Course. Interim Analyses in Clinical Trials

Transcription

1 Course Interim Analyses in Clinical Trials Prof. Dr. Hans-Helge Müller with Rüdiger Laubender IBE Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie MSc Epidemiology, MPH, etc.: Recent Development in Biostatistics 1 1

2 Topics Sequential and Group Sequential Designs Approaches to Group Sequential Design Developing a Group Sequential Design for a Clinical Trial with Practical Estimation in Group Sequential Design Use of a Group Sequential Design in Practice Learning and Flexible Design Adaptation During the Course of a Trial 2 2

3 An Example of a Report of the Results of a Clinical Trial with a Sequential Design Publication: A Comparison of Lipiodol Chemoembolization and Conservative Treatment for Unresectable Hepatocellular Carcinoma N Engl J Med 1995; 332: Exercise: Is the paper scientifically sound, including a comprehensive and understandable presentation of the primary objective, data analysis, interpretation of results, and clinical claim (conclusion and discussion based on adequacy of used methods)? 3 3

4 Critical Appraisal: First step Clinical question with background, collective of patients / probands, objective Research question to be answered? (PICO+) Relevance? Description of patients / probands (eligible for study enrolment) by major inclusion criteria. Study design, from the clinical perspective. Precise and adequate to answer the research question? 4 4

5 Critical Appraisal: Second step (not the focus today) Avoiding systematic error (bias), methodical quality Study design, from the methodical perspective. Are there sources of systematic error? Are the adequate methods to avoid systematic errors applied? Are they applied appropriately? By what could the effect size estimates have been biased? 5 5

6 Critical Appraisal: Third step Results of the study, statistical analysis and control of random errors, statistical quality Study design, from the statistical perspective. Report on quantitative results (listed in text or tables or presented graphically) and (assessment of) their precision. Hypotheses to be tested and results. Is the influence of random adequately controlled? Statistical planning and adherence to statements for reporting (e.g. CONSORT). 6 6

7 Final result (confirmatory result of the fifth interim analysis): Chemoembolization Conservative treatment randomized patients 50 (47) 46 (45) died 39 (20) 40 (27) Relative risk/hazard ratio (95% CI): 1.4 (0.9; 2.2), p=0.13 of log-rank, 1.3 (0.8; 2.1), p=0.31 adjusted for prognostic factors by Cox-r. Conclusion:... did not significantly improve survival.... less than a 50 percent increase in survival after eight months... (P<0.05). 7 7

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11 Critical Appraisal: Forth step Main result(s) and conclusion, relevance for application in clinical practice State the clinically important results needed to answer the research question, mainly the primary result. Do they impact clinical practice? State the clinical conclusions and recommendations. Are they adequately concluded from the results and quality of the study? 11 11

12 Discussion and Criticism The focus on the presentation of decision making was on a properly performed sequential test procedure. For the non-statistician or even the non-expert biometrician, however, the procedure is difficult to understand. Under the assumption of proportional hazards the 50% increase of the survival rate from 50% to 75% at 8 months which was powered by 90% corresponds to a hazard ratio (HR) of 2.41 or roughly to an increase in median survival of almost one year. This is an utopian effect size, particularly in the long time. From the planning with a competing test to demonstrate that HR<2.41 the chance to demonstrate HR>1 was too low. Thus, the trial suffers from an inadequate competing test and too low sample size (precision)