PharmacoEconomics

, Volume 31, Issue 10, pp 841–852

Ruxolitinib for the Treatment of Myelofibrosis: A NICE Single Technology Appraisal

  • Ros Wade
  • Micah Rose
  • Aileen Rae Neilson
  • Lisa Stirk
  • Rocio Rodriguez-Lopez
  • David Bowen
  • Dawn Craig
  • Nerys Woolacott
Review Article

Abstract

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of ruxolitinib (Novartis) to submit clinical and cost-effectiveness evidence for ruxolitinib within its licensed indication (the treatment of disease-related splenomegaly or symptoms in adult patients with myelofibrosis), according to the Institute’s Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA289 issued in June 2013. The ERG critically reviewed the evidence presented in the manufacturer’s submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The main clinical effectiveness data were derived from two phase III, multicentre, randomised controlled trials (RCTs): Controlled myelofibrosis study with oral JAK inhibitor treatment (COMFORT)-II compared ruxolitinib with best available therapy (BAT), and COMFORT-I compared ruxolitinib with placebo. These RCTs demonstrated that ruxolitinib confers significant benefits in terms of spleen size reduction and improvement in symptom burden. In the COMFORT-II trial, a reduction in spleen volume of ≥35 % was achieved in 28 % of ruxolitinib-treated patients compared with 0 % of patients in the BAT group (p < 0.001) at 48 weeks, and there was a mean change in spleen volume of −30.1 versus +7.3 % (p < 0.001). Ruxolitinib also provided significant improvements in myelofibrosis-associated symptoms and health-related quality-of-life compared with BAT and placebo. The ERG concluded that ruxolitinib appears to reduce splenomegaly and its associated symptoms, but that there was considerable uncertainty surrounding the manufacturer’s cost-effectiveness estimates due to limitations in the manufacturer’s model. The manufacturer’s model did not allow for disease progression, did not accurately capture symptomatic relief, had several implausible or unjustified assumptions, and there were several parameter choices that the ERG found sub-optimal. ERG sensitivity analyses found that nearly all plausible adjustments to the model reduced the cost effectiveness of ruxolitinib. It is very likely that the base-case incremental cost-effectiveness ratio of £73,980/quality-adjusted life-year presented by the manufacturer represents a best-case scenario. The NICE Appraisal Committee concluded that ruxolitinib was clinically effective, but could not be considered a cost effective use of National Health Service (NHS) resources for treating disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib is not recommended for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis in NICE TA289.

References

  1. 1.
    National Institute for Health and Clinical Excellence. Guide to the single technology appraisal (STA) process. London: NICE; 2006.Google Scholar
  2. 2.
    Craig D, et al. Ruxolitinib for the treatment of myelofibrosis. Southampton: Health Technology Assessment Programme; 2012.Google Scholar
  3. 3.
    Craig D, et al. Retigabine for the adjunctive treatment of adults with partial-onset seizures in epilepsy with and without secondary generalization. A NICE Single Technology Appraisal. Pharmacoeconomics. 2013;31:101–10.PubMedCrossRefGoogle Scholar
  4. 4.
    Kearns B, et al. Cabazitaxel for the second-line treatment of metastatic hormone refractory prostate cancer. A NICE Single Technology Appraisal. Pharmacoeconomics. 2013;31:479–88.Google Scholar
  5. 5.
    Tosh J, et al. Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs. A NICE Single Technology Appraisal. Pharmacoeconomics. 2013;31:653–61.Google Scholar
  6. 6.
    Armstrong N, et al. Golimumab for the treatment of ankylosing spondylitis. A NICE Single Technology Appraisal. Pharmacoeconomics. 2013;31:415–25.Google Scholar
  7. 7.
    Greenhalgh J, et al. Rituximab for the firstline maintenance treatment of follicular non-Hodgkin’s lymphoma. A NICE Single Technology Appraisal. Pharmacoeconomics. 2013;31:403–13.Google Scholar
  8. 8.
    Simpson EL, et al. Bivalirudin for the treatment of ST-segment elevation myocardial infarction. A NICE Single Technology Appraisal. Pharmacoeconomics. 2013;31(4):269–75.PubMedCrossRefGoogle Scholar
  9. 9.
    Rafia R, et al. Trabectedin for the treatment of advanced metastatic soft tissue sarcoma. A NICE Single Technology Appraisal. Pharmacoeconomics. 2013;31:471–8.Google Scholar
  10. 10.
    Spackman E, et al. Trastuzumab for the treatment of HER2 positive metastatic gastric cancer. A NICE Single Technology Appraisal. Pharmacoeconomics. 2013;31(3):185–94.PubMedCrossRefGoogle Scholar
  11. 11.
    Kilonzo M, Hislop J, Elders A. Pazopanib for the first-line treatment of patients with advanced and/or metastatic renal cell carcinoma. A NICE Single Technology Appraisal. Pharmacoeconomics. 2013;31(1):15–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Sculpher M. Single technology appraisal at the UK National Institute for Health and Clinical Excellence: a source of evidence and analysis for decision making internationally. Pharmacoeconomics. 2010;28(5):347–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Dickson R, et al. Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer after previous platinum-containing chemotherapy. A NICE Single Technology Appraisal. Pharmacoeconomics. 2011;29(12):1051–62.PubMedCrossRefGoogle Scholar
  14. 14.
    Scotland G, et al. Denosumab for the prevention of osteoporotic fractures in post-menopausal women. A NICE Single Technology Appraisal. Pharmacoeconomics. 2011;29(11):951–61.PubMedCrossRefGoogle Scholar
  15. 15.
    Stevenson M, Pandor A. Febuxostat for the management of hyperuricaemia in patients with gout. A NICE Single Technology Appraisal. Pharmacoeconomics. 2011;29(2):133–40.PubMedCrossRefGoogle Scholar
  16. 16.
    McKenna C, et al. Dronedarone for the treatment of atrial fibrillation. A NICE Single Technology Appraisal. Pharmacoeconomics. 2012;30(1):35–46.PubMedCrossRefGoogle Scholar
  17. 17.
    Holmes M, Carroll C, Papaioannou D. Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip or knee surgery. A NICE Single Technology Appraisal. Pharmacoeconomics. 2012;30(2):137–46.PubMedCrossRefGoogle Scholar
  18. 18.
    Yang HQ, et al. Golimumab for the treatment of psoriatic arthritis. A NICE Single Technology Appraisal. Pharmacoeconomics. 2012;30(4):257–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Boyers D, et al. Eltrombopag for the treatment of chronic immune or idiopathic thrombocytopenic purpura. A NICE Single Technology Appraisal. Pharmacoeconomics. 2012;30(6):483–95.PubMedCrossRefGoogle Scholar
  20. 20.
    Burch J, et al. Omalizumab for the treatment of severe persistent allergic asthma in children aged 6–11 years. A NICE Single Technology Appraisal. Pharmacoeconomics. 2012;30(11):991–1004.PubMedCrossRefGoogle Scholar
  21. 21.
    Whyte S, Pandor A, Stevenson M. Bevacizumab for metastatic colorectal cancer. A NICE Single Technology Appraisal. Pharmacoeconomics. 2012;30(12):1119–32.PubMedCrossRefGoogle Scholar
  22. 22.
    Bagust A, et al. Cetuximab for recurrent and/or metastatic squamous cell carcinoma of the head and neck/A NICE Single Technology Appraisal. Pharmacoeconomics. 2010;28(6):439–48.PubMedCrossRefGoogle Scholar
  23. 23.
    Rodgers M, et al. Alitretinoin for severe chronic hand eczema. A NICE Single Technology Appraisal. Pharmacoeconomics. 2010;28(5):351–62.PubMedCrossRefGoogle Scholar
  24. 24.
    National Institute for Health and Clinical Excellence. Myelofibrosis (splenomegaly, symptoms)—ruxolitinib [ID510]. 2013 (cited 2013 February). http://guidance.nice.org.uk/TA/Wave0/615.
  25. 25.
    Girodon F, et al. Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: a population-based study. Haematologica. 2009;94(6):865–9.PubMedCrossRefGoogle Scholar
  26. 26.
    McNally RJ, et al. Age and sex distributions of hematological malignancies in the U.K. Hematol Oncol. 1997;15(4):173–89.PubMedCrossRefGoogle Scholar
  27. 27.
    Phekoo KJ, et al. The incidence and outcome of myeloid malignancies in 2,112 adult patients in southeast England. Haematologica. 2006;91(10):1400–4.PubMedGoogle Scholar
  28. 28.
    Orphanet. Prevalence of rare diseases: bibliographic data, Paris; 2012. p. 30.Google Scholar
  29. 29.
    European Medicines Agency (EMA) and Committee for Orphan Medicinal Products. In: Public summary of opinion on orphan designation. (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate for the treatment of myelofibrosis secondary to polycythaemia vera or essential thrombocythaemia. London: European Medicines Agency; 2011. p. 5.Google Scholar
  30. 30.
    Novartis. Single Technology Appraisal (STA): Ruxolitinib (Jakavi) for the treatment of primary myelofibrosis, post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis. Manufacturer’s submission. 2012. p. 294.Google Scholar
  31. 31.
    Harrison C, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98.PubMedCrossRefGoogle Scholar
  32. 32.
    Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807.PubMedCrossRefGoogle Scholar
  33. 33.
    National Institute for Health and Clinical Excellence (NICE). Final scope for the proposed appraisal of ruxolitinib for the treatment of myelofibrosis. London: National Institute for Health and Clinical Excellence; 2012.Google Scholar
  34. 34.
    Committee for Medicinal Products for Human Use (CHMP). CHMP assessment report: Jakavi Ruxolitinib. EMA/465846/2012. 2012 (cited 2012). http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002464/WC500133226.pdf.
  35. 35.
    Verstovsek S, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117–27.PubMedCrossRefGoogle Scholar
  36. 36.
    Harrison CN, et al. Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF). J Clin Oncol. 2011;29(18 Suppl. 1):LBA6501.Google Scholar
  37. 37.
    Verstovsek S, et al. Long-term outcome of Ruxolitinib treatment in patients with Myelofibrosis: durable reductions in spleen volume, improvements in quality of life, and overall survival advantage in COMFORT-I. Abstract Number 800, in 54th ASH Annual Meeting, Atlanta, 2012.Google Scholar
  38. 38.
    Cervantes F., et al. Long-term safety, efficacy, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy (BAT) for the treatment of myelofibrosis (MF). Abstract Number 801, in 54th ASH Annual Meeting, Atlanta, 2012.Google Scholar
  39. 39.
    Verstovsek S, et al. A phase I/II study of INCB018424, an oral, selective JAK inhibitor, in patients with primary myelofibrosis (PMF) and post polycythemia vera/essential thrombocythemia myelofibrosis (Post-PV/ET MF). J Clin Oncol. 2008;26(15):7004.Google Scholar
  40. 40.
    Cervantes F, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895–901.PubMedCrossRefGoogle Scholar
  41. 41.
    National Institute for Health and Clinical Excellence (NICE). Eribulin for the treatment of advanced metastatic breast cancer (TA250). London: National Institute for Health and Clinical Excellence; 2012. p. 67.Google Scholar
  42. 42.
    Roskell NS, et al. Using a condition-specific measure of patient-reported outcomes to derive utilities in myelofibrosis. In: ISPOR 17th annual international meeting, Washington, DC, 2012.Google Scholar
  43. 43.
    Roskell NS, et al. Using a condition-specific measure of patient-reported outcomes to derive utilities in myelofibrosis. Value Health. 2012;15(4):A224–5.CrossRefGoogle Scholar
  44. 44.
    National Institute for Health and Clinical Excellence. Guide to the methods of technology appraisal. London: NICE; 2008. p. 76.Google Scholar
  45. 45.
    Tefferi A, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood. 2006;108(5):1497–503.PubMedCrossRefGoogle Scholar
  46. 46.
    National Institute for Health and Care Excellence. Ruxolitinib for disease-related splenomegaly or symptoms in adults with myelofibrosis. Appraisal consultation document (ACD). 2013 (cited 2013 April 29). http://guidance.nice.org.uk/TA/Wave0/615/Consultation/DraftGuidance.
  47. 47.
    Verstovsek S, et al. The MD Anderson Cancer Center (MDACC) experience with ruxolitinib, an oral JAK1 and JAK2 inhibitor, in myelofibrosis: long-term follow-up outcomes of 107 patients from a phase I/II study. Blood. 2011;118(21):1646.Google Scholar
  48. 48.
    Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc. 2011;86(12):1188–91.PubMedCrossRefGoogle Scholar
  49. 49.
    National Institute for Health and Care Excellence. Final appraisal determination: Ruxolitinib for disease-related splenomegaly or symptoms in adults with myelofibrosis. 2013 (cited 2013 April 29). http://www.nice.org.uk/nicemedia/live/13687/63722/63722.pdf.

Copyright information

© Crown Copyright  2013

Authors and Affiliations

  • Ros Wade
    • 1
  • Micah Rose
    • 1
  • Aileen Rae Neilson
    • 1
  • Lisa Stirk
    • 1
  • Rocio Rodriguez-Lopez
    • 1
  • David Bowen
    • 2
  • Dawn Craig
    • 1
  • Nerys Woolacott
    • 1
  1. 1.Centre for Reviews and Dissemination (CRD)University of YorkYork YO10 5DDUK
  2. 2.St James’s Institute of OncologyLeedsUK

Personalised recommendations