Subjects randomisation

Tables 4.3 and 4.4 show examples of parallel and crossover designs, with two alternating cohorts of eight subjects randomised to A or P in a dose-escalating design involving eight dose levels.

A review of 20 clinical trials published between 1979 and 2012 showed that subjects randomised to treatment with mixed amphetamine salts demonstrated a statistically significant increase in the resting heart rate [+5.7 bpm (3.6, 7.8), p < 0.0001] and systolic blood pressure [+2.0 mmHg (0.8, 3.2), p = 0.005] compared to subjects randomised to placebo [1 ]. A significant increased risk in resting heart rate >90 bpm [4.2% (n = 50) versus 1.7% (n = 8), odds ratio (OR) = 2.75 (1.3,6.7), p = 0.006] was found [l ]. A retrospective cohort study of new amphetamine users (n = 38,586) showed that the propensity score-adjusted hazard ratio for sudden death/ventricular arrhythmia was 1.18 (95% confidence interval [Cl] 0.55-2.54), for stroke 0.80 (95% Cl 0.44-1.47), for myocardial infarction 0.75 (95% Cl 0.42-1.35), and 0.78 for stroke/myocardial infarction (95% CEO.51-1.19) [2 ]. In a review of claims of privately insured young people, ages 6-21 years, without known cardiovascular risk factors (n = 171,126) that included all methylphenidate and... 

This particular study was a single-centre, investigator-blinded, within-subject randomised, active and vehicle-controlled, intraindividual comparison of six topical products in patients with psoriasis vulgaris. The products evaluated were caldpotriol ointment (50 jig/g), calcipotriol cream (50 jig/g), two-compoxmd ointment (calcipotriol 50 jig/g and betamethasone dipropionate 0.5 mg/g), two-compound gel (calcipotriol 50 jig/g betamethasone dipropionate 0.5 mg/g), an investigational ointment (calcipotriol 25 gg/g hydrocortisone lOmg/g), and a vehicle control. 

A Phase Ilb, randomised, open label study of 121 subjects randomised to MVC 150mg once daily or TDF/FTC (TDF/FTC) 300/200mg once daily+ATV/r 300/100mg once daily found more grade III/FV adverse events in tire maraviroc group (18 vs 11 in the TDF group), which were mainly hyperbilirubinaemia. The overall incidence of serious adverse events was similar in both arms [344 j. 

Immunologic Six individuals developed antibodies to liraglutide over the 2-year period in the same study described above. One subject randomised to liraglutide 1.2 mg developed antibodies that cross-reacted to GLP-1 in vitro at the end of the trial (the subject was exposed to both liraglutide 2.4 and 3.0 mg during the extension period). [47 ]... 

Mourits MJ, Bockermann I, de Vries EG, van derZee AG, ten Hoor KA,van derGraaf WT, Sluiter WJ, Willemse PH (2002) Tamoxifen effects on subjective and psychosexual wellbeing, in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy. Br J Cancer 86 1546-1550... 

Subjects are randomised to receive either A or P throughout the study, that is, parallel groups. 

Subjects are randomised to receive A or P on different occasions in a crossover design. 

Table 4.3 ParaUel-study design with two alternating cohorts of eight subjects and a 6 2 randomisation to active drug (A) or placebo (P) - each subject receives either A on four occasions or P on four occasions...

Individual subjects skip a dose level when they receive placebo so that no pharmacokinetic data are available for this subject/occasion and the subject is exposed to a large dose increment on the next occasion. This disadvantage can be avoided by administering every dose of A to each subject and in addition each subject receives placebo on one randomised occasion. 

The debate about quality of evidence most frequently ranks large randomised controlled trials as the gold standard, at least for efficacy, with controlled observational studies in the middle, and imcontrolled studies and opinions at the bottom. The evaluation of therapeutic benefit and risk is, in fact, never ending because clinicians will subject marketed medicines to comparison with other existing or new medicines, and they will experiment with alternative dosage schedules and combined use with other treatments. 

Finally, a randomised comparative trial with one alternative marketed medicine can only address the choice between the two. Other comparative trials with other treatments build up a picture of overall therapeutic benefit and risk, and these trials may help to define groups of study subjects who differ in their response from the general population. 

A controlled clinical trial is an experiment and, as just mentioned, it deliberately alters the fabric of routine management of study subjects. It does so in two ways. First, it directs which treatment modality will be given to a particular subject, usually by randomised allocation without the doctor or subject knowing which treatment they will receive out of the two or three chosen for the trial. Therefore, a subject may not receive the conventional treatment that the clinician might otherwise have chosen. Second, the selection and... 

Bias in subject selection may not be avoided simply by randomisation. Randomisation will avoid weighted allocation to one treatment regimen rather than another, but it will not avoid selection of the wrong kind of subject in the first place, which will subsequently affect the degree to which the data can be extrapolated. Thus, an investigator may have a preconceived idea about the safety of a drug or about its effectiveness in a particular subset of subjects who nonetheless meet the entry criteria. This prejudice may be avoided by stratification of subjects... 

In order to reduce the number of subjects on placebo in a clinical trial, some investigators employ an rmequal randomisation technique, whereby fewer subjects receive placebo than receive active comparator. For example, the ratio of 1 2, or 1 3 may be chosen in a large clinical study. These designs are not considered acceptable by aU statisticians... 

Ethical issues and randomisation There are ethical issues with randomisation. There are two t)rpes of ethics which are associated with human, medical research - individual and collective ethics. Individual ethics recognises the primacy of the individual and is aimed at doing what is best for the subjects in the current trial. In contrast, collective ethics is aimed at doing what is best for all future patients who will benefit from the results of the current trial. Clearly, there is a tension between these two principles that is recognised in the declaration of Helsinki, which comes down on the side of the individual ... 

Randomisation is clearly a key element in the design of our clinical trials. There are two reasons why we randomise subjects to the treatment groups ... 

Unrestricted (or simple) randomisation is simply a random list of, for example, As and Bs. In a moderately large trial, with say n = 200 subjects, such a process will likely produce approximately equal group sizes. There is no guarantee however that this will automatically happen and in small trials, in particular, this can cause problems. 

To ensure balance in terms of numbers of subjects, we usually undertake block randomisation where a randomisation list is constructed by randomly choosing from the list of potential blocks. For example, there are six ways of allocating two As and two Bs in a block of size four ... 

Dynamic aibcation is an alternative procedure in which the allocation of treatment to a subject is influenced by the current balance of allocated treatments and, in a stratified trial, by the stratum to which the subject belongs and the balance within that stratum. Deterministic dynamic allocation procedures should be avoided and an appropriate element of randomisation should be incorporated for each treatment allocation. ... 

Randomisation to avoid bias in allocating subjects to treatments... 

The intention-to-treat principle implies that the primary analysis should include all randomised subjects. Compliance with this principle would necessitate complete follow-up of all randomised subjects for study outcomes. In practice this ideal may be difficult to achieve, for reasons to be described. In this document the term full analysis set is used to describe the analysis set which is as complete as possible and as close as possible to the intention-to-treat ideal of including all randomised subjects. ... 

For equivalence and non-inferiority trials, therefore, the regulators like to see analyses undertaken on both the full analysis set and the per-protocol set with positive conclusions being drawn from both. In this sense these two analyses are considered co-primary. There is a common misconception here that for equivalence/non-inferiority trials the per-protocol set is primary. This is not the case. The per protocol set is still potentially subject to bias because of the exclusion of randomised patients and so cannot supply the complete answer both analysis sets need to be supporting equivalence/non-inferiority in order to have a robust conclusion. 

Conforming to the principle of intention-to-treat to avoid bias - ITT means all randomised subjects or something very close to that... 

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