DSBS Discussion: Randomisation 20 May 2010 Discussion on Randomisation and Blinding Lars Endahl Biostatistics Novo Nordisk A/S

DSBS Discussion: Randomisation 20 May 2010

Discussion on Randomisation and Blinding

Lars EndahlBiostatistics

Novo Nordisk A/S

DSBS Discussion: Randomisation Slide no 220 May 2010

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 Slide no 320 May 2010 Slide no 3

• 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?

• Is blinding mostly a pestilence?

• Discussion


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.


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


• 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 • 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


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


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?

• 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?

• 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?• 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

• 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

• 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• all equally important?• depends on the trial design and drug?


Blind Data Review?

• 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? • 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?

• 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• 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


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


Documents

DSBS Discussion: Randomisation 20 May 2010 Discussion on Randomisation and Blinding Lars Endahl Biostatistics Novo Nordisk A/S