MacroScan (Printable Version) - Drug Trials: The Newest Service Export

In a way, it is almost surprising that it had not happened earlier. A country like India, with its huge population often desperate for medication of any kind and with socio-legal conditions that provide at best haphazard and at worst non-existent consideration of the rights of patients, is obviously ideal ground for expanding the business of clinical testing of pharmaceutical drugs and other medical devices.

Indeed, situations of extreme poverty have driven people in our country to do much worse than simply agree to be part of medical experiments or tests. We are all familiar with the sale of human organs, such as kidneys, which had become a major export before they were banned and are still probably traded illegally in large numbers. In such a context, the possibility of earning income through volunteering for straightforward medical tests would seem an alternative infinitely preferable to that of trading organs. And since such tests would come so much cheaper for the drug companies, the "comparative advantage" of India in this rather peculiar form of service activity would appear to be a foregone conclusion.

This would in fact mean high savings for multinational drug companies, since clinical trials of drugs are estimated to account for up to one-third of the total costs of developing a new drug. Most of this money is typically spent on trials undertaken in the penultimate phase just before seeking regulatory approval and being able to file patents, and that usually requires large number of human rather than animal subjects.

Because of the greater ease in getting people to agree to be part of such tests and the lower requirements in terms of payment or information to such human guinea-pigs, such clinical trials in countries like India are likely to be much cheaper and faster. In addition, the sheer size and diversity of the Indian population in particular means that virtually all the known diseases, disorders and illnesses (those of the poor and of the rich) can be found here with sufficiently large numbers of cases.

Until a few years, ago, however, rather stringent medical regulation in the countries of the developed world that are still the biggest consumers of drugs, had limited the possibility of relocating such testing to India and similar countries. However, in 1997 the United States, Japan and the European Union agreed on common standards for running clinical drug trials, which meant that trials conducted anywhere in the world would be acceptable as long as they conformed to these standards.

This then cleared the way for a move by contract-research organisations (which are companies specifically directed towards conducting clinical trials and providing related services to pharmaceutical companies) to enter developing countries. Recently, the trend appears to have accelerated.

Thus, a recent report in the London Economist magazine suggests that the real move to increase such medical testing in India is only now becoming evident. A number of major US-based contract-research organisations have entered into joint ventures with Indian partners, such as Quintiles Transnational and Covance.

Indian companies like Nicholas Piramal and Max India have signed up with other foreign concerns to undertake such testing here on a contract basis. The potential return on investment in such activities in India is being described as "tremendous".

Obviously, it cannot and should not be argued that there should be no research in the form of clinical drug trials conducted on human beings. Such research is essential for the development of new drugs, and therefore for enhancing human health and well-being. It is now generally acknowledged, however, that clinical research on drugs, as well as evaluations of newly developed diagnostic agents, medical instruments and related material, should follow certain basic guiding principles. Thus, the benefits of intervention should far outweigh the risks ; the adverse effects should be minimal and transitory; and they should disappear on withdrawal of the drug.

The Indian Council of Medical Research (ICMR) has identified the following main pillars of ethics in biomedical research : (1) essentiality of the proposed research - that is, that valid information would not become available otherwise, (2) voluntariness of the subject, informed consent, confidentiality of the identity/personal data of individual subjects, (3) non-exploitation of subjects' situational or circumstantial position, treatment of research subjects with respect and dignity, (4) professional competence of the investigator(s) or medical team, (5) accountability and transparency of all transactions between the researcher(s), research institution and the volunteer, and finally (6) the public domain, that is, the findings should be made public for the benefit of the society. If these criteria were always observed, there would be no problem in allowing for a huge expansion in medical testing in India. But in that case, it would not be very much cheaper than similar tests in the highly regulated developed countries, and perhaps companies would find it less attractive in terms of returns on investment and cutting costs. Unfortunately, there is often a strong economic or material filter through which ethical issues are viewed, and this area is clearly an example.

The problem - or the possibility of ethics being eroded by considerations of profit - is certainly not unique to India. Thus, in 1997 there was a major controversy over a set of 15 clinical trials testing cheaper drug regimens to prevent maternal-foetal transmission of HIV in Africa and Asia. Some 16,000 pregnant, HIV-positive women were enrolled in the placebo-controlled trials. The problem was that these trials began after a drug called AZT had already been found to prevent such transmission by 50% or more, and furthermore was recommended to all HIV-positive pregnant women in western countries.

In other words, thousands of women in the trials were getting sugar pills to test the efficacy of the new regimens. If they had been enrolled in trials in the West, they would have received a standard course of AZT. When there was a major public outcry over this, the placebo-based tests were eventually discontinued. The response from the companies concerned (and US Center for Disease Control and the US National Institutes for Health which had sponsored the trials) was instructive, however. They acknowledged the "inherent tension between participants' risks and the public's benefits", but argued that the logistic problems of administering AZT in Africa, the drug's toxicity in malnourished women, and the cost, had made them look for "simpler, cheaper alternatives".

In India also there have been similar experiences. In 1997, there were trials relating to drugs for cervical cancer, conducted by the same ICMR which has specified the minimum ethical code necessary for such testing. In these trials, 1,158 women with cervical dysplasia were "monitored" to observe the rates of progression to cancer. Investigators did not obtain written consent from the participants on the grounds that most of the women were illiterate. Seventy-one women developed cancer; at least nine developed invasive cancer without treatment. Sixty-two women developed cervical carcinoma in situ before they were treated.

Apparently, the women were not informed that their lesions were known to progress to cancer. What is even worse is that any treatment seems to have been stopped once the study was over. In other words, the women who took part in the study on the expectation that they would receive better health care than otherwise, were denied medical help even when it was available simply for purposes of the test, and even allowed eventually to die.

The strongly economic aspect to this issue becomes even clearer when it is recognised that in both of these cases, poor women participants agreed to become party to the clinical trials because the known available medicines that could treat their diseases were so expensive as to be out of their reach. This problem of high priced drugs beyond the access of ordinary or poor people, is likely to intensify as the TRIPS agreement strengthens the monopoly patent rights of the very companies that are paying for such trials in the first place.

Regulation can only solve a part of the inherent problem in all this. After a major public campaign by some doctors and activists two years ago, the use of quinacrine pellets as a method of sterilisation was banned by the Indian government. In the few years before then, it is estimated that over 50,000 women in India and south-east Asia who were sterilised with the mutagenic anti-malarial drug quinacrine, administered with an IUD inserter, to cause inflammation and blockage of their fallopian tubes. There are all kinds of adverse side effects (including possibly cancerous growth) associated with this contraceptive method, which was being actively pushed by a few doctors supported by funds from western NGOs obsessed with population control in the developing world.

The banning of such quinacrine use was a major step forward, but it is thought that despite this ban, this contraceptive practice continues in many parts of the country, often with women who are not informed about the full implications and therefore unable too make knowledgeable choices. In some states the practice is fairly open and the justifying argument is made that this form of sterilisation is the preferred choice of the women themselves.

In any case, the whole issue of what is informed or voluntary choice becomes a very complex one, especially when other medical options are very limited and known drugs or medical methods are otherwise too expensive for the patient to afford. In this situation, simply to rely on the legal requirement of the "written consent" of the patient is to make a mockery of the spirit of the law. If in addition to this, the patent is illiterate or insufficiently educated, or is given the relevant information in a way which is barely comprehensible, the ethical issue becomes even starker.

But of course, it is precisely these conditions which make testing in Indian conditions cheaper and therefore more profitable for the companies concerned, which in turn is pushing the current relocation of such clinical trials. It works much in the same way as Lawrence Summers had once called (in an internal memo in the World Bank) for encouraging the export of "polluting" industries to the developing world, on the grounds that the costs of pollution were lower in such countries.

At another level, of course, this means that the Indian economy may have one more booming service sector export to rely on in the near future : one based on the poverty and vulnerability of the greater part of its population, and on the willingness of the system to place corporate gain over social good even in the basic area of human health.



Themes > Current Issues	11.02.2000


Drug Trials: The Newest Service Export

Jayati Ghosh

In a way, it is almost surprising that it had not happened earlier. A country like India, with its huge population often desperate for medication of any kind and with socio-legal conditions that provide at best haphazard and at worst non-existent consideration of the rights of patients, is obviously ideal ground for expanding the business of clinical testing of pharmaceutical drugs and other medical devices. Indeed, situations of extreme poverty have driven people in our country to do much worse than simply agree to be part of medical experiments or tests. We are all familiar with the sale of human organs, such as kidneys, which had become a major export before they were banned and are still probably traded illegally in large numbers. In such a context, the possibility of earning income through volunteering for straightforward medical tests would seem an alternative infinitely preferable to that of trading organs. And since such tests would come so much cheaper for the drug companies, the "comparative advantage" of India in this rather peculiar form of service activity would appear to be a foregone conclusion. This would in fact mean high savings for multinational drug companies, since clinical trials of drugs are estimated to account for up to one-third of the total costs of developing a new drug. Most of this money is typically spent on trials undertaken in the penultimate phase just before seeking regulatory approval and being able to file patents, and that usually requires large number of human rather than animal subjects. Because of the greater ease in getting people to agree to be part of such tests and the lower requirements in terms of payment or information to such human guinea-pigs, such clinical trials in countries like India are likely to be much cheaper and faster. In addition, the sheer size and diversity of the Indian population in particular means that virtually all the known diseases, disorders and illnesses (those of the poor and of the rich) can be found here with sufficiently large numbers of cases. Until a few years, ago, however, rather stringent medical regulation in the countries of the developed world that are still the biggest consumers of drugs, had limited the possibility of relocating such testing to India and similar countries. However, in 1997 the United States, Japan and the European Union agreed on common standards for running clinical drug trials, which meant that trials conducted anywhere in the world would be acceptable as long as they conformed to these standards. This then cleared the way for a move by contract-research organisations (which are companies specifically directed towards conducting clinical trials and providing related services to pharmaceutical companies) to enter developing countries. Recently, the trend appears to have accelerated. Thus, a recent report in the London Economist magazine suggests that the real move to increase such medical testing in India is only now becoming evident. A number of major US-based contract-research organisations have entered into joint ventures with Indian partners, such as Quintiles Transnational and Covance. Indian companies like Nicholas Piramal and Max India have signed up with other foreign concerns to undertake such testing here on a contract basis. The potential return on investment in such activities in India is being described as "tremendous". Obviously, it cannot and should not be argued that there should be no research in the form of clinical drug trials conducted on human beings. Such research is essential for the development of new drugs, and therefore for enhancing human health and well-being. It is now generally acknowledged, however, that clinical research on drugs, as well as evaluations of newly developed diagnostic agents, medical instruments and related material, should follow certain basic guiding principles. Thus, the benefits of intervention should far outweigh the risks ; the adverse effects should be minimal and transitory; and they should disappear on withdrawal of the drug. The Indian Council of Medical Research (ICMR) has identified the following main pillars of ethics in biomedical research : (1) essentiality of the proposed research - that is, that valid information would not become available otherwise, (2) voluntariness of the subject, informed consent, confidentiality of the identity/personal data of individual subjects, (3) non-exploitation of subjects' situational or circumstantial position, treatment of research subjects with respect and dignity, (4) professional competence of the investigator(s) or medical team, (5) accountability and transparency of all transactions between the researcher(s), research institution and the volunteer, and finally (6) the public domain, that is, the findings should be made public for the benefit of the society. If these criteria were always observed, there would be no problem in allowing for a huge expansion in medical testing in India. But in that case, it would not be very much cheaper than similar tests in the highly regulated developed countries, and perhaps companies would find it less attractive in terms of returns on investment and cutting costs. Unfortunately, there is often a strong economic or material filter through which ethical issues are viewed, and this area is clearly an example. The problem - or the possibility of ethics being eroded by considerations of profit - is certainly not unique to India. Thus, in 1997 there was a major controversy over a set of 15 clinical trials testing cheaper drug regimens to prevent maternal-foetal transmission of HIV in Africa and Asia. Some 16,000 pregnant, HIV-positive women were enrolled in the placebo-controlled trials. The problem was that these trials began after a drug called AZT had already been found to prevent such transmission by 50% or more, and furthermore was recommended to all HIV-positive pregnant women in western countries. In other words, thousands of women in the trials were getting sugar pills to test the efficacy of the new regimens. If they had been enrolled in trials in the West, they would have received a standard course of AZT. When there was a major public outcry over this, the placebo-based tests were eventually discontinued. The response from the companies concerned (and US Center for Disease Control and the US National Institutes for Health which had sponsored the trials) was instructive, however. They acknowledged the "inherent tension between participants' risks and the public's benefits", but argued that the logistic problems of administering AZT in Africa, the drug's toxicity in malnourished women, and the cost, had made them look for "simpler, cheaper alternatives". In India also there have been similar experiences. In 1997, there were trials relating to drugs for cervical cancer, conducted by the same ICMR which has specified the minimum ethical code necessary for such testing. In these trials, 1,158 women with cervical dysplasia were "monitored" to observe the rates of progression to cancer. Investigators did not obtain written consent from the participants on the grounds that most of the women were illiterate. Seventy-one women developed cancer; at least nine developed invasive cancer without treatment. Sixty-two women developed cervical carcinoma in situ before they were treated. Apparently, the women were not informed that their lesions were known to progress to cancer. What is even worse is that any treatment seems to have been stopped once the study was over. In other words, the women who took part in the study on the expectation that they would receive better health care than otherwise, were denied medical help even when it was available simply for purposes of the test, and even allowed eventually to die. The strongly economic aspect to this issue becomes even clearer when it is recognised that in both of these cases, poor women participants agreed to become party to the clinical trials because the known available medicines that could treat their diseases were so expensive as to be out of their reach. This problem of high priced drugs beyond the access of ordinary or poor people, is likely to intensify as the TRIPS agreement strengthens the monopoly patent rights of the very companies that are paying for such trials in the first place. Regulation can only solve a part of the inherent problem in all this. After a major public campaign by some doctors and activists two years ago, the use of quinacrine pellets as a method of sterilisation was banned by the Indian government. In the few years before then, it is estimated that over 50,000 women in India and south-east Asia who were sterilised with the mutagenic anti-malarial drug quinacrine, administered with an IUD inserter, to cause inflammation and blockage of their fallopian tubes. There are all kinds of adverse side effects (including possibly cancerous growth) associated with this contraceptive method, which was being actively pushed by a few doctors supported by funds from western NGOs obsessed with population control in the developing world. The banning of such quinacrine use was a major step forward, but it is thought that despite this ban, this contraceptive practice continues in many parts of the country, often with women who are not informed about the full implications and therefore unable too make knowledgeable choices. In some states the practice is fairly open and the justifying argument is made that this form of sterilisation is the preferred choice of the women themselves. In any case, the whole issue of what is informed or voluntary choice becomes a very complex one, especially when other medical options are very limited and known drugs or medical methods are otherwise too expensive for the patient to afford. In this situation, simply to rely on the legal requirement of the "written consent" of the patient is to make a mockery of the spirit of the law. If in addition to this, the patent is illiterate or insufficiently educated, or is given the relevant information in a way which is barely comprehensible, the ethical issue becomes even starker. But of course, it is precisely these conditions which make testing in Indian conditions cheaper and therefore more profitable for the companies concerned, which in turn is pushing the current relocation of such clinical trials. It works much in the same way as Lawrence Summers had once called (in an internal memo in the World Bank) for encouraging the export of "polluting" industries to the developing world, on the grounds that the costs of pollution were lower in such countries. At another level, of course, this means that the Indian economy may have one more booming service sector export to rely on in the near future : one based on the poverty and vulnerability of the greater part of its population, and on the willingness of the system to place corporate gain over social good even in the basic area of human health.



© MACROSCAN 2000