Cautions as Regulators Move to End Exclusive Reliance on Intention to Treat
Authors: Miguel A. Hernán, Daniel Scharfstein
Journal: Annals of Internal Medicine (2018)

Ideas and Opinions3 April 2018Cautions as Regulators Move to End Exclusive Reliance on Intention to TreatMiguel A. Hernán, MD, DrPH and Daniel Scharfstein, ScDMiguel A. Hernán, MD, DrPHHarvard T.H. Chan School of Public Health and Harvard–MIT Division of Health Sciences and Technology, Boston, Massachusetts (M.A.H.) and Daniel Scharfstein, ScDJohns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (D.S.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M17-3354 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Intention-to-treat (ITT) analyses of randomized trials, which analyze participants in their assigned groups regardless of actual receipt of the intervention, have been favored because they alleviate concerns about baseline confounding. However, this benefit comes at a price: ITT analyses estimate the effect of being assigned to an intervention rather than that of actually receiving it. The magnitude of the ITT effect—in statistical parlance, the causal estimand—depends on the degree to which participants receive assigned interventions, and ITT analyses can miss harms and result in erroneous claims of noninferiority (1, 2).Given these shortcomings, some regulators, pharmaceutical companies, and academics advocate ...References1. Goetghebeur E, Loeys T. Beyond intention to treat. Epidemiol Rev. 2002;24:85-90. [PMID: 12119861] CrossrefMedlineGoogle Scholar2. Hernán MA, Hernández-Díaz S. Beyond the intention-to-treat in comparative effectiveness research. Clin Trials. 2012;9:48-55. [PMID: 21948059] doi:10.1177/1740774511420743 CrossrefMedlineGoogle Scholar3. Hernán MA, Robins JM. Per-protocol analyses of pragmatic trials. N Engl J Med. 2017;377:1391-8. [PMID: 28976864] doi:10.1056/NEJMsm1605385 CrossrefMedlineGoogle Scholar4. Hernán MA, Hernández-Díaz S, Robins JM. Randomized trials analyzed as observational studies. Ann Intern Med. 2013;159:560-2. [PMID: 24018844] AbstractGoogle Scholar5. Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The prevention and treatment of missing data in clinical trials. N Engl J Med. 2012;367:1355-60. [PMID: 23034025] doi:10.1056/NEJMsr1203730 CrossrefMedlineGoogle Scholar6. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH harmonized guideline: estimands and sensitivity analysis in clinical trials. ICH E9(R1). Current step 2 version. 16 June 2017. Accessed at www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/E9-R1EWG_Step2_Guideline_2017_0616.pdf on 15 January 2018. Google Scholar7. Causey M. FDA endorses ICH E9 addendum on clinical trials analyses. The Association of Clinical Research Professionals. 31 October 2017. Accessed at www.acrpnet.org/2017/10/31/fda-endorses-ich-e9-addendum-clinical-trials-analyses on 15 January 2018. Google Scholar Author, Article, and Disclosure InformationAffiliations: Harvard T.H. Chan School of Public Health and Harvard–MIT Division of Health Sciences and Technology, Boston, Massachusetts (M.A.H.)Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (D.S.)Financial Support: In part by grant UL1TR001079 from the National Institutes of Health and contract ME-1503-28119 from the Patient-Centered Outcomes Research Institute.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-3354.Corresponding Author: Miguel A. Hernán, MD, DrPH, Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115; e-mail, [email protected]harvard.edu.Current Author Addresses: Dr. Hernán: Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Avenue, Boston, MA 02115.Dr. Scharfstein: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205.Author Contributions: Conception and design: M.A. Hernán, D. Scharfstein.Drafting of the article: M.A. Hernán, D. Scharfstein.Critical revision of the article for important intellectual content: M.A. Hernán, D. Scharfstein.Final approval of the article: M.A. Hernán, D. Scharfstein.Statistical expertise: M.A. Hernán, D. Scharfstein.Obtaining of funding: M.A. Hernán, D. Scharfstein.This article was published at Annals.org on 20 March 2018. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byMultistate models as a framework for estimand specification in clinical trials of complex processesSensitivity analyses for the principal ignorability assumption using multiple imputationAnalysis approaches to address treatment nonadherence in pragmatic trials with point-treatment settings: a simulation studyUsing principal stratification in analysis of clinical trialsImpact of rescue medication in placebo-controlled trials of pharmacotherapy for neuropathic pain and low back painWhy ITT analysis is not always the answer for estimating treatment effects in clinical trialsIncorporating partial adherence into the principal stratification analysis frameworkPrincipal stratum strategy: Potential role in drug developmentSensitivity analyses in pragmatic randomized clinical trialsRethinking the intention-to-treat principle: one size does not fit allRegulatory-grade clinical trial design using real-world dataCounterfactual prediction is not only for causal inferenceContinuation of Annual Screening Mammography and Breast Cancer Mortality in Women Older Than 70 YearsXabier García-Albéniz, MD, PhD, Miguel A. Hernán, MD, DrPH, Roger W. Logan, PhD, Mary Price, PhD, Katrina Armstrong, MD, MSCE, and John Hsu, MD, MBA, MSCEThe Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: Explanation and ElaborationDavid M. Kent, MD, MS, David van Klaveren, PhD, Jessica K. Paulus, ScD, Ralph D'Agostino, PhD, Steve Goodman, MD, MHS, PhD, Rodney Hayward, MD, John P.A. Ioannidis, MD, DSc, Bray Patrick-Lake, MFS, Sally Morton, PhD, Michael Pencina, PhD, Gowri Raman, MBBS, MS, Joseph S. Ross, MD, MHS, Harry P. Selker, MD, MSPH, Ravi Varadhan, PhD, Andrew Vickers, PhD, John B. Wong, MD, and Ewout W. Steyerberg, PhDCausal Inference and Estimands in Clinical TrialsDefining standard of practiceAssessing risk of bias in a randomized trialA constructive critique of the draft ICH E9 AddendumISPOR, the FDA, and the Evolving Regulatory Science of Medical Device ProductsStatistical Appraisal of 6 Recent Clinical Trials in Cardiology 3 April 2018Volume 168, Issue 7Page: 515-516KeywordsCancer treatmentDecision makingDisclosureEpidemiologyPrevention, policy, and public healthTreatment guidelines ePublished: 20 March 2018 Issue Published: 3 April 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...