According to ICH E9(R1), defining the estimand comes before defining the analysis approach, and the strategies for addressing intercurrent events are key components of the estimand. With the composite strategy, the problem of missing data disappears, because it becomes part of the endpoint definition. It is this perspective that we adopt in addressing the problem of missing data. We propose comparing patients in a pairwise manner to determine which patient fared better, one patient from each group, taking into account the reason for and timing of missingness. For purposes of illustration, reasons for missingness are placed into three categories: (1) death or adverse events, (2) administration of rescue medication (treated as missing even if patient continues in the study, or a poor score is assigned), and (3) other reasons such as loss to follow-up or withdrawal of consent. Each pair of patients is compared on the endpoint of interest. The comparison outcomes are determined based on the presence of missing data, its category, and timing. For instance, if both patients in a pair have received rescue medication, the patient with the later time of rescue medication is considered to have fared better. The overall treatment effect is estimated from combining results across all pairwise comparisons. This method allows the reason and timing of missing data to contribute to the assessment of treatment effects, providing a solution to some limitations of existing methods. Thus, the pairwise comparison approach addresses the missing data problem transparently via the composite strategy.
机构:
Univ Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Univ Manchester, Div Canc Sci, Fac Biol Med & Hlth, Manchester M13 9PL, Lancs, EnglandUniv Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Geary, Bethany
Peat, Erin
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Manchester Acad Hlth Sci Ctr, Christie NHS Fdn Trust, Manchester M20 4BX, Lancs, EnglandUniv Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Peat, Erin
Dransfield, Sarah
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Manchester Acad Hlth Sci Ctr, Christie NHS Fdn Trust, Manchester M20 4BX, Lancs, EnglandUniv Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Dransfield, Sarah
Cook, Natalie
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Manchester Acad Hlth Sci Ctr, Christie NHS Fdn Trust, Manchester M20 4BX, Lancs, EnglandUniv Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Cook, Natalie
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Thistlethwaite, Fiona
Graham, Donna
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机构:
Manchester Acad Hlth Sci Ctr, Christie NHS Fdn Trust, Manchester M20 4BX, Lancs, EnglandUniv Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Graham, Donna
Carter, Louise
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机构:
Univ Manchester, Div Canc Sci, Fac Biol Med & Hlth, Manchester M13 9PL, Lancs, England
Manchester Acad Hlth Sci Ctr, Christie NHS Fdn Trust, Manchester M20 4BX, Lancs, EnglandUniv Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Carter, Louise
Hughes, Andrew
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Univ Manchester, Div Canc Sci, Fac Biol Med & Hlth, Manchester M13 9PL, Lancs, EnglandUniv Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Hughes, Andrew
Krebs, Matthew G.
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Univ Manchester, Div Canc Sci, Fac Biol Med & Hlth, Manchester M13 9PL, Lancs, England
Manchester Acad Hlth Sci Ctr, Christie NHS Fdn Trust, Manchester M20 4BX, Lancs, EnglandUniv Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Krebs, Matthew G.
Whetton, Anthony D.
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Univ Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
Univ Manchester, Div Canc Sci, Fac Biol Med & Hlth, Manchester M13 9PL, Lancs, England
Manchester Natl Inst Hlth Res Biomed Res Ctr, Manchester M13 9WL, Lancs, EnglandUniv Manchester, Stoller Biomarker Discovery Ctr, Fac Biol Med & Hlth, Manchester M13 9NQ, Lancs, England
机构:
Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
Mallinckrodt, Craig
Molenberghs, Geert
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机构:
Hasselt Univ, I BioStat, Diepenbeek, Belgium
Katholieke Univ Leuven, I BioStat, Leuven, BelgiumEli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
Molenberghs, Geert
Rathmann, Suchitrita
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Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USAEli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
机构:
Amer Coll Radiol, NRG Oncol Stat & Data Management Ctr, Dept Stat, 50 South 16th St,Suite 2800, Philadelphia, PA 19102 USAAmer Coll Radiol, NRG Oncol Stat & Data Management Ctr, Dept Stat, 50 South 16th St,Suite 2800, Philadelphia, PA 19102 USA
Pugh, Stephanie L.
Brown, Paul D.
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Mayo Clin, Dept Radiat Oncol, Rochester, MN USAAmer Coll Radiol, NRG Oncol Stat & Data Management Ctr, Dept Stat, 50 South 16th St,Suite 2800, Philadelphia, PA 19102 USA
Brown, Paul D.
Enserro, Danielle
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Roswell Park Comprehens Canc Ctr, NRG Oncol Stat & Data Management Ctr, Buffalo, NY USAAmer Coll Radiol, NRG Oncol Stat & Data Management Ctr, Dept Stat, 50 South 16th St,Suite 2800, Philadelphia, PA 19102 USA