Trial and Error

India’s complicated history with cervical cancer

Photo micrograph of a pap smear indicating the possibility of cancer in the cell. SCIENCE SOURCE/DINODIA PHOTO
Photo micrograph of a pap smear indicating the possibility of cancer in the cell. SCIENCE SOURCE/DINODIA PHOTO
01 June, 2018

MEERA DOES NOT KNOW HER AGE. She believes she is between 35 and 40 years old. Her home is in Rajokri, in south-west Delhi, near the financial and technology hub of Gurugram. The area was once a village, and its more than 10,000 people still largely rely on farming for income. Meera and her family live below the poverty line.

For as long as she could remember, Meera always had a mild pain in her lower abdomen. She has lost count of the number of times she had visited the local doctor, who always gave her some paracetamol and told her she was fine.

“No one thought it was anything but a stomach ache,” she told me. “If I hadn’t had screening tests done, I would have continued to take stomach pills.”

In July 2017, CAPED, an organisation focussed on cancer prevention and awareness in north India, organised a screening camp near Meera’s home. That was the first time she heard of cervical cancer. She went for the screening after someone from the organisation informed her that her symptoms may be signs of the disease.

Meera waited three months for a biopsy to confirm what by then she already believed to be true: she had cervical cancer. The constant back and forth to a government hospital that followed wore her down. “When I had to do it on my own, I had to stop,” she said. “The hospital is far away for me.” Finally, in January, she saw a doctor who told her she would have to have a partial hysterectomy to remove her cervix.

For Mridu Gupta, chief operations officer of CAPED, Meera is one of the lucky ones. Most women are unable to seek medical help in time. Even so, her case underlined the perseverance women with cervical cancer need in order to seek and complete treatment. “While she gets treatment from government hospitals, it’s very tedious and costly,” Gupta told me. “It is a reason why people drop out. There’s such a fight to even get basic healthcare, I’m very happy she is still at it.”

Meera’s case illustrates how complex combating a disease like cervical cancer is. It is not just about offering vaccination and screening. The healthcare system needs to be strengthened: women who test positive need to be linked to systems of care—care which is not only affordable, but also efficient. Moreover, there needs to be greater awareness about the disease and methods to deal with the stigma surrounding it.

“Forget about villages, even in schools and colleges, you barely have three women that would raise their hand because they know about cervical cancer,” Gupta said. “These girls and women can afford the vaccine and a pap smear but they don’t get it. Awareness is low and the atmosphere is so uncomfortable. Maybe talking about it will make a difference more than anything.”

CERVICAL CANCER IS THE FOURTH MOST COMMON cancer in women. The World Health Organisation estimates that there are more than 500,000 new cases of the disease every year. It causes 250,000 deaths annually—and India accounts for more than a quarter of these. Nearly all cases of cervical cancer are linked to infection with the Human Papilloma Virus, passed between people through intimate skin-to-skin contact.

Most sexually active women and men will be infected with HPV—and often reinfected—at some point in their lives, most likely around the time of their first sexual experience. However, unlike some other sexually transmitted infections, the majority of HPV strains do not cause symptoms or health problems, and clear up within two years. This makes it difficult for public-health systems to gather data on exactly how many people are affected by it. But persistent infection with specific types of HPV can lead to cervical lesions, which may progress to cancer. Other types of HPV can cause genital warts and rarer diseases such as anal cancer.

Despite India’s huge burden of HPV infection and cervical cancer, it has inadequate screening. That means large numbers of cases are identified, if at all, only after they reach advanced stages. If a woman is lucky enough to make it to a hospital in time, the prospects for effective treatment of late-stage cancer are poor, especially in areas with ill-equipped health systems.

In this scenario, the introduction of HPV vaccination could have an enormous impact. The WHO, along with international public-health experts, have acknowledged that screening and vaccination, when applied together, could prevent more than 70 percent of cervical cancers.

In June 2006, the US Food and Drug Administration approved Gardasil—manufactured by Merck, one of the largest pharmaceutical companies in the world—as the first vaccine to protect against four HPV types, including those that cause cervical cancer. This was heralded as a medical breakthrough, but when several US state legislatures tried to mandate compulsory vaccination for young girls, it led to great controversy. Concerns centred on the nature of Merck’s marketing of the vaccine and its high cost, but also on what some saw as too much state intervention in private life, and on whether the vaccination would encourage sexual behaviour among adolescents. Another HPV vaccine, Cervarix, manufactured by the pharma giant GlaxoSmithKline, was introduced in the European Union in 2007. By the end of 2017, 71 countries had introduced HPV vaccines into their national immunisation programmes.

Both vaccines became available in India’s private medical sector in 2008. They were, however, prohibitively expensive—priced between Rs 2,000 and Rs 3,000 for a single dose, in what is typically a three-dose course—and beyond reach for a large proportion of those who could benefit from it. “The rich can get their children vaccinated,” Sumanya Y, a doctor with Biocon Foundation, a health organisation based in Bengaluru, told me, but “no one else can get it.”

But the high cost of the vaccines is not the only obstacle to HPV prevention in India. In 2010, seven girls participating in an HPV-vaccine study were reported to have died from related complications. This link between the vaccines and deaths was strongly disputed, but not before scrutiny of the study had raised a host of uncomfortable questions about clinical trials, drug regulations and medical ethics in the country. It implicated a major international health organisation, two Indian state governments, and the country’s drug-licensing authority and health ministry in numerous irregularities and violations.

Following a legal petition filed in 2012 asking for the licences granted to the two vaccines to be rescinded, the fate of Gardasil and Cervarix, and the possible inclusion of HPV vaccines in India’s universal immunisation programme, now hinges on a Supreme Court judgment. Among the petition’s arguments is that though the vaccines “are claimed to prevent cervical cancer, the truth is cervical cancer takes 20 or more years to develop. The vaccines have just not been around long enough to prove their efficacy. … If these vaccines are given to women who already are infected with the virus, then they will raise the incidence of cervical cancer.”

Whatever the outcome of the case, the HPV-vaccination controversy will remain a landmark in India’s history with HPV and cervical-cancer prevention. “It was such as major fiasco,” Sanghamitra Singh, a senior manager at the Population Foundation of India, a health-policy think tank, told me. “The media just talked about how clinical trials are a disaster without trying to define the fact that the problem was not the efficacy of the vaccine. That hasn’t been explained very well to a layperson. The one faint recollection the public have of the vaccine is a horrid fiasco from 2009. Can you blame them?”

In June 2006, the US Food and Drug Administration approved Gardasil, the first vaccine to protect against HPV strains that cause cervical cancer. It became available in India in 2008. VOISIN/PHANIE/DINODIA PHOTO

But the implications of India’s trials with the HPV vaccine are likely to be even greater, as they highlight many of the issues the country still faces in responsibly adopting new vaccinations and treatments that are desperately needed by its disease-burdened population. For one, the incident showed that “a huge responsibility lies with health reporters,” Vidya Krishnan, the health and science editor at The Hindu, told me. “But usually horror stories unfold in rural pockets, and by the time the news gets to Delhi, it’s distorted.” In the wake of the controversy, India overhauled its regulations and procedures for clinical trials, but many complain that these remain opaque, and possibly discourage the introduction of new treatments. A 2017 report by the Indian Council for Research on International Economic Relations stated that “although most of these reforms were deeply desired, the absence of adequate regulatory guidance on specific issues, lack of clarity on legal terminologies and dearth of a sound communication strategy on the part of the drug regulator rendered the reform process counterproductive.” As a result, the report added, “the global perception of India in the context of clinical research suffered a serious setback.”

Meanwhile, cervical cancer continues to claim the lives of hundreds of thousands of women in India.

IN 2009, THE SEATTLE-BASED non-profit organisation Program for Appropriate Technology in Health, or PATH, launched a $3.6-million “demonstration project” involving HPV vaccinations in Andhra Pradesh and Gujarat. The organisation worked in collaboration with the two states’ governments and the Indian Council of Medical Research, or ICMR—the apex body in India dealing with biomedical research. The study was funded by the Bill and Melinda Gates Foundation, and was part of a global programme titled “HPV Vaccine: Evidence for Impact,” with similar projects in Uganda, Peru and Vietnam. Its goal, according to PATH, “was to help countries learn how to reach young girls with the vaccine,” and to understand such things as “what sociocultural barriers may impede acceptance of the vaccine.” In India, the study involved vaccinating around 43,000 girls aged between 10 and 14 in Andhra Pradesh with Gardasil, and around 10,000 girls from the same age group in Gujarat with Cervarix.

Several months into the study, in March 2010, news broke that seven girls participating in the study had died—five in Andhra Pradesh and two in Gujarat. Civil-society groups had already voiced concerns over the project, citing inadequate information in the public domain about the vaccines and a lack of transparency in the conduct of the clinical trials. In a 2009 letter to Ghulam Nabi Azad, then the union minister for Health and Family Welfare, several prominent public-health organisations, medical professionals and activists demanded that “all trials and studies to be brought immediately to a halt” till all questions relating to the “safety, efficacy and cost effectiveness of the planned intervention” could be answered. Women’s-rights and public-health activists also added to the pressure to suspend the project after local media reports drew a connection between the vaccines and the deaths.

The government suspended the study and created a committee of inquiry to investigate if there was indeed a link between the two, as well as whether there were “ethical issues of subjecting children of marginalised population to these studies.”

In 2011, the committee concluded that there was “no common pattern to the deaths that would suggest they were caused by the vaccine.” Two of the seven girls were found to have committed suicide by ingesting poison, one had fallen into a well, one had died from snakebite and another of malaria. The causes of death for the other two girls were less certain—one possibly died from high fever, and the second from a suspected cerebral haemorrhage.

As to possible ethical violations, the inquiry report found that other than “several minor deficiencies,” there was “no major violation of any ethical norm.” The most “significant deficiency” noted in the study was its failure to obtain informed consent. In the majority of cases, the committee found, it was school authorities, and not parents, who had signed off on behalf of the young girls who received the vaccinations. The deputy director of the Tribal Welfare Department in Andhra Pradesh’s Khammam district (now in Telangana) had issued a circular advising welfare officers and headmasters to “sign the consent form in behalf of the adolescent girls to have vaccines especially for hostellers at Ashram schools run by both Govt. & Private sector.” The report also noted that the “full explanation, role, usefulness, and pros and cons of vaccination” had not been properly provided to some parents.

All of this contravened the ICMR’s own guidelines as well as existing laws, which state that informed consent must be obtained in writing from either a parent or legal guardian of any child participating in a medical study. The committee emphasised that since “the study included vulnerable populations”—the girls were drawn from poor Adivasi families—“special care should have been taken about obtaining of consent.”

In HPV vaccinations worldwide, a routine report usually indicates common post-vaccine side effects such as nausea, severe allergic reactions and pain at the site of the injection. The follow-up reporting in these instances showed none of this—there was no system in place to document adverse effects at all. The committee found that state authorities “were not even capable of monitoring the adverse effects,” and that “PATH did not provide for urgent medical attention in case of serious adverse events whether known or unexpected.”

PATH has maintained that India’s regulatory frameworks for drug trials did not apply to the study, since it was not trying to establish the efficacy and safety of the vaccines or to research biomedical outcomes, and hence did not qualify as a clinical trial. “The objective of the post-licensure observational study,” it said in a statement when the controversy broke, was “to generate critical data and experience on effective strategies for public-sector HPV immunization programs, as part of a broader cervical cancer prevention and control strategy.” The committee report, however, categorically stated, “The committee is of the opinion that by whatever name you call it, the project proposal has been carried out as research on human participants. And as such it had to follow all the guidelines and statutory requirements applicable for research on human participants.”

Two years later, in August 2013, the Parliamentary Standing Committee on Health and Family Welfare recommended legal action against PATH, accusing it of violating ethical standards and national law. It said the entire matter was “very intriguing and fishy,” arguing that the entire programme’s choice of target countries and populations, and the massive market potential of the vaccines being used, pointed to a “well planned scheme to commercially exploit a situation.” It alleged that the goal of the study was to ultimately generate profits for the pharmaceutical industry, which was “a clear-cut violation of the human rights of these girl children and adolescents.”

The committee questioned the “overenthusiasm” of the ICMR and the department of health to “act as a willing facilitator to the machinations of PATH.” It demanded clarification from the health ministry as to why “permission was given to PATH to conduct such study on the Indian people and whether the programme was a clinical trial or promotional activity.” In a later report, the ministry agreed that given the principles laid out by the Central Drugs Standard Control Organisation and the Drugs and Cosmetics Act, the study should have fallen under legislation governing clinical trials and should not have been designated an observational study. The Drugs and Cosmetics Act states that “all vaccines shall be new drugs unless certified otherwise by the Licensing Authority,” and that “a new drug shall continue to be considered a new drug for a period of four years from the date of its first approval.” At the time of the deaths, it had only been a year since the two HPV vaccines had acquired market approval.

Biocon Foundation, part of the corporate social- responsibility arm of Biocon, is one of a few organisations who run screening camps for poor women. COURTESY BIOCON FOUNDATION

After the parliament’s rebuke of the study, Ramanan Laxminarayan, then the vice president for research at the Public Health Foundation of India, told the media it would “have a freezing effect on all clinical research.” He expressed concern that researchers would give up on clinical trials in India rather than navigate complex regulations.

While the ministry conceded that the whole debacle was “a collective failure,” it said that no single event, individual or agency could be held accountable for the ethical violations that took place. It recommended treating the incident as a “learning experience.” Even if PATH stood to benefit from the arrangement, it continued, the vaccine itself was “linked to benefit human health” and provided a “new opportunity for the prevention of the cancer of cervix, which is an important health burden for the women of our country.”

PATH’s communication team rejected my request for a phone interview with Vivien Tsu, the director of the organisation’s cervical-cancer prevention programme. In an email relayed to me by the communication team, Tsu strongly opposed the standing committee’s findings, which she said disregarded “the evidence and facts.”

“It’s important to be clear that this was not a clinical trial,” Tsu said in her statement. “It was a post-licensure observational study that involved the use of approved, licensed vaccines.” She said that health workers had obtained “written informed consent for the study participants from parents, or authorised guardians,” and that “verbal assent from each girl was taken prior to each dose of the vaccination.” Tsu added that “poor and low-income girls in India should not be denied the right or access to this proven, life-saving and safe vaccine that wealthy and middle-class girls in India and around the world have had.”

IT WAS A MILD WINTER AFTERNOON in early January on the outskirts of India’s IT capital, Bengaluru. Traffic, like everyone had warned me, was at a standstill, even kilometres outside of the city centre. I was travelling to Hennagara, a village about an hour and a half’s drive away. On the way I passed construction sites, new high-rise buildings and simple villages, dotted with palm trees.

I arrived at the Hennagara’s primary health centre to find women, young and old, waiting on old wooden benches inside. The centre, sponsored under a corporate-social-responsibility effort, was a far cry from the public hospitals and health centres I had visited across the country before. It was clean, organised and orderly. The smell of chai bubbling away on a stovetop in one room wafted throughout the premises.

The women, about twenty of them in all, had walked here from neighbouring villages after hearing about a free screening camp for breast and cervical cancer. For many, this was the first time they had heard about either cancer, let alone been screened for it.

Biocon Foundation, part of the corporate social- responsibility arm of Biocon, is one of a few organisations who run screening camps for poor women. RAFIQ MAQBOOL/AP PHOTO

I met Laksmi, a 26-year-old dressed in a red sari, wearing red and gold bangles, and with freshly oiled hair. She was next in line for a pap smear—a routine screening test to check for cervical cancer—but at the last minute she walked out of the doctor’s small office, shaking her head. A community-health worker ran after her and stopped her in the corridor.

“I don’t have any problem,” Laksmi said. “I don’t want to do it. I won’t do it.”

“You should do this. I’ve done it before,” Mangala, the community-health worker, told her. “It’s good to prevent health problems before they come. You can prevent cancer.”

For Mangala, and the other health workers at the centre, Laksmi’s reaction was not a surprise. “That happens once they see the instrument,” Mangala told me. “They will feel shy. They do not want to show their private parts.” The concept of preventive medicine is not well established in India, which is partly why women with cervical cancer or at risk of it usually present late—often too late—for treatment.

The screening camp was run by Biocon Foundation, part of the corporate social-responsibility arm of Biocon, a biopharmaceutical company. The foundation is one of a few organisations providing such screening for women from poor communities in India. Some women who attended were found to have advanced lesions, while many more were found to have untreated reproductive-tract infections. Mangala told me that many women in her village had refused to come for the check-ups, fearful of what doctors might find. “They often refuse to come until they get symptoms,” she said.

A senior programme manager at the foundation, Suchitra Bajaj, told me one of its biggest challenges was getting women who do not feel ill or have symptoms to leave behind their families, household duties or work to come for screening. In other words: women’s circumstances do not allow them to prioritise their health. “With oral cancer you can do population-based screening house to house, but when it comes to cervical cancer, it’s difficult,” Bajaj said.

Any discussion of sexual and reproductive health is highly taboo in India. Too often, women’s health needs are only seen through the lens of reproduction. Other aspects of their well-being—the right to sex education, to decide whether and when to be sexually active or have children, to consent in marital and sexual relations, and to be free from all forms of violence and coercion—are rarely spoken of.

“Awareness about reproductive health is very limited,” Bajaj told me. She cited the high number of women the foundation sees with untreated reproductive tract infections—which are not only preventable but also easily treatable with antibiotics or antifungals. But women are unable to talk about discharge or pain without feeling embarrassed. This sense of shame is often fuelled by the belief that cervical cancer is a direct consequence of promiscuity, and women who develop it are accused of having done something immoral.

Mridu Gupta from CAPED, the cancer-prevention group, told me that stigma about the disease transcended social and economic boundaries. “Even if we do screening for them, it’s not like it is all done,” she told me. “Women who are confirmed to have cervical cancer have a difficult journey. The families can’t afford treatment. I haven’t seen families take women for treatment.”

Singh referred back to the concept of preventive medicine. “The concept of just a routine medical check-up isn’t established as it is in the West or more developed countries. That whole concept comes from an entitled space,” she told me. “At this point in time, screening for cervical cancer is not as big of an issue as other diseases.” Singh had seen women from all walks of life call their cervical cancer something else—anything but a cancer which affects their reproductive organs. “Nothing can remove the stigma,” she said. “We try to explain it can happen to anyone. These women don’t tell anyone, and by the time her family believes that there is something wrong with her, it’s too late.”

Bajaj was clear as to why the disease has been neglected by all realms of society. “Because it is a woman’s problem and only affects women,” she said.

Leela Visaria, a social researcher and honorary professor at the Gujarat Institute of Development Research, was angered that the rhetoric around the HPV vaccine was being pushed by “a bunch of guys,” who, according to her, lacked even a basic scientific understanding of the issue. “The underlying reason why people don’t want the vaccine is the fact it’s given to adolescent girls,” she told me. “They fear that girls will become promiscuous.”

Suspicion of the HPV vaccine is not just confined to India. Japan, Ireland and Denmark have all witnessed anti-vaccination campaigns that caused HPV vaccination rates to plummet. In Japan, coverage rates of young women recieving the vaccine fell from 70 percent in 2013 to less than 1 percent today, after the media reported on a fraudulent study showing that HPV vaccination caused brain damage in mice. Taking advantage of public sentiment, anti-vaccination groups also associated the vaccine with a host of other health problems.

Singh, who is working on a position paper on HPV vaccination to present to the government, said people were too heavily focussed on issues that had nothing to do with the efficacy of the vaccine. “The question here is not about promoting sexual activity,” she told me, “it’s about the efficacy of the vaccine … which is more effective when given to girls before they’re sexually active.” She likened the misconception around HPV vaccination to “educating a young boy about condoms but saying it will encourage him to have sex. It’s very bizarre.”

Soumya Swaminathan, deputy director-general of WHO, agreed. “Social norms are changing,” she told me, speculating that more young people are having sex, regardless of whether they were married. “Therefore it would be better to protect girls rather than think they’re going to become promiscuous because of a vaccine.”

AS A RESULT OF THE HPV CONTROVERSY, in 2013, the regulatory framework for clinical trials underwent a massive overhaul. The reforms included, among other things, stricter approval criteria for clinical trials, setting up new drug advisory committees, requirements for the audio-visual recording of consent, and an amendment to the Drug and Cosmetics Act making provisions for the rights, safety and well-being of trial subjects. It was only after the HPV case that legal provisions for compensation in the event of death or injury during clinical trial were introduced.

ANINDITO MUKHERJEE/REUTERS

In December 2017, the National Technical Advisory Group on Immunisation, the government’s highest advisory body on immunisation, held a meeting with more representatives from the health ministry, independent public-health experts and international partners. Afterwards, the NTAGI recommended that the HPV vaccine be introduced into India’s universal immunisation programme. It stipulated, in accordance with recommendations by the WHO, that girls be vaccinated between the ages of 9 to 14, and that the goal should be to introduce the vaccine country-wide. The group agreed that the use of specific HPV vaccines in the programme was subject to the pending Supreme Court judgment regarding the licensing of Gardasil and Cervarix, but also noted, according to the minutes of the meeting, “The safety of these vaccines has been reviewed by multiple medical authorities and regulatory agencies including World Health Organisation, Global Advisory Committee on Vaccine Safety, Food and Drug Administration. … Available HPV vaccines have an excellent safety profile and nearly 270 million doses have been given globally.”

The NTAGI’s recommendations stoked the controversy again, creating widespread division among the medical community, NGOs and government bodies over its endorsement of HPV vaccination. Last year, the Swadeshi Jagran Manch, an affiliate of the Rashtriya Swayamsevak Sangh, wrote to Prime Minister Narendra Modi asking him to stop the introduction of the vaccine, and recommending “the strongest action against groups that pervert science, which brings ignominy to the scientific community in the country and sells the country to vested interests.” Meanwhile, Rajesh Dikshit, a professor of epidemiology at the Tata Memorial Centre in Mumbai, told the Indian Express that the HPV vaccine “has not been proven to prevent a single cervical cancer death.” Numerous other experts echoed this view.

Sanghamitra Singh, of the Population Foundation of India, told me that, besides the vaccines’ high costs, the country’s many competing health priorities also complicated the nationwide adoption of HPV vaccines. She alluded to major infectious diseases such as tuberculosis, and to the fact that not all children were receiving scheduled vaccines for such things as measles-rubella or pneumonia. While India is receiving support from the international organisation Gavi, the Vaccine Alliance, to vaccinate children against a range of diseases, the country began transitioning away from this support last year and is expected to fully self-finance all its vaccine programmes by 2021. Gavi has offered to assist India in introducing HPV vaccines if the government approves their use, but time is running out.

“It’s important for the government to reflect whether the public healthcare system is ready for it. My view is that the government is not ready to commit to it,” Singh said. “Most people are struggling to access primary healthcare.” Some states, however, have decided to go ahead with the vaccines themselves. In late 2016, Punjab and Delhi, with technical support from WHO, began vaccinating schoolgirls aged 11 to 13 as part of their health programmes.

Meanwhile, women’s rights groups and public-health activists are working to strengthen screening methods. NB Sarojini, the director of Sama, an NGO that works on women’s health, said improving the availability of screening is proven to drastically boost early diagnosis of cervical cancer, and so reduce rates of mortality.

In late 2016, the ministry of health published an operational framework for the country’s first national cancer-screening programme. It outlined mandatory screening for all women aged between 30 and 65 for oral, breast and cervical cancers. Initially set to run in 100 districts, the programme is meant to expand nationwide. The framework stated that village-level health workers would be trained in a method of visual inspection for cervical cancer using acetic acid, as would medical officers and staff nurses at local clinics. While on paper the screening programme sounds promising, more than a year on from the launch, it is unclear whether any progress has been made in the districts. Some experts I contacted did not know that such a programme existed.

There are other problems. Sarojini said that in many states there were not even local health workers at district-level hospitals who could perform the visual inspections, let alone gynaecologists. Even if screening was available, she pointed out, it alone would not be enough. “What happens to the women who are positive? What about the lesions that are found?” she asked. “Treatment is very expensive.”

BACK IN HENNAGARA, women continued to stream in to see the doctor, Sumanya Y, for cervical-cancer screening in the small room she occupied at the health centre. Their next stop was a breast-cancer check in the room next door. While they waited for their names to be called, they sat on the old wooden benches laughing and gossiping.

Laksmi proved impossible to woo back. She left the clinic and walked home alone.

“It’s difficult to convince people,” Sumanya Y told me. “And when you do, it’s too late and too difficult to do anything about it.”


Sophie Cousins is a health journalist and writer. Her work focusses on the systems that perpetuate inequality and the impact this has on women’s and girls’ health.