BMJ Open: first published as 10.1136/bmjopen-2018-023605 on 30 August 2018. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on October 2, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023605 on 30 August 2018. Downloaded from Health Canada’s use of accelerated review pathways and therapeutic innovation, 1995-2016: a cohort study Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-023605 review only Article Type: Research Date Submitted by the Author: 14-Apr-2018 Complete List of Authors: Lexchin, Joel; York University, School of Health Policy & Management Health policy < HEALTH SERVICES ADMINISTRATION & MANAGEMENT, Keywords: accelerated approvals, Health Canada, therapeutic evaluation, therapeutic groups http://bmjopen.bmj.com/ on October 2, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 69 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023605 on 30 August 2018. Downloaded from 1 2 3 1 Health Canada’s use of accelerated review pathways and therapeutic innovation, 1995- 4 5 2 2016: a cohort study 6 7 8 3 Joel Lexchin MSc, MD1,2,3 9 10 4 1Professor Emeritus 11 12 13 5 School of Health Policy and Management 14 15 6 York University 16 2 For peer review only 17 7 Emergency Physician 18 19 8 University Health Network 20 21 9 3Associate Professor 22 23 10 Faculty of Medicine 24 25 26 11 University of Toronto 27 28 12 29 30 13 Correspondence: 31 32 14 Joel Lexchin MD 33 http://bmjopen.bmj.com/ 34 15 School of Health Policy and Management 35 36 16 York University 37 38 39 17 4700 Keele St. 40 18 Toronto, ON M3J 1P3 41 on October 2, 2021 by guest. Protected copyright. 42 43 19 Tel: 416-964-7186 44 45 20 Email: [email protected] 46 47 21 ORCID ID: 0000-0001-5120-8029 48 49 22 Key words: 50 51 52 23 accelerated approvals, Health Canada, health policy, therapeutic evaluation, therapeutic 53 54 24 group 55 56 25 Word count: 57 58 59 1 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 69 BMJ Open: first published as 10.1136/bmjopen-2018-023605 on 30 August 2018. Downloaded from 1 2 3 26 2790 4 5 6 27 Structured summary 7 8 28 Objectives 9 10 11 12 29 This study examines the use of accelerated approval pathways by Health Canada over the 13 14 30 period 1995 to 2016 inclusive and the relationship between the use of these pathways and the 15 16 31 therapeutic gain Foroffered by peer new products. review only 17 18 19 32 Design 20 21 22 33 Cohort study. 23 24 25 26 34 Data sources 27 28 29 35 Therapeutic Products Directorate, Biologics and Genetic Therapies Directorate, Notice of 30 31 36 Compliance database, Notice of Compliance with conditions web site, Patented Medicine 32 33 37 Prices Review Board, La revue Prescrire, World Health Organization (WHO) Anatomical http://bmjopen.bmj.com/ 34 35 38 Therapeutic Chemical (ATC) classification system. 36 37 38 39 39 Interventions 40 41 on October 2, 2021 by guest. Protected copyright. 42 40 None 43 44 45 41 Primary and secondary outcomes 46 47 48 42 Percent of new drugs evaluated by Health Canada that went through an accelerated pathway 49 50 43 between 1995 and 2016 inclusive. Kappa values comparing the review status to assessments 51 52 53 44 of therapeutic value for individual drugs. 54 55 56 45 Results 57 58 59 2 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 69 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023605 on 30 August 2018. Downloaded from 1 2 3 46 438 (70.3%) drugs went through the standard pathway, 185 (29.7%) an accelerated pathway. 4 5 47 Therapeutic evaluations were available for 509 drugs. Health Canada used an accelerated 6 7 48 approval pathway for 159 of the 509 drugs whereas only 55 were judged to be therapeutically 8 9 49 innovative. The Kappa value for the entire period for all 509 drugs was 0.276 (95% CI 0.194, 10 11 50 0.359) or fair. 12 13 14 15 51 Conclusion 16 For peer review only 17 18 52 Health Canada’s use of accelerated approvals was stable over the entire time period. Its 19 20 53 ability to predict which drugs will offer a major therapeutic gain is relatively poor. The 21 22 54 findings in this study should provoke a discussion about whether Health Canada should 23 24 55 continue to use these pathways and if so how their use can be improved. 25 26 27 56 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on October 2, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 3 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 69 BMJ Open: first published as 10.1136/bmjopen-2018-023605 on 30 August 2018. Downloaded from 1 2 3 57 Article Summary 4 5 58 Strengths and limitations of this study 6 7 59 • Examination of the use of accelerated approval pathways by Health Canada over an 8 9 60 extended period of time. 10 11 12 61 • Comparison of use of accelerated approval pathways to independent assessment of 13 14 62 therapeutic evaluation. 15 16 63 • Analysis of approvalsFor andpeer therapeutic review value of therapeutic only subgroups. 17 18 64 • Twenty percent of new drugs approved did not have therapeutic evaluations. 19 20 65 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on October 2, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 4 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 69 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-023605 on 30 August 2018. Downloaded from 1 2 3 66 Introduction 4 5 67 In order to get a new active substance (NAS - a molecule never marketed before in Canada in 6 7 68 any form) approved for marketing in Canada, companies typically file a New Drug 8 9 69 Submission (NDS) which includes preclinical and clinical scientific information about the 10 11 70 product’s safety, efficacy and quality and information about its claimed therapeutic value, 12 13 14 71 conditions for use and side effects (1). Health Canada then has a 300-day period to evaluate 15 16 72 this information Forand make peera decision about review whether to allow only the product to be sold, i.e., 17 18 73 whether to issue a Notice of Compliance (NOC). 19 20 74 21 22 75 In an effort to ensure that promising therapies for serious, life-threatening or debilitating 23 24 76 illnesses can reach Canadians in a timely manner, Health Canada has developed two other 25 26 27 77 pathways for approving NAS. These are described in detail elsewhere (2), but briefly, the 28 29 78 first of these is a priority review that involves the company submitting a complete NDS but 30 31 79 with a review period of 180 days (3). The second is the Notice of Compliance with conditions 32 33 80 (NOC/c) (4) whereby Health Canada will give a conditional approval based on limited http://bmjopen.bmj.com/ 34 35 81 evidence – Phase II clinical trials or trials with only surrogate markers. In return for NOC/c 36 37 82 status, companies commit to further studies that definitively establish efficacy and submit the 38 39 40 83 results of these to Health Canada. A failure to complete these studies or negative results from 41 on October 2, 2021 by guest. Protected copyright. 42 84 them could lead to the marketing authorization being cancelled. 43 44 85 45 46 86 Lexchin has examined how closely Health Canada’s use of the two pathways (priority review 47 48 87 and NOC/c, hereafter collectively termed accelerated review pathways) corresponds to 49 50 88 independent assessments of the therapeutic innovation of drugs at the level of individual 51 52 53 89 drugs.