Methodology in Clinical and Health Services Research
Randomization and allocation concealment: a practical guide for researchers

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Abstract

Although the randomized controlled trial is the most important tool currently available to objectively assess the impact of new treatments, the act of randomization itself is often poorly conducted and incompletely reported. The primary purpose of randomizing patients into treatment arms is to prevent researchers, clinicians, and patients from predicting, and thus influencing, which patients will receive which treatments. This important source of bias can be eliminated by concealing the upcoming allocation sequence from researchers and participants. Although there are many approaches to randomization that are known to effectively conceal the randomization sequence, the use of sequentially numbered, opaque sealed envelopes (SNOSE) is both cheap and effective. The purpose of this tutorial is to describe a step-by-step process for the preparation of SNOSE. We will outline how to prepare SNOSE to preserve allocation concealment in a trial that (a) uses unrestricted (simple) randomization, (b) stratifies randomization on one factor, (c) uses permuted blocks and, and (d) is conducted at more than 1 study site.

Introduction

The randomized controlled trial (RCT) is widely accepted as being the most powerful tool currently available for ensuring the objective evaluation of the true benefits of medical care [1], [2]. Although randomization itself is central to the internal validity of the RCT, the act of randomization is consistently poorly executed [3] and incompletely reported [4].

The primary purpose of randomizing patients into treatment arms is to prevent researchers, clinicians, and patients from predicting, and thus influencing, upcoming group assignments [5], [6]. Concealing the knowledge of upcoming group assignments “prevents researchers from (unconsciously or otherwise) influencing which participants are assigned to a given intervention group” (Definition of allocation concealment. CONSORT Statement Web site. Available at: http://www.consort-statement.org/allocationconcealment.htm. Accessed March 1, 2005). It is well known that trials with inadequate or unclear concealment of the allocation sequence can produce up to 40% larger estimates of treatment effects [7].

Without exception, allocation concealment is achievable in all randomized trials, including animal experiments, bench research, and health services research [8], [9]. There are many randomization methods that are known to effectively maintain allocation concealment; however, most are complex and expensive. Approaches such as pharmacy-controlled randomization, 24-hour central randomization offices (phone-in or Web-based), or even the use of numbered or coded containers in a placebo-controlled trial [10] require extensive infrastructure support that may be beyond the resources available to investigators in single-center trials. When conducted properly, randomizing participants using sequentially numbered, opaque sealed envelopes (SNOSE) is the most accessible and straightforward method of maintaining allocation concealment and does not require the use of specialized technology [11].

There are many published reports of attempts that have been made by individuals to subvert or decipher the allocation sequence in clinical trials. These attempts range in scale from break-and-enter, undertaken to obtain the master randomization list, to screening a sealed envelope using the x-ray viewing box to visualize its contents [3], [10]. Clearly, no approach is immune to an individual dedicated to “break the code.” However, if prepared with care, the use of SNOSE can be as reliable as any other method [11].

Although there are excellent papers that describe how a reader can critically appraise a published article to determine whether allocation concealment was maintained [10], there are very few detailed resources written for the clinical trialist or bench researcher. The purpose of this tutorial is to provide the clinical trialist and bench researcher with a simple but effective step-by-step process for the preparation of SNOSE. Although there are many ways to prepare SNOSE, the method we describe can be used to preserve allocation concealment in a trial that (a) uses unrestricted (simple) randomization, (b) stratifies randomization on one factor, (c) uses permuted blocks and, (d) is conducted at more than 1 study site.

Section snippets

Materials required for a typical 50-patient trial

Obtain 50 identical, opaque, letter-sized envelopes; 50 sheets of standard-size paper; 25 letter-size sheets of single-sided carbon paper; and 2 rolls of household aluminum cooking foil. Complete the kit by purchasing a Tupperware-style plastic container large enough to hold all 50 envelopes.

Additional notes on blocking

Block randomization will not guarantee that an identical number of patients will be enrolled into each arm of the trial, but it will ensure that similar numbers of patients are enrolled into each arm. There are no requirements that group sizes must be identical, merely similar [12]. Furthermore, it is not essential that your chosen block sizes divide evenly into your group size. In our examples, 4 blocks of 4 and 4 blocks of 6 conveniently adds up to 40 patients. We could have chosen to use 5

Study start-up meeting/research team education sessions

Every clinical trial or laboratory experiment must have a formal start-up meeting or educational session. Anyone who will enroll and randomize patients must be formally taught how the study is to be conducted. At the start-up meeting, take time to emphasize that study randomization envelopes must always be opened sequentially (from lowest to next highest number). Before opening, make sure the research team member writes the patient's study identifier (patient study number), the date, and their

Conclusion

The primary purpose of randomizing patients into treatment arms of a clinical trial is to make the allocation sequence unpredictable. Although there are many ways that patients can be randomized into a clinical trial so that the allocation sequence is concealed, most require a methodologist and are expensive. This article describes 1 method for the preparation of SNOSE that is simple, cheap, and effective. The use of SNOSE can be described in a paper's methods section in an extremely efficient

Acknowedgment

This work was partially supported by a grant from the NorthCare Foundation (Sydney, New South Wales, Australia).

References (12)

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