1. Randomised Clinical Trials

2. Randomised trials are special - Ethics (HD)‏ - Statistics (special methodology)‏ - Scientific evidence (basis for highest level of evidence)‏ - Authorities (required for marketing of drugs & devices )‏ - Reporting (CONSORT)‏ - Publishing (public registration and other requirements)‏ - Performance (guidelines & requirements)‏ - Expensive - Professional

3. International regulatory guidelines ICH Topic E9 - Statistical Principles for Clinical Trials EMEA Points to consider: baseline covariates - missing data - multiplicity issues - etc. and similar documents from the FDA These guidelines can all be found on the internet.

4. Uniform Requirements “ When reporting experiments on human subjects, authors should indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).”

5. Uniform Requirements “ The ICMJE member journals will require, as a condition of consideration for publication in their journals, registration in a public trials registry.” “ The ICMJE recommends that journals publish the trial registration number at the end of the Abstract.”

6. Uniform Requirements Scientists have an ethical obligation to submit creditable research results for publication. Moreover, as the persons directly responsible for their work, researchers should not enter into agreements that interfere with their access to the data and their ability to analyze them independently, and to prepare and publish manuscripts.

7. Uniform Requirements Authors should identify individuals who provide writing or other assistance and disclose the funding source for this assistance. Editors should ask corresponding authors to declare whether they had assistance with study design, data collection, data analysis, or manuscript preparation. If such assistance was available, the authors should disclose the identity of the individuals who provided this assistance and the entity that supported it in the published article.

8. Uniform Requirements “ As you may know, US Public Law 110-85, Title VIII, mandates the submission of “basic results” data for certain clinical trials of drugs, biologics, and devices, effective September 27, 2008. The law applies to trials that are not Phase 1 or small device feasibility studies, and that have at least one site in the US, regardless of who sponsors, finances, or conducts the trial. Certain other trials may also be covered by the law. In general, these summary results data must be submitted within 12 months of the completion of data collection for the primary outcome measure.”

9. Let's now focus on methodological aspects

10. 1 Precison 2 Validity

11. Induction Deduction (observational studies) (Randomized trials) 1. Data 1. Hypothesis 2. Pattern 2. Data 3. Statistical test 3. Statistical test 4. Hypothesis 4. Confirmation

12. Induction Deduction (observational studies) (Randomized trials) 1. Data 1. Hypothesis 2. Pattern 2. Data 3. Statistical test 3. Statistical test 4. Hypothesis 4. Confirmation Multiplicity issues

13. Uncertainty of sampling Assume that the cumulative 10-year revision rate of the Oxford knee prosthesis is 8% Patients with knee prostheses Not revised Revised

14. 375 randomly ordered patients of which 30 (8%) are revised within 10 years

16. 6% revised 12% revised Sampling uncertainty

17. 6% revised 12% revised Sampling uncertainty is evaluated using probability theory with a specified type-1 error rate (each comparison has 5% error chance).

18. Multiplicity The overall significance level (OSIGN) or chance of at least one false positive finding OSIGN = 1 - (1 – SIGN) c with independent comparisons where c is the number of performed comparisons and SIGN the significance level (usually 0.05). c = 1 => OSIGN = 0.05 c = 2 => OSIGN = 0.10 c = 5 => OSIGN = 0.23 c = 10 => OSIGN = 0.40

19. Example 1. OSIGN = 0.10

20. Example 2. OSIGN = 0.23

21. Example 3. OSIGN = 0.40

22. Example 4. OSIGN = 0.999

23. How to deal with multiplicity 1. Avoid multiplicity adjustments is possible 2. Use “intelligent design “

24. “ Intelligent design” 1. Distinguish between confirmatory and exploratory analyses. 2. Distinguish between primary and secondary endpoints. 3. Define the primary endpoint in such a way that it consists of only one confirmatory analysis.

25. Endpoints Primary The variable capable of providing the most clinically relevant evidence directly related to the primary objective of the trial Secondary Either measurements supporting the primary endpoint or effects related to secondary objectives

26. 1 Precison 2 Validity

27. Internal vs. external validity Internal validity - no confounding bias - no selection bias - no misclassification bias (at least no differential)‏ External validity - representative (inclusion/exclusion criteria)‏

29. Internal vs. external validity Internally valid - efficacy Externally valid - effectiveness

30. Study populations Intention-to-treat Analyse all randomised subjects (ITT) principle according to planned treatment regimen. Full analysis set The set of subjects that is as close (FAS) as possible to the ideal implied by the ITT-principle. Per protocol The set of subjects who complied (PP) set with the protocol sufficiently to ensure that they are likely to exhibit the effects of treatment according to the underlying scientific model.

31. FAS vs. PP-set FAS + no selection bias - misclassification problem (effect dilution)‏ PP-set + no contamination problem - possible selection bias (confounding)‏ When the FAS and PP-set lead to essentially the same conclusions, confidence in the trial is supported.

32. Study protocol and SAP

33. Study protocol - written prior to randomization - specifies primary endpoint in detail - describes how bias will be avoided and how the type-1 error rate will be preserved SAP (Statistical Analysis Plan)‏ - written prior to code breaking - detailed description of statistical analyses

34. Primary endpoint Very often vague or inexplicit like: - “quality of life” or - “hand strength” Should be “ quality of life as measured by SF-36 PCS at 6 weeks of follow up”, or “ strength in the dominant hand measured using one reading of the Smedley hand dynamometer at two weeks of follow up”.

35. With manuscripts reporting trials Include study protocol and statistical analysis plan - Check endpoint(s) - Sample size - Analysis techniques

39. 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