In late May 2017, about two weeks before he died, Nagaraju Vangaru, a 53-year-old father of three from Telangana’s Karimnagar district, checked into a facility run by Lotus Laboratories, a Bengaluru-based clinical research organisation (CRO). Vangaru was taking part in a clinical trial for a sleep aid called melatonin. The trial was a bioequivalence study, designed to compare the biological behaviour of an unapproved formulation of melatonin with an older, approved formulation that was already available in the market. Vangaru would be paid ₹20,000 for participating, as would the 59 other volunteers in the trial.
On the morning of the trial, Vangaru ate a large breakfast, possibly of chicken, bread and eggs. Then he popped 2 mg of melatonin, so that the meal’s effects could be tested on the medicine’s concentration in his body. (These events are reconstructed from a document called an informed consent form, which Vangaru signed before the trial and of which he kept a copy.) Next, the investigators inserted a thin tube called a cannula into his vein to collect blood. Over a period of a day, the cannula remained in his arm, and blood was collected 11 times. Finally, on May 27, the investigation ended, and Vangaru checked out of the facility. The first round of the trial was over. But Vangaru was to come back for a second one.
The Telangana resident then left Bengaluru for his home – a tiny, mosquito-infested brick house in the cotton fields of Karimnagar’s Nagampet village. He lived there with his wife and three sons. Lotus Labs subsequently lost contact with him. So, the investigators didn’t know when, on May 29, Vangaru grew feverish, with severe back pain and a swelling in his arm. Even though the informed consent form he signed states that volunteers could call the CRO if they felt unwell during the trial, Vangaru never did so. Instead, he visited several doctors near Nagampet, who diagnosed him with thrombophlebitis, an inflammation of the vein, which can occur due to intravenous cannulation. The doctors also said he had a compressed disk in his spine. Even as he began the prescribed treatment, on the evening of June 2, Vangaru suddenly collapsed in his home, dead.
The death set off a series of traumatic events for Vangaru’s family. When they began sorting through his possessions, they discovered the form he had signed to participate in the Lotus Labs study. The family had no idea that Vangaru was a trial volunteer. All they knew was that he worked as a cook at weddings in Hyderabad, earning ₹300 a day. “We thought he was travelling around with catering companies. This was a shock to us,” says 25-year-old Jagadeesh, Vangaru’s youngest son and the only person in the family who has studied beyond high school.
There were more unhappy surprises when the local police station began investigating the case, seeking responses from Lotus Labs. The company revealed that the melatonin study was Vangaru’s ninth such trial with them. More troublingly, Vangaru had lied to Lotus Labs to sign up for the trial. Even though he was over 50, the identity card he submitted to the company showed him to be 38 years old. This was a risky misrepresentation because the study was only for participants under 45 years of age, and the company discovered his true age only when newspapers reported his death.
Vangaru’s case highlights the troubling trend of financially needy people serially volunteering for trials to supplement their income. This is a worldwide phenomenon, including in high-income regions like the U.S. and the European Union. The problem arises when volunteers who are desperate for money deceive investigators, lying about their age, health or other medications, just so they can participate. Such serial volunteers are an especially vulnerable class of people, because of their poverty and low levels of education, says Urmila Thatte, a clinical pharmacologist and bioethicist at Mumbai’s Seth GS Medical College and KEM Hospital.
Under the Indian Drugs and Cosmetics Act, an independent body of doctors and laypersons, known as an ethics committee, must oversee a trial to make sure the rights of such groups are safeguarded. But bioethicists say this isn’t happening. “There is a lot of scope for Indian ethics committees to directly supervise trials, which I don’t think they do,” says Thatte.
Protecting the vulnerable
In Vangaru’s case, Lotus Labs concluded that his death wasn’t due to melatonin, according to the company’s response to the police. Melatonin has been safely used as a sleep aid for over 20 years now, and no published case report links its short-term use with death, they reasoned. Also, with a half-life of 3-4 hours, the drug would have cleared from Vangaru’s body by the time he fell ill. While this reasoning may be correct, there are troubling hints that Lotus Labs and its ethics committee dropped the ball when it came to protecting Vangaru.
In any trial that relies heavily on vulnerable groups like daily wage earners, the ethics committee can choose to monitor subjects intensively, and counsel them on health risks, points out Thatte. There are several tools to do this — the committee can meet participants, or administer questionnaires to gauge their awareness. Shiela N. Rao, a veterinarian and the chairperson of the ethics committee in the melatonin trial, says that though her team did meet participants in some trials, they didn’t meet anyone in the study Vangaru signed up for.
When asked if there was a lapse on the part of Lotus Labs in not identifying that he was 53 years old, Rao said she hadn’t been informed by the company about this finding. And even though the Drugs and Cosmetics Act requires every trial death to be investigated, even if it is not related to the drug, no post-mortem was carried out on Vangaru’s body. “Proving relatedness in a trial is a real challenge,” says Thatte, “but at least the effort should be made.” Rao says a post-mortem didn’t happen because the company was unable to get information from the family about the death. Meanwhile, the results of a forensic investigation launched by the local police station near Vangaru’s village haven’t been released, seven months later.
The pervasiveness of serial volunteering and deception is not just a risk to participants but also taints the quality of data collected by CROs in bioequivalence studies. Volunteers from Hyderabad, Karimnagar and Mumbai interviewed by The Hindu admitted to participating in over 30 studies in a decade, and to have broken rules to make a quick buck. This included hopping from one trial to another without a three-month gap in between, drinking alcohol, and hiding one’s health history. Such behaviour can distort trial data. To avoid this, France and the United Kingdom today have a national registry of volunteers, while the U.S. is contemplating one. India, with its lower levels of income and awareness, could benefit more from such a registry, but has none.
The trials that Vangaru and others participate in are called bioequivalence studies. When the patent on a drug expires, makers of generic versions must prove that these are metabolised by humans the same way as the patented drug. This year, the U.S. drug regulator, the Food and Drug Administration (USFDA), published a list of 267 off-patent drugs for which it was seeking generic versions. All drug-makers looking to address this market will need bioequivalence studies, opening up a large opportunity for Indian CROs. “It’s a big business,” says Thatte.
Yerram Devi Prasad, 33, a resident of Huzurabad, Karimnagar, participated in over 25 clinical trials between 2005 and 2009 for companies such as Dr. Reddy’s Labs. About a year after he stopped, he began experiencing severe seizures and other mental symptoms. A government doctor told him his ailment could be due to the repeated participation in clinical trials. He displays his CT scan film. Next to him is his mother, who earns a living by selling home-made papad.
Unlike phase 2 and 3 trials that test for the first time if a drug is safe and effective in humans, bioequivalence tests involve medicines like melatonin that have already completed phase 2 and 3 trials and have a history of use in people. This makes bioequivalence studies relatively safer. On the other hand, participants in these studies receive no therapeutic benefit like phase 2 and 3 volunteers do, because bioequivalence studies are done on healthy people while the latter recruit patients. The assumption, therefore, is that a participant in a bioequivalence study is taking on the risk out of altruism.
It is important to remember that the risk of bioequivalence trials, while low, varies widely. A search of the Central Trials Registry of India, to which all regulated trials in India must be reported, shows that a range of drugs, including the breast cancer drug endoxifen, recombinant oral insulin, the hepatitis drug peginterferon alfa-2b, and anti-seizure drug phenytoin sodium, were tested on healthy volunteers in India in the last few years. These drugs have dramatically different side effects. But a volunteer viewing such studies purely as a source of income is likely to paint them all with the same brush. “Many trials are probably associated with minimal risks. However, some trials could be associated with potential risks that require careful consideration before consenting. This distinction should not be blurred, as is inevitable when persons volunteer for trials regularly,” says Chittaranjan Andrade, the head of the department of psychopharmacology at Bengaluru’s National Institute of Mental Health and Neurosciences.
The higher the payment, the more likely that a volunteer will ignore the risks, argue some bioethicists. Bioequivalence studies can pay up to ₹25,000 for a week-long commitment, during which a daily wage earner like Vangaru would have otherwise earned a tenth of the amount. The Indian Council of Medical Research’s ethical guidelines for biomedical research on humans suggest that a company only compensate a participant for the inconvenience and loss of earnings due to the trial, and refrain from “undue inducement” or gratuitous payments that can influence decision-making.
Many payments do not fit this guideline. “These participants are not joining because of their dedication to medical science. We say there should be no undue inducement. But there is an inducement,” says Y.K. Gupta, the head of the clinical pharmacology department at New Delhi’s All India Institute of Medical Sciences.
Everybody lies
The large demand for volunteers and the supply of willing subjects has spawned a bustling marketplace for participation in bioequivalence studies. Dozens of groups on the instant messaging platform WhatsApp, with telltale names like “Anytime Money”, share information about ongoing studies.
The Hindu spoke to Kumar (name changed), a 32-year-old serial volunteer from Mumbai and a member of a WhatsApp group called Blood Money. He estimates that he has been in over 40 studies till date. Blood Money has 250 members, and its icon is a stack of currency notes atop a pool of blood. Around half-a-dozen advertisements for bioequivalence studies turn up on the group each day, containing bulleted information that includes the name of the CRO running the trial, the amount of blood to be drawn, and the compensation. Some of the CROs whose calls for volunteers appeared on the group include the Mumbai-based Raptim Research and Watson Pharma, and the Ahmedabad-based Lambda Therapeutic Research Limited.
Kumar says it isn’t uncommon for volunteers to break trial rules and lie. Even though CROs screen for infections such as HIV and hepatitis, and illnesses like anaemia and diabetes, they cannot catch everything. “People tell lies. They say I don’t take any medicines. And then they pass the test,” says Kumar.
Sometimes the cheating is driven by a family emergency. In 2014, when Kumar’s two-year-old son was hospitalised for fever and seizures, he went from one study to another, to gather enough funds. The first trial, for “some brain drug,” according to Kumar, was to pay ₹8,000, but with a delay. The second trial, for medicine for pediatric cough and cold, promised to pay within a week. That swung Kumar’s decision. “That’s the only time I did it. But others do it more often.”
M.S. Swami Chowdhury, who participated in several clinical trials until 2015, when he stopped because he starting experiencing chest pain, says volunteers take iron and folic-acid supplements to mask conditions like anaemia. Drinking liquor between two periods of a study isn’t uncommon, even if it is often prohibited. It is not tough to game the system, according to Boga Rajesh, a serial volunteer from Jammikunta in Telangana. “You will be surprised at the things people do,” he says with a smile.
When disaster strikes
Sometime in 2015, 25-year-old Ashok Chiluveri, a newspaper boy in Karimnagar, took off for Hyderabad to make his fortune from bioequivalence studies. He told his brother Shyamsunder Chiluveri that he had found a new job. “He would keep travelling back and forth,” says Shyamsunder who puts up tents for weddings and other functions in his village. “But we had no idea what he was doing.”
Shyamsunder Chiluveri (in photo) had no idea that his brother Ashok Chiluveri was participating in clinical trials. Ashok said in 2015 that he had found a new job, but no one in the family knew what this job entailed. Only when Ashok began having violent outbursts were his papers discovered. Before admitting Ashok to the Institute of Mental Health in Erragadda, Hyderabad, Shyamsundar and his mother took him to several dargahs and religious sites to pray for his health.
But Ashok’s secret did not remain one for long. When he visited home in October 2017, he began having violent outbursts. He said he was hearing voices telling him to jump off a nearby hill. It was only when Shyamsunder noticed Ashok trying to burn some documents and seized them that he realised what was going on. One of the documents was an identity card from Lotus Labs, while the other was a payment cheque from the Bengaluru-based Apotex Research Private Limited. Upon being questioned, Ashok also named a third company, Syngene International in Bengaluru. In two years, he admitted, he had taken part in over 20 trials.
In December, Ashok was admitted to Hyderabad’s Institute of Mental Health in Erragadda. K. Sudha Rani, a psychiatrist treating him, says he suffered a temporary episode of psychosis, a psychiatric condition in which the patient loses touch with reality. But she cannot say if the psychosis was due to the trials he took part in, because Ashok neither remembers the medicines he took, nor retained any documents from these studies. A long list of drugs can trigger temporary psychosis, from alcohol and cannabis to some antibiotics, steroids and Parkinson’s drugs. For now, Dr. Rani and her team are treating Ashok for his symptoms and expect him to be stable enough to leave for home soon.
To be fair to CROs, wilful deception by volunteers can be hard to flag, say bioethicists. But the problem is compounded by the cultural taboo surrounding trials. Volunteers often keep their families in the dark, leaving them without a safety net when they fall ill or are exploited.
The only way to tackle this trend in its entirety is through social campaigns to improve awareness. But ethics committees must keep up their end of the bargain. CROs have a clear conflict of interest when it comes to recruiting volunteers, says Thatte, because they need to fill studies quickly to earn their revenues. “The main responsibility lies with the ethics committee, because the CRO is totally conflicted. If they don't take up this mandate of continuous monitoring, who will?”
Too famous to volunteer
Thirty-year-old Suresh Boga looks depressed as he works in his footpath shop in the Jammikunta municipality of Karimnagar. The shop is 10 feet by 3 feet by 3 feet in size, enough to hold a man, a shelf full of tools like screwdrivers, and two dogs which come to nap on the floor in the afternoon. While petting them occasionally, Boga repairs portable gas cylinder stoves, a job that earns him ₹6,000 per month. It isn’t enough. But his professional volunteering streak has come to an end, and this is his only source of income now.
Eleven years ago, when Boga was a high school graduate working as a serving boy for a Hyderabad-based catering company, he learnt about the money to be made in bioequivalence studies. He was earning ₹250 a day then. “Many of my friends were already doing it,” he recalls. So he gave it a shot. He remembers that his maiden trial was with Hyderabad’s Vimta Labs, but doesn’t remember the name of the drug. “It was for skin blisters,” he says falteringly, when I ask him what drug it was. “The kind that people say is due to the curse of goddess Poleramma.”
For every clinical trial, the Drugs and Cosmetics Act requires participants to receive a copy of an informed consent form, which explains the trial protocol in great detail. Unless a company is convinced that the participant has understood the risks of the trial, they cannot recruit the patient. But Boga threw his copy of the form away. He didn’t want anyone seeing it, for fear that they would disrespect him for selling his blood for cash.
Boga Suresh threw away the copy of his informed consent form. He feared that if someone saw it, they would disrespect him for selling his blood for cash. Boga has participated in over 20 trials for companies like MacLeoads Pharma in Mumbai and the Hyderabad-based Axis Clinicals, Vimta Labs and GVK Biosciences.
Wasn’t he worried about drug side effects? No, he says. “There are hundreds of side effects. But the company says you may get it, or you may not.” One drug did give him a strong bout of nausea, while another gave several in his group a severe stomach ache. Yet another time, he recalls, the CRO told him to stop pretending, because he couldn’t possibly have gotten the side effect he claimed he had. But the money was a good attraction and kept him going. In all, he has participated in over 20 trials for companies such as the Mumbai-based MacLeods Pharma and the Hyderabad-based Axis Clinicals, Vimta Labs, and GVK Biosciences.
But things went awry for the young man when Ashok Chiluveri, who lives in the same village as him, had psychotic episodes in October this year. Ashok’s family blamed Boga for introducing him to trials, accusing him of being a pharma-company agent exploiting gullible young people.
Boga panicked. “I was afraid to go to jail,” he says. So, he did the one thing he is comfortable with after ten years of volunteering for trials. With a five-millilitre syringe, he drew some of his own blood and squirted it in his mouth. Then he told onlookers that he had vomited the blood. When an ambulance rushed him to the hospital, he told doctors that the vomiting was a side effect of the trials he took part in. With the Nagaraju Vangaru and Ashok Chiluveri cases still fresh in the village’s memory, the doctors believed him. “I was looking for sympathy,” admits Boga. “I wanted people to know that I was only a volunteer, and not an agent.”
The local police eventually saw through his pretence, and Boga confessed that he had put on an act. But by then his name had been splashed across all the local newspapers and television channels. CROs knew that he was a serial volunteer, as did his mother, who was ignorant till then. This brought his volunteering to an end.
Sitting on a cot in their cramped two-room home in Jammikunta, Boga’s mother, who suffers from a kidney ailment, says she is glad he has stopped now. Boga looks on unhappily. He is too famous to take part in trials now. “But there are hundreds of others who are still doing it,” he admits.
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