Abstract
This article tries to lay out these inter-sectional linkages through the means of recent advocacy initiatives against the unethical conduct of trials on marginalised communities along with the broader scope of regulation of the biomedical research industry in India. A special case can also be made for legal clinics for students seeking to explore the intersectionality between law and ethics in the field of biomedical research in India. This is particularly important given the dynamic pace and scope of the industry that creates complex legal and ethical issues, questions and controversies, which often seem to fall through the gaps.
Introduction
Medical research is shaped by a variety of social, political and economic interests. These interests affect, amongst other things, the type of research that gets done, who does it and whether the results are made public. As the world of medical research becomes increasingly globalised, several pharmaceutical companies have started outsourcing drug trials to Contract Research Organisations (CROs) in developing countries which now make up a ‘specialised global industry’ in the recruitment of and research on human participants (Petryna, 2005: 183). In India, trials are increasingly being conducted on foreseeably vulnerable populations, with profits as the bottom line. Exploiting opportunities rather than public health priorities appear to drive this industry. Drug companies’ apparent easy access to such populations raises serious questions about the unequal social contexts in which research is being performed and about how conditions of inequality are at present facilitating a global proliferation of drug trials. These developments reflect high levels of corporate involvement in research and have not only ethical implications for both medical research and practice but also raise relatively newer questions around the conduct of such biomedical research in marginalised or vulnerable populations, particularly in the context of International and National Laws on Human Rights.
It is this disillusionment in the existing system, given the failure of medical councils and other professional bodies to ensure ethical behaviour, that gave birth to the bioethics movement in the country. The movement, although still at a nascent stage in India, has been attempting to expand the traditional boundaries set by the physician–patient relationship and the practice of high-tech medicine in the developed world, towards establishing an ethic that is more responsive to the vagaries of the research industry in the country as well as towards the many public health crises it seeks to address. In this endeavour, multi-dimensional efforts are also on to amalgamate this philosophy into education curricula and to set up formal training courses and workshops for young researchers and scientists, in collaboration with institutions such as the Indian Council of Medical Research (ICMR), now offering post-graduate diplomas in bioethics. A special case can also be made for legal clinics for students seeking to explore the intersectionality between law and ethics in the field of biomedical research in India. This is particularly important given the dynamic pace and scope of the industry that creates complex legal and ethical issues, questions and controversies which often seem to fall between the cracks. This article tries to lay out these inter-sectional linkages through the means of recent advocacy initiatives against the unethical conduct of trials on marginalised communities along with the broader scope of regulation of the biomedical research industry in India. As is further illustrated through the course of this article, there is an urgent need to set out parameters and define a certain direction which regulation of medical research in the country should take, given the existing scenarios of increasing globalisation in the field, albeit with little harmonisation of international guidelines.
Taking on Industrial Proportions—Drug Trials in India
India, with its huge ‘treatment naïve’ patient base, low cost advantage, completion of clinical trials on time, improving infrastructure and strong support from the state, is witnessing an unprecedented growth in its drug trial markets (see Figure 1). Many major pharmaceuticals and Contract Research Organisations 1 have started conducting their clinical trials in India. With state patronisation, ‘improving’ infrastructure, industry friendly regulation and trained workforce, the growth is projected to increase by leaps and bounds (RNCOS, 2007). According to a report by the Associated Chambers of Commerce and Industry, India was set to grab clinical trials business valued at approximately US$ 1 billion by 2010, up from US$ 200 million in 2007 (Chatterjee, 2008). Most pharmaceutical companies conduct trials through Contract Research Organisations (CROs). Its market in India has grown from ₹ 4,230 million in 2005 to ₹ 16,110 million in 2010, while, it is expected to cross ₹ 27,210 million by 2012 (Paliwal, 2011). An industry report predicts that India by 2011 will be conducting more than 15 per cent of the total global clinical trials (RNCOS, 2007). In October 2008, the Drugs Controller General India (DCGI) stated that there were 582 (registered) clinical trials being conducted in India, of which 72 per cent were carried out by the pharmaceutical industry (Srinivasan, 2009).
Major Stakeholders
At the core of the industry are the pharmaceutical companies, whose products are tested through these clinical trials. Particularly striking in this regard are the interests of the Indian pharmaceutical companies that are in the process of retooling their business models in the wake of India signing on to the patent regime imposed by the World Trade Organisation (WTO).
A close second are members of the Contract Research Organisations (CRO) industry, estimated by the Chemical Pharmaceutical Generic Association to be worth between $100 and $120 million in 2005, while growing at 20 to 25 per cent per year (Greene, 2007: 12). These are the most immediate beneficiaries of trials coming to India, and are therefore keen to create conditions for these trials to grow in a sustained and streamlined fashion. Another sub-set in this category would be the physicians who actually conduct the trials, though in the Indian context, they have a relatively marginal presence compared to the CROs in setting the infrastructural and regulatory agenda for research.
A third set of actors consists of the regulatory agents of the state. The Drug Controller General of India (DCGI) and the Ministry of Science and Technology are actively involved through its Department of Biotechnology which looks at clinical research as part of a wider initiative to make India a global biotechnology power.
Thus, while there are convincing market rationales for taking trials to India and an already strong flow of trials through the multinational CRO industry, much of the efforts towards the capacity-building of the industry are still targeted with a profit motive and to encourage further outsourcing of such trials in the future. In this effort, ethics legally enshrined and contractually enforced are integral to the capacity–building efforts around clinical research in India. Not surprisingly, members of the CRO industry are the most active drivers in building ethical regulatory infrastructure. However, the form this ethic takes in no way takes into consideration the structural violence and human rights violations that occur during trials (See Figure 2).
Existing Regulatory Mechanisms in India
Over the last two decade, along with the drive for liberalisation, several debates have emerged over the conduct of clinical trials by CROs, research institutions, pharmaceutical industries, international health NGOs and by the State. The office of the Drug Controller General of India (DCGI) and the Central Drugs Standards Control Organisation (CDSCO) under the Ministry of Health and Family Welfare (MoHFW) are responsible for the regulation of clinical trials in the country. Clinical trials and their regulation, unlike health however, come under the concurrent list.
Schedule Y of the Drugs and Cosmetics Act, 1945
A first in this regard was the incorporation of the Schedule Y in the Drugs and Cosmetics Act 1945. The enforcement that came into existence in 1988 was, at that time, essentially for provision of support specifically designed in such a way so as to further promote the upscaling of indigenous generic pharmaceutical companies through basic guidelines on research. However, with the entry of large pharmaceutical companies along with the several multinationals in field of biomedical research, the existing provision underwent a second amendment in the year 1995, leading to a revised document in line with the ICH-GCP (International Council of Harmonisation Guidelines for Good Clinical Practice). 2 However, the most recent amendment to the Schedule Y, made in the year 2005, has only served to further the interests of the markets and to protect a growing industry that is clearly driven by profits rather than the well-being of the trial participants or public health priorities. This gives rise to what may be seen as an ambiguous and practically ineffective latent regulatory tool (see Figure 3).
Ethical Guidelines for Biomedical Research on Human Participants
The Ethical Guidelines for Biomedical Research on Human Participants first drafted in 1980, formulated by the Indian Council of Medical Research, 3 loosely based on the Declaration of Helsinki, 4 was the first document of its kind, published in 2000, to be devoted solely to prescription of different notions of regulation in this regard. These guidelines, further modified in 2006 along with the guidelines on Good Clinical Practice, have been considered the hallmark in the endeavour to regulate biomedical research in the country. However, the lack of legislative powers has been a major drawback in the proper implementation of these guidelines. A draft bill to make the guidelines legally binding is pending with the Ministry of Health. The law is meant to provide for the setting up of a ‘Biomedical Research Authority’ to oversee research in the country and also to evaluate the functioning of ethics committees.
Registration of Clinical Trials
In an attempt to further transparency and accountability of clinical research, internal validity of clinical trials and to facilitate the oversight of ethical conduct of trials, the ICMR has initiated a process to provide an online facility for the registration of any form of interventional trial. The Clinical Trial Registry of India (CTRI) is this online registry. The registry that began as a voluntary provision has since then been made mandatory by the DCGI for all trials since 15 June, 2009. Any researcher who plans to conduct a trial involving human participants, of any intervention such as drugs, surgical procedures, preventive measures, lifestyle modifications, devices, educational or behavioural treatment, rehabilitation strategies as well as trials being conducted in the purview of the Department of AYUSH have to register the trial in the CTRI before enrolment of the first participant (CTRI, 2010). However, several other research studies continue to go unregistered as ‘observation studies’, ‘operations research’, ‘demonstration projects’ and so on, including several others conducted at private sites by CROs.
Issues of Governance: Where Laws are Treated as Guidelines, and Guidelines are Not Laws
There are many examples of clinical trials that have taken place without proper protocols of consent. Currently, without any independent institutions for monitoring and auditing of drug trials, the infrastructure for regulation, ethics review and monitoring is insufficient. There have been many instances where ethics committees are controlled by the research organisations and cannot act independently. An ICMR survey found that only 40 of 179 institutional ethical committees follow the prescribed legal provisions and function according to various ethical guidelines (Mudur, 2005). Moreover as a study by Srinivasan (2009: 7) shows, ‘there is no central register of EC decisions, and if a protocol is rejected by one local EC it may be submitted elsewhere. The sponsor is not obliged to inform an EC—or the DCGI—if the protocol being submitted to it has been rejected elsewhere’. Similarly, the lack of co-ordination between the various ethics committees in a multi-centric trial raises serious concerns of an absence of rigorous approval processes.
In the absence of such a mechanism, it is difficult to ensure that scientific standards are upheld, and that good research practices and required trial protocols are fulfilled. Moreover, claims that clinical trial protocols and data are protected pose a serious threat to the tenets of transparency and hence accountability in clinical trials in India. Similarly, lack of any form of regulatory control over the mushrooming CRO industry too has raised several pertinent concerns. Further, several concerns have been raised regarding the lack of human resources at DCGI which are consequently not equipped to monitor existing clinical trials in India. The DCGI’s office currently has a staff of four or five professionally qualified people and at present does not inspect clinical trial sites though the government has announced that it is recruiting new staff for this purpose. Audits of clinical trial data are at present only conducted by contract research organisations and sponsors. The United States Food and Drug Administration (USFDA) have recently started auditing trial sites (Srinivasan, 2009).
Recent Experiences of Unethical Conduct of Clinical Trials
HPV Vaccine Trials—‘Minor’ Deficiencies, Lessons for the Future
The recent clinical trials of the Human Papilloma Virus (HPV) vaccine in India illustrate how shifts in the very science of drug development have influenced the nature of participant recruitment in the country. These trials also exemplify how far removed India’s research priorities are with respect to the community’s needs and interests and the country’s public health priority.
In mid-2009, the Indian unit of the US-based Programme for Appropriate Technology in Health (PATH) began a two-year HPV vaccination drive in India, ambiguously termed a ‘demonstration project’. In collaboration with the Indian Council of Medical Research, two state governments and with support from the Bill and Melinda Gates Foundation, over 23,000 girls were given the vaccines Gardasil (by Merck Sharpe and Dohme) and Cervarix (by GlaxoSmithKline) in the southern state of Andhra Pradesh and the western state of Gujarat respectively (Sarojini et al., 2011).
Public health groups, health networks, women’s groups and human rights groups in the country voiced their concerns regarding the unethical promotion of the vaccines in the private and the public sectors; the public health implications of their administration; the lack of transparency surrounding the trials; ambiguity in nomenclature; and the need to account for reported deaths and adverse events post vaccination. Subsequently, a fact finding visit to Bhadrachalam in Khammam district, one of the trial sites in Andhra Pradesh, reported serious breaches in medical ethics of the study. Young girls selected for participation here were from poor and disadvantaged social groups—scheduled tribes, scheduled castes, Muslims and other backward communities. The majority were ethnically tribal and children of agricultural labourers. It became evident that for a population that was particularly vulnerable, adequate information was not provided, appropriate consent or assent was not gathered and no provisions for follow-up care were established (Sarojini et al., 2010).
On 7 April 2010, the government called a halt to all HPV vaccine trials in the country, after a strong campaign by civil society groups and opposition by a Member of Parliament (Dhar, 2010). However, a report from the committee set up by the Ministry of Health and Family Welfare to investigate into the ‘alleged irregularities’ of the project while identifying and verifying reports of several deficiencies in the planning and implementation of the project, consequently failed to impose any liability on any individual or organisation responsible. Instead, a case was made by the committee that these ‘minor’ deficiencies serve as lessons for strengthening clinical research in the future (Sarojini et al., 2011). Moreover, issues of transparency continue to shroud these trials with the attempt to keep the committee’s report and its damning observations away from the public domain.
Unethical Trials at the Bhopal Memorial Hospital and Research Centre (BMHRC)
BMHRC, started in the year 2000, following a directive from the Supreme Court of India, to provide ‘advanced tertiary level super-speciality care to the victims of the Bhopal gas tragedy’ in 1984, has instead become a hotspot for pharma-sponsored clinical trials recruiting a foreseeably vulnerable population of survivors of the disaster as participants (Pandeya, 2010). The drugs tested in these trials included New Chemical Entities (NCEs) or investigational new drugs not approved for human use anywhere and spanning across a large canvas of disorders (MIMS, 2010). From 2004 to 2008, the BMHRC was engaged in ten different drug trials involving several international pharmaceutical companies. Trials were conducted on 279 patients, of which 215 were ‘gas patients’. In response to an RTI inquiry, the hospital stated that 80 per cent of the trial participants were ‘free patients’, that is, those entitled to free services at the hospital, in other words, gas victims (Sama, 2011).
These trials included studies on the effects of the antibiotic televancin, tigecycline, which minimises antibiotic resistance, prasugrel, a drug for cardio-vascular disorders, fondaparinux, which prevents blood clots and a combination of the antibiotic cefoperazone and sulbactum, a chemical salt (MIMS, 2011). Cefoperazone, for instance, is no longer marketed anywhere, while the fixed dose combination was denied approval in the US. Similarly, the telavancin trial was testing the drug for hospital-acquired pneumonia (HAP), an indication for which it had not received approval elsewhere. In fact in the US, the drug is approved for use only in indicating skin infections, while the approval for use in HAP is still pending. In a period of four years (2004–2008) clinical trials were conducted on 151 patents in four departments—cardiology, gastroenterology, pulmonary medicine and anaesthesia (Pandeya, 2010).
Apart for the apparent illegality of the conduct of these trials on a population with reduced autonomy and with unapproved drugs, several questions have been raised regarding the nature of consent taken during the studies, post-trial access and compensation for those suffering from side-effects and for families of the deceased. Moreover, as with the HPV trials, here too the lack of transparency was glaring and the lack of accountability only too visible. Despite repeated requests, the hospital has failed to produce copies of prior approvals from the DCGI that are mandatory for all trials involving human beings and which legally should be in the public domain. Although these trials have since been suspended and an investigation is in process, neither the Centre, medical professionals nor the pharmaceutical companies in question have been held accountable.
Without adequate and necessary regulatory jurisdiction or systematic review, the reliability and validity of medical research is jeopardised. Considerations of transparency and protection of participant rights have to be made a priority for policy that truly engages and respects the public. This is particularly critical in the context of drug and vaccine trials, placebo-controlled trials and genetic studies that are often in violation of both the Declaration of Helsinki, as well as the guiding principles laid down in the ICMR’s ethical guidelines for biomedical research. India requires more substantial regulation and effective implementation that can institutionalise the highest standards of independent inquiry, good clinical practice, protocols, monitoring and follow up so that a strong and science-friendly policy framework can be put in place to enable and empower medical research.
Intervention Strategies—Lessons and Challenges: A Case for Legal Clinics on Health, Ethics and Human Rights
In the Indian context, clinical trials have become a burgeoning industry with globalisation. But without adequate legislation and accompanying implementation, the opportunity to connect science with exemplary research practice and meaningful public engagement stands to be lost. In its capacity as a public enterprise, science makes an invaluable contribution to the lives of the people. This contribution is also an obligation. Within the given context, there is an earnest need for a multi-dimensional engagement to ensure that the rights of participants of research are upheld at all times, particularly in the case of marginalised populations and not only of the burgeoning industry and its players. A formal training on bioethics as a part of medical as well as legal education curricula is an extremely important step in this regard. Health, bioethics and the women’s movement have been working on this front through multi-faceted intervention strategies and advocacy initiatives.
It is these very strategies that also make a strong case for legal clinics in regulation and ethics, for not just law students but also medical professionals and those interested in research on human participants.
Use of Legal Instruments—Right to Information Act, 2005
India’s fledgling Right to Information Act, drafted to provide a platform for citizens to access information under the control of various public authorities and to promote transparency and accountability in the public bodies, also plays an important role in the field of research, particularly with regard to the approval procedures, funding and acquiescence to the law with regard to the actual conduct of the trial. The Act casts an important obligation on public authorities to facilitate citizens in accessing information held under their control.
Ground Realities—Fact Findings and Community based Research and Dissemination
Maintaining a constant touch with the ground realities and the communities involved is of prime importance to the success of any advocacy initiative. In the case of large-scale violations, it is vital to get first hand information and an accurate report of the situation at hand. For instance, in the case of the HPV vaccine trials, members from the advocacy groups themselves travelled to Bhadrachalam block, one of the research sites in Khammam district in Andhra Pradesh. While there, the team spoke to teachers, girls who had received the vaccine, parents of the girls who had died post vaccination and local activist organisations, to examine the extent of violations. Documentation of these visits also played a critical role in monitoring and highlighting the accountability of the state and other institutions.
Engagement with Policy-makers and Parliamentarians
While building a collective consciousness around issues such as these it is extremely important to engage with policy-makers and parliamentarians to share the concerns and lobby for political and legislative changes. This kind of initiative can be of a varied nature and take on different forms, ranging from presenting petitions and memorandums; organising for public meetings; meetings with the individuals/institutions on the issue; making the most of available spaces and opportunities to push for greater change, for example, giving recommendations on regulation of clinical trials to the working group on drugs appointed by the Planning Commission for the 12th Five Year Plan processes. Similarly, processes should also be undertaken to sensitise state officials and parliamentarians on such issues.
The Role of Legal Clinics
Civil Society Organisations, People’s Health Movements, Women’s Movement and Students have contributed significantly to bring about social change. Given the present context, such collaborative actions are presenting themselves as essential tools to combat larger global forces and safeguard the interests of vulnerable groups and communities. Students can play a critical role as they bring in new ideas, enthusiasm and energy to the movements and it is in this way that legal clinics with organisations working on issues of social justice and rights can create a two-way learning process. The initiatives taken by students in their own contexts or as part of larger movements have immense potential to carry ongoing advocacy initiatives forward. It is towards this goal that legal clinics play an extremely important role in creating awareness and empowering students. These clinics could include interning with organisations working on issues of ethics and regulations. Further, students could also partake in the organisation and participate in the National Bio-ethics Conference that is held once every two years to familiarise themselves with ongoing debates and discussions in the area as well as to develop a sense of the direction in which ethical discourse is headed in the country.
Footnotes
Acknowledgements
The author would like to acknowledge Sarojini, N. for her critical inputs and support.