Discussion on Randomisation and Blinding DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing 20 May 2010 10-11 December 2008 Discussion on Randomisation and Blinding Lars Endahl Biostatistics Novo Nordisk A/S

DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing 20 May 2010 10-11 December 2008 Disclaimer The views that may be expressed in this discussion talk do not necessarily represent those of the speaker nor his affiliation! In short: I’m all for randomisation and blinding even though it may not appear this way in the following…

DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing Statistics for Non-statisticians: Hypothesis Testing 3 20 May 2010 Slide no 3 10-11 December 2008 12-13 March 2008 Randomised clinical trial: one of the simplest, most powerful and revolutionary forms of research Alenjandro Jadad-Bechara (2007)

Outline Who is Jadad? Is randomisation any concern for statisticians? DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing 20 May 2010 10-11 December 2008 Outline Who is Jadad? Is randomisation any concern for statisticians? Is blinding mostly a pestilence? Discussion

Who is Jadad? Physician from Oxford DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing 20 May 2010 Who is Jadad? 10-11 December 2008 Physician from Oxford Given name to the most widely used assessment tool for evaluating the quality of an randomised clinical trial Jadad et al. (1996). ”Assessing the quality of reports of randomized clinical trials: Is blinding necessary?”. Controlled Clinical Trials 17 (1): 1–12.

Jadad Score Jadad score (0-5 points) +1 point if trial randomised? DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing 20 May 2010 Jadad Score 10-11 December 2008 Jadad score (0-5 points) +1 point if trial randomised? +1 point if appropriate e.g. table of random numbers, computer generated etc. -1 point if inappropriate e.g. birth date +1 point trial double-blinded? e.g. identical treatments, double-dummy etc. e.g. tablet vs. injection +1 point if adequate description of dropouts i.e. number of and reason for dropouts stated

DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing Statistics for Non-statisticians: Hypothesis Testing 7 20 May 2010 Slide no 7 10-11 December 2008 12-13 March 2008 Randomised clinical trial: a type of experiment that any damn fool can analyse - and frequently does Stephen Senn (2007)

Show of Hands How many of you DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing 20 May 2010 Show of Hands 10-11 December 2008 How many of you have analysed a randomised clinical trial (RCT)? feel that the evidence from a RCT stands and falls with the randomisation? regard the randomisation as being the most important feature of the trial design? e.g. more important that parallel-group / cross-over patient population comparator drug duration of trial

DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing 20 May 2010 A key design feature? 10-11 December 2008 If randomisation is really a key feature of a trial design, why do all block-randomised two-armed 1:1 trials have a block size of four? and why is that a big secret? do statisticians rarely engage themselves in discussions on how a trial should be randomised? forced randomisation? block-randomisation? do we not document the details of the randomisation procedure in the report or publications

DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing 20 May 2010 10-11 December 2008 Is “how” important? Does it really matter how a trial was randomised, as long as we know that some kind of randomisation took place?

Features of randomisation? DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 11 20 May 2010 Slide no 11 12-13 March 2008 10-11 December 2008 Features of randomisation? What are the most important features of a randomisation procedure? Ensure similar group sizes Ensure comparable groups Unpredictable Well-documented Easy to administer Is fool-proof Optimise use of trial drug Electronically founded

Do you agree? Do you agree with this statement? DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 12 20 May 2010 Slide no 12 12-13 March 2008 10-11 December 2008 Do you agree? In a randomised trial, the only difference between the two groups being compared is that of most interest: the intervention under investigation. Mike Clarke, UK Cochrane Centre Do you agree with this statement? randomisation ensures causality???? If comparable groups was the aim of randomisation, why not use minimisation or dynamic allocation procedures

Why randomise? What are the key arguments for randomisation? DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 13 20 May 2010 Slide no 13 12-13 March 2008 10-11 December 2008 Why randomise? What are the key arguments for randomisation? Essential for providing evidence Guidelines requires it Randomisation cannot do any harm Easier to randomise than try to explain why it may not be necessary Seals a sort of contract with the outside community (regulatory authorities) that recruitment is not manipulated

ICH-E9 and Randomisation DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 14 20 May 2010 Slide no 14 12-13 March 2008 10-11 December 2008 ICH-E9 and Randomisation Randomisation provides a sound statistical basis for the quantitative evaluation of the evidence relating to treatment effects. page 9 In combination with blinding, randomisation helps to avoid possible bias in the selection and allocation of subjects arising from the predictability of treatment assignments. Details of the randomisation that facilitate predictability (e.g. block length) should not be contained in the trial protocol. page 10

DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 15 20 May 2010 Slide no 15 Blinding 10-11 December 2008 12-13 March 2008 Blinding is done to avoid potential influence on the trial results caused by subjective behaviour, reporting, evaluation, data processing, and analysis due to personal preference of treatment Also the placebo effect of a trial may differ depending on what treatment the patient think he/she is receiving

Who? Who is most crucial to blind? patients investigators sponsor DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 16 20 May 2010 Slide no 16 Who? 10-11 December 2008 12-13 March 2008 Who is most crucial to blind? patients investigators sponsor all equally important? depends on the trial design and drug?

Blind Data Review? How do we make a blind data review of DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 17 20 May 2010 Slide no 17 Blind Data Review? 10-11 December 2008 12-13 March 2008 How do we make a blind data review of young –elderly phase 1 trial? blind the age of the subjects? how do we check inclusion in right age groups? PK trial with different chemical entities? or where the concentration level would reveal the drug

Analyse All Data? Is a blind data review really necessary? DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 18 20 May 2010 Slide no 18 Analyse All Data? 10-11 December 2008 12-13 March 2008 Is a blind data review really necessary? even when blinding hinders the data cleaning? Why not just analyse all data as they are collected? New EMEA guidance on bioequivalence: “… the decision to exclude a subject from the statistical analysis must be made before bioanalysis… Exclusion of data cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because it is impossible to distinguish the formulation effects from other effects influencing the pharmacokinetics."

DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 19 20 May 2010 Slide no 19 Where? 10-11 December 2008 12-13 March 2008 Is blinding equally important in all trials? confirmatory vs. exploratory superiority vs. non-inferiority vs. equivalence trials (trials with the aim to show no difference) parallel-group vs. cross-over trials phase 1 vs. phase 3 trials what about phase 2 trials? Does blinding play the same role regardless of the trial design and objectives?

ICH-E9 Guidance on Blinding DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 20 20 May 2010 Slide no 20 12-13 March 2008 10-11 December 2008 ICH-E9 Guidance on Blinding If a double-blind trial is not feasible, then the single-blind option should be considered. page 9 In single-blind or open-label trials every effort should be made to minimise the various known sources of bias and primary variables should be as objective as possible. The sponsor should have adequate standard operating procedures to ensure that access to the treatment code is appropriately restricted during the process of cleaning the database prior to its release for analysis.

Blinding vs. Randomisation DSBS Discussion: Randomisation Statistics for Non-statisticians: Hypothesis Testing Statistics for non-statisticians: Multiple Testing 21 20 May 2010 Slide no 21 12-13 March 2008 10-11 December 2008 Blinding vs. Randomisation Is double-blinding and randomisation equally important for the quality of a clinical trial? 2 Jadad points each And are these the most important features determining the quality of a clinical trial? 4 out of 5 Jadad points

Statistics for non-statisticians: Multiple Testing DSBS Discussion: Randomisation Statistics for non-statisticians: Multiple Testing 20 May 2010 10-11 December 2008