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The 2018 Revised FDA Guidance for Early Alzheimer’s Disease: Establishing the Meaningfulness of Treatment Effects

  • Chris J. EdgarEmail author
  • G. Vradenburg
  • J. Hassenstab
Brief Reports

Abstract

The present report reviews the revised 2018 FDA guidance for early AD, with an emphasis on meaningfulness of clinical outcome assessments (COAs). A radical shift is evident in the importance given to establishing the meaningfulness of COAs in the 2018 draft versus the 2013 draft. The implications of this shift include the assertion that cognition is clinically meaningful, but that a persuasive effect on cognition, depending upon disease stage of the participants in the trial, is one that is of enough magnitude, established across multiple relevant domains, and can be supported by biomarkers reflecting underlying AD pathological changes. Meaningfulness is established through an understanding of the conceptual relevance of what is being measured and magnitude of any treatment effect. Precedent exists within other FDA guidance and independent good practices publications as to how meaningfulness may be assessed e.g. via evaluation of content validity and concepts such as minimally important difference. Additionally, FDA is developing a series of methodological Patient Focused Drug Development (PFDD) documents to provide further guidance on this topic, which are aimed at addressing gaps in methodology and recommended best practice. Importantly, application of PFDD approaches to AD is behind that in other areas and there is limited published content validity for COAs and a lack of supportive qualitative research. Initiatives to build robust conceptual models of AD and develop novel direct measures of meaningful health outcomes will have a significant impact on measurement of efficacy in clinical trials and on payer determinations of beneficiary value. Greater recognition of what is meaningful from the perspective of the patient and caregiver will inform regulatory reviews and determinations for payment and coverage of treatments.

Key words

Cognition function clinical relevance patient focused drug development regulatory guidance 

Notes

Acknowledgments

C.J. Edgar, G. Vradenburg, and J. Hassenstab authored this manuscript. B. Hauber of RTI Health Solutions and D. Lappin of FaegreBD Consulting contributed to review of this manuscript.

Funding: No funding was received in support of this work.

Conflict of interest: C.J. Edgar is a full-time employee of Cogstate Ltd.

References

  1. 1.
  2. 2.
    Walton MK, Iii JHP, Hobart J, et al. Clinical Outcome Assessments: Conceptual Foundation — Report of the ISPOR Clinical Outcomes Assessment — Emerging Good Practices for Outcomes Research Task Force. Value Heal. 2015;18:741–752. doi: https://doi.org/10.1016/j.jval.2015.09.2863 CrossRefGoogle Scholar
  3. 3.
    Buckley RF, Ellis KA, Ames D, et al. Phenomenological characterization of memory complaints in preclinical and prodromal alzheimer’s disease. Neuropsychology. 2015. doi: https://doi.org/10.1037/neu0000156 CrossRefGoogle Scholar
  4. 4.
    De Vriendt P, Gorus E, Cornelis E, Velghe A, Petrovic M, Mets T. The process of decline in advanced activities of daily living: A qualitative explorative study in mild cognitive impairment. Int Psychogeriatrics. 2012. doi: https://doi.org/10.1017/S1041610211002766 CrossRefGoogle Scholar
  5. 5.
    Banningh LJW, Vernooij-Dassen M, Rikkert MO, Teunisse JP. Mild cognitive impairment: Coping with an uncertain label. Int J Geriatr Psychiatry. 2008. doi: https://doi.org/10.1002/gps.1855 CrossRefGoogle Scholar
  6. 6.
    Gordon MF, Lenderking WR, Duhig A, et al. Development of a patient-reported outcome instrument to assess complex activities of daily living and interpersonal functioning in persons with mild cognitive impairment: The qualitative research phase. Alzheimer’s Dement. 2016. doi: https://doi.org/10.1016/j.jalz.2015.04.008 CrossRefGoogle Scholar
  7. 7.
    Sikkes SAM, De Lange-De Klerk ESM, Pijnenburg YAL, et al. A new informant-based questionnaire for instrumental activities of daily living in dementia. Alzheimer’s Dement. 2012. doi: https://doi.org/10.1016/j.jalz.2011.08.006 CrossRefGoogle Scholar
  8. 8.
    Hartry A, Aldhouse NVJ, Al-Zubeidi T, Sanon M, Stefanacci RG, Knight SL. The conceptual relevance of assessment measures in patients with mild/mildmoderate Alzheimer’s disease. Alzheimer’s Dement Diagnosis, Assess Dis Monit. 2018. doi: https://doi.org/10.1016/j.dadm.2018.07.006 Google Scholar
  9. 9.
    Richardson E, Burnell J, Adams HR, et al. Developing and Implementing Performance Outcome Assessments: Evidentiary, Methodologic, and Operational Considerations. Therapeutic Innovation and Regulatory Science. 2018.Google Scholar
  10. 10.
    Wang J, Logovinsky V, Hendrix SB, et al. ADCOMS: A composite clinical outcome for prodromal Alzheimer’s disease trials. J Neurol Neurosurg Psychiatry. 2016. doi: https://doi.org/10.1136/jnnp-2015-312383 CrossRefGoogle Scholar
  11. 11.
    Donohue MC, Sperling RA, Salmon DP, et al. The preclinical Alzheimer cognitive composite: Measuring amyloid-related decline. JAMA Neurol. 2014. doi: https://doi.org/10.1001/jamaneurol.2014.803 CrossRefGoogle Scholar
  12. 12.
    Aisen P, Touchon J, Amariglio R, et al. EU/US/CTAD Task Force: Lessons Learned from Recent and Current Alzheimer’s Prevention Trials. J Prev Alzheimer’s Dis. 2017. doi: https://doi.org/10.14283/jpad.2017.13
  13. 13.
    Edgar CJ. Use of Qualitative Data to Support Content Validity of Performance-Based Cognitive Outcome Assessments. Ther Innov Regul Sci. 2017;51(6):671–671. doi: https://doi.org/10.1177/2168479017719934 PubMedGoogle Scholar
  14. 14.
    A. Graf, V. Risson, A. Gustavsson, V. Bezlyak, A. Caputo, P.N. Tariot, J.B. Langbaum, C. Lopez Lopez VV. Assessment of Clinical Meaningfulness of Endpoints in the Generation Program by the Insights to Model Alzheimer’s Progression in Real Life (iMAP) Study. J Prev Alzheimers Dis. 2019;6(2):85089.Google Scholar
  15. 15.
    Mansfield C, Bullok KE, Fuhs J V., et al. The patient voice: Exploring treatment preferences in participants with mild cognitive concerns to inform regulatory decision making. Alzheimer’s Dement. 2017. doi: https://doi.org/10.1016/j.jalz.2017.07.650 CrossRefGoogle Scholar
  16. 16.
    Phillips GA, Wyrwich KW, Guo S, et al. Responder definition of the Multiple Sclerosis Impact Scale physical impact subscale for patients with physical worsening. Mult Scler J. 2014. doi: https://doi.org/10.1177/1352458514530489 CrossRefGoogle Scholar
  17. 17.
    Cella D, Nichol MB, Eton D, Nelson JB, Mulani P. Estimating clinically meaningful changes for the functional assessment of cancer therapy — Prostate: Results from a clinical trial of patients with metastatic hormone-refractory prostate cancer. Value Heal. 2009. doi: https://doi.org/10.1111/j.1524-4733.2008.00409.x CrossRefGoogle Scholar
  18. 18.
    Edgar CJ, Le Scouiller S, Delmar P, Mackey H. Estimating clinically relevant change and difference thresholds for the clinical dementia rating: Sum of boxes (CDR-SB) for early Alzheimer’s disease. Alzheimer’s Dement. 2017.Google Scholar
  19. 19.
    Schrag A, Schott JM. What is the clinically relevant change on the ADAS-Cog? J Neurol Neurosurg Psychiatry. 2012. doi: https://doi.org/10.1136/jnnp-2011-300881 CrossRefGoogle Scholar
  20. 20.
    Cook KF, Victorson DE, Cella D, Schalet BD, Miller D. Creating meaningful cut-scores for Neuro-QOL measures of fatigue, physical functioning, and sleep disturbance using standard setting with patients and providers. Qual Life Res. 2015. doi: https://doi.org/10.1007/s11136-014-0790-9 CrossRefGoogle Scholar
  21. 21.
    Thissen D, Liu Y, Magnus B, et al. Estimating minimally important difference (MID) in PROMIS pediatric measures using the scale-judgment method. Qual Life Res. 2016. doi: https://doi.org/10.1007/s11136-015-1058-8 CrossRefGoogle Scholar
  22. 22.
    Rockwood K, Stolee P, Howard K, Mallery L. Use of goal attainment scaling to measure treatment effects in an anti-dementia drug trial. Neuroepidemiology. 1996. doi: https://doi.org/10.2478/jee-2014-0027 CrossRefGoogle Scholar
  23. 23.
    Rockwood K, Howlett SE, Hoffman D, Schindler R, Mitnitski A. Clinical meaningfulness of Alzheimer’s Disease Assessment Scale-Cognitive subscale change in relation to goal attainment in patients on cholinesterase inhibitors. Alzheimer’s Dement. 2017. doi: https://doi.org/10.1016/j.jalz.2017.02.005 CrossRefGoogle Scholar

Copyright information

© Serdi and Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Cogstate LtdLondonUK
  2. 2.UsAgainstAlzheimer’s and Alzheimer’s Disease Patient and Caregiver Engagement (AD PACE)Washington, DCUSA
  3. 3.Department of NeurologyWashington University School of MedicineSt. LouisUSA

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