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@ARTICLE{Benda:144995,
      author       = {Benda, Norbert and Hänisch, Britta},
      title        = {{E}nrichment designs using placebo nonresponders.},
      journal      = {Pharmaceutical statistics},
      volume       = {19},
      number       = {3},
      issn         = {1539-1604},
      address      = {New York, NY},
      publisher    = {Wiley},
      reportid     = {DZNE-2020-00359},
      pages        = {303-314},
      year         = {2020},
      abstract     = {Enrichment designs that select placebo nonresponders have
                      gained much attention during the last years in areas with
                      high placebo response rates, eg, in depression. Proposals
                      were made that re-randomize patients who did not respond to
                      placebo during a first study phase as the sequential
                      parallel design (SPD). This design uses in a second phase an
                      enriched patient population where the treatment effect is
                      expected to be more pronounced. This may be problematic if
                      an effect in the overall population is claimed. Proposals
                      were made to combine the treatment effects in the overall
                      population from study phase 1 and the enriched population
                      from study phase 2, alleviating but not solving the issue of
                      a potential selection bias. This paper shows how this bias
                      corresponding to the effect difference between the overall
                      population and the enriched population depends on the
                      variability of a potential subject-by-treatment interaction.
                      Sample sizes are given, which lead to a significant result
                      in the combining test with a given probability if actually
                      the average effect in the overall population is zero. If, on
                      the other hand, no subject-by-treatment interaction is
                      given, the enrichment is shown to be inefficient. We
                      conclude that enrichment designs using placebo nonresponders
                      are not able to claim a positive average effect in the
                      overall population if a subject-by-treatment interaction
                      cannot be excluded. It cannot be used to demonstrate
                      positive efficacy in the overall population in a pivotal
                      phase III trial but may be used in early phases to
                      demonstrate varying treatment effects between patients.},
      keywords     = {Data Interpretation, Statistical / Double-Blind Method /
                      Humans / Models, Statistical / Placebo Effect / Randomized
                      Controlled Trials as Topic: statistics $\&$ numerical data /
                      Research Design: statistics $\&$ numerical data / Treatment
                      Outcome},
      cin          = {AG Hänisch ; AG Hänisch},
      ddc          = {610},
      cid          = {I:(DE-2719)1013010},
      pnm          = {345 - Population Studies and Genetics (POF3-345)},
      pid          = {G:(DE-HGF)POF3-345},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31899854},
      doi          = {10.1002/pst.1992},
      url          = {https://pub.dzne.de/record/144995},
}