Newsletter Sept - Dec 2005

In a liberalised economy, medical research is increasingly being carried out by private institutions – non-governmental organisations (NGOs), pharmaceutical companies, private colleges and independent research institutions. With the gains translating directly into huge profits, as in the case of contraceptive research, assisted reproduction, or the Human Genome Project, the need to understand the implications of such research cannot be overstated. While not arguing for increased statism and bureaucratic control, creative and effective ways of checking the ‘free-for-all’ are vital. As our experience with various contraceptive technologies has shown, monitoring by independent bodies is all the more crucial, because issues relating to medical ethics, accountability and monitoring the quality of the clinical research far from being academic subjects, have direct implications for women's health, safety and well-being.


Liberalisation of Health Services in Action 


The Case of Depo Provera


The introduction of the injectable contraceptive Depo Provera (brand name of Depot-medroxyprogesterone acetate or DMPA) into India is representative of several aspects of the impact of privatisation on women’s health. In 1994, Depo Provera was approved for private marketing in the country despite the fact that it had not gone through all the mandatory phases of clinical trial in India. At the time, a case filed by Stree Shakti Sanghatana, Saheli and other women’s groups raising questions about the safety of Net En, another injectable contraceptive (similar in action to Depo Provera) was still pending in the Supreme Court. The Drugs Controller General of India (DGCI), while justifying the introduction of Depo Provera in the name of a liberalised economy, however gave marketing approval on condition that the manufacturers conduct a post marketing surveillance (PMS).


The PMS sponsored by Pharmacia-Upjohn, the manufacturers of Depo-Provera, is illustrative of the adverse impact on women’s health of privately sponsored research. PMS conducted by the pharmaceutical company which directly stands to profit from the results of the research, raises serious doubts regarding "scientific objectivity" of the data collected and its analysis. A concern of most health groups that was well borne out by the nature and findings of the 'study'.


The PMS study on Depo Provera also flouts international guidelines for ethical medical research. The use of lactating women as study subjects is a violation of the Code of the Council for International Organisations of Medical Sciences (CIOMS). Further, the administration of Depo-Provera during lactation could have a serious adverse effect on the health of breast-feeding women because of the association with demineralisation of the bones.


Despite its problematic entry on the Indian scene, Depo Provera is now available in the market, easily procured over the counter. A recent study by Sama, a Delhi-based health group, revealed that Depo Provera was also being prescribed in government hospitals in Delhi. Lack of informed consent and side-effects of the drug were points repeatedly raised by the women interviewed. The study revealed that 42 out of 50 women were not given any information about the side effects, and 48 out of 52 women reported problems after using the injectable and each woman had multiple problems (Sama, 2002). With such a situation in a public hospital, the state of affairs in private establishments can be well imagined.


While the Depo saga relates to spacing methods of contraception, another well known case of private bodies carrying out research and contraceptive outreach is that of quinacrine – a permanent of method of sterilisation.


The Quinacrine Story


Around 1996-97, it came to light that doctors, unregistered medical practitioners and NGOs in West Bengal, Karnataka, Uttar Pradesh, Gujarat, Delhi and Chandigarh for more than 20 years had been using quinacrine, an anti-malarial drug, to sterilise poor and illiterate slum and rural women. Quinacrine is a sclerosing agent, which burns the uterine tissues causing inflammation and the formation of scabs in the uterine lining. The scar tissues block the inner end of the fallopian tubes and prevent the sperm from reaching the ovum. 


Qunicacrine sterilisation (QS) has several short term side-effects such as are severe abdominal pain and cramps, fever, yellow pungent smelling discharge, lower back pain, nausea, headaches and itching. More disturbing are its long-term risks. Quinacrine is a known mutagen and past laboratory studies have pointed to potential risks of cancer, birth defects and toxicity in the foetus in case of acidental pregnancy or undetected pregnancy. 


Developed in the early 70s by Chilean scientist Jaime Zipper, QS has been actively promoted by Dr Elton Kessel of the International Federation of Family Health (IFFH) and Dr Stephen Mumford of the Center for Research on Population and Security (CRPS), both based in the US. Elton Kessel and Mumford first collaborated on Quinacrine trials through the International Fertility Research Program (IFRP), Research Triangle Park, North Carolina, USA, an institution of which Kessel was the founder member. The IFRP has subsequently been renamed the Family Health International (FHI), which describes itself as a non-profit US based organisation dedicated to contraceptive development, family planning and reproductive health and AIDS prevention around the world. Through the FHI, Kessel and his colleagues made two attempts to get the approval of the USFDA on Quinacrine sterilisations, but failed. Kessel, Mumford and their colleagues literally traverse the globe with Quinacrine pellets in their suitcases, urging gynaecologists at meetings and conferences to try Quinacrine sterilisation.  Actual figures of QS are hard to determine because the practice is unregulated and the doctors promoting the method are mainly private doctors and unregistered rural practitioners.


Following an intense campaign by women’s groups in several parts of the country, the DGCI in December 1997 banned the use of quinacrine for female sterilisation. To add weight to the prohibition, the Supreme Court, on 16th March 1998, in response to a petition filed by AIDWA and faculty of the Centre for Social Medicine and Community Health, JNU, passed an order upholding the ban on QS. While the Court did uphold the ban, and directed a official gazette notification, it refused to direct the prosecution of the guilty with retrospective effect. It is only future violations which are punishable. Implementation of the ban has been left to the State Governments.


In India, despite the ban the use of QS has been reported in some pockets of West Bengal (no information on other parts of the country). The practice has only gone ‘underground’ and the price for QS gone up. Quinacrine pellets for QS are still being distributed among others by one of its staunchest advocates in Calcutta, Dr Biral Mullick. From his centre in Kolkata, he also mails to doctors in India QS Newsletters published in the US by the global promoters of QS.  Recently, the Calcutta-based National Association for Reproductive and Child Health of India  (NARCHI) petitioned the DGCI to rescind the ban. To persuade the DGCI decision, NARCHI sent with the appeal news clips of QS trials in countries like the USA, Chile and China.


Ethics of Industry-Sponsored Research


The shift from ‘neutral’ bodies conducting research to research by bodies that have a stake in the outcome of the research has deep implications. Post Marketing Surveillance by pharmaceutical companies in lieu of Phase IV clinical trials conducted by impartial scientific bodies is another outcome of the liberalised economy. These trends are directly related to the phenomenon of the market, where profit is the king. It must not be forgotten that India is one of the largest markets for contraceptives in the world. With almost 40 million potential users the Indian contraceptive market is larger than the entire population of Switzerland, Norway, Sweden, and Australia put together. Little wonder that multinational pharmaceutical companies have been consistently wooing this market with aggressive propaganda.Industry-sponsored research has given rise to a gamut of issues which need to be addressed on a priority basis. When “efficiency-based” standards, and supremacy of “local standards”, which are lower than international standards prevail, there is cause for serious alarm (as in HIV drug trials in Africa). Many investigators have argued for dual standards. They claim that there should be different ethical standards for developing and developed countries [Lancet 1998, quoted by Singh and Mulay, 2000]. There is considerable opposition to this from the scientific community as well; for example inclusion of placebo groups in testing of a variety of treatment regimens with AZT for prevention of HIV transmission to infants by women with AIDS in Africa has been challenged [Lurie and Wolfe 1997, quoted by Singh and Mulay, 2000]. The marketeers of Depo Provera and the proponents of QS have also made similar arguments and argued that the actual living conditions in the country and issues like high maternal mortality should be taken into account when considering ethical guidelines, and Western standards of safety and risks should not be applied.


At the international level, moves to amend standard international ethical codes are a cause for serious concern for all those engaged in matters of medical ethics and their implications for the health of people. The pressures to modify the Helsinki Declaration in the recent past were in part an effort to make clinical research easier in developing countries. The first change sought was to permit “proxy consent” that would eliminate the need for individual informed consent by obtaining permission from a governmental or non-governmental body in a position of authority. The second change sought to stipulate that the standard of care to be provided to people enrolled in clinical trials need not be ‘the best-proven care’ but rather ‘best care available in the country’.


The implications of such moves are directly seen in the watering down of the provisions for mandatory informed consent in the ‘Ethical Guidelines on Biomedical Research Involving Human Subjects' released by the Indian Council of Medical Research [ICMR] or the ‘ICMR Code’, 2000. Following this prescription, the ICMR Code, in its section on “International Collaboration/Assistance in Bio-Medical/Health research” does not provide adequate safeguards against exploitation of research subjects from a developing country. For instance, by talking about “best possible nationally available care”, the Code allows for by-passing international standards, which will work against research subjects.


Ethical guidelines - Need for Debate


A critique of, and detailed recommendations on, the ICMR Code has been published in earlier Saheli Newsletters. The main areas of concern were: informed consent, contraceptive research, assisted reproductive technologies and post - marketing sueveillance. The recent Guidelines on Assisted Reproduction set out by he ICMR are in the process of being finalised. (See box for critique).


Newer Developments

Some new developments have disturbing implications. Most developing countries have poor regulatory processes to conduct even Phase I and Phase II trials, hence it is cheaper and simpler for interested parties to conduct these trials in developing countries provided the data were acceptable to regulatory agencies in the US or in Europe.   India is poised for a major expansion in the clinical trial business for several reasons. First, it has a well-developed infrastructure. Second, it has highly trained personnel and speciality equipment available at a fraction of what it would cost in a developed country. Third, it has a large population base so that trial subjects can be recruited readily. Finally, it has a relatively lax regulatory process and a government that has committed to implement product patents by the year 2005 under the WTO rules. All these factors make it very attractive for pharmaceutical companies and Clinical Research Organizations  (CROs) to conduct trials in India (D’Mello B, 2000).


For instance, according to The Economist, "India promises to become a world center for testing new medicines" (January 29, 2000, quoted in D’Mello B, 2000). CROs which undertake clinical trials and other services for pharmaceutical companies are beginning to find a location advantage in India. Quintiles, a large CRO based in North Carolina and Covance, a CRO based in New Jersey, have started conducting clinical trials in India and are expanding their operations. Corporations like Nicholas Piramal have begun a new clinical trials business, and Max India has entered into a deal with the Harvard Medical School to conduct clinical trials in India and other underdeveloped countries. According to the same news report, a Covance vice-president (global safety and medical therapeutics) expected "tremendous" return on investing in India's infrastructure for conducting clinical trials.


It is claimed that a large part of the total expenditure of around $500 million that is required to discover and develop a drug is spent on clinical trials. Phase III trials use a number of human subjects. If clinical testing can be done faster and cheaper, the additional returns from an earlier launch may fetch "millions of dollars of extra revenue to the patent's owners".  Clinical trials in India can be cheaper and faster. Moreover, India's billion potential guinea-pigs suffer not just from tropical diseases such as malaria and tuberculosis, but increasingly from ailments such as cancer, heart disease and AIDS, which trouble rich countries. The head of Quintile's India venture, Ferzaan Engineer says that for some diseases research in India can dramatically reduce the time for commercial launch of new therapies.


The shifting of research by for-profit organisations to the Third World must be viewed in the light of these norms – both national and international— of medical research. The ICMR Code merely skims over this issue. “Academic institutions conducting research in alliance with industries/commercial companies require a strong review to probe possible conflicts of interest between scientific responsibilities of researchers and business interests (e.g. ownership or part-ownership of a company developing a new product). While the Code leaves it to institutions to set in motion “self-regulatory processes to monitor, prevent and resolve such conflicts of interests”, it does recommend that prospective participants in research “should also be informed of the sponsorship of the research, so that they can be aware of the potential for conflicts of interest and commercial aspects of the research.”


But in an increasingly corporatised world, such vague guidelines on conflict of interest as stated in the ICMR Code are unlikely to reign in the unethical and irresponsible trends like we have seen as in the cases of Depo Provera, QS and AZT etc.  In fact, before we end, we need to at least outline the plethora of concerns that this unleashes for us.


Corporate Conduct : Accountability is the First Victim

On one hand, health groups have been working for greater safeguards for peoples' health in the context of medical research and clinical trials. But failing such protection, the next natural question is the issue of what recourse a trial subject has for adequate medical attention or compensation for damages during the entire process. Unlike the pre-liberalised scenario where the state could be held responsible for the nature, conduct, results and follow-up of clinical trials on human subjects through its health programmes, we have now entered an era of increased vulnerability of peoples' health. From being a 'trial subject', today a woman buying Depo Provera over the counter or undergoing QS in a private clinic has been turned into a 'consumer' with little recourse for justice in a land where the consumer protection movement is yet to find a footing, the inclusion of medical services under the Consumer Protection Act notwithstanding.


Add to this the issue of accountability in the context of corporate takeovers and the scenario becomes cause for greater concern. As we all know, when Dow Chemical took over Union Carbide Corporation (UCC) in February 2001, it created the largest chemical corporation in the world. With the merger, Dow took on UCC's assets, but has refused to take on its liabilities -- the fallout of the world's worst industrial disaster in Bhopal caused by faulty plant design and gross negligence, which according to survivors' organisations killed more than 2,000 people in the immediate aftermath, and about ten times that number over the following 18 years.


Yet, the Indian government attempted (unsuccessfully) to dilute the original charges of culpable homicide against prime accused Warren Anderson -- Chairman of Union Carbide at the time of the disaster. This development illustrates the concern of the Indian Government that prosecuting Warren Anderson, the head of a transnational corporation would "jeopardise the investment climate". Only sustained pressure from people’s organizations has forced the Madhya Pradesh government to announce that it will approach the Supreme Court in a bid to hold Dow Chemicals accountable (Indian Express, October 20, 2002).


Such corporate takeovers and business alliances, though seemingly far removed from people’s lives, have a far-reaching impact. In 1995, a merger of Sweden's Pharmacia with Upjohn of the US resulted in Pharmacia & Upjohn. One can only wonder what impact the Pfizer take-over of Pharmacia-Upjohn, the manufacturers of Depo Provera, in a stock-for-stock transaction valued at $60 billion, will have on women users of Depo Provera in India. The merger, announced in July 2002 is described as creating “a strategic opportunity that immediately creates a global pharmaceutical company with unsurpassed resources and capabilities”.


Such developments give rise to a plethora of questions. How can industrial giants be made to shoulder the liabilities of companies taken over? What are the resources that affected women can garner to fight pharmaceutical giants like these? And what on the other hand, are the strategies with which women can be enabled to safeguard themselves against NGOs, CROs and other private institutions that also dominate the field?


End Note

Conclusions are not possible in a paper like the present one. But a reiteration of some of the questions raised might help us to find answers. While enunciating good guidelines for ethical conduct of clinical research are essential, they are clearly not enough. The problem is more fundamental. Who will ensure that the priorities of research go beyond generating profit to address issues of public health and safety? Who will ensure that trials are conducted within the ethical guidelines? By what means will unethical investigators be held accountable? Finally, if there is no political will or if national agencies do not have the political clout how can we ensure that they will be able to enforce the guidelines?  


New ethical guidelines, in addition to keeping pace with scientific developments, must prioritise safeguarding the rights, health and well-being of research subjects. Corporate profits cannot be put ahead of individual well-being. The manner in which political ideology permeates medical research makes it imperative to develop a pro-people, pro-woman definition of "overall purpose" of research.


[ This is an adaptation of a paper presented at 'Reaching Beyond Figures: State of Women's Health in Goa,' a workshop organised in November 2002 by the Centre for Women's Studies, Goa University and the Goa State Commission for Women]




ICMR Guidelines on Assisted Reproductive Technologies [ART]


The document 'Ethical guidelines for the Biomedical Research on Human Subjects' released by ICMR in 2000 contained a chapter suggesting guidelines for the practice of Assisted Reproductive Technologies [ART]. the current draft guidelines appear to be an effort to broaden the scope of the earlier guidelines. Although the new guidelines attempt to incorporate some issues related to gendr inequality, they still fall short on many fronts, as detailed below. The ethical  guidelines should go beyond technicalities and build effective safeguards so that the unequal power relationship between the providers of new technology and its users is minimised. The Guidelines should also keep in mind the unequal gender balance, and ensure that the rights of women users of these technologies are not compromised in any manner.


For instance, ethical guidelines should not accept social stigma attached to infertility as a norm. Societies have evolved social ways for childless couples to deal with infertility, for instance, adoption, foster-parenthood, etc. The guidelines, should ideally encourage adoption and foster parenthood, and certainly not make loaded statements such as 'Infetility is a tragic condition. The agony and trauma of subfertility is best felt and described by inferile couples themselves' [ in 'Introduction']. We also take this opportunity to stress the need for prevention of infetility as a public health measure, since the country can ill-afford costly techniques of ART.


Scientific developments such as stem cell research have a direct impact on ART. The ethical dilemmas involved in commercial transfer of embryonic material, stem cells etc are deep, and have yet to be played out in the arena of individual lives, the medical establishment and the market. It is still too early to visualise all the knotty and complex situations that could emerge. However, ethcial guidelines for ART need to be broad and flexible in order to accomodate these future scenarios, but stringent enough to prevent violation of individual rights. The present draft guidelies have rather detailed descriptions of technical procedures and lists of indications for the same, so also discussion on the diagnosis of infertility and complications associated with the procedures, all of which are redundant.


The discussion on technical procedures is relevant only in so far as it poses ethical dilemmas that can be foreseen. Moreover, the guidelines have not been drafted keeping in mind a long-term perspective. Scope should be left in the guidelines to consider introduction of new technologies and the debate ensuing from their potential use. This is also true for anticipating future modifications and advances in diagnostic techniques. For example, Laboratory tests which should be carried out for ensuring  sperms are from a healthy, uninfected donor should include ruling out HIV, HBV, HCV, syphilis and othr known sexually transmitted diseases, but not restrict itself only to these infections.


The field of Assisted Reproduction is a rapidly developing one. Newer techniques, modifications of existing ones and new approaches characterise this specialisation. In this context, particular care needs to be taken to ensure that the rights of women subjects of research as well as consumers of these techniques are articulated. For instance, infertile women, due to their intense desire to conceive are particularly vulnerable to commercial interests. Guidelines for ART muct safeguard their interests.


It is unclear whether the Guidelines for Assisted Reproductive Technologies is proposed to be a part of the "Ethical guidelines for the Biomedical Research on Human Subjects' or the ICMR Code of a stand-alone document. If the former is the case, guidelines covering research-specific issues (foe instance clinical trials) have been dealt with in the ICMR Cod. However, if the current ATR Guidelines are to stand on their own, there is a need to reiterate some safeguards for research subjects. This is particularly Necessary in the commercial context where the manufacturer-researchers themselves stand to gain from results of the trials. It is then incumbent upon neutral bodies to ensure that ethical guidelines are adhered ti and also bring to light any violations. For this, well-formulated guidelines drafted with foresight and a long-term vision are a must.