Page |45 Units 40,000,000

Annual 30,000,000

Report

20,000,000

2016

10,000,000 & B leeding

0

Disorder

Time Period

Statistics N.B: Data for St Thomas’ were not submitted 1996-2006.

Figure 19: Shows UK factor IX usage for all diagnoses from 1992 to 2015/16. The numbers over each column are the number of patients for

treated with factor IX (all diagnoses) during the year. This shows a generally steady, year on year increase in usage for most of this period, 201 5 levelling off to some degree over the past four years with some fluctuation broadly in line with the number of patients treated. /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 20 Number of Severe Haemophilia B patients treated per million capita

Figure 20: This shows at least a fourfold range in the frequency of haemophilia per million of population with a cluster in London.

Page | 46 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 21 Factor IX Usage (including inhibitor) divided by number of Severe Haemophilia B patients by commissioning region

Figure 21: This shows usage of factor IX per patient with severe Haemophilia B, giving a measure of the intensity of replacement therapy. There is, again, regional variation in usage.

Page | 47

Table 10 Factor IX usage by region for patients with Severe Haemophilia B (incl. treatment for inhibitors)

Patients Total FIX FIX Units Mean Usage General treated (n) Units (IU) Per Capita Region Severe Population Severe Severe Severe Haemophilia B Haemophilia B Haemophilia B Haemophilia B Birmingham & Black Country 20 5,448,000 272,400 Cumbria, Northumberland & Tyne and Wear 16 3,960,000 247,500 Cheshire, Warrington & Wirral 25 6,089,920 243,597 London 92 21,424,870 232,879 South Yorkshire & Bassetlaw 21 4,780,722 227,653 Page |48

Surrey & Sussex 7 1,483,500 211,929 UKHCDO Bristol, North Somerset & South Gloucestershire 14 2,659,500 189,964 Wessex 37 6,728,870 181,861

Source accreditation: Annual England, NorthernLeicestershire & Lincolnshire Ireland & Wales: Mid-2015 Population estimate 15 2,562,000 170,800

Scotland:East Anglia Mid-2015 Population Estimates supplied by National Re 23 3,919,250 170,402 Report England 54,786,300 259 59,056,632 228,018 1.08

2016 Northern Ireland 1,851,600 8 2,231,100 278,888 1.20

& B

Scotland East 3,021,290 9 2,502,000 278,000 0.83 le e ding Scotland West: Office 2,351,710 for National Statistics 14 licensed under the 2,261,250 Open Gover 161,518 0.96

Walescords 3,099,100 of Scotland under the 10 Open Government 1,392,553 Licence v3.0 © Crow 139,255 0.45 Disorder United Kingdom 65,110,000 300 67,443,535 224,812 1.04

Statistics English regions ranked by mean usage

for

nment Licence v.3.0. 201 5

n Copyright 2016 /201

6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 10: This shows usage by commissioning area team. This shows less variation in treatment intensity than with haemophilia A, although patient numbers for this diagnosis are very much smaller and so between-region comparisons of treatment intensity cannot really be made. Although usage per patient in Northern Ireland appears higher than elsewhere in the UK, no reasonable comparison can be made given that only eight patients with Haemophilia B are treated in the province and there is considerable interpersonal variation in clinical phenotype for this condition. Usage per patient in Wales is lower than elsewhere in the UK.

The English commissioning Area Teams have been mapped to the following geographical regions:

Area Team Name Geographical Region Name

Birmingham and the Black Country West Midlands Bristol, North Somerset and South Gloucestershire South West Cheshire, Warrington and Wirral North West Cumbria, Northumberland, Tyne and Wear North East & Cumbria East Anglia East of England Leicestershire and Lincolnshire East Midlands London London South Yorkshire and Bassetlaw Yorkshire & Humber Surrey and Sussex South East Coast Wessex Thames Valley & Wessex

Page | 49 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 22 Annual FIX usage 2015/16 in Severe Haemophilia B patients aged under 18 years with no current inhibitor, by centre, ranked by median

Oxford

Cambridge

North Hampshire

Great Ormond Street

centres with <=4 patient meeting criteria

Manchester

Bristol

Royal Free

0 2 4 6 8 10-15 >15 Median units (thousands) per kilogram per patient

Indicated outside values show where a patient's usage is more than 1.5 times the IQR from the nearest quartile at centre level

The vertical green line indicates the 95th percentile of units, regardless of centre (8,291 IU/kg)

The vertical red line indicates a break in the axis in order to illustrate extreme outliers

Patients treated at more than 1 centre during the year have all their usage reported against the centre where they received the most units

Figure 22: This shows factor IX usage per kilogram per patient with severe haemophilia B (median, IQR and arithmetic range) in UK children aged under 18 years, without a current inhibitor, broken down by centre. Outliers are also shown. We have aggregated centres with 1 - 4 patients and reported all other centres individually. The vertical green line indicates the 95th percentile of units for the whole UK (8,291 units per kilogram per year). The red line indicates a break in the x-axis in order to indicate outliers. Indicated outside values show where a patient's usage is more than 1.5 times the IQR from the nearest quartile at centre level. The associated table shows summary data including median units per patient per year. These plots include usage of investigational factor IX.

Page | 50 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Data table for Figure 22

Patients Patients treated with Median Median Haemophilia Centre Total Units treated weight Units Units/Kg reported Bristol 5 4 632,500 117,500 5,253 Cambridge 6 6 563,000 62,375 2,994 Great Ormond Street 23 23 2,922,314 123,250 3,909 Manchester 9 9 1,375,500 140,000 4,464 North Hampshire 5 5 547,250 109,000 3,902 Oxford 9 9 1,132,500 64,500 2,462 Royal Free 5 5 1,673,000 344,000 5,707

Centres with <=4 patients meeting criteria 39 35 5,743,152 96,000 4,058

Data table for Figure 23

Patients Patients treated with Median Median Haemophilia Centre Total Units treated weight Units Units/Kg reported Birmingham 10 6 3,312,000 269,000 3,873 Cambridge 14 13 3,149,750 219,250 2,720 Glasgow 11 11 2,059,500 193,000 2,236 Manchester 11 8 4,074,420 368,700 4,514 Newcastle upon Tyne 12 11 3,238,000 298,000 3,200 Oxford 15 15 3,495,620 202,000 2,636 Royal Free 28 28 9,520,288 306,000 3,888 St Thomas' 16 5 3,975,000 260,000 506 Centres with <=4 patients meeting criteria 42 29 11,291,555 240,000 3,467

Centres with 5‐9 patients meeting criteria 39 27 8,721,686 204,000 2,489

Page | 51 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 23 Annual FIX usage 2015/16 in Severe Haemophilia B patients aged 18 years or more with no current inhibitor, by centre, ranked by

median usage

St Thomas'

Glasgow

centres with 5-9 patients meeting criteria

Oxford

Cambridge

Newcastle upon Tyne

centres with <=4 patients meeting criteria

Birmingham

Royal Free

Manchester

0 2 4 6 8 10 >10 Median units (thousands) per kilogram per patient

Indicated outside values show where a patient's usage is more than 1.5 times the IQR from the nearest quartile at centre level

The vertical green line indicates the 95th percentile of units, regardless of centre 6,356 IU/kg)

The vertical red line indicates a break in the axis in order to illustrate extreme outliers

Patients treated at more than 1 centre during the year have all their usage reported against the centre where they received the most units Figure 23: This shows factor IX usage per patient with severe haemophilia B (median, IQR and arithmetic range) of UK patients aged 18 years or older without a current inhibitor, and broken down by centre. Statistical outliers are shown. These are defined as usage greater than 1.5 times the IQR from the nearest quartile at centre level, so a patient who may be an outlier in one centre may not be if they used the same amount of factor IX but were managed by other centres whose general usage was higher. Only those centres managing 10 or more patients with severe haemophilia B are identified and the remainder are aggregated according to centre size. The vertical green line indicates the 95th percentile of units for the whole UK (6,356 units per kilogram per year). Excluding St Thomas’, due to largely missing weight data, this shows a twofold range in treatment intensity. Summary data for this figure are shown in the associated table. These plots include investigational factor IX.

Page | 52 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 11 Products used to treat Haemophilia B (including inhibitors) between April 2015 & March 2016

Manufacturer Product Total Units

Baxalta FEIBA 2,204,000

BPL Replenine 2,686,610

CSL Behring Mononine 540,000

Grifols Alphanine 6,338,600

Novo Nordisk NovoSeven (mg) 8,295

BeneFIX 79,040,670 Pfizer ReFacto AF 500

SOBI/Biogen ALPROLIX 54,000

Various Manufacturers Investigational Factor IX 4,361,406

Total 95,234,081

Units in IU unless otherwise stated

Table 11: This gives a breakdown of the products used to treat haemophilia B in the UK in 2015/16, organised by supplier. These figures have been cross-checked with sales figures provided by the suppliers. Whilst we would not expect a perfect match between manufacture's sales figures and NHD usage figures, there was a high level of correlation except for low-usage products. Sales figures are not reported for reasons of confidentiality. Note that more than 4 million units of investigational factor IX were used in the year. This is almost 20% down on last year, and it is likely to decline further since some trials have come to an end. We have deliberately aggregated and anonymised these products to avoid any breach of confidentiality agreements and to take account of commercial sensitivities. We are unable to distinguish between normal and extended half-life investigational products for that reason. We appreciate that ideally they should be reported separately, as they will be once licensed. We would advise that data on trial products should be shared at a local level with commissioners so that they have a realistic estimate of product consumption and avoid any inadvertent reduction in future budget. A significant proportion of factor IX used was plasma derived, mainly for patients who do not “get on with” BeneFIX. The proportion of this supplied by BPL has declined, reflecting manufacturing and supply issues affecting that company.

Page | 53 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 12 Factor IX units issued by UK Haemophilia Centres between April 2015 & March 2016, broken down by diagnosis

Patients Plasma Recombinant Investigational Total Coagulation Defect Treated FIX (IU) FIX (IU) FIX (IU) FIX (IU)

Haemophilia A 1 ‐ 1,000 ‐ 1,000

Haemophilia B 628 9,565,210 79,308,170 4,361,406 93,234,786

Haemophilia B Carrier 41 78,000 338,500 ‐ 416,500

Combined Diagnoses 1 ‐ 5,000 ‐ 5,000

Total 671 9,643,210 79,652,670 4,361,406 93,657,286

N.B: Haemophilia B includes patients with FIX Leyden Haemophilia B Carrier includes Females with FIX deficiency and FIX Leyden carriers

The patient with Haemophilia A treated with 1000iu of rFIX was treated in error

Table 12: This shows UK factor IX issued between 2015/16, broken down by product type and diagnosis. Note that this includes the use of over 4,000,000 units of investigational recombinant factor IX. This represents a smaller proportion of the total FIX units issued compared to last year. For reasons of study confidentiality, we are unable to break down this table into short and long half-life products.

Page | 54

Figure 24 Market Share of factor IX concentrates issued by UK Haemophilia Centres during 2015/16

Investigational Recombinant BPL ‐ Plasma CSL Behring ‐ Plasma FIX Grifols ‐Plasma 2.87% 0.58% 4.66% 6.85%

SOBI/Biogen ‐ Recombinant 0.06% UKHCDO Page |55

Annual

Report

2016

& B leeding

Disorder

Statistics

Pfizer ‐ Recombinant

84.99% for

201 5 Figure 24 This shows the market breakdown of factor IX. /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

2.3 Von Willebrand Disease

Page | 56

Table 13 Patients with von Willebrand Disease registered and treated April 2015 - March 2016

<18 years ≥18 years von Willebrand (VWD Activity iu/dl) (VWD Activity iu/dl) Total Treated disease Sub Sub <10 10 ‐ 29 ≥30 N/K <10 10 ‐ 29 ≥30 N/K Total Total Males Type 1 26 155 285 15 481 81 344 641 105 1,171 1,652 76 Type 2A 33348176 90 70 38 3 201 277 65 Type 2B 6103019 12 30 15 2 59 78 17 Type 2M 1955029 26 27 10 3 66 95 12 UKHCDO

Page |57 Type 2N 0020 2 3222633 35 1 Type 2 Unspecified 4 8 6 0 18 11 12 8 1 32 50 5

Type 3 3232 54 54 86 61 Annual Type Unreported 53 114 244 10 421 158 335 611 58 1,162 1,583 96

Report Sub Total Males 3,856 333

Females 2016

Type 1 25 105 238 6 374 126 532 1,737 215 2,610 2,984 101 & B

Type 2A 2922100 61 11199667283 344 68 leeding Type 2B 3 5 10 0 18 14 43 38 1 96 114 22

Type 2M 7208136 48 51 20 7 126 162 28 Disorder Type 2N 0110 2 6748566 68 6

Type 2 Unspecified 4 1 0 0 5 18 21 20 2 61 66 3 Statistics Type 3 1818 50 50 68 42 Type Unreported 50 137 219 10 416 208 583 1,557 172 2,520 2,936 141

for

Sub Total Females 6,742 411 201 5 Grand Total ‐ Males and Females 10,598 744 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 13: This shows a breakdown of von Willebrand disease registrations broken down by age, activity level, subtype and gender. The Annual Report review meeting suggested that, whilst there is no generally agreed severity classification for VWD, we alter the VW activity subdivisions from “<30 and ≥30” to “<10, 10-29 and ≥30” to give some indication of the distribution of severity amongst the UK cohort. The table has been amended to follow this recommendation.

A VW subtype is reported for 57% of patients. We believe most of the remainder are type 1 but cannot be sure. Efforts are ongoing to tidy up this part of the database but problems include changing classification with time; very old data entries; and changing opinion in relation to the diagnosis of mild type 1 VWD, which may have been over-diagnosed in the past. The report form has been redesigned to facilitate this tidy-up. There remains an excess of blood group O patients and females, reflecting referral bias and over-diagnosis of mild type 1 VWD.

Table 14: This shows that 399 new patients with von Willebrand disease were registered in the past year, 229 of whom were registered without indicating a subtype. Whilst this is disappointing, the Von Willebrand Disease Working Party has redesigned and updated the reporting page. This will be rolled out shortly and will hopefully improve reporting in the future. In the meantime, the database continues to chase centres for missing data. As one would expect, the previously reported relative excess of female registrants only becomes apparent after menarche. New registrations of von Willebrand disease are approximately equally distributed between genders in patients under 18 years of age.

Page | 58

Table 14 New Registrations of von Willebrand Disease between April 2015 - March 2016, by age at mid-year, severity, and gender

<18 years ≥18 years von Willebrand (VWD Activity iu/dl) (VWD Activity iu/dl) Total disease Sub Sub <10 10 ‐ 29 ≥30 N/K <10 10 ‐ 29 ≥30 N/K Total Total Males Type 1 3 9 12 0 24 079016 40 Type 2A 1 4 0 0 5 0320 510 Type 2B 0 0 0 0 0 1010 22 Type 2M 1 0 0 0 1 0100 12 UKHCDO Page |59 Page |59 Type 2N 0 0 0 0 0 0021 33 Type 2 Unspecified 0 0 0 0 0 0000 00

Type 3 01011Annual Type Unreported 8 19 30 0 57 3138 3 27 84

Sub Total Males 142 Report

Females 2016

Type 1 1 10 10 0 21 014541 69 90 & B

Type 2A 2 5 0 0 7 2100 310 leeding Type 2B 0 0 0 0 0 0110 22

Type 2M 0 2 1 0 3 2100 36 Disorder Type 2N 0 0 0 0 0 0020 22

Type 2 Unspecified 0 0 0 0 0 0000 00 Statistics Type 3 11112 Type Unreported 5 24 25 1 55 416673 90 145

for

Sub Total Females 257 201

Grand Total ‐ Males and Females 399 5 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 15 Concentrates used to treat von Willebrand Disease (including inhibitors) between April 2015 & March 2016

Manufacturer Product Total Units

Baxalta Advate 14,500

BPL FVIII 8Y 40,000

Haemate P 7,625,150 CSL Behring Voncento 5,353,350

Alphanate 780,000 Grifols Fanhdi 4,000

LFB Biomedicaments Willfact /Wilfactin 555,000

Novo Nordisk NovoSeven (mg) 1,956

Octaplex 500 Octapharma Wilate 5,710,000

Pfizer ReFacto AF 29,000

Investigational rVWF *

*Anonymised for confidentiality purposes Units in IU unless otherwise stated Products containing VWF and FVIII are reported in FVIII units

Table 15: This shows a breakdown of concentrates used to treat von Willebrand disease in the UK ordered by supplier. These are generally listed by and priced by their labelled factor VIII content, with the exception of Willfact VWF concentrate (LFB), which is labelled and priced only by its VWF content.

Potentially anomalous product use in Table 15 is accounted for as follows:  Advate used to treat a patient who is allergic to VWF products  NovoSeven was given to patients with either type 3 von Willebrand disease or an inhibitor.  ReFacto AF: confirmed von Willebrand disease patient. Treated with rFVIII last year too

Page | 60 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

2.4 Inhibitors: Congenital and Acquired Haemophilia A, Haemophilia B and von Willebrand Disease

Page | 61

Table 16 Inhibitors by Disease Severity – Haemophilia A, Haemophilia B & von Willebrand Disease

Inhibitors Severity / Coagulation Defect In Register * Subtype Newly Reported Ongoing Current Historical n (%) n (%) n (%) n (%) < 1 iu/dl 1,845 19 (1.0) 145 (7.9) 164 (8.9) 412 (22.3) 1 ‐ 5 iu/dl 882 4 (0.5) 38 (4.3) 42 (4.8) 96 (10.9) Haemophilia A >5 ‐ <40 iu/dl 3,203 6 (0.2) 18 (0.6) 24 (0.7) 63 (2.0) Total 5,930 29 (0.5) 201 (3.4) 230 (3.9) 571 (9.6) < 1 iu/dl 340 2 (0.6) 10 (2.9) 12 (3.5) 17 (5.0) UKHCDO Page |62 1 ‐ 5 iu/dl 358 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) N.B: Haemophilia B includes patients with FIX Leyden

Haemophilia B >5 ‐ <40 iu/dl 516 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Annual New=new in year Ongoing=inhibitor in year but not newUnknown in year 1 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

Report Current=Sum of New + Ongoing Total 1,215 2 (0.2) 10 (0.8) 12 (1.0) 17 (1.4) Historical=history of inhibitor, but not current

Type 1 4,626 0 (0.0) 0 (0.0) 0 (0.0) 1 (0.0) 2016

Type 3 154 0 (0.0) 6 (3.9) ** 6 (3.9) 6 (3.9) & von Willebrand disease B Others 5,819 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) leeding

Total 10,599 0 (0.0) 6 (0.1) 6 (0.1) 7 (0.1) Disorder ** two of these patients had no t * Including patients not regularly treated

Statistics

reatment in the reporting year

for

201

5 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 16: This table shows the incidence of new inhibitors in the past year, the prevalence of inhibitors ever registered and the prevalence of those still considered active for haemophilia A, B and von Willebrand disease, broken down by disease severity. Those labelled new were reported for the first time in the year 2015/16. Those labelled “ongoing” are those reported in previous years which have not been eradicated and which remain clinically significant. Those labelled Current are all inhibitors that have not been eradicated i.e., new plus ongoing. Those reported as historical are previously eradicated inhibitors. This shows that inhibitor history is about twice as common in severe than moderate haemophilia A and ten times commoner than in mild haemophilia A. The proportion of patients with non-severe haemophilia A, thought to have eliminated their inhibitor cannot be known with certainty since some may have an undetectable inhibitor which may reappear as soon as they have factor VIII replacement. Similarly, many “ex inhibitor” patients with severe haemophilia probably continue to have some low-level inhibitor activity, below the level of detection of the Bethesda assay. Inhibitors in haemophilia B are fortunately far less common, with a prevalence of 1% of patients registered with haemophilia B. These arise early in the patient’s treatment history and only in severe haemophilia B. The type 3 von Willebrand Disease patient with a historical, but not current inhibitor, remitted in 2010.

Page | 63

Table 17 Annual concentrate usage by patients with congenital bleeding disorders who were inhibitor positive at any time within 2015/16

von Willebrand Combined Manufacturer Product Haemophilia A Haemophilia B F.VII deficiency F.XI deficiency Disease Diagnoses Advate 17,572,750 ‐ ‐ ‐ ‐ ‐ Baxalta FEIBA 36,174,573 2,204,000 ‐ ‐ ‐ 932,500

Bayer Kogenate 5,596,000 ‐ ‐ ‐ ‐ ‐

FVIII 8Y 256,620 ‐ ‐ ‐ ‐ ‐ BPL FXI ‐ ‐ ‐ ‐ 2,785 ‐

Optivate 3,934,460 ‐ ‐ ‐ ‐ ‐ UKHCDO Page |64 Page |64 Haemate P 201,000 ‐ 197,000 ‐ ‐ ‐

CSL Behring Helixate Nexgen 1,940,250 ‐ ‐ ‐ ‐ ‐

Voncento ‐ ‐ 34,500 ‐ ‐ ‐ Annual

Grifols Fanhdi 12,885,600 ‐ ‐ ‐ ‐ ‐ Report Novo Nordisk NovoSeven (mg) 23,020 8,295 1,481 573 8 892

Nuwiq 121,250 ‐ ‐ ‐ ‐ ‐ 2016 Octapharma

Octanate 2,361,000 ‐ ‐ ‐ ‐ ‐ & B leeding Benefix ‐ 2,000 ‐ ‐ ‐ ‐ Pfizer

ReFacto AF 12,014,500 ‐ 10,000 ‐ ‐ ‐ Disorder Various Investigational Factor 143,681 ‐ ‐ Manufacturers VIII

Statistics Units in IU unless otherwise stated

Table 17: Shows reported product use for UK patients with a current inhibitor during 2015/16, broken down by diagnosis and supplier. All for

product usage for these patients in that year is shown. 201 5 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 18 Concentrates used to treat Acquired Inhibitors

Acquired Acquired Acquired Acquired Manufacturer Product Haemophilia A von Willebrands F.VII Deficiency F.XIII Deficiency

Baxalta FEIBA 5,263,050 ‐ 18,000 ‐ Bayer Optivate 32,000 ‐ ‐ ‐

Fibrogammin P ‐ ‐ ‐ 9,000 CSL Behring Haemate P ‐ 263,500 ‐ ‐ Voncento ‐ 108,300 ‐ ‐ Grifols Fanhdi 55,000 ‐ ‐ ‐ IDEC Pharmaceuticals Rituximab 9,315 ‐ ‐ ‐ Novo Nordisk NovoSeven (mg) 2,246 ‐ ‐ ‐ Octapharma Wilate ‐ 548,000 ‐ ‐

Pfizer ReFacto AF 48,000 ‐ ‐ ‐ Units in IU unless otherwise stated

Table 18: This shows reported product use for UK patients with an acquired inhibitor reported or ongoing during 2015/16, broken down by diagnosis and supplier.

Page | 65 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 19 FEIBA® usage: breakdown by diagnosis

Number of Total Coagulation Defect Patients (u) Haemophilia A 98 36,176,573 Haemophilia B 6 2,204,000 Acquired Haemophilia A 88 5,263,050 F.XI Deficiency 1 2,000 Acquired Deficiency (other) 2 18,000 Combined Diagnoses 2 932,500 197 44,596,123

Table 20 NovoSeven® usage: breakdown by diagnosis

Number of Total Coagulation Defect Patients (mg) Haemophilia A 77 23,124 Haemophilia B 10 8,295 von Willebrand disease 3 1,956 Acquired Haemophilia A 29 2,246 F.V deficiency 2 10 F.VII deficiency 52 2,174 F.XI Deficiency 2 16 Combined Diagnoses 3 894 Bernard Soulier 8 378 Glanzmann's Thrombasthenia 48 1,404 Platelet defects 3 37 Unclassified 2 30 239 40,565

Table 19 & 20: These show in greater detail how much FEIBA® and NovoSeven® were used for each diagnoses. Patients with any hereditary or acquired bleeding disorder, either with or without inhibitors, are included. There is no estimate given for off-label usage or usage for reversal of over-anticoagulation, for which we do not have data.

Page | 66 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

2.5 Rarer Bleeding Disorders

Table 21 Patients with rarer types of bleeding disorders registered and treated

April 2015 & March 2016

Number of Patients in Register % Coagulation Defect Treated Total Males Females Treated Probable von Willebrand disease 185 48 137 11 5.95% Platelet‐type Pseudo von Willebrand Disease 19 9 10 2 10.53% F.V deficiency 200 79 121 12 6.00% F.VII deficiency 1,148 558 590 54 4.70% F.X deficiency 241 100 141 35 14.52% F.XI Deficiency 2,853 1,202 1,651 85 2.98% F.XIII Deficiency 66 37 29 53 80.30% Combined II+VII+IX+X Deficiency 4 1 3 0 0.00% Combined V+VIII Deficiency 27 13 14 6 22.22% Other combined diagnoses 321 144 177 39 12.15% Prothrombin Deficiency 14 5 9 3 21.43% Afibrinogenemia 12 8 4 10 83.33% Dysfibrinogenemia 426 166 260 25 5.87% Hypofibrinogenemia 115 47 68 6 5.22% Hypodysfibrinogenemia 1 0 1 1 100.00% Fibrinogen Deficiency 432122920.93% Acquired Haemophilia A 475 236 239 102 21.47% Acquired Haemophilia B 2 2 0 0 0.00% Acquired von Willebrands 117 62 55 36 30.77% Acquired Prothrombin Deficiency 5 3 2 0 0.00% Acquired F.XIII Deficiency 3 2 1 1 33.33% Acquired F.V Deficiency 4 0 4 0 0.00% Acquired Deficiency (other) 6 5 1 2 33.33% Glanzmann's Thrombasthenia 125 53 72 52 41.60% Bernard Soulier 854243910.59% Other platelet defects 2,222 695 1,527 115 5.18% Miscellaneous 248 66 182 11 4.44% Unclassified bleeding disorder 359 56 303 14 3.90% Haemophilia A with Liver Transplant 10 10 0 1 10.00% Haemophilia B with Liver Transplant 3 3 0 0 0.00% von Willebrand with Liver Transplant 2 2 0 0 0.00% Total 9,341 3,675 5,666 694 7.43%

Page | 67 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 21 This shows patients registered with rarer disorders and the proportion treated during the year. We suspect that liver transplantation is under-reported. We have only registered unclassified bleeding disorders for the past four years and suspect that the number registered will continue to increase.

Table 22 Patients with selected rarer bleeding disorders registered and

treated April 2015 - March 2016, by disease severity

Number of Patients (factor level iu/dl) Coagulation Defect <5 ≥5 N/K Total In Reg Treated In Reg Treated In Reg Treated In Reg Treated F.V deficiency 46 8 154 4 0 0 200 12 F.VII deficiency 123 23 1025 31 0 0 1148 54 F.X deficiency 37 25 204 10 0 0 241 35 F.XI Deficiency 225 24 2629 61 0 0 2854 85

Total 431 80 4,012 106 ‐ ‐ 4,443 186

<2 ≥2 N/K Total Coagulation Defect In Reg Treated In Reg Treated In Reg Treated In Reg Treated

F.XIII Deficiency 36 33 30 20 0 0 66 53

Total 36 33 30 20 ‐ ‐ 66 53

Table 22: It is acknowledged that these rarer disorders have no recognised classification of disease severity. However, the table above gives an idea of the range of registered levels. In the case of factor XIII 62% of those treated are registered with severe deficiency (<2%). As prophylaxis is established very, very early in these patient’s lives, the baseline level may be difficult to find in case records. We suspect that all patients on regular prophylaxis are severely affected, but some may have been registered with a post-infusion trough level. New registrations should be checked by a nurse specialist or member of medical staff to ensure that the level reported to the database is, in fact, the patient’s baseline level and not a level taken to monitor replacement therapy. Where a plasma level cannot be found severity may be inferred from genotypic data.

Page | 68 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 23 New registrations of rarer bleeding disorders between April 2015 & March 2016 showing their coagulation defect and gender

Coagulation Defect Male Female Total

Haemophilia A with Liver Transplant 3 0 3 Haemophilia B with Liver Transplant 1 0 1 Platelet‐type Pseudo von Willebrand Disease 3 4 7 Probable von Willebrand disease 7 20 27 F.V deficiency 1 7 8 F.VII deficiency 61 73 134 F.X deficiency 4 10 14 F.XI Deficiency 102 134 236 F.XIII Deficiency 0 1 1 Afibrinogenemia 2 2 4 Dysfibrinogenemia 28 59 87 Hypofibrinogenemia 26 33 59 Fibrinogen Deficiency 0 1 1 Prothrombin Deficiency 0 2 2 Acquired Haemophilia A 63 43 106 Acquired F.V deficiency 0 1 1 Acquired F.XIII Deficiency 1 0 1 Acquired Prothrombin Deficiency 1 1 2 Acquired von Willebrands 15 9 24 Glanzmann's Thrombasthenia 3 4 7 Bernard Soulier 4 3 7 Other platelet defects 85 199 284 Other combined diagnoses 17 19 36 Miscellaneous 6 31 37 Unclassified bleeding disorder 16 76 92 Total 449 732 1,181

Table 23: This table shows new registrations during the year. As usual, this continues to show a consistent excess of female registrations for all autosomal disorders, presumably reflecting referral and diagnostic bias of women with menorrhagia.

Page | 69

Table 24 Concentrates used to treat Rarer Bleeding Disorders between April 2015 & March 2016

F.V deficiency F.VII deficiency F.IX Leyden F.IX Leyden Carrier F.X deficiency F.XI Deficiency F.XIII Deficiency Manufacturer Product Pts Pts Pts Pts Pts Pts Pts Units Units Units Units Units Units Units treated treated treated treated treated treated treated FEIBA ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 1 2,000 ‐ ‐ Baxalta FVII ‐ ‐ 2 105,600 ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ FX ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 15 820,615 ‐ ‐ ‐ ‐ BPL FXI ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 62 160,700 ‐ ‐ Beriplex ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 15 692,000 ‐ ‐ ‐ ‐ Page |70

Fibrogammin P ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 52 780,914 UKHCDO CSL Behring FXIII ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 1 1,250

Riastap (mg) ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 1 2 ‐ ‐ Annual LFB Biomedicaments Hemoleven ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 4 8,000 ‐ ‐

NovoSeven (mg) 2 10 53 2,174 ‐ ‐ ‐ ‐ ‐ ‐ 2 16 ‐ ‐ Report Novo Nordisk NovoThirteen ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 1 30,000

2016 Octaplas (units) 9 451 ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 16 1,908 ‐ ‐

Octapharma &

Octaplex ‐ ‐ ‐ ‐ ‐ ‐ ‐ ‐ 12 486,000 ‐ ‐ ‐ ‐ B leeding Pfizer BeneFIX ‐ ‐ ‐ ‐ 7 213,500 1 17,500 ‐ ‐ ‐ ‐ ‐ ‐

Units in IU unless otherwise stated Disorder

Statistics Table 24: This gives a breakdown of product use during 2015/16 for UK patients with rarer bleeding disorders, broken down by diagnosis and supplier.

for

201 5 /201 6

UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

2.6 Adverse Events

Table 25 Adverse Events reported between April 2015 & March 2016

Number of Number of Adverse Event Patients Events

Allergy Event 5 5

Infection Event 0 0

Inhibitor Event 22 22

Intracranial Haemorrhage 5 5

Malignancy Event 13 13

Other Event 0 0

Poor Efficacy Event 1 1

Thrombotic Event 2 2

Total 48 48

See table 16 for breakdown of inhibitors by disease severity in Haemophilia A, B and von Willebrand disease

Allergy Events:

Haemate P: Anaphylaxis, Shortness of breath, facial flushing 20 minutes after dose. Outcome: Resolved. Centre considers the relationship to concentrate to be Definite Optivate: Rash 20 minutes after dose. Outcome: Resolved. Centre considers the relationship to concentrate to be Possible Voncento: Rash 15 minutes after dose. Outcome: Resolved. Centre considers the relationship to concentrate to be Unlikely Octaplas: Rash 41 days after dose. Outcome: Resolved. Centre considers the relationship to concentrate to be Probable FXI (BPL): within few minutes of infusion patient was feeling unwell 10 minutes after dose. Outcome: Resolved. Centre considers the relationship to concentrate to be Possible

Page | 71 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Malignancy Events

Uterine/ovarian cancer Liver cancer Renal cancer Metastatic liver cancer following Ca bowel 2013 Diffuse large B cell non-Hodgkin’s lymphoma Adeno carcinoma of lung with bone metastasis Stage IVb diffuse large b cell Lymphoma Acute myeloid leukaemia Cancer of unknown primary Malignant Melanoma Pancreatic cancer Large B cell lymphoma stage 2AE Oesophageal adenocarcinoma, T3, N1

Poor Efficacy:

One-year old child being treated for ICH. Initially maintaining satisfactory levels on 75iu/kg TDS but subsequently developed increasing factor requirements. Eventually on 200iu/kg 6 hourly with a 6-hour trough of 17iu/dl. Suspected inhibitor but not detectable on testing. Has continued to have high factor requirement but inhibitor assays remain negative. Presumed inhibitor despite negative Bethesda assay.

Thrombotic Event:

Thrombotic Stroke x2

Page | 72 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 26 Summary of patients ‘at risk’ of vCJD for public health purposes who received UK sourced plasma products as reported by Centres

Summary table of ‘at risk’ bleeding disorder patients who received UK sourced plasma products Implicated Non‐implicated Combined batches batches Alive 691 2593 3284 Current status of ‘at risk’ Dead 118 623 741 patients Total 809 3216 4025 MM ‐ ‐ 5 MV ‐ ‐ 4 Genotype VV ‐ ‐ 1 Not known 809 3216 M 769 2639 3408 Sex F 40 577 617 0‐19 0 28 28 20‐39 326 825 1151 Current age band of living 40‐59 267 1058 1325 ‘at risk’ patients 60‐79 90 570 660 80+ 8 110 118 Not known 0 2 2 These data were last updated on 30/06/2016.

Page | 73 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

2.7 Morbidity and Mortality

Table 27 Causes of death in patients with Haemophilia A, Haemophilia B and

all Carriers of Haemophilia A & B between April 2015 & March 2016

Severity (factor level iu/dl) Cause of Death Total

< 1 1 ‐ 5 >5 & <40 ≥ 40 Unknown Amyloidosis 0 0 1 0 0 1 ARDS 100001 Carcinoma 014016 Cerebral haemorrhage 0 0 1 0 0 1 Haemorrhage (Misc)301004 Hepatocellular Carcinoma 0 0 1 0 0 1 Infection (Bacterial) 0 0 3 1 0 4 Ischaemic Heart Disease 1 1 2 0 0 4 Leukaemia 001001 Liver Failure 510006 Parkinson's Disease 0 0 2 0 0 2 Post‐operative complications 0 1 0 0 0 1 Stroke (Unknown) 0 0 1 0 0 1 Unknown 2 5 20 4 0 31 Total 12 9 37 5 1 64

N.B: Includes FIX Leyden and FIX Leyden carriers

Table 27 and 28: These show the causes of death amongst patients with Haemophilia A and B and carriers of Haemophilia A and B, broken down by severity (Table 27) and for other bleeding disorders (Table 28) during 2015/16.

Page | 74 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 28 Causes of death in other coagulation defects

Coagulation Defect Cause of Death Total

Haemorrhage (Misc) 1 Haemophilia A with Liver Transplant Unknown 1 ARDS 1 F.V deficiency Unknown 1 Carcinoma 2 Ischaemic Heart Disease 1 F.VII deficiency Liver Failure 1 Lymphoproliferative Malignancy 1 Unknown 5 Motor Neurone Disease 1 F.X deficiency Unknown 1 Carcinoma 4 COAD 1 F.XI Deficiency Infection (Bacterial) 3 Ischaemic Heart Disease 1 Unknown 16 Ischaemic Heart Disease 1 Combined diagnoses Unknown 1 Combined V+VIII Deficiency Renal Failure 1 AIDS 1 ARDS 1 Carcinoma 4 Cerebral haemorrhage 2 COAD 2 Acquired Haemophilia A Infection (Bacterial) 4 Intestinal Obstruction 1 Ischaemic Heart Disease 3 Liver Failure 1 Senility/Alzheimer's disease 1 Unknown 51 Acquired F.V deficiency Unknown 1 Acquired F.XIII Deficiency Unknown 1 Infection (Bacterial) 1 Acquired von Willebrand Disease Lymphoproliferative Malignancy 1 Unknown 3 Fibrinogen Deficiency Unknown 3 Carcinoma 1 Dysfibrinogenemia Intestinal obstruction 1 Unknown 3 Continued overleaf

Page | 75 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Table 28 Causes of death in other coagulation defects (continued)

Coagulation Defect Cause of Death Total

Hypofibrinogenemia Unknown 2 Carcinoma 3 Ischaemic Heart Disease 1 Platelet defects Liver Failure 1 Stroke (Unknown) 2 Unknown 7 Miscellaneous Unknown 1 Carcinoma 1 Unclassified Cerebral haemorrhage 1 Unknown 1 AIDS 1 ARDS 1 Carcinoma 10 Cerebral haemorrhage 2 von Willebrand disease Dissecting Aortic Aneurysm 1 Haemorrhage (Misc) 1 Infection (Bacterial) 6 Ischaemic Heart Disease 2 Unknown 38 Total 212

Page | 76 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 25 Cumulative incidence chart of deaths from hepatocellular carcinoma or liver failure in UK patients with bleeding disorders 1969 - 2015

300 Hepatocellular Liver Failure Total Carcinoma 250

200

150

100 Cumulative Patient Deaths

50

0

Year of death

Hepatocellular Liver Hepatocellular Liver Year Total Year Total Carcinoma Failure Carcinoma Failure 1969 0 2 2 1995 0 77 1970 0 2 2 1996 0 10 10 1972 0 2 2 1997 0 10 10 1973 0 1 1 1998 0 99 1974 0 1 1 1999 0 4 4 1975 0 1 1 2000 0 15 15 1979 0 2 2 2001 1 6 7 1980 0 1 1 2002 3 9 12 1983 0 2 2 2003 2 2 4 2004 3 4 7 1984 0 3 3 2005 1 2 3 1985 0 4 4 2006 4 59 1986 0 7 7 2007 2 3 5 1987 0 5 5 2008 3 6 9 1988 1 2 3 2009 2 8 10 1989 0 5 5 2010 2 9 11 1990 0 4 4 2011 2 5 7 1991 0 9 9 2012 3 8 11 1992 0 9 9 2013 9 9 18 1993 0 15 15 2014 0 4 4 1994 0 13 13 2015 2 9 11 Total 40 232 272

Page | 77 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 25: This appears to show some levelling off of deaths from hepatocellular carcinoma (HCC) if not from hepatocellular failure. As HCV is eradicated from a higher and higher proportion of patients, one would expect a reduction in the incidence of HCC, which declines dramatically after viral eradication, even in the presence of ongoing cirrhosis. There may be a delay before we see a reduction in deaths from hepatocellular failure, however, since many patients do have advanced cirrhosis and not all are either suitable for transplant or have a donor. However, successful viral eradication will result in recovery for patients with early cirrhosis or less advanced liver disease and they should not go on to develop cirrhosis.

Page | 78 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Figure 26 Total number of patients with Haemophilia A, Haemophilia B or von Willebrand Disease treated by UK Haemophilia Centres

14

12

10

8

6 Number of Centres 4

2

0

Number of treated patients

Figure 27 Total number of patients with severe Haemophilia A and Haemophilia B treated by UK Haemophilia Centres

14

12

10

8

6 Number of Centres 4

2

0

Number of treated patients

Page | 79 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

Appendix 1 Quarterly Returns - Participating Centres

Centre Name Aberdeen Leicester Abergavenny Lewisham Bangor Lincoln Barnstaple Liverpool (R. I.) Belfast ‐ Adult's Liverpool Children's Belfast ‐ Children's Manchester (Adults) Birmingham (Queen Elizabeth) Manchester Children's Birmingham Children's Newcastle upon Tyne Bournemouth / Poole North Hampshire (Basingstoke) Bradford North Staffordshire (Stoke on Trent) Brighton Norwich Bristol (Infirmary & Children's) Nottingham Cambridge Oxford Canterbury Peterborough Cardiff Plymouth Chichester Portsmouth Coventry Royal Free Derby Salisbury Dundee Sheffield (Children's) Edinburgh Sheffield (Royal Hallamshire) Exeter Shrewsbury Glasgow (R.H.S.C.) Southampton Glasgow (R.I.) St George's Hospital, London Great Ormond Street St Thomas' and Guy's Hospital Hammersmith Hospital, London Swansea Inverness Taunton / Yeovil Ipswich The Royal London Hospital Kettering Torquay Kingston upon Hull (Hull) Truro Lancaster Wolverhampton Leeds York

Page | 80 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 3. Data Management Working Party

Membership Representing Dr David Keeling (until 2016 AGM) Dr Ri Liesner

Nancy Brodie UK Haemophilia Data Managers Forum Christina Burgess The Haemophilia Society Liz Carrol CEO, The Haemophilia Society Prof Peter Collins Representing Wales / Chair Therapeutics Task Force Lynne Dewhurst National Haemophilia Database Bartholomew Flynn Patient Representative Claire Foreman NHS England Emma Franklin Haemophilia Nurses Association Prof Charles Hay UKHCDO Ltd & National Haemophilia Database Dr Rob Hollingsworth Medical Data Solutions and Services Ben Palmer Medical Statistician Jane Pearson-Moore NHS England Dr Hua Xiang National Haemophilia Database

UKHCDO Working Party Chairs Dr Elizabeth Chalmers Paediatric Working Party Dr Gerry Dolan Musculoskeletal Working Party Dr Dan Hart Inhibitor Working Party Prof John Pasi Genetics Working Party Prof Mike Laffan Von Willebrand Working Party

Meetings The working party met on 29th January and 1st July 2016.

Activities The UKHCDO Data Management Working Party (DMWP) remains the key group for overseeing all aspects of collecting and analysing data from patients with inherited bleeding disorders in the UK. The DMWP works closely with NHD to ensure that accurate and relevant data are collected from patients and centres. The work of the NHD is regulated by the Data Protection Act and is governed by the data Protection Officer for Central Manchester Foundation Trust. The range and quality of data collected have yielded important information about the patterns and intensity of treatment and have helped the Haemophilia Centres and commissioners understand and manage services. The research potential of data generated by the National Haemophilia Database is clear. This remains an important function of NHD and this aspect of activity is overseen by the DMWP and by UKHCDO. There has been collaboration with the pharmaceutical industry. These projects have been limited to anonymised data mainly to help with regulatory requirements.

Page | 81 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

NHD data-analysis has been pivotal in convincing NHS England to allow introduction of new EHL products. NHD continues to collect genetic mutation results from centres. Adverse Events emails reminders are now going out. Platelet aggregation results and platelet nucleotides can now be recorded on NHD. Registration for VWD has been completely re-organised. For severity classification of haemophilia, it has been agreed to use the ISTH classification. Severe haemophilia < 1 Moderate haemophilia 1 - 5 Mild haemophilia >5 - <40 So patients registered as 1% would be classified as moderately severe

Haemtrack A new CQUIN was negotiated between commissioners and clinicians. Identifying money that haemophilia centres don’t already have: For recruitment up to 50% £12.000/year For compliance >50% <70% - £800/pt/year Compliance >70% - £6000/pt above 70% For those already doing well, the middle payment will not apply. Baseline was taken at Q3 (Sept – Dec 2015). The commissioners for England and the devolved countries of the UK fully support the use of Haemtrack as a means of capturing individual patient events and treatment. The goal is to have all patients on home treatment using this system. NHS England are making Haemtrack use a pre-condition for using EHL products.

IT update HCIS: Version 2.1 of HCIS is currently in development with a number of updates to improve integration with NHD. Also included will be an interface to MyPKFiT (when activated in MyPKFiT). The Joint score form is again being updated in response to feedback Haemtrack Redevelopment: The Haemtrack system now has over 850,000 treatment records on the system and 2751 patients registered. A new responsive website is in development which will enable use on all smartphone platforms, simplifying maintenance and also enabling clinician use on mobile devices. There is also the option of language translation. Haemtrack Video Consultation – Haemtrack now has the ability for clinicians to hold patient video consultations within the Haemtrack system. The system also has the ability to be used as an educational tool with the possibility of recording consultations should this be required. Video consultations will now be trialled in a number of centres.

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UKHCDO Website: A new UKHCDO website has been developed which uses new technologies to allow the NHD to directly maintain the content of the site without IT input. The new website will also display appropriately formatted on mobile devices.

UKHCDO owes gratitude to many individuals involved in the management of data from the UK. We wish to thank Professor Hay for managing the National Haemophilia Database on behalf of the UKHCDO. Thanks also to Rob Hollingsworth and MDSAS for their continued support and maintenance of our national information systems. Lynne Dewhurst, Ben Palmer, Katie Allen, Helen Brown, Rachel Lockwood, Sarah Rooney, Tom Sharpe, Jessica Broughton Smith and Hua Xiang of the National Haemophilia Database have been invaluable in their very high quality work on our behalf. We also wish to acknowledge all the important work done at the Centre level and for the support of all the patients for supporting this important work.

Dr David Keeling Chair UKHCDO Data Management Working Party Prof Charles RM Hay, Director NHD

Page | 83 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 4. Haemtrack Group

Membership Dr Gerry Dolan Mrs Nancy Brodie Dr Elizabeth Chalmers Dr Pratima Chowdary Lynne Dewhurst Prof Charles Hay Dr Rob Hollingsworth Dr Lishel Horn Dr Ri Liesner Mr Enis Muminovic Mr Ben Palmer Prof John Pasi Mr Antony Woolcomb Dr Hua Xiang Dr Dan Hart The Group met twice, in February and June 2016.

High level data from the Haemtrack Database: Number of treatment entries: 912,000 (Prophylaxis: 752,253, Bleed treatments: 104,000) Number of users: 2800+ Number of sites: 51

Activities The main activities of the group during the year were to carry out a survey of patients, data managers and clinicians; oversee and guide Haemtrack system development; Participate in the formation of a new Haemtrack CQUIN. Results of the Haemtrack Surveys: There were 419 responses from patients/carers, 45 responses from Data Managers or Lead Nurses and 40 responses from clinicians. The results of the survey provided extremely valuable insight into the use of Haemtrack and also provided guidance towards future development work for Haemtrack. Haemtrack CQUIN: The group was involved in the development of the Haemtrack CQUIN. Some centres have taken this up and others, including centres that were keen to participate have not, usually because their commissioners did not choose this CQUIN. In many cases they did not consider this financially worthwhile. Smaller centres were reluctant to pay the operational expenses of £1000 to NHD or felt that it was not worth their while because of the small numbers of patients under their care. NHD have calculated the baseline Denominator for each centre, having cross-checked with participating centres, and requested from centres what their target recruitment and compliance was.

Page | 84 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

The NHD is now calculating the ongoing compliance of patients. The number of infusions per week was looked at as a measure of compliance. This is proving difficult due to the prescribing practice of centres. E.g. The NHD collects information on what the patient is issued. If the patient is issued 4 months of treatment then this is incomparable to quarterly Haemtrack (HT) usage data. It was decided to look at comparing the 6 months data up to the end of December 2015 initially. NHSE need to know how many patients per centre are using / compliant with HT and how many new patients sign up and use HT compliantly.

Other areas of work carried out by the group during the year included:

Encouraging clinical use of Haemtrack: Supplying all clinicians / Nurses / Data Managers with a test Haemtrack Patient account enabling Clinicians/Nurses to encourage patients to use the system, showing the patient how important the data is. Use for research or as a research platform: Modifications to Haemtrack now enable it to be used as a study diary, thus avoiding duplication of effort for patients participating in such studies. The system would export the relevant data for the specific studies. If required, the Haemtrack dataset can also be extended according to required study data collection fields. It is being used for the ECHO study and may be used for other studies. The US ECHO group plan to pilot the new version of Haemtrack. Validation: There is now an option to block validate prophylaxis and looking closer at bleed treatments. Recent Updates to Haemtrack:  Information about how often an incorrect password can be entered and what to do if you cannot remember the password.  Allowing centres to unlock patient user accounts.  Video consultations are currently being piloted.  Barcode scanning. Baxalta and Pfizer products are included. Other companies are being approached  The app has been updated to show the number of treatments awaiting sync  Enable the management of more than one account through the app (where parents/carers are managing accounts for more than one child). Future developments: MDSAS is developing a new version of Haemtrack. The first version was developed in 2008 but has been modified since. The new version will use the latest browser technology and mobile devices technology. Combined with video consultation, this means that whole clinics could be managed by mobile phone or computer if required. The US will pilot this. A video consultation module will be developed as a separate application for use outside of Haemtrack for telephone clinics for mild bleeders who would not otherwise use Haemtrack. Dr Rob Hollingsworth & Lynne Dewhurst December 2016

Page | 85 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 5. Genetics Working Party

Membership John Pasi Chair Keith Gomez Mike Laffan Nicola Curry Steve Keaney Gerry Dolan

Remit 1. Continue role as oversight committee for issues related to genetics in haemophilia 2. Annual guideline review 3. Support thrombogenomics programme and roll out through bioresource programme 4. Achieving full genetic analysis of all patients on NHD 5. Gene therapy – trials and consent issues

Meetings and work streams

The group meet to discuss the remit and review the state of current issues within the field of genetics related to haemophilia. The thrombogenomics programme and support for it was seen to be the primary role of the group, and will be discussed at the AGM. A proposal to draw up a ‘best practice’ guideline for consent issues related to gene therapy trials has been discussed at the Advisory Group subsequently and considered a useful way forward.

Professor John Pasi Chairman, Genetics Working Party September 2016

Page | 86 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 6. Genetic Laboratory Network (UKHCDO-GLN)

Background The UKHCDO GLN was formed in 2002, arising out of the UKHCDO Genetic Working Party, with the aim of improving collaboration between laboratories and of ensuring quality and equity of service across the U.K. The network currently comprises 13 laboratories, 12 across the UK plus Dublin, involved in the molecular genetic analysis of haemophilia and related inherited bleeding disorders (many of the laboratories are also involved in other areas as well). Representatives of the Network attend meetings of the UK Genetic Testing Network (UKGTN) and the UKHCDO GWP.

Meetings The UKHCDO GLN holds bi-annual meetings and met on 23 November 2015 in Cambridge and 17 May 2016 in Oxford. The next meeting is scheduled for 22 November in Birmingham.

Chair & Secretary Steve Keeney continued as Chair. Vince Jenkins stepped down from his Secretary role and Catriona Keenan took over this function.

Current activities 1. UK Genetic Testing Network (UKGTN) revised remit – UKHCDO-GLN registration Individual UKHCDO GLN labs that are not registered with the UKGTN had previously been advised that they may wish to consider applying for membership if they perceive it is in their interest. The UKGTN has since run a “grandfathering” exercise to allow laboratories to submit pared back additional provider forms for inclusion on the UKGTN providers list. Several eligible laboratories (already UKGTN registered) went through this process. Note that the NHS England genetic laboratory re-designation exercise is still ongoing. 2. Laboratory Audit – ISO 15189 Clinical Pathology Accreditation (CPA) have implemented the ISO 15189 quality standard applicable to laboratories. The GLN continues to share practical advice and knowledge as the revised inspection process is applied to member laboratories, sharing examples of good practice and implementing a sample exchange scheme for disorders not covered by external quality assessment. 3. National Haemophilia Database Genetics Portal The inclusion of a portal to the National Haemophilia Database for the upload of genetic mutation data is in use across the GLN. Problems had been encountered in terms of matching input data with that on the NHD, leading to data entry failure in a significant number of cases. Consultation between the GLN and NHD has led to modification of data entry criteria and these problems have largely been eliminated.

Page | 87 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

4. Bleeding Disorder Genetic Analysis Best Practice Guidelines The BPGs for Haemophilia A and Haemophilia B are still considered current, although nearing a review. The VWD genetic analysis guideline update is ongoing. 5. Haemophilia Genetics NEQAS scheme The Haemophilia Genetics EQA scheme, run by UK NEQAS in Sheffield, continues with bi- annual distributions. The results for each round of the scheme are reviewed and discussed at the following network meeting and any relevant comments fed back to the steering group. The scheme currently includes F8, F9 and VWF gene analysis. 6. Participation in other groups A representative from the network attends the:  Clinical and Scientific Advisory Group UK Genetics Testing Network (see item 1 above)  Representatives of the Network input to the UKHCDO GWP.

Steve Keeney Chairman, UKHCDO Genetic Laboratory Network September 2016

Page | 88 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 7. Inhibitor Working Party

Membership Dan Hart Chairman Kate Talks Secretary Trevor Baglin Liz Chalmers Peter Collins Charles Hay Ri Liesner Mike Makris Ben Palmer Savita Rangarajan Anne Riddel Mike Williams Olly Tunstall stepped down owing to conflicting commitments

Meetings The group has met 3 times since the last AGM.

Activities UKHCDO response to SIPPET study (Survey of Inhibitors in Plasma-Products Exposed Toddlers) We have authored and disseminated our consensus position statement on the SIPPET study. A copy of our statement is available via the UKHCDO website. Revised ITI recommendations – UKHCDO website and NHS England (NHSE) policy. Our revised consensus guidance for inhibitor screening in PUPs and initiating ITI are also available on the UKHCDO website and have been adopted formally by NHSE. There are two fundamental changes of note: To start ITI as soon as practicable after a reproducible inhibitor titre has been detected, i.e. to no longer wait for a reduction to below 10BU prior to commencing ITI. A commissioning expectation of reporting prospective data to the NHD We have commenced the prospective collection of data, which will be key to underpin our continued advocacy for adequate funding for ITI. Since November 2015, 14 PUP/MTP patients from 10 centres have been reported to have an inhibitor and on the ITI pathway. The ITI protocol document, available on the UKHCDO website, is explicit about both ITI dosing initiation, monitoring frequency and response interpretation, concluding with clear advice about de-escalation of dosing or necessity for second line/cessation considerations. Acquired Haemophilia A prospective outcome data reporting In parallel to the above ITI data collection, a similar rationale underpins the implementation of prospective data reporting of Acquired Haemophilia A outcomes. Since implementation in March 2016, 66 patients have been reported from 27 centres and now on the prospective data collection track. As another high cost area of haemostasis care, we recognized the need to

Page | 89 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 report outcomes at a national level to continue to advocate for our patient group. This is timely both for the existing bypassing agent availability as well as understanding how recombinant porcine FVIII might fit into a future treatment algorithm. On behalf of the UKHCDO and CRG, I will input the clinical contribution to the NHSE evaluation of Obizur, which is just commencing. Laboratory contact As our Biomedical scientist representative on the group, Anne Riddel has been liaising with NEQAS colleagues to coordinate both a national written survey of laboratory practice for inhibitor surveillance as well as a NEQAS exercise for detection of anti-porcine-FVIII antibodies. Both these exercises should now be taking place together in Oct/Nov 2016. Please highlight these to your laboratory Chief Biomedical Scientist/team. Anne is also procuring a laboratory contact cascade for comprehensive care centres’ laboratories to enable a closer relationship between UKHCDO working parties, particularly the inhibitor and paeds groups, and laboratory colleagues. This will facilitate communication to clarify existing assay practice and offer support/guidance about the laboratory implications of new products. NHD Inhibitor reporting portal revision Discussions have taken place with MDSAS to explore revising the NHD Inhibitor reporting portal. Although not quite ready to launch, these revisions aim to align the required data to the clinical background of severe haemophilia A, severe haemophilia B or non-severe haemophilia A. THUNDER project (Treatment of Haemophilia, Unmet Need, and Disease Epidemiology in the Real world) This is a recently initiated collaboration between the working party, NHD and Roche aiming to describe the prevalence of inhibitors in patients with haemophilia A of all severities and consequent national burden of care for inhibitor occurrences at all stages of life. The project aims to report in early 2017. European Medicines Agency meta-analysis collaboration We have been collaborating with the independent investigators from the Paul-Ehrlich Institute, Germany, led by Dr Brigitte Keller-Stanislawski. Ben Palmer and the NHD team worked hard to share our agreed data sets to enable the UKHCDO, FranceCoag and PedNet data to be analysed together. Dr Keller-Stanislawski presented her preliminary analysis at the World Federation of Hemophilia congress in July 2016 and publication of a peer-reviewed manuscript is imminent.

Dr Dan Hart, Chairman, Inhibitor Working Party October 2016

Page | 90 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 8. Musculoskeletal Working Party

Membership Dr Gerry Dolan Chairman Dr Pratima Chowdary Mr Peter Briggs Mr Stephen Classey Dr Desmond Creagh Prof Simon Frostick Mr Nicholas Goddard Dr John Hanley Dr Angela McKernan Mr Paul McLaughlin Mrs Angela Westoby Mr Mark Wood

The Musculoskeletal (MSK) Working Party met once this year.

There was a detailed review of the work of the previous group and from this, the work of the reformed working party was planned.

Activities/Plans

The work of the previous working party was reviewed and the guidelines were completed and have been submitted to Haemophilia. The working party plan to work with NHS England (NHSE) in producing guidelines for radioactive synovectomy in the UK, to agree a list of centres to administer this treatment to PWH and to facilitate a clear commissioning pathway. The Working Party will agree a method with NHD for prospective audit of these procedures – to assess efficacy and cost effectiveness. We plan to compile a list of reference centres for arthroplasty – particularly for elbow and knee replacements for PWH. A pathway for commissioning this work with also be agreed with NHSE. With UKHCDO, we plan to produce information on joint arthroplasty and synovectomy for patients and to hold joint educational events on orthopaedic surgery for haemophilic arthropathy. Dr Gerry Dolan Chairman, Musculoskeletal Working Party October 2016

Page | 91 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 9. Paediatric Working Party

Membership Elizabeth Chalmers Chair Glasgow Jeanette Payne Secretary Sheffield Mike Williams Birmingham Mary Mathias GOSH, London Mike Richards Leeds Peter Collins Cardiff Jayanthi Alamelu Evelina, London Oliver Tunstall Bristol

Working Party timeline: due to complete current term October 2016.

Meetings Two per annum with additional telecoms as required. Summary of current activities 1. Follow up of Immune tolerance therapy in the UK Retrospective outcome data on the results of immune tolerance therapy in the UK (2003- 2015 inclusive) has been collected from 8 UK CCCs treating children with inhibitors. Initial results were presented at the ISTH meeting in 2015. This has now been updated to include data up to the end of 2015. Results of this analysis will presented at the AGM meeting & a manuscript is being prepared for publication. The results highlight variation in outcomes in different ethnic groups and the results of second & third line ITI. 2. Management & outcome of Immune tolerance using a standardised regimen - ongoing data collection in collaboration with the Inhibitor Working Party A standard ITI protocol has been agreed based on the published UKHCDO Guideline on management of inhibitors. New inhibitors are reported to the NHD and prospective data collection on ITI outcomes is now being collected. 3. Intracranial haemorrhage in inherited bleeding disorders Retrospective data collection (2003-2015) on cases of ICH occurring in children <16yrs of age in the UK has been completed. Initial data was presented at the ISTH meeting in 2015. This has now been updated and the results will be presented at the AGM meeting. The data highlight the continuing risk of this complication in very young children with severe bleeding disorders. Prospectively data collection on ICH in both children and adults has been added to the NHD adverse events reporting scheme. 4. Audit of prophylaxis in haemophilia against current BCSH/UKHCDO Guideline Data collection is complete. Baseline data has been collected from all centres relating to the use of prophylaxis in children. More detailed information on the use of prophylaxis has been collected from CCCs represented on the WP. The results were presented at the ISTH previously and the intention is to submit a short manuscript on the findings.

Page | 92 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016

5. Use of subcutaneous DDAVP in children with haemophilia and vWD Results are currently being collated.

Guidelines This working party is responsible for two current BCSH/UKHCDO guidelines: 1. Prophylaxis in children with haemophilia A. Published 2010 This guideline is now > 5yrs old and is due for review. 2. Management of haemophilia in the fetus and newborn. Published 2011 It is envisaged that much of the content of this guideline will be incorporated into the RCOG/UKHCDO guideline on the management of pregnancy in women with inherited bleeding disorders which is currently in preparation. The current guideline will be reviewed following completion of the RCOG guideline and a decision will then be made on the need for a separate guideline covering neonatal issues.

The Working Party also regularly reviews new guidelines in order to discuss their impact on paediatric practice.

Presentations/publications PROPHYLAXIS IN CHILDREN WITH SEVERE AND MODERATE HAEMOPHILIA: A SURVEY OF UK PRACTICE. Ryan Rodgers* 1, Jay Alamelu2, Peter Collins3, Mary Mathias4, Jeanette Payne5, Mike Richards6, Oliver Tunstall7, Mike Williams8, David Young9, Tina Biss10, Angela Thomas11, Elizabeth Chalmers1 on behalf of On behalf of the Paediatric Working Party of UKHCDO. Journal of Thromb Haemostas 2015; Vol 13 S2: OR10 ITI FOR INHIBITORY ANTIBODIES IN BOYS WITH SEVERE HAEMOPHILIA A AT EIGHT UK CHILDREN’S CENTRES 2003-2013 Mary Mathias* 1, Jayanthi Alamelu2, Peter Collins3, Jeanette Payne4, Mike Richards5, Oliver Tunstall6, Mike Williams7, Tina Biss8, Elizabeth Chlamers9. Journal of Thromb Haemostas 2015; Vol 13 S2: OR145 INTRACRANIAL HAEMORRHAGE IN CHILDREN WITH INHERITED BLEEDING DISORDERS IN THE UK 2003-2013. Elizabeth Chalmers* 1, Jayanthi Alamelu2, Peter Collins3, Mary Mathias4, Jeanette Payne5, Mike Richards6, Oliver Tunstall7, Mike Williams8, Ben Palmer9, Andrew Mumford10 on behalf of On behalf of the Paediatric and Rare Disorders Working Parties of UKHCDO. Journal of Thromb Haemostas 2015; Vol 13 S2: OR386

Dr Elizabeth Chalmers Chairman, Paediatric Working Party October 2016

Page | 93 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 10. von Willebrand Disease Working Party

The VWD working party has met twice formally since last year’s report including the meeting at the AGM in Manchester. Additional work has been carried out in two teleconferences and the chair attended the NHD on one occasion for review of the database amendments. Membership and Attendance Prof M Laffan (Chairman) 2/2 Dr C Millar 1/2 Prof A Goodeve 2/2 Dr J O’Donnell 0/2 Dr D Keeling 2/2 Prof RC Tait 2/2 Dr W Lester 1/2 Dr A Will 2/2

Activities

Database and VWD registration Following discussion at the AGM last year the WP met to further develop the new registration process and complete the planning of the new pages. These were then reviewed with the NHD and MDSAS to prepare for implementation. The agreed pages are now with NHD/MDSAS awaiting implementation. As previously discussed, the implementation will be accompanied by a review of registrations and a planned migration to archive and to the new category of low VWF. Where the registered diagnosis and the submitted data are not compatible, the centres will be invited to resubmit.

Data correlation and the NHS workload This proposal was submitted to the DMWP and approved in principal. However, it has not progressed because it remains unclear whether data linking permission or requirement of article 251 permission to do this is needed. It may be possible to pursue this via the DMWP.

Future work The WP is now reaching the end of its term and will be disbanded pending any further projects.

Professor Mike Laffan Chairman, von Willebrand Disease Working Party September 2016

Page | 94 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 11. Obstetric Task Force

Membership (multidisciplinary) Dr Sue Pavord Chair Dr Rachel Rayment Dr Bella Madan Dr Tony Cumming Dr Liz Chalmers Dr Will Lester Dr Bethan Myers Dr Helena Maybury (Obstetrician) Dr Claire Tower (Obstetrician) Dr Rezan Kadir (Obstetrician)

Advice was also provided by Dr Gabriella Gray (Obstetrician), Dr Nuala Lucas (anaesthetist), Juliette Webster (specialist midwife)

Remit and Activities

The task force was initially established by Charlie Hay, to revise and update the 2006 UKHCDO guidelines on the management of pregnancy in women with congenital bleeding disorders, or carriers thereof. Chairmanship was handed over to Sue Pavord in 2015. The guidelines have been developed in conjunction with the Royal College of Obstetricians and Gynaecologists and the scoping and literature search has been conducted in accordance with their usual procedures. The completed guideline has been reviewed by the RCOG and UKHCDO advisory committees and is currently on the RCOG website for wider consultation. This closes on Sunday 25 September and the comments will be collated and returned to the developers to address. The RCOG plan to publish this green topped guideline in March 2017. It is targeted at haematologists, obstetricians, neonatologists and anaesthetists. Peer review from the UKHCDO and BSH obstetric Haematology Group will be requested in parallel with the RCOG, in early 2016

Dr Sue Pavord Chairman, Obstetric Task Force September 2016

Page | 95 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 12. Therapeutic task force on enhanced half-life products

Membership Peter Collins Chairman Elizabeth Chalmers Pratima Chowdary David Keeling Mary Mathias James O’Donnell John Pasi Savita Rangarajan Angela Thomas Meetings A document was developed by email and teleconference

Aims 1. To write pragmatic advice on the use of enhanced half-life products in haemophilia A and B in UK. 2. To discuss tendering options to put forward to UKHCDO for consideration It is recognised that published evidence is evolving rapidly. Areas to cover in document 1. Background of products and technologies 2. Treatment strategy when switching to enhanced half-life products 3. Management of previously untreated patients and minimally treated patients 4. Management of bleeds 5. Prophylaxis 6. Surgery 7. Laboratory monitoring 8. Advice to UKHCDO regarding adverse event reporting through NHD Each area will consider issues specific to individual products and the implications of age.

Current position:

Document is completed and has been published, Haemophilia 22:487-98, 2016. The document helped to inform the tendering exercise during 2016. The document underpins the English Clinical Reference Group “Criteria for the Prescribing of Enhanced Half-Life Blood Factors”. The Taskforce has been disbanded. Professor Peter Collins Chairman, Therapeutics Task Force September 2016

Page | 96 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 13. UK Haemophilia Data Managers’ Forum Group

As with all groups in Haemophilia, 2016 has been a very busy year so far for Haemophilia Data Managers. Increasing data collection, ongoing updates and changes to data collection as well as inclusion of new products to databases and reports, continue to add challenges to the data management role. A meeting of this Group was held in April this year and as well as the normal updates (HCIS, NHD and Haemtrack etc.) other agenda topics included: • The tendering process and how now products are included in the National Framework • Congenital and Acquired Inhibitor Event reporting changes • Issues facing new data managers • Education Sessions for data managers Following on from plans discussed in last year’s report, this year saw the publication of a series of booklets to assist new and existing haemophilia data managers with some basic haemophilia information to help with the understanding for their role. Titles of these are  An Overview of Haemophilia for Data Managers  Haemophilia A: An Introduction for Data Managers  Haemophilia B: An Introduction for Data Managers  Service Delivery: A guide for Data Managers These have been edited by Dr Dan Hart and endorsed by the UKHCDO Data Management Working Party. It is planned that these booklets will be distributed at education sessions which are being planned for data managers in the coming year. The mentoring system continues to be available to new haemophilia data managers whereby they can spend time at the National Haemophilia Database office plus a day in a Comprehensive Care Centre where an experienced data manager can show how they carry out their role. This person and then be contacted for advice should any problems be encountered or understanding necessary to assist the new data manager in their role. A poster on this subject, the “Development of a UK Haemophilia Data Managers’ Programme of Education”, was presented and well received at the World Federation of Haemophilia meeting in Orlando in July this year. Organisation of meetings in the past year has been less challenging thanks to sponsorship being made available from Baxalta who sponsored the April meeting and SOBI who have agreed to sponsor the next meeting organised for November 2016. To close, I would take this opportunity to thank Dr Liesner, Dr Keeling, Professor Hay and all members of the UKHCDO Data Management Working Party and Advisory Group for their continued support, guidance and mentoring. Finally, I would extend our thanks to Dr Dan Hart for ongoing support of the UK Haemophilia Data Managers’ Forum Group, presenting at our meetings and also for editing our educational material prior to it being printed. Nancy Brodie Chairman, UK Haemophilia Data Managers’ Forum September 2016

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14. Haemophilia Nurses’ Association

Committee Dr Kate Khair Chair Cathy Harrison Vice-chair Sarah Johns Secretary Jayne Keaney April Jones Jenna Stanley Simon Fletcher

The Haemophilia Nursing Association (HNA) represents specialist nurses involved in the care of people with bleeding disorders in the UK. In addition to a very successful AGM and conference, 2016 has witnessed several new initiatives introduced through our charity, Haemnet (www.haemnet.com).

We have developed a new training course. “Contemporary Care of People with Bleeding Disorders” replaces the old Essentials and Advancing haemophilia nurse training courses. This course really is unique – it is not a dry, academic course but a very practical, hands-on course developed and delivered by nurses from four key UK centres, supplemented by invited experts. This year we have trained 20 nurses and physios from across the UK and Ireland. We will run the course again in 2017 and we’re already getting much interest from nurses in other European countries. At the other end of the nursing spectrum, you will know that several of the UK’s senior haemophilia nurses have recently retired or are likely to do so soon. To ensure that we have nurses ready and able to lead the profession in the future, Haemnet this year launched ASPIRE, a unique 6 - 8 month leadership development programme. We plan to run this again in 2017. Haemnet also has several research studies and action learning projects currently underway. Each of these is designed to enhance the level of practice and professionalism of nurses currently practising in the UK. This year we presented final results of the nurse-physio collaborative study at the WFH congress in Orlando. We were able to provide financial assistance so that nurses who had posters accepted for WFH could travel to Orlando. Haemophilia nurses provide the crucial interface between patients and members of the multi- disciplinary team and provide the backbone that keeps centres functioning efficiently. We believe that participation in our events greatly enhances the sense of community among HNA members and will go some way towards ensuring a happy and well educated haemophilia nurse establishment. We need UKHCDO centre directors to ensure that haemophilia nurses are supported to attend our AGM and the growing number of educational opportunities that we offer. Dr Kate Khair Chairman, Haemophilia Nurses’ Association September 2016

Page | 98 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 15. Haemophilia Chartered Physiotherapists’ Association

The Haemophilia Chartered Physiotherapists’ Association (HCPA) consists of chartered specialist physiotherapists with an interest in the physiotherapy management of people with haemophilia and allied bleeding disorders. The group aims to define, promote and encourage best practice for physiotherapy within haemophilia care, providing professional leadership and directing national physiotherapy policy. The group has a strong focus on research, with a dedicated core research team who encourage, facilitate and drive research and development. The HCPA provides an exciting forum to promote the exchange of ideas between those working in the specialism of haemophilia, and to promote and facilitate continuous professional development and educational opportunities for its members. The annual HCPA educational meeting and AGM, funded by an educational grant from Bayer Healthcare, was held in Birmingham in February 2016. Celebrating its 10th anniversary, this meeting looked back over the past 10 years of physiotherapy in haemophilia in the UK and Ireland. The group was able to reflect on the advances made, including 32 publications involving HCPA members, and it encouraged all of us to continue to advance the quality of care for patients and the academic achievements of the group as a whole. The agenda for the educational meeting reflected attendee feedback from the previous year, and included sessions on psychology and the latest evidence in Kinesio taping, intra articular injections and proprioception. The popular ‘free paper’ session had excellent submissions and participation from those chosen to present a synopsis of their work. The presentations were judged independently and Lou Sayers (Belfast) was awarded the CPD bursary for her work on the star excursion balance test. At the AGM Paul McLaughlin and Melanie Bladen stepped down in their roles as Chair and Vice- Chair of the group, with myself voted in as Chair and David Hopper from Newcastle voted in as Vice-Chair. Alongside the annual national educational meeting, the HCPA runs a North and South meeting. The South meeting held in December 2015 focussed on synovitis, outcome measures and research ideas. The North meeting held in May 2016 focussed on developing a business case, radiosynovectomy, GAITRITE and outcome measures. The 9th Annual Congress of EAHAD, held in Malmo, Sweden in February 2016, had three abstracts accepted from HCPA members to be presented as posters. In July 2016, the 32nd WFH World congress was held in Orlando, Florida. The turnout from the UK was strong, as was participation. The HCPA members had three free paper presentations, one moderated poster, one invited speaker and seven posters. The HCPA continues to be represented on a national level in the UKHCDO Musculoskeletal Working Party and in the National CRG for Haemophilia. It is also represented in the EAHAD Physiotherapy committee. I would finally like to thank Paul McLaughlin and Melanie Bladen for their dedication and hard work over the past 10 years. It is with credit to them that the HCPA has developed into such a supportive, collaborative group which is now recognised for its expertise and research on an international level. Anna Wells Chairman, Haemophilia Chartered Physiotherapists’ Association August 2016

Page | 99 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 16. BCSH Haemostasis and Thrombosis Task Force

Membership Prof Mike Laffan Chairman Dr Keith Gomez Secretary Dr Ian Jennings UK NEQAS representative Prof Isobel Walker UK NEQAS representative Dr Elaine Gray NIBSC representative Dr Raza Alikhan Dr Will Lester Dr Tina Biss Dr Deepa Arachchillage

Dr Gomez has been the UKHCDO representative in the last but as he has recently become the secretary the UKHCDO will either need to appoint one of the existing members as their representative or recruit a new representative from the membership.

Guidelines Published in Last Year HT/042 Peri-Operative Management of Anti-Coagulation and Anti-Platelet Therapy. David Keeling, Campbell Tait and Henry Watson UKHCDO protocol for first line immune tolerance induction for children with severe haemophilia A. UKHCDO Inhibitor and Paediatric Working Parties HT/034H Guidelines for Clinical Genetics Services for Haemophilia. John Pasi, Ted Tuddenham, Keith Gomez, Mike Laffan, Chris Ludlam, Mike Mitchell, Tony Cumming, Alan Fryer, Heather Skirton, Rezan Kadir, Diane Marshall

Guidelines in Preparation HT/035H The treatment and prevention of bleeding in heritable platelet disorders (09/09/11) Andrew Mumford (c), Simon Stanworth, Ri Liesner, Mike Makris. HT/041 Laboratory measurement of new factor VIII and IX molecules (24/1/14) Elaine Gray (c), Ian Jennings, Keith Gomez, Steve Kitchen HT/043 Use of TEG and TEM in clinical practice. Nicola Curry, Mike Laffan, Andrew Mumford. Liz Chalmers Management of Inherited Bleeding Disorders in Pregnancy. Sue Pavord, Rachel Rayment, Bella Madan, Tony Cumming, Will Lester, Liz Chalmers, Bethan Myers, Helena Maybury, Claire Tower, Rezan Kadir

BCSH Guidelines Process This year has seen some significant changes in BCSH with the aim of making the guidelines process consistent with NICE standards. The proposed changes were set out in last year’s

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report. In February 2016 the BCSH met with representation from all the task forces to consider how best to implement the changes. As a result: BCSH does not currently adhere to NICE standards partly because there is not a satisfactory process in place to review and update guidelines. The task force has introduced the following process: • Each current guideline to be reviewed by a committee member prior to each meeting • Every 5 years a formal literature review for each guideline would be undertaken. This would be undertaken by the chairman of the writing group or working party For UKHCDO guidelines that are not BCSH approved a similar process is required.

Laboratory Accreditation of Platelet Function Testing The task force has written to UKAS to because of concerns regarding consistency in the assessment of platelet functions testing by laboratories during accreditation. Proposals for what should be considered acceptable for proficiency testing have been drawn up in conjunction with NEQAS BC and sent to UKAS. The task force is considering publication of guidance on this issue.

Keith Gomez October 2015

Page | 101 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 17. Haemophilia Society

Introduction We are the only UK-wide charity for everyone affected by an inherited bleeding disorder, a community which includes family members, healthcare professionals and other supporters. Since 1950 we have campaigned for better treatment, been a voice and a source of information and support, and have helped members to lead fulfilling lives and inspire others to do so. Around 26,000 people in the UK have a diagnosis of an inherited bleeding disorder. Approaching 7000 are males with haemophilia, but there are also around 2000 females registered as carrying a defective gene who also often have low levels of factor VIII and have haemophilia. The largest proportion of people who have an inherited bleeding disorder have Von Willebrand Disease, but there are many rarer bleeding disorders that affect both men and women. This year The Haemophilia Society celebrated its 65th year. We celebrated by hosting our first ever arts weekend where families could come together, be creative and have fun together while exploring what a bleeding disorder means for them. We were joined by member who were still toddlers to some of our longest standing member. Our special guest was member Linda Wild who was 65 on the same day as The Society. This was a year of significant development and growth, particularly for our services and members support. Early in 2015 we published our three-year strategy and plan outlining how we will develop new services, increase our funding and strengthen our governance to ensure a sustainable future for the organisation that is relevant to our membership and forward thinking. This led to the development of our 7 Key life stages strategy. This identified 7 key times in our members’ lives when they felt the need for additional support and information. Our services and activities are now focussed at these points. In addition to these 7 key life stages we identified other groups or situations where our members looked to us for support. This included people with an inhibitor and women with bleeding disorders. We worked with our members to prioritise areas to focus on and what services should include. We are sorry to share the sad news that the Reverend Alan Tanner passed away on 5th August this year after a short illness, aged 90. Born in 1925, Alan – whose son Mark was diagnosed with haemophilia and later died as a result of contaminated blood – was a founding member of The Haemophilia Society and a staunch lifelong supporter of our charity and our community. Having chaired our board of trustees for 22 years from 1975 to 1997, and arranged and led the annual service of thanksgiving and remembrance for nearly 25 years. Alan played a huge part in the lives of so many of our community, guiding and supporting families through some of the darkest times of life. Alan also served as chairman of the World Federation of Hemophilia, and – in their early days – of The Macfarlane Trust and the Eileen Trust. He remained as our vice- president until his death. The Society will always be immensely grateful to him, and his daughter Mary-Ann, for supporting so many of our members over the years.

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Key risks and uncertainties (I would put this much further down the order) Financial Significant reliance on charitable contributions from members, corporates and other sources, and lack of certainty over the sustainability and security of these sources of funds.

Governance Managing the risk of non-compliance with relevant legal and regulatory requirements.

Reputation Managing reputational risk which could be impacted in any various ways, such as, perceived failure to represent specific member(s) views on a particular issue; failure to successfully influence government or NHS decisions on key issues; failure to safeguard a vulnerable adult or child at one of the Society’s events or services.

Each risk was carefully monitored and mitigation procedures put in place to reduce the likelihood and impact of the risk. The Board of Trustees reviewed the risks and mitigation quarterly.

Development and service delivery. Life Stage 1 Newly diagnosed families Members told us a child’s diagnosis is often traumatic and a lonely time. Many of our families also experienced suspicion that bruising was caused by violence facing very difficult situations before a diagnosis was finally made. Many families talked of isolation and fear. In light of this we developed our Newly Diagnosed Families weekends further and for the two week-ends carried out this year a total of 27 families including 48 children attended. Weekends include sessions on ‘What does your bleeding disorder mean to you’ and ‘What do Dads think Mums think?’ The weekend exceeded expectations and more: a massive weight has been lifted. To be with other families who actually ‘get it’ made the world of difference. I cannot recommend this enough to other parents. Key life stage two Starting nursery and school It is often nerve wracking for parents when their children start nursery or school, but when your child has a bleeding disorder this is heightened. Many schools and nurseries are unsure of how to care for a child with a bleeding disorder and many parents find it difficult to provide the information the school needs. This year we supported many families in this situation and spoke to nursery and school staff reassuring them that children should be treated as any child would be as long as precautions are taken and staff are aware of what to do in case of injury or a bleed. During the year we worked with parents and teachers on the content of a new school’s booklet that will be available in 2016. Key life stage three Learning to self-treat With so many UK haemophilia centres promoting home treatment children are beginning to learn to do their own treatment from the age of 8. However, it isn’t easy to treat yourself so we

Page | 103 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 encourage all of our younger members from 8 – 18 to attend our youth weekends. We held 4 weekends this year with 37 young people attending including supporting 13 children to attend Barretstown in Ireland, a sailing weekend, an Arts week-end, a Shropshire week-end and one in Wales. At the weekends, as well as having lots of fun abseiling and climbing, serious conversations and learning took place. Each weekend is attended by haemophilia nurses and physios as well as some of our youth ambassadors. Everyone attending has their treatment together, under the supervision of our nursing volunteers. They share techniques, discuss worries and challenges and learn from each other. Our youth ambassadors share experiences of their own and talk about the importance of having treatment regularly and what happens if you miss a treatment. As you reach teenage years and become more responsible for your own treatment it is easy to forget or skip treatment, because you have never had a problem and forget that this is mainly due to your regular treatment. Teenagers of ten tell us they don’t realise how important it is to keep taking your treatment until they miss it and experience the pain of a spontaneous bleed. We hope by hearing from our youth ambassadors our younger members will understand and remember their treatment regularly, however focussed they are on other activities. Having had several conversations at the week-end about the impact of bleeding it seemed reassuring to the young people that we had managed our conditions in a way that allowed us to progress in our lives. Ria Peake, Youth Ambassador Key life stage four Transition to adulthood Just as you are finally getting to grips with life with a bleeding disorder and you have survived your early teens, it is time to move form children’s care to an adult haemophilia centre. For some this is very smooth and painless, but for others it can be a very difficult time. We have been working with the organisation Haemnet to undertake some research into the challenges of transition and what we can do to support members at this time. Our youth ambassadors spent time phoning families to understand their experiences and as a result we recruited two new youth ambassadors to join the team. As we understand more about this, we will look to develop resources or services to support members at this time. Key life stage five Choosing a career Whether you have a bleeding disorder yourself, or care for someone who has, your career options can be affected. We have been sharing members’ stories and helping people make appropriate choices and ensure they understand how the law can help when you have a bleeding disorder. Key life stage six Relationship planning When you are in a relationship or thinking about a future with a partner the prospect of your children inheriting your bleeding disorder can have an impact. This year we held a conference for women with bleeding disorders including carriers where 50 women and their partners came to together to discuss the concerns and challenges of living with or being a genetic carrier of a bleeding disorder. The day included sessions on ‘Emotional impact’ and ‘What medical choices are available to me?’ Beforehand I was both nervous and excited. For the first time I’d be meeting with young people in the same position; so also for the first time I’d be faced with the reality of being a carrier. I needn’t have worried- I found I could air my fears and speak freely about my parent’s experiences with my brother. I’m less nervous about my future now.

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Key life stage seven Ageing with a bleeding disorder As you age life can feel uncertain as previous generations often didn’t make it to older age, the specialist health teams are learning with you about how people with bleeding disorders experience the everyday challenges of getting older. This year we began a major new project to look at ageing and bleeding disorders. This began with an ageing Information Day and has let on to us filming members of our community and their family to fully understand the impact this has. We have also filmed health professionals and are using this information to help shape our services and advocacy work in the future. The films will be available in 2016 and will lead the way in ensuring our older members receive the service and support you need in the coming years. As you get older, with the right care and support and limiting yourself to what is right for you, there’s no need to feel negative. I feel more positive than ever – especially now we’re in touch with The Haemophilia Society as my husband and I feel we’ve joined a big, happy family! Living with an inhibitor Life can be tough with an inhibitor with more bleeds, more pain and more treatment. We know it increases hospital visits and has a huge impact on the whole family’s life. Our focus has been to dig deeper into what this means for you and how we can support you through the challenges you face. We started with an inhibitor Information Day bringing together 23 members and their families who live with an inhibitor. We have developed a film to better understand members’ experiences. This is just the start of a long term project, but has already helped reduce the isolation so many of our members affected by an inhibitor feel. When we deal with his bleeds in joints and muscles it can be tough on the family, especially since we are all very active. Until some miracle happens we are content to deal with our little boy’s inhibitor as part of his life that is just as much a part of ours. World Haemophilia Day This year we undertook some market research to understand the public’s perceptions of bruising. We know many of our members experience difficulties when people see their bruises, jumping to conclusions. Whether you are a parent accused of abusing your child or a woman hearing comments about how you must be being beaten, it is often enough to make members feel uncomfortable and self-conscious. Our Bruised not abused radio and newspaper campaign reached almost 48,000,000 listeners on via radio stations across the UK. Our members also took on the challenge of raising awareness by holding events around the UK and raising funds too. Talking Red Our Talking Red awareness campaign went from strength to strength this year with even more women taking part in events and raising awareness of women and bleeding disorders. This year Celebrities Gok Wan, Emilia Fox and Carol Smillie supported the event. Emelia Fox said ‘Talking Red encourages women to be able to talk about bleeding disorders. Just one cation could help them reach someone currently suffering in silence because they think their symptoms are normal’.

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Advocacy and influencing This has been a frustrating and busy year continuing our campaign to bring about a fair resolution for our members who were infected by contaminated blood products in the 1970’s and 1980’s. Early in the year the long awaited Penrose Report was published in Scotland. Despite this being delayed by many years the outcome was a disappointment to many. Although a great deal of evidence was clearly documented in the report, no useful recommendations were made and many of our members were left feeling angry and disillusioned. The Society reviewed the evidence and published a response to the report and continued to work with governments across the UK to bring about a fair settlement for those affected by each devolved government. In May 2015 we wrote to the Prime Minister setting out what we believed needed to be done to bring about a fair settlement. We continued working with our colleagues from Haemophilia Scotland who were able to engage very effectively with the Scottish Government, who were open to discussions. It was harder to achieve this level of open dialogue with the Department of Health in England. In October 2015 The Department of Health established a reference group to inform the development of a consultation on support for those affected which we were able to attend with others from the community. Unfortunately, the recommendations from the reference group were not reflected in the consultation that was launched by the Department of Health in February 2016. Throughout this time we have continued to act as the Secretariat for the APPG (all party parliamentary Group on Haemophilia and Contaminated Blood) and have worked very closely with MPs to ensure this issue remains high on the political agenda and MPs are informed of the impact government proposals and activity have. Details of our work are available on our website. This has also been a year of significant change for our members affected by Hepatitis C. With the introduction of a new class of treatment with high levels of success and few side effects than previous treatment, there was the real potential for our community to finally receive effective treatment. We were able to respond to several NICE consultations and were hopeful that treatment would be quickly made available. This became reality in Scotland Northern Ireland and Wales. However, NHS England challenged NICE and requested a delay in treatment starting and introduced a phased treatment plan, meaning many of our community would not receive treatment in a timely way. We continue to work closely with the commissioners and APPG to call for access to treatment. Worldwide connections We have strengthened our relationships with the UK Haemophilia Centre Doctor’s Organisation (UKHCDO), Haemophilia Nurses Association, Haemophilia Physio’s, The European Haemophilia Consortium (EHC) and World Federation of Hemophilia (WFH). We are members of the Clinical Reference Group providing advice to NHS England on treatment for bleeding disorders and are an active member of the Factor Tender panel who make recommendations on treatment access and availability. As the host nation for the WFH Congress in 2018 we have already started making plans and have been working with the WFH team do ensure we have a positive presence at the next Congress in July 2016 in Orlando Florida.

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CHESS study As the Chair of the Steering group for this research study Liz Carroll has been working closely with HCD Economics who undertook the research and analysis to ensure the data can support our work in calling for improved treatment and care in the UK, as well as enabling our partners in the four other European nations to do the same. The study is the largest ever undertaken into the burden of severe haemophilia and had produced some fascinating data to support our activity. Our thanks go to our Trustee Jamie O’Hara for all his work on this study. Local Groups Our local groups continue to grow and provide an invaluable support to people in their local communities, providing information and support as well as fundraising and awareness. Without our local group volunteers, we wouldn’t be able to provide the local support so desperately needed. AGM and Conference Over 100 members, aged from just 15 weeks old to 75, and from as far afield as Aberdeen and Bournemouth, came along to The Haemophilia Society’s annual general meeting (AGM) and conference in Leeds on Saturday 7th November. This year, our theme challenged everyone to ‘be the best you can be’, as we celebrated 65 years of our charity. Afternoon workshops were packed, including sessions from a physio and dietician, incredible motivational speaker Chris Moon, art therapy with Simon Bell and a touch of drumming with Sam! We revealed our ‘Haemophilia Hero’ the late Alf Morris: Lord Morris of Wythenshawe who was voted by our members and the winner of our Swim Around Britain photo competition, and ended the day with a fabulous performance from our young members who had been rehearsing all day, all topped off by a birthday cake and tea. A lively discussion about whether our charity should consider changing its name also took place: thank you to all who shared their views. The debate began with two speeches from members with opposing opinions, and was then opened up to the floor. As anticipated, there are strong feelings and opinion is divided. Many members who have a bleeding disorder other than haemophilia feel very excluded, and took years to find us because our name suggests we’re not relevant to them. Even those who know about our services often feel ‘second best’ to those who have haemophilia. Others feel that our long history is more important, and that our heritage as the world’s first Haemophilia Society, or our charity’s profile, might suffer if we change our name. We will continue talking and listening to our members in the months to come. ‘We really enjoyed this AGM and conference, we covered lots of issues and it was so welcoming.’ ‘Thank you. I’m so glad to see the Society is taking a good look at itself and being very positive about the way forward.’ Fundraising This year our fundraisers have been even bigger and better with more of our community than ever before running marathons, jumping from airplanes, climbing mountains. Cakes have been baked and events planned. Without our community fundraisers we couldn’t achieve anything

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like the amount we do, so one of our biggest thank you’s goes to our amazing fundraising teams. Volunteering This year we have had some incredible support form volunteers, both in the office and out and about across the UK, however one or two volunteers have given above and beyond and we would like to thank them personally. Dave Gort has worked with us to improve our website and publications and never tires of us asking for one more change to make it a bit better. It’s a work in progress, but we are getting there. Keith Colthorpe has also travelled up and down the country taking photographs of our service and events to ensure we can share images with our members and bring our service to life. We also know we couldn’t run most of our services without the incredible nurses and physiotherapists who volunteer at all our newly diagnosed family weekends, youth weekends and conferences. One particular nurse Cathy Benfield has given up more than her fair share of weekends to volunteer for us. Thank you Cathy. Youth Ambassadors This year we created our Youth Ambassador programme and recruited 6 youth ambassadors. Four young men and two young women all with a bleeding disorder. As a team they have attended services, talked about their experiences with members, and supporters and have attended training sessions to enable them to support us on the development of the charity and bring a younger person’s perspective to the work we do. We would like to thank Rob Barnard, Luke Pembroke, Ria Peake, Laurence Woollard, Hannah Yarnall and Matthew Minshall for their tireless enthusiasm and energy. We remember We remember our members, friends and volunteers who have died during the year: they have left us with hope and determination; hope that we can support our members to live full and positive lives and to ensure the tragedies of the past are resolved and will never happen again. Future plans In 2016-17 we will continue to develop and grow our services, with a particular focus on delivering services as a result of our work this year on inhibitors and ageing. Using the knowledge gained we will create new services and information in partnership with our members. We will also develop and publish booklets and factsheets on the key issues faced by our members and ensure these are available online, and where possible in print. We will continue to act as the secretariat to the APPG and will look to bring final resolution to the longstanding issues faced by our community affected by contaminated blood, but also begin to address other issues impacting haemophilia care and treatment such as access to new drugs and benefit access. We also aim to increase our support to our Local groups with new ideas and opportunities to bring the local face of the Society to communities across the UK. In our fundraising we will expand our offer and work with a greater range of companies and offer more events to diversify and increase funding again. We aim to ensure a balanced income and expenditure in 2016-17. We will also continue the discussion on whether our name and logo are fit for the inclusive modern charity we are today. We will ask members to decide if our name and logo should

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Liz Carroll Chief Executive Officer, The Haemophilia Society October 2016

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In May 2016, the board appointed Alasdair Murray, a Trustee since February 2014, as the new Chair of the Macfarlane Trust. This followed the resignation earlier the same month of Roger Evans, who had been an MFT Trustee since January 2007, and Chair since April 2012. Roger made a major contribution to the development of MFT during his years with the organisation, and had also been one of the founding Trustees of The Caxton Foundation, one of MFT’s sister organisations, when it was set up in 2011. During the year, Eileen Jackman also retired, having served a full three year term as a Trustee. In the run up to the start of the new financial year, the MFT board continued to press the Department of Health (DH) for an increase to its annual financial allocation. However, additional funds for 2015/16 were not forthcoming and the allocation remained frozen at £2.2 million, in spite of clear evidence that this was insufficient to meet the needs of beneficiaries. The board has been determined to maintain the level of support it provides to beneficiaries, even though the DH allocation has not been adequate to do this. In April 2015 the board therefore decided to continue its policy of supplementing the DH allocation from funds held in reserve. The MFT board has made it clear to DH that supplementing the annual allocation from reserves cannot continue indefinitely, as the level of reserves is reducing year on year. Consequently, the MFT board continues to press for an increase in annual funding to an adequate level. In 2015/16 the political focus on contaminated blood, which had started the previous year, increased, with the publication by DH in January 2016 of a long-awaited consultation on reform of financial and other support to those infected with HIV and Hepatitis C as a result of contaminated blood, and their families. MFT’s analysis of the proposals set out in the consultation gave significant cause for concern, as it appeared that MFT beneficiaries who were mono-infected with HIV, or co-infected with HIV and Hepatitis C at Stage 2 were likely to be worse off financially under the new proposals. MFT beneficiaries who were co-infected with Hepatitis C at Stage 1, who would be eligible to apply for an individual health assessment under the new proposals, might be better or worse off, depending on the level of payment they were to receive as a result of the assessment. With regard to the bereaved, beneficiaries might be better or worse off, depending on whether or not someone chose a lump sum, and the level of this, and depending on what the Government envisaged by “ongoing discretionary support” for those who opted not to take the lump sum. The consultation document also proposed replacing the existing Alliance House organisations – including MFT - with a single entity. In January we therefore wrote to all beneficiaries with an analysis of the proposals, encouraging them to read and respond to the consultation, whether they agreed with the proposals or not, to ensure the Department of Health heard the views of as many of those affected as possible. During 2015/16 MFT worked closely with the other four Alliance House organisations which support people infected with HIV and Hepatitis C as a result of contaminated blood on matters of common interest. The Chief Executive and Chairs of the five organisations met with Jane Ellison MP, Under Secretary of State for Public Health, before the consultation was launched. We also held several meetings with Department of Health officials. Following the launch of the consultation, MFT and the other four organisations submitted a joint response to the proposals,

Page | 110 UKHCDO Annual Report 2016 & Bleeding Disorder Statistics for 2015/2016 highlighting the many ways in which the proposals would disadvantage beneficiaries if they were implemented. On 13 July 2016, during David Cameron MP’s final Prime Minister’s Questions, the Government announced its response to the consultation. The model of future support it announced applies to England only. There are some improvements to support for beneficiaries compared with the original proposals, including an increase to non-discretionary payments (currently made through the Skipton Fund and MFET), the introduction of regular payments for those at Stage 1 Hepatitis C infection, and the retention of the link to CPI. The announcement that discretionary support will also be retained was welcomed, although until there is further clarity on this, it is not clear whether any beneficiaries will be disadvantaged by then new arrangements; there are concerns that some will. During 2015/16 the Scottish Government established a Review Group to examine the financial support provided to those infected in Scotland, and their families. In March 2016 the Scottish Government announced that it would be adopting the recommendations made by the Review Group to increase financial support to those infected in Scotland. The model of support which has been adopted for Scotland is considerably more generous than that which currently exists in the rest of the UK, and the payments are greater than those announced for England. At the time of writing, it is not known which model of support Wales and Northern Ireland will adopt. However, there will no longer be a unified system of support across the UK. The Government also announced that for the future, there will be a single scheme administrator which will become operational during 2017/18. At the current time, we have no further information regarding the future of MFT, but we are hoping that the Department of Health will clarify the future administrative arrangements as a matter of urgency, and work in partnership with the Alliance House organisations, including MFT, to implement a new scheme administrator which retains the knowledge, experience and expertise of the existing group of dedicated staff.

Jan Barlow Chief Executive, Macfarlane Trust August 2016

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