Paragraph 10 reads: “Concerns about the ethics of clinical trials do not exist merely in the realm of speculation. The GVK exposés are not unusual. An increasing number of reports are coming to light of unethical and illegal practices that exploit people’s social and economic vulnerability, subject them to serious risks without their knowledge and consent, and do not even assure them of access to the drugs developed from the trials. Certain types of trials depend on paid volunteers who desperately need money. In Gujarat, unemployed diamond workers and migrants from Uttar Pradesh and Bihar get paid between INR 5000 and INR 20,000 to take part in bioequivalence trials – sums large enough for them to put money over personal safety. Indeed, trial participants may be both financially and socially vulnerable. It is reported that Surender, who died in the Hyderabad felodipine trial, was one of a number of Dalit students being recruited for clinical trials in that city. Likewise, some years ago, a 22-year-old Adivasi youth died in a bioequivalence trial of the antidepressant citalopram [Celexa] by the Sun Pharma Advanced Research Centre in Vadodara. ”
Bodies for hire; The outsourcing of clinical trials August 2009
By: Sandhya Srinivasan
Medical testing by Western countries is having a staggering impact on India, if only we were to care to pay attention. And the government’s own policies are encouraging this.
In November 2008, the Hindustan Times’ LiveMint broke the story of an infant in Bangalore having died after being administered a vaccine in a drugs trial. The Drugs Controller-General of India (DCGI), Dr Surinder Singh, halted the testing, reportedly the first time that the office of the DCGI had taken such action. The trial, for a new pneumonia vaccine, was being conducted by a Hyderabad-based contracted research organisation, GVK Biotech, for the US-based multinational Wyeth Pharmaceuticals. The infant had been recruited from St. John’s Medical College, a reputed private medical institution in Bangalore.
GVK’s spokesperson claimed that the vaccine had nothing to do with the death, as the child had received an approved and widely used vaccine – not the experimental product. However, the DCGI’s investigation revealed that the infant had a heart condition, and that the trial had been meant to be conducted only on healthy babies. According to C M Gulhati, editor of the Monthly Index of Medical Specialities, India and a Delhi-based expert on clinical-trial regulations, the investigation revealed a number of other irregularities as well: the informed-consent document had not been signed before the child was recruited; and the St John’s ethics committee had not been properly constituted, as it was not chaired by an external member to ensure independent functioning.
Yet the infant’s death was not an aberration. In December 2008, 25-year-old K Surender, of Hyderabad, died in a ‘bioequivalence’ trial of a blood-pressure drug, felodipine. Bioequivalence trials test generic versions of drugs to ensure that they are as effective as the original, and involve administering the drug and then monitoring the individual through blood tests and other investigations. These tests are conducted on healthy people who are paid for their participation. The Hyderabad trial also happened to be run by GVK Biotech, which subsequently issued a statement that Surender had simultaneously been part of many bioequivalence studies, with GVK as well as other contracted research organisations. This multiple trial participation could have accounted for his death, argued the company.
Such an explanation is unconvincing. If Surender had taken part in many trials, it would only have been for the money, which would amount to an inducement according to national and international ethical guidelines for research – an inducement that might have made him overlook the risks of the trials. And, in any case, why did the company let him take part in the felodipine trial when it was aware that he had taken part in many others? The answer to this question lies in the compulsions of the global pharmaceutical industry. The GVK trials are among the increasing number of international clinical trials that are taking place in India – and the concerns that they raise will come up increasingly frequently in the future. The reports of various government and private bodies put the potential of the clinical-trial industry into billions of dollars, though the method of calculating these numbers is not available. One market-research company, Frost and Sullivan, reportedly estimates a USD two billion turnover by 2010.
The growth of the outsourced clinical-trial industry in India followed changes in the law in January 2005 that encourage clinical research in India. The most important of these was an amendment to the Drugs and Cosmetics Rules, permitting clinical trials in India to be carried out at the same time that they are done in other countries, rather than waiting until the results of drug trials in other countries were made public. Previously, this ‘phase lag’ had ensured that India was of no interest to big pharmaceutical companies to test their drugs. At that time, Phase II trials were permitted in India only after the results of a Phase III trial abroad were declared. And Phase I trials of foreign drugs were simply not permitted. (Phase I or safety trials are done on healthy ‘volunteers’, Phase II trials look at the drug’s safety and effectiveness on patients, and Phase III trials also look at safety and effectiveness, but in large numbers of patients.) It should be noted, though, that an exception was made for drugs deemed of importance to India. While the Drugs and Cosmetics Rules do not specify, such drugs would probably include the HIV vaccine.
This changed in January 2005, and India is now prominently on the radar screen of the international pharmaceutical industry in terms of clinical trials, given its vast population of potential trial subjects. As of today, the bulk of clinical trials are still located in rich countries. To illustrate, as of 19 July 2009, the US government clinical-trial database lists a total of 76,018 trials, of which 44,758 have sites in North America and 17,878 have sites in Europe – accounting for the bulk of trials. In contrast, only 1021 clinical trials have sites in India, in addition to 122 in Pakistan, 61 in Bangladesh and 12 each in Nepal and Sri Lanka.
However, the number of trials in India is growing fast. Figures given by the DCGI’s office show that the number of newly approved trials every year went from 100 in 2005, when the new rules kicked in, to about 500 in 2008. What is of concern here is that many of the trials that come to countries such as India are likely to be those rejected as unethical in Western countries. As trials shift to countries such as India, there has been an international debate on ethical concerns of the outsourcing boom. This debate has been partly responsible for amendments in the World Medical Association’s Declaration of Helsinki, “Ethical Principles for Medical Research Involving Human Subjects” in 1996, 2000 and in October 2008. Drug regulators in Europe and the US require that clinical trials submitted to them adhere to the Declaration.
Some of these changes have dealt with placebos or ‘sugar pills’. The October 2008 revision took a strong stance against the use of a placebo in a trial when a treatment exists. Clinical trials compare the effect of an experimental drug to an existing drug. If there is no drug for the condition, the experimental drug may be compared to a placebo. Using a placebo when a treatment exists deprives the trial participant of effective treatment. The ethical guidelines of the Indian Council of Medical Research and the World Medical Association’s Declaration of Helsinki both forbid the use of a placebo when an effective treatment exists, with certain specific exceptions. While both of these documents have been a bit ambiguous in the past, the 2008 revision of the Helsinki Declaration is clear: placebos can be used only when absolutely methodologically necessary, and when the risk to the participant is low. This revision was reportedly preceded by behind-the-scenes lobbying by the drug industry to permit greater use of placebo controls.
In the same month that the revised Declaration was announced, the US Food and Drug Administration (FDA) amended its own requirements for clinical trials. While placebos are rarely necessary, regulatory bodies such as the FDA require placebo-controlled trials to give marketing approval to new drugs. Yet as of October 2008, trials conducted for FDA approval no longer had to adhere to the Declaration of Helsinki – an internationally accepted document, but not binding unless incorporated into national regulations. The FDA would continue to require placebo controls, and no one was going to tell them otherwise.
Concerns about the ethics of clinical trials do not exist merely in the realm of speculation. The GVK exposés are not unusual. An increasing number of reports are coming to light of unethical and illegal practices that exploit people’s social and economic vulnerability, subject them to serious risks without their knowledge and consent, and do not even assure them of access to the drugs developed from the trials. Certain types of trials depend on paid volunteers who desperately need money. In Gujarat, unemployed diamond workers and migrants from Uttar Pradesh and Bihar get paid between INR 5000 and INR 20,000 to take part in bioequivalence trials – sums large enough for them to put money over personal safety. Indeed, trial participants may be both financially and socially vulnerable. It is reported that Surender, who died in the Hyderabad felodipine trial, was one of a number of Dalit students being recruited for clinical trials in that city. Likewise, some years ago, a 22-year-old Adivasi youth died in a bioequivalence trial of the antidepressant citalopram by the Sun Pharma Advanced Research Centre in Vadodara.
Certain types of trials are more likely to be conducted in India and other countries where regulatory and monitoring mechanisms are weak, or regulators are too willing to please drug companies. The use of placebos is a good example, as it is not difficult to conduct placebo trials in India. In 2005-06, Indian patients with schizophrenia were taken off their regular medication and given either a new, ‘extended-release’ formulation of an approved drug (quetiapine, marketed by AstraZeneca) or a placebo, to compare the time it took for people in each group to have a relapse attack of schizophrenia. The trial was conducted by a Contract Research Organisation (CRO) called Quintiles, in India as well as a number of countries in Eastern Europe. One patient (not in India) who was on the placebo committed suicide. Experts are unanimous in their view that a placebo was methodologically unnecessary in that trial, as the new formulation could have been compared to the existing ‘immediate-release’ drug. But the European regulators required a placebo-controlled trial, noted Irene Schipper and Francis Weyzig of the Dutch research organisation Centre for Research on Multinational Corporations, in a 2008 report. They also argued that placebo-controlled trials for severe conditions, which put the participants at greater risk, are more likely to be conducted in developing countries.
Trials in government hospitals in India can also be of special concern. In one trial, 290 people who had been hospitalised because they were having a severe attack of acute mania were given either a drug (risperidone, marketed by Johnson & Johnson) or a placebo. The idea, of course, was to examine how many people recovered with the drug, and how many with the placebo. This subjected seriously ill people to harm. The majority of patients in this India-only trial, also conducted by Quintiles, were recruited from government hospitals where, according to the principal investigator of the trial, the most seriously ill patients could be found. It is also where patients can be recruited easily, because trial participation ensures a hospital bed and free, quality treatment.
Another concern about trials in government hospitals is that they are conducted on poor people who may have no access to the drugs tested on them after the trial is over. In August 2008, the media reported that 49 children died in 42 clinical trials that were conducted over two and a half years in the Department of Paediatrics at the All India Institute of Medical Sciences (AIIMS) in Delhi. An investigation ordered by the National Human Rights Commission concluded that the trials were conducted properly: the children in the trials were seriously ill, and all the deaths occurred because of the serious illnesses, not the treatments. However, the committee’s report left many questions unanswered. What, for instance, was the purpose of these trials? Would they help other poor children in India?
One of these trials tested the blood-pressure drug valsartan, supplied by its manufacturer Novartis. Paediatric hypertension is indeed a serious condition, but companies conduct paediatric trials for various reasons, including to get information for the benefit of doctors who prescribe the drug to children. Another reason is because the US FDA extends a drug’s exclusive marketing rights when it is tested on children; this provision is meant to encourage research on children who are otherwise prescribed drugs based on the results of research on adults. However, companies also use this clause to maximise their profits. Another trial was linked to gene-activated human glucocerebrosidase, a treatment for Gaucher’s disease, a serious genetic condition in which a fatty substance (lipid) gets deposited in cells and specific organs. The drug for this trial was provided by the US-based Shire Human Genetic Therapies. Will the drug be made available in India once it is proved effective? Both the Helsinki Declaration and the ICMR’s guidelines emphasise that a community on which a drug is tested should have access to the drugs, if proven effective, once the trial is over. Unfortunately, this is rarely the case. Although all of the new drugs being tested in India will indeed be available in India, this will be at prices unaffordable to the very people who agree to have them tested on their bodies.
More generally, but of no less concern, AIIMS has stated that the trials did not “target” children from poor backgrounds. But there is no need to target poor people at AIIMS – they constitute the majority of patients at this government referral hospital. The simple fact is that the vast majority of people seeking care at the AIIMS centre would be there because they cannot afford treatment elsewhere.
The pharmaceutical industry depends on constantly getting new drugs into the market. New drugs include new uses for old drugs (a cancer drug that can also be used for infertility?) or ‘improved’ or ‘me-too’ versions of older drugs (all those antacids, blood-pressure and cholesterol-lowering drugs, anti-depressants or antibiotics). These drugs must be tested on human beings before they can go into the market. Permission has to be obtained, patients have to be recruited, trials carried out and the results filed – all at top speed, because time is money.
This is where the Contract Research Organisation – the CRO, such as GVK Biotech referred to earlier – steps in. The CRO undertakes all aspects of the process involved in getting regulatory clearance: getting the necessary permissions, tying up with doctors and hospitals to recruit patients on whom the drugs are to be tested, analysing the data that emerges from the trials, monitoring the trial to make sure that the information collected meets standards, putting together reports and even ghostwriting articles for publication in medical journals. Of course, the most important aspects of all this is the recruitment of patients. The best place to recruit patients for, say, a diabetes-drug trial, is a country with a large diabetic population. And diabetics who have not received treatment make better trial subjects, as the results of drugs tested on them will not be ‘contaminated’ with the results of drugs that they have already used.
Clinical trials in developing countries depend not only on physical infrastructure – hospitals and laboratories – and trained human power. They also depend on drug companies getting access to bodies on which they can test their drugs. So, CROs in India market Indian bodies. In a 2006 advertisement on their website (which has since been removed), a CRO named Igate advertised the ‘India advantage’ as “40 million asthmatics, about 34 million diabetics, 8-10 million people HIV positive, 8 million epileptic patients, 3 million cancer patients.”
CROs in India all claim to have ‘access’ to patients with various health problems for which drugs can be tested. For instance, a research group called Veeda claims to have “access to vast patient populations and has specific expertise in recruiting patients with cardiovascular disease, oncology, diabetes, renal disease”. The CRO Quintiles India once boasted that, for a paediatric-flu-vaccine trial, it recruited 201 one- to three-year-olds from three sites in India in just six days. What kind of network does Quintiles have, and what kind of influence does it have with the medical profession, that it can round up 200 children and convince their parents to let them get an experimental flu shot – all in just six days flat?
It seems that at least some of this is able to take place through wilful misinformation. Spectrum Clinical Research specialises in recruiting patients, collecting patients through networks of private clinics, hospitals, specialists and family physicians. It also runs ‘awareness campaigns’ – for instance, a “white ribbon initiative” on osteoporosis, co-organised with the women’s magazine Femina of the Times of India stable, collected data on 2000 patients with osteoporosis. Another campaign, this time to “defeat diabetes”, collected data on 1000 patients with diabetes. In these ways, people who think they are joining patient-support groups are actually being tracked so they can potentially be put on a trial.
Behind a veil
Other than the boasts of CROs, there is little information available on the hundreds of clinical trials being conducted in India. This is despite the evidence that many of these trials are conducted for the benefit of international drug companies, at unacceptable cost to the local population; that trial subjects could be put at risk; that subjects often have not given their informed consent to participate; that they might be provided care that is of lower quality than if they had been recruited for a trial in the West; that injuries during a trial might not be investigated thoroughly, and that those injured may not receive treatment of the highest standard, or even compensation; and that drugs that are tested are often too expensive for people who need them in India.
The only institution to have direct power over the conduct of a trial is the ethics committee (EC). Research institutions appoint their own institutional ethics committee to conduct an ethics review of all research proposals from within the institution. Independent or freelance ethics committees undertake ethics review for a fee, from anyone who applies – usually the CRO or drug company who coordinates the trial at a number of small nursing homes or private clinics, which don’t have their own ethics committee. The EC is a collection of specialists from various fields who review trial documents, including the trial design, the manner in which subjects are recruited, the patient information sheet and the informed-consent form, and approve or reject the application. These committees also have the authority to investigate a trial, and even to stop it if they feel that something is not right.
Ethicist Amar Jesani points out that ethics committees have a lot of power, as the DCGI requires that all trials be passed by such an appointed group. In fact, the DCGI only requires approval by an ethics committee, since it does not monitor the actual conduct of the trial – it does not check that informed consent is taken, that the investigators do their job correctly, that subjects are not harmed, and so on. Thus, says Jesani, it is the ethics committee, not the DCGI, that is the real regulator of clinical trials.
Yet the effectiveness of an ethics committee depends entirely on the setting in which it functions. Important factors, for instance, include the institution that funds the committee’s work or that determines its level of independence, the training of its members, and their competence in terms of doing a proper ethics review. Likewise ‘independent’ or freelance ethics committees are more accountable to the companies that pay for their services. Even the patient information sheet and informed-consent document are treated as confidential documents by the ethics committee – and, of course, the trial’s sponsor. These contain the information on the purpose of the trial, its risks and benefits, and an assurance that a patient’s treatment will not be jeopardised by refusal to participate, or withdrawal from a trial. There is nothing here of proprietary value – on the contrary, everything in these documents is of public interest, and they should be available to the public. Ethics committees are also often poorly educated in their responsibilities.
The reports of people dying in trials are likely to be merely the tip of the proverbial iceberg. And many more are likely to suffer an injury related to the trial drug, injuries that require treatment and that could result in temporary or permanent disability. Indian guidelines require that trial participants be compensated for injuries suffered during research. However, a study by Urmila Thatte and others in a 2009 issue of the UK-based Journal of Medical Ethics found that many trial investigators as well as ethics committee members are not even aware of this requirement. The guidelines of trial sponsors – such as drug companies – provide for medical treatment of any participant who suffers a trial-related injury, or reimbursement of their medical costs. However, Thatte and her colleagues found that none of the companies sponsoring trials, or ethics committees reviewing their trials, had a policy of compensation for trial-related disability or death. Yet for ethics committees to be a law unto themselves is hardly surprising, given the overall environment of lax regulation and monitoring.
Now, the FDA’s decision to do away with the Declaration of Helsinki will create a dilemma for the DCGI. If CROs in India are to follow the FDA requirements – such as using a placebo even when it is not absolutely necessary, and when it might put subjects at risk – they will be violating Indian regulations, which require that the Declaration of Helsinki be followed. The latest revision of the Declaration is quite clear that the placebo may be used in very few circumstances. At the moment, however, the DCGI’s record – permitting a number of unethical trials – suggests that his office places greater value on the potential financial returns of clinical trial outsourcing than on protecting the people who take part in drug trials in India.
Sandhya Srinivasan is a Bombay-based journalist specialising in public health and development issues. She is executive editor of the Indian Journal of Medical Ethics.