E ND OF THE D EFICIENCIES OF THE C URRENT B ILATERAL R ECURSIVE S YSTEM ?
II. Casación positiva y derecho al recurso
r The ISIS (International Studies of Infarct Survival) investigators compared various treatments for myocardial infarction (heart attack), including the use of aspirin and streptokinase in ISIS-2 (ISIS-2 Collaborative Group, 1988). More than 100,000 patients throughout the world were recruited into these studies.
r In the early 1950s, one of the largest epidemiological studies, and almost certainly the largest formal human ‘experiment’, was conducted in the USA. This was a field trial of polio vaccine in which over 400,000 school children were assigned to receive either the vaccine or a placebo (inactive) injection. The trial clearly demonstrated both the efficacy and the safety of the vaccine, which was then given to millions of children throughout the world (Francis et al., 1955). This has led to a major drop in the incidence of polio not only in industrialised countries but also in many developing countries, which have recently been declared polio-free by the WHO.
r In the US Physicians’ Health Study (we have already met the British Doctors and the US Nurses’ Health studies!), 22,000 physicians were randomly allocated to take aspirin, in an attempt to reduce cardiovascular morbidity and mortality, and/or capsules ofβ-carotene, in an attempt to reduce rates of cancer (Hennekens and Eberlein, 1985). After 12 years of follow-up, rates of cancer were very similar in theβ-carotene and placebo groups, and, while aspirin was shown to lower the rates of heart attack, so few of these very healthy doctors died that the trial could not determine whether aspirin saved lives from cardiovascular disease.
r A randomised, controlled community trial was conducted to evaluate the effectiveness of vitamin A supplementation to prevent childhood mortality in Indonesia (Sommer et al., 1986). In 229 villages, children aged 1–5 years were given two doses of vitamin A while children in the 221 control villages were not given vitamin A until after the study. Mortality among children in the control villages was 50% higher than that in the villages given
vitamin A.
Randomised controlled trials (RCTs)
The best way to evaluate a new treatment is to identify a group of patients with the same condition and then allocate them to receive the various treatments at random. A preventive trial differs only in that it involves people who are disease- free but thought to be at risk of developing disease. Random allocation (also
called randomisation2) ensures that all of the groups are as similar as possi- ble at the start of the study. (Note that equality of the groups at baseline is highly dependent on group size – with very small groups it is unlikely that the groups will be similar in terms of all important variables that could affect the out- come.) Random allocation is important because if one group were in some way more ill (or less healthy) than the other at the start, this might make this group look worse, even if the intervention really had no effect. (This problem is called
confounding and we will discuss it in more detail in Chapter 8.) It is because
of this aspect of RCTs – the close similarity of the groups in all respects other than the intervention – that they are generally considered to give the best evi- dence of all epidemiological studies. In a cohort study investigating potentially harmful risk factors, people cannot be randomly allocated to the various study groups and, for example, a group of alcohol drinkers will certainly differ from a group of non-drinkers in more ways than just their alcohol consumption. While we can deal with some of these factors in our analysis, there may also be other important factors that we either do not know about or cannot measure well. The real strength of randomisation is that, on average, it will also balance these other unknown or unmeasured factors across the groups.
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Randomised controlled trials also include a control or comparison group so that outcomes in the treated group can be compared with those in a group that is not treated. Generally, the patients in the control group either receive no treat- ment or, preferably, they are given a placebo (something that resembles the real treatment but is not active). If an acceptable standard treatment is available the 2 Note the important distinction between ‘random selection’, where we select people at random to be
in our study but we do not control whether or not they are exposed (unless it is also a RCT), and ‘randomisation’, where we do control exposure by randomly allocating people to the exposed and non-exposed groups in an intervention study.
Intervention studies 115 Time Direction of inquiry Defined population Random allocation Exposed Disease No disease Not exposed Disease No disease
Figure 4.4 The design of a randomised controlled trial.
control group must be given this – it would be unethical to withhold it – and this is compared with the new experimental treatment. Figure 4.4 shows the design features of a simple randomised controlled trial. In practice it is just a special form of the standard prospective cohort study – the only difference being that participants are allocated to the exposed and unexposed groups at random.
Ideally, both the trial investigators and the participants should be unaware of whether the participant is in the active intervention or placebo group, creating a ‘double-blind’ or ‘masked’ study. If only the patient is unaware of their allocation, it is a single-blind study. Blinding is important because knowledge of the treat- ment might affect both the participant’s response – quite a few people feel better after taking a placebo simply because they believe it will do them good – and an observer’s measurement of outcome. In some situations (e.g. comparing med- ical treatment with surgery) there may be no feasible way of blinding patients and study personnel to the differences in treatments. Minimising measurement bias in this situation may be best accomplished by bringing in an independent ‘blinded’ observer whose only involvement is to assess the outcome measure. Blinding of outcome measurements obviously becomes more crucial as the mea- surement becomes more subjective. When the outcome measure is objective and less dependent on interpretation, as in a biochemical parameter or death, blind- ing is less important.
Apart from participants and trial investigators, there are many others (e.g. healthcare providers, data collectors, outcome assessors, data analysts) involved in the conduct of a trial who can introduce bias through their knowledge of treat- ment allocation. For this reason there is a growing tendency to abandon the terms single- and double-blind in favour of a transparent reporting of the blind- ing status of each group involved in the trial.
As for a cohort study, the other crucial feature of an RCT is good follow-up. It is important to know what has happened to all of the participants in the study.
Community trials are preventive trials in which the intervention is imple-
mented at the community level and are generally conducted when it would be impossible to offer (or evaluate) the intervention at the individual level. An example is the studies of water fluoridation and dental health conducted in various countries. When investigators wanted to study the effects of adding flu- oride to the water supply on dental health it was clearly impossible to add flu- oride to some people’s water and not to others’, so whole towns were allocated to receive fluoride in their water or not. The controlled trial of water fluorida- tion which gave the most striking results was carried out in the towns of New- burgh and Kingston in New York State, USA. After 10 years of fluoridation, the DMF (decayed, missing or filled teeth) score for Newburgh children aged 6–16 was 50% lower than that for children in the unfluoridated town of Kingston (Ast and Schlesinger, 1956). The assumption underlying this result was that, apart from the water, there was no other major difference between the towns that could explain the effect (i.e. there was no confounding). (Note that, although this and other studies clearly showed the benefits of low levels of fluoride on den- tal health, continuing controversy about the possible adverse effects of fluoride on other organs in the body, particularly the bones, has meant that universal fluoridation of water supplies has not occurred.) Because only two towns were included in this study, in practice it is little different from a non-randomised comparison. Other cluster designs involve larger numbers of groups, so that the random allocation of multiple groups to intervention or no intervention gives more of the benefits of randomisation in terms of balancing out other factors across the groups (e.g. the vitamin A study, Box 4.7).
Crossover trials
Randomised trials can be categorised as either parallel group or crossover trials. Figure 4.4 shows the design of a parallel group RCT, in which patients are ran- domly allocated to one of the two groups, which are then followed in parallel. In a crossover design, the participants serve as their own controls (this is analogous to the case–crossover study we described earlier). For example, in a simple two- period crossover study to assess the efficacy of an intervention we would assign each participant to either the intervention or the control (I or C) for a specified period of time and then the alternative for a similar period of time. The order in which each participant receives I and C is randomly assigned. Thus, approxi- mately half of the participants receive the intervention in the sequence I–C and the other half in the sequence C–I. This eliminates any trend from the first period to the second period from the estimate of group differences in response. One of the biggest advantages of this design is that it can produce statistically and clinically valid results with fewer participants than would be required with a par- allel design. However, not all interventions are suitable for assessment in this way. If the effects of the intervention during the first period are likely to carry
A word about ethics 117
over into the second period then this design is clearly inappropriate, as it is for assessing long-term benefits and harms.
n-of-1 trials
A variant of the crossover trial is the single patient trial, often called an n-of-1
trial.3An individual patient receives the experimental and control treatments in random order on multiple occasions, with specific outcomes being moni- tored throughout the trial period. Ideally both the patient and the treating doc- tor are blinded to the treatment being received and the trial usually ends when it becomes clear that there are (or are not) important differences between the treatments. Although the results of n-of-1 trials are not generalisable to the same extent as those of typical RCTs, they do provide a good guide to individual clinical decisions.
Other intervention designs
The fact that a study is described as a trial or clinical trial does not necessarily mean that it is a randomised trial. Probably the most common non-randomised design in the health setting is one that uses ‘historical controls’, where health outcomes following the introduction of a new treatment or preventive measure are compared to the outcomes experienced by the same population before the change in practice. For example, in many countries mortality rates from road traffic accidents fell dramatically after the introduction of legislation requiring drivers to wear seat belts. Similarly, patient survival rates might be compared before and after the introduction of a new surgical technique. The main problem with this design is that it does of course assume that the only (or most impor- tant) thing that has changed is the new legislation or the type of surgery and that may not be the case. While RCTs remain the gold standard for initial evaluation of new clinical and public health interventions, the effectiveness of these inter- ventions in practice can often only be determined from these very simple ‘before and after’ comparisons in whole communities or populations. You will see many examples of this throughout the book, and particularly when we discuss preven- tion in Chapter 14 and screening in Chapter 15.
A word about ethics
We touched on this under Record linkage above but it would be remiss of us to end this discussion of study design without some consideration of the subject of research ethics. Before conducting any research on humans 3 Note ‘n’ is often used to denote the sample size in a study; an n-of-1 study is thus a study where n= 1