Evaluation of drugs in humans

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Chapter 4 Evaluation of drugs in humans

Synopsis

This chapter is about evidence-based drug therapy.

New drugs are progressively introduced by clinical pharmacological studies in rising numbers of healthy and/or patient volunteers until sufficient information has been gained to justify formal therapeutic studies. Each of these is usually a randomised controlled trial, in which a precisely framed question is posed and answered by treating equivalent groups of patients in different ways.

The key to the ethics of such studies is informed consent from patients, efficient scientific design and review by an independent research ethics committee. The key interpretative factors in the analysis of trial results are calculations of confidence intervals and statistical significance. Potential clinical significance develops within the confines of controlled clinical trials. This is best expressed by stating not only the percentage differences, but also the absolute difference or its reciprocal, the number of patients who have to be treated to obtain one desired outcome. The outcome might include both efficacy and safety.

Surveillance studies and the reporting of spontaneous adverse reactions respectively determine the clinical profile of the drug and detect rare adverse events. Further trials to compare new medicines with existing medicines are also required. These form the basis of cost–effectiveness comparisons.

Topics include:

Experimental therapeutics

After preclinical evidence of efficacy and safety have been obtained in animals, potential medicines are tested in healthy volunteers and volunteer patients. Studies in healthy normal volunteers can help to determine the safety, tolerability, pharmacokinetics and, for some drugs (e.g. anticoagulants and anaesthetic agents), their dynamic effect and likely dose range. For many drugs, the dynamic effect and hence therapeutic potential can be investigated only in patients, e.g. drugs for parkinsonism and antimicrobials will have no measurable efficacy in subjects without movement disorder or infection, respectively.

Modern medicine is sometimes accused of callous application of science to human problems and of subordinating the interest of the individual to those of the group (society).1 Official regulatory bodies rightly require scientific evaluation of drugs. Drug developers need to satisfy the official regulators and they also seek to persuade the medical profession to prescribe their products. Patients, too, are more aware of the comparative advantages and limitations of their medicines than they used to be. To some extent, this helps encourage patients to participate in trials so that future patients can benefit, as they do now, from the knowledge gained from such trials. An ethical framework is required to ensure that the interests of the individual participant take precedence over those of society (and, more obviously, those of an individual or corporate investigator).

Ethics of research in humans4

Some dislike the word ‘experiment’ in relation to humans, thinking that its mere use implies a degree of impropriety in what is done. It is better that all should recognise from the true meaning of the word, ‘to ascertain or establish by trial’,5 that the benefits of modern medicine derive almost wholly from experimentation and that some risk is inseparable from much medical advance.

The issue of (adequately informed) consent is a principal concern for Research Ethics Committees (also called Institutional Review Boards). People have the right to choose for themselves whether or not they will participate in research, i.e. they have the right to self-determination (the ethical principle of autonomy). They should be given whatever information is necessary for making an adequately informed choice (consent) with the right to withdraw at any stage. Consent procedures, especially information on risks, loom larger in research than they do in medical practice. This is appropriate given that in research, patients may be submitting themselves to extra risks, or simply to extra inconvenience (e.g. more or longer visits). It is a moot point whether more consent in routine practice might not go amiss. It is also likely that patients participating in well-conducted trials receive more, and sometimes better, care and attention than might otherwise be available. Sometimes the unintended consequences of ethical procedures include causing unnecessary apprehension to patients with long, legalistic documents, and creating a false impression of clinical researchers as people from whom patients need protection.

The moral obligation of all doctors lies in ensuring that in their desire to help patients (the ethical principle of beneficence) they should never allow themselves to put the individual who has sought their aid at any disadvantage (the ethical principle of non-maleficence) for ‘the scientist or physician has no right to choose martyrs for society’.6

In principle, it may be thought proper to perform a therapeutic trial only when doctors (and patients) have genuine uncertainty as to which treatment is best.7 Not all trials are comparisons of different treatments. Some, especially early phase trials of new drugs, are comparisons of different doses. Comparisons of new with old should usually offer patients the chance of receiving current best treatment with one which might be better. Since this is often rather more than is offered in resource-constrained routine care, the obligatory patient information sheet mantra that ‘the decision whether to take part has no bearing on your usual care’ may be economical with the truth. But it is also simplistic to view the main purpose of all trials with medicines as comparative.

The past decade has seen the pharmaceutical industry struggle to match the pace of new understanding about disease pathogenesis, and models of research are being adapted to the complexity of common disease that is now apparent. In diseases where many good medicines already exist, the industry spent much time developing minor modifications which were broadly equivalent to current therapy with possible advantages for some patients. With many of the standard blockbusters now off patent, new drugs for such diseases are unattractive, and the industry is concentrating more on harder therapeutic targets where no satisfactory treatment yet exists. Just as in basic science, non-hypothesis-led ‘fishing expedition’ research – genome scans, microarrays – is no longer frowned upon, so the imaginative clinical investigator must throw his stone – a new medicine – into the pond, and be able to make sense of the ripples. One such approach is to move away from trial design in which it is the average response of the group which is of interest towards the design in which the investigator attempts to match differences in response to differences – ethnic, gender, genetic – among the patients. Matches at a molecular level give clues both to how the drug may best be used, and who will benefit most.

The ethics of the randomised and placebo-controlled trial

Providing that ethical surveillance is rooted in the ethical principles of justice,8 there should be no difficulty in clinical research adapting to current needs. And even if the nature of early phase research is changing, the randomised controlled trial will remain the cornerstone of how cause and effect is proven in clinical practice, and how drugs demonstrate the required degree of efficacy and safety to obtain a licence for their prescription.

The use of a placebo (or dummy) raises both ethical and scientific issues (see placebo medicines and the placebo effect, Ch. 2). There are clear-cut cases when placebo use would be ethically unacceptable and scientifically unnecessary, e.g. drug trials in epilepsy and tuberculosis, when the control groups comprise patients receiving the best available therapy.

The pharmacologically inert (placebo) treatment arm of a trial is useful:

To distinguish the pharmacodynamic effects of a drug from the psychological effects of the act of medication and the circumstances surrounding it, e.g. increased interest by the doctor, more frequent visits, for these latter may have their placebo effect. Placebo responses have been reported in 30–50% of patients with depression and in 30–80% with chronic stable angina pectoris.

To distinguish drug effects from natural fluctuations in disease that occur with time, e.g. with asthma or hay fever, and other external factors, provided active treatment, if any, can be ethically withheld. This is also called the ‘assay sensitivity’ of the trial.

To avoid false conclusions. The use of placebos is valuable in Phase 1 healthy volunteer studies of novel drugs to help determine whether minor but frequently reported adverse events are drug related or not. Although a placebo treatment can pose ethical problems, it is often preferable to the continued use of treatments of unproven efficacy or safety. The ethical dilemma of subjects suffering as a result of receiving a placebo (or ineffective drug) can be overcome by designing clinical trials that provide mechanisms to allow them to be withdrawn (‘escape’) when defined criteria are reached, e.g. blood pressure above levels that represent treatment failure. Similarly, placebo (or new drug) can be added against a background of established therapy; this is called the ‘add on’ design.

To provide a result using fewer research subjects. The difference in response when a test drug is compared with a placebo is likely to be greater than that when a test drug is compared with the best current, i.e. active, therapy (see later).

Investigators who propose to use a placebo, or otherwise withhold effective treatment, should justify their intention. The variables to consider are:

The severity of the disease.

The effectiveness of standard therapy.

Whether the novel drug under test aims to give only symptomatic relief, or has the potential to prevent or slow up an irreversible event, e.g. stroke or myocardial infarction.

The length of treatment.

The objective of the trial (equivalence, superiority or non-inferiority; see p. 45). Thus it may be quite ethical to compare a novel analgesic against placebo for 2 weeks in the treatment of osteoarthritis of the hip (with escape analgesics available). It would not be ethical to use a placebo alone as comparator in a 6-month trial of a novel drug in active rheumatoid arthritis, even with escape analgesia.

The precise use of the placebo will depend on the study design, e.g. whether crossover, when all patients receive placebo at some point in the trial, or parallel group, when only one cohort receives placebo. Generally, patients easily understand the concept of distinguishing between the imagined effects of treatment and those due to a direct action on the body. Provided research subjects are properly informed and give consent freely, they are not the subject of deception in any ethical sense; but a patient given a placebo in the absence of consent is deceived and research ethics committees will, rightly, decline to agree to this. (See also: Lewis et al (2002) in Guide to further reading, at the end of this chapter.)

Rational introduction of a new drug to humans

When studies in animals predict that a new molecule may be a useful medicine, i.e. effective and safe in relation to its benefits, then the time has come to put it to the test in humans. Most doctors will be involved in clinical trials at some stage of their career and need to understand the principles of drug development. When a new chemical entity offers a possibility of doing something that has not been done before or of doing something familiar in a different or better way, it can be seen to be worth testing. But where it is a new member of a familiar class of drug, potential advantage may be harder to detect. Yet these ‘me too’ drugs are often worth testing. Prediction from animal studies of modest but useful clinical advantage is particularly uncertain and, therefore, if the new drug seems reasonably effective and safe in animals it is rational to test it in humans. From the commercial standpoint, the investment in the development of a new drug can be over £500 million, but will be substantially less for a ‘me too’ drug entering an already developed and profitable market.

Phases of clinical development

Human experiments progress in a commonsense manner that is conventionally divided into four phases (Fig. 4.1). These phases are divisions of convenience in what is a continuous expanding process. It begins with a small number of subjects (healthy subjects and volunteer patients) closely observed in laboratory settings, and proceeds through hundreds of patients, to thousands before the drug is agreed to be a medicine by a national or international regulatory authority. It is then licensed for general prescribing (though this is by no means the end of the evaluation). The process may be abandoned at any stage for a variety of reasons, including poor tolerability or safety, inadequate efficacy and commercial pressures. The phases are:

image

Fig. 4.1 The phases of drug discovery and development.

(With permission of Pharmaceutical Research and Manufacturers of America.)

Official regulatory guidelines and requirements12

For studies in humans (see also Ch. 6) these ordinarily include:

Studies of pharmacokinetics and bioavailability and, in the case of generics, bioequivalence (equal bioavailability) with respect to the reference product.

Therapeutic trials (reported in detail) that substantiate the safety and efficacy of the drug under likely conditions of use, e.g. a drug for long-term use in a common condition will require a total of at least 1000 patients (preferably more), depending on the therapeutic class, of which (for chronic diseases) at least 100 have been treated continuously for about 1 year.

Special groups. If the drug will be used in, for example, the elderly or children, then these populations should be studied. New drugs are not normally studied in pregnant women. Studies in patients having disease that affects drug metabolism and elimination may be needed, such as patients with impaired liver or kidney function.

Fixed-dose combination products will require explicit justification for each component.

Interaction studies with other drugs likely to be taken simultaneously. Plainly, all possible combinations cannot be evaluated; a rational choice, based on knowledge of pharmacodynamics and pharmacokinetics, is made.

The application for a licence for general use (marketing application) should include a draft Summary of Product Characteristics for prescribers. A Patient Information Leaflet must be submitted. These should include information on the form of the product (e.g. tablet, capsule, sustained-release, liquid), its uses, dosage (adults, children, elderly where appropriate), contraindications, warnings and precautions (less strong), side-effects/adverse reactions, overdose and how to treat it.

The emerging discipline of pharmacogenomics seeks to identify patients who will respond beneficially or adversely to a new drug by defining certain genotypic profiles. Individualised dosing regimens may be evolved as a result (see p. 101). This tailoring of drugs to individuals is consuming huge resources from drug developers but has yet to establish a place in routine drug development.

Therapeutic investigations

With few exceptions, none of these is easy to answer definitively within the confines of a pre-registration clinical trials programme. Effectiveness and safety have to be balanced against each other. What may be regarded as ‘safe’ for a new oncology drug in advanced lung cancer would not be so regarded in the treatment of childhood eczema. The use of the term ‘dose’, without explanation, is irrational as it implies a single dose for all patients. Pharmaceutical companies cannot be expected to produce a large array of different doses for each medicine, but the maxim to use the smallest effective dose that results in the desired effect holds true. Some drugs require titration, others have a wide safety margin so that one ‘high’ dose may achieve optimal effectiveness with acceptable safety. There are two classes of endpoint or outcome of a therapeutic investigation:

Use of surrogate effects presupposes that the disease process is fully understood. They are best justified in diseases for which the true therapeutic effect can be measured only by studying large numbers of patients over many years. Such long-term outcome studies are indeed always preferable but may be impracticable on organisational, financial and sometimes ethical grounds prior to releasing new drugs for general prescription. It is in areas such as these that the techniques of large-scale surveillance for efficacy, as well as for safety, under conditions of ordinary use (below), would be needed to supplement the necessarily smaller and shorter formal therapeutic trials employing surrogate effects. Surrogate endpoints are of particular value in early drug development to select candidate drugs from a range of agents.

Therapeutic evaluation

The aims of therapeutic evaluation are three-fold:

The process of therapeutic evaluation may be divided into pre- and post-registration phases (Table 4.1), the purposes of which are set out below.

When a new drug is being developed, the first therapeutic trials are devised to find out the best that the drug can do under conditions ideal for showing efficacy, e.g. uncomplicated disease of mild to moderate severity in patients taking no other drugs, with carefully supervised administration by specialist doctors. Interest lies particularly in patients who complete a full course of treatment. If the drug is ineffective in these circumstances there is no point in proceeding with an expensive development programme. Such studies are sometimes called explanatory trials as they attempt to ‘explain’ why a drug works (or fails to work) in ideal conditions.

If the drug is found useful in these trials, it becomes desirable next to find out how closely the ideal may be approached in the rough and tumble of routine medical practice: in patients of all ages, at all stages of disease, with complications, taking other drugs and relatively unsupervised. Interest continues in all patients from the moment they are entered into the trial and it is maintained if they fail to complete, or even to start, the treatment; the need is to know the outcome in all patients deemed suitable for therapy, not only in those who successfully complete therapy.14

The reason some drop out may be related to aspects of the treatment and it is usual to analyse these according to the clinicians’ initial intention (intention-to-treat analysis), i.e. investigators are not allowed to risk introducing bias by exercising their own judgement as to who should or should not be excluded from the analysis. In these real-life, or ‘naturalistic’, conditions the drug may not perform so well, e.g. minor adverse effects may now cause patient non-compliance, which had been avoided by supervision and enthusiasm in the early trials. These naturalistic studies are sometimes called ‘pragmatic’ trials.

The methods used to test the therapeutic value depend on the stage of development, who is conducting the study (a pharmaceutical company, or an academic body or health service at the behest of a regulatory authority), and the primary endpoint or outcome of the trial. The methods include:

Formal therapeutic trials are conducted during Phase 2 and Phase 3 of pre-registration development, and in the post-registration phase to test the drug in new indications. Equivalence trials aim to show the therapeutic equivalence of two treatments, usually the new drug under development and an existing drug used as a standard active comparator. Equivalence trials may be conducted before or after registration for the first therapeutic indication of the new drug (see p. 46 below for further discussion). Safety surveillance methods use the principles of pharmacoepidemiology (see p. 51) and are concerned mainly with evaluating adverse events and especially rare events, which formal therapeutic trials are unlikely to detect.

Need for statistics

In order truly to know whether patients treated in one way are benefited more than those treated in another, it is essential to use numbers. Statistics has been defined as ‘a body of methods for making wise decisions in the face of uncertainty’.15 Used properly, they are tools of great value for promoting efficient therapy. More than 100 years ago Francis Galton saw this clearly:

Concepts and terms

Hypothesis of no difference

When it is suspected that treatment A may be superior to treatment B, and the truth is sought, it is convenient to start with the proposition that the treatments are equally effective – the ‘no difference’ hypothesis (null hypothesis). After two groups of patients have been treated and it has been found that improvement has occurred more often with one treatment than with the other, it is necessary to decide how likely it is that this difference is due to a real superiority of one treatment over the other.

To make this decision we need to understand two major concepts, statistical significance and confidence intervals.