James Gillray, The Cow Pock (1802)
Library of Congress, Prints & Photographs Division
James Gillray, The Cow Pock (1802) Library of Congress, Prints & Photographs Division

Trials and tribulations

Ethics of clinical trials and vaccine research in India.
James Gillray, The Cow Pock (1802)<br />Library of Congress, Prints &amp; Photographs Division
James Gillray, The Cow Pock (1802)
Library of Congress, Prints & Photographs Division

In January 2005, the Indian Parliament amended the Drugs and Cosmetics Act, 1940, to permit trials of drugs being developed and tested abroad to be tested at the same time and in the same phase in India. The drug development process requires human subjects. Phase I safety trials are usually conducted on a small number of healthy people. Phase II trials are conducted on patients to evaluate the drug's effectiveness. Phase III trials are conducted on a larger number of people to confirm the evidence from earlier phase trials towards obtaining marketing approval of the drug. After a drug obtains marketing approval, phase IV trials are conducted to monitor for side effects that become evident only when the drug is used by a large number of people. Until 2005, Indian regulators required that international trials in India could be conducted only with a phase lag – phase II trials could be conducted in India only after the phase III trial had been conducted abroad, and phase I trials of foreign drugs were generally not permitted. The amendment in the Act brought multinational pharmaceutical companies and contract research organisations to the country in droves.

As a result, for more than a decade now, India has been the site of drug trials outsourced from companies based in the US and Europe, which now operate research sites in metropolitan cities as well as small towns. By 30 June 2010, 1078 clinical trials were registered in the Clinical Trials Registry-India (CTRI), of which 666 were for drugs, most of these for private pharmaceutical companies.

Contract-research organisations (CROs) are commercial entities that, among other things, conduct and support services such as clinical trials for pharmaceutical and biotechnology industries on a contract basis. India has seen a sharp rise in these organisations since the early 2000s. According to one CRO, Clinexa Life Sciences:

India holds almost 16% of the world population with a large and diverse patient pool in almost every therapeutic area with most of the populations tolerant to pharmacogenomic sampling. India also has different regions with conserved population gene pools. This gives India an added advantage in clinical research apart from the direct economic benefits.

Quintiles India, another CRO, has the same pitch: it has "solid relationships with leading medical centers and experienced English-speaking investigators". Offering up the Indian population for drug research, it adds, "urban India's literate population provides fast, efficient access to broad population groups with common and special disease profiles, allowing for rapid patient recruitment and faster study start-ups." It proudly declares that it produces fast results because of "innovative study strategies" and "regulatory staff who have built credibility with Indian investigators and regulatory authorities." It promises access to electronic health records through links with international databases and "streamlined study execution and patient recruitment through improved physician and patient targeting". Electronic health records are confidential documents, access to which is limited to healthcare providers and the patient, so the access of CROs' to this is very likely in violation of the approved use of such databases.

For its part, the government too has touted the benefits to these foreign drug companies citing the availability of trained human resources and infrastructure, and claiming that such work can get done faster and more cheaply in India. In 2003, a committee chaired by Raghunath Mashelkar, director  general of the Council for Scientific and Industrial Research, sounded not too different from the CROs: "India's highly skilled medical fraternity, many world-class medical institutions and a large treatment-naive population has given a hope that India's potential as a global hub for clinical research can be reached sooner rather than later. Cost competitiveness will enable Indian industries and research institutions to contribute to global drug development in a significant way since the technology infrastructure required to support clinical trials will surely give a India definite advantage over other countries."

This is good advertising, since the agenda of outsourcing companies is to test drugs in various stages of development in an environment which brings together healthcare infrastructure, fast recruitment rates and lower costs. In addition, the clinical trial industry in India has been given various tax breaks on the argument that it is a source of revenue for the country. Some people in the industry have even argued that Indians are morally obliged to participate in trials if they want access to new drugs approved through these trials.

Few people outside the pharmaceutical and clinical trial industries have had any such illusions. If there are major innovative drugs being tested here, they are unlikely to become available at affordable prices. The changes in the Drugs and Cosmetics Act were in line with the 2005 amendments in the 1970 Indian Patent Act, which now recognises product patents. Until 2005, under the Patent Act, patents could be obtained only on the manufacturing process, but not the product itself. The pharmaceutical industry in India was thus able to manufacture drugs through reverse engineering of the original drug, and provide life-saving medicines at prices a fraction of those charged by multinational companies. However, according to Amit Sengupta, national co-convenor of the Jan Swasthya Abhiyan or the People's Health Movement, "Most new drugs marketed after 2005 are being sold by multinational corporations at exorbitant prices that are well beyond the reach of most Indian patients." Although the amended patent law contains provisions for the government to permit local manufacture of essential drugs under patent, or their import at lower prices, this provision has rarely been used. Cancer drugs are a good example of how expensive life-saving drugs are under the new patent act, even if they are tested in India, as was lapatinib, a drug for advanced breast cancer, which was tested on women with terminal breast cancer.

From the very beginning, activists have been warning of the dangers of offering up the bodies of India's poor for experimentation. Affordable healthcare is a mirage for most Indians. Sengupta notes, "The public health sector in India is in a state of neglect and large sections of the population depend on a poorly regulated private sector increasingly dominated by big hospitals, which have an infamous track record of unethical practices". More than 80 percent of outpatient care, and 60 percent of inpatient care, is offered by the private sector. These are not regulated for quality, cost or ethical practice. Private insurance is available at high premiums and only for certain types of inpatient care. So most Indians, whatever their economic status, must pay for health services out of their pockets. Medical expenses continue to be a major reason for people going into debt.

Within this context, people do turn to drug trials in the hope that they will get treatment of some kind. Some are encouraged by trusted doctors, who reinforce the misconception that participation in drug trials would actually benefit them. This was confirmed in a survey conducted by a CRO Excel Life Sciences in 2008 of people enrolled in its trials – 97 percent of the patients entered clinical trials on the advice of their primary care physician; 21 percent said their physician was the principal investigator of the trial. Twenty six percent stated they were looking for free care, or higher quality of care.

Due to lax regulatory standards, permission is sometimes granted to research that would not be approved in the US or Europe. For example, placebo-controlled trials of drugs for serious psychiatric conditions have sometimes withheld effective treatment from the control group of patients. A placebo-controlled trial is one in which a group of participants in the 'experimental arm' is given the drug. This is compared to the group of participants in the 'control arm' in which they are given a placebo or a sugar pill. Ethical guidelines for human research, by both the Indian Council of Medical Research and the World Medical Association, state that experimental drugs must normally be tested against other effective drugs. If an effective drug for a condition exists, a placebo may not be used unless it is methodologically essential. Further, its use should not cause serious or irreversible harm to the trial participant. The US Food and Drugs Administration requires placebo-controlled trials for marketing approval but generally balks at conducting the more risky of such trials in their own territories; the European regulatory authorities do the same. In fact, in 2006-2007, India was one of the sites of a placebo-controlled trial conducted by Quintiles of the drug quetiapine (marketed by Astra Zeneca) to prevent relapse of schizophrenia.

How many of these trials were of drugs most needed in India? And of those relevant, life-saving drugs that were approved on the basis of testing in India, how many were made available at affordable rates to Indians? What was the composition of the ethics committees that reviewed these trials to protect research subjects from harm, and how did they function? Who were they accountable to? And what happened when a participant was harmed or died in a trial?

Research runs riot

The public was made aware of these issues as journalists and advocacy organisations unearthed evidence of deaths in clinical trials – such as in December 2008 when a young man died in a blood pressure drug trial, or when an infant with a cardiac condition died in January 2009 after being entered into a pneumonia vaccine trial that was restricted to healthy infants. Meanwhile, doctors were getting incentives to recruit their own patients into trials. Charitable hospitals were making money testing new drugs on unsuspecting patients. Between 2004 and 2008, the Bhopal Memorial Hospital & Research Centre, which was set up to provide free treatment to survivors of the 1984 gas leak, had conducted drug trials at the behest of foreign pharmaceutical companies. The vast majority of participants were gas survivors, but none of the drugs tested were for conditions specific to gas-affected people. At least 14 participants died. It is perhaps not surprising that a government inquiry on these deaths in Bhopal concluded that though there were a number of violations of regulations, including poor documentation and lack of follow-up, none of the deaths were related to the trials.

The regulators were ill-equipped to handle the rush of outsourced research, and the industry was effectively answerable only to foreign regulators who monitored sites in India to ensure the 'integrity' of the data being generated. The 2012 Parliamentary Standing Committee report confirmed that the entire testing and approval process was tainted, run by industry with the support of a coterie of its own paid 'experts', and the regulators turned a blind eye to patently fabricated documents. The government told the Supreme Court that 3458 people had died, and another 14,320 suffered serious adverse events, in clinical trials between January 2005 and December 2012. These were figures reported by the the companies conducting the trials. However, only 89 of the deaths and 506 of the serious adverse events were attributed to the trials. The method by which this was decided was never explained.

Despite these setbacks, advocacy, lobbying and public interest litigation by health organisations such as the Delhi-based Sama Resource Group for Women and Health and the Indore-based Swasthya Adhikar Manch have contributed to the small but potentially valuable changes in the regulatory systems governing clinical trials. These include monitoring of trial sites, registering ethics committees, and CROs, as well as forming regulations on compensation for trial-related injury. But we are yet to find out how well they will be implemented in the face of industry opposition.

Research for the people, on the people?

The medical testing industry appears to be largely centred on its own profits, with trial participants amounting to not much more than diseases, drugs and data. Even a cursory look at the website of any contract research organisation, pitching to its clientele of multinational drug companies shows this attitude towards trial participants. One might assume things to be different when the trial is for a disease of significance to public health.

On 11 March 2016, Melinda Gates, co-chair of the Bill and Melinda Gates Foundation (BMGF), informed the world that India would introduce an injectable contraceptive into its family-planning programme. "I'm encouraged that the government of India is finally, really coming back to family planning," Gates told a journalist. She also mentioned that she was "glad" that the Indian government was set to introduce the rotavirus vaccine for diarrhoea caused by the viral infection. She was to meet government officials shortly. Apparently the Gates Foundation, a private foundation, has direct access to the Indian government, and has regular meetings at the ministry.

There has been little or no mention following Gates' announcement about the controversy surrounding injectable and other hormone-based contraceptives which now seem to be making an entry into the public health system, partly because of pressure from funders such as BMGF. Research on the injectable contraceptive, spoken about so blithely by Gates, has been opposed by Indian women's rights activists because of safety concerns as well as its potential for abuse. Concerns have been raised about evidence of reduced bone density and increased cancer risk among women using the contraceptive, as well as 'less serious' side effects such as amenorrhoea, excessive bleeding, weakness and pain, all quite serious for poor Indian women among whom anaemia is rampant. As provider-controlled contraceptives, injectables and implants are prone to misuse by a 'family planning' programme with a reputation for coercion in order to control women's reproduction. Depo-Provera, an injectable contraceptive, was approved in India without testing in the country, bypassing regulations. "The American multinational Upjohn (since bought over by Pfizer) thus gained access to one of the largest markets for contraceptives without following requirements," health activists pointed out in a 2005 statement to the then health minister. "Women's groups, health groups and human rights groups have opposed the introduction of injectables given the potential for abuse, non-completion of mandatory trials and the lack of accountability of pharmaceutical agencies."

While India has been the target site for commercially sponsored drug trials, it, like other countries in the Subcontinent, is the site of many dozens of trials whose results are meant to be used over all over the region. They are supported by a partnership of funding organisations and government, non-governmental and private bodies, with the shared aim of developing solutions to the health problems of the poor.

What is the larger agenda within which this research is conceptualised, funded, conducted, reviewed and implemented? Are researchers held accountable to the community in which they work? How is such research related to the type and quality of healthcare that the poor can expect? Will these studies result in better healthcare for Indians? These are questions we need to think about when looking at the public health trials being conducted in this country, and around the Subcontinent.

Research in the name of public health may well be as lucrative as pills for diabetes or hypertension. There are trials on public health interventions being carried out all across the Subcontinent, on the poor, and for solutions to the problems of the poor. For the last two decades, at least, a particular perspective on the role of government in public health is coming to dominate the type of public health research being conducted in India. This in turn is shaping people's access to healthcare.

The rise of philanthrocapitalism

Public sector health services had been taking a knock in India long before the World Bank's 1993 World Development Report 'Investing in Health'. The report primarily articulated as a policy recommendation that the privatisation of the health sector should be extended further and the public sector should limit its involvement in healthcare. Since then, government policy has been geared towards breaking public health services down into a few cost-effective, disease-specific interventions. These interventions often ignore the conditions in which the diseases thrive, as well as those that make people vulnerable to these diseases. For example, health workers might step over open gutters to administer a polio vaccine to malnourished infants who play in faeces-contaminated water, while the polio virus is transmitted through ingestion of water contaminated with human faeces. The healthcare industry seized the opportunities that opened up with this policy using a new financial model – philanthrocapitalism.

Philanthrocapitalism, or the notion that pursuing one's self interest can result in social good, dates back more than a century, notes sociologist Linsey McGoey of this "businesslike approach to charity" in her 2015 book No Such Thing as a Free Lunch: The Gates Foundation and the price of philanthropy. This principle was articulated by the industrialists behind large foundations, such as Andrew Carnegie and John D Rockefeller. The difference, writes McGoey, is that the new philanthropists are explicit that giving is actually profitable to the giver.

The largest of these foundations is the Bill and Melinda Gates Foundation (BMGF), set up in the 1990s, to support research into innovative health solutions for developing countries and their introduction into government programmes. According to their website, it has given away USD 39.6 billion since its inception in the late 1990s. With this money, it has influenced the policies of both international organisations and national governments. The foundation's promotion of a technology-driven approach to all health problems is clearly linked to the interests of the companies which collaborate with it.

BMGF has been a key player in facilitating the health industry's access into public health programmes. In fact, BMGF's board is dominated by the pharmaceutical industry, which benefits from the very projects the foundation promotes. Its strategy is to build alliances between government and non-profit organisations, with grants that give it leverage to influence policy and programmes. This strategy is described on the foundation website: "Because our resources alone are not enough to advance the causes we care about, we engage in advocacy efforts to promote public policies that advance our work, build strategic alliances with governments and the public and private sectors, and foster greater public awareness of urgent global issues." Thus, BMGF supports projects that identify the key technological interventions needed for public health problems and conduct market studies for this intervention. On this basis, it persuades governments to conduct research; or get others to do it for them. It will also help bring the product to the market, persuading governments to 'incentivise' industry in this process, through tax subsidies, commitments to buying the product, as well as grant patents for products developed through public funds. This is, in essence, the 'product development partnership' in which BMGF has invested heavily. A substantial proportion of the department of biotechnology's budget is for public-private partnerships to support private research for the development of innovative health technology, whose patent rests with the private company. In fact, at the centre of this strategy is government support for development of technologies and their patenting by private companies.

For Big Pharma, such alliances represent large new markets with bulk sales through governments, especially when these vaccines are manufactured with incentives for industry, as well as clauses that protect it from losses. BMGF's tentacles reach into every possible relevant organisation, institution and activity, from universities and non-governmental organisations, to national governments and the World Health Organisation. The foundation's influence with the Indian government is such that Bill Gates and his team can walk into the health minister's office to spend an hour and a half discussing the immunisation programme and how they will be involved. UK-based public health researcher David McCoy and his colleagues found that more than a third of BMGF funding up to 2007 was for research and development on technologies, especially vaccines. Then in 2010, Bill Gates committed USD 10 billion on vaccines over the next decade.

The story of how new vaccines are being introduced into India and in the immunisation programme exemplifies how foundations like BMGF leverage their influence in the government and the scientific community to shape research and public health programmes, deciding the research agenda on public health interventions and healthcare for the poor. BMGF is the major funder of the Global Alliance of Vaccines and Immunization (GAVI), an alliance of the vaccine industry, bilateral organisations and governments. The job of GAVI is to identify markets for particular vaccines, raise funds for their research, development and commercialisation, and persuade governments to buy them. In India, GAVI has been responsible for introducing the Hepatitis B vaccine into the Universal Immunization Programme (UIP), a vaccination programme launched by the Indian government in 1985. It is now focused on the pentavalent vaccine, a combination vaccine against diphtheria, pertussis, tetanus, Hepatitis B and Haemophilus influenzae b. A writ petition in the Supreme Court was filed by paediatrician and public health professional, Yogesh Jain, which called for a ban on the pentavalent vaccine, which has been linked with a number of deaths. Many of these vaccines have been introduced despite questions about their safety, efficacy, public health relevance and cost. Critics also note that GAVI subsidises these vaccines for governments initially, but this 'concession' is eventually withdrawn and the government is left with new vaccines in its programme at very high prices.

Dubious practices

Vaccine research was shifting out of the public sector by 1998, specialist Y Madhavi noted in a 2008 review of vaccine technology. These technologies developed in the public sector were transferred to private companies. In 2008, public sector production facilities that supplied the bulk of vaccines for the government programme were shut down and vaccine manufacture for the government programme, too, was taken over by the private companies – at much higher rates. By this time, five of the top six revenue earning vaccine manufacturers in India were private: all having received funding from BMGF and the Indian government's department of biotechnology.

One of these is a vaccine for rotavirus infection, a water-borne disease that kills some 80,000 children in India every year. Little is done to improve access to clean drinking water and sanitation, but research has been conducted into a vaccine against the rotavirus. The Indian company Bharat Biotech developed a rotavirus vaccine with material from a government institution, and funding support from the department of biotechnology and BMGF. The vaccine development process was fast tracked and very soon after Phase III trials of the vaccine were completed in May 2013, it received marketing approval, and was to be introduced in the UIP starting in 2014. The trial researchers who authored a Lancet article reporting the Phase III trial results strongly advocated for its inclusion in the programme even while admitting to its low efficacy and high cost on the argument that the manufacturer was offering a special 'discounted' price – which was more than the cost of all the UIP vaccines put together. Public health advocates have questioned the introduction of this vaccine into the national immunisation programme, despite the low efficacy and despite reports of serious vaccine-related complications. Their request for access to the raw data from the trial has been stonewalled by the researchers. Clearly, research supposedly meant for the public's health is opaque and the public has no voice in determining whether the product should be part of a public health programme.

Cervical cancer, associated with infection by the Human papillomavirus (HPV),kills 73,000 women every year in India alone and can justifiably be described as a public health priority. In developed countries, screening women for pre-cancerous lesions and treatment before they develop into cancer – as part of comprehensive health services – has reduced the incidence and death from this cancer. Inexpensive screening techniques that can be conducted by trained health workers are definitely needed in countries like India.

In recent years, screening has been overshadowed by vaccines against HPV, though the vaccine cannot replace screening. In countries like India, there is a lot of focus on the use of vaccines, though the HPV vaccines available cover only 70 percent of all HPV infections. Questions about the vaccines' safety, efficacy, relevance and costs have been dismissed, as have concerns about the use of a vaccine in order to avoid the obligation to provide comprehensive care. Instead the government collaborated with a BMGF subsidiary, PATH, and the two vaccine manufacturers, Merck Sharpe and Dohme (MSD) and GlaxoSmithKline (GSK), in highly unethical clinical trials disguised as 'demonstration projects' which were also meant to lay the ground for introduction of MSD's and GSK's vaccine in the immunisation programme. These trials, conducted in 2010 on 25,000 girls from marginalised groups in Andhra Pradesh and Gujarat, were funded by BMGF and implemented by PATH along with state health officers, while the vaccines were supplied by the two companies. An investigation led by Sama Resource Group found a number of major violations. Among these: the girls had been administered the vaccines without their parents' informed consent, signatures on the consent forms were forged, and there was no follow-up. The girls were not contacted to monitor for injury or death, investigate its cause, and provide treatment. At least seven girls died before the trials were halted. In the absence of proper monitoring, it was not possible to know whether their deaths were linked to the trial.

A similar disregard for the poor, and a confidence that research may be done any which way, is evident in at least two other BMGF-funded trials on cervical cancer: two of three large trials (the third was funded by the US National Institutes of Health) of visual inspection with acetic acid, or VIA. VIA is a cervical cancer screening method that is cheaper than the standard test, the Pap smear, and can be used by trained health workers; the health worker would apply a few drops of dilute acetic acid on the woman's cervix. This highlights suspect tissue that could be pre-cancerous. If pre-cancerous tissue is identified, this would be followed up with further testing and treatment if needed.

In these three trials, around 375,000 women in slums and villages were used to evaluate how well health workers, auxiliary nurse midwives and nurses could use VIA to detect pre-cancerous cervical lesions in the community. In order to do this, women in the 'experimental arm' of each trial received VIA screening and more than 140,000 women in the 'control arms' received only health education and no screening at all. The idea was to see how many women developed cancer, and died, in each arm, so that the researchers could evaluate the efficacy of VIA. In the control arm, 254 women not screened for cervical cancer died of the disease. This, like the placebo-controlled drug trials mentioned earlier, is a violation of national and international guidelines on the use of a placebo control (in this case a no-screening, or no-testing control). Interestingly, while all these trials tested a cheap technique, the journal articles reporting the findings of these trials all refer to an expensive screening technology, for the presence of HPV infection, as the best test which should eventually be introduced in India. And of course, BMGF has also funded HPV tests.

Studies like the cervical cancer screening trials, or the rotavirus vaccine trials, raise questions on how such research is being formulated and by whom. How is consent obtained in these large trials, and are they monitored to protect participants' rights and health? If participants are injured in this research is this investigated and are they treated and compensated? Finally, who are the true beneficiaries of the products of research? Are they the people who are offered vaccines without the essentials of a healthy life – food, clean water, decent working conditions, housing and healthcare?

The wave of technologies of questionable relevance and safety being researched in public-private 'collaborations' across the region and introduced in government programmes at high costs, suggests that the true beneficiary is the pharmaceutical industry.

~ Sandhya Srinivasan is a Mumbai-based freelance journalist and researcher. She is consulting editor of the Indian Journal of Medical Ethics.

Note: This article has drawn from her 2014 paper, 'Shifts in medical research: influence of private capital' published in India: Social development report 2014: challenges of public health by Oxford University Press

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