Clinical Trial Perspective Berger & Antsygina A review of randomization methods in clinical trials 5 Clinical Trial Perspective 2015/11/28 A review of randomization methods in clinical trials Clin. Invest. (Lond.) In many respects, clinical trials can be seen as an art as well as a science, in that there Vance W Berger*,1 & Olga is ample discretion for investigators to select research methods reflecting their own Antsygina2 individual preferences. In fact, new research methods are developed on a fairly 1National Cancer Institute & University of Maryland Baltimore County, Biometry regular basis, not all of them improvements over existing methods. But the opposite Research Group, National Cancer trend also remains in effect, as researchers often follow established precedent, Institute, 9609 Medical Center Drive, rather than thinking through the issues relevant to the current trial so as to come Rockville, MD 20850, USA up with the research methods that are optimal in this case. These two forces pulling 2University of South Florida, College in opposite directions, individuality and inertia, compete in many aspects of clinical of Public Health, Department of Epidemiology & Biostatistics, research, including the specific methods of randomization. New randomization 13201 Bruce B Downs, MDC56 Tampa, methods are constantly proposed, while at the same time more and more researchers FL 33612, USA seem to be using the established standards of permuted blocks randomization or *Author for correspondence: minimization (which, in its most extreme form, is not even true randomization at Tel.: 240 276 7142 all). A comprehensive review of all randomization methods is beyond the scope of [email protected] this work, but we will review these two established standards, as well as the newer (and vastly better) maximum tolerated imbalance procedures, including the big stick, Chen’s procedure and the maximal procedure. Keywords: allocation concealment • big stick • Chen’s procedure • clinical trial • maximal procedure • minimization • MTI • permuted blocks • randomization methods 10.4155/cli.15.53 • weak encryption In many respects, clinical trials can be seen posed, while at the same time more and more as an art as well as a science, in that there is researchers seem to be using the established ample discretion for investigators to select standards of permuted blocked randomiza- 12 research methods reflecting their individual tion (which provides only weak encryption) preferences. In fact, new research methods are or minimization (which, in its most extreme developed on a fairly regular basis, not all of form, is not even true randomization at all). them improvements over existing methods. Because so many new randomization meth- 2015 But the opposite trend also remains in effect, ods are proposed, a comprehensive review of as researchers often follow the established all randomization methods is beyond the precedent, rather than thinking through the scope of this work, but we will review the issues relevant to the current trial so as to aforementioned two established standards, come up with the research methods that are permuted blocks and minimization, as well optimal in this case [1] . So we have, simultane- as the newer maximum tolerated imbalance ously, too much conformity and too little con- (MTI) procedures, including the big stick [2], formity. These two forces pulling in opposite Chen’s procedure [3] and the maximal proce- directions, individuality and inertia, compete dure [4], with an eye toward comparing and in many aspects of clinical research, including contrasting them in terms of their ability to the specific methods of randomization. New simultaneously control both chronological part of randomization methods are constantly pro- bias [5] and selection bias [6]. 10.4155/cli.15.53 © 2015 Future Science Ltd Clin. Invest. (Lond.) (2015) 5(12), 00–00 ISSN 2041-6792 1 Clinical Trial Perspective Berger & Antsygina In ‘quasi-randomization’ we shall distinguish true alternation as long as there is even the chance of any randomization from quasi-randomization. In the allocations becoming unmasked. Therefore, alterna- ‘Minimization & adaptive procedures’ section, we shall tion precludes the possibility of allocation concealment discuss minimization and other adaptive procedures. and it discredits results of trial. In the ‘The permuted blocks design (PBD)’ section, In recognition of the distinction between alternation we offer a somber critique of the popular permuted (and related procedures) and true randomization, some blocks procedure. In ‘MTI procedures’ we discuss the researchers refer to alternation as quasi-randomization. much more appropriate MTI procedures (the big stick, In fact, we too have done so in this paper, but this is Chen’s procedure and the maximal procedure). In the done only to ensure that the procedures we condemn ‘Mixing & matching’ section, we discuss combining are recognized for what they are, since some research- various different randomization procedures so as to ers know them only as quasi-randomization, and never come up with something that is more robust than any actually call them alternation. So there might other- one of the basic methods that was used to produce it. wise be some danger that some readers would agree In the ‘Executive summary’, we offer a summary and with our analysis, but then carry on using alternation our conclusions regarding how randomization should thinking that they are using not alternation (which and should not be conducted. we condemn) but, rather, quasi-randomization, on which we remain silent. To be absolutely clear, then, Quasi-randomization we decided not to remain silent on the alter ego, and There are quite a few problems that plague clinical to instead call it out by name. This is not to suggest research, and these forces conspire to result in medi- that we endorse or agree with the use of this highly cal studies that, taken as a whole, are not reproduc- misleading term. ible. In fact, Altman [7] referred to medical research The term ‘quasi-randomization’ suggests something as a ‘scandal’, and Ioannidis [8] noted that most pub- just shy of true randomization but close enough that lished research findings are false. One of the problems for all practical purposes we may safely ignore the tech- that has helped to get us there is a general tolerance nical distinction. It is all semantics anyway. But it is for imprecise reporting. An overwhelming number not all semantics. The distinction is real, and carries of trial reports provide no information whatsoever massive ramifications for the validity of the trial (or regarding the precise methods of randomization used, lack thereof), as we have already discussed. For truth beyond making the claim that the trial was random- in advertising, this misleading term should no longer ized. Unfortunately, this claim is often false, and the be used. Instead we should refer to alternation in an misleading claim of randomization is almost never rec- honest and transparent manner. It is not randomiza- ognized as such, given this environment of trust with- tion in any sense of the word. No partial credit is due out verifying. for going through the motions with the old college try. Berger and Bears [9] distinguished quasi-randomiza- Any given trial is properly randomized, or is not. There tion from true randomization, and noted how infre- really is no in between, and if alternation is used, then quently true randomization could be deduced from the the trial is not properly randomized and its results can- descriptions that accompanied the claims of random- not be trusted. This remains true, by the way, even if ization. Far too often it turns out that alternation is an element of randomization is used to select between used instead of randomization, and yet randomization the two allocations sequences ABABABAB … and is claimed anyway. In practice, we almost never know BABABABA … Speaking about element of random- the difference, since authors are almost never held to ization such as blocks we should mention that it cannot any real standards in reporting what they did. And yet guarantee the comparability of groups and, therefore, the distinction is a crucial one in terms of trial quality, internal validity of the study remains questionable. reliability and validity. In future sections we will highlight the differ- Minimization & adaptive procedures ence between the MTI procedures, with their strong Even among the enlightened group of researchers who encryption and permuted blocks, with its weak encryp- recognize the folly in using alternation, there still seems tion. But for now, we note that alternation offers no to be overwhelming tolerance for minimization (and encryption at all. Indeed, in the case of an unmasked other similar adaptive allocation procedures), which trial conducted with alternation instead of randomiza- is not generally equated with alternation or cast under tion, once we observe the identity of the first alloca- the umbrella of quasi-randomization. In fact, even so tion, we will know with certainty all future ones as prominent a research group as the Cochrane Collabo- well. In other words, allocation concealment is impos- ration explicitly exempts minimization from the perils sible in this situation, and it remains impossible with of being considered less than true randomization. The 2 Clin. Invest. (Lond.) (2015) 5(12) future science group A review of randomization methods in clinical trials Clinical Trial Perspective risk of bias assessment tool [10] states that “minimization general good intentions of all investigators when evalu- may be implemented without a random element, and ating a system. Therefore, when designing a system, we this is considered to be equivalent to being random.” must impose a stress test based upon a worst-case sce- Let us examine this statement. In fact minimiza- nario. Along these lines, we consider how much damage tion is not one single allocation procedure, but, rather, an investigator can do, if so inclined, when minimiza- represents an entire family of procedures, indexed by tion is used in its pure form.