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Recifercept is an investigational drug for treating children with achondroplasia aged 2\u201310\u2009years. An alternative efficacy evaluation method, instead of a placebo control arm, was employed in the phase II study. Prior to participating in the phase II study, participants completed a natural history (NH) study. Based on the NH data, a multi\u2010variate linear mixed effects natural disease course model of three anthropometric end points (standing height, sitting height, and arm span) was developed. The model was validated using published growth charts of children with achondroplasia. Subsequently, the model was used to simulate the natural growth trajectories (without any treatment) of the three anthropometric end points for the individuals enrolled in the phase II study. To quantify the efficacy of recifercept, the simulations were compared with the observations post\u2010recifercept treatment in the phase II study. For all the tested doses of recifercept, at the individual level, the observations were comparable to the simulations at 6 and 12\u2009months post\u2010recifercept treatment, suggesting no treatment effect. The results contributed to the decision of terminating recifercept clinical development. This work delivers a framework that could eliminate the need for placebo in clinical trials yet provide sufficient evidence for evaluating the efficacy of an investigational drug.<\/jats:p>","DOI":"10.1002\/psp4.13143","type":"journal-article","created":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T04:39:56Z","timestamp":1714451996000},"page":"1103-1116","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Natural disease course modeling of achondroplasia to evaluate the efficacy of recifercept in the absence of a placebo control arm in phase II study"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2703-1101","authenticated-orcid":false,"given":"Wenlian","family":"Qiao","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Translational Sciences, Oncology Pfizer Inc  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7588-2255","authenticated-orcid":false,"given":"Martin","family":"Boucher","sequence":"additional","affiliation":[{"name":"Pharmacometrics and Systems Pharmacology, Translational Clinical Sciences Pfizer Inc  Sandwich Kent UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5853-9200","authenticated-orcid":false,"given":"Alison","family":"Slade","sequence":"additional","affiliation":[{"name":"Medical Affairs Pfizer Inc  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7388-2057","authenticated-orcid":false,"given":"Vikas K.","family":"Dawra","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology, Translational Clinical Sciences Pfizer Inc  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.32485"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61289"},{"issue":"2","key":"e_1_2_10_4_1","first-page":"368","article-title":"Achondroplasia is defined by recurrent G380R mutations of FGFR3","volume":"56","author":"Bellus GA","year":"1995","journal-title":"Am J Hum Genet"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(78)81152-4"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2020.115579"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01287-7"},{"key":"e_1_2_10_8_1","unstructured":"FDA.Rare Diseases: Common Issues in Drug DevelopmentGuidance for Industry 2019. 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