By Sandhya Srinivasan

In the '70s and '80s, over 1,000 women with precancerous lesions of the cervix were left untreated, without their knowledge, to see how many developed cancer. In 1999, 25 patients of oral cancer were given an experimental drug without their knowledge or consent. How ethical are clinical trials in India?

Monitoring the progress of cervical cancer

From 1976 to 1988, researchers at the Institute for Cytology and Preventive Oncology in New Delhi studied what happened to different stages of cervical dysplasia or precancerous lesions of the cervix in 1,158 women -- by leaving them untreated to see how many developed cancer.

Women with mild, moderate and severe dysplasias were observed to see how many lesions progressed to cancer, and how many regressed. The study was sponsored by the Indian Council for Medical Research.

The women were not informed of what was done, let alone asked for consent. The researchers argued that they took verbal consent from the women who were illiterate. They also argued that there was "no conclusive evidence" that all severe dysplasias would progress to cancer, hence it was okay to monitor them to see what happened. But the study could not have been done in the West, as it was generally accepted that severe dysplasias needed treatment to prevent them from progressing to cancer.

Result: By the end of the study 71 women had developed malignancies. For at least nine women, the lesions progressed to invasive cancer. Sixty-two women were treated only after they developed localised cancer. Ten women with severe dysplasias were lost to follow-up. After the controversy about the study became public in 1997, the ICMR started developing ethical guidelines for biomedical research in humans, finalised in 2000.

Barefoot doctors and cowboy "research"

In the 1990s, a pair of US-based "barefoot researchers" led a massive, illegal multi-country trial of the potentially hazardous anti-malarial drug quinacrine as a terminal contraceptive -- the drug was inserted into a woman's uterus where it caused inflammation and literally burned and scarred the fallopian tubes to seal them off. The procedure had been halted in the West after the WHO asked for the results of toxicology studies before proceeding any further. The Americans smuggled the drug into the country and distributed it directly to practitioners in West Bengal and elsewhere. More than 30,000 women in India were sterilised using this illegal and untested method, at least 10,000 in West Bengal alone. (Thousands of poor women in Vietnam, Bangladesh and other developing countries were experimented on as well.)

Result: Following a case in the Supreme Court filed by activists, quinacrine sterilisation was banned in India. But the doctors simply shifted to testing another drug -- the antibiotic erythromycin -- for the same purpose. They even got their results published in an international journal.  And quinacrine continues to be available -- illegally -- in rural West Bengal, as journalist Rajashri Dasgupta found out in a study of the after-effects of the drug.

Experimental cancer drug tested without people's consent

Starting in November 1999, 25 people with oral cancer who went to the government-run Regional Cancer Centre in Thiruvananthapuram were given an experimental drug, the chemical tetra-O-methyl nor-dihydro-guaiaretic acid (M4N) or tetraglycinyl nor-dihydro-guaiaretic acid (G4N), though there was an established treatment for their condition. They were not told that they were taking part in an experiment or that they were being denied an established treatment. Only later did it become known that the trial had not been approved by the Drugs Controller of India (approval was obtained retroactively). Further, the sponsor institution, the Johns Hopkins University in the United States, had not given ethical clearance to the study, but managed to release the money for research anyway.

Result: The Indian Council of Medical Research conducted an inquiry into this trial but the results have not been made public.

 Diabetes drug tested on humans before toxicology studies completed

In 2002, the multinational company Novo Nordisk conducted multi-centre phase III clinical trials of a diabetes drug before receiving the results of animal studies. The study report found that the drug, ragaglitazar, caused urinary bladder tumours in rats -- and this should have been known before the drug went for phase I trials, let alone phase II and phase III. Ragaglitazar was developed by Dr Reddy's Laboratories, Hyderabad, and licensed to Novo Nordisk which conducted the trials.

The trials were conducted on 650 people from North America, 200 from Latin America, 100 from Australia / New Zealand, 800 from the European Union, 200 from non- EU Europe and 550 from Asia -- including 130 people from eight centres in India. Half of these people received the experimental drug.

Result: Novo Nordisk refused to give further details on the Indian centres and whether the people were affected, citing "confidentiality".

Drug promotion as "research"

In 2003, Mumbai-based Sun Pharmaceutical Industries Limited launched a promotional-cum-"research" programme by getting private doctors to prescribe the anti-cancer drug Letrozole to more than 400 women as a fertility drug for ovulation induction. They then publicised the doctors' reports to other doctors as "research", using their network of medical representatives. 

Result: Off-label prescription of drugs was banned in India, prompting the Indian Medical Association to launch a campaign to permit off-label prescription.

Research in emergency situations

In 2003-2004 the drug company Shantha Biotech ran a bioequivalence study testing its version of the "clot-buster" streptokinase against the established one. Streptokinase is given as emergency life-saving treatment to stroke patients. While there were various controversies about whether the company had taken the correct permissions to conduct the study, the important questions are: could the patients have given their consent to participate in the trial? And second, while deaths were expected in the trial since the patients were in a critical condition, was any compensation discussed or offered?

Result: The company launched an investigation and found that its attackers were a competing pharmaceutical company. But that doesn't answer the questions: what assurance does the public have that participants in this trial of an emergency drug gave their informed and voluntary consent? And as trial participants, were they not entitled to compensation in the event of a severe adverse event -- even an expected one?

Could they have given their consent to this trial?

In 2002, Dharmesh Vasava was among a number of daily wage workers who were given a psychiatric drug as part of a bioequivalence study sponsored by the Mumbai-based Sun Pharmaceuticals. He developed pneumonia and died. The People's Union of Civil Liberties, Vadodara, conducted an investigation into the death. PUCL suggested that the participants were unlikely to have been able to give their voluntary informed consent to participate. Second, was their health checked properly before entering the trial, and monitored closely during it? Incidentally, bioequivalence studies are conducted by drug exporters, to prove that their product is as effective as the approved branded version. They are not needed by Indian regulatory authorities.

Result: The daily wage workers were nomadic tribals. It is not possible to trace them and see what happened to the entire group.

Contraceptive research adventures

In the late-1980s, the National Institute of Immunology conducted trials of a contraceptive vaccine on a total of 162 women. Only 94 of them "volunteered" for long-term follow-up. What happened to the rest?

Starting in 2001, the government has been conducting trials of the injectable contraceptive Net-En in 12 medical colleges, as a prelude to introducing it in the government family planning programme -- though there have been reams of material suggesting that the drug has a number of health risks, requires extensive screening that is not possible in a health system such as India's, and is likely to be used without the woman's consent, given India's history of unethical practice in contraceptive research and practice.

Result: The Indian government has started a publicity campaign in the press about how popular the injectable is with poor women. The public has no information on what kind of informed consent the women gave to participate in the trial, the extent and quality of follow-up, or whether participants suffered any adverse events, including death.

These reports have been gathered from various articles by Ganapati Mudur in the British Medical Journal and Amit Sengupta in the Indian Journal of Medical Ethics.

InfoChange News & Features, November 2005

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