Superiority not shown
Fig. 4.1 Relationship between significance tests and confidence intervals for the comparisons between a new treatment and control.The treatment differences a, b, c are all in favour of'New treatment', but superiority is shown only in A and B. In C, superiority has not been shown.This may be because the effect is small and not detected.The result, nevertheless, is compatible with equivalence or noninferiority. Adequate precision and power are assumed for all the trials.
relating to treatment effects, and tends to produce treatment groups that have a balanced distribution of prognostic factors, both known and unknown. Together with blinding, it helps to avoid possible bias in the selection and allocation of subjects.
Randomisation may be accomplished in simple or more complex ways such as:
• Sequential assignments of treatments (or sequences in crossover trials).
• Randomising subjects in blocks. This helps to increase comparability of the treatment groups when subject characteristics change over time or there is a change in recruitment policy. It also gives a better guarantee that the treatment groups will be of nearly equal size.
• By dynamic allocation, in which treatment allocation is influenced by the current balance of allocated treatments
Blinding. The fact that both doctors and patients are subject to bias due to their beliefs and feelings has led to the invention of the double-blind technique, which is a control device to prevent bias from influencing results. On the one hand it rules out the effects of hopes and anxieties of the patient by giving both the drug under investigation and a placebo (dummy) of identical appearance in such a way that the subject (the first 'blind' man) does not know which he is receiving. On the other hand, it also rules out the influence of preconceived hopes of, and unconscious communication by, the investigator or observer by keeping him (the second 'blind' man) ignorant of whether he is prescribing a placebo or an active drug. At the same time, the technique provides another control, a means of comparison with the magnitude of placebo effects. The device is both philosophically and practically sound.25
A nonblind trial is called an open trial. The double-blind technique should be used wherever possible and especially for occasions when it might at first sight seem that criteria of clinical improvement are objective when in fact they are not. For example, the range of voluntary joint movement in rheumatoid arthritis has been shown to be greatly influenced by psychological factors, and a moment's thought shows why, for the amount of pain patients will put up with is influenced by their mental state.
Blinding should go beyond the observer and the observed. None of the investigators should be aware of treatment allocation, including those who evaluate endpoints, assess compliance with the protocol and monitor adverse events. Breaking the blind (for a single subject) should be considered only when the subject's physician deems knowledge of the treatment assignment essential in the subject's best interests.
Sometimes the double-blind technique is not possible, because, for example, side-effects of an active drug reveal which patients are taking it or tablets look or taste different; but it never carries a disadvantage ('only protection against biased data'). It is not, of course, used with new chemical entities
25Modell W 1958 Journal of the American Medical Association 167: 2190.
fresh from the animal laboratory, whose dose and effects in man are unknown, although the subject may legitimately be kept in ignorance (single-blind) of the time of administration. Single-blind techniques have a place in therapeutics research but only when the double-blind procedure is impracticable or unethical.
Ophthalmologists are understandably disinclined to refer to the double-blind technique; they call it double-masked.
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