Randomised Controlled Trials

Randomised Controlled Trials
Ninian Peckitt
FRCS FFD RCS FDS RCS FACCS
Oral and Maxillofacial Surgeon / Facial Plastic Surgeon
Adjunct Associate Professor of Engineering Assisted Surgery
Massey University New Zealand

Classification of Randomised Trials
• Parallel Group
– Randomly assigned to 2 groups
– Treatment vs non treatment
• Crossover
– Over time random sequence of intervention
• Split Body
– eg Right vs Left Random treatment vs No Treatment
• Cluster
– Pre-existing Groups eg Villages/Schools
• Factorial
– Combination of interventions / non interventions in Random groups

By outcome of interest (efficacy vs. effectiveness)
• RCTs - "explanatory"
– Test efficacy
– Highly selected participants
– Highly Controlled conditions
• RCTs – “pragmatic.”
– Test effectiveness in every day practice
– Unselected Participants
– Flexible Conditions
– Give informed decisions about practice

By hypothesis (superiority vs. noninferiority vs. equivalence)
• "superiority trials" (most)
– statistically significant
• "noninferiority trials”
– new treatment no worse than existing Rx
• "equivalence trials"
- x2 Rx indistiguishable

Randomisation
Advantages of proper randomisation
• choosing a randomization procedure - generate unpredictable sequence
• eg simple random assignment to any of the groups at equal probabilities,
– may be "restricted,"
– or may be "adaptive."
• allocation concealment,
– precautions to ensure group assignment not revealed prior to allocating to groups.
– Non-random "systematic" methods of group assignment, such as alternating subjects
between one group and the other, can cause "limitless contamination possibilities" and can
cause a breach of allocation concealment

Randomisation - Goals
• Equal Group Sizes for Adequate Statistical Power
(Especially Subgroup Analyses)
• Low selection bias
(investigator cannot predict the next subject's group
assignment by examining which group has been
assigned the fewest subjects up to that point)
• Low probability of confounding
(i.e., a low probability of "accidental bias"),
(i.e. a balance in covariates across groups).

Simple Randomisation
• commonly used
• intuitive procedure
• similar to "repeated fair coin-tossing
• AKA "complete" or "unrestricted" randomization
• robust against selection and accidental biases
• possibility of imbalanced group sizes in small RCTs
• recommended only for RCTs > 200 subjects

Restricted Randomisation
To balance group sizes in smaller RCTs
• Permuted-block randomization or blocked randomization:
– a "block size" and "allocation ratio" (number of subjects in one group versus the other group) are specified,
– and subjects are allocated randomly within each block.
– For example, a block size of 6 and an allocation ratio of 2:1 would lead to random assignment of 4 subjects
to one group and 2 to the other.
–
• This type of randomization can be combined with "stratified randomization", for example by
center in a multicenter trial, to "ensure good balance of participant characteristics in each group."
[2]
• A special case of permuted-block randomization is random allocation,
– in which the entire sample is treated as one block.[29]
• The major disadvantage of permuted-block randomization is that even if the block sizes are large
and randomly varied, the procedure can lead to selection bias.[30]
• Another disadvantage is that "proper" analysis of data from permuted-block-randomized RCTs
requires stratification by blocks.[32]

Restricted Randomisation
• Adaptive biased-coin randomization methods
• urn randomization is the most widely-known type):
• In these relatively uncommon methods, the probability of being
assigned to a group decreases if the group is over-represented and
increases if the group is under-represented.[29]
• The methods are thought to be less affected by selection bias than
permuted-block randomization.[32]

Adaptive Randomisation
• Covariate-adaptive randomization,
• minimization:
– The probability of being assigned to a group varies in order to minimize
"covariate imbalance."[32]
– Minimization is reported to have "supporters and detractors";[29]
because only the first subject's group assignment is truly chosen at
random
– the method does not necessarily eliminate bias on unknown factors.[2]

Adaptive Randomisation
Response-adaptive randomization, (outcome-adaptive):
• The probability of being assigned to a group increases if the
responses of the prior patients in the group were favorable.[32]
• Although arguments have been made that this approach is more
ethical than other types of randomization when the probability that a
treatment is effective or ineffective increases during the course of an
RCT, ethicists have not yet studied the approach in detail.[33]

Allocation Concealment
"Allocation concealment“
(protecting the randomisation process
so that the treatment to be allocated is not known before the patient is entered into the study")
• desirable in RCTs.[34]
• In pratice difficult to maintain impartiality.
• Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to
dictate the assignment of their next patient.[29] Such practices introduce selection bias and confounders (both of which should be
minimized by randomization), thereby possibly distorting the results of the study.[29]
• Adequate allocation concealment should defeat patients and investigators from discovering treatment allocation once a study is underway
and after the study has concluded. Treatment related side-effects or adverse events may be specific enough to reveal allocation to
investigators or patients thereby introducing bias or influencing any subjective parameters collected by investigators or requested from
subjects.
• Some standard methods of ensuring allocation concealment include sequentially-numbered, opaque, sealed envelopes (SNOSE);
sequentially-numbered containers; pharmacy controlled randomization; and central randomization.[29]
• It is recommended that allocation concealment methods be included in an RCT's protocol, and that the allocation concealment methods
should be reported in detail in a publication of an RCT's results; however, 2005 study determined that most RCTs have unclear allocation
concealment in their protocols, in their publications, or both.[35] On the other hand, a 2008 study of 146 meta-analyses concluded that the
results of RCTs with inadequate or unclear allocation concealment tended to be biased toward beneficial effects only if the RCTs'
outcomes were subjective as opposed to objective.[36]

Blinding (Masking)
• Prevent from knowing which intervention was received."[36]
• Unlike allocation concealment, blinding is sometimes inappropriate or impossible to perform in an RCT; for
example, if an RCT involves a treatment in which active participation of the patient is necessary (e.g.,
physical therapy), participants cannot be blinded to the intervention.
• Traditionally, blinded RCTs have been classified as "single-blind," "double-blind," or "triple-blind"; however, in
2001 and 2006 two studies showed that these terms have different meanings for different people.[37][38]
• The 2010 CONSORT Statement specifies that authors and editors should not use the terms "single-blind,"
"double-blind," and "triple-blind"; instead, reports of blinded RCT should discuss "If done, who was blinded after
assignment to interventions (for example, participants, care providers, those assessing outcomes) and how."[2]
• RCTs without blinding are referred to as "unblinded",[39] "open",[40] or (if the intervention is a medication) "
open-label".[41]
• In 2008 a study concluded that the results of unblinded RCTs tended to be biased toward beneficial effects only if
the RCTs' outcomes were subjective as opposed to objective;[36]
(e.g. in an RCT of treatments for multiple sclerosis, unblinded neurologists (but not blinded neurologists) felt that
the treatments were beneficial.[42] In pragmatic RCTs, although the participants and providers are often
unblinded, it is "still desirable and often possible to blind the assessor or obtain an objective source of data for
evaluation of outcomes."[27]

Analysis of Data from RCTs
• For dichotomous (binary – good/bad) outcome data
– logistic regression (e.g., to predict sustained virological response after
receipt of peginterferon alfa-2a for hepatitis C[43]) and other methods
can be used.
• Continuous data, analysis of covariance (e.g., for changes in blood
lipid levels after receipt of atorvastatin after
acute coronary syndrome[44]) tests the effects of predictor variables
• For time-to-event outcome data that may be censored,
survival analysis (e.g., Kaplan–Meier estimators and
Cox proportional hazards models for time to coronary heart disease
after receipt of hormone replacement therapy in menopause[45]) is
appropriate.

Analysis of RCT Data
• Whether a RCT should be stopped early due to interim results. For
example, RCTs may be stopped early if an intervention produces "larger
than expected benefit or harm," or if "investigators find evidence of no
important difference between experimental and control interventions."[2]
• The extent to which the groups can be analyzed exactly as they existed
upon randomization (i.e., whether a so-called "intention-to-treat analysis" is
used). A "pure" intention-to-treat analysis is "possible only when complete
outcome data are available" for all randomized subjects;[46] when some
outcome data are missing, options include analyzing only cases with known
outcomes and using imputed data.[2] Nevertheless, the more that analyses
can include all participants in the groups to which they were randomized, the
less bias that an RCT will be subject to.[2]
• Whether subgroup analysis should be performed. These are "often
discouraged" because multiple comparisons may produce false positive
findings that cannot be confirmed by other studies.[2]

Reporting of RCT Results
The CONSORT 2010 Statement
"an evidence-based, minimum set of recommendations for reporting RCTs."[47]
The CONSORT 2010 checklist
– 25 items (many with sub-items)
focusing on "individually randomised, two group, parallel trials"
(which are the most common type of RCT) [1]
For other RCT study designs, "CONSORT extensions" are published.[1]

Advantages RCTs
Advantages
• RCTs - the most reliable form of scientific evidence in the
hierarchy of evidence that influences healthcare policy and practice
because RCTs reduce spurious causality and bias. Results of RCTs
may be combined in systematic reviews which are increasingly
being used in the conduct of evidence-based medicine.

Hierarchy of Evidence
Greenhalgh suggests that:
"The hierarchy of evidence Standard notation for the relative weight carried by the different types of primary study when making decisions
about clinical interventions (the “hierarchy of evidence”) puts them in the following order*:
1. Systematic reviews and meta-analyses
2. RCTs with definitive results
(confidence intervals that do not overlap the threshold clinically significant effect)
3. RCTs with non-definitive results
(a point estimate suggests a clinically significant effect but confidence intervals overlap threshold for this effect)
4. Cohort studies
5. Case-control studies
6. Cross sectional surveys
7. Case reports."
(Greenhalgh, T. 1997. p244.) ref* to Guyatt et al 1995.

Disadvantages - RCTs
Limitations of external validity
• Where the RCT was performed
(e.g., what works in one country may not work in another)
• Characteristics of the patients
(e.g., include better prognosis / exclude "women, children, the elderly, and common medical conditions"[62])
• Study procedures
(pts may receive Rx/care difficult to achieve in the "real world")
• Outcome measures
(e.g., RCTs may use composite measures infrequently used in clinical practice)
• Incomplete reporting of adverse effects of interventions
• Cost

Relative Importance of RCTs
• Two studies published in The New England Journal of Medicine in 2000 found that
observational studies and RCTs overall produced similar results.[64][65]
• Doubt?
– "observational studies should not be used for defining evidence-based medical care“
– RCTs' results are "evidence of the highest grade."[64][65]
• Journal of the American Medical Association 2001
– "discrepancies beyond chance do occur
– differences in estimated magnitude of treatment effect are very common"
– observational studies vs RCTs.[66]
• If study designs ranked by their potential for new discoveries, then hierarchy becomes:
1. anecdotal evidence
2. observational studies
3. followed by RCTs.[67]
• RCTs may be unnecessary for treatments that have dramatic and rapid effects relative to
the expected stable or progressively worse natural course of the condition treated.[59]
[68]

RCT Difficulties
Difficulty in studying rare events
• Infrequent events /uncommon outcomes
– RCTs with extremely large sample sizes
– may therefore best be assessed by observational studies.[59]
Difficulty in studying outcomes in distant future
• It is costly to maintain RCTs for the years or decades that would
be ideal for evaluating some interventions.[59][60]

RCTs – Industrial Bias?
Pro-industry findings in industry-funded RCTs
• A systematic review 2003 - four 1986-2002 articles
• industry-sponsored vs nonindustry-sponsored RCTs
• correlation - industry sponsorship / positive study outcome all studies [70]
• Study 2004 (1999-2001 RCTs )
– leading medical and surgical journals industry-funded RCTs
– "more likely statistically significant pro-industry findings."[71]
• One possible reason for the pro-industry results in industry-funded
published RCTs is publication bias.[71]

Therapeutic Misconception
• informed consent usual
• since 1982 RCT subjects believe that they are certain to
receive treatment that is best for them personally
• that is, they do not understand the difference between
research and treatment.[72][73]
• Further research is necessary to determine the
prevalence of and ways to address this "
therapeutic misconception".[73]

Statistical Error
RCT Errors
• type I ("false positive")
– typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT
will falsely find two equally effective treatments significantly different.[74]
• type II ("false negative")
– Paper 1978 - sample sizes of many "negative" RCTs
– too small to make definitive conclusions about the negative results,[75]
– by 2005-2006 a sizeable proportion of RCTs still had inaccurate or
incompletely-reported sample size calculations.[76]

Cultural Effects
• RCT method creates cultural effects
• Poorly understood[77]
• Terminal pts may attempt to join trials
– as a last ditch attempt at treatment,
– even when treatments are unlikely to be successful

References
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