Randomised control trials simply involve the random allocation of individuals to receive one of two or more interventions. Random allocation means that all participants have an equal chance of assignment to each of the available interventions. Allocation is not determined by the investigator, clinicians, or participants and allocation is not predictable. The key to randomised controlled trials lies in the random allocation process. Now you'll learn why it is important to randomly allocate participants in a trial, and the steps involved in the random allocation process. Randomisation involves two steps: first, generation of the allocation sequence and second, implementation of the allocation, which requires allocation concealment to be effective. First, you need to generate the allocation sequence. Let's imagine I have a classroom of 30 students, and I'm going to do a trial. Half will be allocated to drug A, and the other half to drug B. How do I make the two groups similar at baseline? Do I just say this half of the room take drug A and that half take drug B? No, because the problem is that people who sit on the left hand side and the right hand side of the classroom are different, because most people in this half are late for class, and the other half are early. People who are late are different from those who come in early. What you could do is put all of the student names into a hat, and then take them out allocating A, B, A, B etc. This is an example of simple randomisation. Obviously you're not going to do that with a trial of 10,000 participants. Good methods of generating a random allocation sequence include using a random numbers table, or a computer software program, that generates the random sequence. As long as the number of participants in the study is large enough, and that's critical, hair length, hair presence, colour of hair, colour of eyes, everything will be identical in the two groups. The only thing that's different is whether you're on drug A, or drug B. The next step is allocation concealment. This is required to ensure that implementation of the random allocation sequence occurs without anyone knowing which patient will receive which treatment, as knowledge of the next assignment could influence whether a patient is included, or excluded, based on perceived prognosis. For example, imagine a surgeon has been working on a new kind of treatment. The surgeon believes using his new method of treatment is better than the current method, and he wants to demonstrate this advantage in a randomised controlled trial. Let's also assume that the randomised sequence has been generated, and he knows the order. Let's say it's gone new, old, new, old, new, old, so far. So he now knows that the new treatment method is the next treatment to be given. The next patient seen by the surgeon has comorbidities, and that makes the surgeon believe that this patient will not do well with his new treatment. And so, the surgeon might subconsciously justify not enrolling the patient. This is an example of why it's important to ensure allocation concealment in trials. Allocation concealment can be achieved using a number of techniques. One commonly used method is sequentially numbered opaque envelopes. Envelopes containing the treatment allocation are opened by the recruiting clinician on participant enrolment. To be robust the envelopes should be truly opaque, sequentially numbered, and opened in the correct order. The clinicians should not open the envelope in advance, and should ensure that the envelope seal has not been broken. Here is an example of how things can go wrong. The Captopril Prevention Project, CAP, was a randomised intervention trial, comparing the effects of an ACE inhibitor and conventional therapy on cardiovascular morbidity and mortality, in almost 11,000 patients with hypertension. In the CAP trial, allocation was implemented by envelopes, supposedly opened in order. Sadly, the allocation could be read through the envelopes, and the investigators having read what treatment was coming next, allocated the drugs differentially to the patients they believed would do best. This slide shows the impact on the imbalance in patients groups at baseline. Here all five variables shown are highly significantly different between the randomised groups, which with 11,000 patients could never happen. This reflects the fact that some of the doctors believe that ACE inhibitors would be more effective at lowering blood pressure, and better for patients with congestive heart failure and diabetes. Hence, those with higher pressure, heart failure and diabetes were more likely to be allocated an ACE inhibitor. So, even with concealed envelopes, we cannot guarantee that envelopes have not been opened in advance to allow strategic scheduling of patient appointments to match the recruiters preferred allocation. To overcome this, central randomisation is often used. This usually involves the investigator, on recruiting a patient, telephoning a central randomisation service which issues a treatment allocation. Now you know why and how random allocation is generated, and concealed, in a trial. Randomisation is vital for preventing selection bias in a trial, and ensuring the integrity of the randomisation process throughout a trial is essential.
