statistical sections in as non‐technical a way as possible. In a first reading of this book, these sections could be omitted. Throughout the book, we stress the collaborative nature of clinical trials activity and would hope that readers would consult their more experienced colleagues on aspects of our coverage.
The business of clinical trials is an ongoing process, and as we write, trials are currently being designed (particularly with respect to the coronavirus), opened, conducted, closed, analysed, reported, results filtered into current practice and the next planned. To describe the key features of this process, it is difficult to know where to start as each stage interacts with each of the others to some extent. For example, in designing a trial the investigators need to be mindful of the eventual analysis to be undertaken as this governs (but it is only one aspect of) how large a trial should be launched. Some of the steps are intellectually challenging, for example, defining the key therapeutic question, whilst others may perhaps appear more mundane, such as defining the data forms or the data entry procedures but all steps (whether large or small: major or minor) underpin the eventual successful outcome – the influence on clinical practice once the trial results are available. For many of these aspects of the process, whole books have been written. We can only provide an introduction to these.
Numerous terms including ‘clinical trial’ itself need to be introduced. As a consequence, we have included a Glossary of Terms, which is mainly extracted from Day (2007) Dictionary of Clinical Trials. Thus, the Glossary defines: clinical trial: any systematic study of the effects of a treatment in human subjects. These definitions may not be exhaustive in the sense, that ‘treatment’ used here may be substituted by, for example, ‘intervention’ depending on the specific context of the clinical trial under consideration.
Clinical trials require a multidisciplinary approach in which all partners play a key role at some stage of the trial process. Furthermore, ‘Evidence‐Based Medicine’ (EBM) requires that it is important to consider critically all the available evidence about whether, for example, a treatment works, before recommending it for clinical practice. In this respect, it is therefore vital that one can clearly see that a proposed trial addresses a key question which will have a clinically meaningful outcome, is well designed, conducted and reported, and the results are persuasive enough to change clinical practice if appropriate.
Despite perhaps not having a professional interest in the science of clinical trials, everyone has a vested interest in them as potential patients requiring care. How many of us have never been to see a doctor, had a hospital admission or taken medication? All of us may be, have been, or certainly will be, recipients of clinical trial results whether during prebirth, at birth or in childhood for vaccination and minor illness, as an adult for fertility, sports injuries, minor and major non‐life‐threatening or life‐threatening illnesses, and in old age for care related to our mental or physical needs.
1.2 Some completed trials
As we have indicated, there are countless ongoing trials and many have been successfully conducted and reported. To give some indication of the range and diversity of application, we describe a selection of clinical trials that have been conducted. Their designs include some features that we also draw upon as examples in later chapters.
Example 1.1 Small parallel two‐group design – gastrointestinal function
Lobo, Bostock, Neal, et al. (2002) describe a randomised trial in which 20 patients with colonic cancer either received postoperative intravenous fluids in accordance with current hospital standard practice (S) or according to a restricted intake regimen (R). A primary endpoint measure in each patient was the solid‐phase gastric emptying time on the fourth postoperative day. The observed difference between the median emptying times was shorter with R by 56 minutes with 95% confidence interval (CI) from 12 to 132 minutes. The trial also included preoperative and postoperative (days 0, 1, 3 and 5) measures of the concentrations of serum albumin, haemoglobin and blood urea in a repeated measures design.
Key features include the following:
Design: Randomised comparison of a standard and test, single‐centre participation, unblinded assessment,
Endpoint: Gastric emptying time,
Size: 21 patients following colonic resection,
Analysis: Mann–Whitney U‐test1 for comparing two medians,
Conclusion: The restricted intake group had shorter delays in returning to gastrointestinal function.
1This can also be referred to as the Wilcoxon rank‐sum test.
Example 1.2 Parallel two‐group design – hepatitis B
Levie, Gjorup, Skinhøj and Stoffel (2002) compared a 2‐dose regimen of recombinant hepatitis B vaccine including the immune stimulant AS04 with the standard 3‐dose regimen of HbsAg in healthy adults. The rationale behind testing a 2‐dose regimen was that fewer injections would improve compliance.
Key features include the following:
Design: Two centres, open‐label randomised two‐group comparison,
Endpoint: Seroprotection rate,
Size: 340 healthy adults aged between 15 and 40 years,
Analysis: Fisher's exact test,
Conclusion: The 2‐dose regimen compared favourably with the standard.
Example 1.3 Unstructured three‐group design – newly diagnosed type 2 diabetes
The randomised trial of Weng, Li, Xu, et al. (2008) compared, in newly diagnosed patients with type 2 diabetes, three treatments: multiple daily insulin injections (MDI), continuous subcutaneous insulin infusion (CSII) and oral hypoglycaemic agent (OHA).
Key features include the following:
Design: Nine centres, randomised three‐group comparison,
Endpoint: Time of glycaemic remission,
Size: 410 newly diagnosed patients with type 2 diabetes,
Analysis: Cox proportional‐hazards regression model,
Conclusion: Early intensive therapy has favourable outcomes on recovery and maintenance of β‐cell function and protracted glycaemic remission compared to OHA.
Example 1.4 Small dose–response design – pain prevention following hand surgery
Stevinson, Devaraj, Fountain‐Barber, et al. (2003) conducted a randomised double‐blind, placebo‐controlled
