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Review ArticleReview Article

Development of Novel, Value-Based, Digital Endpoints for Clinical Trials: A Structured Approach Toward Fit-for-Purpose Validation

M. D. Kruizinga, F. E. Stuurman, V. Exadaktylos, R. J. Doll, D. T. Stephenson, G. J. Groeneveld, G. J. A. Driessen and A. F. Cohen
Martin Michel, ASSOCIATE EDITOR
Pharmacological Reviews October 2020, 72 (4) 899-909; DOI: https://doi.org/10.1124/pr.120.000028
M. D. Kruizinga
Centre for Human Drug Research, Leiden, The Netherlands (M.D.K., F.E.S., V.E., R.J.D., G.J.G., A.F.C.); Juliana Children’s Hospital, HAGA Teaching Hospital, The Hague, The Netherlands (M.D.K., G.J.A.D.); Leiden University Medical Center, Leiden, The Netherlands (M.D.K., F.E.S., G.J.G., A.F.C.); and Critical Path for Parkinson’s Consortium, Critical Path Institute, Tucson, Arizona (D.T.S.)
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F. E. Stuurman
Centre for Human Drug Research, Leiden, The Netherlands (M.D.K., F.E.S., V.E., R.J.D., G.J.G., A.F.C.); Juliana Children’s Hospital, HAGA Teaching Hospital, The Hague, The Netherlands (M.D.K., G.J.A.D.); Leiden University Medical Center, Leiden, The Netherlands (M.D.K., F.E.S., G.J.G., A.F.C.); and Critical Path for Parkinson’s Consortium, Critical Path Institute, Tucson, Arizona (D.T.S.)
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V. Exadaktylos
Centre for Human Drug Research, Leiden, The Netherlands (M.D.K., F.E.S., V.E., R.J.D., G.J.G., A.F.C.); Juliana Children’s Hospital, HAGA Teaching Hospital, The Hague, The Netherlands (M.D.K., G.J.A.D.); Leiden University Medical Center, Leiden, The Netherlands (M.D.K., F.E.S., G.J.G., A.F.C.); and Critical Path for Parkinson’s Consortium, Critical Path Institute, Tucson, Arizona (D.T.S.)
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R. J. Doll
Centre for Human Drug Research, Leiden, The Netherlands (M.D.K., F.E.S., V.E., R.J.D., G.J.G., A.F.C.); Juliana Children’s Hospital, HAGA Teaching Hospital, The Hague, The Netherlands (M.D.K., G.J.A.D.); Leiden University Medical Center, Leiden, The Netherlands (M.D.K., F.E.S., G.J.G., A.F.C.); and Critical Path for Parkinson’s Consortium, Critical Path Institute, Tucson, Arizona (D.T.S.)
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D. T. Stephenson
Centre for Human Drug Research, Leiden, The Netherlands (M.D.K., F.E.S., V.E., R.J.D., G.J.G., A.F.C.); Juliana Children’s Hospital, HAGA Teaching Hospital, The Hague, The Netherlands (M.D.K., G.J.A.D.); Leiden University Medical Center, Leiden, The Netherlands (M.D.K., F.E.S., G.J.G., A.F.C.); and Critical Path for Parkinson’s Consortium, Critical Path Institute, Tucson, Arizona (D.T.S.)
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G. J. Groeneveld
Centre for Human Drug Research, Leiden, The Netherlands (M.D.K., F.E.S., V.E., R.J.D., G.J.G., A.F.C.); Juliana Children’s Hospital, HAGA Teaching Hospital, The Hague, The Netherlands (M.D.K., G.J.A.D.); Leiden University Medical Center, Leiden, The Netherlands (M.D.K., F.E.S., G.J.G., A.F.C.); and Critical Path for Parkinson’s Consortium, Critical Path Institute, Tucson, Arizona (D.T.S.)
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G. J. A. Driessen
Centre for Human Drug Research, Leiden, The Netherlands (M.D.K., F.E.S., V.E., R.J.D., G.J.G., A.F.C.); Juliana Children’s Hospital, HAGA Teaching Hospital, The Hague, The Netherlands (M.D.K., G.J.A.D.); Leiden University Medical Center, Leiden, The Netherlands (M.D.K., F.E.S., G.J.G., A.F.C.); and Critical Path for Parkinson’s Consortium, Critical Path Institute, Tucson, Arizona (D.T.S.)
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A. F. Cohen
Centre for Human Drug Research, Leiden, The Netherlands (M.D.K., F.E.S., V.E., R.J.D., G.J.G., A.F.C.); Juliana Children’s Hospital, HAGA Teaching Hospital, The Hague, The Netherlands (M.D.K., G.J.A.D.); Leiden University Medical Center, Leiden, The Netherlands (M.D.K., F.E.S., G.J.G., A.F.C.); and Critical Path for Parkinson’s Consortium, Critical Path Institute, Tucson, Arizona (D.T.S.)
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Martin Michel
Roles: ASSOCIATE EDITOR
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Abstract

Novel digital endpoints gathered via wearables, small devices, or algorithms hold great promise for clinical trials. However, implementation has been slow because of a lack of guidelines regarding the validation process of these new measurements. In this paper, we propose a pragmatic approach toward selection and fit-for-purpose validation of digital endpoints. Measurements should be value-based, meaning the measurements should directly measure or be associated with meaningful outcomes for patients. Devices should be assessed regarding technological validity. Most importantly, a rigorous clinical validation process should appraise the tolerability, difference between patients and controls, repeatability, detection of clinical events, and correlation with traditional endpoints. When technically and clinically fit-for-purpose, case building in interventional clinical trials starts to generate evidence regarding the response to new or existing health-care interventions. This process may lead to the digital endpoint replacing traditional endpoints, such as clinical rating scales or questionnaires in clinical trials. We recommend initiating more data-sharing collaborations to prevent unnecessary duplication of research and integration of value-based measurements in clinical care to enhance acceptance by health-care professionals. Finally, we invite researchers and regulators to adopt this approach to ensure a timely implementation of digital measurements and value-based thinking in clinical trial design and health care.

Significance Statement Novel digital endpoints are often cited as promising for the clinical trial of the future. However, clear validation guidelines are lacking in the literature. This paper contains pragmatic criteria for the selection, technical validation, and clinical validation of novel digital endpoints and provides recommendations for future work and collaboration.

Footnotes

  • https://doi.org/10.1124/pharmrev.120.000028.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 72 (4)
Pharmacological Reviews
Vol. 72, Issue 4
1 Oct 2020
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Review ArticleReview Article

Fit-for-Purpose Validation of Novel Digital Endpoints

M. D. Kruizinga, F. E. Stuurman, V. Exadaktylos, R. J. Doll, D. T. Stephenson, G. J. Groeneveld, G. J. A. Driessen and A. F. Cohen
Pharmacological Reviews October 1, 2020, 72 (4) 899-909; DOI: https://doi.org/10.1124/pr.120.000028

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Review ArticleReview Article

Fit-for-Purpose Validation of Novel Digital Endpoints

M. D. Kruizinga, F. E. Stuurman, V. Exadaktylos, R. J. Doll, D. T. Stephenson, G. J. Groeneveld, G. J. A. Driessen and A. F. Cohen
Pharmacological Reviews October 1, 2020, 72 (4) 899-909; DOI: https://doi.org/10.1124/pr.120.000028
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  • Article
    • Visual Overview
    • Abstract
    • I. Introduction
    • II. Potential Advantages of Value-Based Digital Endpoints
    • III. Selection of Candidate Digital Endpoints
    • IV. Technical Validation
    • V. Clinical Validation
    • VI. Case Building
    • VII. Discussion
    • VIII. Conclusion
    • Acknowledgments
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