Trial design
secret of mesmerism’s success. To put their theory to the test, the commission carried out a series of what, in today’s terms, might be called sham procedures. Inviting Mesmer’s patients to engage with ‘magnetised’ objects – many of which hadn’t been magnetised at all – swoons, convulsions, and shrieks ensued. The first placebo controlled blind trial had been inaugurated.
The blind leading the blind Today, the blinded trial is often considered the ‘gold standard’ in clinical research, as Professor Mike Clarke, director of the Northern Ireland Clinical Trials Unit at Queen’s University Belfast, explains. Why? “Because of minimising bias”, he adds. “Because [blinding] is saying that you do not know what it is you’re getting, and therefore your outcomes cannot be influenced by your knowledge or someone else’s knowledge”. To put it simply, blinding refers to a process whereby somebody – be it the patient, clinician, outcome assessor, statistician or the research team, or a combination of these – is kept in the dark about one or more details of the trial. “The classic example”, as Matthew Sydes, professor of clinical trials and methodology at UCL’s MRC Clinical Trials Unit, explains, is “a placebo”, which he defines as “a tool for protecting treatment allocation”. In the Mesmer case, the non-magnetised objects comprised the placebo, the trial participants remaining ‘blind’ to which items had received magnetic charge. In today’s trials, the placebo tends to take the form of a dummy drug, which, as Sydes explains, “looks and tastes and feels and weighs and is packaged exactly the same [as the active drug]”. In a placebo-controlled trial, participants will usually be split into two (or more) groups, one taking the active drug, the other taking the dummy. While certain members of the trial – say, the doctors and the patients – remain ‘blind’ as to which group has been allocated which treatment, there will still be those – the trial managers and the statisticians, for example – who remain in the know from first to last. For each trial, details will vary – dummy drugs may be substituted for ‘sham procedures’; doctors may be aware of the facts, while assessors are blinded – but the principle remains the same. “The trial is protected,” Sydes notes, “from somebody important knowing something important.”
The pros and cons
The advantages to blinding are not difficult to apprehend. By stripping out bias, the blinded trial permits researchers to “remove all the noise”, is how Clarke neatly puts it, in order to keep the trial as objective as possible. Yet both Clarke and Sydes raise legitimate concerns around the unquestioning treatment of blinding as the gold standard in clinical research. For one thing, the blinded trial does not offer an accurate reflection of medical interventions in
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everyday life. As Clarke points out, in “routine practice, the medicine will not be rolled out in a placebo- controlled trial, and influencing factors will occur”. Then there’s the question of cost. Because, as Sydes explains, not only does it cost “an absolute fortune” to put together a placebo, there’s also a carbon cost. “We’re making tablets that don’t do anything, and which we may not need,” he adds. “We’re putting them, maybe, in non-recyclable packaging; we’re transporting them; we’re taking up pharmacy time; we’re storing them cold. All of the ways in which carbon may be spent, we may well be doing for a placebo when maybe we didn’t need to do it at all.” There are also further concerns around safety and ethics. In most cases, the taking of a dummy pill will not cause harm to the participant. But what about when it comes to sham procedures, like false injections or operations? As Sydes notes, asking “somebody [to] sit down for 15 minutes or an hour [to] inject saline solution into them”, or “putting somebody out for an operation, waking them up, bandaging them, and making them think they’ve [undergone surgery]” can be distressing for the patient, not to mention complicated, costly and time consuming for hospitals and staff.
“[Blinding] is saying that you do not know what it is you’re getting, and therefore your outcomes cannot be influenced by your knowledge or someone else’s knowledge.”
Professor Mike Clarke Of course, the vast majority of sham procedures
won’t come with physical risks attached, and the question of ethics, as Clarke notes, is usually “dealt with by fully informed consent”. In other words, patients are made aware before trial enrolment of which element of the trial will be blinded. Yet, while it remains ethically essential, foreknowledge of a blinded trial can have an adverse effect on recruitment. As Clarke explains, “There are a number of studies that [have] compared open control trials with placebo-controlled trials for recruitment, and placebo trials recruit worse than open control, potentially because of this sense that I’ll have to do something, or you’ll inject me, or I’ll take some pills, and there’s a 50/50 chance that the [treatment will be ineffectual].”
Is it all a sham? All of this, however, is not to say that we don’t need to blind some clinical trials. Rather, as Sydes says, it indicates the fact that we should be “thinking carefully about whether or not [we] really need to do this”. He adds: “Is it worth the time and effort?
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