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 <b>Primary Subject Evidence based practice Heading</b>: 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. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 59 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 Evidence-Based 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 Evidence-Based 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 98195-6390 33 http://bmjopen.bmj.com/ 34 35 36 Carl J. Heneghan 37 38 39 University of Oxford, Centre for Evidence-Based 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 ultra-orphan 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, ultra-orphan 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.