Generation of Allocation Sequences in Randomised Trials (PDF)

Reprinted from: The Lancet 2002 February 9; j~YlYJU)): )lb-)l~. LUUL-O EPIDE\UOLOGY SERIES IEpidemiology series I...

Reprinted from: The Lancet 2002 February 9; j~YlYJU)): )lb-)l~. LUUL-O EPIDE\UOLOGY SERIES IEpidemiology series I Generation of allocation sequences in randomised trials: chance, not choice Notice: This ".'c:c::',,: 1.:21 3a ProteclEd !)~' _ '.' -:,: ,::::1 Q.~-.'" (Tiitle 17 U.v. '...!....,~.0). Kenneth F Schulz, David A Grimes The randomised controlled trial sets the gold standard of clinical research. However, randomisation persists as perhaps the least-understood aspect of a trial. Moreover, anything short of proper randomisation courts selection and confounding biases. Researchers should spum all systematic, non-random methods of allocation. Trial participants should be assigned to comparison groups based on a random process. Simple (unrestricted) randomisation, analogous to repeated fair coin-tossing, is the most basic of sequence generation approaches. Furthennore. no other approach, irrespective of its complexity and sophistication, surpasses simple randomisation for prevention of bias. Investigators should, therefore, use this method more often than they do, and readers should expect and accept disparities in group sizes. Several other complicated restricted randomisation procedures limit the likelihood of undesirable sample size imbalances in the intervention groups. The most frequently used restricted sequence generation procedure is blocked '-;, randomisation. If this method is used, investigators should randomly vary the block sizes and use larger block sizes, particularly in an unblinded trial. other restricted procedures, such as urn randomisation, combine beneficial attributes of simple and restricted randomisation by preserving most of the unpredictability while achieving some balance. The effectiveness of stratified randomisation depends on use of a restricted randomisation approach to balance the allocation sequences for each stratum. Generation of a proper randomisation sequence takes little time and effort but affords big rewards in scientific accuracy and credibility. Investigators should devote appropriate resources to the generation of properly randomised trials and reporting their methods clearly. "... having used a random allocation, the sternest critic is Panel 1: History of randomJsed controlled trials unable to say when we eventually dash into print that quite The controlled trial gained increasing recognition during the probably the groups were differentially biased through our 20th century as the best approach for assessment of heatth predilections or through our stupidity." I care and prevention attematives. R A Fishe~ developed randomisation as a basic principle of experimental design in Until recently, investigators shunned fonnally the 1920s. and used the technique predominantfy in controlled experimentation when designing trials agricuttural research. The successful adaptation of mndornised (panel I).~;; Now, however, the randomised controlled controlled trials to health care took place in the late 1940s, trial sets the methodological standard of excellence in largely because of the advocacy and developmental WOfk of Sir medical research (panel 2).1.0 The unique capability of Austin Bradford Hill (figure) while at the london School of randomised controlled trials to reduce bias depends on Hygiene and Tropical Medicine.) His efforts culminated in the investigators being able to implement their principal bias- first experimental' and publishe