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  'Everything is political'

It is increasingly common for pharmaceutical products intended for the western market to be trialed in developing countries. In these trials, ethics are not always the primary concern. Doctors must not close their eyes to what is happening, argues Indian researcher Sandhya Srinivasan. 

Sandhya Srinivasan (picture: Marco Okhuizen)

'We want to practice medicine, not play politics,’ was the line taken by western doctors at a conference recently attended by Indian researcher and medical journalist Sandhya Srinivasan. ‘It’s such a ridiculous thing to say,’ she asserts. ‘Everything is political.’ According to Srinivasan, a doctor has to know how the world works and accept responsibility even for things that take place in other countries.
Srinivasan is investigating the ethical aspects of clinical trials in India. Drugs companies are increasingly getting their products – most of which are intended for western markets – tested in developing and low-wage countries. Factors driving the migration are cost, light-touch regulation, the short time needed to complete a trial and the ease of finding subjects. Reports of drugs companies failing to follow international ethical guidelines and research codes in these trials have been emerging for some time. And the picture was confirmed by Srinivasan’s study, the findings of which were published earlier this year by the Centre for Studies in Ethics and Rights in Mumbai.
On behalf of the Dutch development organization Wemos and the Centre for Research on Multinational Corporations (SOMO), Srinivasan examined three clinical trials conducted in India (see box text). In her report, Srinivasan argues that multinational drugs companies are exploiting the vulnerable position of Indian patients, who are often poor, illiterate and without medical insurance. The nation’s underdeveloped healthcare system means that ‘ordinary’ treatment is unavailable to them or unaffordable, making participation in a clinical trial the only option for many.

Radical activists
Doctors cannot and must not close their eyes to such practices, argues Srinivasan, who is also the executive editor of the Indian Journal of Medical Ethics. ‘Doctors need to know how drugs companies are behaving around the world,’ she says. ‘I’m not suggesting that medical people have to become radical activists, but they should at least possess a degree of social and moral awareness. Out of responsibility towards their patients, towards society and towards the world as a whole.’
Western doctors and their professional associations need to take a clear line; it shouldn’t be possible to get pharmaceutical products registered for use in Europe or the United States on the basis of unethical studies conducted elsewhere.
However, pressure from doctors alone will not be sufficient to bring about change, the Indian campaigner acknowledges. Politicians, consumers and other stakeholders need to make their views known. Awareness needs to be raised. Srinivasan draws parallels with the growing interest in labour conditions in the developing world: ‘You wouldn’t buy a carpet made by child labourers in some far-off country. People are aware of that sort of thing nowadays. We need to make unethically tested drugs similarly unacceptable.’

Responsibility for examining the moral aspects of a clinical trial lies primarily with the local ethical review committee. In poor countries, however, supervision by such committees is often wanting, due to lack of personnel or training or a lax attitude. Part of the problem is that governments are keen to welcome the pharmaceutical industry, with all its capital. In India, for example, the rules governing drugs companies have been loosened to bring in more clinical trial work.
‘There are developing countries that take a firmer line, saying ‘No’ to placebo-controlled studies and to trials of products intended exclusively for western markets. Such countries negotiate with the drugs companies, but India doesn’t,’ Srinivasan points out. ‘The Indian government simply says: it’s cheap to do your research here, we have people with the medical conditions you are interested in and our population is genetically varied. It’s a scandalous policy. If you can’t rely on your government to protect you, who can you rely on?’
According to Srinivasan, there is little opposition to ethically flawed studies from India’s medical profession either. ‘The doctors aren’t too bothered,’ she observes. ‘For one thing, they can earn good money from the trials. And they don’t see any conflict of interests there.’
‘Some doctors take the view that, through a clinical trial, you can at least offer your patient some sort of treatment. They present participation as a treatment option. But it isn’t. A clinical trial is an experiment, whose outcome and dangers are uncertain,’ Srinivasan continues. ‘Then they say it is the patient’s choice, but that is missing the point. If you have no proper health care and no money, there are no other options open to you – you have no choice. It is unethical for companies and researchers to take advantage of the position that people find themselves in.’
Srinivasan believes that subjects are often unable to give genuine informed consent. ‘Many people are illiterate. What’s more, the doctor-patient relationship is very hierarchical in India. If a doctor tells a patient to take part in a trial, the patient will usually do so.’

‘I am not opposed to global drug trials per se. They are a necessary part of health care – of science – and they can be beneficial to society,’ Srinivasan stresses. ‘But much depends on what is being tested, why, how and who stands to gain. It is not acceptable, for example, for a drug to be tested on a population group that cannot possibly benefit later, because the drug will not be available or affordable locally.’
The World Medical Association’s Declaration of Helsinki (DoH), which sets out the ethical principles applicable to medical research with human subjects, says that research is justified only if there is a reasonable probability that the research population will benefit from the outcome. The DoH is internationally regarded as one of the most authoritative ethical reference documents; registration authorities all over the world make compliance with the DoH a condition for national and international clinical trials. However, there has been insufficient supervision at the European level. ‘The European authorities have approved drugs despite knowing that the trials were unethical,’ claims Srinivasan, on the basis of a recent SOMO report and other sources.
Earlier this year, the European Medicines Agency (EMEA) announced that it would be monitoring compliance with ethical guidelines more closely when considering applications to admit pharmaceutical products that have been trialed outside the EU. On the other hand, the US Food and Drug Administration (FDA) officially indicated late last year that it would be setting aside the DoH when assessing clinical trials conducted in other countries. Instead, the FDA now works on the basis of the Good Clinical Practice (GCP) standards of the International Conference on Harmonisation. The GCP standards are broadly consistent with the DoH principles, but less strict on certain ethical points.
For example, the GCP standards indicate that, where an efficient treatment already exists, it should be up to the patients, researchers and registration authorities to decide whether a placebo-controlled study is acceptable. By contrast, the DoH states that a new product should be tested against the best existing treatment; the use of a placebo is not precluded, but a very cautious line is recommended.

Western registration authorities such as the EMEA and FDA often still require placebo-controlled research, although most western ethical review boards will no longer approve it. ‘So they are forcing the drugs companies to have their trials done elsewhere,’ observes Srinivasan, shaking her head.
Srinivasan does not see herself as an ethical relativist. The DoH is based on ethical principles that apply everywhere, regardless of the local circumstances, she says. She also makes the point that India’s own guidelines on drugs trials make reference to the DoH. ‘It’s enforcement that’s the problem. We need greater transparency everywhere. All too often, information about the planning, conduct and approval of drug trials is not made public, even when it really ought to be.’
Difficult though it may be to obtain, Srinivasan continues to search out information. ‘My report shows only the tip of the iceberg. I intend to continue my research and to build up a body of knowledge, which hopefully can be used to bring about action and change.’

Unethical studies in India
In its report, the Indian Centre for Studies in Ethics and Rights looks at the clinical trials for the breast cancer drug lapatinib (Tyverb), the anti-psychotic risperidon (Risperdal) and the schizophrenia drug quetiapine (Seroquel XR). The trials took place in India, but have been used to obtain marketing authorization in Europe.
According to the report, the three trials contravened the ethical guidelines of the Indian Council of Medical Research and the international guidelines contained in the Declaration of Helsinki.
In the lapatinib trial, the subjects were women with advanced, untreatable breast cancer. Most Indians who develop breast cancer cannot afford mainstream treatment, and would consequently regard participation in a trial as the only way of getting any help at all. It is therefore argued that the trial exploited the economic vulnerability of the patients.
Lapatinib has been conditionally approved by the European Medicines Agency and is available in the Netherlands and elsewhere. In India, however, it is unaffordable for most people. Yet ethical guidelines state that people participating in a trial should stand to gain from the outcome.
The psychiatric drugs considered in the report were tested in placebo-controlled trials, even though it was not necessary to do so, the report contends. As a result, the subjects suffered unnecessary harm. Again, the vulnerability of the subjects appears to have been exploited, since they would probably have seen participation as a way of gaining access to better or free treatment.

Download the full report.

The Dutch version of this article by journalist Babs Verblackt was published before in: Medisch Contact, Dutch journal for medical doctors and medical students, 28 May 2009, 64 no. 22. See:
Wemos included, with permission from Medisch Contact, minor changes in the above version. Translation: Taalcentrum-VU.

5 February 2010



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