A Concise Guide to Clinical Trials E-Book

Allan Hackshaw

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 388

Veröffentlichungsjahr: 2011

Beschreibung

Clinical trials have revolutionized the way disease is prevented, detected and treated, and early death avoided, and they continue to be an expanding area of research. They are central to the work of pharmaceutical companies, and there are many academic and public sector organizations that conduct trials on a wide variety of interventions, including drugs, devices, surgical techniques, and changes in behaviour and lifestyle. A Concise Guide to Clinical Trials provides a comprehensive yet easy-to-read overview of the design, conduct and analysis of trials. It requires no prior knowledge on the subject as the important concepts are introduced throughout. There are chapters that distinguish between the different types of trials, and an introduction to systematic reviews, health-related quality of life and health economic evaluation. The book also covers the ethical and legal requirements in setting up a clinical trial due to an increase in governance responsibilities and regulations. This practical guidebook is ideal for busy clinicians and other health professionals who do not have enough time to attend courses or search through extensive textbooks. It will help anyone involved in undertaking clinical research, or those reading about trials. The book is aimed at: * Those wishing to learn about clinical trials for the first time, or as a quick reference guide, for example as part of a taught course on clinical trials * Health professionals who wish to conduct their own trials, or participate in other people's studies * People who work in pharmaceutical companies, grant funding organisations, or regulatory agencies

Leseprobe

Contents

Preface

Foreword

1 Fundamental concepts

1.1 What is a clinical trial?

1.2 Early trials

1.3 Why are research studies, such as clinical trials, needed?

1.4 Alternatives to clinical trials

1.5 A randomised trial may not always be the best study design

1.6 Types of clinical trials

1.7 Four key design features

1.8 Small trials

1.9 Summary points

2 Types of outcome measures and understanding them

2.1 ‘True’ versus surrogate outcome measures

2.2 Types of outcomes

2.3 Counting people

2.4 Taking measurements on people

2.5 Time-to-event data

2.6 Summary points

3 Design and analysis of phase I trials

3.1 Design

3.2 Non-toxicity endpoints

3.3 Statistical analysis and reporting the trial results

3.4 Summary points

4 Design and analysis of phase II trials

4.1 Purpose of phase II studies

4.2 Design

4.3 Choosing outcome measures

4.4 Sample size

4.5 Stopping early for toxicity

4.6 Statistical analysis

4.7 Interpreting and reporting phase II studies

4.8 Summary points

5 Design of phase III trials

5.1 Objectives of phase III trials

5.2 Types of phase III trials

5.3 Choosing outcome measures

5.4 Composite outcome measures

5.5 Having several outcome measures (multiple endpoints)

5.6 Fundamental information needed to estimate sample size

5.7 Method of sample-size calculation

5.8 Examples of sample-size calculations

5.9 The importance of having large enough trials, and specifying realistic effect sizes

5.10 Reasons for increasing the sample size

5.11 Other considerations in designing phase III trials

5.12 Summary

6 Randomisation

6.1 Simple randomisation

6.2 Stratified randomisation

6.3 Minimisation

6.4 Unequal randomisation

6.5 Which method of randomisation to use?

6.6 Eligibility

6.7 Randomising in practice

6.8 Checking that the randomisation process worked: examining baseline characteristics

6.9 Summary

7 Analysis and interpretation of phase III trials

7.1 Outcome measures based on counting people

7.2 Outcome measures based on taking measurements on people

7.3 Outcome measures based on time-to-event data

7.4 Interpreting different types of phase III trials

7.5 More on confidence intervals

7.6 More on p-values

7.7 Relationship between confidence intervals, the no-effect value and p-values

7.8 Intention-to-treat and per-protocol analyses

7.9 Randomised subjects who are ineligible and subject withdrawals

7.10 Sub-group analyses

7.11 Safety, toxicity or adverse events

7.12 Interim analyses and stopping trials early

7.13 Clinical versus statistical significance: more on interpreting results

7.14 Summary

Appendix: Further introduction to p-values

8 Systematic reviews and meta-analyses

8.1 The need for systematic reviews of clinical trials

8.2 What is a systematic review?

8.3 Sources of published systematic reviews

8.4 Interpreting systematic reviews

8.5 Considerations when reading a systematic review

8.6 Why systematic reviews are important

8.7 Key points

9 Health-related quality of life and health economic evaluation

9.1 Health-related quality of life

9.2 Health economic evaluation

9.3 Summary

10 Setting up, conducting and reporting trials

10.1 Pre-trial

10.2 Trial set up

10.3 Trial conduct

10.4 End of trial

10.5 Monitoring adverse events

10.6 Reporting clinical trials in the literature

10.7 Summary

11 Regulations and guidelines

11.1 The need for regulations

11.2 International Conference on Harmonisation (ICH)

11.3 Good Clinical Practice (GCP) and the EU Clinical Trials Directives

11.4 Independent audit or inspection of clinical trials

11.5 Regulations surrounding research in special populations

11.6 Non-EU countries

11.7 Summary

Reading list

Statistical formulae for calculating some 95% confidence intervals

Index

This edition first published 2009, © 2009 by Allan Hackshaw

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ISBN: 978-1-4051-6774-1

Preface

Clinical trials have revolutionised the way disease is prevented, detected or treated, and early death avoided. They continue to be an expanding area of research. They are central to the work of pharmaceutical companies, which cannot make a claim about a new drug or medical device until there is sufficient evidence on its efficacy. Trials originating from the academic or public sector are more common because they also evaluate existing therapies in different ways, or interventions that do not involve a commercial product.

Many health professionals are expected to conduct their own trials, or to participate in trials by recruiting subjects. They should have a sufficient understanding of the scientific and administrative aspects, including an awareness of the regulations and guidelines associated with clinical trials, which are now more stringent in many countries, making it more difficult to set up and run trials.

This book provides a comprehensive overview of the design, analysis and conduct of trials. It is aimed at health professionals and other researchers, and can be used as an introduction to clinical trials, as a teaching aid, or as a reference guide. No prior knowledge of trial design or conduct is required because the important concepts are presented throughout the chapters. References to each chapter and a reading list are provided for those who wish to learn more. Further details of trial set up and conduct can also be found from country-specific regulatory agencies.

The contents have come about through over 18 years of teaching epidemiology and medical statistics to undergraduates, postgraduates and health professionals, and designing, setting up and analysing clinical studies for a variety of disorders. Sections of this book have been based on successful short courses. This has all helped greatly in determining what researchers need to know, and how to present certain ideas. The book should be an easy-to-read guide to the topic.

I am most grateful to the following people for their helpful comments and advice on the text: Dhiraj Abhyankar, Roisin Cinneide, Hannah Farrant, Christine Godfrey, Nicole Gower, Michael Hughes, Naseem Kabir, Iftekhar Khan, Alicja Rudnicka, and in particular Roger A’Hern. Very special thanks go to Jan Mackie, whose thorough editing was invaluable. And final thanks go to Harald Bauer.

Allan HackshawDeputy Director of the Cancer Research UK & UCL Cancer Trials Centre

Foreword

No one would doubt the importance of clinical trials in the progress and practice of medicine today. They have developed enormously over the last 60 years, and have made significant contributions to our knowledge about the efficacy of new treatments, particularly in quantifying the magnitude of their effects. Crucial in this development was the acceptance, albeit with considerable initial opposition, to randomisation – essentially tossing a coin to determine treatment allocation. Over the past 60 years clinical trials have become highly sophisticated, in their design, conduct, statistical analysis and the processes required before new medicines can be legally sold. They have become expensive and requiring large teams of experts covering pharmacology, mathematics, computing, health economics and epidemiology to mention only a few. The systematic combination of the results from many trials to provide clearer results, in the form of meta-analyses, have themselves developed their own sophistication and importance.

In all this panoply of activity and complexity it is easy to lose sight of the elements that form the basis of good science and practice in the conduct of clinical trials. Allan Hackshaw, in this book, achieves this with great skill. He informs the general reader of the essential elements of clinical trials; how they should be designed, how to calculate the number of people needed for such trials, the different forms of trial design, and importantly the recognition that a randomised clinical trial is not always the right way to obtain an answer to a particular medical question.

As well as dealing with the scientific issues, this book is useful in describing the terminology and procedures used in connection with clinical trials, including explanations of phase I, II, III and IV trials. The book describes the regulations governing the conduct of clinical trials and those that relate to the approval and sale of new medicines – an area that has become extremely complicated, with few people having a grasp of the “whole” picture.

This book educates the general medical and scientific reader on clinical trials without requiring detailed knowledge in any particular area. It provides an up to date overview of clinical trials with commendable clarity.

Professor Sir Nicholas WaldDirector, Wolfson Institute of Environmental & Preventive MedicineBarts and The London School of Medicine & Dentistry

CHAPTER 1

Fundamental concepts

This chapter provides a brief background to clinical trials, and why they are considered to be the ‘gold standard’ in health research. This is followed by a summary of the main types of trials, and four key design features. Further details on design and analysis are given in Chapters 3–7.

1.1 What is a clinical trial?

There are two distinct study designs used in health research: observational and experimental (Box 1.1). Observational studies do not intentionally involve intervening in the way individuals live their lives, or how they are treated. However, clinical trials are specifically designed to intervene, and then evaluate some health-related outcome, with one or more of the following objectives:

to diagnose or detect diseaseto treat an existing disorderto prevent disease or early deathto change behaviour, habits or other lifestyle factors.

Some trials evaluate new drugs or medical devices that will later require a licence (or marketing authorisation) for human use from a regulatory authority, if a benefit is shown. This allows the treatment to be marketed and routinely available to the public. Other trials are based on therapies that are already licensed, but will be used in different ways, such as a different disease group, or in combination with other treatments.

An intervention could be a single treatment or therapy, namely an administered substance that is injected, swallowed, inhaled or absorbed through the skin; an exposure such as radiotherapy; a surgical technique; or a medical/ dental device. A combination of interventions can be referred to as a regimen, such as, chemotherapy plus surgery in treating cancer. Other interventions could be educational or behavioural programmes, or dietary changes. Any administered drug or micronutrient that is examined in a clinical trial with the specific purpose of treating, preventing or diagnosing disease is usually referred to as an Investigational Medicinal Product (IMP) or Investigational

Box 1.1Study designs in health research