PRAGMATIC RANDOMIZED CONTROLLED
TRIALS IN HEALTHCARE
  METHODS FOR RANDOMIZATION AND STRATIFICATION
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Introduction
Randomization introduces a deliberate element of chance into the assignment of treatments to participants in a clinical trial. It tends to produce treatment groups in which the distributions of prognostic factors, known and unknown, are similar. In combination with blinding, randomization helps to avoid possible bias in the selection and allocation of participants arising from the predictability of treatment assignments. It also provides a strong statistical basis for the quantitative evaluation of the evidence relating to treatment effects.

The method of allocation generation should be specified in the protocol, such as a random-number table or a computerized random-number generator. The sequence may be generated by the process of simple randomization or restricted randomization. Simple randomization is based on a single sequence of random assignments and is particularly suited to large trials. It is possible that by chance alone the groups might be imbalanced in important prognostic factors. Restricted randomization describes procedures used to control the randomization to achieve balance between groups in size or characteristics. Examples of restricted randomization include: blocking; stratification; minimization. This has greater potential benefit in small trials.

In multi-centre trials the randomization procedures should be organized centrally. This can entail, for example, generation of separate random schemes for each centre or provision of telephone randomization where the collaborating centers phone up the co-ordinating office for the next allocation.

Sometimes we cannot allocate individuals to treatments, but must allocate a group (‘cluster’) of subjects together in a cluster randomized trial. The procedures for randomizing clusters to trial interventions are identical to those described above.

In addition to knowing the methods used, it is also important to state how the random sequence will be implemented: specifically, who will generate the allocation sequence, who will enroll participants, and who will assign participants to trial groups. Whatever the methodological quality of the randomization process, failure to separate the creation of the allocation sequence from assignment to study group may introduce bias.

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Things to consider when writing a protocol

  • Describe the methods used to generate the random allocation sequence.
  • Describe the factors used for any restricted .randomization
  • Explain who will generate the allocation sequence.
  • Explain who will enroll participants.
  • Explain who will assign participants to their groups.

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Illustrative example - Example 1
‘In this trial all units (hospitals) enters the study at the same time, and all prognostic variable are known in advance. In this situation a computer algorithm can choose by random one allocation sequence among a set of sequences that minimizes the imbalance between groups. Such algorithm will be used to allocate hospitals in this study.

There are four hospital characteristics that were selected as important prognostic variables. These are the variables that will be included in the minimization algorithm to assure balance between groups.

  1. Teaching hospital with residents (Yes-No).
  2. Country (Argentina-Uruguay).
  3. Hospital size (less than 2000 – 2000 or more deliveries per year).
  4. Region (Montevideo, Salto/Paisandu, Rosario, Buenos Aires).

The minimization algorithm will minimize the imbalance between groups, assigning more priority to variables 1 and 2.

After the baseline data collection period the dataset will be analyzed by RTI. RTI will then apply the inclusion criteria to assess the eligibility of preselected hospital according to the baseline rate of episiotomy and active management. The statistician at CLAP will elaborate a computer program implementing the minimization algorithm. The source code of the algorithm will be made available in advance to RTI and UNC-CH for audit and testing. This computer program will be used by the statistician at RTI to allocate eligible hospitals to either intervention or control without participation of others. The assignment will then be communicated to CLAP. Thus, there will be a clear separation between the generator of the intervention assignment and the CLAP study coordination. (CLAP Trial - go to protocol )

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Illustrative example - Example 2
Simple randomization will be conducted independently for each study site by the Development and Research Training in Human Reproduction (HRP) of the Department of Reproductive Health and Research (RHR) statistical unit at WHO headquarters and provided to the pharmaceutical manufacturer.

The random allocation sequence will be generated using computer-generated random numbers. Randomization will be to the two arms of the trial and stratified by country. Blocking with randomly varying groups of 6-8 will be used to restrict randomization within the strata (country) (SAS Software, CopyrightÆÉ 1989, 1994 SAS Institute, Inc., N.C., USA).

Random allocation technique consists of allocating consecutively numbered treatment boxes for each woman, including in each box seven independent bottles, each of them with tablets for four weeks of treatment. Each bottle contains 100 tablets. Therefore each subject will have seven bottles with the same randomization number. Treatment boxes will be kept at the clinic. Bottles will be provided consecutively as needed every month after randomization. When the woman comes for antenatal care, she will return the used bottle from the previous month and will be given the next month's bottle from her box. She will return the bottle after 4 weeks, regardless of whether she finished the tablets or not. Each bottle is numbered from 1 to 7 within the box and should be used sequentially. (WHO Multicentre Randomized Trial of Calcium Supplementation for the Prevention of Pre-eclampsia - go to protocol)

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Illustrative example - Example 3
Hospitals with access to the 24-hour telephone randomization service

Women are entered into the trial by means of a telephone call to the 24-hour randomization service in Oxford. During this telephone call brief baseline details from the Trial Entry page in the Women’s Booklet (Appendix 3) are requested, and recorded on a computer, before the treatment allocation can be given. At the end of the call a two-digit pack number (and the four digit number of the box from which it should be taken) is issued, and this number should be recorded immediately. Once this pack number is allocated, the woman is irrevocably entered into the trial, irrespective of whether the treatment pack is opened. Randomization is balanced for major prognostic variables; severity of pre-eclampsia, gestational age at randomization, whether delivered, whether given anticonvulsants drugs before trial entry, whether a multiple pregnancy and country.

Hospitals using a local pack system

This system is only for hospitals that do not have access to the 24-hour telephone randomization service. When a woman has given consent to participate in the trial the clinician completes the Trial Entry page in the Women’s Booklet (Appendix 4). This page must be completed BEFORE the treatment pack is opened, it records brief baseline details about the woman and the number of the next treatment pack. The treatment packs MUST be used in the order in which they are removed through the slot in the box, which is lowest number first. Once the Trial Entry page has been completed the woman is entered into the trial, irrespective of whether the treatment pack is opened. (Magpie trial - go to protocol )

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Need more help?
Checklist for randomization
This checklist has been contributed by Dave Sackett, who prepared it for the forthcoming 3rd edition of Clinical Epidemiology; A Basic Science for Answering Questions about Health Care, to be published by Lippincott, Williams & Wilkins in 2004.

  • Make it easy for collaborating clinicians – they are busy people.
  • Be realistic and practical (no good planning telephone randomisation if participating centres have no reliable access to phone systems).
  • Make sure you consider: where participants will be recruited; who will randomize the participants; when randomisation will take place.
  • Develop the most appropriate randomisation systems for the project (consider the options below) central/local; phone/fax/email; treatment box; envelopes.
  • Ensure that participant details are recorded before treatment allocation is made.
  • Ensure that the treatment allocation is adequately concealed.

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Random Number Table
This is an example of a random number table (as a pdf).

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Randomization by using a pre-packed, sequentially numbered trial case
This is presentation has been contributed by Zhengming Chen and illustrates randomization by using a pre-packed, sequentially numbered trial case instead of 24-h telephone or fax system.

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Directory of randomization software and services

This is a directory of randomization software and services for clinical trials, including both simple do-it-yourself software and 24 hour telephone randomization services. It is intended to help people planning and seeking funding for clinical trials.

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Notes on randomization in clinical trials

These notes are part of a guide to planning a research project for researchers in health care. It is written for applicants for NHS R&D funding, but will be useful for everyone trying to set up healthcare research projects.

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Commercial randomization services
There are services available that provide 24-hour automated telephone randomization. However, these services are not free so you must agree their involvement before applying for your grant. These can be found by searching the Internet.

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Further reading

  • Pocock SJ. (1983) Clinical Trials: A Practical Approach. John Wiley and Sons, Chichester.
  • Altman DG, Bland JM. How to randomize. BMJ 1999; 319: 703-704 .

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