Designing Trials of Disease Modifying Agents for Early and Preclinical Alzheimer’s Disease Intervention: What Evidence is Meaningful to Patients, Providers, and Payers?
Drug development for disease modifying agents in Alzheimer’s disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer’s. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs.
to create multi-stakeholder–vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer’s disease (AD).
A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members.
The in-person meeting was held in Baltimore, MD
In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers.
Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer’s prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include “digital independence.”
Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multistakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers.
Key wordsAlzheimer’s disease drug development disease modifying agents disease interception coverage and reimbursement
- 3.Reiman EM, Quiroz YT, Fleisher AS, et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case–control study. The Lancet Neurology. 2012;11(12):1048–1056. doi: https://doi.org/10.1016/S1474-4422(12)70228-4 CrossRefGoogle Scholar
- 6.Head E, Powell D, Gold BT, Schmitt FA. Alzheimer’s Disease in Down Syndrome. Eur J Neurodegener Dis. 2012;1(3):353–364.Google Scholar
- 9.Walsh C, Drinkenburg WHIM, Ahnaou A. Neurophysiological assessment of neural network plasticity and connectivity: Progress towards early functional biomarkers for disease interception therapies in Alzheimer’s disease. Neurosci Biobehav Rev. 2017;73:340–358. doi: https://doi.org/10.1016/j.neubiorev.2016.12.020 CrossRefGoogle Scholar
- 10.US Food and Drug Administration. Early Alzheimer’s Disease: Developing Drugs for Treatment, Guidance for Industry (Draft Guidance). February 2018. https://doi.org/www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM596728.pdf. Accessed February 23, 2018.
- 11.Jack CR, Bennett DA, Blennow K, et al. 2018 NIA–AA Research Framework to Investigate the Alzheiemr’s Disease Continuum (DRAFT). September 2017. https://doi.org/alz.org/aaic/_downloads/draft-nia-aa-7-18-17.pdf. Accessed February 6, 2018.Google Scholar
- 15.Lin P–J, Zhong Y, Fillit HM, Chen E, Neumann PJ. Medicare Expenditures of Individuals with Alzheimer’s Disease and Related Dementias or Mild Cognitive Impairment Before and After Diagnosis. Journal of the American Geriatrics Society. 2016;64(8):1549–1557. doi: https://doi.org/10.1111/jgs.14227 CrossRefGoogle Scholar
- 16.Sano M, Zhu CW, Whitehouse PJ, et al. ADCS Prevention Instrument Project: pharmacoeconomics: assessing health–related resource use among healthy elderly. Alzheimer Disease & Associated Disorders. 2006;20(Supplement 3):S191–S202.Google Scholar
- 21.Nuffield Council on Bioethics. Dementia: Ethical Issues. London: Nuffield Council on Bioethics; 2009.Google Scholar
- 23.Progress and Challenges in Alzheimer’s Disease Drug Development: An Update on Scientific, Clinical, and Regulatory Considerations from an Industry Perspective Global CEO Initiative on Alzheimer’s Disease. https://doi.org/www.ceoalzheimersinitiative.org/node/90. Accessed February 2, 2018.
- 25.Pearson SD, Ollendorf DA, Colby JA. Diagnostic Tests for Alzheimer’ s Disease: Generating and Evaluating Evidence to Inform Insurance Coverage Policy. December 2012. https://doi.org/pdfs.semanticscholar.org/2750/577ecc59b14aaaaa8d0bffb02aebba8c8498.pdf. Accessed January 5, 2018.Google Scholar
- 26.Holtzman DM, Corriveau RA. 2016 Alzheimer’s Disease–Related Dementias Summit: Report to the National Advisory Neurological Disorders and Stroke Council. https://doi.org/www.ninds.nih.gov/sites/default/files/ADRD2016_summit_council_rpt_508Cpdf.pdf. Published September 15, 2016. Accessed November 16, 2017.Google Scholar
- 27.Agency for Healthcare Research and Quality. Interventions To Prevent Age–Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer’s–Type Dementia. https://doi.org/ahrq-ehc-application.s3.amazonaws.com/media/pdf/cognitive-decline_research-2017.pdf. Published Maarch 2017. Accessed November 16, 2017.
- 29.Home:: Core Outcome Measures in Effectiveness Trials Initiative (COMET). https://doi.org/www.comet-initiative.org/. Accessed November 16, 2017.
- 30.Webster L, Groskreutz D, Grinbergs–Saull A, et al. Core outcome measures for interventions to prevent or slow the progress of dementia for people living with mild to moderate dementia: Systematic review and consensus recommendations. PlosOne. June 2017. doi: https://doi.org/10.1371/journal.pone.0179521 Google Scholar