Abstract
Background
Considerable advances have been made in modeling Alzheimer’s disease (AD), with a move towards individual-level rather than cohort models and simulations that consider multiple dimensions when evaluating disease severity. However, the possibility that disease-modifying agents (DMAs) may emerge requires an update of existing modeling frameworks.
Objectives
The aim of this study was to develop a simulation allowing for economic evaluation of DMAs in AD.
Methods
The model was developed based on a previously published, well-validated, discrete event simulation which measures disease severity on the basis of cognition, behaviour, and function, and captures the interrelated changes in these measures for individuals. The updated model adds one more domain, patient dependence, in addition to cognition, behaviour, and function to better characterize disease severity. Furthermore, the model was modified to have greater flexibility in assessing the impact of various important assumptions, such as the long-term effectiveness of DMAs and their impact on survival, on model outcomes. A validation analysis was performed to examine how well the model predicted change in disease severity among patients not receiving DMA treatment by comparing model results to those observed in two recent phase III clinical trials of bapineuzumab. In addition, various hypothetical scenarios were tested to demonstrate the improved features of the model.
Results
Validation results show that the model closely predicts the mean changes in disease severity over 18 months. Results from different hypothetical scenarios show that the model allows for credible assessment of those major uncertainties surrounding the long-term effectiveness of DMAs, including the potential impact of improved survival with DMA treatment. They also indicate that varying these assumptions could have a major impact on the value of DMAs.
Conclusions
The updated economic model has good predictive power, but validation against longer-term outcomes is still needed. Our analyses also demonstrate the importance of designing a model with sufficient flexibility such that the model allows for assessment of the impact of key sources of uncertainty on the value of DMAs.
Similar content being viewed by others
References
Personal Social Services Research Unit (PSSRU); Institute of Psychiatry. Dementia UK: a report into the prevalence and cost of dementia. London: Alzheimer’s Society; 2007.
Corbett A, Ballard C. New and emerging treatments for Alzheimer’s disease. Expert Opin Emerg Drugs. 2012;17(2):147–56.
Getsios D, Blume S, Ishak KJ, et al. Cost effectiveness of donepezil in the treatment of mild to moderate Alzheimer’s disease: a UK evaluation using discrete-event simulation. Pharmacoeconomics. 2010;28(5):411–27.
Guo S, Getsios D, Hernandez L, et al. Florbetaben PET in the early diagnosis of Alzheimer’s disease: a discrete event simulation to explore its potential values and key data gaps. Int J Alzheimers Dis. 2012;2012:548157.
Cohen JT, Neumann PJ. Decision analytic models for Alzheimer’s disease: state of the art and future directions. Alzheimers Dement. 2008;4(3):212–22.
Gustavsson A, Van Der Putt R, Jonsson L, et al. Economic evaluation of cholinesterase inhibitor therapy for dementia: comparison of Alzheimer’s disease and Dementia with Lewy bodies. Int J Geriatr Psychiatry. 2009;24(10):1072–8.
Stallard E, Kinosian B, Zbrozek AS, et al. Estimation and validation of a multiattribute model of Alzheimer disease progression. Med Decis Mak. 2010;30(6):625–38.
Green C, Shearer J, Ritchie CW, et al. Model-based economic evaluation in Alzheimer’s disease: a review of the methods available to model Alzheimer’s disease progression. Value Health. 2011;14(5):621–30.
Skoldunger A, Johnell K, Winblad B, et al. Mortality and treatment costs have a great impact on the cost-effectiveness of disease modifying drugs in Alzheimer’s disease. Curr Alzheimer Res. 2012;10(2):207–16.
Getsios D, Blume S, Ishak KJ, et al. An economic evaluation of early assessment for Alzheimer’s disease in the United Kingdom. Alzheimers Dement. 2012;8(1):22–30.
Hartz S, Getsios D, Tao S, et al. Evaluating the cost effectiveness of donepezil in the treatment of Alzheimer’s disease in Germany using discrete event simulation. BMC Neurol. 2012;12:2.
Gelinas I, Gauthier L, McIntyre M, et al. Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther. 1999;53(5):471–81.
Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370(4):322–33.
Stern Y, Albert SM, Sano M, et al. Assessing patient dependence in Alzheimer’s disease. J Gerontol. 1994;49(5):M216–22.
Lenderking WR, Wyrwich KW, Stolar M, et al. Reliability, validity, and interpretation of the Dependence Scale in mild to moderately severe Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2013;28(8):738–49.
McLaughlin T, Buxton M, Mittendorf T, et al. Assessment of potential measures in models of progression in Alzheimer disease. Neurology. 2010;75(14):1256–62.
Zhu CW, Leibman C, McLaughlin T, et al. The effects of patient function and dependence on costs of care in Alzheimer’s disease. J Am Geriatr Soc. 2008;56(8):1497–503.
Zhu CW, Leibman C, McLaughlin T, et al. Patient dependence and longitudinal changes in costs of care in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2008;26(5):416–23.
CERAD: Consortium to Establish a Registry for Alzheimer’s Disease. Available from: http://cerad.mc.duke.edu/Default.htm. Accessed 9 Jan 2013
Mohs RC, Doody RS, Morris JC, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology. 2001;57(3):481–8.
Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology. 2001;57(3):489–95.
Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology. 2001;57(4):613–20.
Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology. 1998;50(1):136–45.
Rogers SL, Doody RS, Mohs RC, et al. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med. 1998;158(9):1021–31.
Black SE, Doody R, Li H, et al. Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology. 2007;69(5):459–69.
Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet. 2006;367(9516):1057–65.
Lacey LA, Jones RW, Trigg R, et al. Caregiver burden as illness progresses in Alzheimer’s disease (AD): association with patient dependence on others and other factors: results from the Dependence in AD in England (DADE) study. Vancouver: AAIC; 2012.
King D, Knapp M, Romeo R, et al. Relationship between healthcare and social care costs and patient dependence on others as illness progresses in Alzheimer’s disease (AD): results from the Dependence in AD in England (DADE) study. Vancouver: AAIC; 2012.
Trigg R, Jones RW, Lacey LA, et al. Relationship between patient self- assessed and proxy-assessed quality of life (QoL) and patient dependence on others as illness progresses in Alzheimer’s disease (AD): results from the Dependence in AD in England (DADE) study. Vancouver: AAIC; 2012.
Jones RW, Lacey LA, Knapp M, et al. Relationship between patient dependence on others and clinical measures of cognitive impairment, functional disability and behavioural problems in Alzheimer’s disease (AD): results from the Dependence in AD in England (DADE) study. Vancouver: AAIC; 2012.
British National Formulary (BNF) September 2012. Available from: http://www.bnf.org/bnf/index.htm. Accessed 9 Jan 2013;
National minimum wage rates. 2013. Available from: https://www.gov.uk/national-minimum-wage-rates. Accessed 10 Mar 2013
Teipel SJ, Ewers M, Reisig V, et al. Long-term cost-effectiveness of donepezil for the treatment of Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci. 2007;257(6):330–6.
Di Carlo M, Giacomazza D, San Biagio PL. Alzheimer’s disease: biological aspects, therapeutic perspectives and diagnostic tools. J Phys Condens Matter. 2012;24(24):244102.
de la Torre JC. A turning point for Alzheimer’s disease? Biofactors. 2012;38(2):78–83.
Holland D, McEvoy LK, Desikan RS, et al. Enrichment and stratification for predementia Alzheimer disease clinical trials. PLoS One. 2012;7(10):e47739.
Acknowledgments
The authors would like to thank Drs. Peter Neumann and Linus Jönsson for their helpful feedback during the development of the model and the manuscript.
Funding
This study was sponsored by Pfizer Inc. and Janssen Alzheimer Immunotherapy Research & Development, LLC.
Role of the funding source
Gwilym Thompson and Maren Gaudig are employees of Janssen Alzheimer Immunotherapy Research & Development, LLC. Loretto Lacey was an employee of Janssen Alzheimer Immunotherapy Research & Development, LLC, at the time this research was conducted. Joel Bobula is an employee of Pfizer Inc. All were involved in the design and conduct of the study.
Conflicts of interest
Denis Getsios and Shien Guo are employees of Evidera, who were paid consultants to Pfizer Inc. and Janssen Alzheimer Immunotherapy Research and Development, LLC, in connection with the development of this manuscript. Nikhil Revankar and Peng Xu were employees of Evidera at the time this research was conducted.
Author contributions
Shien Guo, Dennis Getsios, Nikhil Revankar, Peng Xu, Gwilym Thompson, Loretto Lacey, Joel Bobula and Maren Gaudig participated in the design of the model, identification of data sources, conduct of data analyses, and implementing the design. Each author also contributed to the interpretation of data and results, drafting the manuscript, and approved the final version. Shien Guo will serve as guarantor for the overall content of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Additional information
L. Lacey was formerly affiliated with Janssen Alzheimer Immunotherapy, Dublin, Ireland and M. Gaudig was formerly affiliated with Alzheimer Immunotherapy, Dublin, Ireland.
Rights and permissions
About this article
Cite this article
Guo, S., Getsios, D., Revankar, N. et al. Evaluating Disease-Modifying Agents: A Simulation Framework for Alzheimer’s Disease. PharmacoEconomics 32, 1129–1139 (2014). https://doi.org/10.1007/s40273-014-0203-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40273-014-0203-5