CHAPTER 1

Introduction: The Rationale of Clinical Trials

The evaluation of possible improvements in the treatment of disease has historically been an inefficient and haphazard process. Only in recent years has it become widely recognized that properly conducted clinical trials, which follow the principles of scientific experimentation, provide the only reliable basis for evaluating the efficacy and safety of new treatments. The major objective of this book is therefore to explain the main scientific and statistical issues which are vital to the conduct of effective and meaningful clinical research. In addition, some of the ethical and organizational problems of clinical trials will be discussed. The historical perspective, current status and future strategy for clinical trials provide a contextual framework for these methodological aspects.

In section 1.1, I discuss what constitutes a clinical trial and how clinical trials may usefully be classified. Section 1.2 deals with the underlying rationale for randomized controlled clinical trials and their relation to the scientific method. Section 1.3 goes on to describe one particular example, a clinical trial for primary breast cancer, as an illustration of how adherence to sound scientific principles led to an important advance in treatment.

1.1 TYPES OF CLINICAL TRIAL

Firstly, we need to define exactly what is meant by a'clinical trial': briefly the term may be applied to any form of planned experiment which involves patients and is designed to elucidate the most appropriate treatment of future patients with a given medical condition. Perhaps the essential characteristic of a clinical trial is that one uses results based on a limited sample of patients to make inferences about how treatment should be conducted in the general population of patients who will require treatment in the future.

Animal studies clearly do not come within this definition and experiments on healthy human volunteers are somewhat borderline in that they provide only indirect evidence of effects on patients. However, such volunteer studies (often termed phase I trials) are an important first step in human exposure to potential new treatments and hence are included in our definition when appropriate.

Field trials of vaccines and primary prevention trials for subjects with presymptomatic conditions (e.g. high serum cholesterol) involve many of the same scientific and ethical issues as in the treatment of patients who are clearly diseased, and hence will also be mentioned when appropriate.

An individual case study, whereby one patient's pattern of treatment and response is reported as an interesting occurrence, does not really constitute a clinical trial. Since biological variation is such that patients with the same condition will almost certainly show varied responses to a given treatment, experience in one individual does not adequately enable inferences to be made about the general prospects for treating future patients in the same way. Thus, clinical trials inevitably require groups of patients: indeed one of the main problems is to get large enough groups of patients on different treatments to make reliable treatment comparisons.

Another issue concerns retrospective surveys which examine the outcomes of past patients treated in a variety of ways. These unplanned observational studies contain serious potential biases (e.g. more intensive treatments given to poorer prognosis patients may appear artificially inferior) so that they can rarely make a convincing contribution to the evaluation of alternative therapies. Hence, except in chapter 4 when considering the inadequacies of non-randomized trials, such studies will not be considered as clinical trials.

It is useful at this early stage to consider various ways of classifying clinical trials. Firstly, there is the type of treatment: the great majority of clinical trials are concerned with the evaluation of drug therapy more often than not with pharmaceutical company interest and financial backing. However, clinical trials may also be concerned with other forms of treatment. For instance, surgical procedures, radiotherapy for cancer, different forms of medical advice (e.g. diet and exercise policy after a heart attack) and alternative approaches to patient management (e.g. home or hospital care after inguinal hernia operation) should all be considered as forms of treatment which may be evaluated by clinical trials. Unfortunately, there has generally been inadequate use of well-designed clinical trials to evaluate these other non-pharmaceutical aspects of patient treatment and care, a theme which I shall return to later.

Drug trials within the pharmaceutical industry are often classified into four main phases of experimentation. These four phases are a general guideline as to how the clinical trials research programme for a new treatment in a specific disease might develop, and should not be taken as a hard and fast rule.

Phase I Trials: Clinical Pharmacology and Toxicity

These first experiments in man are primarily concerned with drug safety, not efficacy, and hence are usually performed on human volunteers, often pharmaceutical company employees. The first objective is to determine an acceptable single drug dosage (i.e. how much drug can be given without causing serious side-effects). Such information is often obtained from dose-escalation experiments, whereby a volunteer is subjected to increasing doses of the drug according to a predetermined schedule. Phase I will also involve studies of drug metabolism and bioavailability and, later, studies of multiple doses will be undertaken to determine appropriate dose schedules for use in phase II. After studies in normal volunteers, the initial trials in patients will also be of the phase I type. Typically, phase I studies might require a total of around 20-80 subjects and patients.

Phase II Trials: Initial Clinical Investigation for Treatment Effect

These are fairly small-scale investigations into the effectiveness and safety of a drug, and require close monitoring of each patient. Phase II trials can sometimes be set up as a screening process to select out those relatively few drugs of genuine potential from the larger number of drugs which are inactive or over-toxic, so that the chosen drugs may proceed to phase III trials. Seldom will phase II go beyond 100-200 patients on a drug.

Phase III Trials: Full-scale Evaluation of Treatment

After a drug is shown to be reasonably effective, it is essential to compare it with the current standard treatment(s) for the same condition in a large trial involving a substantial number of patients. To some people the term 'clinical trial' is synonymous with such a full-scale phase III trial, which is the most rigorous and extensive type of scientific clinical investigation of a new treatment. Accordingly , much of this book is devoted to the principles of phase III trials.

Phase IV Trials: Postmarketing Surveillance

After the research programme leading to a drug being approved for marketing, there remain substantial enquiries still to be undertaken as regards monitoring for adverse effects and additional large-scale, long-term studies of morbidity and mortality. Also the term 'phase IV trials' is sometimes used to describe promotion exercises aimed at bringing a new drug to the attention of a large number of clinicians, typically in general practice. This latter type of enquiry has limited scientific value and hence should not be considered part of clinical trial research.

This categorization of pharmaceutical company sponsored drug trials is inevitably an oversimplification of the real progress of a drug's clinical research programme. However, it serves to emphasize that there are important early human studies (phases I/II), with their own particular organizational, ethical and scientific problems, which need to be completed before full-scale phase III trials are undertaken. The Food and Drug Administration (1977) have issued guidelines for drug development programmes in the United States. The guidelines include recommendations on how phase I-III trials should be structured for drugs in 15 specific disease areas.

It should be remembered that each pharmaceutical company has an equally important preclinical research programme, which includes the synthesis of new drugs and animal studies for evaluating drug metabolism and later for testing efficacy and especially potential toxicity of a drug. The scale and scientific quality of these animal experiments have increased enormously, following legislation in many countries prompted by the thalidomide disaster. In particular any drug must pass rigorous safety tests in animals before it can be approved for clinical trials.

The phase I-III classification system may also be of general guidance for clinical trials not related to the pharmaceutical industry. For instance, cancer chemotherapy and radiotherapy research programmes, which take up a sizeable portion of the U.S. National Institutes of Health funding, can be conveniently organized in terms of phases I-III. In this context, phase I trials are necessarily on patients, rather than normal volunteers, due to the highly toxic nature of the treatments.

Development of new surgical procedures will also follow broadly similar plans, with phase I considered as basic development of surgical techniques. However, there is a paucity of well-designed phase III trials in surgery.

1.2 CONTROLLED CLINICAL TRIALS AND THE SCIENTIFIC METHOD

I will now concentrate on full-scale (phase III) trials and consider...