Transcript Discussion on Randomisation and Blinding

DSBS Discussion: Randomisation
20 May 2010
Discussion on
Randomisation and Blinding
Lars Endahl
Biostatistics
Novo Nordisk A/S
DSBS Discussion: Randomisation
20 May 2010
Slide no 2
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
20 May 2010
Slide no 3
• Randomised clinical trial: one of the simplest,
most powerful and revolutionary forms of
research
• Alenjandro Jadad-Bechara (2007)
DSBS Discussion: Randomisation
20 May 2010
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Outline
• Who is Jadad?
• Is randomisation any concern for statisticians?
• Is blinding mostly a pestilence?
• Discussion
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Who is Jadad?
• 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.
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20 May 2010
Slide no 6
Jadad Score
• 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?
• +1 point if appropriate
• e.g. identical treatments, double-dummy etc.
• -1 point if inappropriate
• e.g. tablet vs. injection
• +1 point if adequate description of dropouts
• i.e. number of and reason for dropouts stated
DSBS Discussion: Randomisation
20 May 2010
Slide no 7
• Randomised clinical trial: a type of
experiment that any damn fool can analyse and frequently does
• Stephen Senn (2007)
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Show of Hands
• 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
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•
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parallel-group / cross-over
patient population
comparator drug
duration of trial
DSBS Discussion: Randomisation
20 May 2010
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A key design feature?
• 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
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Is “how” important?
• Does it really matter how a trial was
randomised, as long as we know that some kind
of randomisation took place?
DSBS Discussion: Randomisation
20 May 2010
Features of randomisation?
• What are the most important features of a
randomisation procedure?
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Ensure similar group sizes
Ensure comparable groups
Unpredictable
Well-documented
Easy to administer
Is fool-proof
Optimise use of trial drug
Electronically founded
Slide no 11
DSBS Discussion: Randomisation
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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
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Why randomise?
• What are the key arguments for randomisation?
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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
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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.
• page 9
• Details of the randomisation that facilitate predictability
(e.g. block length) should not be contained in the trial
protocol.
• page 10
Blinding
DSBS Discussion: Randomisation
20 May 2010
Slide no 15
• 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?
DSBS Discussion: Randomisation
20 May 2010
• Who is most crucial to blind?
• patients
• investigators
• sponsor
• all equally important?
• depends on the trial design and drug?
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Blind Data Review?
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• 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?
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• 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."
Where?
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• 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?
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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.
• page 9
• 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.
• page 9
DSBS Discussion: Randomisation
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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
DSBS Discussion: Randomisation
20 May 2010
Slide no 22