This edition is divided into three sections: I Basic Considerations, II Adaptions of the Basic Design and III Further Topics. As the title suggests, the first section is intended to cover topics that are relevant to all randomised trials of whatever design and complexity. Thus, it may be the key section for those who are new to clinical trials and an aide‐memoire for those more experienced in this area. For this purpose, it concentrates on the parallel two‐group controlled trial with a single outcome measure where patients are randomised individually to one of the two interventions concerned.
The second section expands on the individually randomised design in several ways by considering paired designs, repeated assessments of the (same) outcome measure over time, more than two interventions and non-inferiority trials. It also includes cluster trials, and stepped wedge designs in which groups rather than individuals are randomised to the interventions concerned. The final section deals with genomic targets, feasibility and pilot studies, and a final chapter on miscellaneous topics including adaptive designs, large simple trials and very small trials with new additions describing alpha spending functions and the predictive probability test for use in interim analyses.
We are grateful to many colleagues, collaborators and numerous investigators who have contributed directly or indirectly to this book over many years.
We thank Isaac Koh for the cover design and Leo Liu for his professional advice on this.
David Machin
Peter M. Fayers
Bee Choo Tai
Leicester and Sheffield, Aberdeen, and Singapore
PS
As we read the proofs of this book, under lockdown conditions imposed by Covid-19, results of successful randomised trials with respect to treatments for those who have contracted the disease and protective vaccines against the pandemic have been published. These include the use of dexamethasone as described by The RECOVERY Collaborative Group (2020) and the Pfizer-BioNTech mega-sized vaccine trial against Covid-19 tested by Polack, Thomas, Kitchin, et al. (2020). To overcome the challenges in conducting clinical trials as a result of lockdown and the need to minimise face-to-face contact due to the infectious nature of the coronavirus, the use of e-consent is briefly discussed in Chapter 3.
CHAPTER 1 Introduction
A very large number of clinical trials with human subjects have been conducted in a wide variety of contexts. Many of these have been concerned, for example, with improving (in some way) the management of patients with disease and others the prevention of the disease or condition in the first place. The essence of a clinical trial is the comparison of a standard strategy with an alternative (perhaps novel) intervention. The aim of this chapter is to illustrate some of the wide variety of clinical trials that have been conducted and to highlight some key features of their design, conduct and analysis.
1.1 Introduction
The aim of this book is to introduce those who are to become involved with randomised clinical trials to the wide range of challenges that are faced by those who conduct such trials. Thus, our intended readership is expected to range from healthcare professionals of all disciplines who are concerned with patient care to those more involved with the non‐clinical aspects such as the statistical design, data processing and subsequent analysis of the results. We assume no prior knowledge of clinical trial processes, and we have attempted to explain the more 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.