Advertisement

Decision Models for Assessing the Cost Effectiveness of Treatments for Pediatric Drug-Resistant Epilepsy: A Systematic Review of Economic Evaluations

  • Jesse ElliottEmail author
  • Sasha van Katwyk
  • Bláthnaid McCoy
  • Tammy Clifford
  • Beth K. Potter
  • Becky Skidmore
  • George A. Wells
  • Doug Coyle
Systematic Review

Abstract

Background

Drug-resistant epilepsy affects about one-third of children with epilepsy and is associated with high costs to the healthcare system, yet the cost effectiveness of most treatments is unclear. Use of cannabis-based products for epilepsy is increasing, and the cost effectiveness of such strategies relative to conventional pharmacologic treatments must be considered.

Objective

The objective of this systematic review was to identify economic evaluations of cannabis-based treatments for pediatric drug-resistant epilepsy. We also sought to identify and appraise decision models that have been used in economic evaluations of pharmacologic treatments (i.e., antiepileptic drugs) in this population.

Methods

Electronic searches of MEDLINE, EMBASE, and the Cochrane library, as well as a targeted grey literature search, were undertaken (11 June 2018). Model-based full economic evaluations involving cannabis-based treatments or pharmacologic treatments for drug-resistant epilepsy in children were eligible for inclusion. Two independent reviewers selected studies for inclusion, and study quality was assessed by use of the Drummond and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklists. Study findings, as well as model characteristics, are narratively summarized.

Results

Nine economic evaluations involving children with drug-resistant epilepsy were identified; however, none involved cannabis-based treatments. All studies involved pharmacologic treatments compared with other pharmacologic treatments or non-pharmacologic treatments (i.e., ketogenic diet, epilepsy surgery, vagus nerve stimulation). Few studies have assessed the cost effectiveness of pharmacologic treatments in specific drug-resistant epilepsy syndromes, including Dravet and Lennox-Gastaut syndromes. Five included studies involved use of Markov models with a similar structure (i.e., health states based on seizure frequency relative to baseline). There was a wide range of methodological quality, and few studies fully addressed context-specific issues such as weight gain and treatment switching.

Conclusion

Whether cannabis-based treatments for pediatric drug-resistant epilepsy represent good value for money has yet to be investigated. Economic evaluations of such treatments are needed and should address issues of particular importance in pediatric epilepsy, including weight gain over time, switching or discontinuation of treatments, effectiveness of interventions and comparators, and long-term effectiveness beyond the duration of available clinical studies.

PROSPERO Registration

CRD42018099591.

Notes

Compliance with Ethical Standards

Funding

No specific funding was obtained for this study. Jesse Elliott is supported by an Ontario Graduate Scholarship.

Conflict of interest

Bláthnaid McCoy is principal investigator in a study of cannabinoids for Dravet syndrome. Jesse Elliott, Sasha van Katwyk, Tammy Clifford, Beth Potter, Becky Skidmore, George Wells, and Doug Coyle have no conflicts of interest to declare.

Author contributions

JE, TC, DC, BP, BM, GW, and DC designed the study. BS developed and executed the search strategy. JE, SVK, and DC selected studies for inclusion and extracted data. JE analyzed the data and wrote the first draft of the manuscript, which was critically revised for intellectual content by all authors. All of the authors contributed to the conception and planning of the study, the analysis and/or interpretation of the data, drafting and critical revision of the manuscript, and approved the final version submitted for publication.

Data Availability Statement

All data generated or analyzed during this study are included in this published article (and its supplementary information files [Electronic Supplementary Material]).

Supplementary material

40273_2019_816_MOESM1_ESM.docx (167 kb)
Supplementary material 1 (DOCX 167 kb)

References

  1. 1.
    World Health Organization. Epilepsy. 2018. http://www.who.int/mediacentre/factsheets/fs999/en/. Accessed 18 Feb 2018.
  2. 2.
    Lee SK. Old versus new: why do we need new antiepileptic drugs? J Epilepsy Res. 2014;4:39–44.CrossRefGoogle Scholar
  3. 3.
    Téllez-Zenteno JF, Hernández-Ronquillo L, Buckley S, Zahagun R, Rizvi S. A validation of the new definition of drug-resistant epilepsy by the International League Against Epilepsy. Epilepsia. 2014;55:829–34.CrossRefGoogle Scholar
  4. 4.
    Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51:1069–77.CrossRefGoogle Scholar
  5. 5.
    Wilmshurst JM, Berg AT, Lagae L, Newton CR, Cross JH. The challenges and innovations for therapy in children with epilepsy. Nat Rev Neurol. 2014;10:249–60.CrossRefGoogle Scholar
  6. 6.
    Sillanpää M, Shinnar S. SUDEP and other causes of mortality in childhood-onset epilepsy. Epilepsy Behav. 2013;28:249–55.CrossRefGoogle Scholar
  7. 7.
    Sillanpää M, Anttinen A, Rinne JO, Joutsa J, Sonninen P, Erkinjuntti M, et al. Childhood-onset epilepsy five decades later. A prospective population-based cohort study. Epilepsia. 2015;56:1774–83.CrossRefGoogle Scholar
  8. 8.
    Cramer JA, Wang ZJ, Chang E, Powers A, Copher R, Cherepanov D, et al. Healthcare utilization and costs in children with stable and uncontrolled epilepsy. Epilepsy Behav. 2014;32:135–41.CrossRefGoogle Scholar
  9. 9.
    Jacoby A, Buck D, Baker G, McNamee P, Graham-Jones S, Chadwick D. Uptake and costs of care for epilepsy: findings from a UK regional study. Epilepsia. 1998;39:776–86.CrossRefGoogle Scholar
  10. 10.
    Riechmann J, Strzelczyk A, Reese JP, Boor R, Stephani U, Langner C, et al. Costs of epilepsy and cost-driving factors in children, adolescents, and their caregivers in Germany. Epilepsia. 2015;56:1388–97.CrossRefGoogle Scholar
  11. 11.
    Begley CE, Durgin TL. The direct cost of epilepsy in the United States: a systematic review of estimates. Epilepsia. 2015;56:1376–87.CrossRefGoogle Scholar
  12. 12.
    Wilmshurst JM, Burman R, Gaillard WD, Cross JH. Treatment of infants with epilepsy: common practices around the world. Epilepsia. 2015;56:1033–46.CrossRefGoogle Scholar
  13. 13.
    Hartmann N, Neininger MP, Bernhard MK, Syrbe S, Nickel P, Merkenschlager A, et al. Use of complementary and alternative medicine (CAM) by parents in their children and adolescents with epilepsy—prevelance, predictors and parents’ assessment. Eur J Paediatr Neurol. 2016;20:11–9.CrossRefGoogle Scholar
  14. 14.
    Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 2013;29:574–7.CrossRefGoogle Scholar
  15. 15.
    Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:1085–96.CrossRefGoogle Scholar
  16. 16.
    Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med. 2018;378:1888–97.CrossRefGoogle Scholar
  17. 17.
    Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011.CrossRefGoogle Scholar
  18. 18.
    Elliott J, DeJean D, Clifford T, Coyle D, Potter BK, Skidmore B, et al. Cannabis-based products for pediatric epilepsy: a systematic review. Epilepsia. 2019;60:6–19.CrossRefGoogle Scholar
  19. 19.
    Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol. 2009;62:1006–12.CrossRefGoogle Scholar
  20. 20.
    McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS peer review of electronic search strategies: 2015 guideline statement. J Clin Epidemiol. 2016;75:40–6.CrossRefGoogle Scholar
  21. 21.
    CADTH. Grey matters: a practical tool for searching health-related grey literature. 2015. https://www.cadth.ca/resources/finding-evidence/grey-matters. Accessed 5 Jun 2018.
  22. 22.
    Drummond M, Schulpher M, Torrance G, O’Brian B, Stoddart G. Methods for the economic evaluation of health care programmes. 3rd ed. New York: Oxford University Press; 2005.Google Scholar
  23. 23.
    Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. Value Health. 2013;16:e1–5.CrossRefGoogle Scholar
  24. 24.
    Anderson R. Systematic reviews of economic evaluations: utility or futility? Health Econ. 2010;19:350–64.CrossRefGoogle Scholar
  25. 25.
    Clements KM, Skornicki M, O’Sullivan AK. Cost-effectiveness analysis of antiepileptic drugs in the treatment of Lennox-Gastaut syndrome. Epilepsy Behav. 2013;29:184–9.CrossRefGoogle Scholar
  26. 26.
    Benedict A, Verdian L, Maclaine G. The cost effectiveness of rufinamide in the treatment of Lennox-Gastaut syndrome in the UK. Pharmacoeconomics. 2010;28:185–99.CrossRefGoogle Scholar
  27. 27.
    Bowen J, Snead O, Chandra K, Blackhouse G, Goeree R. Epilepsy care in Ontario: an economic analysis of increasing access to epilepsy surgery. Ont Health Technol Assess Ser. 2012;12:1–41.Google Scholar
  28. 28.
    Elliott J, McCoy B, Clifford T, Wells GA, Coyle D. Economic evaluation of stiripentol for Dravet syndrome: a cost-utility analysis. Pharmacoeconomics. 2018;36:1253–61.CrossRefGoogle Scholar
  29. 29.
    Fallah A, Weil AG, Wang S, Lewis E, Baca CB, Mathern GW. Cost-utility analysis of competing treatment strategies for drug-resistant epilepsy in children with tuberous sclerosis complex. Epilepsy Behav. 2016;63:79–88.CrossRefGoogle Scholar
  30. 30.
    Gharibnaseri Z, Kebriaeezadeh A, Nikfar S, Zamani G, Abdollahiasl A. Cost-effectiveness of adding-on new antiepileptic drugs to conventional regimens in controlling intractable seizures in children. Daru. 2012;20:17.CrossRefGoogle Scholar
  31. 31.
    Keene D, Ventureyra EC. Epilepsy surgery for 5- to 18-year old patients with medically refractory epilepsy—is it cost efficient? Childs Nerv Syst. 1999;15:52–4.CrossRefGoogle Scholar
  32. 32.
    de Kinderen R, Postulart D, Aldenkamp AP, Evers SM, Lambrechts DA, Louw AJ, et al. Cost-effectiveness of the ketogenic diet and vagus nerve stimulation for the treatment of children with intractable epilepsy. Epilepsy Res. 2015;110:119–31.CrossRefGoogle Scholar
  33. 33.
    Verdian L, Yi Y. Cost-utility analysis of rufinamide versus topiramate and lamotrigine for the treatment of children with Lennox-Gastaut Syndrome in the United Kingdom. Seizure. 2010;19:1–11.CrossRefGoogle Scholar
  34. 34.
    Widjaja E, Li B, Schinkel CD, Puchalski RL, Weaver J, Snead OC, et al. Cost-effectiveness of pediatric epilepsy surgery compared to medical treatment in children with intractable epilepsy. Epilepsy Res. 2011;94:61–8.CrossRefGoogle Scholar
  35. 35.
    Dieticians of Canada. WHO growth charts for Canada: 2 to 19 years: boys. 2014. https://www.dietitians.ca/Downloads/Public/HFA-WFA_2-19_BOYS_EN.aspx. Accessed 21 Jan 2019.
  36. 36.
    Chiron C, Marchand MC, Tran A, Rey E, D’Athis P, Vincent J, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO Study Group. Lancet. 2000;356:1638–42.CrossRefGoogle Scholar
  37. 37.
    Guerrini R, Tonnelier S, D’Athis P, Rey E, Vincent J, Pons G. Stiripentol in severe myoclonic epilepsy in infancy (SEMI): a placebo-controlled Italian trial. Epilepsia. 2002;43:155.CrossRefGoogle Scholar
  38. 38.
    Overwater IE, Bindels-De Heus K, Rietman AB, Ten Hoopen LW, Vergouwe Y, Moll HA, et al. Epilepsy in children with tuberous sclerosis complex: chance of remission and response to antiepileptic drugs. Epilepsia. 2015;56:1239–45.CrossRefGoogle Scholar
  39. 39.
    Coyle D, Lee KM, Cooper NJ. Use of evidence in decision models. In: Shemilt I, Mugford M, Val L, Marsh K, Donaldson C, editors. Evidence-based decisions and economics: health care, social welfare, education and criminal justice. Oxford: Blackwell Publishing; 2010. p. 106–13.CrossRefGoogle Scholar
  40. 40.
    Brigo F, Igwe SC. Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy. Cochrane Database Syst Rev. 2015;10:CD010483.Google Scholar
  41. 41.
    Inoue Y, Ohtsuka Y. Long-term safety and efficacy of stiripentol for the treatment of Dravet syndrome: a multicenter, open-label study in Japan. Epilepsy Res. 2015;113:90–7.CrossRefGoogle Scholar
  42. 42.
    Selai C, Kaiser S, Trimble M, Price M. Evaluation of the relationship between epilepsy severity and utility [abstract no. PNP15]. ISPOR Fifth Annual European Conference, 3–5 Nov 2002, Rotterdam, The Netherlands; 2002.Google Scholar
  43. 43.
    Selai C, Kaiser S, Trimble M, Price M. Evaluation of the relationship between epilepsy severity and utility [abstract no. PNP15]. Value Health. 2002;5:512–3. http://linkinghub.elsevier.com/retrieve/pii/S1098301510613599. Accessed 4 June 2019.
  44. 44.
    Verdian L, Oyee J, Heyes A, Tolley K, Yi Y. Eliciting preferences for health states associated with Lennox-Gastaut syndrome (LGS) [abstract no 1.352]. In: 62nd meeting of the American Epilepsy Society, 5–9 Dec 2008, Seattle. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/8833. Accessed 4 June 2019.
  45. 45.
    Messori A, Trippoli S, Becagli P, Cincotta M, Labbate MG, Zaccara G. Adjunctive lamotrigine therapy in patients with refractory seizures: a lifetime cost-utility analysis. Eur J Clin Pharmacol. 1998;53:421–7.CrossRefGoogle Scholar
  46. 46.
    National Institute for Health and Care Excellence (NICE). Cannabidiol for adjuvant treatment of seizures associated with Dravet syndrome or Lennox-Gastaut syndrome. 2018. https://www.nice.org.uk/guidance/indevelopment/gid-ta10274. Accessed 2 Dec 2018.
  47. 47.
    Herzog S, Shanahan M, Grimison P, Tran A, Wong N, Lintzeris N, et al. Systematic review of the costs and benefits of prescribed cannabis-based medicines for the management of chronic illness: lessons from multiple sclerosis. Pharmacoeconomics. 2018;36:67–78.CrossRefGoogle Scholar
  48. 48.
    Strzelczyk A, Schubert-Bast S, Reese JP, Rosenow F, Stephani U, Boor R. Evaluation of health-care utilization in patients with Dravet syndrome and on adjunctive treatment with stiripentol and clobazam. Epilepsy Behav. 2014;34:86–91.CrossRefGoogle Scholar
  49. 49.
    Strzelczyk A, Kalski M, Bast T, Wiemer-Kruel A, Bettendorf U, Kay L, et al. Burden-of-illness and cost-driving factors in Dravet syndrome patients and carers: a prospective, multicenter study from Germany. Eur J Paediatr Neurol. 2019.  https://doi.org/10.1016/j.ejpn.2019.02.014 (Epub 2019 Feb 28).Google Scholar
  50. 50.
    Whittington MD, Knupp KG, Vanderveen G, Kim C, Gammaitoni A, Campbell JD. The direct and indirect costs of Dravet syndrome. Epilepsy Behav. 2018;80:109–13.CrossRefGoogle Scholar
  51. 51.
    US Food and Drug Administration. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm. Accessed 23 Dec 2018.
  52. 52.
    McCoy B, Wang L, Zak M, Al-Mehmadi S, Kabir N, Alhadid K, et al. A prospective open-label trial of a CBD/THC cannabis oil in Dravet syndrome. Ann Clin Transl Neurol. 2018;5:1077–88.CrossRefGoogle Scholar
  53. 53.
    Wijnen BFM, van Mastrigt GAPG, Evers SMAA, Gershuni O, Lambrechts DAJE, Majoie MHJM, et al. A systematic review of economic evaluations of treatments for patients with epilepsy. Epilepsia. 2017;58:706–26.CrossRefGoogle Scholar
  54. 54.
    Brigo F, Igwe SC, Bragazzo NL. Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy. Cochrane Database Syst Rev. 2017;5:CD010483.Google Scholar
  55. 55.
    Hancock E, Cross JH. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev. 2013;2:CD003277.Google Scholar
  56. 56.
    Panju AH, Bell CM. Policy alternatives for treatments for rare diseases. CMAJ. 2010;182:E787–92.CrossRefGoogle Scholar
  57. 57.
    Rizzardo S, Bansback N, Dragojlovic N, Douglas C, Li KH, Mitton C, et al. Evaluating Canadians’ values for drug coverage decision making. Value Health. 2019;22:362–9.  https://doi.org/10.1016/j.jval.2018.08.008.CrossRefGoogle Scholar
  58. 58.
    Sculpher MJ, Claxton K, Drummond M, McCabe C. Whither trial-based economic evaluation for health care decision making? Health Econ. 2006;15:677–87.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.School of Epidemiology and Public HealthUniversity of OttawaOttawaCanada
  2. 2.Department of PediatricsUniversity of TorontoTorontoCanada
  3. 3.Division of NeurologyThe Hospital for Sick Children TorontoTorontoCanada
  4. 4.Independent Information SpecialistOttawaCanada
  5. 5.Cardiovascular Research Methods Centre, University of Ottawa Heart InstituteOttawaCanada

Personalised recommendations