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(10) Ethics in medicine

 Principles of Medical Ethics

MEDICAL ETHICS MANUAL

EM10

Is medical research the new imperialism?

. . . a kind, forgiving, charitable, pleasant time; the only time I know of, in the long calendar of the year, when men and women seem by one consent to open their shut-up hearts freely, and to think of people below them as if they really were fellow-passengers to the grave, and not another race of creatures bound on other journeys.

(Charles Dickens, A Christmas Carol)

Tomorrow’s medicine is today’s research. That is why the question of how we allocate resources to research is at least as important as the question of how we allocate resources to health care itself. But this is not a question that you will find has been the focus of much ethical discussion. Most discussion about the ethics of medical research addresses the question of how research should be regulated. Indeed, medical research is in many ways much more strictly regulated than medical practice. From a perusal of the innumerable guidelines on medical research you could be forgiven for thinking that medical research, like smoking, must be bad for your health; that in a liberal society, since it cannot be altogether banned, strict regulation is needed to minimize the harm that it can do.

The reason for this strict control lies in history. The appalling experiments carried out by some Nazi doctors led, in 1946, to the first internationally agreed guidelines on medical research involving people – the Nuremberg Code. This code consisted of ten principles and these were incorporated by the medical profession into the Declaration of Helsinki, which was first published by the World Medical Association in 1964 and last updated in 2000. The Declaration of Helsinki has many offspring of varying legitimacy in the form of guidelines for medical research. These guidelines highlight four main issues: respect for the autonomy of the potential participants in research; the risk of harm; the value and quality of the research; and aspects of justice. The position taken on the risk of harm is rather interesting. Guidelines agree that research participants should not be put at more than ‘minimal risk of harm’. This is the case even if the participant is a competent adult fully informed about the risks and benefits and who voluntarily agrees to take part. Although it is not entirely clear what is meant by minimal harm, it seems to be set at a level taken by somewhat risk-averse people in their normal lives. In other words the guidelines are highly paternalistic.

Why should risk of harm be more carefully controlled, and more restrictive, in the context of medical research, than it is in other areas of our lives? We do not prevent the sale or purchase of skis, motorbikes, or hang-gliders, although these expose purchasers to moderate risks. Why should the control of medical research be different?

Double standards

This is only one example where the regulation of medical research imposes standards that seem out of keeping with other areas of life. Another example is with regard to the amount of information provided to patients who are being asked to take part in a clinical trial.

Contrast these two situations:

Clinical case

Dr A sees patient B in the outpatient department. B is suffering from depression of a type likely to be helped with antidepressants. There are several slightly different antidepressants available. Dr A advises B to take a particular antidepressant (drug X) – the one with which he is most familiar and which is suitable for B. Dr A informs B about the likely benefits and the side effects of drug X. However, he says nothing about the other antidepressants that he could have prescribed instead.

Research case

A randomized controlled trial is under way to compare two antidepressants: drug X and drug Y. Although Dr A tends to prescribe drug X, on reflection he does not think that there is currently good evidence to prefer X to Y. It could be important to establish the relative effectiveness, and adverse effects, of each. Dr A therefore agrees to ask suitable patients whether they would be prepared to take part in the trial. Dr A sees B in the outpatient department. B is suffering from depression and would be a suitable candidate for the trial. In order to conform to the standards laid down by research ethics guidelines Dr A must obtain valid consent for B to enter the trial. He must inform B about the trial and its purpose. He must also inform B about both drugs X and Y and tell B that a random process will be used to choose which will be prescribed.

In the research case the guidelines and research ethics committees (also called institutional review boards) require Dr A to inform B about both drugs, and about the method of choosing which to prescribe. In the clinical case this standard of informing is not the norm. Is this difference justified? If it is, then the standards are simply different. If it is not then we are operating ‘double standards’ – i.e. standards that are different and where the difference is not justifiable. Double standards are an example of inconsistency. They tell us that at least one of the standards needs to be changed.

Medical research in the Third World

It is a third example of different standards on which I want to focus in this chapter. Under scrutiny here is not a comparison between research and ordinary life, nor between research and medical practice, but between research in rich countries and research in poor countries.

The Council for International Organizations of Medical Sciences laid down the following principle in its 1993 guidelines:

The ethical implications of research involving human subjects are identical in principle wherever the work is undertaken; they relate to respect for the dignity of each individual subject as well as to respect for communities, and protection of the rights and welfare of human subjects.

Marcia Angell, the former editor of the New England Journal of Medicine, wrote: ‘Human subjects in any part of the world should be protected by an irreducible set of ethical standards.’ Was this principle of equity breached by the following research studies? Angell thought that it was.

Preventing HIV transmission to infants in poor countries

The Human Immunovirus (HIV) causes the disease AIDS. A pregnant woman, infected with the HIV, may pass the infection on to her child. This is known as ‘vertical transmission’. Treatment of a pregnant woman, infected with the HIV, with zidovudine (known as the ACTG 076 regimen) reduces the chance of vertical transmission. This regimen involves taking zidovudine by mouth (orally) during pregnancy, and being given it by injection into a vein during labour; and includes further doses to the newborn infant.

This regimen is too expensive to be generally available in poor countries. A cheaper, but effective, regimen would potentially prevent a very large number of babies being infected with the HIV in poor countries. Without a cheaper regimen there is no available treatment in poor countries to prevent vertical transmission of HIV. In 1997 the ACTG 076 regimen was the standard in the US because it was the only one that had been shown to be effective. It was thought possible that a cheaper regimen involving only oral zidovudine might be effective. Two possible designs of trials to be carried out in poor countries are scientifically reasonable. The first is to compare the cheaper regimen with a placebo. The second is to compare the cheaper regimen with the expensive regimen (ACTG 076). The first design is aimed at answering the question: is the cheap treatment better than nothing (placebo)? The second design is aimed at answering the question: is the cheap regimen as effective as the expensive regimen? In this case it was not realistic to introduce the expensive regimen as standard treatment into poor countries so the key question to be answered by the research was whether the cheaper regimen was better than nothing. This question can be answered more quickly, will involve fewer patients, and be cheaper using the first (placebo-controlled) design and it was this design that had been used in several studies, funded by rich countries, but conducted in poor countries.

It is generally accepted that the control group in a treatment trial should receive whatever is standard treatment (i.e. they should not be disadvantaged by the fact of taking part in the trial compared with people who are not in the trial). If you were taking part in a treatment trial in the UK or the US, a trial that was evaluating a new promising blood pressure drug, then you would be treated either with the new drug, or with what is current best treatment.

You would not be given a placebo. That would be unethical because there is already known effective treatment. Thus it would have been unethical in the sponsoring country (the US) to have carried out a placebo-controlled trial of the cheaper regimen because standard treatment in the US is the expensive (ACTG 076) regimen. On the principle of equity, therefore, many commentators thought that it was unethical to carry out a placebo-controlled study in the poor country: a double standard was operating. Furthermore the study was in breach of the Declaration of Helsinki which states that controls in treatment studies should receive the best current treatment.

But there are powerful arguments against this position. If the trial were conducted in a rich country it would be wrong for any patient in the trial to receive placebo, since in normal clinical practice they would be receiving an active treatment. And this active treatment is known to be better than placebo. Now consider the case in a poor country. In normal clinical practice a patient would not receive any treatment. Indeed, many pregnant women infected with HIV would not receive any health care at all. The principle, stated in the Declaration of Helsinki, that those in the control arm should receive current best treatment is ambiguous. Does current best treatment mean best anywhere in the world, or best in the country where the research is being carried out? Those who believe that the placebo-controlled trial in the poor country was unethical think that the responsible ethics committee should not have allowed a trial using placebo control to be undertaken. But without the trial no one in the poor country would be receiving treatment to prevent vertical transmission. No one, therefore, receives worse treatment as a result of the placebo-controlled trial, and several people (those receiving the new treatment regimen) are likely to receive better treatment (although until the trial is carried out we don’t know for certain that the new regimen is beneficial). And this is in marked contrast with the situation if a placebo-controlled trial were being carried out in a rich country, because in that case those given placebo would be worse off than patients not in the trial. In short, no one is harmed as a result of the placebo-controlled trial if it takes place in a poor country and some people stand to benefit. The conclusion from this argument is that it would be better overall, for people in the poor country, that the placebo-controlled trial takes place. Those in the poor country also stand to benefit in the future from the trial as it may lead to the development of a treatment to prevent vertical transmission that is affordable for poor countries. If the trial were prevented from taking place, on the grounds that it is unethical because inequitable to people in poor countries, those in the poor country would be worse off. If equitable treatment means no treatment at all, give me inequitable treatment. Against this it might be argued that, although the placebo controlled trial is better than no trial, it would be better still to use the expensive regimen as control. But this would cost more. Who should pay? Perhaps those in rich countries should pay more to poor countries but it is not clear that this should be imposed on the sponsors of this research. Nor is it clear that the money is best spent on providing expensive HIV treatment for those who are allocated to the control arm of this trial. The extra money might be better spent in other ways – in ways, for example, that have greater beneficial effect on the health of those in poor countries. In conclusion, the placebo study is not unethical – no one is harmed as a result of the study and some benefit. It would be worse for those in the poor country if the study did not take place. The principle stated in the Declaration of Helsinki and quoted above should be interpreted to mean that the control group should receive best treatment in the society in which the study takes place, not best treatment anywhere in the world. There is an ethical issue about the low level of health care available to those in poor countries – this is a major problem of justice. But this question needs to be tackled by governments and industry. This deep underlying and   fundamental inequity should not be used to block research that, overall, benefits those in poor countries.

I have put forward two opposed positions.

1. That it is unethical to use a placebo control in a clinical trial carried out in a poor country when such a control would not be thought ethical had the research been carried out in a rich country. The ethics committee should not have allowed the trial described above to have taken place.

2. That the placebo control was not unethical, even if not ideal, and that it was right that the ethics committee allowed the trial to go ahead.

The first position seems to be on the side of the angels, making a bold claim of principle that those of us in rich countries should not treat people in poor countries any differently from ourselves.

The second position uses the cold knife of rational argument to cut through our humane intuition and show that it is misguided. What should we do when rational argument contradicts humane intuition? The answer must be: re-examine both our intuitions and our arguments. Why does the first position seem to be on the side of the angels? Because we feel that it is treating those who are less privileged than ourselves as we would be treated. If we act according to the second view we have a niggling feeling that we are exploiting the poor. But the criticism of the first position seems valid: that by being precious about setting the same standards in poor countries that we would in rich countries we are making a decision (stopping the research) that will take away benefit from the very people towards whom we are wanting to be fair. The clue to the way out of this impasse lies in the phrase ‘exploiting the poor’. Someone can benefit from something but still be exploited. Consider coffee pickers in South America employed by an international company and paid low wages. Without such employment they may be even worse off. But if the company is making large profits, it is exploiting the pickers. The benefits should be fairly shared: that is what ‘Fair-trade’ is all about. Both of the opposed positions that we have been considering are too narrow.

The first position is right in highlighting the issue of equity, an issue closely related to exploitation. But it is wrong in blindly applying a principle (that controls should be given best treatment) that has been developed in a quite different context. The second position is right in showing that applying the principle is not in the best interests of those in poor countries, but it is wrong in considering only two possibilities. A much broader perspective is needed, and the starting point for that broader perspective is that the overarching ethical concern is the huge disparity in wealth and health care between rich and poor countries.

The implications of this perspective for international medical research include:

(a) That the research must be conducted in ways that provide appropriate benefits to those in the poor country; and the benefits between rich and poor must be appropriately shared;

(b) That a realistic view be taken as to what can be sustained in the poor country in order to properly evaluate how the benefits to poor countries can be maximized;

(c) That the researchers have responsibilities not only to those in the poor countries who take part in the research but to the wider population. A public health perspective is therefore needed. A narrow focus on the best interests of the research participants only, without regard to the population, is excessively individualistic.

Henry Ford famously said: ‘History is more or less bunk’. It has also been said, although I do not by whom: ‘Those who are ignorant of history are condemned to repeat it’. The current international regulation of medical research grows, distorted by the long shadow of the Nazi past. This regulation is reactive, and obsessed with one main concern: to protect research participants from being abused.

Important though this is there has been a failure to tackle the ethical implications of asking the constructive question: how can the good from medical research be maximized? Nowhere is this constructive approach more urgently needed than in research in poor countries.

Benatar and Singer write:

There is thus a need to go beyond the reactive research ethics of the past. A new, proactive research ethics must be concerned with the greatest ethical challenge – the huge inequalities in global health.

Precisely so.

Clinical trials

These are the standard method of assessing the value of a medical treatment. Suppose e.g. that the standard current treatment for disease D is drug X. A new drug, Y, has been developed. Preliminary studies suggest that Y may be an effective treatment for D, and possibly better than X. The best way to find out which drug is better is to give some patients with the disease drug X and others drug Y, and then see which group of patients does better. The group of patients receiving the new experimental drug (Y) is called the ‘experimental’ group. The group receiving the conventional treatment (X) is called the ‘control’ group. It is important that the two groups of patients (the experimental and control groups) are broadly similar. The trial results would be misleading if there were e.g. significantly more severely ill patients in one group than in the other group. The best way of ensuring that there are no significant differences between the groups is to use a random method (‘tossing a coin’) for allocating patients to each group, and to have a large number of patients in the trial. The best clinical trials are large randomized controlled trials (RCTs). When a treatment, such as a drug, is developed (treatment Y) for a condition where there is no current (conventional) treatment, the control group is given a ‘placebo’ – a dummy drug. Thus, if Y is a new drug that is taken as a tablet, the placebo would be a tablet that looks like the tablet containing Y but does not contain the active drug (Y). This is important because, for many conditions, patients can improve to some extent simply by believing that they are receiving active treatment. Doctors, furthermore, can be biased, when assessing a patient’s improvement in health, by knowing whether the patient has been taking active treatment. It is therefore important that neither the patient nor the doctors know whether the patient is in the experimental or control groups.

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