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When should the primary analysis of a trial not be intention to treat? Group 6

When should the primary analysis of a trial not be intention to treat? Group 6. Lakshmi Bhaskara , Allison Dostal , Diego Garcia- Huidobro Tina Gunderson, Linda Hanson, Chay Lim, Logan Stuck. Intention to Treat Analysis . “ once randomized always analyzed ”

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When should the primary analysis of a trial not be intention to treat? Group 6

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  1. When should the primary analysis of a trial not be intention to treat?Group 6 Lakshmi Bhaskara, Allison Dostal, Diego Garcia-Huidobro Tina Gunderson, Linda Hanson, ChayLim, Logan Stuck

  2. Intention to Treat Analysis “once randomized always analyzed” • All randomized subjects are followed, assessed, and analyzed as members of that group, regardless of… • Compliance • Errors in entry criteria • Protocol deviations • Treatment received • Withdrawal from treatment

  3. Intention to Treat Analysis • Pros • Effectiveness of treatments • Subjects may be noncompliant due to Tx response • Preserves sample size & statistical power • Reflects clinical practice

  4. Non-Intention to Treat Analysis • To estimate the effect of treatment as delivered or as receivedin eligible &compliant evaluable subjects • “per protocol” • Includes patients adherent to the protocol • “as treated” • Includes patients adherent to the intervention

  5. When Is It a Appropriate to do Non ITT? • Non-inferiority trials • Estimating adverse effects of treatment • Treatment crossover & non-compliance

  6. Adverse Effects of Treatment

  7. JAMA 2003; 289:3243-3253 Figure 1. Sensitivity Analysis of Invasive Breast Cancers in Adherent Participants by Treatment Group Figure 2 Invasive Breast Cancer & Estrogen + Progestin Intention to Treat Analysis Per-Protocol Analysis

  8. Nonadherence

  9. JAMA, November 22/29-296(20) • ITT: “for each measure at each point, the treatment favors surgery. The treatment effects for the primary outcomes were small and not statistically significant.” • As-Treated Analysis: “yielded far different treatment results from the ITT analysis, with strong statistically significant advantages for surgery at follow-up through 2 years.”

  10. Take Home • ITT Analysis is preferred • Non-ITT or modified ITT can have significant methodological impacts • Non-ITT as a Secondary Analysis • Effects of Harm • Nonadherence • Non-inferiority trials

  11. References • ChlebowskiRT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy post-menopausal women. The Women’s Health Initiative Randomized Trial. JAMA2003;289:3243-3253 • Gupta, SK. Intention to Treat Concept. A Review. PerspectClin Res. 2011 Jul-Sep; 2(3): 109–112. • SnappinSM. Noninferiority Trials. Curr Control Trials Cardiovasc Med. 2000; 1(1): 19–21. • ICHExpert Working Group. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceutical s in Humans • FDA Guidance. ICH: Guidance on statistical princicplesfor clinical trials. • Weinstein et al. Surgical versus nonoperative treatment for lumbar disc herniation. The Spine Patient Outcomes Research Trial (SPORT): A Randomized Trial. JAMA. 2006 November 22; 296(20): 2441–2450. • ICH Topic E9 Statistical Principles for Clinical Trials. European Medicines Agency. Sept 1998.

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