{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T04:40:35Z","timestamp":1789533635497,"version":"build-2803163510"},"reference-count":19,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceutical Statistics"],"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Since the publication of ICH E9 (R1), \u201cAddendum to statistical principles for clinical trials: on choosing appropriate estimands and defining sensitivity analyses in clinical trials,\u201d there has been a lot of debate about the hypothetical strategy for handling intercurrent events. Arguments against the hypothetical strategy are twofold: (1) the clinical question has limited clinical\/regulatory interest; (2) the estimation may need strong statistical assumptions. In this article, we provide an example of a hypothetical strategy handling use of rescue medications in the acute pain setting. We argue that the treatment effect of a drug that is attributable to the treatment alone is the clinical question of interest and is important to regulators. The hypothetical strategy is important when developing non\u2010opioid treatment as it estimates the treatment effect due to treatment during the pre\u2010specified evaluation period whereas the treatment policy strategy does not. Two widely acceptable and non\u2010controversial clinical inputs are required to construct a reasonable estimator. More importantly, this estimator does not rely on additional strong statistical assumptions and is considered reasonable for regulatory decision making. In this article, we point out examples where estimators for a hypothetical strategy can be constructed without any strong additional statistical assumptions besides acceptable clinical inputs. We also showcase a new way to obtain estimation based on disease specific clinical knowledge instead of strong statistical assumptions. In the example presented, we clearly demonstrate the advantages of the hypothetical strategy compared to alternative strategies including the treatment policy strategy and a composite variable strategy.<\/jats:p>","DOI":"10.1002\/pst.2359","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T00:29:49Z","timestamp":1705019389000},"page":"399-407","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Application of hypothetical strategies in acute pain"],"prefix":"10.1002","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6249-112X","authenticated-orcid":false,"given":"Jinglin","family":"Zhong","sequence":"first","affiliation":[{"name":"Date Science Sumitomo Pharma America  Marlborough Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Petullo","sequence":"additional","affiliation":[{"name":"Department of Biometrics AstraZeneca  1 Medimmune Way Gaithersburg MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,11]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"ICH.E9 (R1): addendum on estimands and sensitivity analysis to the guideline on statistical principles for clinical trials.2019."},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7033"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.2056"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43441-019-00061-x"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.2019"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.1705"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/10543406.2019.1684308"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","DOI":"10.1016\/S1470-2045(20)30319-3","article-title":"Demystifying the estimand framework: a case study using patient\u2010reported outcomes in oncology","volume":"21","author":"Fiero MH","year":"2020","journal-title":"Lancet Oncol"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-020-04546-1"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1177\/1740774519853573"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cct.2020.106093"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.2078"},{"key":"e_1_2_11_14_1","unstructured":"EMA.Guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease.2018."},{"key":"e_1_2_11_15_1","unstructured":"EMA.Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus.2024."},{"key":"e_1_2_11_16_1","unstructured":"EMA.Question and answer on adjustment for cross\u2010over in estimating effects in oncology trials.2018."},{"key":"e_1_2_11_17_1","unstructured":"FDA.Guidance for industry. Acute myeloid leukemia: developing drugs and biological products for treatment.2022."},{"key":"e_1_2_11_18_1","unstructured":"US Food & Drug Administration Center for Drug Evaluation and Research.Statistical review and evaluation: ANJESO meloxicam injection 30 mg\/ml.2020https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2020\/210583Orig1s000StatR.pdf"},{"key":"e_1_2_11_19_1","volume-title":"Development of Non\u2010Opioid Analgesics for Acute Pain","author":"FDA","year":"2022"},{"key":"e_1_2_11_20_1","unstructured":"FDA Briefing Document.Anesthetic and Analgesic Drug Products Advisory Committee October 11.2018https:\/\/www.fda.gov\/media\/121233\/download"}],"container-title":["Pharmaceutical Statistics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pst.2359","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T02:57:12Z","timestamp":1716173832000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pst.2359"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,11]]},"references-count":19,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1002\/pst.2359"],"URL":"https:\/\/doi.org\/10.1002\/pst.2359","archive":["Portico"],"relation":{},"ISSN":["1539-1604","1539-1612"],"issn-type":[{"value":"1539-1604","type":"print"},{"value":"1539-1612","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,11]]},"assertion":[{"value":"2022-12-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-13","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}