As the number of potential medicines produced increases, the problem of whom to test them on grows. There are two main groups: healthy volunteers and volunteer patients (plus, rarely, nonvolun-teer 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. For most drugs the dynamic effect and hence therapeutic potential can be investigated only in patients, e.g. drugs for parkinsonism and antimicrobials. These two groups of subjects for drug testing are complementary, not mutually exclusive in drug development. Introduction of novel agents into both groups poses ethical and scientific problems (see below).
There are four main reasons why doctors should have a grounding in the knowledge and application of the principles of experimental therapeutics:
1. The optimal selection of a specific dose of a drug for a specific patient should be based on good clinical research. To some extent, every new administration to a patient is an exercise in experimental therapeutics.
2. Increasingly, doctors are personally involved.
3. Good therapeutic research alters clinical practice.
4. Such study provides an exercise in ethical and logical thinking.
Plainly, doctors cannot read in detail and evaluate for themselves all the published studies (often hundreds) that might influence their practice. They therefore turn to specialist research articles and abstracts1 including meta-analyses (p. 66) for guidance, but readers must approach these critically.
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).2 Official regulatory bodies rightly require scientific evaluation of drugs. Drug developers need to satisfy the official regulators and they also seek to persuade an increasingly sophisticated medical profession to prescribe their products. Patients are also far more aware of the comparative advantages and limitations of their medicines than they used to be. For these reasons scientific drug evaluation as described here is likely to increase in volume and the doctors involved will be held responsible for the ethics of what they do even if they played no personal part in the study design.
1 Many review articles (and there are whole journals devoted to reviews) are of poor quality, merely reporting uncritically the opinions of the original authors. But high-quality critical reviews are to be treasured. Ajournal titled Evidence-Based Medicine was launched in 1995.
Therefore we provide a brief discussion of some relevant ethical aspects (and particularly of the randomised controlled trial).
RESEARCH3 INVOLVING HUMAN SUBJECTS
A distinction may be made between:
• Therapeutic: that which may actually have a therapeutic effect or provide information that can be used to help the participating subjects and
• Nontherapeutic: that which provides information that cannot be of direct use to them, e.g. healthy volunteers always and patients sometimes.
This is a somewhat artificial separation, because some trials that are 'therapeutic', i.e. involve use of new potential medicines, may by their design and intent have no therapeutic benefit for the participants. For example, a dose ranging study of an antihypertensive drug may employ four doses, one of which is expected to be too low and another too high, in order to describe the shape and position of
2 Guidance to researchers in this matter is clear. The World Medical Association declaration of Helsinki (Edinburgh revision 2000) states that'.. .considerations related to the well-being of the human subject should take precedence over the interests of science and society.' The General Assembly of the United Nations adopted in 1966 the International Covenant on Civil and Political Rights, of which Article 7 states, 'In particular, no one shall be subjected without his free consent to medical or scientific experimentation.' This means that subjects are entitled to know that they are being entered into research even though the research be thought to be 'harmless'. But there are people who cannot give (informed) consent, e.g. the demented. The need for special procedures for such is now recognised, for there is a consensus that without research, they and the diseases from which they suffer will become therapeutic 'orphans'.
3 "The definition of research continues to present difficulties.
The distinction between medical research and innovative medical practice derives from the intent. In medical practice the sole intention is to benefit the individual patient consulting the clinician, not to gain knowledge of general benefit, though such knowledge may incidentally emerge from the clinical experience gained. In medical research the primary intention is to advance knowledge so that patients in general may benefit; the individual patient may or may not benefit directly.' (Royal College of Physicians of London 1996 Guidelines on the practice of ethics committees in medical research involving human subjects).
the dose-response curve. Furthermore, many such trials are frequently too short to bring lasting benefit to participants even if the right dose is selected.
Research may also be experimental (involving psychologically intrusive or physically invasive intervention) or solely observational (sometimes called noninterventional) (including epidemiology).
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 informed choice (consent) and the right to withdraw at any stage.
The issue of (informed) consent5 looms large in discussions of the ethics of research involving human subjects and is a principal concern of the Research Ethics Committees that are now the norm in medical research.
Some dislike the word 'experiment' in relation to man, thinking that its mere use implies a degree of impropriety in what is done. It is better, however, that all should recognise the true meaning of the word, 'to ascertain or establish by trial',6 that the benefits of modern medicine derive almost wholly from experimentation and that some risk is inseparable from much medical advance. The moral obligation of all doctors lies in ensuring that in their desire to help patients (the ethical principal of beneficence) they should never allow themselves to put the individual who has sought their aid at any disadvantage (the ethical principal of non-maleficence)
4 For extensive practical detail, see International ethical guidelines for biomedical research involving human subjects; prepared by the Council for International Organisations of Medical Sciences (CIOMS) in collaboration with the World Health Organisation (WHO): Geneva, (1993, and revisions). (WHO publications are available in all UN member countries), also the Guideline for Good Clinical Practice. International Conference on Harmonisation Tripartite Guideline. EU Committee on Proprietary Medicinal Products (CPMP/ICH/135/95). Also: Smith T1999 Ethics in Medical Research. A Handbook of Good Practice. Cambridge University Press, Cambridge.
5 Consent procedures, e.g. information, especially on risks, loom larger in research, particularly where it is non-therapeutic, than they do in medical practice.
for 'the scientist or physician has no right to choose martyrs for society'.7
It is, of course, only proper to perform a therapeutic trial when the doctors genuinely do not know which treatment is best, and when they are prepared to withdraw individual patients or to stop the whole trial when at any time they become convinced that it is in the patients' interest to do so.
If it is truly not known whether one treatment is better than another, i.e. there is equipoise,8 then nothing is lost, at least in theory, by allotting patients at random to those treatments under test, and it is in everybody's interest that good treatments should be adopted and bad treatments abandoned as soon as possible. It is, of course, more difficult to justify a new treatment when existing treatments are good than when they are bad, and this difficulty is likely to grow. It involves weighing the needs of future patients who may benefit from the results of a study against those of the patients who are actually taking part, some of whom will receive new (and possibly less effective) treatment, i.e. the ethical principle of justice.9
The ethics of the randomised and placebo controlled trial
History, including recent history, is replete with examples of even the best-intentioned doctors being wrong about the efficacy and safety of (new)
6 Oxford English Dictionary.
7 Kety S. Quoted by Beecher H K 1959 Journal of the American Medical Association 169:461.
8 In this situation it has been urged that it need to be no concern of patients that they are entered into a research study. Even if it should be the case that there is true equipoise, this (convenient) belief does not allow the requirement for (informed) consent to be bypassed; and doctors often have opinions that would be of interest to patients if they were told of them, which they may not be.
9 In a disabling disease having no proved treatment, the advent of a potentially effective medicine, unavoidably in limited supply, heightens the emotions of all concerned. This was the situation for the first study of interferon beta in multiple sclerosis. The manufacturer, seeking to be fair, arranged a lottery for patients (having a certified diagnosis) to enter a randomised placebo-controlled trial. Some patients, when they understood that they might be allocated placebo, became angry (and said so on television). (British Medical Journal 1993 307: 958; Lancet 1993 343: 169). It is not obvious how this situation could have been made fairer.
treatments and that this situation can and should be remedied by the ethical employment of science. This was well summarised in a Report.10
An analysis of the ethical problems of therapeutic trials might begin with a question long familiar to moral philosophy: what is the nature and degree of certitude required for an ethical decision? More precisely, is there any ethically relevant difference between the use of statistical methods and the use of other ways of knowing, such as experience, common sense, guessing, etc.? When decisions are to be made in uncertainty, is it more or less ethical to choose and abide by statistical methods of defining 'certitude' than to be guided by one's hunch or striking experience? These questions are raised by the assertion that it is ethically imperative to conclude a clinical trial when a 'trend' appears... the choice of statistical methods can constitute in many circumstances an acceptable ethical approach to the problem of decision in uncertainty.
The use of a placebo (or dummy) raises both ethical and scientific issues. There are clear-cut cases when its 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. But the use of a placebo does not necessarily require that patients be deprived of effective therapy (where it exists). New drug and placebo may be added against a background of established therapy e.g. in heart failure. This is the so-called 'add on' design.
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. These are common in trials of antidepressants, antiobesity drugs and antihypertensives.
• To distinguish drug effects from fluctuations in disease that occur with time and other external factors, provided active treatment, if any, can be ethically withheld. This is also called the 'assay sensitivity' of the trial.
10 European Journal of Clinical Pharmacology 1980 18:129.
• To avoid false conclusions. The use of placebos is valuable in Phase I healthy volunteer studies of novel drugs to help determine whether minor but frequently reported adverse events are drug-related or not. Placebos are also helpful to distinguish between real and imaginary responses in short-term trials with new analgesic agents.
While the use of 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.
Investigators who propose to use a placebo or otherwise withhold effective treatment should specifically 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 symptomatic relief only, 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 noninferiority, see p. 61)
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 freely give consent, they are not the subject of deception in any ethical sense; but a patient
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