NEW DELHI—In another sharp blow for researchers hoping to conduct clinical trials in India, a parliamentary panel has excoriated a U.S. nonprofit and its Indian partner for alleged ethical violations in a trial of a vaccine to protect against cervical cancer caused by the human papillomavirus (HPV). The panel's report "will have a freezing effect on all clinical research," predicts epidemiologist Ramanan Laxminarayan, vice president for research at the Public Health Foundation of India in New Delhi.
HPV infection is a leading cause of cervical cancer; each year, nearly 73,000 women in India die from the disease—about one-quarter of the global disease burden. A vaccine against the virus has been available in the United States since 2006. Hoping to broaden the vaccine's use in the developing world, the Program for Appropriate Technology in Health (PATH), a nonprofit based in Seattle, in 2009 launched a $3.6 million HPV trial, funded by the Bill & Melinda Gates Foundation, in 24,777 adolescent girls in Andhra Pradesh and Gujarat states. PATH conducted what it calls similar "post licensure demonstration projects" in Uganda, Peru, and Vietnam. But several months into the Indian trial, the government pulled the plug after news outlets reported the deaths of seven girls.
State investigations absolved the trial's managers—PATH and the Indian Council of Medical Research (ICMR) in New Delhi—of responsibility in the deaths. Five were evidently unrelated to the vaccine: One girl drowned in a quarry; another died from a snake bite; two committed suicide by ingesting pesticides; and one died from complications of malaria. The causes of death for the other two girls were less certain: one possibly from pyrexia, or high fever, and a second from a suspected cerebral hemorrhage. Government investigators concluded that pyrexia was "very unlikely" to be related to the vaccine, and likewise they considered a link between stroke and the vaccine as "unlikely." ICMR's director general, microbiologist Vishwa Mohan Katoch, categorically rejects a connection: "Based on the enquiry, it is certain that causality of the seven deaths was not at all related to the HPV vaccine," he insists. Other experts say that in the absence of autopsies, it is impossible to pinpoint the actual cause of death.
Probing deeper, a panel appointed by the Indian health ministry in 2010 uncovered a number of shortcomings and alleged ethical lapses in the vaccine trial. Its report in 2011 noted that the trial on several occasions failed to obtain proper informed consent of participants. It also revealed that trial managers did not set up a mechanism for reporting any adverse effects, and it criticized the lack of a control group and the trial's inclusion of girls from India's protected tribal communities without gaining individual consent. "The HPV trial was not handled well. The trial did not comply and meet the standards of good clinical practice," says Maharaj Kishan Bhan, an immunologist who led a large clinical trial on a rotavirus vaccine approved earlier this year in which PATH was also a partner.
Now, an all-party parliamentary panel has come down even more harshly on PATH—and on ICMR and the Drugs Controller General of India as well. Its 30 August report blasts PATH and ICMR for failing to have conducted postmortem examinations of the girls who died during the trial. And it levels an astonishing allegation: Rather than endeavoring to protect women's health, PATH, it charged, was a willing tool of foreign drug companies hoping to convince the Indian government to include the HPV vaccine in its universal vaccine program, a roster of mandatory immunizations that the government is required to pay for. (HPV vaccine continues to be available in the Indian private sector.) ICMR, the panel's report asserts, has "completely failed to perform [its] mandated role and responsibility as the apex body for medical research in the country. … Rather, in [its] over-enthusiasm to act as a willing facilitator of the machinations of PATH, [it has] even transgressed into the domain of other agencies which deserves the strongest condemnation and strictest action against [it]."
Some commentators see merit in that argument. The three-dose HPV series costs approximately $150 in India. The fact that Merck, which makes Gardasil, and GlaxoSmithKline, maker of Cervarix, donated almost $6 million worth of their vaccines to the PATH trial "was not philanthropy," asserts Chandra M. Gulhati, editor of the Monthly Index of Medical Specialities, an influential journal in India. "It is shocking to see how an American organization used surreptitious methods to establish itself in India," he charges. "This is an obvious case where Indians were being used as guinea pigs," contends Samiran Nundy, a gastrointestinal expert at the Sir Ganga Ram Hospital in New Delhi and editor emeritus of the National Medical Journal of India.
In a statement, PATH said that "we strongly disagree with the findings, conclusions, and tone of the released report and its disregard of the evidence and facts." Contacted by ScienceInsider, Vivien Davis Tsu, director of the Cervical Cancer Prevention Project at PATH, did not comment on the report's allegations. "We remain committed to our legacy of ethical, evidence-based work on transformative innovations that save lives," she says. The Gates Foundation noted in a statement that the World Health Organization, the International Federation of Gynecology and Obstetrics, and the Federation of Obstetric and Gynaecological Societies of India all have recommended vaccination "as a proven and highly effective preventive measure for cervical cancer."
Katoch acknowledges lapses in trial management. "Our conduct in terms of monitoring the study could have been better," he says. New clinical trial regulations now being drafted by Parliament will tighten procedures governing trials, he says. "India will come out stronger after this episode."
Still, the fallout from the parliamentary panel's report could be severe. "After this episode, it will be harder to do clinical trials in India," predicts geneticist Krishnaswamy VijayRaghavan, secretary of the Department of Biotechnology. Laxminarayan worries that researchers will give up on clinical trials in India rather than navigate a maze of complex regulations that he believes are bound to be introduced in the wake of the HPV trial. All eyes are now on the Supreme Court, which on 26 September will resume hearings on a case broadly looking at clinical trials in India. Biomedical scientists better brace for trouble: In July, the court's two-judge bench observed that while foreign companies "are treating India as a heaven for clinical trials, it is proving hell for India."
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