Guinea pigs: story of unethical drug trials in India

Bhopal Gas Tragedy Memorial
Bhopal Gas Tragedy Memorial

With its lakes and hillocks, Bhopal, the capital city of Madhya Pradesh in central India, is rather beautiful at this time of the year. The monsoon clouds over Upper Lake, or Bhoj Taal –Asia’s largest man-made lake – have not only brought relief from the scorching summer heat but also worked magic to the city’s lush green splendour.

I walk by the lake with the mercury at a pleasant 27 degrees Celsius on a late-June Saturday, but don’t find anything in this modern part of the city to suggest that this place was where 26 years ago a gas-leak from a pesticide factory had resulted in the world’s worst industrial disaster, killing more than 15,000 people and affecting more than120,000. The after-effects saw birth of deformed babies and environmental pollution, mainly ground-water contamination, endangering the health of Bhopal residents even today. The exposure to the gas caused health problems such as cancer, blindness, respiratory diseases and it also affected the immune, the neurological and the female reproductive systems.

The ugly past in mind, I am rather taken aback by the city’s almost serene beauty. “Now, now, were you expecting to find gas chambers here?,” I chide myself as cars zoom past by me, music invariably loud, and people mill around to make the best of a pleasant weekend.

The cruel juxtaposition of beauty, truth and the ugly is revealed to me when I reach the Yaadgar-e-Sahajahan Park, where a motley crowd of about 50 odd people are huddled together to discuss what they have been for the past 26 years—how to get justice? The meeting, now weekly, has been a ritual among the gas victims since the 1984 tragedy. The discussion topics still remain the same—compensation, legalities, health care and victim’s rights; it’s just that the list now has a new addition—clinical trials.

Adding a new insult to an old injury, Bhopal Memorial Hospital and Research Centre (BMHRC), Bhopal’s only super-speciality hospital, had carried out clinical trials on the gas victims for drugs made by foreign companies, many of them European, between 2004 and 2008, when it was suddenly stopped following a drug-trial related controversy at the All India Institute of Medical Sciences, New Delhi. The revelation happened as late as December 2010 through a media exposé and the gas victims are still groping in the dark as they try to find out what it was all about.

Guinea Pigs?

They gave him some medicines that they give to rats

Laxmi Bai with her daughter
Laxmi Bai with her daughter

Right across the street from the walled Union Carbide factory premises at Jaiprakash Nagar is a memorial built to commemorate the tragedy. It is a buff-coloured statute of a woman, holding a baby in one hand and covering her nose with the other, while her other child, barely knee-high, is clutching at her from behind. Lane number 10 where Laxmi Bai lives is not far from here, children playing cricket on the road tell me. On reaching house number 420, a modest two-storeyed but small building, on the far

end of the lane barely wide enough for a small car, I find she’s not there. I collect her number from her tenants and get directions to her brother’s house near Karod Chowraha on the other side of the Union Carbide factory.

After crossing three pairs of kirane ki dukan (grocery shop) and atta chakki (a shop where wheat is ground into flour)—all that she had said as address for the home in Janta Nagar colony—I manage to locate her, finishing the last leg of the adventure on foot, jumping on stray bricks and stones to avoid falling into the puddle spread over the narrow mud lane. She greets me with a ‘Hello’, not ‘Namaste’, and I immediately understand the influence of foreign media teams visiting her.

She was eight-month pregnant when the gas-leak happened. “A green dead baby was born to me after that,” she says as we converse on the floor mat, her 10-year-old daughter Hemlata sitting beside her and a little older son Raj listening from the door. The gas exposure resulted in three more miscarriages before the eldest son, Rohit (18), was born to Laxmi and her husband Shankar Lal, who died in August 2010. The couple, who lived in Jaiprakash Nagar shanties, one of the worst-hit areas, has also had to battle chest and abdominal problems.

Still at a loss to figure out what caused her husband’s death, all she says is “Kya pata”, meaning “what do I know?” in Hindi. Shankar Lal, a plumber by profession, was admitted to BMHRC for three days in September, 2007, following breathlessness. “They gave him some medicines that they give to rats,” she says, now that she has got to know that Shankar was put under drug trial.

The fact that 55-year-old Shankar Lal was put under trial for new drugs would have remained charred with his bones in the funeral pyre, had it not been for Rachna Dhingra, a member of Bhopal Group for Information and Action, who knocked at Ms Laxmi’s door one day. “I was doing a survey of gas-affected widows as state had announced pension of Rs 1,000. We wanted to show the government that several gas victims have died due to gas exposure related illness and untimely deaths continue even till today,” says Ms Dhingra, whom I meet later at Sambhavana Clinic, off Berasia Road. Managed by her gas activist husband Sattinath Sarangi, the clinic was set up with proceeds from the “Il était minuit cinq à Bhopal“, written by French author Dominique Lapierre.

In Shankar Lal’s discharge summary he was prescribed ‘Study Drug’ among six others. “That perked my ears,” says 33-year-old Dhingra, a Delhi girl educated in the United States. In 2003, she came to Bhopal to take up fulltime activism soon after she quit her job with Accenture in the US where Dow Chemicals, of which Union Carbide is a subsidiary, was one of the clients she handled. Shankar Lal was on the Plato trial of the cardiology department and was administered with Ticagrelor, she tells me, basing on her investigation of BMHRC records that she carried out soon after.

Shankar may or may not have died because of the trial, but the issue here is different. It’s betrayal that these gas victims are coming to terms with. “We had no clue; we had taken him for treatment, not for experiments,” says Laxmi Bai.

Ramadhar Shrivastava, 62-year-old gas victim from Patti Mill Colony, got to know he was a trial subject from a local journalist, Rahul Singh. “I got the shock of my life,” he recalls, thanking God that he’s alive. He has written to the State Human Rights Commission and is awaiting response. He was admitted to BMHRC for six days in November, 2007 following a cardiac arrest (heart attack). His discharge summary prescribed Tab Clopidogrel Plato 4244593. Plato trial was AstraZeneca sponsored “randomised, double blind, parallel group Phase III; Efficacy and safety study of AZD6140 (Ticagrelor) compared with Clopidogrel for prevention of vascular events in patients.”

Ramadhar Srivastava
Ramadhar Srivastava

A Developing story

It was when the trials were ordered to be ended that we got to know that trials taken place there

Abdul Jabbar
Abdul Jabbar

Bhopal Drug Trial is a story told from the end. “It was when the trials were ordered to be ended that we got to know that trials taken place there,” says Abdul Jabbar, in between playfully chiding Hasina bi for not coming regularly to the Saturday meetings of gas victims. Hasina Bi and other senior members are just back from the meeting to share some conversation, jokes and tea with their most-loved leader at the Swabhiman Kendra, where about 2000 men and women learn vocational skills, such as tailoring.

Last year, Mr Jabbar, convenor of Bhopal Gas Pidit Mahila Udyog Sangathan, a key organisation of over 30,000 gas victims, got hold of an internal circular dated August 25, 2008, from the BMHRC director directing the principal investigators to suspend all ongoing and proposed trials. “Shocked is a meek term to describe how I felt,” Mr Jabbar says.

Rachna Dhingra at her office.
Rachna Dhingra at her office.

It was then that Rahul Singh, who was the Principal Correspondent of Times Now news channel, picked up the story. Armed with the letter, he went to BMHRC. Though evasive at first, the principal investigators gave him some details of the trials. They also gave him details of some cases, showed Mr Singh the consent forms. They had nothing much to worry about, or so they thought, because the forms had signatures of the patients and their families. But that was not to be. “None of the five patients I contacted knew they were trial subjects. And one of them, Panna Lal, who was tried for Mometasone drug, was dead. It was I who told his son that his father was a trial subject,” Mr Singh tells me later at the Delhi head office of Headlines Today (a 24-hour news channel owned by the India Today Group), where he is now a Senior Special Correspondent.

The only “hint” perhaps, as I understand after speaking to Laxmi Bai and Srivastav, was that patients were asked to return the container/ packages/foils of the “particular” medicines that were being tried on them after every use.

Mr Singh was told that over 160 patients were recruited for the trials.

“It’s 279,” says Ms Dhingra.

She is pretty upbeat when I go to see her and her husband Sarangi at Sambhavana Clinic a few days later. “Look at this,” she says, as she takes out one document after another from a thick folder. She is just back from Delhi with some documents that she has managed to get hold of with the help of Right to Information (RTI) Act and Rajya Sabha, Upper House of Indian Parliament.

“Now we have the proof”, she exclaims, showing me the document enlisting 10 deaths. “Give me three weeks to identify the patients. And then we’ll see what we can do with these people playing the fool with the lives of already harried victims.” In the documents the patients have not been named, but indentified by their enrolment numbers. Five subjects have died in the Fondaparinux trial, sponsored by Sanofi and GSK, three in Televancin trial sponsored by Therevance and two in Tigecycline trial sponsored by Wyeth.

According to a letter dated February 22, 2011 from Brig. Dr. K.K. Maudar, BMHRC director, to Dr. R Ramakrishna, deputy drugs controller of India, Mumbai, as many as 279 patients were recruited for trials in four departments. Of the 218 patients in Cardiology department alone, 160 were gas victims; in Gastro-Intestinal Surgery department the number of gas victims is 45 out of 49; in case of Pulmonary Medicine all five were gas patients and in Anaesthesiology, five of the seven patients were gas victims.

DSC_0922

Earlier in March this year, responding to a separate RTI petition by gas survivor and activist Hazra Bee, the Drug Controller General of India (DCGI) had revealed that as many as seven multi-centric trials were conducted at BMHRC, involving drugs such as fondaparinux, tigecycline, televancin, ticagrelor, clopidogrel and mometasone. Some of the companies sponsoring the trials included Sanofi, AstraZeneca, Pfizer, Theravance and Wyeth. And, the hospital made over Rs 10 million (1euro= roughly Rs 60).

With BMHRC authorities staying mum over the issue, the full picture is yet to emerge and activists are trying to piece together information trickling in from various sources. “I’m afraid they (BMHRC authorities) are tampering the documents and doctoring evidences,” Mr Sarangi says.

Mum’s the word

BMHRC
BMHRC

I first try to call them over phone, hoping to fix an appointment. Dr Skand Kumar Trivedi, professor and head of the Cardiology department in BMHRC, who was principal investigator in a number of trials, including that of fondaparinux, refused to speak. “I am a government doctor and not authorised to speak to the press,” he says, adding: “Go to CTRI site (Clinical Trials Registry of India), you will find more than 500 trials. Why are you singling out BMHRC alone?” Brig. Dr. Maudar just hung the phone on me with a “sorry” that was far from polite. Interestingly, he was also the part of BMHRC’s institutional review board (ethics committee), a body whose secretary was his wife, Prabha Desikan.

I head for BMHRC, a sprawling 350-bed super-speciality clinic spread over 84 acres, more than 5km from the Union Carbide factory. With a well-manicured garden around, the building is a modern five-storey structure housing 14 departments. As a referral hospital, it has eight units spread across Bhopal. Together they see a foot-fall of 4,000-4,500 gas victims in the out-patient department daily. As I take a walk past a gas victim memorial, ‘Homage & Hope’, in the garden right in front of the director’s office, I am reminded of Mr Jabbar’s words: “It all seems like a part of a huge design, you see. First they killed the people with poisonous gas; now they are killing the survivors with drugs made in their countries. It’s Union Carbide money out there. What more do you expect?”

BMHRC was set up in 2000 to provide free treatment to the victims with funds generated through the sale of Union Carbide’s assets in the Indian subsidiary that was confiscated following criminal trial. It used to be run by the BMHRC Trust till July last year when the Supreme Court ordered it to be taken over by the Government of India. Since it is Bhopal’s only super-speciality clinic, it also offers treatment to non-gas victims against a price.

Dr Trivedi refuses to see me. He sends a message through a staff, to whom I had given my business card, asking me to see the director instead. I try calling him once again from outside the closed door. Looks like he had saved my number from my earlier call; he does not answer, neither calls back.

Director, Brig (Dr) Maudar, at least lets me inside his office and offers me a seat too. “That’s only because you are a lady,” he tells me, vehemently refusing to say anything on clinical trials because the “issue is under investigation”. I do not ask what he would have done if I were a man because I for the next 21 minutes I try in different ways to get him to respond to my questions. “Nothing, nothing. Let us not talk about anything,” was his stock answer to all the questions. In the end he advises me to go to “higher authorities”.

Public Relations Officer Mazharullah Khan is a little more forthcoming even though he maintains that nothing can be said about the trials. He tells me the story of BMHRC since its inception and even offers me a glass of water. I take the chance to ask him about the trials. “Did you ensure that all ethical procedures were followed? Was the informed consent taken,” to which he replies, “Yes, of course.”

Encouraged, I ask him, “It’s clear why a hospital or a doctor would want to conduct a trial, but why did the patients say ‘yes’? What was their incentive?” He doesn’t get the question at first, and I explain again: “If I come here for treatment and you offer to try a drug on me, why would I say yes?” Bewildered, he replies: “It’s difficult to say. The patients should be able to answer this.”

Later on, I get to meet Dr Salim Naik, a senior consultant in the surgical gastroenterology department of Batra Hospital and Medical Research Centre, in South Delhi. Three years ago, he was a senior resident and part of three trials at the Bhopal Memorial Hospital and Research Centre, where he completed a Diplomate of National Board course in Gastro-Intestinal Surgery. “The trials were seen as a major source of income for the hospital,” says the 38-year-old Kashmir-born, Delhi-educated, doctor, whose doctor wife Swati was also with him at BMHRC during that time. Depending on the trial, the hospital earning per recruited patient could go to as high as Rs 300,000 (for a critical care trial). The money, he says, was shared between the hospital and principal investigators.

I ask him if the rules were followed regarding trials and he says: “Well if you see it on paper, all the procedures were followed as per the law.”

I then shoot him a more direct question: “Did the principal investigators ensure that a proper informed consent was taken from the patients.” And to this he quickly replies: “That you go and ask the subjects.”

Were you under pressure from your seniors to select patients for trials even if they did not meet the standards in the evaluation, given that it meant big money, I ask him, to which he replies: “I would not like to comment on that. It would not be ethical to give out the internal details of my previous workplace, now that I don’t work there anymore.”

In Bhopal, my next stop is National Rural Health Mission office in the new city. Dr K.L. Sahu, the joint director, does not betray any emotion when I show him my business card. The last time that we had spoken was about a month ago. He had said he was in a meeting in Delhi and asked me to call back. I had called him several times but he had never answered the phone. Reminding him of my phone call, I ask him about the report he was preparing on the BMHRC trials. “I have submitted it to the government,” he answers. He refuses to share with me his findings and before I am able to ask him my third question, he gets a phone call and he suddenly leaves the room. “Should I wait? Should I come again?,” I ask. No answer. As I walk out towards the elevators, I see that he is already on the elevator that’s going down, but he neither invites me into the lift, nor makes an effort to stop the doors from closing, nor even pretends to be apologetic. Downstairs, all the while that he called his car and left without a word, I stood at the porch but he wouldn’t as much look at me from the front seat of his SUV.

Violations Galore

Dr Gulhati
Dr Chandra Gulhati

Why would anybody be so rude, I wonder. “This unwillingness on their part to interact with the media is just the proof of their wrongdoing,” Mr Singh tells me on the phone after hearing my story. He will know; he had suffered similar fate in December last year when he broke the story.

First, these gas victims are people with no autonomy, Dr Chandra Gulhati explains to me in his Delhi office. “The guidelines say that trials cannot be conducted on people with reduced autonomy. Bhopal gas victims have zero autonomy because they are entirely dependent on the treatment provided at BMHRC,” adds the editor of Monthly Index of Medical Specialities, a monthly journal of “ethical formulations” selling 470,000 copies in India. Through his hard-hitting editorials, he has been speaking against clinical trials very often.

There is a clear conflict of interest when the principal investigator and the treating physician are the same person. I am reminded of Munna Lal whom I met in his shanty at Banganga in new Bhopal. He got to know that he was trial subject (for mometasone drug) from Rahul Singh. “They asked me to sign the papers and I had done that, but I did not know what they were for,” he had told me. “Did you ask your doctor why he did that,” I had asked him and he had replied: “How could I? I had to go to him for treatment again. I don’t have the money to seek treatment elsewhere.”

Second, the trials were mixed with treatment without the knowledge of the patients. Informed consent, in which the subjects are explained clearly the risks of the trial, is mandatory. In all the cases that I studied in Bhopal (and elsewhere), the principal investigators had obtained signatures from the subjects, which keep them on the right side of the law, but the subjects insist that the trials were kept a secret from them. None of the subjects were even given a copy of the consent form. It cannot be a coincidence that none of the patients, who have kept all the files meticulously in folders, should have only one piece of paper missing—the consent form.

Thirdly, conflict of interest in the ethics committee. Guidelines mandate that the trials must be cleared and monitored by an independent body called the institutional review board or ethics committee. At BMHRC Skand Trivedi was a member of the committee of which his wife Prabha Desikan was the secretary. “With such conflict of interests, can a body be expected to be impartial?” Dr Gulhati asks.

Lastly, the trials started in 2004 when phase III trials of new medicines discovered abroad were not allowed in the country unless the same were approved for sale in developed countries.  “Except fondaparinux, other agents tested in Bhopal were all investigational new drugs not approved for human use anywhere. Therefore, their side effects were not fully known when the trials started in Bhopal,” Dr Gulhati points out.

New Outsourcing Boom

Not just in Bhopal, clinical trials are taking place all over India, making it the latest outsourcing destination. A search on the website of the Clinical Trial Registry of India, which was set up in 2009 making it mandatory for all trials to be registered, yield 1335 results for all trials, across all phases, across the country.

Ever since India joined the Product Patent Regime in 2005, there has been a spurt in clinical research outsourcing. According to a report by Ziven Consulting, a Gurgaon-based (near Delhi) clinical trial consulting firm, India’s clinical research (CR) market, which evolved in the late 1990s, is growing at 2.5 times higher than the global CR market of 12% annually. By 2012, it expects India to conduct 5% of global clinical trials. In 2010, India’s clinical trial industry was worth US$ 320 million, a leap from USD 140 millions in 2006. From 100 in 2005 to 1,430 in 2010, the number of trials has also shot up considerably, says the report that was mailed to me by Preeti Sharma, a spokesperson for the company on July 11, 2011.

Clinical trials, according to McKinsey article ‘Pharma Leaps Offshore’, represent 50-60% of a new drug’s development cost and take place mostly in the US, Europe and Japan. Extending these trials globally offers a huge opportunity not only to save cost, but also time. (Timeliness is important, deadline for patent protection being only 20 years). “By broadening the base of physicians and patients to include low-cost countries, companies reduce their costs per patient by 40-60 per cent and speed up recruitment by 20-30 per cent,” says the McKinsey report.

With its whopping population of 1.2 billion of diverse ethnicities and vast pool of “treatment-naive” patients, India— projected to be one of the top 10 pharma sales markets in the world by 2020 by PwC — looks like the next destination for clinical research outsourcing. No wonder that India comes just after China in the Country Attractiveness Index for Clinical Trials, prepared by A.T. Kearney, a Chicago-based global management consulting firm. In its publication titled ‘Make Your Move: Taking Clinical Trials to the Best Location’ (http://www.atkearney.com/index.php/Publications/make-your-move.html), which is available on its website, it says: “India offers a vast population and a growing market. The capabilities and expertise of the country’s scientists are on par with the highest international standards. Also, strong overall economic growth is bound to lead to improvements in the health-care infrastructure.”

Pharma companies, too, vouch for it. In response to an email query, Annette Wiedenbach, head of global media relations and issue management, Bayer Schering Pharma AG, told me: “We have increased our clinical trial activity in India over the past five years from initially 2 trials to 9 trials today. We are conducting global clinical trials in India in Phases II and III where we find good conditions and highly-qualified doctors to work with. Having access to large patient pools and to experts fluent in the English language makes India an attractive country to include into our overall global clinical trial network.” Bayer has so far launched two products — Nexavar for the treatment of kidney and liver cancer and Xarelto for the prevention of thromboembolism in patients after elective hip and knee surgery— from trials which were also conducted India.

No wonder the boom has led to an overnight rise in the number of contract research organisations (CROs) all over India. There are presumably more than 100 CROs in the country; I say ‘presumably’ because their registration has not been mandated by the law yet.

While the trials are all subject to Indian Council of Medical Research (ICMR) guidelines and Good Clinical Practice guidelines (provided by the International Conference on Harmonisation) and Schedule ‘Y’ of the Drugs and Cosmetics Act, 1940, lack of stringency in implementation is one reason why companies find it easier to conduct tests in India.

Rich God vs Poor Patients

Dr Anand Roy
Dr Anand Rai

Less than 200 kms away from Bhopal is Indore, Madhya Pradesh’s “commercial capital”, where Mahatma Gandhi Memorial Medical College and Hospital in Indore has become a hotbed of controversy of late with there being some “exposé” or the other in the newspapers every day.

Opthalmologist and ant-trial activist Anand Rai, who used to be a senior resident doctor at the hospital and was the one to blow the whistle on the trials, is armed with a series of replies to his many petitions trough RTI and Parliamentary Questions. Sample this; each of the six doctors involved in the trials have earned anything between Rs 40,00,000- 56,00,000 in the past five years. A government doctor’s salary is about Rs 75,000 per month. The trials for private companies were conducted in the government hospital premises, and the money from the trials was deposited in their personal bank accounts, says Dr Rai.

Dr Rai says he has filed as many as 420 RTI petitions on the issue and even as we talk at his Radio Colony home, he gets replies to two of his petitions. “This one is regarding the trial of Tadalafil drug,” he says about one.

I later meet Hemant Jain, one of the principle investigators in the thick of the controversy, at his consultation chamber at his Tokoganj South residence. He is a famous paediatrician of Indore and the queue of parents waiting with their fidgety babies only proves that. “It is all a media trial you see,” he tells me. “Utterly baseless and unscientific creation by the media, it is. Can a drug be released to the market without a trial?”

I ask him about the money he made (about Rs 56,00,000). “It’s part of the commissioned research and we are allowed to do to that. And 10% of the earnings, we have paid to the hospital,” he explains.

He also rubbishes all claims that informed consent of patients were not taken. “Informed consent is taken in 100 per cent of the cases,” he stresses.

“What does he mean by it?” says Ajay Naik, father of one-year-old Yathart Naik, who was put on a randomised double-blind trial for a bivalent oral poliovirus vaccine when he was just two days old. “Would we have risked our only son’s life to participate in the trial?” Yatharth developed white patches all over his body during trial. Dr Rai attributes it to side effects of the trial. Dr Jain outright denies that the patches were related to the trial.

A question often arises as to why the people put their signatures blindly on documents whose contents they do not know. Illiteracy is an important reason, but more than that is the trust that patients place in their doctors. Doctors are almost looked upon as Gods and I have seen people, especially in the villages, touching the feet of the doctors as a mark of respect. Doctors do not explain much and are neither questioned, because doctor is above any question. Since most trials are being done by doctors of repute—Dr Anand Rai says this is to ensure a huge pool of patients—it is more unlikely for patients to doubt them.

“It is this trust that the doctors are exploiting,” Dr Gulhati says. This explains why, despite her education, Laxmi Misra, a retired doctor in Bhopal (not a gas victim) was put on the Oasis trial sponsored by Sanofi Aventis at BMHRC to evaluate the different doses of clopidogrel drug. She realised the mistake of trusting her fraternity and putting signatures randomly only after Rahul Singh came to her house and broke to her the news that she was a trial subject.

There are many patients who enter trials “voluntarily”, but these are patients for whom the trial is perhaps the only way to get any treatment, thanks to India’s poverty. And there are those who risk the trials for money to run households or pay university fees. “After the Gujarat riots of 2002, many women were rendered widows with the responsibility of looking after their families,” Noorjehan Abdul Hamid Diwan, Gujarat state convenor of Bharatiya Muslim Mahila Andolan (Indian Muslim Women Agitation) tells me in a telephone conversation from Ahmedabad in western India. “This situation was a good hunting ground for the agents of the CROs. These women give in to the offer of trying drugs for money ranging from Rs 5,000-10,000 per drug, which is a lot compared to the Rs 1,000 that they can earn by working as a domestic help. Many women even registered for two or more trials at the same time,” she adds. Phase I trials are more rampant in Gujarat.

You see, it’s an unfair war, Dr Gulhati tells me in Delhi, where I go from Indore. “On the one side is the company, the CRO, the principal investigator, the hospital and the government, all of whom who make money; and on the other is the poor patient alone,” he adds. Apart from cash, doctors are pampered with freebies such as fully-paid foreign trips (often in the excuse of conference) and expensive cars.

“The ethics committees are supposed to look into the interests of the patients, but they function more like the lawyers of the trial-sponsoring companies,” Amar Jesani, founder of Indian Journal for Medical Ethics, tells me in a telephonic conversation after I am back in Calcutta.

The patient hardly gets insured— guidelines have it that trial subject should be provided with insurance cover, but that seldom happens. As it is health insurance penetration in India is very low and the government does not provide health insurance cover. In any case, in India health insurance companies do not cover complications arising out of drug trials. On the other hand, the companies enjoy what is called the clinical trial liability insurance to provide cover against legal liability arising out of lack of care, negligence, resulting in injury or death of a subject during a trial. The irony couldn’t be starker.

In case of any issue raised by the patient or otherwise, the onus to conduct an investigation and prove the case lies with the CROs. “Isn’t this a complete conflict of interest?” asks Mr Jesani. “How can a CRO make a fair assessment of its own trials? There is no independent authority to monitor the trials and regulations are very week.”

This is why, few mortality cases have been identified as fallout of drug trial. “So far at least 1,514 subjects have died during clinical trials in the past two years and eight months and not even one person has been compensated,” Mr Gulhati had said earlier.

One of the most controversial drug trials in India was that of Merck’s HPV (human papilloma virus) vaccine, gardasil, conducted as a “demonstration” project in Andhra Pradesh and Gujarat states by US-based NGO, PATH International. Indian government ordered the trials of the vaccine, meant to prevent cervical cancer among girls, to be stopped following controversy surrounding deaths of six girls. In all 23,500 girls were vaccinated of which six had died. Two deaths were said to be due to poisoning, one because of drowning, and another due to pyrexia of unknown origin. The two deaths in Gujarat were attributed to malaria and snake bite.

In the case of BMHRC too, the Central Drugs Standard and Control Organisation, in its inspection report, which I had collected from Rachna Dhingra, of the Oasis 6 trial (Fondaparinux sodium and glucose insulin potassium infusion) has said: “The root cause of the deaths on prima facie suggests that the deaths were due to natural history of the disease (acute myocardial infraction) rather than the investigational product.”

Only about 26 deaths of the reported 671 have been recognised as being caused by trials in 2010. Eli Lilly, Amgen, Bayer, Bristol Squib Myers, Boehringer, Quintiles, Sanofi Aventis and Pfizer are among the companies whose clinical trials figure in this list of 26 cases, a media report had revealed.

While Sanofi did not respond to repeated mails and reminder calls, Bayer’s Weidenbach wrote: “Bayer has agreed to compensate the legal heirs in the cases brought forward by the DCGI. Accordingly, Bayer has actively worked with the investigators and the partner company involved in the monitoring of those studies, to identify the heirs entitled to receive the compensation in order to provide the compensation. We have provided initial compensation to the five cases referred by DCGI but are still awaiting further guidance by the Ethics Committee on two of these cases.”

The studies referred to by the DCGI in their enquiry involved patients with an underlying disease, which in itself and left untreated exposed them to the risk of fatality. Accordingly, the deaths reported from those studies were not completely unexpected, Ms Weidenbach adds further in the emailed questionnaire.

Ajay Naik with his family.
Ajay Naik with his family.

Would we have risked our only son’s life to participate in the trial?

Global Concern

While rising business figures ethical concerns are also rising.

“Every year about 800 trials are being approved to be conducted in India,” says Mr Jesani. “Do we at all need those many trials? Are they at all relevant for India? What is the purpose of having a trial done on Indian subjects, when the drugs are so expensive for the people to afford when they come to the market?” he asks.

I shoot emails to couple of global bodies to get their perspective.

Stringent ethical standards in EU are forcing companies to offshore tests to countries like India. In an email interview, Irene Schipper, senior researcher, Centre for Research on Multinational Corporations (SOMO), an independent, non-profit research and network organisation working on social, ecological and economic issues related to sustainable development, says: “SOMO identified 20 Seroquel trials (including Seroquel immediate release as well as extended release) which were conducted in low and middle-income countries (by AstraZeneca). There is a noticeable difference between the trials partly conducted in high-income countries and the trials which are exclusively conducted in low and middle-income countries. The latter clearly have a higher risk profile: the placebo trials with schizophrenic patients or treating acute mania are almost exclusively located in low and middle-income countries. AstraZeneca explains this by saying that almost all Western European Research Ethics Committees (RECs) no longer approve this kind of trials because of the ethical concerns and AstraZeneca is therefore compelled to look for locations outside Western Europe as these placebo-controlled studies are still required by the EMEA and the FDA for market authorisation.”

One Indian patient committed suicide during the trial, says SOMO report ‘Ethics for Drug Testing in Low and Middle-Income Countries’ of 2008.

In an email interview, Isabelle Jouin, head of speciality care communications, AstraZeneca, cexplains: “We used a rigorous study design that was intended to minimise the risk to patients. The design included monitoring by an external Data and Safety Monitoring Board in order to address ethical considerations. The study protocol was approved by the relevant local ethics committees. It is important to remember that schizophrenia is a serious and debilitating mental illness and unfortunately, the incidence of suicide is high in patients with schizophrenia – ten per cent of people with schizophrenia commit suicide in their lifetime.”

Annelies den Boer, International Health Advocate, Wemos, Netherlands-based organisation for the right to public health of people in developing countries (financed by the Dutch ministry of foreign affairs) says over phone from Amsterdam: “The rights of trial participants in developing countries are insufficiently protected. Trial participants in developing countries are more vulnerable than those in the developed world. Health systems in developing countries often function inadequately, leaving the poor without access to essential treatment. As a result poorer citizens in need of medical attention find themselves forced to participate in a trial.”

“One of the most fundamental requirements for clinical trials is that subjects are well informed in advance about the nature of the trial and the risks involved,” says Annelies den Boer. “Any agreement to take part must be voluntary.”

Thirdly, she adds, the care providers who carry out clinical trials in developing countries have not always followed the training needed to conduct such trials according to ethical standards.

“Furthermore, conflicts of interest may occur when doctors involved in clinical trials are paid large sums of money to recruit patient,” says Annelies den Boer.

“Several studies indicate that the protective mechanisms in developing countries are not functioning properly which fuels our concern for trial participants in these countries. A 2005 study by the Indian Council of Medical Research revealed that less than a quarter of all Indian ethical review committees followed the prescribed guidelines and that in half of all such committees possible conflicts of interest could not be ruled out,” she adds.

“It is very important that the clinical trials address the public health priorities of the host countries. A trial should not be carried out if it does not address the public healthcare needs. If a drug is tested in a country, it should be made available in that country at a price that is affordable,” Annelies den Boer points out.

Ms Schipper adds: “Healthy volunteers earn money and sometimes participate in two trails at the same time or do not observe the requested time period of three months between two trials… It happens that western companies take advantage of the vulnerable position of patients, patients cannot afford treatment and therefore they accept the risks entailed in an experimental drug. After the trial treatment is no longer available. Also, informed consent procedures are not followed correctly.” Of the 18 inspections to clinical trials sites monitored by CROs, 11 failed to report adverse events, she points out.

Concerned over the unethical practices, global bodies have been demanding stricter rules in giving market authorisation to the drugs by the EMA. “Market authorisation must be denied to drugs that have not been ethically tested. Well, we are hopeful that by end of this year, the EMA will put in place some stringent regulations which are expected to make this possible,” she adds.

“Our overall indications are that the quality of trials carried out is influenced mainly by the quality of the sponsor organisations and their CROs, when they use CROs, rather than the countries in which the trials take place”, says Fergus Sweeney, head of sector, compliance and inspection, in an email interview.

“We have in the last two years further developed our strategy in relation to clinical trials that are submitted to us as part of marketing authorisation applications and which were conducted outside of the European Union.  That strategy has involved increases in the number of inspections, increased interaction with regulatory authorities outside of EU and contribution to capacity building for inspectors and ethics committees,” he further adds.

“Is is very important that patients participating in clinical trials are properly protected wherever in the world those trials are conducted.  Ethical principles are universal and not negotiable. Equivalent ethical and scientific standards should be applied everywhere in the world regardless of the current strengths or weaknesses of regulatory or other systems… . Patients’ views should be included from early on in this process to ensure the adequate protection of clinical trial subjects,” Sweeney asserts.

I cannot elicit any response from the DCGI despite several attempts through mail and phone. However, Dr Viswa Mohan Katoch (secretary to govt. of India department of health research (ministry of health & family welfare) & director general, Indian Council of Medial Research, says over phone from Delhi: “It is not right to interpret that these trials are not closely monitored in India. The process has been improving actually.”

“DCGI approves the trials which are subject to ethical clearances, other clearances and they are all on the websites of the ICMR,” he added.

Dr Katoch says his department is now in the process of drafting a Bill on biomedical research on human beings. “We plan to place the Bill in Parliament by the end of this year,” Dr Katoch said. “The Bill will address all aspects of clinical trials. There will be an authority taking care of all the aspects. There will be a coherent legislative structure in one place under which trials can be conducted.”

So till that time the Bill is in place, people are supposed to go on dying? Mr Jesani asks when I tell him about my conversation with Dr Katoch some days ago. “We’ve been hearing about the Bill since far too long to actually believe it will happen,” he adds.

LIVING IN SUSPICION

But for patients like Bhopal’s gas victims, the trust has somewhere snapped and it is constant suspicion and fear that engulfs them like MIC smoke of the fateful December night. Nasir Khan (34) of Nawab Colony died in August last year. Salma Bi, his widow and mother of four (the youngest, Moushin, being born the same day that Nasir died) is suspicious her husband was also a victim of drug trial. His prescription reads: “Blood Thinner Alert! You have been prescribed blood thinners (Aspirin and Clopidogrel). Please check your CBC with platelets every three months or if experiencing bleeding tendencies.” There’s nothing as such to indicate that Nasir was a trial subject; “but there’s nothing to prove that he was not either,” she insists.

Not all clinical trials went wrong at BMHRC and some may have even been beneficial to the gas victims, but it still is a story of mistrust piling upon mistrust like dust in the abandoned Union Carbide gas factory. And the same goes for the whole of India.

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An edited, shortened version of this article was published in French in Asies, August 2011 issue, with the headline Pharmacie du Bhopal.

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