BMJ Open BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

The effectiveness, safety and costs of orphan drugs: an evidence-based review

ForJournal: peerBMJ Open review only Manuscript ID: bmjopen-2014-007199

Article Type: Research

Date Submitted by the Author: 14-Nov-2014

Complete List of Authors: Onakpoya, Igho; University of Oxford, Primary Care Health Sciences Spencer, Elizabeth; University of Oxford, Primary Care Health Sciences Thompson, Matthew; Oxford University, Department of Primary Care Health Sciences Heneghan, Carl; Oxford University, Primary Health Care

Primary Subject Evidence based practice Heading:

Evidence based practice, Pharmacology and therapeutics, General practice Secondary Subject Heading: / Family practice

GENERAL MEDICINE (see Internal Medicine), PRIMARY CARE, ORPHAN Keywords: DRUGS http://bmjopen.bmj.com/ http://bmjopen.bmj.com/

on September 28, 2021 by guest. Protected copyright. on September 28, 2021 by guest. Protected copyright.

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1 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 The effectiveness, safety and costs of orphan drugs: an evidence-based review 4 5 6 7 Igho J. Onakpoya 8 9 10 University of Oxford, Centre for EvidenceBased Medicine, Nuffield Department of Primary 11 12 Care Health Sciences, New Radcliffe House, Radcliffe Observatory Quarter, Oxford, United 13 14 Kingdom OX2 6GG 15 For peer review only 16 17 18 19 Elizabeth A. Spencer 20 21 University of Oxford, Centre for EvidenceBased Medicine, Nuffield Department of Primary 22 23 Care Health Sciences, New Radcliffe House, Radcliffe Observatory Quarter, Oxford, United 24 25 Kingdom OX2 6GG 26 27 28 29 30 Matthew J. Thompson 31 32 Department of Family Medicine, University of Washington, Seattle, USA WA 981956390

33 http://bmjopen.bmj.com/ 34 35 36 Carl J. Heneghan 37 38 39 University of Oxford, Centre for EvidenceBased Medicine, Nuffield Department of Primary 40 41 Care Health Sciences, New Radcliffe House, Radcliffe Observatory Quarter, Oxford, United on September 28, 2021 by guest. Protected copyright. 42 43 Kingdom OX2 6GG 44 45 46 47 Corresponding author: Igho Onakpoya, University of Oxford, Nuffield Department of Primary Care 48 49 Health Sciences, New Radcliffe House, Radcliffe Observatory Quarter, Oxford, United Kingdom 50 51 OX2 6GG. Email: [email protected]. Tel: +44 (0)1865 289672 52 53 54 55 56 Keywords: orphan drugs; cost; prevalence; effectiveness; safety; review 57 58 Word count: 4,340 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 59

2 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 ABSTRACT 4 5 Introduction: Several orphan drugs have been approved by the European Medicines Agency 6 7 (EMA) over the past two decades. However, the prices of the drugs are expensive, and in 8 9 10 some instances, the evidence for effectiveness is not convincing at the time of regulatory 11 12 approval. Our objective was to evaluate the clinical effectiveness of orphan drugs which have 13 14 been granted marketing licenses in Europe, determine the annual costs of each drug, compare 15 For peer review only 16 the costs of branded orphan drugs against their generic equivalents, and explore any 17 18 19 relationships between orphan disease prevalence and annual costs. 20 21 Methods: We searched the EMA database to identify orphan drugs granted marketing 22 23 authorization up till April, 2014. Electronic searches were also conducted in Pubmed, 24 25 Embase, and Google Scholar to assess data on effectiveness, safety and annual costs. Two 26 27 reviewers independently evaluated the levels and quality of evidence and extracted data. 28 29 30 Results: We identified 74 orphan drugs, with 54 (73%) demonstrating moderate quality of 31 32 evidence. 85% showed significant clinical effects, but serious adverse events were reported in

33 http://bmjopen.bmj.com/ 34 86.5%. Their annual costs were between £726 and £378,000. There was a significant 35 36 relationship between disease prevalence and annual costs (p = 0.01); this was largely due to 37 38 39 the influence of the ultraorphan diseases. We could not determine whether the balance 40 41 between effectiveness and safety influenced annual costs. For 10 drugs where generic on September 28, 2021 by guest. Protected copyright. 42 43 alternatives were available, the branded drugs were 1.4 to 82,000 times more expensive. 44 45 Conclusion: The available evidence suggests that there is inconsistency in the quality of 46 47 evidence of approved orphan drugs, and there is no clear mechanism for determining their 48 49 50 prices. In some cases far cheaper generic agents appear to be available. A more robust, 51 52 transparent and standard mechanism for determining annual costs is imperative. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 59 BMJ Open

3 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Strengths and limitations 4 5 • We employed a robust strategy to search for the best quality evidence for effectiveness 6 7 8 • We used standardized methods to rate the quality and level of evidence for each orphan 9 10 drug 11 12 • We also used reliable data to document the prevalence of each orphan disease and identify 13 14 the annual cost of each orphan drug 15 For peer review only 16 17 • Because we could not document the R and D costs associated with the approval of each 18 19 orphan drug, the influence of this variable on their annual costs could not be ascertained 20 21 • The inconsistencies in the quality of evidence for some orphan drugs limits the 22 23 conclusions that could be drawn regarding their effectiveness and safety 24 25

26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 28, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 59

4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 INTRODUCTION 4 5 Orphan drugs are therapeutic agents designed for the management of orphan diseases,1 which 6 7 are defined as medical conditions with a low prevalence. In the United States (US), orphan 8 9 2 10 diseases are defined as those affecting approximately 1 in 1,500 persons [ ], while in Europe 11 2,3 12 it is 1 in 2,000. In Europe, ultraorphan designations are used to specify rare diseases with 13 14 prevalence less than 1 in 50,000.2,4 15 For peer review only 16 17 18 19 Because low patient volumes make it unfavourable for commercial investment in orphan drug 20 21 research, drug regulatory authorities have incentives in place to encourage their development 22 23 and manufacture by pharmaceutical companies. In the US, these include exclusive licencing 24 25 to market such drugs for seven years, faster assessment procedures, and tax incentives.1 In 26 27 Europe, incentives include exclusive licensing for 10 years, reduction in the fees paid for 28 29 1,5 30 regulatory activities, and (provision of scientific advice by drug regulatory bodies. Despite 31 32 these incentives, the costs of orphan drugs are still high, especially when generic versions of

33 http://bmjopen.bmj.com/ 34 the same agent are available.6 In the United Kingdom for example, some funders of care 35 36 under the National Health Service have refused to fund the orphan drugs because they are not 37 38 7 39 considered cost effective. Factors which reportedly influence their price setting include 40 41 research and development (R & D) costs, clinical effectiveness, drug quality, and disease on September 28, 2021 by guest. Protected copyright. 42 43 prevalence.8,9 However, the effectiveness of some orphan drugs has not been clearly 44 45 demonstrated, and the evidence regarding their safety is often sparse at the time of regulatory 46 47 approval.10 48 49 50 51 52 A previous systematic review of 11 orphan drugs approved in the Netherlands concluded that 53 54 there is scarcity of information on the cost effectiveness of the drugs.11 A more recent 55 56 systematic review of orphan drug legislation in Europe also advocated for more stringent 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 59 BMJ Open

5 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 approval criteria for evaluating the clinical and cost effectiveness of orphan drugs.12 Another 4 5 systematic review of orphan drugs used in cancers showed that they have varying levels in 6 7 quality of evidence and dearth of information on economic value.13 While the first two 8 9 10 reviews did not evaluate the quality of the evidence, the third review focussed only on drugs 11 12 marketed in the US. 13 14 15 For peer review only 16 The objective of this review was to evaluate the effectiveness and safety of all orphan drugs 17 18 19 which have been granted marketing licenses in Europe, determine the annual costs of each 20 21 drug, compare the costs of branded orphan drugs against their generic equivalents, and 22 23 explore the relationship between orphan disease prevalence and annual costs. 24 25 26 27 METHODS 28 29 30 We searched the European Medicines Agency (EMA) database for orphan drugs and their 31 32 approved indications using the search modality '' http://www.ema.europa.eu/ema/ > find

33 http://bmjopen.bmj.com/ 34 medicine > human medicines > Browse by type > Orphan medicine: “Include authorised 35 36 medicine, withdrawn postapproval and suspended” > SUBMIT ''. Orphan drugs granted 37 38 39 marketing authorisation up until 30th April, 2014 were identified. Drugs which have been 40 41 designated with “orphan status”, but have not received EMA marketing authorisation were on September 28, 2021 by guest. Protected copyright. 42 43 excluded. The EMA Orphanet Report Series (April, 2014)14 was also assessed to verify the 44 45 identified drug approvals. 46 47 48 49 50 For each identified drug, electronic searches were then conducted in the following databases: 51 52 Pubmed, Embase, the Clinical Trials database and National Electronic Library for Medicines. 53 54 The search terms used included: “orphan drug name” AND “metaanalysis”, systematic 55 56 review”, “randomised”, “clinical trial”, “placebo”, “followup study”, “retrospective 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 59

6 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 studies”, “caseseries”, “cohort”, “followup studies”, “adverse events”. The prevalence of 4 5 the orphan diseases was documented using the reference values reported in the Orphanet 6 7 Report Series Bibliographic data15 and the Orphanet portal for rare diseases and orphan 8 9 16 10 drugs. 11 12 13 14 We also searched the UK Medicines Information, the National Electronic Library for 15 For peer review only 16 Medicines, North East Treatment Advisory Group (NETAG), Scottish Medicines 17 18 19 Consortium, and All Wales Medicines Strategy Group databases for the most recent evidence 20 21 relating to the annual costs of each drug. Where these were inadequate to compute the annual 22 23 costs of a specific drug, we searched The Pharma Letter (www.pharmaletter.com) and 24 25 PharmaTimes (www.pharmatimes.com) websites, and Google Scholar for the most recent 26 27 data on annual costs. The costs of treatment with drugs not used on an annual basis/duration 28 29 30 were computed as annual costs. 31 32

33 http://bmjopen.bmj.com/ 34 For each orphan drug identified from the EMA database, we determined the level of available 35 36 evidence regarding effectiveness using the Oxford Centre for Evidence Based Medicine 37 38 17 39 (OCEBM) Levels of Evidence which comprises four levels: Level 1: systematic reviews; 40 41 Level 2: randomized trial or observational study with dramatic effect; nonrandomized on September 28, 2021 by guest. Protected copyright. 42 43 controlled cohort/followup study; Level 3: caseseries, casecontrol studies, or historically 44 45 controlled studies; Level 4: mechanismbased reasoning. 46 47 48 49 50 The quality and strength of the overall body of evidence for each orphan drug was then 51 52 evaluated using a checklist adapted from the Grades of Recommendation, Assessment, 53 54 Development and Evaluation (GRADE) criteria18 which assesses the five domains: study 55 56 design; consistency of evidence; directness of the evidence; precision; and reporting biases. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 59 BMJ Open

7 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Based on the quality of overall evidence, 1 of 4 possible grades could be allocated: high, 4 5 moderate, low, and very low. 6 7 8 9 10 Evidence for effectiveness for each orphan drug from the highest levels of evidence for each 11 12 orphan drug was prioritised using the following order: metaanalysis/systematic review > 13 14 RCTs > nonrandomised studies. If two or more systematic reviews evaluated the same 15 For peer review only 16 orphan drug, the most recent review was included. If two or more drugs were approved for 17 18 19 treating same orphan disease, we determined whether the level of effectiveness was related to 20 21 their annual costs. Scatter plots were used to explore the relationships between orphan disease 22 23 prevalence and annual costs. If three or more drugs were approved for same indication, we 24 25 used scatter plots to test whether there was a relationship between approval year and annual 26 27 cost. Where systematic reviews or metaanalyses did report adverse events, we searched for 28 29 30 adverse event publications using the evidence from systematic searches using the following 31 32 priority: RCTs > retrospective/followup/cohort > casecontrol/caseseries. Adverse events (≥

33 http://bmjopen.bmj.com/ 34 Grade 3) associated with the use of such drug were documented. For drugs which had been 35 36 withdrawn or suspended, we documented the reasons for such decisions by accessing the 37 38 19 39 EMA European Public Assessment Reports (EPAR) for human medicines. 40 41 on September 28, 2021 by guest. Protected copyright. 42 43 Two reviewers [IO & ES] independently evaluated the level and quality and strength of the 44 45 evidence, and extracted data. These were then crosschecked by two other reviewers [MT and 46 47 CH]. Disagreements were resolved through consensus. 48 49 50 51 52 RESULTS 53 54 The EMA database searches identified a total of 74 drugs approved for managing 63 orphan 55 56 conditions, with approval dates ranging from 15/05/2002 to 04/04/2014 (Figure 1). Twenty 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 59

8 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 nine (39%) of these drugs are used in the management of cancers, while 24 (32.4%) are used 4 5 for inborn errors of metabolism or immune disorders. The remaining 21 drugs were approved 6 7 for a variety of other orphan conditions, with pulmonary arterial hypertension accounting for 8 9 10 5 (23%) of the approvals. Of the 74 approved drugs, five drugs (6.8%) were granted 11 12 conditional approval, while 15 (20%) were granted approval under “exceptional” 13 14 circumstances. Two drugs, Cholic acid FGK and Orphacol, both contained the same active 15 For peer review only 16 ingredient and were approved for same indication; however, Orphacol was granted license 17 18 19 under “exceptional” circumstances. Two drugs, Onsenal and Rilonacept, were withdrawn by 20 21 the EMA after approval because of unfavourable risktobenefit profile and commercial 22 23 reasons respectively. Details of the approval dates, levels and quality of evidence, results of 24 25 clinical effectiveness, annual costs, and relevant references have been included as web 26 27 appendices 14. 28 29 30 31 32 Levels and quality of evidence

33 http://bmjopen.bmj.com/ 34 Using the OCEBM criteria, 25 (33.8%) orphan drugs had Level 1 evidence, 35 (47.3%) were 35 36 Level 2 and 14 (18.9%) were Level 3 (Figure 2a). Based on the GRADE criteria, the overall 37 38 39 quality of evidence could be rated as moderate in 54 (73.0%) drugs, low in 16 (21.6%), and 40 41 very low in 4 (5.4%) (Figure 2b). None of the approved drugs showed evidence of high on September 28, 2021 by guest. Protected copyright. 42 43 overall quality. Relevant references for the level and quality of evidence are included as web 44 45 Appendix 1. 46 47 48 49 50 Evidence for effectiveness 51 52 Of the 29 drugs approved for management of cancer, six (20.7%) showed evidence of 53 54 significant benefits for both progressionfree survival and overall survival; seven (24.1%) 55 56 showed evidence of significant improvement only in progressionfree survival, while nine 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 59 BMJ Open

9 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 (31.0%) had evidence of only significantly increasing overall survival (web Appendix 2; 4 5 Table 1). Of the 24 orphan drugs approved for treating inborn errors of metabolism, 21 (75%) 6 7 showed evidence of beneficial effect on at least one outcome measure (web Appendix 2; 8 9 10 Table 2). Of the remaining 21 drugs used for managing other orphan diseases, 20 (95.2%) 11 12 showed evidence of significant beneficial effects (web Appendix 2; Table 3). 13 14 15 For peer review only 16 Evidence for safety 17 18 19 Twenty eight (96.6%) of the orphan drugs approved for treating cancerous conditions had 20 21 evidence of serious adverse events (web Appendix 2; Table 1). The most common events 22 23 were bone marrow suppression (58.6%) and hepatotoxicity (20.7%). Adverse events with 24 25 Dacogen and Evoltra were severe enough to warrant premature termination of clinical trials. 26 27 28 29 30 Six out of 24 drugs (25%) approved for treating inborn errors of metabolism had no evidence 31 32 of serious adverse events, while another (Cholic acid) did not have any preclinical safety

33 http://bmjopen.bmj.com/ 34 studies prior to approval (web Appendix 2; Table 2). The most common events involved the 35 36 gastrointestinal and respiratory systems (25% and 20.8% respectively). 37 38 39 40 41 Eighteen of the 21 drugs (85.7%) approved for treating other orphan conditions had evidence on September 28, 2021 by guest. Protected copyright. 42 43 of serious adverse events (web Appendix 2; Table 3). Gastrointestinal adverse events were 44 45 the most common (23.8%). Other notable adverse events included cardiotoxicity (9.5%), 46 47 metabolic abnormalities (9.5%), and possible risk of suicide with Prialt (ziconotide). 48 49 50 51 52 Annual costs of orphan drugs 53 54 The annual cost with ranged between £726 and £378,000 (median £31,012). 24% of the drugs 55 56 cost less than £10,000 annually, 58% cost between £10,000 and £100,000, while 18% cost ≥ 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 59

10 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 £100,000 annually. For cancer drugs the range was £1,800 to £92,000, compared with £726 4 5 to £378,000 for inborn errors of metabolism. 6 7

8 9 10 Association between disease prevalence and annual cost of orphan drugs 11 12 A scatter plot of prevalence against annual cost (Figure 3) revealed a significant inverse 13 14 relationship (p = 0.01). In contrast, we did not observe a significant relationship when a sub 15 For peer review only 16 area of more frequent activity (similar range of disease prevalence and annual costs) was 17 18 analysed (p = 0.56; Figure 3 inset). A significant inverse association was also observed for 19 20 21 the relationship between annual cost and the prevalence for 21 drugs approved for managing 22 23 ultraorphan diseases (p = 0.04; Figure 4). However, a scatter plot of the subset of the 53 24 25 drugs approved for orphan diseases with prevalence >1 per 100,000 revealed a non 26 27 significant relationship (p = 0.18). Scatter plots of prevalence against annual cost did not 28 29 30 reveal significant relationships when cancers or inborn errors of metabolism were 31 32 individually tested (data not shown).

33 http://bmjopen.bmj.com/ 34 35 36 Association clinical effectiveness and annual cost 37 38 Because of discrepancies in outcome measures and time points for outcome measurements, 39 40 41 we could not use scatter plots to explore associations between clinical effectiveness and on September 28, 2021 by guest. Protected copyright. 42 43 annual costs. All orphan drugs approved for managing pulmonary arterial hypertension 44 45 showed comparative level of effectiveness at improving sixminute work distance and 46 47 decreasing clinical worsening irrespective of annual cost (web Appendix 3). Similar findings 48 49 50 were observed for progressionfree survival and overall survival for orphan drugs approved 51 52 for treating cancers. The annual costs of two drugs approved for treating Pseudomonas in 53 54 cystic fibrosis were comparable. We could not determine whether the risk or occurrence of 55 56 serious adverse events played a role in the annual costs of approved orphan drugs. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 59 BMJ Open

11 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Association between approval year and annual cost 4 5 Two or more orphan drugs were approved by the EMA for treating seven orphan conditions 6 7 (web Appendix 3). Scatter plot of annual cost against approval year for the five drugs 8 9 10 approved for pulmonary arterial hypertension suggested a trend towards a significant 11 12 relationship for higher annual costs with more recent approvals (p = 0.06). A significant 13 14 relationship between annual cost and approval year was observed with four drugs approved 15 For peer review only 16 for the management of chronic myeloid leukemia (p = 0.03). There was no significant 17 18 19 relationship between annual cost and approval year for drugs approved for treatment of acute 20 21 lymphoblastic leukemia (p = 0.38); however, exclusion of the most recently approved drug 22 23 whose approval was based on a historical perspective (Xaluprine) resulted in a significant 24 25 relationship being observed (p = 0.01). 26 27 28 29 versus 30 Branded orphan drugs generic or unlicensed versions 31 32 We found 15 approved drugs with generic versions, out of which data on annual cost of

33 http://bmjopen.bmj.com/ 34 generic or unlicensed versions for 10 (13.5%) were available. Figure 5 shows a price 35 36 comparison for annual costs for branded orphan drugs compared with their 37 38 39 unlicensed/generic equivalents. While branded mercaptopurine (Xaluprine) was only 1.4 40 41 times more costly than its generic counterpart, the branded version of intravenous ibuprofen on September 28, 2021 by guest. Protected copyright. 42 43 (Pedea), used for closure of patent ductus arteriosus (PDA) in preterm infants was 82,000 44 45 times more expensive than its oral equivalent. 46 47

48 49 50 DISCUSSION 51 52 Main findings 53 54 Our results show that of the 74 EMA approved orphan drugs over a 12year period, none has 55 56 shown an overall high quality in available evidence for their effectiveness; there is a 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 59

12 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 moderate level of evidence for threequarters, while a fifth are low in evidence. Our analyses 4 5 of annual drug costs revealed several interesting and potentially concerning findings. We 6 7 found a significant inverse relationship between annual costs of orphan drugs and the 8 9 10 prevalence of orphan diseases in other words the drugs for the most rare diseases and cheaper 11 12 than those for more common diseases , largely driven by the drug costs for the ultraorphan 13 14 diseases. We also found that drugs that had been approved more recently cost more than 15 For peer review only 16 those approved even over the previous decade. Finally, the annual costs of the drugs did not 17 18 19 appear to be related to their clinical effectiveness, and for the subset of the branded orphan 20 21 drugs which had generic equivalents we found several extremely large differences in cost. 22 23 24 25 While the clinical trial evidence for over twothirds of EMAapproved orphan drugs suggests 26 27 that they have clinically significant beneficial effects; the evidence for about onefifth 28 29 30 indicates that either they do not have clinically beneficial effects, or more importantly may do 31 32 harm. The results of systematic reviews for several of the drugs are also inconclusive, either

33 http://bmjopen.bmj.com/ 34 because of deficiency in trial reporting or due to a lack of available clinical trials. Our 35 36 inability to determine whether the level of clinical effectiveness influences annual costs for 37 38 39 orphan diseases with two or more approved indications indicates uncertainty about how this 40 41 variable determines price setting. on September 28, 2021 by guest. Protected copyright. 42 43 44 45 The findings from our review show that except for the very rare (ultraorphan) diseases, there 46 47 is no significant inverse relationship between disease prevalence and annual cost. There were 48 49 50 inconsistencies in the strengths of correlation between approval year and annual costs when 51 52 three or more drugs used for same orphan condition were compared. This indicates that there 53 54 is no standardized process for setting the prices of orphan drugs. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 59 BMJ Open

13 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Comparison with existing literature 4 5 The results of our review confirm a previous research report which concluded that orphan 6 7 disease prevalence is inversely associated with annual costs for only the very rare diseases.8 8 9 10 Our results also corroborate results a from previous review which showed that approved 11 13 12 orphan drugs vary in the quality of evidence, and support the evidence from two previous 13 14 reviews which suggested that there is no clarity about how the clinical effectiveness is used to 15 For peer review only 16 determine their costs of orphan drugs.11,12 In contrast to the previous reports, our review is 17 18 19 more systematic, and by far more comprehensive. We also determined whether approval year 20 21 has any influence in determining costs, and we compared branded versions of the orphan 22 23 drugs with their unlicensed or generic versions. 24 25 26 27 Strengths and limitations 28 29 30 We employed a robust strategy to search for the best quality evidence for effectiveness, 31 32 safety and annual costs of each orphan drug, and we used standardized methods to rate the

33 http://bmjopen.bmj.com/ 34 quality and level of evidence for each identified drug. We also used reliable data to document 35 36 the prevalence of each orphan disease and identify the annual cost of each orphan drug. 37 38 39 40 41 However, we do recognize several limitations. Because we could not document the R and D on September 28, 2021 by guest. Protected copyright. 42 43 costs associated with the approval of each orphan drug, the influence of this variable on their 44 45 annual costs could not be ascertained. The heterogeneity in clinical outcomes across different 46 47 diseases, discrepancies in time points for outcome measurements, and the inconsistency in the 48 49 50 levels of outcome reporting also limited the type of analyses and therefore the conclusions 51 52 that could be drawn regarding the effectiveness and safety of some orphan drugs. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 59

14 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Implications for research 4 5 Our finding that the trial evidence for the effectiveness and safety of 65% of drugs have not 6 7 been systematically reviewed suggests an urgent need for prioritizing reviews for these drugs. 8 9 10 Moreover, systematic reviews evaluating the effectiveness and safety of some EMA 11 12 approved orphan drugs are now outdated because more recent clinical trials have become 13 14 available, and consequently such reviews need to be updated. Given the value of systematic 15 For peer review only 16 reviews for clinicians and health policy makers, we suggest that the formation of a Cochrane 17 18 19 Collaboration review group focused on orphan drugs as one way of improving these gaps. . 20 21 22 23 In addition, further independent and industryfunded trials are also warranted, especially for 24 25 drugs which currently have poor quality and level of evidence. Clinical trial investigators 26 27 should adequately report any suspected adverse events observed in the course of trials; and 28 29 30 statements made in some primary studies that such events, if any, were not related to the drug 31 32 in question (or not serious enough) may be premature. The importance of close postapproval

33 http://bmjopen.bmj.com/ 34 monitoring cannot be overemphasized. Finally, given the inconsistencies we found in drug 35 36 costs, a more detailed and transparent analysis of the relationship between R & D costs and 37 38 annual costs of orphan drugs is now imperative. 39 40 41 on September 28, 2021 by guest. Protected copyright. 42 43 Implications for policy 44 45 The use of novel therapeutic agents has resulted in improvements in clinical outcome for 46 47 several orphan diseases. It is also rational that drug companies should aim to make recoup 48 49 50 investment in R&D costs through sales and reimbursements for these drugs, even though the 51 20 52 size of the market for such drugs is quite small. However, the overall benefits on both 53 54 clinical and economic terms need to be taken into consideration when setting prices.21 In fact, 55 56 unfavorable costtobenefit analysis has led to the rejection of orphan drug approval 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 59 BMJ Open

15 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 applications by the UK National Institute for Health and Care Excellence.22,23 More recently, 4 5 NHS England threatened to stop purchasing some orphan drugs used for cancer management, 6 7 24 unless the manufacturers reduced their prices. 8 9 10 11 12 The high costs of orphan drugs are reportedly due to the large amounts of funds invested in 13 14 R&D by the drug manufacturers.25 However, Light and Lexchin26 reported that drug 15 For peer review only 16 companies spend only 1.3% of their revenue on basic research in order to discover novel 17 18 molecules. In addition, the disparity in prices when these branded drugs are compared with 19 20 21 their generic versions makes it doubtful if the quoted R&D costs are sufficiently robust. For 22 23 example, Pedea costing 82,000 times as much as generic ibuprofen. It is unclear the extent to 24 25 which the incentives offered by the EMA and other drug regulatory authorities to encourage 26 27 the development of these drugs influenced the prices of these branded drugs. Furthermore, 28 29 30 research evidence has shown that Pedea is no superior to oral ibuprofen in clinical 31 27 32 effectiveness regarding closure of PDA. This raises the question of whether large national

33 http://bmjopen.bmj.com/ 34 health systems like the NHS should choose generic versions of orphan drugs where available, 35 36 particularly given current pressure on health care expenditures.28 In 2013 for example, the 37 38 drug company Novartis AG lost its patenting right for Glivec (imatinib) in India largely due 39 40 29 41 to its very high price compared with its generic alternative. on September 28, 2021 by guest. Protected copyright. 42 43 44 45 The marketing authorizations granted some orphan drugs such as Ceplene, Firdapse and 46 47 Xaluprine were based on a historical perspective, i.e., these compounds have previously been 48 49 30 50 used in patient management prior to being designated with orphan status. Therefore, in 51 52 cases such as these, it does not seem plausible for drug companies to claim huge R&D costs 53 54 because they are not new therapies. Indeed, the approval application of Ceplene for its 55 56 designation as an orphan drug was refused in Canada due to a failure of the drug company to 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 59

16 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 prove that its development was innovative.31 Similarly, it would be expected that the prices of 4 5 drugs for which there are alternative therapeutic options for their stated indications be 6 7 competitively based. 8 9 10 11 12 The postapproval withdrawal of some orphan drugs suggests that pre and postmarketing 13 14 surveillance is not stringently assessed (or evaluated) during the clinical trial and drug 15 For peer review only 16 approval process. For example, Onsenal (celecoxib) was also withdrawn eight years post 17 18 approval after it was discovered that the risks outweighed its benefits in its use for managing 19 20 32 21 familial adenomatous polyposis. Thelin (sitaxentan) lost its orphan designation (and was 22 33 23 withdrawn from the market) due to fatal hepatotoxicity ; clinical trial results had shown that 24 25 the drug had adverse effects on the liver, but these were not considered serious enough to 26 27 prevent its approval. The serious adverse events associated with some of approved drugs lend 28 29 credence to the view that safety does not appear to be a factor when determining the costs of 30 31 32 the drugs.

33 http://bmjopen.bmj.com/ 34 35 36 CONCLUSION 37 38 There is inconsistency in the level and quality of evidence for approved orphan drugs. While 39 40 41 some orphan drugs have demonstrated evidence of significant benefits, evidence of on September 28, 2021 by guest. Protected copyright. 42 43 effectiveness is lacking for several others, and some are associated with serious unwanted 44 45 adverse effects. The available evidence suggests that except for the ultraorphan diseases, the 46 47 annual costs of orphan drugs approved in Europe are not influenced by the disease 48 49 prevalence. There is inadequate data to determine whether clinical effectiveness influences 50 51 52 the price setting of orphan drugs. Further research into the effectiveness and safety of orphan 53 54 drugs is required, and a standard, transparent and robust mechanism for determining their 55 56 prices should be a priority. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 59 BMJ Open

17 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Authors’ contribution 4 5 IJO was involved with literature searches, data extraction, data analysis and interpretation, 6 7 and codrafting of the review. EAS was involved with literature searches, data extraction, 8 9 10 data analysis, and codrafting of the review. MJT was involved with data analysis and 11 12 interpretation, and codrafting of the review. CJH was involved with data analysis and 13 14 interpretation, and codrafting of the review. 15 For peer review only 16 17 18 19 Competing interests 20 21 Prof Heneghan receives payment for running educational courses at the University of Oxford 22 23 and University of Oxford ISIS consulting services for external teaching and training. He also 24 25 receives royalties for books (Evidence Based Toolkit series by Blackwell BMJ Books). 26 27 Dr. Onakpoya, Dr. Spencer and Prof. Thompson have no interests to disclose. 28 29 30 31 32 Funding

33 http://bmjopen.bmj.com/ 34 This research was funded by the National Institute for Health Research (NIHR) School for 35 36 Primary Care Research (SPCR). 37 38 39 40 41 Disclaimer on September 28, 2021 by guest. Protected copyright. 42 43 This article presents independent research funded by the National Institute for Health 44 45 Research (NIHR). The views expressed are those of the author(s) and not necessarily those 46 47 of the NHS, the NIHR or the Department of Health. 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 59

18 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 REFERENCES 4 5 6 1 Dear JW, Lilitkarntakul P, Webb DJ. Are rare diseases still orphans or happily adopted? 7 8 9 The challenges of developing and using orphan medicinal products. BJCP 2006; 623: 264 10 11 271. 12 13 2 Sharma A, Jacob A, Tandon M, Kumar D. Orphan drug: Development trends and 14 15 strategies.For J Pharm Bioallied peer Sci. 2010 review Oct;2(4):2909. doi: 10.4103/09757406.72128only 16 17 3 18 European Medicines Agency (EMA): Orphan drugs and rare diseases at a glance. 19 20 http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500069805. 21 22 pdf 23 24 4 National Institute for Clinical Excellence. NICE Citizens Council Report Ultra Orphan 25 26 Drugs. London, NICE, 2004. 27 28 29 http://www.nice.org.uk/niceMedia/pdf/Citizens_Council_Ultraorphan.pdf 30 31 5 Hughes DA, Tunnage B, Yeo ST. Drugs for exceptionally rare diseases: do they deserve 32

33 special status for funding? QJM 2005; 98: 829836. http://bmjopen.bmj.com/ 34 35 6 Simoens S, Cassiman D, Picavet E, Dooms M. Are some orphan drugs for rare diseases 36 37 38 too expensive? A study of purchase versus compounding costs. Drugs and Therapy 39 40 Perspectives 2011; 27(10): 2426. 41 on September 28, 2021 by guest. Protected copyright. 42 7 Hawkes N, Cohen D. What makes an orphan drug? BMJ. 2010 Nov 16;341:c6459. 43 44 8 Scherer FM. The Pharmaceutical Industry Price and Progress. N Engl J Med 2004; 351: 45 46 927932. 47 48 49 9 van Ekdom L. Price setting orphan drugs. Identifying the influential factors on the price 50 51 setting of Orphan Drugs. Msc thesis, 2006. Available at: 52 53 http://www.ppge.ufrgs.br/ats/disciplinas/1/vanekdom2006.pdf [Accessed 20th March, 54 55 2013]. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 59 BMJ Open

19 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 10 McCabe C, Claxton K, Tsuchiya A. Orphan drugs and the NHS: should we value rarity? 5 6 BMJ 2005;331:1016–9. 7 8 9 11 Kanters TA, de SonnevilleKoedoot C, Redekop WK, Hakkaart L. Systematic review of 10 11 available evidence on 11 highpriced inpatient orphan drugs. Orphanet J Rare Dis. 2013; 12 13 8(1):124. doi: 10.1186/175011728124. 14 15 12 Joppi R, Bertele'For V, Garattinipeer S. Orphan review drugs, orphan diseases. only The first decade of orphan 16 17 drug legislation in the EU. Eur J Clin Pharmacol. 2013; 69(4):100924. 18 19 20 13 Cheng MM, Ramsey SD, Devine EB, Garrison LP, Bresnahan BW, Veenstra DL. 21 22 Systematic review of comparative effectiveness data for oncology orphan drugs. Am J 23 24 Manag Care. 2012; 18(1):4762. 25 26 14 Orphanet Report Series. Orphan drug collection. List of medicinal products for rare 27 28 29 diseases in Europe. April, 2014. Available at: 30 31 http://www.orpha.net/orphacom/cahiers/docs/GB/list_of_orphan_drugs_in_europe.pdf. 32

33 [Accessed 24th April, 2014]. http://bmjopen.bmj.com/ 34 35 15 Orphanet Report Series Prevalence of rare diseases: Bibliographic data. Available at: 36 37 http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphab 38 39 40 etical_list.pdf 41 on September 28, 2021 by guest. Protected copyright. 42 16 Orphanet: The portal for rare diseases and orphan drugs. Available at: 43 44 http://www.orpha.net/consor/cgibin/index.php?lng=EN 45 46 17 OCEBM Levels of Evidence Working Group*. "The Oxford 2011 Levels of Evidence". 47 48 49 Oxford Centre for EvidenceBased Medicine. http://www.cebm.net/index.aspx?o=5653 50 51 18 Guyatt GH1, Oxman AD, Vist GE, Kunz R, FalckYtter Y, AlonsoCoello P, Schünemann 52 53 HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of 54 55 evidence and strength of recommendations. BMJ 2008; 336: 924926. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 59

20 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 19 European Medicines Agency. European public assessment reports. Available at: 5 6 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp& 7 8 9 mid=WC0b01ac058001d125 10 11 20 Drummond MF, Wilson DA, Kanavos P, Ubel P, Rovira J. Assessing the economic 12 13 challenges posed by orphan drugs. Int J Technol Assess Health Care 2007; 23:3642. 14 15 21 Picavet E,For Morel T, Cassimanpeer D, Simoens review S. Shining a light only in the black box of orphan 16 17 drug pricing. Orphanet J Rare Dis. 2014 Apr 27;9:62. 18 19 20 22 UK cost agency says "no" to Novartis blood cancer drug Jakavi. Available from: 21 22 http://www.reuters.com/article/2013/02/13/usnovartisbritainjakavi 23 24 idUSBRE91C00Y20130213 [Accessed March 1st, 2013]. 25 26 23 Pharmafile. NICE rejects Pfizer blood cancer drug. 16/07/2013. 27 28 29 http://www.pharmafile.com/news/180127/nicerejectspfizerbloodcancerdrug [Accessed 30 31 25th April, 2014] 32

33 24 BBC News Health. NHS England push to rein in cancer drug prices. http://bmjopen.bmj.com/ 34 35 http://www.bbc.co.uk/news/health28938022 [Accessed 28th August, 2014] 36 37 25 Simoens S. Pricing and reimbursement of orphan drugs: the need for more transparency. 38 39

40 Orphanet J Rare Dis 2011, 6:42. doi:10.1186/17501172642 41 on September 28, 2021 by guest. Protected copyright. 42 26 Light DW, Lexchin J. Foreign free riders and the high price of US medicines. BMJ 2005; 43 44 331: 95860. 45 46 27 Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or 47 48 49 intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a 50 51 systematic review and metaanalysis. Neonatology. 2012;102(1):915 52 53 28 Gov.Uk. Policy. Making NHS more efficient and less bureaucratic. March 25, 2013. 54 55 Available from: https://www.gov.uk/government/policies/makingthenhsmoreefficient 56 57 andlessbureaucratic [Accessed 21st May, 2013]. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 59 BMJ Open

21 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 29 BBC News. Novartis: India rejects patent plea for cancer drug Glivec. Available from: 5 6 http://www.bbc.co.uk/news/business21991179 [Accessed 1st April, 2013]. 7 8 30 9 Wirtz PW, van Dijk JG, van Doorn PA et al. The epidemiology of the LambertEaton 10 11 myasthenic syndrome in the Netherlands. Neurology 2004;63:3978. 12 13 31 Epicept Corporation v. Canada (Health). 2010 FC 956, [2010] 4 F.C.R. D9. 14 15 http://reports.fja.gc.ca/eng/2010/2010fc956.pdfFor peer review [Accessed 3rdonly September, 2014] 16 17 18 32 European Medicines Agency. Assessment Report for Celecoxib for the reduction of the 19 20 number of adenomatous intestinal polyps in familial adenomatous polyposis, as an adjunct 21 22 to surgery and further endoscopic surveillance. Available from: 23 24 http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/06/WC500107627 25 26 .pdf [Accessed 28th January, 2013]. 27 28 29 33 European Medicines Agency. Thelin (sitaxentan) to be withdrawn due to cases of 30 31 unpredictable serious liver injury. Available from: 32

33 http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/12/WC5000 http://bmjopen.bmj.com/ 34 35 99707.pdf [Accessed 22nd February, 2013]. 36 37 38 39 40 41 on September 28, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

Figure 1: Flow chart showing process BMJfor inclusionOpen of EMA-approved orphan drugs Page 22 of 59

1 2 3 4 5 6 7 8 For peer review only 9 10 11 12 http://bmjopen.bmj.com/ 13 14 15 16 17 18 19

20 on September 28, 2021 by guest. Protected copyright. 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

PageFigure 23 of 59 2: Pie charts showing the levels and quality of evidenceBMJ Open of EMA-approved orphan drugs by proportion1,2

1 2 3 4 5 6 7 8 2a: Levels of evidenceFor peer review only2b: Quality of evidence 9 10 5% 11 12 http://bmjopen.bmj.com/ 13 19% 22% 14 Moderate 15 34% Low 16 Level 1 17 Level 2 Very low 18 Level 3 19

73% on September 28, 2021 by guest. Protected copyright. 20 21 47% 22 23 24 None of the approved drugs showed evidence of high overall quality. Of 25Of the 29 drugs approved for treatment of cancers, 7 (24.1%) had Level 1 the 29 drugs approved for treatment of cancers, 18 (62.1%) had moderate 26evidence, 16 (55.2%) had Level 2, and 6 (20.7%) were Level 3. Of the 24 quality, 10 (34.5%) had low quality, and 1 (3.4%) was very low in quality. 27drugs approved for treatment of inborn errors of metabolism, 11 (45.8%) Of the 24 drugs approved for treatment of inborn errors of metabolism, 17 28had Level 1 evidence, 7 (29.2%) had level 2, and 6 (25.0%) were Level 3. 29 (70.8%) had moderate quality, 4 (16.7%) had low quality, and 3 (12.5%) 30 were very low in quality. 31 32 331The level of available evidence regarding effectiveness was determined using the Oxford Centre for Evidence Based Medicine (OCEBM) Levels of Evidence [16] which comprises four levels: Level 1: systematic 34reviews; Level 2: randomized trial or observational study with dramatic effect; non-randomized controlled cohort/follow-up study; Level 3: case-series, case-control studies, or historically controlled studies; Level 4: 35mechanism-based reasoning. The levels of evidence could be graded down on the basis of study quality, imprecision, indirectness, inconsistency between studies, or very small absolute effect sizes; levels were graded 36up if there was a large or very large effect size. In the OCEBM system, a systematic review is generally better than an individual study.

372The quality and strength of the overall body of evidence for each orphan drug was evaluated using a checklist adapted from the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) 38criteria [17] which assesses the five domains: study design; consistency of evidence; directness of the evidence; precision; and reporting biases. Based on the quality of overall evidence, 1 of 4 possible grades could be 39allocated: high, moderate, low, and very low. 40 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

Figure 3: Scatter plot of orphan disease prevalence againstBMJ annual Open cost. The p value of the relationship was 0.01;Page 24 of 59 when the ultra-orphan diseases are removed from this plot, p value was 0.18. 1 2 60 3 4 14 5 6 12 7 50 8 For peer review only 9 10 10 R² = 0.0081 11 8 12 http://bmjopen.bmj.com/ 13 40 6 14 15 4 16 17 2 18 19 30

20 0 on September 28, 2021 by guest. Protected copyright. 21 0 10000 20000 30000 40000 50000 60000 22 23 24

25 100,000per Prevalence 20 26 27 28 29 30 10 31 32 33 34 35 36 0 37 0 50000 100000 150000 200000 250000 300000 350000 400000 38 39 40 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtmlAnnual cost (£) 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

PageFigure 25 of 59 4: Scatter plot of ultra-orphan disease prevalenceBMJ against Open annual cost. The p value of the relationship was 0.04

1 2 3 4 1.2 5 6 7 8 For peer review only 9 10 1 11 12 http://bmjopen.bmj.com/ 13 14 15 0.8 16 17 18 19

20 on September 28, 2021 by guest. Protected copyright. 21 0.6 22 23 24 25 26 Prevalence per 100,000per Prevalence 0.4 27 28 29 R² = 0.1933 30 31 0.2 32 33 34 35 36 37 0 38 0 50,000 100,000 150,000 200,000 250,000 300,000 350,000 400,000 39 40 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtmlAnnual cost (£) 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

Figure 5: Price comparison of branded orphanBMJ Open drugs versus generic/unlicensed versions Page 26 of 59

1 Ratio of annual cost of orphan drugs versus generics 2 2100 3 Mercaptopurine 1.4 1560 4 5 6 1800 Celecoxib 2.6 7 690 Branded orphan drugs 8 For peer review only 9 Generic/unlicensed 2920 10 Hydrocortisone 3.0 versions 973 11 12 http://bmjopen.bmj.com/ 13 46580 Betaine anhydrous 5.0 14 9316 15 16 726 17 Zinc acetate 5.5 132 18 19 20 4482 on September 28, 2021 by guest. Protected copyright. Sildenafil 6.0 21 750 Orphan drugOrphan 22 23 6084 24 Hydroxycarbamide 10.0 608 25 26 27 47000 Amifampridine 60.0 28 783 29 30 2630 31 Aminolevulinic acid 18 146.0 32 33 34 6575 *Ibuprofen 35 0.08 82000.0 36 37 0 5000 10000 15000 20000 25000 30000 35000 40000 45000 50000 38 39 40 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtmlAnnual cost (£) 41 42 *Cost for 0.01 gramme of drug 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 27 of 59 BMJ Open

1 2 3 Appendix 1: Level and quality of evidence with relevant references for EMA-approved orphan drugs 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 5 6 Orphan drug Active ingredient †Level ‡Quality Reference 7 Adcetris Brentuximab vedotin 3 L [1,2] 8 Adempas Riociguat 2 M [3] 9 10 Arzerra Ofatumumab 1 L [4] 11 Atriance Nelarabine 3 L [5,6,7] 12 Bosulif Bosutinib (monohydrate) 3 L [8] 13 Bronchitol Inhaled mannitol 1 M [9] 14 Carbaglu Carglumic acid 3 VL [10] 15 Cayston Aztreonam 1 M [11] 16 Ceplene Histamine dihydrochloride 2 L [12] 17 For peer review only 18 Cholic Acid FGK Cholic acid 3 VL [13] 19 Cometriq Cabozantinib 2 L [14] 20 Cystadane Betaine anhydrous 3 VL [15,16] 21 Dacogen Decitabine 2 M [17,18,19] 22 Defitelio Defibrotide 1 L [20] 23 Diacomit Stiripentol 2 M [21] 24 Elaprase Idursulfase 1 M [22] 25 Esbriet Pirfenidone 1 M [23] 26 27 Evoltra Clofarabine 3 VL [24,25] 28 Exjade Deferasirox 1 M [26,27] 29 Firazyr Icatibant acetate 1 M [28] 30 Firdapse Amifampridine 1 L [29] 31 Gliolan 5-aminolevulinic acid 2 M [30] 32 Glybera Alipogene tiparvovec 2 M [31,32] 33 Iclusig Ponatinib 3 L [33] 34 Increlex Mecasermin 2 M [34] 35 36 Inovelon Rufinamide 1 M [35] 37 Jakavi Ruxolitinib 2 M [36,37] 38 Kalydeco Ivacaftor 1 M [38] http://bmjopen.bmj.com/ 39 Kuvan Sapropterin 1 M [39] 40 Litak Cladribine 2 M [40,41,42,43,44] 41 Lysodren Mitotane 2 M [45,46] 42 Mepact Mifamurtide 2 L [47] 43 Mozobil Plerixafor 2 M [48,49] 44 45 Myozyme Alglucosidase alfa 1 M [50] 46 Naglazyme Gasulfase 1 L [51] on September 28, 2021 by guest. Protected copyright. 47 Nexavar Sorafenib 1 M [52,53,54,55] 48 Nexobrid Bromelain 3 L [56,57] 49 Nplate Romiplostim 2 M [58,59] 50 Onsenal Celecoxib 2 M [60,61] 51 Orfadin Nitisinone 3 M [62,63,64] 52 Pedea IV Ibuprofen 1 M [65] 53 54 Peyona Caffeine citrate 2 M [66,67] 55 Photobarr Porfimer sodium 2 M [68,69] 56 Plenadren Hydrocortisone 2 M [70,71] 57 Prialt Ziconotide 2 M [72,73] 58 Procysbi Mercaptamine bitartrate 2 L [74] 59 Revatio Sildenafil I M [75,76] 60 Revestive Teduglutide 2 M [77,78] Revlimid Lenalidomide 2 M [79,80,81]

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 59

1 2 3 Rilonacept Regeneron Rilonacept 2 M [82] 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 5 Savene Dexrazoxane 3 M [83] 6 Signifor Pasireotide 3 M [84] 7 Siklos Hydroxycarbamide 1 M [85] 8 Sirturo Bedaquiline fumarate 2 M [86] 9 Soliris Eculizumab 2 M [87,88,89] 10 Sprycel Dasatinib 1 L [90] 11 Tasigna Nilotinib 1 L [90] 12 Tepadina Thiotepa 2 M [91,92,93,94,95] 13 14 Thalidomide Celgene Thalidomide 1 M [96] 15 Thelin Sitaxentan sodium 1 H [97,98,99,100] 16 Tobi Podhaler Tobramycin 1 M [101] 17 Torisel ForTemsirolimus peer review1 M only[55,102,103] 18 Tracleer Bosentan 1 M [75,76,104,105] 19 Trisenox Arsenic Trioxide 2 M [106,107,108] 20 Ventavis Iloprost 1 M [75,76,109] 21 Vidaza Azacitidine 1 M [110,111] 22 23 Volibris Ambrisentan 2 M [112] 24 Votubia Everolimus 2 M [17,18] 25 Vpriv Velaglucerase alfa 2 M [113,114] 26 Vyndaqel Tafimidis 2 M [115] 27 Wilzin Zinc acetate dihydrate 3 L [116,117,118] 28 Xagrid Anagrelide 2 M [119,120] 29 Xaluprine Mercaptopurine 2 M [121,122] 30 Yondelis Trabectedin 2 M [123,124,125,126] 31 32 Zavesca Miglustat 2 M [127,128,129,130,131] 33 34 35 † Adapted from the Oxford Centre for Evidence-Based Medicine tool kit. 1: Systematic review of randomized trials or 36 n-of-1 trials; 2: Randomized trial or observational study with dramatic effect; 3: Non-randomized controlled 37 cohort/follow-up study; 4: Case-series, case-control studies, or historically controlled studies; 5: Mechanism-based http://bmjopen.bmj.com/ 38 reasoning 39 40 ‡ Adapted from GRADE tool kit. H: high quality - Further research is very unlikely to change our confidence in the 41 estimate of effect; M: moderate quality - Further research is likely to have an important impact on our confidence in the 42 estimate of effect and may change the estimate; L: low quality - Further research is very likely to have an important 43 impact on our confidence in the estimate of effect and is likely to change the estimate; VL: Very low quality - Any 44 45 estimate of effect is very uncertain 46 on September 28, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective 5 6 randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab 97: 473–481 7 71 Benson S, Neumann P, Unger N, Schedlowski M, Mann K, Elsenbruch S, Petersenn S (2012) Effects of 8 9 standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, 10 crossover study in patients with secondary adrenal insufficiency. Eur J Endocrinol 167(5): 679-85. 11 12 72 Rauck RL, Wallace MS, Leong MS, Minehart M, Webster LR, Charapata SG, Abraham JE, Buffington DE, 13 Ellis D, Kartzinel R; Ziconotide 301 Study Group (2006) A randomized, double-blind, placebo-controlled 14 15 study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage 31(5):393-406. 16 73 Wallace MS, Charapata SG, Fisher R, Byas-Smith M, Staats PS, Mayo M, McGuire D, Ellis D; Ziconotide 17 For peer review only 18 Nonmalignant Pain Study 96-002 Group (2006) Intrathecal ziconotide in the treatment of chronic 19 nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation 9(2): 75- 20 21 86 22 74 Langman CB, Greenbaum LA, Sarwal M, Grimm P, Niaudet P, Deschênes G, Cornelissen E, Morin D, 23 24 Cochat P, Matossian D, Gaillard S, Bagger MJ, Rioux P. A randomized controlled crossover trial with 25 delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine 26 27 levels and comparison of safety. Clin J Am Soc Nephrol. 2012 Jul;7(7):1112-20 28 75 He B, Zhang F, Li X, Tang C, Lin G, Du J, Jin H (2010) Meta-analysis of randomized controlled trials on 29 30 treatment of pulmonary arterial hypertension. Circ J 74(7): 1458-64 31 76 Chen YF, Jowett S, Barton P, Malottki K, Hyde C, Gibbs JS, Pepke-Zaba J, Fry-Smith A, Roberts J, Moore 32 D (2009) Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for 33 34 pulmonary arterial hypertension within their licensed indications: a systematic review and economic 35 evaluation. Health Technol Assess 13(49): 1-320 36 37 77 Jeppesen PB, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O'keefe SJ, Forbes A, Heinze H, Joelsson B 38 http://bmjopen.bmj.com/ (2012) Teduglutide reduces need for parenteral support among patients with short bowel syndrome with 39 40 intestinal failure. Gastroenterology 6: 1473–1481 41 78 Jeppesen PB, Gilroy R, Pertkiewicz M, Allard JP, Messing B, O'Keefe SJ (2011) Randomised placebo- 42 43 controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in 44 patients with short bowel syndrome. Gut 60(7): 902-14. 45 46 79 Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, on September 28, 2021 by guest. Protected copyright. 47 Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple 48 49 Myeloma (010) Study Investigators (2007) Lenalidomide plus dexamethasone for relapsed or refractory 50 multiple myeloma. N Engl J Med 357: 2123-32 51 52 80 Dimopoulos M, Alegre A, Stadtmauer EA, Goldschmidt H, Zonder JA, de Castro CM, Masliak Z, Reece D, 53 Olesnyckyj M, Yu Z, Weber DM (2010) The efficacy and safety of lenalidomide plus dexamethasone in 54 55 relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer 116(16): 3807-14 56 81 Chanan-Khan AA, Lonial S, Weber D, Borrello I, Foà R, Hellmann A, Dimopoulos M, Swern AS, Knight R 57 58 (2012) Lenalidomide in combination with dexamethasone improves survival and time-to-progression in 59 patients ≥65 years old with relapsed or refractory multiple myeloma. Int J Hematol 96(2): 254-62 60 82 Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, Weinstein SP, Belomestnov P, Yancopoulos GD, Stahl N, Mellis SJ (2008) Efficacy and safety of rilonacept (interleukin-1 Trap) in patients

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1 2 3 APPENDIX 2: Summary of evidence tables and annual costs of orphan drugs approved by the EMA 4 5 6 Table 1: Summary of evidence and main results of orphan drugs for the management of cancers 7 Orphan drug Active ingredient Indication 1Level of 2Quality of Annual cost Summary of main results Severe adverse events (SAEs) 8 evidence evidence per patient (£) 9 Adcetris Brentuximab CD30⁺ Hodgkins & ALCL 3 Low 42,500 Median OS for Hodgkins was 40.5 mos (95% CI: 28.7, – [range, 1.8 Anaemia, neutropenia, thrombocytopenia, 10 vedotin to 48.3+ mos]) and the estimated 36-mo survival rate was 54% (44 to peripheral sensory neuropathy 11 For peer review64). Median OS not reached only for ALCL 12 13 Arzerra Ofatumumab Resistant CLL 1 Low 40,586 Insufficient evidence; impact on OS unclear Infections, neutropenia

14 Atriance Nelarabine T-ALL & T-LBL 3 Low 50,000 Response rates 31-50%; insufficient evidence on OS; severe Neurotoxicity, thrombocytopenia, neutropenia 15 toxicities 16 http://bmjopen.bmj.com/ 17 Bosulif Bosutinib Ph+ CML 3 Low 44,799 PFS at 2 years was 79%; overall survival at 2 years was 92% Thrombocytopenia, neutropenia, anemia, diarrhea, vomitting, rash, increased AST 18 19 Ceplene Histamine Acute myeloid leukemia 2 Low 35,450 Over 3 years, sig ↑ leukaemia-free survival vs control group (p < Headache, pyrexia 20 dihydrochloride 0.01). No sig effects on OS 21 Cometriq Cabozantinib Metastatic medullary thyroid 2 Low 70,664 PFS was 11.2 months for cabozantinib versus 4.0 months for placebo Diarrhea, palmarplantar erythrodysesthesia, and 22 CA (HR= 0.28; 95% CI, 0.19 to 0.40; p < 0.001); no statistically sig fatigue, GIT perforations, fistula development, 23 difference in OS (HR= 0.98; 95% CI: 0.63 to 1.52) and hemorrhage, mucosal inflammation, 24 hypocalcemia, pulmonary embolism, 25 on September 28, 2021 by guest. Protected copyright. hypertension

26 Dacogen Decitabine Acute myeloid leukemia 2 Moderate 58,300 Sig ↑ in PFS vs control (3.7 months: 2.7 to 4.6). No sig effect on OS Sig ↑ in risk of SAE compared with placebo (p = 27 compared with controls (p = 0.11). 1 RCT discontinued due to ↑d 0.002) 28 relapse rates 29 Evoltra Clofarabine Acute lymphoblastic 3 Very low 43,200 Response rates of 30-44%; no data on PFS; limited data on OS Infections, multiorgan failure, hepatotoxicity, 30 leukemia death 31 Gliolan 5-ALA Malignant glioma 2 Moderate 2,630 Sig diff in number of complete resections compared with None 32 conventional white light (p < 0.0001). Higher 6 month PFS 33 compared with white light (p = 0.0003); sig ↑ in OS

34 35 Iclusig Ponatinib Chronic myeloid leukemia 3 Low 68440 PFS 55% at 12 months; OS 84% at 12 months Pancreatitis, abd pain, increased lipase, diarrhea, 36 fever, MI, thrombocytopenia, anemia, 37 neutropenia, febrile neutropenia, pancytopenia. 18 deaths in study; 5 of which were attributed to 38 ponatinib 39 Imnovid Pomalidomide Multiple myeloma 2 Moderate 105600 Median PFS vs dexamethasone was 4 vs 1.9 months (HR = 0.48; Significant increase in risk of neutropenia and 40 95% CI: 0.39 to 0.60; p < 0.0001); Median OS 12.7 vs 8.1 months pneumonia 41 (HR=0.74; 95% CI: 0.56 to 0.97; p=0.0285) 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 4 Jakavi Ruxolitinib Primary myelofibrosis 2 Moderate 43,200 Sig ↓ in reduction of splenic vol compared with placebo (p < 0.001 ); Anemia, neutropenia, thrombocytopenia; ↑d in 5 trend towards ↑d OS ( p = 0.076; 0.009 at 3 yrs) risk of hematologic SAEs compared with 6 placebo (p < 0.0001)

7 Litak Cladribine Hairy cell leukemia 2 Moderate 35,000 Improved rates of OS. 12 year survival rate of 79% in one study Asthenia, fever, rigor 8 9 Lysodren Mitotane Adrenocortical CA 2 Moderate 51,900 Improvement on the duration of tumor regression. Estimate on Fever, rigor 10 overall survival not precise (no studies comparing lysodren with placebo or other supportive therapies) 11 For peer review only 12 Mepact Mifamurtide Osteosarcoma 2 Low 92,000 Did not improve 3-year EFS rate compared with standard ↑d ALT 13 chemotherapy 14 Mozobil Plerixafor Multiple myeloma & NHL 2 Moderate 34,179 Sig ↑ in median CD34⁺ count compared with placebo (p < 0.001); no Diarrhea, fatigue 15 sig diff in OS 16 http://bmjopen.bmj.com/ 17 Nexavar Sorafenib Liver CA & Advanced RCC 1 Moderate 38,852 Improvement in PFS; sig improvement in OS compared with placebo Hand & foot syndrome, sig ↑in risk of 18 hypertension compared with placebo (p < 0.0001) 19 20 Onsenal Celecoxib Familial adenomatous 2 Moderate 1,800 Sig ↓ in incidence of adenoma compared with placebo at 5 years (p < Sig ↑ in risk of CVS and GI disorders compared 21 polyposis 0.001); reverse was the case at 2 years (p < 0.0001) with placebo (p = 0.034) 22 Revlimid Lenalidomide Multiple myeloma 2 Moderate 53,363 PFS significantly greater in revlimid compared with placebo (p < Sig ↑ in risk of hematological and thrombotic 23 0.0001); no sig diff in median OS SAE (p < 0.0001) 24 25 Savene Dexrazoxane Anthracycline extravasation 3 Moderate 6,750 Almost 100% ↓ in the need for surgical debridment on September 28, 2021 by guest. Protected copyright. Wound infection, neutropenia 26 Sprycel Dasatinib CML & resistant ALL 1 Low 32,000 Sig ↑ in PFS compared with imatinib in CML (p = 0.0012); ≥90% Fluid retention, dyspnea, pleural effusion, 27 complete remission in 2 non-RCTs for ALL; impact on OS unclear cytopenia, hemorrhage 28 29 Tasigna Nilotinib Chronic phase CML 1 Low 30,000 Rates of molecular and cytogenetic response significantly greater Thrombocytopenia, anemia, neutropenia, and 30 compared with imatinib (p < 0.001); impact on OS unclear asthenia

31 Tepadina Thiotepa HPCT 2 Moderate 20,608 Results from phase III RCTs have been mixed Cytopenia, hemorrhagic cystitis, acute and 32 chronic GvHD 33 34 Thalidomide Thalidomide Multiple myeloma 1 Moderate 25,200 Improved PFS & OS when combined with standard therapy (p = Sig ↑ in risk of VTE compared with control (p < Celgene 0.05) 0.0001) 35 36 Torisel Temsirolimus RCC & mantle cell 1 Moderate 36,000 Sig ↑ in OS & PFS compared with interferon in RCC; no sig effect Bowel perforation, neutropenia, anemia, 37 lymphoma on median OS in mantle cell lymphoma dyspnea, hyperglycemia 38 Vidaza Azacitidine Myelodysplastic syndromes 1 Moderate 45,000 Sig. improvement in OS compared with placebo Neutropenia, thrombocytopenia, anemia 39 40 Votubia Everolimus SECA assoc with TSC 2 Moderate 15,000 ↓d primary SECA vol by ≥ 50% in 35% of patients compared with Pneumonia, bronchitis, abscess 41 placebo (p < 0.0001) 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 4 Xaluprine Mercaptopurine Acute lymphoblastic 2 Moderate 2,100 Sig diff in duration of remission vs placebo (p < 0.01); no sig diff in Hypersensitivity, thrombocytopenia 5 leukemia median OS 6 Yondelis Trabectedin STS & ovarian neoplasm 2 Moderate 24,898 Improved OS compared with standard care (p = 0.02). Analyses for Rhabdomyolysis, neutropenia, ↑bilirubin, 7 platinum-resistant not specified congestive heart failure 8 9 Abbreviations: 10 ALCL: Anaplastic large cell lymphoma; FVC: forced vital capacity; 6MWD: 6-minute walk distance; CLL: chronic lymphocytic leukemia; OS: overall survival; T-ALL: T-cell acute lymphoblastic leukemia; T-LBL: T-cell 11 lymphoblastic lymphoma; 5-ALA: 5-aminolevulinic acid;For PFS: progression-free peersurvival; CML: chronic myeloid review leukemia; ALT: alanine transaminase; onlyAST: aspartate transaminase; NHL: non-hodgkins lymphoma; RCC: renal cell 12 carcinoma; HPCT: haematopoietic progenitor cell transplant; GvHD: graft versus host disease; VTE: venous thromboembolism; SECA: subependymal giant cell astrocytoma; TSC: tuberous sclerosis complex; STS: soft tissue sarcoma 13 14 15 16 http://bmjopen.bmj.com/ 17 18 19 20 21 22 23 24

on September 28, 2021 by guest. Protected copyright. 25 26 27 28 29 30 31 32 33

34 35 36 37

38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Table 2: Summary of evidence and main results of orphan drugs for management of inborn errors of metabolism and immune disorders 4 Orphan drug Active ingredient Indication 1Level of 2Quality of Annual cost Summary of main results Severe adverse events (SAE) 5 evidence evidence per patient (£) 6 7 Bronchitol Inhaled mannitol Cystic Fibrosis 1 Moderate 6,040 Sig ↑ in FEV1 vs placebo in adults (p < 0.001). No sig reduction in Nasopharyngeal pain, bronchospasm 8 pulmonary exacerbations

9 Carbaglu Carglumic acid Hyperammonaemia 3 Very low 245,000 ↓d blood ammonia conc. , ↓ in metabolic decompensation, ↓d None 10 neurological sequelae 11 For peer review only 12 Cayston Aztreonam Cystic Fibrosis 1 Moderate 15,399 Sig ↓ in Pseudomonas spp. density compared with placebo; no sig None-related diff on CFQ-RRS 13 14 Cholic acid Cholic acid IEM in primary bile acid 3 Very low N/A No statistically significant changes in urinary bile acids and No formal preclinical safety studies have been 15 FGK synthesis due to Sterol 27- transaminases conducted 16 hydroxylase Cystadane Betaine anhydrous Homocystinuria 3 Very low 46,580 No sig benefit on BMD; evidence from several casehttp://bmjopen.bmj.com/ series very Cerebral edema 17 limited 18 19 Elaprase Idursulfase Hunter syndrome 1 Moderate 309,660 Sig ↑ in 6MWD vs placebo (p =0.013); sig ↓ in spleen vol vs Carpal tunnel syndrome, airway obstruction, 20 placebo (p < 0.0001); no sig diff in FVC sleep apnea

21 Exjade Deferasirox Iron overload in beta-thalassemia 1 Moderate 25,000 Comparable in efficacy with deferoxamine Transient transaminitis 22 23 Firazyr Icatibant acetate Hereditary angioedema 1 Moderate 16740 Sig ↓ in recovery times from attacks vs placebo (p < 0.001) None 24

Glybera Alipogene Lipoprotein lipase deficiency 2 Moderate 216,150 Sig ↓ in serum TG's and chylomicrons compared on September 28, 2021 by guest. Protected copyright. with pre- Fever 25 tiparvovec treatment levels; sig ↓ in incidence of pancreatitis episodes 26 compared with pre-treatment levels 27 28 Increlex Mecasermin Insulin growth factor-1 deficiency 2 Moderate 18,000 Growth at 6 months was > 3 times that achieved with placebo Papilledema

29 Kalydeco Ivacaftor Cystic Fibrosis 1 Moderate 182,625 The mean difference in change in % of predicted FEV1 was 10.5 Epistaxis, diarrhea, asthenia 30 (95% CI: 8.5 to 12.5) % points in the adults' study and 10.0 (95% 31 CI 4.5 to 15.5) %points in the children's study at 48 weeks 32 Kuvan Sapropterin Hyperphenylalaninaemia 1 Moderate 36,336 Sig ↓ in serum PHA conc compared with placebo (p < 0.001) None 33 34 Myozyme Alglucosidase alfa Pompe disease 1 Moderate 230,000 ≥67% of patients were stabilized or had improvement in muscular Tracheal hemorrhage, emphysema, 35 and respiratory function; sig ↑ in 6MWT, FVC & maximum pneumothorax 36 expiratory pressure compared with placebo

37 Naglazyme Gasulfase Mucopolysaccharidosis VI 1 Low 170,000 No statistical difference compared with placebo in both 12MWT Anaphylaxis 38 and 3MSCT 39 40 Orfadin Nitisinone Hereditary tyrosinemia 1 3 Moderate 24,744 Sig ↓ in number of hospitalisations and liver transplantation Corneal opacities, convulsion, GI hemorrhage 41 compared with controls (p < 0.001) 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 4 Orphacol Cholic acid IEM in primary bile acid 3 Low N/A 500-fold ↓ in 3β -HSD; 30-fold ↓ in Δ4-3-oxo-R deficiency Well tolerated 5 synthesis due to Sterol 27- 6 hydroxylase Procysbi Mercaptamine Nephropathic cystinosis 2 Low 148659 Sig ↓in peak WBC cyctine level compared with conventional GI AEs were 3-fold greater with procysbi 7 bitartrate Cystagon 0.08±0.04 nmol 1/2 cystine/mg protein (95.8% CI: 0– 8 0.16) 9 Siklos Hydroxycarbamide Sickle cell disease 1 Moderate 6,085 Sig ↓ in no & severity of crises yearly compared with placebo (p < Neutropenia 10 0.001)

11 Soliris Eculizumab PNH & aHUS For 2 peerModerate 378review,000 Sig diff in stabilization ofonly Hb levels in the absence of transfusion Abdominal distension, renal impairment 12 compared with placebo in PNH (p < 0.0001); complete reversal of 13 aHUS post-transplantation 14 Tobi Podhaler Tobramycin Pseudomonas in cystic fibrosis 1 Moderate 1540 (28 days) Sig ↑in FEV1 compared with placebo (p = 0.002) Exacerbation of cystic fibrosis 15 16

Vpriv Velaglucerase alfa Gaucher's disease type 1 2 Moderate 146,660 Sustained maintenance of Hb conc, and platelet counts,http://bmjopen.bmj.com/ as well as Anaphylaxis 17 liver and spleen volumes; sig ↑ in BMD (p < 0.01) 18 Vyndaqel Tafimidis Transthyretin amyloidosis 2 Moderate 112,051 Trend toward more NIS-LL responders in the tafamidis group than Urinary tract infection 19 in the placebo group (p = 0.068) 20 21 Wilzin Zinc acetate Wilson's disease 3 Low 726 Sig ↑ in urinary copper excretion at 4 wks; slight ↓ in ALT, AST Safer compared with penicillamine 22 dihydrate and ϒ-GTP

23 Zavesca Miglustat Type 1 Gaucher disease & 2 Moderate 58,400 Sig ↑ in BMD (p < 0.001), no sig diff in Hb conc, as well as liver Diarrhea, weight loss 24 Niemann-Picks Disease Type C and spleen vol b/w groups in Gauchers; no sig diff between groups 25 for HSEM for NPD-C (p=0·091) on September 28, 2021 by guest. Protected copyright. 26 Abbreviations: 27 FVC: forced vital capacity; 6MWD: 6-minute walk distance; FEV1: forced expiratory volume in one minute; CFQ-RRS : cystic fibrosis questionnaire-revised respiratory score; BMD: bone mineral density; NIS-LL: Neuropathy 28 Impairment Score-Lower Limbs; ALT: alanine transaminase; AST: aspartate transaminase; TG: triglycerides; IGF-1 : Insulin growth factor-1; PHA: phenylalanine; 12MWT: 12-minute walk test; WBC: White blood cell count; 3MSCT: 3-minute stair climb test; 3β-HSD: 3β-hydroxy-Δ5-C -steroid oxido reductase ; PNH: paroxysmal nocturnal hemoglobinuria; aHUS: atypical haemolytic uremic syndrome; GTP: gamma-glutamyl transpeptidase; NPD- 29 27 ϒ- C: Niemann-Pick’s disease type C; HSEM: horizontal sadistic eye movement. 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Table 3: Summary of evidence and main results of orphan drugs for managing other conditions 4 Orphan drug Active ingredient Indication 1Level of 2Quality of Annual cost Summary of main results Severe adverse events (SAE) 5 evidence evidence per patient (£) 6 7 Adempas Riociguat PAH Class II to III 2 Moderate 53495 Sig ↑ in 6MWD vs placebo MD: 46m; 95% CI: 25 to 67; p < 0.001; Sig Syncope, gastritis, acute renal failure, 8 ↓ in pulm vascular resistance vs placebo MD: –246 dyn · sec · cm–5; hypotension 95% CI, –303 to –190; P<0.001 9 10 Revatio Sildenafil PAH Class II & III 1 Moderate 4482 Sig improvement in 6MWD compared with placebo (p < 0.001) Left ventricular dysfunction, postural 11 For peer review only hypertension 12 Tracleer Bosentan PAH III; digital ulcers 1 Moderate 19463 Sig ↑in 6MWD compared with placebo; sig ↓ in the number of new ↑LFTs 13 digital ulcers compared with placebo 14 15 Opsumit Macitentan PAH Class II to III 2 Moderate 27,979 Sig ↑ in 6MWD vs placebo (3mg macitentan: 16.8 m; 97.5% CI, −2.7 Haematemesis, sudden cardiac death, 16 to 36.4; P = 0.01) 10mg macitentan: 22.0 m; 97.5% CI, 3.2 to 40.8; P = cardiorespiratory failure, nasopharyngitis, 0.008). Time to death: 3mg HR=0.70; 97.5% CI: http://bmjopen.bmj.com/ 0.52 to 0.96; p = 0.01 anemia 17 and 10 mg HR = 0.55; 97.5% CI: 0.39 to 0.76; p < 0.001 18 19 Volibris Ambrisentan PAH III & III 2 Moderate 20088 Sig ↑in 6MWT compared with placebo (p < 0.005) Gastroenteritis, intracranial bleeding, 20 headache, facial edema

21 Diacomit Stiripentol SMEI, Dravet’s syndrome 2 Moderate 7600 Sig ↓ in freq of seizures vs placebo (p < 0.0001) Drowsiness 22 23 Defitelio Defibrotide Veno-occlusive disease (VOD) 1 Low Overall mean incidence of VOD compared with other was 4.7% vs None 24 13.7% (p < 0.005); no sig difference in severity (0.8% 95% CI, 0.2–

1.4) or RR (0.31; 95% CI, 0.09–1.06) of VOD on September 28, 2021 by guest. Protected copyright. 25 26 Esbriet Pirfenidone Idiopathic Pulm Fibrosis 1 Moderate 26172 Sig ↓ in risk of disease progression vs placebo (p = 0.002); sig Cardiotoxicity, respiratory infections 27 improvement in FVC and VC vs placebo (p = 0.0006). No evidence on 28 OS

29 Firdapse Amifampridine LEMS in adults 1 Low 47000 Sig improvements in QMG score & (CMAP); p < 0.0001) Rare 30 31 Inovelon Rufinamide Lennox Gastaut syndrome 1 Moderate 3000 Efficacious in doses up to 45mg/kg/day when used as adjunct; sig ↓ in Convulsion, weight loss 32 the incidence of seizures compared with placebo (p < 0.0001)

33 Nexobrid Bromelain Debridement 3 Moderate ? Sig ↓ in perceived full-thickness wound area & skin-graft use (p < Fever 34 0.0001) 35 36 Nplate Romiplostim Idiopathic thrombocytopenic 2 Moderate 40102 Sig ↑ in platelet response rate compared with placebo (p < 0.0001) Thrombosis purpura 37 Pedea IV Ibuprofen Patent ductus arteriosus 1 Moderate 6575 No advantage in closure rates compared with oral ibuprofen Comparable to oral ibuprofen 38 39 Peyona Caffeine citrate Primary apnea 2 Moderate 6300 Sig ↑ in rate of survival compared with placebo (p = 0.008); sig ↓in the NEC, seizures 40 incidence of severe retinopathy compared with placebo (p = 0.017) 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Plenadren Hydrocortisone Adrenal insufficiency 2 Moderate 2920 Sig ↓ in body weight, blood pressure and heart rate compared with Gastroenteritis, intracranial bleeding, 4 thrice daily hydrocortisone; limited evidence headache, facial edema 5 6 Prialt Ziconotide Intractable chronic pain 2 Moderate 20000 Sig ↓in pain compared with placebo (p < 0.04); sig ↑ in risk of SAE Dizziness, confusion, urinary retention, compared with placebo (p = 0.006) possible suicide link 7 8 Revestive Teduglutide Short-bowel syndrome 2 Moderate 200000 (US Sig improvement in graded response score (GRS) compared with Catheter-site infection and sepsis 9 estimates) placebo at high dose (p = 0.007) 10 Rilonacept Rilonacept Cryopyrin-associated periodic 2 Moderate 212000 (US Sig improvement in symptom score compared with placebo (p < None 11 Regeneron syndrome (CAPS) For peer estimates)review 0.0001) only 12 13 Signifor Pasireotide Cushing's disease 3 Moderate 47000 Sig ↓ in urinary cortisol levels at medium and high does (p < 0.001) Hyperglycemia, diabetes mellitus 14 Sirturo Bedaquiline Multi-drug resistant TB 2 Moderate N/A Sig ↓ in time to conversion to a -ve sputum culture compared with Diabetic ketoacidosis 15 fumarate PLA, HR= 11.8; 95% CI: 2.3 to 61.3; P = 0.003 16 http://bmjopen.bmj.com/ 17 Xagrid Anagrelide High risk essential 2 Moderate 5000 Significantly more patients in the hydroxyurea group reached the Arterial and venous thrombosis, hemorrhage 18 thrombocythemia primary end point at 39 months (p = 0.04)

19 Abbreviations: 20 PAH: pulmonary arterial hypertension; FVC: forced vital capacity; 6MWD: 6-minute walk distance; FEV1: forced expiratory volume in one minute; SMEI: severe myoclonic epilepsy in infancy; LEMS: Lambert-Eaton myoclonic 21 syndrome; QMG: Quantitative Myasthenia Gravis; CMAP: compound muscle action potential 22 23 24 25 on September 28, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 1 Based on the Oxford Centre for Evidence-Based Medicine criteria [16]. 1: Systematic review of randomized trials or n-of-1 trials; 2: Randomized trial or observational study with dramatic effect; 3: Non-randomized controlled 36 cohort/follow-up study; 4: Case-series, case-control studies, or historically controlled studies; 5: Mechanism-based reasoning 2 37 Based on the GRADE criteria [17]. High quality - Further research is very unlikely to change our confidence in the estimate of effect; Moderate quality - Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low quality - Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality - Any 38 estimate of effect is very uncertain 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Appendix 3: Mechanisms of action, approval dates, clinical effectiveness and annual costs for drugs approved for same orphan disease 4 5 Pulmonary Arterial Hypertension 6 Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) 7 ingredient 8 Adempas Riociguat Soluble guanylate cyclase (sGC) 27/03/2014 Sig ↑ in 6MWD vs placebo MD: 46m; 95% CI: 25 to 67; p < Syncope, gastritis, acute renal failure, hypotension 53,495 stimulator 0.001; Sig ↓ in pulm vascular resistance vs placebo MD: –246 dyn 9 · sec · cm–5; 95% CI, –303 to –190; p<0.001 10 11 Opsumit Macitentan Endothelin-receptor antagonistFor 20/12/2013 peerSig ↑ in 6MWD vs placebo review (3mg macitentan: 16.8 m; 97.5% CI, onlyNS 27,979 12 −2.7 to 36.4; P = 0.01) 10mg macitentan: 22.0 m; 97.5% CI, 3.2 to 40.8; P = 0.008). Time to death: 3mg HR=0.70; 97.5% CI: 0.52 to 13 0.96; p = 0.01 and 10 mg HR = 0.55; 97.5% CI: 0.39 to 0.76; p < 14 0.001 15 Revatio Sildenafil Phosphodiesterase inhibitor 28/10/2005 Sig ↑ in 6MWD compared with placebo (p < 0.001); sig ↓ in Left ventricular dysfunction, postural hypertension 4,482 16 clinical worsening compared with placebo (p = 0.02) http://bmjopen.bmj.com/ 17 Tracleer Bosentan Endothelin-receptor antagonist 15/05/2002 Two RCTs showed sig ↑ in 6MWD (p < 0.001; 0.021) and time to ↑LFTs 19,463 18 clinical worsening compared with placebo (0.03 and 0.01) 19 20 Volibris Ambrisentan Endothelin-receptor antagonist 21/04/2008 Sig ↑in 6MWT compared with placebo (p < 0.005); sig ↓in clinical Gastroenteritis, intracranial bleeding, headache, facial edema 20,088 21 worsening (p < 0.001)

22 23 Multiple myeloma 24

Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events on September 28, 2021 by guest. Protected copyright. Annual cost (£) 25 ingredient 26 Imnovid Pomalidomide Direct inhibition of angiogenesis 05/08/2013 Median PFS vs dexamethasone was 4 vs 1.9 months (HR = 0.48; Significant increase in risk of neutropenia and pneumonia 105,600 27 and myeloma growth 95% CI: 0.39 to 0.60; p < 0.0001); Median OS 12.7 vs 8.1 months 28 (HR=0.74; 95% CI: 0.56 to 0.97; p=0.0285). Significant increase in risk of neutropenia and pneumonia 29 30 Mozobil Plerixafor Blocks ‘CXCR4 chemokine 31/07/2009 Sig ↑ in number of patients collecting ≥ 6 x 10⁶ CD34⁺ cells/kg Diarrhea, fatigue 34,179 31 receptor’ activity compared with placebo (p < 0.001); no sig diff in OS; several 32 adverse effects

33 Revlimid Lenalidomide Immunomodulation (IL-2, IL-6, 14/06/2007 PFS significantly greater in revlimid compared with placebo (p < Sig ↑ in risk of hematological and thrombotic SAE (p < 53,363 34 NK-cells) 0.0001). No sig diff between groups on median OS; sig ↑ in risk 0.0001) 35 of hematologic and thrombotic SAE 36 Thalidomide Thalidomide Immunomodulation (IL-2, IL-6, 16/04/2008 Improved median and overall survival when combined with Sig ↑ in risk of VTE compared with control (p < 0.0001) 25,200 37 NK-cells) standard therapy (p = 0.05); sig ↑ in risk of hematologic and 38 thrombotic SAE 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Acute lymphoblastic leukemia 4 Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) 5 ingredient 6 Atriance Nelarabine Cytotoxicity via DNA synthesis 22/08/2007 Response rates 31-50%; insufficient evidence on OS; severe Neurotoxicity, thrombocytopenia, neutropenia 50,000 7 inbibition toxicity

8 Evoltra Clofarabine Cytotoxicity via DNA synthesis 29/05/2006 30-44% response rates; limited data on OS; patient deaths due to Infections, multiorgan failure, hepatotoxicity, death 43,200 9 inbibition drug-related adverse events reported 10 11 Sprycel Dasatinib Protein kinase inhibitionFor 20/11/2006 peer Sig ↑ in PFS compared review with imatinib (p = 0.0012). No evidence only Fluid retention, dyspnea, pleural effusion, cytopenia, 32,000 of greater benefit on OS hemorrhage 12 13 Xaluprine Mercaptopurine Competes for hypoxanthine and 09/03/2012 Sig diff in duration of remission vs placebo (p < 0.01); no sig diff Hypersensitivity, thrombocytopenia 2,100 14 guanine for HGPRTase in median OS 15 16 http://bmjopen.bmj.com/ 17 18 19 20 Chronic myeloid leukemia Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) 21 ingredient 22 Bosulif Bosutinib Tyrosine kinase inhibitor 27/03/2013 PFS at 2 years was 79%; overall survival at 2 years was 92% Thrombocytopenia, neutropenia, anemia, diarrhea, vomitting, 44,799 23 rash, increased AST 24 Iclusig Ponatinib Tyrosine kinase inhibitor 01/07/2013 PFS 55% at 12 months; OS 84% at 12 months Pancreatitis, abd pain, increased lipase, diarrhea, fever, MI, 68,440

thrombocytopenia, on September 28, 2021 by guest. Protected copyright. anemia, neutropenia, febrile neutropenia, 25 pancytopenia. 18 deaths in study; 5 of which were attributed 26 to ponatinib 27 Sprycel Dasatinib Protein kinase inhibition 20/11/2006 Sig ↑ in PFS compared with imatinib (p = 0.0012). No evidence Fluid retention, dyspnea, pleural effusion, cytopenia, 32,000 28 of greater benefit on OS hemorrhage

29 Tasigna Nilotinib Protein kinase inhibition 19/11/2007 Rates of molecular and cytogenetic response significantly greater Thrombocytopenia, anemia, neutropenia, and asthenia 30,000 30 compared with imatinib (p < 0.001). No evidence on OS 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Acute myeloid leukemia 4 Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) 5 ingredient 6 Ceplene Histamine Immunomodulator; combined 07/10/2008 Over 3 years, leukaemia free survival was 40% for HDC/IL-2 vs Headache, pyrexia 35,450 7 dihydrochloride with IL-2 26% in control group. No results for OS

8 Dacogen Decitabine Inhibition of DNA 20/09/2012 RCTs show no sig improvement in OS compared with controls. Sig ↑ in risk of SAE compared with placebo (p = 0.002) 58,300 9 methyltransferases Sig ↑ in risk of SAE compared with placebo (p = 0.002). 1 RCT 10 was discontinued due to SAE 11 For peer review only 12 13 14 15 Pseudomonas in Cystic Fibrosis 16 Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) ingredient http://bmjopen.bmj.com/ 17 Cayston Aztreonam Bactericidal 21/09/2009 Modest effects on respiratory symptoms; sig improvements in Sig ↓ in Pseudomonas spp. density compared with placebo; 2567 (28 days) 18 FEV1 compared with placebo no sig diff on CFQ-RRS 19 20 TobiPodhaler Tobramycin Bactericidal 20/07/2011 Sig ↑in FEV1 compared with placebo (p = 0.002) Sig ↑in FEV1 compared with placebo (p = 0.002) 1540 (28 days) 21 22 23 24 25 on September 28, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 51 of 59 BMJ Open

1 2 3 Appendix 4: Approval dates and references used to document annual costs of orphan drugs 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 5 6 Orphan drug EMA approval date Annual cost (£) Reference 7 Adcetris 25/10/2012 42,500 [1] 8 Adempas 27/03/2014 53,495 [2] 9 10 Arzerra 19/04/2010 40,586 [3] 11 Atriance 22/08/2007 50,000 [4] 12 Bosulif 27/03/2013 44,799 [5] 13 Bronchitol 13/04/2012 6,040 [6] 14 15 Carbaglu 24/01/2003 245,000 [7] 16 Cayston 21/09/2009 15,399 [8] 17 Ceplene For07/10/2008 peer review35,450 only [9] 18 Cholic Acid FGK 04/04/2014 N/A N/A 19 Cometriq 21/03/2014 70,664 [10] 20 21 Cystadane 15/02/2007 46,580 [11] 22 Dacogen 20/09/2012 58,300 [12] 23 Defitelio 18/10/2013 N/A N/A 24 Diacomit 04/01/2007 7,600 [13] 25 26 Elaprase 08/01/2007 309,660 [14] 27 Esbriet 28/02/2011 26,172 [15] 28 Evoltra 29/05/2006 43,200 [16] 29 Exjade 28/08/2006 25,000 [17] 30 Firazyr 11/07/2008 16,740 [18] 31 32 Firdapse 23/12/2009 47,000 [19] 33 Gliolan 07/09/2007 2,630 [20] 34 Glybera 29/10/2012 216,151 [21] 35 Iclusig 01/07/2013 68,440 [22] 36 37 Imnovid 05/08/2013 105,600 [23] 38 Increlex 03/08/2007 18,000 [24] http://bmjopen.bmj.com/ 39 Inovelon 16/01/2007 3,000 [25] 40 Jakavi 23/08/2012 43,200 [26] 41 Kalydeco 23/07/2012 182,625 [27] 42 43 Kuvan 02/12/2008 36,336 [28] 44 Litak 14/04/2004 35,000 [29] 45 Lysodren 28/04/2004 51,900 [30] on September 28, 2021 by guest. Protected copyright. 46 Mepact 06/03/2009 92,000 [31] 47 48 Mozobil 31/07/2009 34,179 [32] 49 Myozyme 29/03/2006 230,000 [33] 50 Naglazyme 24/01/2006 170,000 [34] 51 Nexavar 19/07/2006 38,852 [35] 52 53 Nexobrid 03/09/2012 N/A N/A 54 Nplate 04/02/2009 40,102 [36] 55 Onsenal 17/10/2003 1,800 [37] 56 Opsumit 20/12/2013 27,979 [38] 57 Orfadin 21/02/2005 24,744 [39] 58 59 Orphacol 12/09/2013 N/A N/A 60 Pedea 29/07/2004 6,575 [40] Peyona 02/07/2009 6,300 [41]

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1 2 3 Plenadren 03/11/2011 2,920 [42] 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 5 Prialt 21/02/2005 20,000 [43] 6 Procysbi 06/09/2013 148,659 [44] 7 Revatio 28/10/2005 4,482 [45] 8 Revestive 30/08/2012 200,000 (US estimates) [46] 9 10 Revlimid 14/06/2007 53,363 [47] 11 Rilonacept Regeneron 23/10/2009 212,000 (US estimates) [48] 12 Savene 28/07/2006 6,750 (3 doses) [49] 13 Signifor 24/04/2012 47,000 [50] 14 15 Siklos 29/06/2007 6,085 [51] 16 Sirturo 05/03/2014 N/A N/A 17 Soliris For20/06/2007 peer review378, 000only [52] 18 Sprycel 20/11/2006 32,000 [53] 19 Tasigna 19/11/2007 30,000 [54] 20 21 Tepadina 15/03/2010 20,608 [55] 22 Thalidomide Celgene 16/04/2008 25,200 [56] 23 Tobi Podhaler 20/07/2011 1,540 (28 days) [57] 24 Torisel 16/09/2003 36,000 [58] 25 26 Tracleer 15/05/2002 19,463 [45] 27 Ventavis 16/09/2003 38,000 [45] 28 Vidaza 17/12/2008 45,000 [59] 29 Volibris 21/04/2008 20,088 [60] 30 Votubia 02/09/2011 15,000 [61] 31 32 Vpriv 26/08/2010 146,660 [62] 33 Vyndaqel 16/11/2011 112,051 [63] 34 Wilzin 13/10/2004 726 [64] 35 Xagrid 16/11/2004 5,000 [65] 36 37 Xaluprine 09/03/2012 2,100 [66] 38 Yondelis 17/09/2007 24,898 (6 cycles) [67] http://bmjopen.bmj.com/ 39 Zavesca 20/11/2002 58,400 [68] 40 *N/A: Not available 41 42 43 44 45 46 on September 28, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 45 Greater Manchester Medicines Management Group. Current therapeutic strategies for pulmonary arterial 5 6 hypertension. March 2009. Available from: www.nyrdtc.nhs.uk/docs/eva/PAH.pdf [Accessed 6th March, 7 2013] 8 9 46 UK Medicines Information. New Drugs Online Report for teduglutide. Available from: 10 http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4135 [Accessed 28 February, 11 12 2013] 13 47 London New Drugs Group. APC/DTC Briefing. Lenalidomide (Revlimid) for relapsed or refractory multiple 14 15 myeloma. May 2008. Available from: 16 http://www.medicinesresources.nhs.uk/upload/documents/Evidence/Drug%20Specific%20Reviews/Lenalido 17 For peer review only 18 mide%20(Revlimid)%20may%2008.pdf [Accessed 6th March, 2013] 19 48 Kapur S, Bonk ME (2009) Rilonacept (arcalyst), an interleukin-1 trap for the treatment of cryopyrin- 20 21 associated periodic syndromes. P. T. 34(3): 138–141 22 49 The National Extravasation Information Service. Position Statement on dexrazoxane in the Treatment of 23 24 Anthracycline Extravasation. Available from: http://www.extravasation.org.uk/Dexrazoxane.htm [Accessed 25 6th March, 2013] 26 27 50 Erhorn S (2012) Pasireotide for Cushing’s disease. North East Treatment Advisory Group. June 2012 28 51 West Midlands Strategic Commissioning Group. Commissioning Policy (WM/26) - Siklos® for Sickle cell 29 30 anaemia. Version 1 – September 2010 31 52 Regional Drugs and Therapeutic Centre (Newcastle). Evaluation report: The use of eculizumab in atypical 32 haemolytic uremic syndrome. July 2012. Available from: 33 34 http://www.nyrdtc.nhs.uk/docs/eva/Ecilizumab_ER_FINAL_for_web.pdf [Accessed 5th March, 2013] 35 53 National Institute for Health and Clinical Excellence. Price discount means NICE can recommend a new 36 37 drug for chronic myeloid leukaemia. Available from: 38 http://bmjopen.bmj.com/ http://www.nice.org.uk/newsroom/pressreleases/DasatinibImatinibAndNilotinibForIRIICMLFAD.jsp 39 40 [Accessed 5th March, 2013] 41 54 PharmaTimes Mobile. NICE final draft "yes" for Tasigna, Glivec, "no" to Sprycel. Available from: 42 43 http://www.pharmatimes.com/mobile/12-03- 44 22/NICE_final_draft_yes_for_Tasigna_Glivec_no_to_Sprycel.aspx [Accessed 5th March, 2013] 45 46 55 Scottish Medicines Consortium. Thiotepa 15mg and 100mg powder for concentrate for solution for infusion. on September 28, 2021 by guest. Protected copyright. 47 (Tepadina®). SMC No. 790/12 48 49 56 Yorkshire and the Humber Specialized Commissioning Group. General Policy 03/09. Thalidomide. 50 Available from: http://www.sheffield.nhs.uk/services/resources/thalidomidepolicy.pdf [Accessed 5th March, 51 52 2013] 53 57 UK Drug Information Pharmacists Group. New medicines on the Market. Tobramycin. 54 55 http://www.ukmi.nhs.uk/NewMaterial/html/docs/tobramyc.pdf [Accessed 20th June, 2014] 56 58 Claim Secure. Drug Review. Recently introduced products. Torisel™ and Revlimid® – New Cancer Drugs. 57 58 Available from: http://www.claimsecure.com/en-CA/content/pdfs/en- 59 CA/DrugReviews/DrugReview_Vol7_Issue2_en.pdf [Accessed 6th March, 2013] 60

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 59 Regional Drug and Therapeutic Centre (Newcastle). The use of azaticidine for the management of 5 6 myelodysplastic syndromes. May 2009. Available from: 7 http://www.nyrdtc.nhs.uk/docs/eva/RDTC_Azacitidine.pdf [Accessed 7th March, 2013] 8 9 60 All Wales Medicines Strategy Group Final Appraisal Report: Ambrisentan (Volibris®) – April 2009 10 61 PharmaTimes Online. Novartis launches Votubia in the UK. January 8, 2013. Available from: 11 12 http://www.pharmatimes.com/Article/13-01-08/Novartis_launches_Votubia_in_the_UK.aspx [Accessed 7th 13 March, 2013] 14 15 62 Scottish Medicines Consortium. Velaglucerase alfa 400 units powder for solution for infusion (VPRIV®). 16 SMC No. 681/11 17 For peer review only 18 63 The Pharmaletter. Portuguese hospitals block access to new medicines as retail drug sector expected to meet 19 savings goal. 30th September, 2011. Available from: 20 21 http://www.thepharmaletter.com/file/107734/portuguese-hospitals-block-access-to-new-medicines-as-retail- 22 drug-sector-expected-to-meet-savings-goal.html [Accessed 10th March, 2013] 23 24 64 NHS Evidence Library. Wilzin. British National Formulary – NHS Evidence. Available from: 25 www.evidence.nhs.uk/formulary/bnf/current/9.../wilzin [Accessed 10th March, 2013] 26 27 65 East Lancashire Medicines Management Board. New Drug Recommendation – Anagrelide. (Xagrid 28 ™capsules 0.5mg, Shire Pharmaceuticals Ltd). Available from: 29 30 http://www.elmmb.nhs.uk/EasySiteWeb/getresource.axd?AssetID=2082&type=... [Accessed 10th March, 31 2013] 32 66 AWMSG Secretariat Assessment Report (Limited Submission). Advise No. 2412. Mercaptopurine 33 34 (Xaluprine®). 20 mg/ml oral suspension. Available from: 35 http://www.wales.nhs.uk/sites3/Documents/371/Mercaptopurine%20(XALUPRINE)%20ASAR%20W.pdf 36 37 [Accessed 10th March, 2013] 38 http://bmjopen.bmj.com/ 67 National Horizon Scanning Centre. Trabectedin (Yondelis) for advanced and/or metastatic translocation- 39 40 related sarcomas – first line. May 2011. 41 68 Wyatt K, Henley W, Anderson L, Anderson R, Nikolaou V, Stein K, Klinger L, Hughes D, Waldek S, 42 43 Lachmann R, Mehta A, Vellodi A, Logan S (2012) The effectiveness and cost-effectiveness of enzyme and 44 substrate replacement therapies: a longitudinal cohort study of people with lysosomal storage disorders. 45 46 Health Technol Assess 16(39): 1-543. doi: 10.3310/hta16390 on September 28, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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foreach meta ) ) For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 2 registration registration informationincluding registration number. Describe the Describe methods of handling dataand combining ofresults studies, if done, includingmeasures of consistency I (e.g., State the State principal summarymeasures (e.g., risk ratio,means). difference in Describe methods Describe used for assessing risk studies of of bias individual (including specification of this whether was the study at done outcomeor andhow this level), information be usedto is in any datasynthesis. List and define List variables all for data which sought were (e.g., PICOS,fundingsources) any assumptionsand and simplificationsmade. Describe method Describe of dataextraction from reports(e.g., forms, piloted inindependently, duplicate) and any processes forand confirming obtaining datafrom investigators. State the State process for studies selecting (i.e., screening, eligibility, includedin systematic and,if review, applicable, includedin the meta Present full electronicPresent search strategyfor least one at database, including limits any used, such that it could be repeated. Describe all Describe information sources databases (e.g., of with dates coverage, contact study with authors to identify studies) additional in the search and datelast searched. Specify study Specify characteristics PICOS, (e.g., length of follow - Indicate Indicate review if a protocolexists, if andcan it where Webaccessed (e.g.,be address), and, if available, provide Provide anProvide statement explicit of questions being addressedwithreference to participants, interventions,comparisons, outcomes,study and (PICOS). design Describe the Describe rationale for review inthe the context of what already is known. Provide a structured a Provide summary including, asapplicable: background; objectives;datasources; study eligibilitycriteria, participants,and interventions; study appraisal and synthesis methods; results; limitations;conclusions and implicationsoffindings; key systematic registration review number. Identify the Identify report systematic asa meta-analysis, review, both.or Checklist item item Checklist For peer review language, publicationstatus) ascriteria used for eligibility, rationale. giving only

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Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. From: Funding Funding FUNDING FUNDING Conclusions Limitations Summaryof evidence 24 DISCUSSION DISCUSSION Riskacross of bias studies 22 Synthesisof results Results of Results individual studies 20 Riskstudies within of bias 19 Study characteristics Study 18 Study selection Study RESULTS RESULTS Riskacross of bias studies 15 Section/topic Section/topic doi:10.1371/journal.pmed1000097 doi:10.1371/journal.pmed1000097 Additional Additional analysis Additional Additional analyses Page 59 of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

The effectiveness, safety and costs of orphan drugs: an evidence-based review

ForJournal: peerBMJ Open review only Manuscript ID: bmjopen-2014-007199.R1

Article Type: Research

Date Submitted by the Author: 13-May-2015

Complete List of Authors: Onakpoya, Igho; University of Oxford, Primary Care Health Sciences Spencer, Elizabeth; University of Oxford, Primary Care Health Sciences Thompson, Matthew; Oxford University, Department of Primary Care Health Sciences Heneghan, Carl; Oxford University, Primary Health Care

Primary Subject Evidence based practice Heading:

Evidence based practice, Pharmacology and therapeutics, General practice Secondary Subject Heading: / Family practice

GENERAL MEDICINE (see Internal Medicine), PRIMARY CARE, ORPHAN Keywords: DRUGS http://bmjopen.bmj.com/

on September 28, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 60 BMJ Open

1 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 The effectiveness, safety and costs of orphan drugs: an evidence-based review 4 5 6 7 Igho J. Onakpoya 8 9 10 University of Oxford, Centre for EvidenceBased Medicine, Nuffield Department of Primary 11 12 Care Health Sciences, New Radcliffe House, Radcliffe Observatory Quarter, Oxford, United 13 14 Kingdom OX2 6GG 15 For peer review only 16 17 18 19 Elizabeth A. Spencer 20 21 University of Oxford, Centre for EvidenceBased Medicine, Nuffield Department of Primary 22 23 Care Health Sciences, New Radcliffe House, Radcliffe Observatory Quarter, Oxford, United 24 25 Kingdom OX2 6GG 26 27 28 29 30 Matthew J. Thompson 31 32 Department of Family Medicine, University of Washington, Seattle, USA WA 981956390

33 http://bmjopen.bmj.com/ 34 35 36 Carl J. Heneghan 37 38 39 University of Oxford, Centre for EvidenceBased Medicine, Nuffield Department of Primary 40 41 Care Health Sciences, New Radcliffe House, Radcliffe Observatory Quarter, Oxford, United on September 28, 2021 by guest. Protected copyright. 42 43 Kingdom OX2 6GG 44 45 46 47 Corresponding author: Igho Onakpoya, University of Oxford, Nuffield Department of Primary Care 48 49 Health Sciences, New Radcliffe House, Radcliffe Observatory Quarter, Oxford, United Kingdom 50 51 OX2 6GG. Email: [email protected]. Tel: +44 (0)1865 289672 52 53 54 55 56 Keywords: orphan drugs; rare diseases; evidence; cost; effectiveness; safety; review 57 58 Word count: 4,526 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 60

2 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 ABSTRACT 4 5 Introduction: Several orphan drugs have been approved by the European Medicines Agency 6 7 (EMA) over the past two decades. However, the drugs are expensive, and in some instances, 8 9 10 the evidence for effectiveness is not convincing at the time of regulatory approval. Our 11 12 objective was to evaluate the clinical effectiveness of orphan drugs which have been granted 13 14 marketing licenses in Europe, determine the annual costs of each drug, compare the costs of 15 For peer review only 16 branded orphan drugs against their generic equivalents, and explore any relationships 17 18 19 between orphan disease prevalence and annual costs. 20 21 Methods: We searched the EMA database to identify orphan drugs granted marketing 22 23 authorization up till April, 2014. Electronic searches were also conducted in PubMed, 24 25 Embase, and Google Scholar to assess data on effectiveness, safety and annual costs. Two 26 27 reviewers independently evaluated the levels and quality of evidence and extracted data. 28 29 30 Results: We identified 74 orphan drugs, with 54 (73%) demonstrating moderate quality of 31 32 evidence. 85% showed significant clinical effects, but serious adverse events were reported in

33 http://bmjopen.bmj.com/ 34 86.5%. Their annual costs were between £726 and £378,000. There was a significant inverse 35 36 relationship between disease prevalence and annual costs (p = 0.01); this was largely due to 37 38 39 the influence of the ultraorphan diseases. We could not determine whether the balance 40 41 between effectiveness and safety influenced annual costs. For 10 drugs where generic on September 28, 2021 by guest. Protected copyright. 42 43 alternatives were available, the branded drugs were 1.4 to 82,000 times more expensive. 44 45 Conclusion: The available evidence suggests that there is inconsistency in the quality of 46 47 evidence of approved orphan drugs, and there is no clear mechanism for determining their 48 49 50 prices. In some cases far cheaper generic agents appear to be available. A more robust, 51 52 transparent and standard mechanism for determining annual costs is imperative. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 60 BMJ Open

3 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Strengths and limitations 4 5 • We employed a robust strategy to search for the best quality evidence for effectiveness 6 7 8 • We used standardized methods to rate the quality and level of evidence for each orphan 9 10 drug 11 12 • We also used reliable data to document the prevalence of each orphan disease and identify 13 14 the annual cost of each orphan drug 15 For peer review only 16 17 • Because we could not document the research and development costs associated with the 18 19 approval of each orphan drug, the influence of this variable on their annual costs could not 20 21 be ascertained 22 23 • The inconsistencies in the quality of evidence for some orphan drugs limits the 24 25 conclusions that could be drawn regarding their effectiveness and safety 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38

39 40 41 on September 28, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51

52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 60

4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 INTRODUCTION 4 5 Orphan drugs are therapeutic agents designed for the management of orphan diseases,1 which 6 7 are defined as medical conditions with a low prevalence. In the United States (US), orphan 8 9 2 10 diseases are defined as those affecting approximately 1 in 1,500 persons [ ], while in Europe 11 2,3 12 it is defined as 5 in 10,000. In Europe, ultraorphan designations are used to specify rare 13 14 diseases with prevalence less than 1 in 50,000.2,4 15 For peer review only 16 17 18 19 Because low patient volumes make it unfavourable for commercial investment in orphan drug 20 21 research, drug regulatory authorities have incentives in place to encourage their development 22 23 and manufacture by pharmaceutical companies. In the US, these include exclusive licencing 24 25 to market such drugs for seven years, faster assessment procedures, and tax incentives.1 In 26 27 Europe, incentives include exclusive licensing for 10 years, reduction in the fees paid for 28 29 1,5 30 regulatory activities, and provision of scientific advice by drug regulatory bodies. Despite 31 32 these incentives, the costs of orphan drugs are still high, especially when generic versions of

33 http://bmjopen.bmj.com/ 34 the same agent are available.6 In the United Kingdom for example, some funders of care 35 36 under the National Health Service have refused to fund the orphan drugs because they are not 37 38 39 considered cost effective, thereby denying patients access to potentially useful drug 40 7 41 interventions. Factors which reportedly influence their price setting include research and on September 28, 2021 by guest. Protected copyright. 42 43 development (R & D) costs, clinical effectiveness, drug quality, and disease prevalence.8,9 44 45 However, the effectiveness of some orphan drugs has not been clearly demonstrated, and the 46 47 evidence regarding their safety is often sparse at the time of regulatory approval.10 48 49 50 51 52 A previous systematic review of 11 orphan drugs approved in the Netherlands concluded that 53 54 there is scarcity of information on the cost effectiveness of the drugs.11 A more recent 55 56 systematic review of orphan drug legislation in Europe also advocated for more stringent 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 60 BMJ Open

5 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 approval criteria for evaluating the clinical and cost effectiveness of orphan drugs.12 Another 4 5 systematic review of orphan drugs used in cancers showed that they have varying levels in 6 7 quality of evidence and dearth of information on economic value.13 While the first two 8 9 10 reviews did not evaluate the quality of the evidence, the third review focussed only on drugs 11 12 marketed in the US. 13 14 15 For peer review only 16 The objective of this review was to evaluate the effectiveness and safety of all orphan drugs 17 18 19 which have been granted marketing licenses in Europe, determine the annual costs of each 20 21 drug based on UK estimates, compare the costs of branded orphan drugs against their generic 22 23 equivalents, and explore the relationship between orphan disease prevalence and annual 24 25 costs. 26 27 28 29 30 METHODS 31 32 We searched the European Medicines Agency (EMA) database for orphan drugs and their

33 http://bmjopen.bmj.com/ 34 approved indications using the search modality '' http://www.ema.europa.eu/ema/ > find 35 36 medicine > human medicines > Browse by type > Orphan medicine: “Include authorised 37 38 39 medicine, withdrawn postapproval and suspended” > SUBMIT ''. Orphan drugs granted 40 41 marketing authorisation up until 30th April, 2014 were identified. Drugs which have been on September 28, 2021 by guest. Protected copyright. 42 43 designated with “orphan status”, but have not received EMA marketing authorisation were 44 45 excluded. The EMA Orphanet Report Series (April, 2014)14 was also assessed to verify the 46 47 identified drug approvals. 48 49 50 51 52 For each identified drug, electronic searches were then conducted in the following databases: 53 54 PubMed, Embase, the Clinical Trials database and National Electronic Library for Medicines. 55 56 The search terms used included: “orphan drug name” AND “metaanalysis”, systematic 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 60

6 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 review”, “randomised”, “clinical trial”, “placebo”, “followup study”, “retrospective 4 5 studies”, “caseseries”, “cohort”, “followup studies”, “adverse events”. The prevalence of 6 7 the orphan diseases was documented using the reference values reported in the Orphanet 8 9 15 10 Report Series Bibliographic data and the Orphanet portal for rare diseases and orphan 11 16 12 drugs. 13 14 15 For peer review only 16 We estimated the annual average cost in the UK for each orphan drug. Costs of orphan drug 17 18 19 regimens might vary according to the individual patient’s needs including body size, disease 20 21 progression, or complications of disease. However, we did not have information on these 22 23 factors, and so we used the most recent data to estimate the average annual cost in the UK. 24 25 We searched the UK Medicines Information, the National Electronic Library for Medicines, 26 27 North East Treatment Advisory Group (NETAG), Scottish Medicines Consortium, and All 28 29 30 Wales Medicines Strategy Group databases for the most recent evidence relating to the 31 32 annual costs of each drug. Where these were inadequate to compute the annual costs of a

33 http://bmjopen.bmj.com/ 34 specific drug, we searched The Pharma Letter (www.pharmaletter.com) and PharmaTimes 35 36 (www.pharmatimes.com) websites, and Google Scholar for the most recent data on annual 37 38 39 costs. The costs of treatment with drugs not used on an annual basis/duration were computed 40 41 as annual costs. Where orphan drugs were approved for two or more indications, we on September 28, 2021 by guest. Protected copyright. 42 43 documented the annual costs of treatment separately for each indication. 44 45 46 47 For each orphan drug identified from the EMA database, we determined the level of available 48 49 50 evidence regarding effectiveness using the Oxford Centre for Evidence Based Medicine 51 17 52 (OCEBM) Levels of Evidence which comprises four levels: Level 1: systematic reviews; 53 54 Level 2: randomized trial or observational study with dramatic effect; nonrandomized 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 60 BMJ Open

7 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 controlled cohort/followup study; Level 3: caseseries, casecontrol studies, or historically 4 5 controlled studies; Level 4: mechanismbased reasoning. 6 7 8 9 10 The quality and strength of the overall body of evidence for each orphan drug was then 11 12 evaluated using a checklist adapted from the Grades of Recommendation, Assessment, 13 14 Development and Evaluation (GRADE) criteria18 which assesses the five domains: study 15 For peer review only 16 design; consistency of evidence; directness of the evidence; precision; and reporting biases. 17 18 19 Based on the quality of overall evidence, 1 of 4 possible grades could be allocated: high, 20 21 moderate, low, and very low. 22 23 24 25 Evidence for effectiveness for each orphan drug from the highest levels of evidence for each 26 27 orphan drug was prioritised using the following order: metaanalysis/systematic review > 28 29 30 RCTs > nonrandomised studies. If two or more systematic reviews evaluated the same 31 32 orphan drug, the most recent review was included. If two or more drugs were approved for

33 http://bmjopen.bmj.com/ 34 treating same orphan disease, we determined whether the level of effectiveness was related to 35 36 their annual costs. Scatter plots were used to explore the relationships between orphan disease 37 38 39 prevalence and annual costs. If three or more drugs were approved for same indication, we 40 41 used scatter plots to test whether there was a relationship between approval year and annual on September 28, 2021 by guest. Protected copyright. 42 43 cost. Where systematic reviews or metaanalyses did report adverse events, we searched for 44 45 adverse event publications using the evidence from systematic searches using the following 46 47 priority: RCTs > retrospective/followup/cohort > casecontrol/caseseries. Adverse events (≥ 48 49 50 Grade 3) associated with the use of such drug were documented. For drugs which had been 51 52 withdrawn or suspended, we documented the reasons for such decisions by accessing the 53 54 EMA European Public Assessment Reports (EPAR) for human medicines.19 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 60

8 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Two reviewers [IO & ES] independently evaluated the level and quality and strength of the 4 5 evidence, and extracted data. These were then crosschecked by two other reviewers [MT and 6 7 CH]. Disagreements were resolved through consensus. 8 9 10 11 12 RESULTS 13 14 The EMA database searches identified a total of 74 approved drugs (authorised medicines or 15 For peer review only 16 medicines withdrawn postapproval) for managing 63 orphan conditions, with approval dates 17 18 19 ranging from 15/05/2002 to 04/04/2014 (Figure 1). Twenty nine (39%) of these drugs are 20 21 used in the management of cancers, while 24 (32.4%) are used for inborn errors of 22 23 metabolism or immune disorders. The remaining 21 drugs were approved for a variety of 24 25 other orphan conditions, with pulmonary arterial hypertension accounting for 5 (23%) of the 26 27 approvals. Of the 74 drugs, five (6.8%) were granted conditional approval, while 15 (20%) 28 29 30 were granted approval under “exceptional” circumstances. Two drugs, Cholic acid FGK and 31 32 Orphacol, both contained the same active ingredient and were approved for same indication;

33 http://bmjopen.bmj.com/ 34 however, Orphacol was granted license under “exceptional” circumstances. Two drugs, 35 36 Onsenal and Rilonacept, were withdrawn by the EMA after approval because of unfavourable 37 38 39 risktobenefit profile and commercial reasons respectively. Details of the approval dates, 40 41 levels and quality of evidence, results of clinical effectiveness, annual costs, and relevant on September 28, 2021 by guest. Protected copyright. 42 43 references have been included as web appendices 14. 44 45 46 47 Levels and quality of evidence 48 49 50 Using the OCEBM criteria, 25 (33.8%) orphan drugs had Level 1 evidence, 35 (47.3%) were 51 52 Level 2 and 14 (18.9%) were Level 3 (Figure 2a). Based on the GRADE criteria, the overall 53 54 quality of evidence could be rated as moderate in 54 (73.0%) drugs, low in 16 (21.6%), and 55 56 very low in 4 (5.4%) (Figure 2b). None of the 74 drugs showed evidence of high overall 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 60 BMJ Open

9 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 quality. Relevant references for the level and quality of evidence are included as web 4 5 Appendix 1. 6 7 8 9 10 Evidence for effectiveness 11 12 Of the 29 drugs approved for management of cancer, six (20.7%) showed evidence of 13 14 significant benefits for both progressionfree survival and overall survival; seven (24.1%) 15 For peer review only 16 showed evidence of significant improvement only in progressionfree survival, while nine 17 18 19 (31.0%) had evidence of only significantly increasing overall survival (web Appendix 2; 20 21 Table 1). Of the 24 orphan drugs approved for treating inborn errors of metabolism, 21 (75%) 22 23 showed evidence of beneficial effect on at least one outcome measure (web Appendix 2; 24 25 Table 2). Of the remaining 21 drugs used for managing other orphan diseases, 20 (95.2%) 26 27 showed evidence of significant beneficial effects (web Appendix 2; Table 3). 28 29 30 31 32 Evidence for safety

33 http://bmjopen.bmj.com/ 34 Twenty eight (96.6%) of the orphan drugs approved for treating cancerous conditions had 35 36 evidence of serious adverse events (web Appendix 2; Table 1). The most common events 37 38 39 were bone marrow suppression (58.6%) and hepatotoxicity (20.7%). Adverse events with 40 41 Dacogen and Evoltra were severe enough to warrant premature termination of clinical trials. on September 28, 2021 by guest. Protected copyright. 42 43 44 45 Six out of 24 drugs (25%) approved for treating inborn errors of metabolism had no evidence 46 47 of serious adverse events, while another (Cholic acid) did not have any preclinical safety 48 49 50 studies prior to approval (web Appendix 2; Table 2). The most common events involved the 51 52 gastrointestinal and respiratory systems (25% and 20.8% respectively). 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 60

10 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Eighteen of the 21 drugs (85.7%) approved for treating other orphan conditions had evidence 4 5 of serious adverse events (web Appendix 2; Table 3). Gastrointestinal adverse events were 6 7 the most common (23.8%). Other notable adverse events included cardiotoxicity (9.5%), 8 9 10 metabolic abnormalities (9.5%), and possible risk of suicide with Prialt (ziconotide). 11 12 13 14 Annual costs of orphan drugs 15 For peer review only 16 The annual cost with ranged between £726 and £378,000 (median £31,012) (details of the 17 18 19 annual costs and the references used for documenting the evidence are shown in web 20 21 Appendix 3). 24% of the drugs cost less than £10,000 annually, 58% cost between £10,000 22 23 and £100,000, while 18% cost ≥ £100,000 annually. For cancer drugs the range was £1,800 to 24 25 £92,000, compared with £726 to £378,000 for inborn errors of metabolism. 26 27

28 29 30 Association between disease prevalence and annual cost of orphan drugs 31 32 A scatter plot of prevalence against annual cost (Figure 3) revealed a significant inverse

33 http://bmjopen.bmj.com/ 34 relationship (p = 0.01). In contrast, we did not observe a significant relationship when a sub 35 36 area of more frequent activity (similar range of disease prevalence and annual costs) was 37 38 analysed (p = 0.56; Figure 3 inset). A significant inverse association was also observed for 39 40 41 the relationship between annual cost and the prevalence for 21 drugs approved for managing on September 28, 2021 by guest. Protected copyright. 42 43 ultraorphan diseases (p = 0.04; Figure 4). However, a scatter plot of the subset of the 53 44 45 drugs approved for orphan diseases with prevalence >1 per 100,000 revealed a non 46 47 significant relationship (p = 0.18). Scatter plots of prevalence against annual cost did not 48 49 50 reveal significant relationships when cancers or inborn errors of metabolism were 51 52 individually tested (data not shown). 53 54 55 56 Association clinical effectiveness and annual cost 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 60 BMJ Open

11 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 Because of discrepancies in outcome measures and time points for outcome measurements, 4 5 we could not use scatter plots to explore associations between clinical effectiveness and 6 7 annual costs. All orphan drugs approved for managing pulmonary arterial hypertension 8 9 10 showed comparative level of effectiveness at improving sixminute work distance and 11 12 decreasing clinical worsening irrespective of annual cost (web Appendix 4). Similar findings 13 14 were observed for progressionfree survival and overall survival for orphan drugs approved 15 For peer review only 16 for treating cancers. The annual costs of two drugs approved for treating Pseudomonas in 17 18 19 cystic fibrosis were comparable. We could not determine whether the risk or occurrence of 20 21 serious adverse events played a role in the annual costs of approved orphan drugs. 22 23 24 25 Association between approval year and annual cost 26 27 Two or more orphan drugs were approved by the EMA for treating seven orphan conditions 28 29 30 (web Appendix 4). Scatter plot of annual cost against approval year for the five drugs 31 32 approved for pulmonary arterial hypertension suggested a trend towards a significant

33 http://bmjopen.bmj.com/ 34 relationship for higher annual costs with more recent approvals (p = 0.06). A significant 35 36 relationship between annual cost and approval year was observed with four drugs approved 37 38 39 for the management of chronic myeloid leukemia (p = 0.03). There was no significant 40 41 relationship between annual cost and approval year for drugs approved for treatment of acute on September 28, 2021 by guest. Protected copyright. 42 43 lymphoblastic leukemia (p = 0.38); however, exclusion of the most recently approved drug 44 45 whose approval was based on a historical perspective (Xaluprine) resulted in a significant 46 47 relationship being observed (p = 0.01). 48 49 50 51 52 Branded orphan drugs versus generic or unlicensed versions 53 54 We found 15 approved drugs with generic versions, out of which data on annual cost of 55 56 generic or unlicensed versions for 10 (13.5%) were available. Figure 5 shows a price 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 60

12 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 comparison for annual costs for branded orphan drugs compared with their 4 5 unlicensed/generic equivalents. While branded mercaptopurine (Xaluprine) was only 1.4 6 7 times more costly than its generic counterpart, the branded version of intravenous ibuprofen 8 9 10 (Pedea), used for closure of patent ductus arteriosus (PDA) in preterm infants was 82,000 11 12 times more expensive than its oral equivalent. 13 14 15 For peer review only 16 DISCUSSION 17 18 19 Main findings 20 21 Our results show that of the 74 EMA approved orphan drugs over a 12year period, none has 22 23 shown an overall high quality in available evidence for their effectiveness; there is a 24 25 moderate level of evidence for threequarters, while a fifth are low in evidence. Our analyses 26 27 of annual drug costs revealed several interesting and potentially concerning findings. We 28 29 30 found a significant inverse relationship between annual costs of orphan drugs and the 31 32 prevalence of orphan diseases in other words the drugs for the most rare diseases and cheaper

33 http://bmjopen.bmj.com/ 34 than those for more common diseases , largely driven by the drug costs for the ultraorphan 35 36 diseases. We also found that drugs that had been approved more recently cost more than 37 38 39 those approved even over the previous decade. Finally, the annual costs of the drugs did not 40 41 appear to be related to their clinical effectiveness, and for the subset of the branded orphan on September 28, 2021 by guest. Protected copyright. 42 43 drugs which had generic equivalents we found several extremely large differences in cost. 44 45 46 47 While the clinical trial evidence for over twothirds of EMAapproved orphan drugs suggests 48 49 50 that they have clinically significant beneficial effects; the evidence for about onefifth 51 52 indicates that either they do not have clinically beneficial effects, or more importantly may do 53 54 harm. The results of systematic reviews for several of the drugs are also inconclusive, either 55 56 because of deficiency in trial reporting or due to a lack of available clinical trials. Our 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 60 BMJ Open

13 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 inability to determine whether the level of clinical effectiveness influences annual costs for 4 5 orphan diseases with two or more approved indications indicates uncertainty about how this 6 7 variable determines price setting. 8 9 10 11 12 The findings from our review show that except for the very rare (ultraorphan) diseases, there 13 14 is no significant inverse relationship between disease prevalence and annual cost. There were 15 For peer review only 16 inconsistencies in the strengths of correlation between approval year and annual costs when 17 18 19 three or more drugs used for same orphan condition were compared. This indicates that there 20 21 is no standardized process for setting the prices of orphan drugs. It is important to realise that 22 23 many orphans target very small patient numbers and are for conditions with few treatment 24 25 alternatives, allowing their price to be relatively higher than nonorphan drugs. 26 27

28 29 30 Comparison with existing literature 31 32 The results of our review confirm a previous research report which concluded that orphan

33 http://bmjopen.bmj.com/ 34 disease prevalence is inversely associated with annual costs for only the very rare diseases.8 35 36 Our results also corroborate results a from previous review which showed that approved 37 38 13 39 orphan drugs vary in the quality of evidence, and support the evidence from two previous 40 41 reviews which suggested that there is no clarity about how the clinical effectiveness is used to on September 28, 2021 by guest. Protected copyright. 42 43 determine their costs of orphan drugs.11,12 In contrast to the previous reports, our review is 44 45 more systematic, and by far more comprehensive. We also determined whether approval year 46 47 has any influence in determining costs, and we compared branded versions of the orphan 48 49 50 drugs with their unlicensed or generic versions.Our results support the findings of a 51 52 qualitative analysis which examined reimbursement for orphan drug prescriptions in Belgium 53 54 suggested that more standardisation of how orphan drugs are priced is needed.20 However, we 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 60

14 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 investigated all orphan drugs approved for use in Europe, and assessed the quality of 4 5 evidence for effectiveness and safety. 6 7 8 9 10 Strengths and limitations 11 12 We employed a robust strategy to search for the best quality evidence for effectiveness, 13 14 safety and annual costs of each orphan drug, and we used standardized methods to rate the 15 For peer review only 16 quality and level of evidence for each identified drug. We also used reliable data to document 17 18 19 the prevalence of each orphan disease and identify the annual cost of each orphan drug. 20 21 22 23 However, we do recognize several limitations. Because we could not document the R and D 24 25 costs associated with the approval of each orphan drug, the influence of this variable on their 26 27 annual costs could not be ascertained. The heterogeneity in clinical outcomes across different 28 29 30 diseases, discrepancies in time points for outcome measurements, and the inconsistency in the 31 32 levels of outcome reporting also limited the type of analyses and therefore the conclusions

33 http://bmjopen.bmj.com/ 34 that could be drawn regarding the effectiveness and safety of some orphan drugs. 35 36 37 38 39 Implications for research 40 41 Our finding that the trial evidence for the effectiveness and safety of 65% of drugs have not on September 28, 2021 by guest. Protected copyright. 42 43 been systematically reviewed suggests an urgent need for prioritizing reviews for these drugs. 44 45 Moreover, systematic reviews evaluating the effectiveness and safety of some EMA 46 47 approved orphan drugs are now outdated because more recent clinical trials have become 48 49 50 available, and consequently such reviews need to be updated. Given the value of systematic 51 52 reviews for clinicians and health policy makers, we suggest the formation of a Cochrane 53 54 Collaboration review group focused on orphan drugs as one way of reducing these gaps in 55 56 knowledge. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 60 BMJ Open

15 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 5 In addition, further independent and industryfunded trials are also warranted, especially for 6 7 drugs which currently have poor quality and low levels of evidence. Clinical trial 8 9 10 investigators should adequately report any suspected adverse events observed in the course of 11 12 trials; and statements made in some primary studies that such events, if any, were not related 13 14 to the drug in question (or not serious enough) may be premature. The importance of close 15 For peer review only 16 postapproval monitoring cannot be overemphasized. Finally, given the inconsistencies we 17 18 found in drug costs, a more detailed and transparent analysis of the relationship between R & 19 20 21 D costs and annual costs of orphan drugs is now imperative. 22 23 24 25 Implications for policy 26 27 The use of novel therapeutic agents has resulted in improvements in clinical outcome for 28 29 30 several orphan diseases. It is also rational that drug companies should aim to recoup 31 32 investment in R&D costs through sales and reimbursements for these drugs, even though the

33 http://bmjopen.bmj.com/ 34 size of the market for such drugs is quite small.21 However, the overall benefits on both 35 36 clinical and economic terms need to be taken into consideration when setting prices.22 In fact, 37 38 unfavourable costtobenefit analysis has led to the rejection of orphan drug approval 39 40 23,24 41 applications by the UK National Institute for Health and Care Excellence. More recently, on September 28, 2021 by guest. Protected copyright. 42 43 NHS England threatened to stop purchasing some orphan drugs used for cancer management, 44 45 unless the manufacturers reduced their prices.25 Since the costeffectiveness of orphan drugs 46 47 is difficult to assess, considering opportunity costs might help make decisions about funding 48 49 50 the provision of orphan drugs. 51 52 53 54 The high costs of orphan drugs are reportedly due to the large amounts of funds invested in 55 56 R&D by the drug manufacturers.26 However, Light and Lexchin27 reported that drug 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 60

16 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 companies spend only 1.3% of their revenue on basic research in order to discover novel 4 5 molecules. In addition, the disparity in prices when these branded drugs are compared with 6 7 their generic versions makes it doubtful if the quoted R&D costs are sufficiently robust. It is 8 9 10 unclear the extent to which the incentives offered by the EMA and other drug regulatory 11 12 authorities to encourage the development of these drugs influenced the prices of these 13 14 branded drugs. For example, Pedea costs 82,000 times as much as generic ibuprofen, yet, 15 For peer review only 16 research evidence has shown that Pedea is no superior to oral ibuprofen in clinical 17 18 28 19 effectiveness regarding closure of PDA. This raises the question of whether large national 20 21 health systems like the NHS should choose generic versions of orphan drugs where available, 22 23 particularly given current pressure on health care expenditures.29 In 2013 for example, the 24 25 drug company Novartis AG lost its patenting right for Glivec (imatinib) in India largely due 26 27 30 to its very high price compared with its generic alternative. 28 29 30 31 32 The marketing authorizations granted some orphan drugs such as Ceplene, Firdapse and

33 http://bmjopen.bmj.com/ 34 Xaluprine were based on a historical perspective, i.e., these compounds have previously been 35 36 used in patient management prior to being designated with orphan status.31 Therefore, in 37 38 39 cases such as these, it does not seem plausible for drug companies to claim huge R&D costs 40 41 because they are not new therapies. Indeed, the approval application of Ceplene for its on September 28, 2021 by guest. Protected copyright. 42 43 designation as an orphan drug was refused in Canada due to a failure of the drug company to 44 45 prove that its development was innovative.32 Similarly, it would be expected that the prices of 46 47 drugs for which there are alternative therapeutic options for their stated indications be 48 49 50 competitively based. 51 52 53 54 The postapproval withdrawal of some orphan drugs suggests that pre and postmarketing 55 56 surveillance is not stringently assessed (or evaluated) during the clinical trial and drug 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 60 BMJ Open

17 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 approval process. For example, Onsenal (celecoxib) was also withdrawn eight years post 4 5 approval after it was discovered that the risks outweighed its benefits in its use for managing 6 7 familial adenomatous polyposis.33 Thelin (sitaxentan) lost its orphan designation (and was 8 9 34 10 withdrawn from the market) due to fatal hepatotoxicity ; clinical trial results had shown that 11 12 the drug had adverse effects on the liver, but these were not considered serious enough to 13 14 prevent its approval. The serious adverse events associated with some of approved drugs lend 15 For peer review only 16 credence to the view that safety does not appear to be a factor when determining the costs of 17 18 19 the drugs. 20 21 22 23 CONCLUSION 24 25 There is inconsistency in the level and quality of evidence for approved orphan drugs. While 26 27 some orphan drugs have demonstrated evidence of significant benefits, evidence of 28 29 30 effectiveness is lacking for several others, and some are associated with serious unwanted 31 32 adverse effects. The available evidence suggests that except for the ultraorphan diseases, the

33 http://bmjopen.bmj.com/ 34 annual costs of orphan drugs approved in Europe are not influenced by the disease 35 36 prevalence. There is inadequate data to determine whether clinical effectiveness influences 37 38 the price setting of orphan drugs. Further research into the effectiveness and safety of orphan 39 40 41 drugs is required, and a standard, transparent and robust mechanism for determining their on September 28, 2021 by guest. Protected copyright. 42 43 prices should be a priority. 44 45 Authors’ contribution 46 47 IJO was involved with literature searches, data extraction, data analysis and interpretation, 48 49 50 and codrafting of the review. EAS was involved with literature searches, data extraction, 51 52 data analysis, and codrafting of the review. MJT was involved with data analysis and 53 54 interpretation, and codrafting of the review. CJH was involved with data analysis and 55 56 interpretation, and codrafting of the review. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 60

18 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 5 Competing interests 6 7 Prof Heneghan receives payment for running educational courses at the University of Oxford 8 9 10 and University of Oxford ISIS consulting services for external teaching and training. He also 11 12 receives royalties for books (Evidence Based Toolkit series by Blackwell BMJ Books). 13 14 Dr. Onakpoya, Dr. Spencer and Prof. Thompson have no interests to disclose. 15 For peer review only 16 17 18 19 Funding 20 21 This research was funded by the National Institute for Health Research (NIHR) School for 22 23 Primary Care Research (SPCR). 24 25 Data Sharing 26 27 No additional data available. 28 29 30 Disclaimer 31 32 This article presents independent research funded by the National Institute for Health

33 http://bmjopen.bmj.com/ 34 Research (NIHR). The views expressed are those of the author(s) and not necessarily those 35 36 of the NHS, the NIHR or the Department of Health. 37 38 39 40 41 Figure legends on September 28, 2021 by guest. Protected copyright. 42 43 Figure 1: Flow chart showing process for inclusion of EMAapproved orphan drugs 44 45 Figure 2: Pie charts showing the levels and quality of evidence of EMAapproved orphan 46 47 drugs by proportion 48 49 50 Figure 3: Scatter plot of orphan disease prevalence against annual cost 51 52 Figure 4: Scatter plot of ultraorphan disease prevalence against annual cost 53 54 Figure 5: Price comparison of branded orphan drugs versus generic/unlicensed versions 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 60 BMJ Open

19 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 5 REFERENCES 6 7 8 9 1 Dear JW, Lilitkarntakul P, Webb DJ. Are rare diseases still orphans or happily adopted? 10 11 The challenges of developing and using orphan medicinal products. BJCP 2006; 623: 264 12 13 271. 14 15 2 Sharma A,For Jacob A, Tandonpeer M, Kumar review D. Orphan drug: Development only trends and 16 17 strategies. J Pharm Bioallied Sci. 2010 Oct;2(4):2909. doi: 10.4103/09757406.72128 18 19 20 3 European Medicines Agency (EMA): Orphan drugs and rare diseases at a glance. 21 22 http://www.ema.europa.eu/docs/en_GB/document_library/Other/2010/01/WC500069805. 23 24 pdf 25 26 4 National Institute for Clinical Excellence. NICE Citizens Council Report Ultra Orphan 27 28 29 Drugs. London, NICE, 2004. 30 31 http://www.nice.org.uk/proxy/?sourceUrl=http://www.nice.org.uk/niceMedia/pdf/boardme 32

33 eting/brdjan05item4.pdf [Accessed 7 May 2015] http://bmjopen.bmj.com/ 34 35 5 Hughes DA, Tunnage B, Yeo ST. Drugs for exceptionally rare diseases: do they deserve 36 37 38 special status for funding? QJM 2005; 98: 829836. 39 40 6 Simoens S, Cassiman D, Picavet E, Dooms M. Are some orphan drugs for rare diseases 41 on September 28, 2021 by guest. Protected copyright. 42 too expensive? A study of purchase versus compounding costs. Drugs and Therapy 43 44 Perspectives 2011; 27(10): 2426. 45 46 7 Hawkes N, Cohen D. What makes an orphan drug? BMJ. 2010 Nov 16;341:c6459. 47 48 49 8 Scherer FM. The Pharmaceutical Industry Price and Progress. N Engl J Med 2004; 351: 50 51 927932. 52 53 9 van Ekdom L. Price setting orphan drugs. Identifying the influential factors on the price 54 55 setting of Orphan Drugs. Msc thesis, 2006. Available at: 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 60

20 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 http://www.ppge.ufrgs.br/ats/disciplinas/1/vanekdom2006.pdf [Accessed 20th March, 5 6 2013]. 7 8 9 10 McCabe C, Claxton K, Tsuchiya A. Orphan drugs and the NHS: should we value rarity? 10 11 BMJ 2005;331:1016–9. 12 13 11 Kanters TA, de SonnevilleKoedoot C, Redekop WK, Hakkaart L. Systematic review of 14 15 available Forevidence on peer11 highpriced inpatientreview orphan drugs. only Orphanet J Rare Dis. 2013; 16 17 8(1):124. doi: 10.1186/175011728124. 18 19 20 12 Joppi R, Bertele' V, Garattini S. Orphan drugs, orphan diseases. The first decade of orphan 21 22 drug legislation in the EU. Eur J Clin Pharmacol. 2013; 69(4):100924. 23 24 13 Cheng MM, Ramsey SD, Devine EB, Garrison LP, Bresnahan BW, Veenstra DL. 25 26 Systematic review of comparative effectiveness data for oncology orphan drugs. Am J 27 28 29 Manag Care. 2012; 18(1):4762. 30 31 14 Orphanet Report Series. Orphan drug collection. List of medicinal products for rare 32

33 diseases in Europe. April, 2014. Available at: http://bmjopen.bmj.com/ 34 35 http://www.orpha.net/orphacom/cahiers/docs/GB/list_of_orphan_drugs_in_europe.pdf. 36 37 [Accessed 24th April, 2014]. 38 39 40 15 Orphanet Report Series Prevalence of rare diseases: Bibliographic data. Available at: 41 on September 28, 2021 by guest. Protected copyright. 42 http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphab 43 44 etical_list.pdf 45 46 16 Orphanet: The portal for rare diseases and orphan drugs. Available at: 47 48 49 http://www.orpha.net/consor/cgibin/index.php?lng=EN 50 51 17 OCEBM Levels of Evidence Working Group*. "The Oxford 2011 Levels of Evidence". 52 53 Oxford Centre for EvidenceBased Medicine. http://www.cebm.net/index.aspx?o=5653 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 60 BMJ Open

21 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 18 Guyatt GH1, Oxman AD, Vist GE, Kunz R, FalckYtter Y, AlonsoCoello P, Schünemann 5 6 HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of 7 8 9 evidence and strength of recommendations. BMJ 2008; 336: 924926. 10 11 19 European Medicines Agency. European public assessment reports. Available at: 12 13 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp& 14 15 mid=WC0b01ac058001d125For peer review only 16 17 20 Denis A, Mergaert L, Fostier C, Cleemput I, Hulstaert F, Simoens S. Critical assessment 18 19 20 of belgian reimbursement dossiers of orphan drugs. Pharmacoeconomics. 2011 21 22 Oct;29(10):88393 23 24 21 Drummond MF, Wilson DA, Kanavos P, Ubel P, Rovira J. Assessing the economic 25 26 challenges posed by orphan drugs. Int J Technol Assess Health Care 2007; 23:3642. 27 28 29 22 Picavet E, Morel T, Cassiman D, Simoens S. Shining a light in the black box of orphan 30 31 drug pricing. Orphanet J Rare Dis. 2014 Apr 27;9:62. 32

33 23 UK cost agency says "no" to Novartis blood cancer drug Jakavi. Available from: http://bmjopen.bmj.com/ 34 35 http://www.reuters.com/article/2013/02/13/usnovartisbritainjakavi 36 37 idUSBRE91C00Y20130213 [Accessed March 1st, 2013]. 38 39 40 24 Pharmafile. NICE rejects Pfizer blood cancer drug. 16/07/2013. 41 on September 28, 2021 by guest. Protected copyright. 42 http://www.pharmafile.com/news/180127/nicerejectspfizerbloodcancerdrug [Accessed 43 44 25th April, 2014] 45 46 25 BBC News Health. NHS England push to rein in cancer drug prices. 47 48 49 http://www.bbc.co.uk/news/health28938022 [Accessed 28th August, 2014] 50 51 26 Simoens S. Pricing and reimbursement of orphan drugs: the need for more transparency. 52 53 Orphanet J Rare Dis 2011, 6:42. doi:10.1186/17501172642 54 55 27 Light DW, Lexchin J. Foreign free riders and the high price of US medicines. BMJ 2005; 56 57 331: 95860. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 60

22 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 28 Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or 5 6 intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: a 7 8 9 systematic review and metaanalysis. Neonatology. 2012;102(1):915 10 11 29 Gov.Uk. Policy. Making NHS more efficient and less bureaucratic. March 25, 2013. 12 13 Available from: https://www.gov.uk/government/policies/makingthenhsmoreefficient 14 15 andlessbureaucraticFor peer[Accessed 21st May,review 2013]. only 16 17 30 BBC News. Novartis: India rejects patent plea for cancer drug Glivec. Available from: 18 19 20 http://www.bbc.co.uk/news/business21991179 [Accessed 1st April, 2013]. 21 22 31 Wirtz PW, van Dijk JG, van Doorn PA et al. The epidemiology of the LambertEaton 23 24 myasthenic syndrome in the Netherlands. Neurology 2004;63:3978. 25 26 32 Epicept Corporation v. Canada (Health). 2010 FC 956, [2010] 4 F.C.R. D9. 27 28 29 http://reports.fja.gc.ca/eng/2010/2010fc956.pdf [Accessed 3rd September, 2014] 30 31 33 European Medicines Agency. Assessment Report for Celecoxib for the reduction of the 32

33 number of adenomatous intestinal polyps in familial adenomatous polyposis, as an adjunct http://bmjopen.bmj.com/ 34 35 to surgery and further endoscopic surveillance. Available from: 36 37 38 http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/06/WC500107627 39 40 .pdf [Accessed 28th January, 2013]. 41 on September 28, 2021 by guest. Protected copyright. 42 34 European Medicines Agency. Thelin (sitaxentan) to be withdrawn due to cases of 43 44 unpredictable serious liver injury. Available from: 45 46 http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/12/WC5000 47 48 49 99707.pdf [Accessed 22nd February, 2013]. 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 254x190mm (300 x 300 DPI) http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 28, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 254x190mm (300 x 300 DPI) http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 28, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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33 254x190mm (300 x 300 DPI) http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 28, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

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1 2 3 Appendix 1: Level and quality of evidence with relevant references for EMA-approved orphan drugs 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 5 6 Orphan drug Active ingredient †Level ‡Quality Reference 7 Adcetris Brentuximab vedotin 3 L [1,2] 8 Adempas Riociguat 2 M [3] 9 10 Arzerra Ofatumumab 1 L [4] 11 Atriance Nelarabine 3 L [5,6,7] 12 Bosulif Bosutinib (monohydrate) 3 L [8] 13 Bronchitol Inhaled mannitol 1 M [9] 14 Carbaglu Carglumic acid 3 VL [10] 15 Cayston Aztreonam 1 M [11] 16 Ceplene Histamine dihydrochloride 2 L [12] 17 For peer review only 18 Cholic Acid FGK Cholic acid 3 VL [13] 19 Cometriq Cabozantinib 2 L [14] 20 Cystadane Betaine anhydrous 3 VL [15,16] 21 Dacogen Decitabine 2 M [17,18,19] 22 Defitelio Defibrotide 1 L [20] 23 Diacomit Stiripentol 2 M [21] 24 Elaprase Idursulfase 1 M [22] 25 Esbriet Pirfenidone 1 M [23] 26 27 Evoltra Clofarabine 3 VL [24,25] 28 Exjade Deferasirox 1 M [26,27] 29 Firazyr Icatibant acetate 1 M [28] 30 Firdapse Amifampridine 1 L [29] 31 Gliolan 5-aminolevulinic acid 2 M [30] 32 Glybera Alipogene tiparvovec 2 M [31,32] 33 Iclusig Ponatinib 3 L [33] 34 Increlex Mecasermin 2 M [34] 35 36 Inovelon Rufinamide 1 M [35] 37 Jakavi Ruxolitinib 2 M [36,37] 38 Kalydeco Ivacaftor 1 M [38] http://bmjopen.bmj.com/ 39 Kuvan Sapropterin 1 M [39] 40 Litak Cladribine 2 M [40,41,42,43,44] 41 Lysodren Mitotane 2 M [45,46] 42 Mepact Mifamurtide 2 L [47] 43 Mozobil Plerixafor 2 M [48,49] 44 45 Myozyme Alglucosidase alfa 1 M [50] 46 Naglazyme Gasulfase 1 L [51] on September 28, 2021 by guest. Protected copyright. 47 Nexavar Sorafenib 1 M [52,53,54,55] 48 Nexobrid Bromelain 3 L [56,57] 49 Nplate Romiplostim 2 M [58,59] 50 Onsenal Celecoxib 2 M [60,61] 51 Orfadin Nitisinone 3 M [62,63,64] 52 Pedea IV Ibuprofen 1 M [65] 53 54 Peyona Caffeine citrate 2 M [66,67] 55 Photobarr Porfimer sodium 2 M [68,69] 56 Plenadren Hydrocortisone 2 M [70,71] 57 Prialt Ziconotide 2 M [72,73] 58 Procysbi Mercaptamine bitartrate 2 L [74] 59 Revatio Sildenafil I M [75,76] 60 Revestive Teduglutide 2 M [77,78] Revlimid Lenalidomide 2 M [79,80,81]

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1 2 3 Rilonacept Regeneron Rilonacept 2 M [82] 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 5 Savene Dexrazoxane 3 M [83] 6 Signifor Pasireotide 3 M [84] 7 Siklos Hydroxycarbamide 1 M [85] 8 Sirturo Bedaquiline fumarate 2 M [86] 9 Soliris Eculizumab 2 M [87,88,89] 10 Sprycel Dasatinib 1 L [90] 11 Tasigna Nilotinib 1 L [90] 12 Tepadina Thiotepa 2 M [91,92,93,94,95] 13 14 Thalidomide Celgene Thalidomide 1 M [96] 15 Thelin Sitaxentan sodium 1 H [97,98,99,100] 16 Tobi Podhaler Tobramycin 1 M [101] 17 Torisel ForTemsirolimus peer review1 M only[55,102,103] 18 Tracleer Bosentan 1 M [75,76,104,105] 19 Trisenox Arsenic Trioxide 2 M [106,107,108] 20 Ventavis Iloprost 1 M [75,76,109] 21 Vidaza Azacitidine 1 M [110,111] 22 23 Volibris Ambrisentan 2 M [112] 24 Votubia Everolimus 2 M [17,18] 25 Vpriv Velaglucerase alfa 2 M [113,114] 26 Vyndaqel Tafimidis 2 M [115] 27 Wilzin Zinc acetate dihydrate 3 L [116,117,118] 28 Xagrid Anagrelide 2 M [119,120] 29 Xaluprine Mercaptopurine 2 M [121,122] 30 Yondelis Trabectedin 2 M [123,124,125,126] 31 32 Zavesca Miglustat 2 M [127,128,129,130,131] 33 34 35 † Adapted from the Oxford Centre for Evidence-Based Medicine tool kit. 1: Systematic review of randomized trials or 36 n-of-1 trials; 2: Randomized trial or observational study with dramatic effect; 3: Non-randomized controlled 37 cohort/follow-up study; 4: Case-series, case-control studies, or historically controlled studies; 5: Mechanism-based http://bmjopen.bmj.com/ 38 reasoning 39 40 ‡ Adapted from GRADE tool kit. H: high quality - Further research is very unlikely to change our confidence in the 41 estimate of effect; M: moderate quality - Further research is likely to have an important impact on our confidence in the 42 estimate of effect and may change the estimate; L: low quality - Further research is very likely to have an important 43 impact on our confidence in the estimate of effect and is likely to change the estimate; VL: Very low quality - Any 44 45 estimate of effect is very uncertain 46 on September 28, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective 5 6 randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab 97: 473–481 7 71 Benson S, Neumann P, Unger N, Schedlowski M, Mann K, Elsenbruch S, Petersenn S (2012) Effects of 8 9 standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, 10 crossover study in patients with secondary adrenal insufficiency. Eur J Endocrinol 167(5): 679-85. 11 12 72 Rauck RL, Wallace MS, Leong MS, Minehart M, Webster LR, Charapata SG, Abraham JE, Buffington DE, 13 Ellis D, Kartzinel R; Ziconotide 301 Study Group (2006) A randomized, double-blind, placebo-controlled 14 15 study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage 31(5):393-406. 16 73 Wallace MS, Charapata SG, Fisher R, Byas-Smith M, Staats PS, Mayo M, McGuire D, Ellis D; Ziconotide 17 For peer review only 18 Nonmalignant Pain Study 96-002 Group (2006) Intrathecal ziconotide in the treatment of chronic 19 nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation 9(2): 75- 20 21 86 22 74 Langman CB, Greenbaum LA, Sarwal M, Grimm P, Niaudet P, Deschênes G, Cornelissen E, Morin D, 23 24 Cochat P, Matossian D, Gaillard S, Bagger MJ, Rioux P. A randomized controlled crossover trial with 25 delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine 26 27 levels and comparison of safety. Clin J Am Soc Nephrol. 2012 Jul;7(7):1112-20 28 75 He B, Zhang F, Li X, Tang C, Lin G, Du J, Jin H (2010) Meta-analysis of randomized controlled trials on 29 30 treatment of pulmonary arterial hypertension. Circ J 74(7): 1458-64 31 76 Chen YF, Jowett S, Barton P, Malottki K, Hyde C, Gibbs JS, Pepke-Zaba J, Fry-Smith A, Roberts J, Moore 32 D (2009) Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for 33 34 pulmonary arterial hypertension within their licensed indications: a systematic review and economic 35 evaluation. Health Technol Assess 13(49): 1-320 36 37 77 Jeppesen PB, Pertkiewicz M, Messing B, Iyer K, Seidner DL, O'keefe SJ, Forbes A, Heinze H, Joelsson B 38 http://bmjopen.bmj.com/ (2012) Teduglutide reduces need for parenteral support among patients with short bowel syndrome with 39 40 intestinal failure. Gastroenterology 6: 1473–1481 41 78 Jeppesen PB, Gilroy R, Pertkiewicz M, Allard JP, Messing B, O'Keefe SJ (2011) Randomised placebo- 42 43 controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in 44 patients with short bowel syndrome. Gut 60(7): 902-14. 45 46 79 Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, on September 28, 2021 by guest. Protected copyright. 47 Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple 48 49 Myeloma (010) Study Investigators (2007) Lenalidomide plus dexamethasone for relapsed or refractory 50 multiple myeloma. N Engl J Med 357: 2123-32 51 52 80 Dimopoulos M, Alegre A, Stadtmauer EA, Goldschmidt H, Zonder JA, de Castro CM, Masliak Z, Reece D, 53 Olesnyckyj M, Yu Z, Weber DM (2010) The efficacy and safety of lenalidomide plus dexamethasone in 54 55 relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer 116(16): 3807-14 56 81 Chanan-Khan AA, Lonial S, Weber D, Borrello I, Foà R, Hellmann A, Dimopoulos M, Swern AS, Knight R 57 58 (2012) Lenalidomide in combination with dexamethasone improves survival and time-to-progression in 59 patients ≥65 years old with relapsed or refractory multiple myeloma. Int J Hematol 96(2): 254-62 60 82 Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, Weinstein SP, Belomestnov P, Yancopoulos GD, Stahl N, Mellis SJ (2008) Efficacy and safety of rilonacept (interleukin-1 Trap) in patients

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from A, Grogan DR (2012) Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, 5 6 controlled trial. Neurology 79(8): 785-92. 7 116 Shimizu N, Fujiwara J, Ohnishi S, Sato M, Kodama H, Kohsaka T, Inui A, Fujisawa T, Tamai H, Ida S, 8 9 Itoh S, Ito M, Horiike N, Harada M, Yoshino M, Aoki T (2010) Effects of long-term zinc treatment in 10 Japanese patients with Wilson disease: efficacy, stability, and copper metabolism. Transl Res 156(6): 350-7 11 12 117 Brewer GJ, Dick RD, Johnson VD, Fink JK, Kluin KJ, Daniels S (2001) Treatment of Wilson's disease with 13 zinc XVI: treatment during the pediatric years. J Lab Clin Med 137(3): 191-8. 14 15 118 Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JK (1998) Treatment of Wilson's disease 16 with zinc: XV long-term follow-up studies. J Lab Clin Med. 132:264-78 17 For peer review only 18 119 Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, 19 Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR; United Kingdom Medical Research Council 20 21 Primary Thrombocythemia 1 Study (2005) Hydroxyurea compared with anagrelide in high-risk essential 22 thrombocythemia. N Engl J Med 353: 33-45 23 24 120 Birgegård G, Björkholm M, Kutti J, Lärfars G, Löfvenberg E, Markevärn B, Merup M, Palmblad J, 25 Mauritzson N, Westin J, Samuelsson J (2004) Adverse effects and benefits of two years of anagrelide 26 27 treatment for thrombocythemia in chronic myeloproliferative disorders. Haematologica 89: 520-527 28 121 Escherich G, Richards S, Stork LC, Vora AJ; Childhood Acute Lymphoblastic Leukaemia Collaborative 29 30 Group (CALLCG) (2011) Meta-analysis of randomised trials comparing thiopurines in childhood acute 31 lymphoblastic leukaemia. Leukemia. (6): 953-9 32 122 Gehan EA, Freireich EJ (2011) The 6-MP versus placebo clinical trial in acute leukemia. Clin Trials. 8(3): 33 34 288-97 35 123 Krasner CN, Poveda A, Herzog TJ, Vermorken JB, Kaye SB, Nieto A, Claret PL, Park YC, Parekh T, 36 37 Monk BJ (2012) Patient-reported outcomes in relapsed ovarian cancer: results from a randomized Phase III 38 http://bmjopen.bmj.com/ study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD alone. Gynecol Oncol. 127(1): 39 40 161-7 41 124 Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, Pujade-Lauraine E, Park YC, 42 43 Parekh TV, Poveda AM (2012) Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in 44 recurrent ovarian cancer: overall survival analysis. Eur J Cancer 48(15): 2361-8 45 46 125 Poveda A, Vergote I, Tjulandin S, Kong B, Roy M, Chan S, Filipczyk-Cisarz E, Hagberg H, Kaye SB, on September 28, 2021 by guest. Protected copyright. 47 Colombo N, Lebedinsky C, Parekh T, Gómez J, Park YC, Alfaro V, Monk BJ (2011) Trabectedin plus 48 49 pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive 50 (platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol. 51 52 22(1): 39-48 53 126 Grosso F, D'Incalci M, Cartoafa M, Nieto A, Fernández-Teruel C, Alfaro V, Lardelli P, Roy E, Gómez J, 54 55 Kahatt C, Soto-Matos A, Judson I (2012) A comprehensive safety analysis confirms rhabdomyolysis as an 56 uncommon adverse reaction in patients treated with trabectedin. Cancer Chemother Pharmacol 69(6): 1557- 57 58 65 59 127 Pastores GM, Elstein D, Hrebícek M, Zimran A (2007) Effect of miglustat on bone disease in adults with 60 type 1 Gaucher disease: a pooled analysis of three multinational, open-label studies. Clin Ther. 29(8): 1645- 54

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1 2 3 APPENDIX 2: Summary of evidence tables and annual costs of orphan drugs approved by the EMA 4 5 6 Table 1: Summary of evidence and main results of orphan drugs for the management of cancers 7 Orphan drug Active ingredient Indication 1Level of 2Quality of Annual cost Summary of main results Severe adverse events (SAEs) 8 evidence evidence per patient (£) 9 Adcetris Brentuximab CD30⁺ Hodgkins & ALCL 3 Low 42,500 Median OS for Hodgkins was 40.5 mos (95% CI: 28.7, – [range, 1.8 Anaemia, neutropenia, thrombocytopenia, 10 vedotin to 48.3+ mos]) and the estimated 36-mo survival rate was 54% (44 to peripheral sensory neuropathy 11 For peer review64). Median OS not reached only for ALCL 12 13 Arzerra Ofatumumab Resistant CLL 1 Low 40,586 Insufficient evidence; impact on OS unclear Infections, neutropenia

14 Atriance Nelarabine T-ALL & T-LBL 3 Low 50,000 Response rates 31-50%; insufficient evidence on OS; severe Neurotoxicity, thrombocytopenia, neutropenia 15 toxicities 16 http://bmjopen.bmj.com/ 17 Bosulif Bosutinib Ph+ CML 3 Low 44,799 PFS at 2 years was 79%; overall survival at 2 years was 92% Thrombocytopenia, neutropenia, anemia, diarrhea, vomitting, rash, increased AST 18 19 Ceplene Histamine Acute myeloid leukemia 2 Low 35,450 Over 3 years, sig ↑ leukaemia-free survival vs control group (p < Headache, pyrexia 20 dihydrochloride 0.01). No sig effects on OS 21 Cometriq Cabozantinib Metastatic medullary thyroid 2 Low 70,664 PFS was 11.2 months for cabozantinib versus 4.0 months for placebo Diarrhea, palmarplantar erythrodysesthesia, and 22 CA (HR= 0.28; 95% CI, 0.19 to 0.40; p < 0.001); no statistically sig fatigue, GIT perforations, fistula development, 23 difference in OS (HR= 0.98; 95% CI: 0.63 to 1.52) and hemorrhage, mucosal inflammation, 24 hypocalcemia, pulmonary embolism, 25 on September 28, 2021 by guest. Protected copyright. hypertension

26 Dacogen Decitabine Acute myeloid leukemia 2 Moderate 58,300 Sig ↑ in PFS vs control (3.7 months: 2.7 to 4.6). No sig effect on OS Sig ↑ in risk of SAE compared with placebo (p = 27 compared with controls (p = 0.11). 1 RCT discontinued due to ↑d 0.002) 28 relapse rates 29 Evoltra Clofarabine Acute lymphoblastic 3 Very low 43,200 Response rates of 30-44%; no data on PFS; limited data on OS Infections, multiorgan failure, hepatotoxicity, 30 leukemia death 31 Gliolan 5-ALA Malignant glioma 2 Moderate 2,630 Sig diff in number of complete resections compared with None 32 conventional white light (p < 0.0001). Higher 6 month PFS 33 compared with white light (p = 0.0003); sig ↑ in OS

34 35 Iclusig Ponatinib Chronic myeloid leukemia 3 Low 68440 PFS 55% at 12 months; OS 84% at 12 months Pancreatitis, abd pain, increased lipase, diarrhea, 36 fever, MI, thrombocytopenia, anemia, 37 neutropenia, febrile neutropenia, pancytopenia. 18 deaths in study; 5 of which were attributed to 38 ponatinib 39 Imnovid Pomalidomide Multiple myeloma 2 Moderate 105600 Median PFS vs dexamethasone was 4 vs 1.9 months (HR = 0.48; Significant increase in risk of neutropenia and 40 95% CI: 0.39 to 0.60; p < 0.0001); Median OS 12.7 vs 8.1 months pneumonia 41 (HR=0.74; 95% CI: 0.56 to 0.97; p=0.0285) 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 4 Jakavi Ruxolitinib Primary myelofibrosis 2 Moderate 43,200 Sig ↓ in reduction of splenic vol compared with placebo (p < 0.001 ); Anemia, neutropenia, thrombocytopenia; ↑d in 5 trend towards ↑d OS ( p = 0.076; 0.009 at 3 yrs) risk of hematologic SAEs compared with 6 placebo (p < 0.0001)

7 Litak Cladribine Hairy cell leukemia 2 Moderate 35,000 Improved rates of OS. 12 year survival rate of 79% in one study Asthenia, fever, rigor 8 9 Lysodren Mitotane Adrenocortical CA 2 Moderate 51,900 Improvement on the duration of tumor regression. Estimate on Fever, rigor 10 overall survival not precise (no studies comparing lysodren with placebo or other supportive therapies) 11 For peer review only 12 Mepact Mifamurtide Osteosarcoma 2 Low 92,000 Did not improve 3-year EFS rate compared with standard ↑d ALT 13 chemotherapy 14 Mozobil Plerixafor Multiple myeloma & NHL 2 Moderate 34,179 Sig ↑ in median CD34⁺ count compared with placebo (p < 0.001); no Diarrhea, fatigue 15 sig diff in OS 16 http://bmjopen.bmj.com/ 17 Nexavar Sorafenib Liver CA & Advanced RCC 1 Moderate 38,852 Improvement in PFS; sig improvement in OS compared with placebo Hand & foot syndrome, sig ↑in risk of 18 hypertension compared with placebo (p < 0.0001) 19 20 Onsenal Celecoxib Familial adenomatous 2 Moderate 1,800 Sig ↓ in incidence of adenoma compared with placebo at 5 years (p < Sig ↑ in risk of CVS and GI disorders compared 21 polyposis 0.001); reverse was the case at 2 years (p < 0.0001) with placebo (p = 0.034) 22 Revlimid Lenalidomide Multiple myeloma 2 Moderate 53,363 PFS significantly greater in revlimid compared with placebo (p < Sig ↑ in risk of hematological and thrombotic 23 0.0001); no sig diff in median OS SAE (p < 0.0001) 24 25 Savene Dexrazoxane Anthracycline extravasation 3 Moderate 6,750 Almost 100% ↓ in the need for surgical debridment on September 28, 2021 by guest. Protected copyright. Wound infection, neutropenia 26 Sprycel Dasatinib CML & resistant ALL 1 Low 32,000 Sig ↑ in PFS compared with imatinib in CML (p = 0.0012); ≥90% Fluid retention, dyspnea, pleural effusion, 27 complete remission in 2 non-RCTs for ALL; impact on OS unclear cytopenia, hemorrhage 28 29 Tasigna Nilotinib Chronic phase CML 1 Low 30,000 Rates of molecular and cytogenetic response significantly greater Thrombocytopenia, anemia, neutropenia, and 30 compared with imatinib (p < 0.001); impact on OS unclear asthenia

31 Tepadina Thiotepa HPCT 2 Moderate 20,608 Results from phase III RCTs have been mixed Cytopenia, hemorrhagic cystitis, acute and 32 chronic GvHD 33 34 Thalidomide Thalidomide Multiple myeloma 1 Moderate 25,200 Improved PFS & OS when combined with standard therapy (p = Sig ↑ in risk of VTE compared with control (p < Celgene 0.05) 0.0001) 35 36 Torisel Temsirolimus RCC & mantle cell 1 Moderate 36,000 Sig ↑ in OS & PFS compared with interferon in RCC; no sig effect Bowel perforation, neutropenia, anemia, 37 lymphoma on median OS in mantle cell lymphoma dyspnea, hyperglycemia 38 Vidaza Azacitidine Myelodysplastic syndromes 1 Moderate 45,000 Sig. improvement in OS compared with placebo Neutropenia, thrombocytopenia, anemia 39 40 Votubia Everolimus SECA assoc with TSC 2 Moderate 15,000 ↓d primary SECA vol by ≥ 50% in 35% of patients compared with Pneumonia, bronchitis, abscess 41 placebo (p < 0.0001) 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 4 Xaluprine Mercaptopurine Acute lymphoblastic 2 Moderate 2,100 Sig diff in duration of remission vs placebo (p < 0.01); no sig diff in Hypersensitivity, thrombocytopenia 5 leukemia median OS 6 Yondelis Trabectedin STS & ovarian neoplasm 2 Moderate 24,898 Improved OS compared with standard care (p = 0.02). Analyses for Rhabdomyolysis, neutropenia, ↑bilirubin, 7 platinum-resistant not specified congestive heart failure 8 9 Abbreviations: 10 ALCL: Anaplastic large cell lymphoma; FVC: forced vital capacity; 6MWD: 6-minute walk distance; CLL: chronic lymphocytic leukemia; OS: overall survival; T-ALL: T-cell acute lymphoblastic leukemia; T-LBL: T-cell 11 lymphoblastic lymphoma; 5-ALA: 5-aminolevulinic acid;For PFS: progression-free peersurvival; CML: chronic myeloid review leukemia; ALT: alanine transaminase; onlyAST: aspartate transaminase; NHL: non-hodgkins lymphoma; RCC: renal cell 12 carcinoma; HPCT: haematopoietic progenitor cell transplant; GvHD: graft versus host disease; VTE: venous thromboembolism; SECA: subependymal giant cell astrocytoma; TSC: tuberous sclerosis complex; STS: soft tissue sarcoma 13 14 15 16 http://bmjopen.bmj.com/ 17 18 19 20 21 22 23 24

on September 28, 2021 by guest. Protected copyright. 25 26 27 28 29 30 31 32 33

34 35 36 37

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1 2 3 Table 2: Summary of evidence and main results of orphan drugs for management of inborn errors of metabolism and immune disorders 4 Orphan drug Active ingredient Indication 1Level of 2Quality of Annual cost Summary of main results Severe adverse events (SAE) 5 evidence evidence per patient (£) 6 7 Bronchitol Inhaled mannitol Cystic Fibrosis 1 Moderate 6,040 Sig ↑ in FEV1 vs placebo in adults (p < 0.001). No sig reduction in Nasopharyngeal pain, bronchospasm 8 pulmonary exacerbations

9 Carbaglu Carglumic acid Hyperammonaemia 3 Very low 245,000 ↓d blood ammonia conc. , ↓ in metabolic decompensation, ↓d None 10 neurological sequelae 11 For peer review only 12 Cayston Aztreonam Cystic Fibrosis 1 Moderate 15,399 Sig ↓ in Pseudomonas spp. density compared with placebo; no sig None-related diff on CFQ-RRS 13 14 Cholic acid Cholic acid IEM in primary bile acid 3 Very low N/A No statistically significant changes in urinary bile acids and No formal preclinical safety studies have been 15 FGK synthesis due to Sterol 27- transaminases conducted 16 hydroxylase Cystadane Betaine anhydrous Homocystinuria 3 Very low 46,580 No sig benefit on BMD; evidence from several casehttp://bmjopen.bmj.com/ series very Cerebral edema 17 limited 18 19 Elaprase Idursulfase Hunter syndrome 1 Moderate 309,660 Sig ↑ in 6MWD vs placebo (p =0.013); sig ↓ in spleen vol vs Carpal tunnel syndrome, airway obstruction, 20 placebo (p < 0.0001); no sig diff in FVC sleep apnea

21 Exjade Deferasirox Iron overload in beta-thalassemia 1 Moderate 25,000 Comparable in efficacy with deferoxamine Transient transaminitis 22 23 Firazyr Icatibant acetate Hereditary angioedema 1 Moderate 16740 Sig ↓ in recovery times from attacks vs placebo (p < 0.001) None 24

Glybera Alipogene Lipoprotein lipase deficiency 2 Moderate 216,150 Sig ↓ in serum TG's and chylomicrons compared on September 28, 2021 by guest. Protected copyright. with pre- Fever 25 tiparvovec treatment levels; sig ↓ in incidence of pancreatitis episodes 26 compared with pre-treatment levels 27 28 Increlex Mecasermin Insulin growth factor-1 deficiency 2 Moderate 18,000 Growth at 6 months was > 3 times that achieved with placebo Papilledema

29 Kalydeco Ivacaftor Cystic Fibrosis 1 Moderate 182,625 The mean difference in change in % of predicted FEV1 was 10.5 Epistaxis, diarrhea, asthenia 30 (95% CI: 8.5 to 12.5) % points in the adults' study and 10.0 (95% 31 CI 4.5 to 15.5) %points in the children's study at 48 weeks 32 Kuvan Sapropterin Hyperphenylalaninaemia 1 Moderate 36,336 Sig ↓ in serum PHA conc compared with placebo (p < 0.001) None 33 34 Myozyme Alglucosidase alfa Pompe disease 1 Moderate 230,000 ≥67% of patients were stabilized or had improvement in muscular Tracheal hemorrhage, emphysema, 35 and respiratory function; sig ↑ in 6MWT, FVC & maximum pneumothorax 36 expiratory pressure compared with placebo

37 Naglazyme Gasulfase Mucopolysaccharidosis VI 1 Low 170,000 No statistical difference compared with placebo in both 12MWT Anaphylaxis 38 and 3MSCT 39 40 Orfadin Nitisinone Hereditary tyrosinemia 1 3 Moderate 24,744 Sig ↓ in number of hospitalisations and liver transplantation Corneal opacities, convulsion, GI hemorrhage 41 compared with controls (p < 0.001) 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 4 Orphacol Cholic acid IEM in primary bile acid 3 Low N/A 500-fold ↓ in 3β -HSD; 30-fold ↓ in Δ4-3-oxo-R deficiency Well tolerated 5 synthesis due to Sterol 27- 6 hydroxylase Procysbi Mercaptamine Nephropathic cystinosis 2 Low 148659 Sig ↓in peak WBC cyctine level compared with conventional GI AEs were 3-fold greater with procysbi 7 bitartrate Cystagon 0.08±0.04 nmol 1/2 cystine/mg protein (95.8% CI: 0– 8 0.16) 9 Siklos Hydroxycarbamide Sickle cell disease 1 Moderate 6,085 Sig ↓ in no & severity of crises yearly compared with placebo (p < Neutropenia 10 0.001)

11 Soliris Eculizumab PNH & aHUS For 2 peerModerate 378review,000 Sig diff in stabilization ofonly Hb levels in the absence of transfusion Abdominal distension, renal impairment 12 compared with placebo in PNH (p < 0.0001); complete reversal of 13 aHUS post-transplantation 14 Tobi Podhaler Tobramycin Pseudomonas in cystic fibrosis 1 Moderate 1540 (28 days) Sig ↑in FEV1 compared with placebo (p = 0.002) Exacerbation of cystic fibrosis 15 16

Vpriv Velaglucerase alfa Gaucher's disease type 1 2 Moderate 146,660 Sustained maintenance of Hb conc, and platelet counts,http://bmjopen.bmj.com/ as well as Anaphylaxis 17 liver and spleen volumes; sig ↑ in BMD (p < 0.01) 18 Vyndaqel Tafimidis Transthyretin amyloidosis 2 Moderate 112,051 Trend toward more NIS-LL responders in the tafamidis group than Urinary tract infection 19 in the placebo group (p = 0.068) 20 21 Wilzin Zinc acetate Wilson's disease 3 Low 726 Sig ↑ in urinary copper excretion at 4 wks; slight ↓ in ALT, AST Safer compared with penicillamine 22 dihydrate and ϒ-GTP

23 Zavesca Miglustat Type 1 Gaucher disease & 2 Moderate 58,400 Sig ↑ in BMD (p < 0.001), no sig diff in Hb conc, as well as liver Diarrhea, weight loss 24 Niemann-Picks Disease Type C and spleen vol b/w groups in Gauchers; no sig diff between groups 25 for HSEM for NPD-C (p=0·091) on September 28, 2021 by guest. Protected copyright. 26 Abbreviations: 27 FVC: forced vital capacity; 6MWD: 6-minute walk distance; FEV1: forced expiratory volume in one minute; CFQ-RRS : cystic fibrosis questionnaire-revised respiratory score; BMD: bone mineral density; NIS-LL: Neuropathy 28 Impairment Score-Lower Limbs; ALT: alanine transaminase; AST: aspartate transaminase; TG: triglycerides; IGF-1 : Insulin growth factor-1; PHA: phenylalanine; 12MWT: 12-minute walk test; WBC: White blood cell count; 3MSCT: 3-minute stair climb test; 3β-HSD: 3β-hydroxy-Δ5-C -steroid oxido reductase ; PNH: paroxysmal nocturnal hemoglobinuria; aHUS: atypical haemolytic uremic syndrome; GTP: gamma-glutamyl transpeptidase; NPD- 29 27 ϒ- C: Niemann-Pick’s disease type C; HSEM: horizontal sadistic eye movement. 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Table 3: Summary of evidence and main results of orphan drugs for managing other conditions 4 Orphan drug Active ingredient Indication 1Level of 2Quality of Annual cost Summary of main results Severe adverse events (SAE) 5 evidence evidence per patient (£) 6 7 Adempas Riociguat PAH Class II to III 2 Moderate 53495 Sig ↑ in 6MWD vs placebo MD: 46m; 95% CI: 25 to 67; p < 0.001; Sig Syncope, gastritis, acute renal failure, 8 ↓ in pulm vascular resistance vs placebo MD: –246 dyn · sec · cm–5; hypotension 95% CI, –303 to –190; P<0.001 9 10 Revatio Sildenafil PAH Class II & III 1 Moderate 4482 Sig improvement in 6MWD compared with placebo (p < 0.001) Left ventricular dysfunction, postural 11 For peer review only hypertension 12 Tracleer Bosentan PAH III; digital ulcers 1 Moderate 19463 Sig ↑in 6MWD compared with placebo; sig ↓ in the number of new ↑LFTs 13 digital ulcers compared with placebo 14 15 Opsumit Macitentan PAH Class II to III 2 Moderate 27,979 Sig ↑ in 6MWD vs placebo (3mg macitentan: 16.8 m; 97.5% CI, −2.7 Haematemesis, sudden cardiac death, 16 to 36.4; P = 0.01) 10mg macitentan: 22.0 m; 97.5% CI, 3.2 to 40.8; P = cardiorespiratory failure, nasopharyngitis, 0.008). Time to death: 3mg HR=0.70; 97.5% CI: http://bmjopen.bmj.com/ 0.52 to 0.96; p = 0.01 anemia 17 and 10 mg HR = 0.55; 97.5% CI: 0.39 to 0.76; p < 0.001 18 19 Volibris Ambrisentan PAH III & III 2 Moderate 20088 Sig ↑in 6MWT compared with placebo (p < 0.005) Gastroenteritis, intracranial bleeding, 20 headache, facial edema

21 Diacomit Stiripentol SMEI, Dravet’s syndrome 2 Moderate 7600 Sig ↓ in freq of seizures vs placebo (p < 0.0001) Drowsiness 22 23 Defitelio Defibrotide Veno-occlusive disease (VOD) 1 Low Overall mean incidence of VOD compared with other was 4.7% vs None 24 13.7% (p < 0.005); no sig difference in severity (0.8% 95% CI, 0.2–

1.4) or RR (0.31; 95% CI, 0.09–1.06) of VOD on September 28, 2021 by guest. Protected copyright. 25 26 Esbriet Pirfenidone Idiopathic Pulm Fibrosis 1 Moderate 26172 Sig ↓ in risk of disease progression vs placebo (p = 0.002); sig Cardiotoxicity, respiratory infections 27 improvement in FVC and VC vs placebo (p = 0.0006). No evidence on 28 OS

29 Firdapse Amifampridine LEMS in adults 1 Low 47000 Sig improvements in QMG score & (CMAP); p < 0.0001) Rare 30 31 Inovelon Rufinamide Lennox Gastaut syndrome 1 Moderate 3000 Efficacious in doses up to 45mg/kg/day when used as adjunct; sig ↓ in Convulsion, weight loss 32 the incidence of seizures compared with placebo (p < 0.0001)

33 Nexobrid Bromelain Debridement 3 Moderate ? Sig ↓ in perceived full-thickness wound area & skin-graft use (p < Fever 34 0.0001) 35 36 Nplate Romiplostim Idiopathic thrombocytopenic 2 Moderate 40102 Sig ↑ in platelet response rate compared with placebo (p < 0.0001) Thrombosis purpura 37 Pedea IV Ibuprofen Patent ductus arteriosus 1 Moderate 6575 No advantage in closure rates compared with oral ibuprofen Comparable to oral ibuprofen 38 39 Peyona Caffeine citrate Primary apnea 2 Moderate 6300 Sig ↑ in rate of survival compared with placebo (p = 0.008); sig ↓in the NEC, seizures 40 incidence of severe retinopathy compared with placebo (p = 0.017) 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Plenadren Hydrocortisone Adrenal insufficiency 2 Moderate 2920 Sig ↓ in body weight, blood pressure and heart rate compared with Gastroenteritis, intracranial bleeding, 4 thrice daily hydrocortisone; limited evidence headache, facial edema 5 6 Prialt Ziconotide Intractable chronic pain 2 Moderate 20000 Sig ↓in pain compared with placebo (p < 0.04); sig ↑ in risk of SAE Dizziness, confusion, urinary retention, compared with placebo (p = 0.006) possible suicide link 7 8 Revestive Teduglutide Short-bowel syndrome 2 Moderate 200000 (US Sig improvement in graded response score (GRS) compared with Catheter-site infection and sepsis 9 estimates) placebo at high dose (p = 0.007) 10 Rilonacept Rilonacept Cryopyrin-associated periodic 2 Moderate 212000 (US Sig improvement in symptom score compared with placebo (p < None 11 Regeneron syndrome (CAPS) For peer estimates)review 0.0001) only 12 13 Signifor Pasireotide Cushing's disease 3 Moderate 47000 Sig ↓ in urinary cortisol levels at medium and high does (p < 0.001) Hyperglycemia, diabetes mellitus 14 Sirturo Bedaquiline Multi-drug resistant TB 2 Moderate N/A Sig ↓ in time to conversion to a -ve sputum culture compared with Diabetic ketoacidosis 15 fumarate PLA, HR= 11.8; 95% CI: 2.3 to 61.3; P = 0.003 16 http://bmjopen.bmj.com/ 17 Xagrid Anagrelide High risk essential 2 Moderate 5000 Significantly more patients in the hydroxyurea group reached the Arterial and venous thrombosis, hemorrhage 18 thrombocythemia primary end point at 39 months (p = 0.04)

19 Abbreviations: 20 PAH: pulmonary arterial hypertension; FVC: forced vital capacity; 6MWD: 6-minute walk distance; FEV1: forced expiratory volume in one minute; SMEI: severe myoclonic epilepsy in infancy; LEMS: Lambert-Eaton myoclonic 21 syndrome; QMG: Quantitative Myasthenia Gravis; CMAP: compound muscle action potential 22 23 24 25 on September 28, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 1 Based on the Oxford Centre for Evidence-Based Medicine criteria [16]. 1: Systematic review of randomized trials or n-of-1 trials; 2: Randomized trial or observational study with dramatic effect; 3: Non-randomized controlled 36 cohort/follow-up study; 4: Case-series, case-control studies, or historically controlled studies; 5: Mechanism-based reasoning 2 37 Based on the GRADE criteria [17]. High quality - Further research is very unlikely to change our confidence in the estimate of effect; Moderate quality - Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low quality - Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality - Any 38 estimate of effect is very uncertain 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 49 of 60 BMJ Open

1 2 3 Appendix 3: Approval dates and references used to document annual costs of orphan drugs 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 5 6 Orphan drug EMA approval date Annual cost (£) Reference 7 Adcetris 25/10/2012 42,500 [1] 8 Adempas 27/03/2014 53,495 [2] 9 10 Arzerra 19/04/2010 40,586 [3] 11 Atriance 22/08/2007 50,000 [4] 12 Bosulif 27/03/2013 44,799 [5] 13 Bronchitol 13/04/2012 6,040 [6] 14 15 Carbaglu 24/01/2003 245,000 [7] 16 Cayston 21/09/2009 15,399 [8] 17 Ceplene For07/10/2008 peer review35,450 only [9] 18 Cholic Acid FGK 04/04/2014 N/A N/A 19 Cometriq 21/03/2014 70,664 [10] 20 21 Cystadane 15/02/2007 46,580 [11] 22 Dacogen 20/09/2012 58,300 [12] 23 Defitelio 18/10/2013 N/A N/A 24 Diacomit 04/01/2007 7,600 [13] 25 26 Elaprase 08/01/2007 309,660 [14] 27 Esbriet 28/02/2011 26,172 [15] 28 Evoltra 29/05/2006 43,200 [16] 29 Exjade 28/08/2006 25,000 [17] 30 Firazyr 11/07/2008 16,740 [18] 31 32 Firdapse 23/12/2009 47,000 [19] 33 Gliolan 07/09/2007 2,630 [20] 34 Glybera 29/10/2012 216,151 [21] 35 Iclusig 01/07/2013 68,440 [22] 36 37 Imnovid 05/08/2013 105,600 [23] 38 Increlex 03/08/2007 18,000 [24] http://bmjopen.bmj.com/ 39 Inovelon 16/01/2007 3,000 [25] 40 Jakavi 23/08/2012 43,200 [26] 41 Kalydeco 23/07/2012 182,625 [27] 42 43 Kuvan 02/12/2008 36,336 [28] 44 Litak 14/04/2004 35,000 [29] 45 Lysodren 28/04/2004 51,900 [30] on September 28, 2021 by guest. Protected copyright. 46 Mepact 06/03/2009 92,000 [31] 47 48 Mozobil 31/07/2009 34,179 [32] 49 Myozyme 29/03/2006 230,000 [33] 50 Naglazyme 24/01/2006 170,000 [34] 51 Nexavar 19/07/2006 38,852 [35] 52 53 Nexobrid 03/09/2012 N/A N/A 54 Nplate 04/02/2009 40,102 [36] 55 Onsenal 17/10/2003 1,800 [37] 56 Opsumit 20/12/2013 27,979 [38] 57 Orfadin 21/02/2005 24,744 [39] 58 59 Orphacol 12/09/2013 N/A N/A 60 Pedea 29/07/2004 6,575 [40] Peyona 02/07/2009 6,300 [41]

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1 2 3 Plenadren 03/11/2011 2,920 [42] 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 5 Prialt 21/02/2005 20,000 [43] 6 Procysbi 06/09/2013 148,659 [44] 7 Revatio 28/10/2005 4,482 [45] 8 Revestive 30/08/2012 200,000 (US estimates) [46] 9 10 Revlimid 14/06/2007 53,363 [47] 11 Rilonacept Regeneron 23/10/2009 212,000 (US estimates) [48] 12 Savene 28/07/2006 6,750 (3 doses) [49] 13 Signifor 24/04/2012 47,000 [50] 14 15 Siklos 29/06/2007 6,085 [51] 16 Sirturo 05/03/2014 N/A N/A 17 Soliris For20/06/2007 peer review378, 000only [52] 18 Sprycel 20/11/2006 32,000 [53] 19 Tasigna 19/11/2007 30,000 [54] 20 21 Tepadina 15/03/2010 20,608 [55] 22 Thalidomide Celgene 16/04/2008 25,200 [56] 23 Tobi Podhaler 20/07/2011 1,540 (28 days) [57] 24 Torisel 16/09/2003 36,000 [58] 25 26 Tracleer 15/05/2002 19,463 [45] 27 Ventavis 16/09/2003 38,000 [45] 28 Vidaza 17/12/2008 45,000 [59] 29 Volibris 21/04/2008 20,088 [60] 30 Votubia 02/09/2011 15,000 [61] 31 32 Vpriv 26/08/2010 146,660 [62] 33 Vyndaqel 16/11/2011 112,051 [63] 34 Wilzin 13/10/2004 726 [64] 35 Xagrid 16/11/2004 5,000 [65] 36 37 Xaluprine 09/03/2012 2,100 [66] 38 Yondelis 17/09/2007 24,898 (6 cycles) [67] http://bmjopen.bmj.com/ 39 Zavesca 20/11/2002 58,400 [68] 40 *N/A: Not available 41 42 43 44 45 46 on September 28, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 References

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 15 Pharmatimes.com. NICE opens public consultation on Esbriet. Available from : 5 6 http://www.pharmatimes.com/Article/12-11-30/NICE_opens_public_consultation_on_Esbriet.aspx [6th 7 March, 2013] 8 9 16 Scottish Medicines Consortium. Clofarabine (Evoltra®) for acute lymphoblastic leukaemia. SMC ISSUES 10 ADVICE ON NEW DRUGS. Available from: 11 12 http://www.scottishmedicines.org.uk/Press_Statements/Clofarabine Evoltra for acute lymphoblastic 13 leukemia [Accessed 6th March, 2013] 14 15 17 Horsley W. Deferasirox (Exjade®) for the treatment of chronic iron overload. January 2010. Available from: 16 http://www.netag.nhs.uk/files/appraisal-reports/Deferasirox-Exjade-NETAG-appraisal-report-Jan10.pdf 17 For peer review only 18 [Accessed 6th March, 2013] 19 18 All Wales Medicines Strategy Group Final Appraisal Report: Icatibant acetate (Firazyr®▼) – October 2008 20 21 19 Horsley W. Amifampridine phosphate (Firdapse®) for the symptomatic treatment of Lambert-Eaton 22 Myasthenic Syndrome (LEMS). November 2011. Available from: http://www.netag.nhs.uk/files/appraisal- 23 24 reports/Firdapse%20-%20NETAG%20appraisal%20report%20-%20Nov%202011%20- 25 WEB%20VERSION.pdf [Accessed 6th March, 2013] 26 27 20 Brain Tumour Alliance Australia Inc. Fact Sheet. Status of access to Gliolan in neurosurgery for GBM 28 patients in Australia. Available from: http://www.btaa.org.au/GliolanFAQ.html [Accessed 6th March, 2013] 29 30 21 The Pharmaletter. CHMP positive on first gene therapy, Glybera; and more opinions. 23 July, 2012. 31 Available from: http://www.thepharmaletter.com/file/115112/chmp-positive-on-first-gene-therapy-glybera- 32 and-more-opinions.html [Accessed 4th March, 2013] 33 34 22 RedOrbit. FDA approves new drug for treatment of rare leukemia. December 16, 2012. 35 http://www.redorbit.com/news/health/1112749220/fda-approval-for-ariad-ponatinib-leukemia-drug-121612/ 36 37 [Accessed 25/04/2014] 38 http://bmjopen.bmj.com/ 23 National Institute for Health and Care Excellence. Relapsed and refractory multiple myeloma: 39 40 pomalidomide. http://www.nice.org.uk/Advice/ESNM32 [Accessed 25th April, 2014] 41 24 Hertfordshire Medicines Management Committee. Mecasermin for the treatment of growth failure in 42 43 children and adolescents with severe primary insulin-like growth factor-1 deficiency (SPIGFD). Available 44 from: 45 46 http://www.hertfordshire.nhs.uk/pharmacy/images/Local_Decisions/HMMC/Mecasermin_for_SPIGFD_- on September 28, 2021 by guest. Protected copyright. 47 _2011_April_HMMC.pdf [Accessed 1st March, 2013] 48 49 25 Horsley W (2013) Rufinamide in the management of Lennox-Gastaut syndrome. Available from: 50 www.netag.nhs.uk/files/.../Rufinamide%20for%20LGS%20.../at.../file [Accessed 1st March, 2013] 51 52 26 UK Medicines Information. New Drugs Online Report for ruxolitinib. Available from: 53 http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4830 [Accessed 1st March, 54 55 2013] 56 27 UK Medicines Information. New Drugs Online Report for ivacaftor. Available from: 57 58 http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5084 [Accessed 1st March, 59 2013] 60 28 Horsley W. Sapropterin (Kuvan®) in the management of phenylketonuria. Available from: http://www.netag.nhs.uk/files/appraisal-

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from reports/Sapropterin%20for%20PKU.%20NETAG%20Appraisal%20Report.%20April%202009.pdf 5 6 [Accessed 1st March, 2013] 7 29 British National Formulary. Litak® (Lipomed). BNF 2012; 64: 546 8 9 30 London Cancer New Drugs Group—APC/DTC Briefing. Mitotane for the adjuvant treatment of 10 adrenocortical carcinoma. September 2011. Available from: www.nelm.nhs.uk/en/Download/?file...pdf 11 12 [Accessed 1st March, 2013] 13 31 Johal S, Knight C, Bell MJ, Ralston S (2011) Long-term fiscal implications of mepact in the treatment of 14 15 adrenocortical carcinoma. Poster presentation. Available from: 16 http://www.rtihs.org/request/index.cfm?fuseaction=display&PID=17963 [Accessed 28th February, 2013] 17 For peer review only 18 32 All Wales Medicines Strategy Group Final Appraisal Report. Plerixafor (Mozobil®▼) – March 2010 19 33 Scottish Medicines Consortium. Alglucosidase alfa 50mg powder for concentrate for solution for infusion 20 21 (Myozyme). No. 352/07. 9 February 2007 22 34 UK Medicines Information. New Drugs Online Report for galsulfase. Available from: 23 24 http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4143 [Accessed 28th 25 February, 2013] 26 27 35 NHS North Yorkshire and York. Updated PCT service specification - HCTB DRAFT submission. March 28 2009. Available from: 29 30 http://www.nyypct.nhs.uk/AdviceInformation/MakingDecisions/docs/ServiceSpecifications/Sorafenib%20M 31 ar%2009.pdf [Accessed 3rd March, 2013] 32 36 National Institute for Health and Clinical Execellence. Thrombocytopenic purpura - romiplostim: appraisal 33 34 consultation document. Available from: http://www.nice.org.uk/guidance/index.jsp?action=article&o=45987 35 [Accessed 28th February, 2013] 36 37 37 Van Ekdom L (2006) Price setting orphan drugs. Identifying the influential factors on the price setting of 38 http://bmjopen.bmj.com/ Orphan Drugs. MSc Thesis Science and Innovation management, Utrecht University, the Netherlands. 39 40 December 2006. 41 38 Scottish Medicine Consortium. macitentan (Opsumit). 42 43 http://www.scottishmedicines.org.uk/SMC_Advice/Advice/952_14_macitentan_Opsumit/macitentan_Opsu 44 mit [Accessed 25th April, 2014] 45 46 39 National Institute for Health and Clinical Excellence. Nisitinone. NHS Evidence search. Available from: on September 28, 2021 by guest. Protected copyright. 47 https://www.evidence.nhs.uk/medicine/nitisinone [Accessed 28th February, 2013] 48 49 40 Cox TM (2010) Orphan drug pricing may warrant a competition law investigation. BMJ 341:c6471 50 41 National Institute for Health and Clinical Excellence. Peyona® : BNF for children. NHS Evidence search. 51 52 Available from: www.evidence.nhs.uk/formulary/bnfc/current/3.../peyona [Accessed 3rd March, 2013] 53 42 UK Medicines Information. New Medicines Profile. Hydrocortisone modified-release. Issue No. 12/01. 54 55 October 2012 56 43 NHS North Yorkshire and York. PCT service specification. Approved May 2011 Medicines & Technologies 57 58 Board. Name of Service: Intrathecal Drug Delivery Systems (ITDD) 59 44 Clinical Matters. New Flash. Procysbi Approved for Nephropathic Cystinosis. May 3, 2013. 60 https://www.afspa.org/wp-content/uploads/2013/05/This-is-an-Express-Scripts-Clinical-Flash-3-May- 2013.pdf [Accessed 25th April, 2014]

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 45 Greater Manchester Medicines Management Group. Current therapeutic strategies for pulmonary arterial 5 6 hypertension. March 2009. Available from: www.nyrdtc.nhs.uk/docs/eva/PAH.pdf [Accessed 6th March, 7 2013] 8 9 46 UK Medicines Information. New Drugs Online Report for teduglutide. Available from: 10 http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=4135 [Accessed 28 February, 11 12 2013] 13 47 London New Drugs Group. APC/DTC Briefing. Lenalidomide (Revlimid) for relapsed or refractory multiple 14 15 myeloma. May 2008. Available from: 16 http://www.medicinesresources.nhs.uk/upload/documents/Evidence/Drug%20Specific%20Reviews/Lenalido 17 For peer review only 18 mide%20(Revlimid)%20may%2008.pdf [Accessed 6th March, 2013] 19 48 Kapur S, Bonk ME (2009) Rilonacept (arcalyst), an interleukin-1 trap for the treatment of cryopyrin- 20 21 associated periodic syndromes. P. T. 34(3): 138–141 22 49 The National Extravasation Information Service. Position Statement on dexrazoxane in the Treatment of 23 24 Anthracycline Extravasation. Available from: http://www.extravasation.org.uk/Dexrazoxane.htm [Accessed 25 6th March, 2013] 26 27 50 Erhorn S (2012) Pasireotide for Cushing’s disease. North East Treatment Advisory Group. June 2012 28 51 West Midlands Strategic Commissioning Group. Commissioning Policy (WM/26) - Siklos® for Sickle cell 29 30 anaemia. Version 1 – September 2010 31 52 Regional Drugs and Therapeutic Centre (Newcastle). Evaluation report: The use of eculizumab in atypical 32 haemolytic uremic syndrome. July 2012. Available from: 33 34 http://www.nyrdtc.nhs.uk/docs/eva/Ecilizumab_ER_FINAL_for_web.pdf [Accessed 5th March, 2013] 35 53 National Institute for Health and Clinical Excellence. Price discount means NICE can recommend a new 36 37 drug for chronic myeloid leukaemia. Available from: 38 http://bmjopen.bmj.com/ http://www.nice.org.uk/newsroom/pressreleases/DasatinibImatinibAndNilotinibForIRIICMLFAD.jsp 39 40 [Accessed 5th March, 2013] 41 54 PharmaTimes Mobile. NICE final draft "yes" for Tasigna, Glivec, "no" to Sprycel. Available from: 42 43 http://www.pharmatimes.com/mobile/12-03- 44 22/NICE_final_draft_yes_for_Tasigna_Glivec_no_to_Sprycel.aspx [Accessed 5th March, 2013] 45 46 55 Scottish Medicines Consortium. Thiotepa 15mg and 100mg powder for concentrate for solution for infusion. on September 28, 2021 by guest. Protected copyright. 47 (Tepadina®). SMC No. 790/12 48 49 56 Yorkshire and the Humber Specialized Commissioning Group. General Policy 03/09. Thalidomide. 50 Available from: http://www.sheffield.nhs.uk/services/resources/thalidomidepolicy.pdf [Accessed 5th March, 51 52 2013] 53 57 UK Drug Information Pharmacists Group. New medicines on the Market. Tobramycin. 54 55 http://www.ukmi.nhs.uk/NewMaterial/html/docs/tobramyc.pdf [Accessed 20th June, 2014] 56 58 Claim Secure. Drug Review. Recently introduced products. Torisel™ and Revlimid® – New Cancer Drugs. 57 58 Available from: http://www.claimsecure.com/en-CA/content/pdfs/en- 59 CA/DrugReviews/DrugReview_Vol7_Issue2_en.pdf [Accessed 6th March, 2013] 60

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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from 59 Regional Drug and Therapeutic Centre (Newcastle). The use of azaticidine for the management of 5 6 myelodysplastic syndromes. May 2009. Available from: 7 http://www.nyrdtc.nhs.uk/docs/eva/RDTC_Azacitidine.pdf [Accessed 7th March, 2013] 8 9 60 All Wales Medicines Strategy Group Final Appraisal Report: Ambrisentan (Volibris®) – April 2009 10 61 PharmaTimes Online. Novartis launches Votubia in the UK. January 8, 2013. Available from: 11 12 http://www.pharmatimes.com/Article/13-01-08/Novartis_launches_Votubia_in_the_UK.aspx [Accessed 7th 13 March, 2013] 14 15 62 Scottish Medicines Consortium. Velaglucerase alfa 400 units powder for solution for infusion (VPRIV®). 16 SMC No. 681/11 17 For peer review only 18 63 The Pharmaletter. Portuguese hospitals block access to new medicines as retail drug sector expected to meet 19 savings goal. 30th September, 2011. Available from: 20 21 http://www.thepharmaletter.com/file/107734/portuguese-hospitals-block-access-to-new-medicines-as-retail- 22 drug-sector-expected-to-meet-savings-goal.html [Accessed 10th March, 2013] 23 24 64 NHS Evidence Library. Wilzin. British National Formulary – NHS Evidence. Available from: 25 www.evidence.nhs.uk/formulary/bnf/current/9.../wilzin [Accessed 10th March, 2013] 26 27 65 East Lancashire Medicines Management Board. New Drug Recommendation – Anagrelide. (Xagrid 28 ™capsules 0.5mg, Shire Pharmaceuticals Ltd). Available from: 29 30 http://www.elmmb.nhs.uk/EasySiteWeb/getresource.axd?AssetID=2082&type=... [Accessed 10th March, 31 2013] 32 66 AWMSG Secretariat Assessment Report (Limited Submission). Advise No. 2412. Mercaptopurine 33 34 (Xaluprine®). 20 mg/ml oral suspension. Available from: 35 http://www.wales.nhs.uk/sites3/Documents/371/Mercaptopurine%20(XALUPRINE)%20ASAR%20W.pdf 36 37 [Accessed 10th March, 2013] 38 http://bmjopen.bmj.com/ 67 National Horizon Scanning Centre. Trabectedin (Yondelis) for advanced and/or metastatic translocation- 39 40 related sarcomas – first line. May 2011. 41 68 Wyatt K, Henley W, Anderson L, Anderson R, Nikolaou V, Stein K, Klinger L, Hughes D, Waldek S, 42 43 Lachmann R, Mehta A, Vellodi A, Logan S (2012) The effectiveness and cost-effectiveness of enzyme and 44 substrate replacement therapies: a longitudinal cohort study of people with lysosomal storage disorders. 45 46 Health Technol Assess 16(39): 1-543. doi: 10.3310/hta16390 on September 28, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Appendix 4: Mechanisms of action, approval dates, clinical effectiveness and annual costs for drugs approved for same orphan disease 4 5 Pulmonary Arterial Hypertension 6 Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) 7 ingredient 8 Adempas Riociguat Soluble guanylate cyclase (sGC) 27/03/2014 Sig ↑ in 6MWD vs placebo MD: 46m; 95% CI: 25 to 67; p < Syncope, gastritis, acute renal failure, hypotension 53,495 stimulator 0.001; Sig ↓ in pulm vascular resistance vs placebo MD: –246 dyn 9 · sec · cm–5; 95% CI, –303 to –190; p<0.001 10 11 Opsumit Macitentan Endothelin-receptor antagonistFor 20/12/2013 peerSig ↑ in 6MWD vs placebo review (3mg macitentan: 16.8 m; 97.5% CI, onlyNS 27,979 12 −2.7 to 36.4; P = 0.01) 10mg macitentan: 22.0 m; 97.5% CI, 3.2 to 40.8; P = 0.008). Time to death: 3mg HR=0.70; 97.5% CI: 0.52 to 13 0.96; p = 0.01 and 10 mg HR = 0.55; 97.5% CI: 0.39 to 0.76; p < 14 0.001 15 Revatio Sildenafil Phosphodiesterase inhibitor 28/10/2005 Sig ↑ in 6MWD compared with placebo (p < 0.001); sig ↓ in Left ventricular dysfunction, postural hypertension 4,482 16 clinical worsening compared with placebo (p = 0.02) http://bmjopen.bmj.com/ 17 Tracleer Bosentan Endothelin-receptor antagonist 15/05/2002 Two RCTs showed sig ↑ in 6MWD (p < 0.001; 0.021) and time to ↑LFTs 19,463 18 clinical worsening compared with placebo (0.03 and 0.01) 19 20 Volibris Ambrisentan Endothelin-receptor antagonist 21/04/2008 Sig ↑in 6MWT compared with placebo (p < 0.005); sig ↓in clinical Gastroenteritis, intracranial bleeding, headache, facial edema 20,088 21 worsening (p < 0.001)

22 23 Multiple myeloma 24

Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events on September 28, 2021 by guest. Protected copyright. Annual cost (£) 25 ingredient 26 Imnovid Pomalidomide Direct inhibition of angiogenesis 05/08/2013 Median PFS vs dexamethasone was 4 vs 1.9 months (HR = 0.48; Significant increase in risk of neutropenia and pneumonia 105,600 27 and myeloma growth 95% CI: 0.39 to 0.60; p < 0.0001); Median OS 12.7 vs 8.1 months 28 (HR=0.74; 95% CI: 0.56 to 0.97; p=0.0285). Significant increase in risk of neutropenia and pneumonia 29 30 Mozobil Plerixafor Blocks ‘CXCR4 chemokine 31/07/2009 Sig ↑ in number of patients collecting ≥ 6 x 10⁶ CD34⁺ cells/kg Diarrhea, fatigue 34,179 31 receptor’ activity compared with placebo (p < 0.001); no sig diff in OS; several 32 adverse effects

33 Revlimid Lenalidomide Immunomodulation (IL-2, IL-6, 14/06/2007 PFS significantly greater in revlimid compared with placebo (p < Sig ↑ in risk of hematological and thrombotic SAE (p < 53,363 34 NK-cells) 0.0001). No sig diff between groups on median OS; sig ↑ in risk 0.0001) 35 of hematologic and thrombotic SAE 36 Thalidomide Thalidomide Immunomodulation (IL-2, IL-6, 16/04/2008 Improved median and overall survival when combined with Sig ↑ in risk of VTE compared with control (p < 0.0001) 25,200 37 NK-cells) standard therapy (p = 0.05); sig ↑ in risk of hematologic and 38 thrombotic SAE 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Acute lymphoblastic leukemia 4 Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) 5 ingredient 6 Atriance Nelarabine Cytotoxicity via DNA synthesis 22/08/2007 Response rates 31-50%; insufficient evidence on OS; severe Neurotoxicity, thrombocytopenia, neutropenia 50,000 7 inbibition toxicity

8 Evoltra Clofarabine Cytotoxicity via DNA synthesis 29/05/2006 30-44% response rates; limited data on OS; patient deaths due to Infections, multiorgan failure, hepatotoxicity, death 43,200 9 inbibition drug-related adverse events reported 10 11 Sprycel Dasatinib Protein kinase inhibitionFor 20/11/2006 peer Sig ↑ in PFS compared review with imatinib (p = 0.0012). No evidence only Fluid retention, dyspnea, pleural effusion, cytopenia, 32,000 of greater benefit on OS hemorrhage 12 13 Xaluprine Mercaptopurine Competes for hypoxanthine and 09/03/2012 Sig diff in duration of remission vs placebo (p < 0.01); no sig diff Hypersensitivity, thrombocytopenia 2,100 14 guanine for HGPRTase in median OS 15 16 http://bmjopen.bmj.com/ 17 18 19 20 Chronic myeloid leukemia Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) 21 ingredient 22 Bosulif Bosutinib Tyrosine kinase inhibitor 27/03/2013 PFS at 2 years was 79%; overall survival at 2 years was 92% Thrombocytopenia, neutropenia, anemia, diarrhea, vomitting, 44,799 23 rash, increased AST 24 Iclusig Ponatinib Tyrosine kinase inhibitor 01/07/2013 PFS 55% at 12 months; OS 84% at 12 months Pancreatitis, abd pain, increased lipase, diarrhea, fever, MI, 68,440

thrombocytopenia, on September 28, 2021 by guest. Protected copyright. anemia, neutropenia, febrile neutropenia, 25 pancytopenia. 18 deaths in study; 5 of which were attributed 26 to ponatinib 27 Sprycel Dasatinib Protein kinase inhibition 20/11/2006 Sig ↑ in PFS compared with imatinib (p = 0.0012). No evidence Fluid retention, dyspnea, pleural effusion, cytopenia, 32,000 28 of greater benefit on OS hemorrhage

29 Tasigna Nilotinib Protein kinase inhibition 19/11/2007 Rates of molecular and cytogenetic response significantly greater Thrombocytopenia, anemia, neutropenia, and asthenia 30,000 30 compared with imatinib (p < 0.001). No evidence on OS 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 Acute myeloid leukemia 4 Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) 5 ingredient 6 Ceplene Histamine Immunomodulator; combined 07/10/2008 Over 3 years, leukaemia free survival was 40% for HDC/IL-2 vs Headache, pyrexia 35,450 7 dihydrochloride with IL-2 26% in control group. No results for OS

8 Dacogen Decitabine Inhibition of DNA 20/09/2012 RCTs show no sig improvement in OS compared with controls. Sig ↑ in risk of SAE compared with placebo (p = 0.002) 58,300 9 methyltransferases Sig ↑ in risk of SAE compared with placebo (p = 0.002). 1 RCT 10 was discontinued due to SAE 11 For peer review only 12 13 14 15 Pseudomonas in Cystic Fibrosis 16 Drug Active Mechanism of action Approval date Main results of effectiveness Serious adverse events Annual cost (£) ingredient http://bmjopen.bmj.com/ 17 Cayston Aztreonam Bactericidal 21/09/2009 Modest effects on respiratory symptoms; sig improvements in Sig ↓ in Pseudomonas spp. density compared with placebo; 2567 (28 days) 18 FEV1 compared with placebo no sig diff on CFQ-RRS 19 20 TobiPodhaler Tobramycin Bactericidal 20/07/2011 Sig ↑in FEV1 compared with placebo (p = 0.002) Sig ↑in FEV1 compared with placebo (p = 0.002) 1540 (28 days) 21 22 23 24 25 on September 28, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 4 Reported Section/topic # Checklist item 5 on page # 6 7 TITLE 8 Title 1 Identify the report as a systematic review, meta-analysis, or both. N/A 9 10 ABSTRACT 11 Structured summary 2 ProvideFor a structured peer summary including, review as applicable: background; onlyobjectives; data sources; study eligibility criteria, 2 12 participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and 13 implications of key findings; systematic review registration number. 14 15 INTRODUCTION 16 Rationale 3 Describe the rationale for the review in the context of what is already known. 17 4 18 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions,http://bmjopen.bmj.com/ comparisons, N/A 19 outcomes, and study design (PICOS). 20 21 METHODS 22 Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide N/A 23 registration information including registration number. 24 25 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, N/A

26 language, publication status) used as criteria for eligibility, giving rationale. on September 28, 2021 by guest. Protected copyright. 27 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify 5 28 additional studies) in the search and date last searched. 29 30 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be 5-7 31 repeated. 32 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, 5-7 33 included in the meta-analysis). 34 35 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes 6-7 36 for obtaining and confirming data from investigators. 37 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and 6-7 38 simplifications made. 39 40 Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was 6-7 41 studies done at the study or outcome level), and how this information is to be used in any data synthesis. 42 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 43 N/A 44 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency N/A 2 45 (e.g., I ) for each meta-analysis. 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 Page 1 of 2 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2014-007199 on 24 June 2015. Downloaded from

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1 2 3 4 Reported Section/topic # Checklist item 5 on page # 6 7 Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective N/A 8 reporting within studies). 9 Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating N/A 10 which were pre-specified. 11 For peer review only 12 RESULTS 13 Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at N/A 14 each stage, ideally with a flow diagram. 15 16 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and N/A 17 provide the citations. http://bmjopen.bmj.com/ 18 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 19 N/A 20 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each N/A 21 intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 22 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 23 N/A 24 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). N/A 25 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 26 on September 28, 2021 by guest. Protected copyright. N/A 27 28 DISCUSSION 29 Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to 12 30 key groups (e.g., healthcare providers, users, and policy makers). 31 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of 32 14 identified research, reporting bias). 33 34 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 17 35 36 FUNDING 37 Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the 38 18 systematic review. 39 40 41 From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. 42 doi:10.1371/journal.pmed1000097 43 For more information, visit: www.prisma-statement.org. 44 Page 2 of 2 45 46 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Open Access Miscellaneous Correction

Onakpoya IJ, Spencer EA, Thompson MJ, et al. Effectiveness, safety and costs of orphan drugs: an evidence-based review. BMJ Open 2015;24;5:e007199. There have been corrections to the online supplement as follows: In Appendix 1, Orphacol has been added to the list, and the appropriate refer- ences used in the quality and level of the evidence for Orphacol and Cholic Acid FGK are: – Cholic Acid FGK: European Medicines Agency. Assessment report. Cholic acid FGK. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_ assessment_report/human/002081/WC500165386.pdf – Orphacol: European Medicines Agency. Orphacol, INN-cholic acid - Annex 1. Summary of product characteristics http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Product_Information/human/001250/WC500150993. pdf In Appendix 2, table 2, the authors have revised the indications for Orphacol, and added ‘deficiency’ to the indication for Cholic Acid FGK: Cholic Acid FGK: IEM in primary bile acid synthesis due to Sterol 27-hydroxylase deficiency. Orphacol: IEM in primary bile acid synthesis due to 3beta-Hydroxy-delta5-C27-steroid oxidoreductase deficiency or delta4-3-Oxosteroid-5beta-reductase. In Appendix 2, table 2, and in Appendix 3, the authors have revised the annual cost of Litak to £835 (1 cycle) based on correspondence with the manufacturers. BMJ Open 2015;5:e007199corr1. doi:10.1136/bmjopen-2014-007199corr1

BMJ Open 2015;5:e007199corr1. doi:10.1136/bmjopen-2014-007199corr1 1