We thank Dr. Cummings for his support of the development of the SPIRIT/CONSORT‐SURROGATE extensions and his correction that the primary outcome of the aducanumab trials in early Alzheimer's disease is the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB) rather than the biomarker of magnetic resonance imaging–assessed amyloid load. However, this reply gives us the opportunity to clarify that the concept of surrogate endpoints in trials extends beyond biomarkers and includes intermediate outcomes. 1 Unlike biomarkers, intermediate outcomes can be directly perceived and be valued by trial participants but are intended as a substitute and predictor for a more distal patient‐relevant final outcome. Whether an intermediate outcome should be considered a patient‐relevant final outcome or surrogate endpoint depends on the aims of a trial and how that trial informs health‐care policy. 2 A key question for regulators, payers, health‐care professionals, and patients for the assessment of new treatments in this field is whether intermediate outcomes such as CDR‐SB or Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) should be valued as final outcomes in their own right or, rather, as surrogate endpoints for the more severe disease progression, including residential care facility admission and/or premature death. If the latter, validation is required that the treatment‐related improvements in CDR‐SB seen in recent trials is strongly associated with an improvement in these more distal outcomes. 3
We hope the completed SPIRIT‐SURROGATE and CONSORT‐SURROGATE checklists will clarify definitions of surrogate endpoints and guide trialists in improving transparency and completeness in their reporting.
CONFLICTS OF INTEREST
The authors declare no conflicts. Author disclosures are available in the supporting information.
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ACKNOWLEDGMENTS
SPIRIT‐SURROGATE/CONSORT‐SURROGATE is a Medical Research Council Better Research Better Health (MR/V038400/1)–funded project. Project Management Group: Philippa Davies, Derek Stewart, Christopher J. Weir, Amber E. Young; International Project Advisory Executive Committee members: Joseph S. Ross (Chair), Martin Offringa, Nancy J. Butcher, An‐Wen Chan, Gary S. Collins, Sylwia Bujkiewicz, Dalia Dawoud, Mario Ouwens.
The development of SPIRIT and CONSORT extensions has been funded by the UK Medical Research Council (grant number MR/V038400/1). The funder has no role in the development of the extensions.
REFERENCES
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