1. 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

2. 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…

3. 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)

4. 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

5. 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.

6. 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

7. 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)

8. 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

9. 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

10. 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?

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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?

17. 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

18. 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."

19. 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?

20. 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.

21. 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

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