By Priya Shetty of Nature magazine

A clinical trial that came under fire in India threatens to have a dual legacy: inflaming unfounded fears about a lifesaving vaccine and raising new questions about the management of medical research in the country. After four teenage girls taking part in a test of human papillomavirus (HPV) vaccines died last year, the Indian government faced accusations that its citizens were being used as guinea pigs to test dangerous vaccines. A scientific investigation has exonerated the vaccines but uncovered a more familiar problem in India: ethical irregularities.

The study, funded by the Bill & Melinda Gates Foundation and run by the international health charity PATH and the Indian Council of Medical Research (ICMR), vaccinated more than 23,000 girls aged 10-14 against HPV, which can cause cervical cancer. The vaccines--Merck's Gardasil and GlaxoSmithKline's Cervarix--are already in widespread use in the developed world, and the study was designed to assess the feasibility of launching an HPV-immunization program in the Indian health system. The researchers hoped to gauge public acceptance of the vaccines and assess the costs of administering it in different parts of the country.

A committee of three scientists from the All India Institute of Medical Sciences (AIIMS) in New Delhi, commissioned by the government to look into the trial, confirmed that the deaths were not linked to the vaccines--two of the girls died of poisoning, one of drowning and the fourth of a fever. But its report, leaked to India's media last month, said that the study involved several serious ethical violations. According to media reports, participants were recruited from vulnerable tribal populations, consent was improperly obtained--headmasters of the girls' schools signed the forms--and adverse events were poorly recorded.

The scientists also criticized Indian regulators for classifying the HPV study as an observational rather than a clinical trial, which meant that it was subject to different regulations, including looser reporting of side effects. The expert committee deemed it to be a clinical trial because it was a "study of a pharmaceutical product carried out on human participants" and "4 of 5 primary outcome measures proposed related to evaluation of the safety of the vaccine".

Vivien Tsu, director of PATH's HPV vaccines project, says that the procedures criticized in the report had all been approved by state ethics boards in India and an independent review board in the United States. "The problems the report raises, over the poor reporting of adverse events, for instance, were the sorts of issues that the study was intended to tease out," she says. Vishwa Katoch, director-general of the ICMR, says that his organization "had advised on ethical issues when the study was being planned. All necessary ethical approvals were there; the problem was how different individuals or teams implemented it."

Still, the verdict could pose a setback to the country's ambitions to become a hub for international clinical trials, luring drug developers with its large patient population and low costs. Rani Kumar, dean of the AIIMS, who assisted the investigating committee, declined to speak to Nature. But India's weak ethical infrastructure has been heavily criticized in the past for having few well-trained ethicists, and poorly run ethics boards. A clinical-trials registry was introduced in 2007 in a bid to better regulate clinical research, but "India still needs clear national guidelines on the ethical conduct of clinical trials", says Ramanan Laxminarayan, vice-president of policy and research at the Public Health Foundation of India in New Delhi. Shortly after the HPV report hit the headlines, the Drugs Controller General of India produced, for the first time, draft guidelines on the reporting of adverse events in clinical trials.

Heidi Larson, an anthropologist at the London School of Hygiene & Tropical Medicine who studies the social acceptance of vaccines, says that the collapse of the HPV trial highlights one of the key problems in research collaborations between developed and developing countries. Ultimately, she says, international researchers are obliged to work within the ethics capacity of the host country, regardless of whether or not it is robust. Trying to align different expectations over research ethics can be especially tricky, Larson adds. "How do you negotiate local versus national versus international tensions?"

Meanwhile, India's vaccination plans could suffer collateral damage from the controversy. India decided in 2008 to roll out a new pentavalent vaccine against diphtheria, pertussis, tetanus, Haemophilus influenzae type b (Hib) and hepatitis B. Public objections over fears of dangerous side effects reported in Sri Lanka and the vaccine's high cost delayed the program. Vaccination is finally due to start next month, but only in Tamil Nadu and Kerala, southern states chosen because their routine immunization coverage is already high, says Ajay Khera, deputy commissioner of India's Universal Immunisation Programme.

Vaccination fears that have made headlines in the West are now taking hold in countries such as India, says Larson (H. J. Larson et al. Lancet doi:10.1016/S0140-6736(11)60678-8; 2011). Because most of the vaccines now in development are aimed at diseases common in the developing world, such as malaria, tuberculosis, leishmaniasis and helminth infections, anti-vaccination movements in such countries could have a major impact on public health, adds Richard Moxon, a pediatrician at the John Radcliffe Hospital in Oxford, UK.

Jacob Puliyel, head of pediatrics at St Stephen's Hospital in Delhi, has been a vocal opponent of both the HPV vaccines and the pentavalent vaccine. He does not endorse the vaccine fears that gripped the public after the four girls' deaths, but he told Nature that too little is known about the prevalence of Hib and HPV-related cervical cancer in India to justify the new vaccines. At a time when India is already struggling to achieve universal coverage with existing vaccines--coverage for basic childhood immunizations is just 63 percent, according to Khera--the country simply cannot afford them, Puliyel says.

This article is reproduced with permission from the magazine Nature. The article was first published on June 22, 2011.