Re-randomisation in trials
Simon Gates
25 April 2007
Contents
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Introduction: the problem
Inclusion issues
Analysis issues
Discussion
The problem
• Recruitment period of trials can last a long
time
• A participant may be randomised and have
trial treatment, then re-present with the same
problem and be eligible again later.
• Randomising again is equivalent to
randomising episodes of disease rather than
patients.
Examples
• Trauma
• Pregnancy
– Recruitment period of 2 or 3 years is long enough
for some women to participate in trial, then get
pregnant and become eligible again
• Acute asthma
– People are eligible when they attend hospital with
acute asthma
– People will recover within a short period
– Some may have attacks several times in a year.
What should we do with these
people?
• Randomise again or not?
• If not, what treatment should they
receive?
• Should their second episode be
included in analyses?
• If so, how should they be analysed?
Is this an important question?
• Number of participants affected usually
small and hence low potential for bias in
the results.
• Example MAGPIE trial (magnesium
sulphate for pre-eclampsia): 15 out of
10141 women randomised twice.
Is this an important question?
• Major issue in some fields
• Cochrane review “Colony stimulating factors for
chemotherapy-induced febrile neutropenia.”
• 4/13 trials randomised episodes; contained 25% of
episodes and patients in the review.
• Re-randomisation stated by methodology consensus
statement to be an acceptable design.
Immunocompromised Host Society. The design, analysis, and reporting of
clinical trials on the empirical antibiotic management of the neutropenic patient.
Report of a consensus panel J. Infect Dis 1990, 161(3):397-401.
Is this an important question?
• Problem occurs in many trials.
• Much time and effort invested by triallists
and statisticians in dealing with it (reinventing the wheel)
• No agreed best practice.
Literature
• Very little published on this issue
• One methodological paper:
Hozo I, Djulbegovic B, Clark O, Lyman GH.
Use of re-randomized data in metaanalysis. BMC Med Res Methodol. 2005
May 10;5(1):17.
Inclusion issues
Include or not?
• Randomise again and include in analysis as a
separate data point
• Allocate treatment deterministically (i.e. not
by randomisation), and include second
participation in analyses
– treatment originally allocated
– treatment not originally allocated
– intervention group
– control group
Include or not?
• Randomise or allocate deterministically to a
treatment option but do not include second
participation in analyses
• Do not give any of the trial treatments (and do
not include second episode in analysis)
Factors affecting decision
• Best strategy is likely to vary depending
on the nature of the trial
• Need to consider what strategy is best
under what conditions
Duration of follow-up?
• If participants are still being followed up from
their first participation, do not want them to
receive a different treatment.
• Participants would be in both groups
simultaneously
• Erodes difference between groups
• Allocate to original treatment?
• Include second episode in analysis or not?
Follow-up
• Trial comparing new treatment versus
usual care with long-term follow-up.
• Likely that a proportion of the new
treatment group will receive usual care
during follow-up for subsequent
episodes (e.g. at hospitals not in the
trial).
• Triallists may not know about this.
Recovery from first episode
• Outcomes of second episodes of
disease within a short period may be
different.
• Treatment received during first episode
may affect the outcome of the second.
Patient preferences
• Patients who participate once and have
a good outcome may be keen to
participate again
• Is it ethically acceptable to refuse, or to
include them and not use the data?
Identifying previous participants
• Patients who present for a second time
may not be identified as previous
participants
• May therefore not be possible to
allocate them to desired treatment
• They may be randomised in belief that it
is first presentation
Identifying previous participants
• Planning of strategy for rerandomisation must consider
practicalities of identifying participants.
• Example: patient presents to a different
hospital for second episode.
Analysis issues
Analysis
• Main problem in analysis is that
observations from the same individual
are not independent
• Some individuals may be randomised
more than once even if the trial protocol
forbids this – so problem is likely to
arise in most trials where this is possible
Analytical strategies
Ignore
• Analyse as if two randomisations were
independent
• Probably the commonest approach
Analytical strategies
Include data from only one randomisation
for each patient
• Ensures there is no non-independence
• Second participation will be ignored
• Is it ethical/scientifically acceptable to
randomise (or otherwise include) with
the intention of ignoring the data?
Multiple participations with the
same treatment
• Equivalent to cluster randomised trials
• Standard methods for analysis
• Have been used for situations like
multiple pregnancies
Multiple participations with
different treatments
• Analysis not so straightforward
• If treatments always different, similar to
crossover trial
• If a mixture of the same and different,
???
Discussion
Discussion
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