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Unethical cancer trials in India may have led to 254 pointless deaths, claims American doctor

But researchers behind the study say that their findings have led to the implementation of large-scale cervical cancer screenings across the developing world.

Cervical cancer is recognised as one of the leading causes of cancer-related deaths among Indian women, killing an average of 72,000 women every year. Since 1997, however, at least 254 such deaths may have occurred because Indian women from lower-income groups were misinformed and not given basic pre-cancer screening tests even as they participated in research studies on cervical cancer.

This is a contention that Dr Eric Suba, an American pathologist and medical ethics proponent, has been making for several years in relation to three major long-term cervical cancer studies conducted in India between 1997 and 2012. All three studies received funding from prominent agencies in the United States: the US National Cancer Institute and the Bill and Melinda Gates Foundation. They were conducted by reputed institutions, namely the Tata Memorial Hospital in Mumbai and the World Health Organisation’s International Agency for Research on Cancer. They were conducted on 363,553 women – all from lower-income backgrounds – from Mumbai, Osmanabad district in Maharashtra and Dindigul district in Tamil Nadu.

Dr Suba’s contentions that the studies were "scientifically gratuitous" and ethically questionable have received considerable attention in international medical circles in the past few years, but were virtually unheard of in India.

On February 4, in a bid to draw more public attention to the controversy, Suba presented his analysis of the three studies in a lecture on the ethics of international public health research at Mumbai’s KEM Hospital. “In my opinion, these studies are the worst betrayals of science and ethics anywhere in the world in the 21st century,” alleged Suba in an interview with Scroll.in two days before his Mumbai lecture.

However, doctors from Tata Memorial Hospital, who were also present at the lecture, refuted Suba's claims and maintained that the studies were not unethical and have in fact led to the implementation of large-scale cervical cancer screenings across the developing world.

Putting women at risk of death?

Suba, who also heads the non-profit Viet/American Cervical Cancer Prevention Project, spent several years pushing for Pap smear screenings at the public-health level to prevent cervical cancer in Vietnam, and these efforts have borne fruit in the past 15 years. Across the world, he says, the medical community has long established that screening women for pre-cancerous lesions – through tests like the Pap smear, the HPV, or visual inspection with acetic acid (VIA) – and then treating those lesions, successfully prevents the development of cervical cancer later.

The main problem with the three studies in India, said Suba, is that they compared one group of women who received some form of screening for pre-cancerous lesions (the “intervention” group) with another group of women who received no screening at all (the “control” group). At the outset, the presence of the control group would imply that the studies broadly aimed to determine which group showed lower incidences of cervical cancer and lower rates of cancer deaths.

This, according to Suba, is an instance of “contemplating a question that has already been answered”, making the studies “scientifically pointless”: since screening is already a medically well-established means of detecting lesions that could later develop into cancer, it is obvious that the unscreened control groups would show higher incidences of cancer and higher death rates.

More disturbingly, says Suba, not screening women in the control group effectively meant letting potential lesions go undetected. If those lesions then developed into cervical cancer, the unscreened women would be diagnosed with the disease only at a later stage, when symptoms such as pelvic pain or vaginal bleeding became apparent. This is tantamount to putting participants at risk for cancer and death for the sake of a research study.

If Suba’s contention is legitimate, then the human cost of the three research trials is staggering. Of the 363,553 women who signed up for the trials, 138,624 were in the control group. Of these, 254 eventually died of cervical cancer. The intervention groups had a larger number of women – 224,929 – and of them, 208 died of cancer.

“All over the world, in cervical cancer trials, all participating women are screened, and different groups are created to study the effectiveness of different forms of screening tests,” said Suba, who believes the 138,624 women in the control groups of the studies were victims of misinformation, because no well-informed woman would wilfully choose the risks of cancer and death. “How could women choose to participate in the no-screening group and still be informed?”

Ironically, in a paper defending their stance, the doctors who conducted the studies claimed that the aim of the trials was to “provide an affordable, feasible, effective and evidence-based way of preventing cervical cancer in low and middle-income countries”. After Suba's February 4 lecture, Dr Rajendra Badwe, the director of the Tata Memorial Centre and one of the doctors on the team that conducted the Mumbai study, said that the aim of that study was "mortality reduction".

According to Suba, this actually legitimises his claim that the control group was, in fact, redundant, because deciding against screening women is not a way to prevent cervical cancer or reduce mortality.

Relative standards of care?

The three studies that Suba has been questioning in various academic papers since 2004 have been published in reputed medical journals. The doctors heading the trials have presented them at international forums as landmark studies that have led to the implementation of large-scale cervical cancer screening not just in India but also in other developing countries.

The doctors behind the studies – most notably Dr Rengaswamy Sankaranarayanan and Dr Surendra Shastri – have refuted and dismissed Suba’s allegations in a joint paper published in the Indian Journal of Medical Ethics in June 2014.

Their paper – a response to Suba’s own paper published in the same journal – argues that women in the control groups, in Mumbai as well as the other two studies, were not misinformed, but offered cancer education in their local languages.

“In our studies, the control group women were taught about cervical precursor lesions and cancer and how it can be detected early through screening and prevented, and they were given information on where they can seek screening,” said Dr Sankaranarayanan, the head of the cancer screening group of the International Agency for Research on Cancer, in an email to Scroll.in.

The US National Cancer Institute, which funded the Mumbai trials with grants amounting to $2.6 million from 1997 to 2014, also told Scroll.in that the participants were "educated" about cancer screening: "All women enrolled in the trial, in the experimental and control groups, received education about cancer screening and had access to cancer screening, if they sought it, at Tata Memorial Hospital."

These women were not actively screened for pre-cancerous lesions because the control group was meant to represent the regular standard of care for cervical cancer screening in India – as opposed to the intervention group, which would represent the higher standards of care given through one form of screening or the other.

In a 2014 interview with Global Oncology about the Mumbai study, Dr Surendra Shastri claimed that “since the standard of care for cervical cancer screening in India is no screening, we were ethically justified in having a no-screening control group”. For many medical ethicists, this itself is a controversial argument, as they believe that standards of care cannot be relative to the economic situation of a country.

Relative standards of care?

The ethical questions that Suba has raised have, in recent years, drawn more media attention and concern from organisations in the field of research ethics. In 2011, Suba filed a complaint against the Mumbai study by Tata Memorial Hospital with the US government’s Office for Human Research Protections. Unlike the Osmanabad and Dindigul district studies that were funded by the private Bill and Melinda Gates Foundation, the 15-year Mumbai study was funded by US government’s National Cancer Institute and could thus be investigated by another US government agency.

Suba’s complaint was that using death rates as a “yardstick” for the study’s success was unethical and “scientifically gratuitous”, and that the participating women – particularly those in the no-screening control group – were misinformed.

After investigating Suba’s complaint, the OHRP in 2012 found informed consent had not been satisfactorily taken from participating women. In an official letter to the Tata Memorial Hospital research team, the OHRP stated: "We determined that the subjects were not adequately informed of the alternative procedures or courses of treatment regarding screening for breast cancer or cervical cancer, namely, mammography and Pap testing...we determined that the subjects were not provided, in writing, with information about the possible alternative of seeking...screening outside of the research."

As per the OHRP’s requirements for corrective action, the women in the control group of the Mumbai study were eventually screened for lesions – but by this time, the 15-year study period was already over and several of the women had died.

“Through all of this, the researchers did not think it necessary to inform the women and their families about the fact that they had been misinformed,” said Suba.

Commercial interests alleged

At the start of the three studies, the researchers had contended that Pap smears were not a feasible screening option for lower and middle-income nations like India. They now claim that their studies have successfully popularised other screening tests like HPV and VIA in these nations, particularly VIA, an acetic acid-based test.

“After the three studies, there is increasingly more implementation of VIA-based screening in Tamil Nadu, Gujarat and Sikkim and in certain regions of India,” said Sankaranarayanan, who claims the studies have also led to the implementation of national-level screening programmes with VIA or HPV testing in at least 14 African countries and multiple Latin American nations. “These studies are regarded very highly in scientific and public health circles globally.”

Suba, meanwhile, is not so sure if the lives of low-income women in India have changed much since the trials. “The political purpose behind allowing such research is to give power to research and commercial interests, like companies producing HPV vaccines,” he alleged.

In the Osmanabad study, says Suba, researchers used an HPV test brand called Hybrid Capture 2, which is now being sold in India at a price of approximately Rs 2,000 per test. The Pap smear test, he claims, is much cheaper than that, at roughly Rs 80 per test, but this has not been prominently reported in the media. Pap smears, says Suba, are in fact a feasible means of detecting pre-cancerous lesions.

For now, Suba is waiting for the US Office of Research Integrity – another government-run ethics watchdog – to complete its investigation into the Mumbai study. The investigation began in May 2015 and may take a few years. “Meanwhile, I am trying to get leading physicians across the world to speak out about this,” he said.

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