Ethics on trial

Three groundbreaking clinical trials on cervical cancer raise uncomfortable questions

Last year, the findings of what has been called a ‘revolutionary’ study in India were made public. It showed that cervical cancer, that dreaded disease which kills over 70,000 Indian women every year, need not necessarily be screened only by Pap smears or Human Papillomavirus (HPV) tests. Common vinegar could prove almost as effective. All that was required was a simple application of vinegar to the cervix. If the affected region turns white—because acetic acid or vinegar makes cancer and pre-cancerous cells change colour—it indicated the possibility of cancer. The findings were the culmination of a mammoth study that began in 1998 and involved the tracking of a total of 151,538 women from 20 slum clusters in Mumbai. Conducted by researchers from India’s premier cancer institute, Tata Memorial Hospital, and funded by the National Cancer Institute (NCI) in the US, the study proved that so-called vinegar testing could reduce deaths by 31 per cent.

In India, where access to healthcare is poor and Pap smears and HPV tests are often unaffordable, this study offered much promise. Unsurprisingly, it was widely applauded and fêted, both by the scientific community and the press. Maharashtra is now expected to run a pilot programme on the basis of this study, using vinegar to test the possibility of cervical cancer, in six districts of the state for two years.

It now turns out that there are some questionable aspects of the study, and of two other recent studies on cervical cancer screening that were funded by the Bill Melinda Gates Foundation (BMGF) and conducted in Maharashtra’s Osmanabad district and Tamil Nadu’s Dindigul district. Some critics argue that the studies were unethical and perhaps even scientifically pointless.

In the case of the NCI-funded test, 151,000 women were separated into two groups, one of which was screened by vinegar, also known as ‘visual inspection by acetic acid’ (VIA), while the other had no screening. It is now being claimed that adequate informed consent was not taken from those in the unscreened group; and that, even as the study went on for several years, the researchers continued to stand by and monitor the unscreened group even as some of them started developing cancer and dying of it. Uptill 2013, when the findings were made public, a total of 98 women had died. Another 67 died in the screened group. Similar accusations of inadequate informed consent and not screening those in the control group even as some of them started developing and dying of cervical cancer are also being levied against conductors of the two BMGF-sponsored studies. In the study conducted in Dindigul, also to examine the efficacy of vinegar as a screening agent, of the 30,958 women who did not receive screening, 92 women died between 2000 and 2007, when the study was published. Another 83 died of the 49,311 women who were screened by VIA in the same timeframe. In the Osmanabad study, designed to examine the efficacy of various screening methods, women were divided into four groups—those that received HPV tests, VIA, Pap smears, and a control group that got no screening. When the findings were published in 2009, they showed that between 2000 and 2007, 64 women in the control group had died. Another 34 had died in the HPV-testing group, 54 in the Pap smear group, and 56 in the VIA group.

According to Dr Eric Suba, a San Francisco-based pathologist who ran a Pap smear programme in Vietnam and has been a vociferous critic of the three studies, what he finds troubling is how the researchers tracked a large group of women for cervical cancer but didn’t screen them, instead monitoring how many would develop cervical cancer and die, so their death rates could be compared with those who were being screened. ‘No-screening groups were maintained,’ he says over email, ‘even after the efficacy of screening for reducing cervical cancer death rates had (predictably) been confirmed.’ In a recent article he wrote for Indian Journal of Medical Ethics (IJME), he elaborates, ‘It is also unsettling that such measurements were continued among unscreened women in Mumbai and Osmanabad even after the mortality benefit of a single round of VIA screening had been established in Tamil Nadu… the no-screening arms in all three US-funded studies should have been closed after the demonstration of the mortality benefit of VIA had been documented in 2007.’

In all three studies, women in the control groups were told they would not be screened or treated. They were instead given health-care information and told they could seek screening on their own. All of them signed consent forms. In the case of the NCI study, all participants from the screened and unscreened groups were given ‘health cards’, which enabled them to seek free treatment at Tata Memorial Hospital. According to researchers associated with the study, a small number of women from the unscreened group did seek cervical cancer screening on their own. According to these researchers, after information on the importance of screening was provided, a total of 1,956 women from the unscreened group in Osmanabad got themselves screened with Pap-smears and 951 women from the unscreened group in Dindigul got themselves tested with VIA screening. These women were then excluded from the studies.

In 2011, Dr Suba filed a complaint about the three studies with the Office of Human Research Protection (OHRP), a body that looks into the unethical use of human subjects in research experiments. The Office did not investigate the two BMGF-funded studies since they had not been funded by the US government. However, in the case of the NIC study, OHRP found that those in the control group had not been adequately informed of how they could seek screening from nearby healthcare facilities. Kristina C Borror, director of the Division of Compliance Oversight at OHRP, wrote in 2012, ‘We have determined that the subjects were not provided, in writing, with information about the possible alternative of seeking breast or cervical cancer screening outside of the research… When such information is only provided verbally, subjects may not recall the information later, or may not fully understand what is told to them orally.’ Apart from VIA, the study is also looking into the efficacy of clinical breast examinations conducted by health workers. According to Dr Surendra Shastri, head of preventive oncology at Tata Memorial Hospital and the lead researcher of this study, Pap smears and mammography—standard screening processes the world over—found no mention in the consent form, although these were explained verbally, because it would be akin “to insulting them”.

According to Dr R Sankaranarayanan, the lead researcher of the Osmanabad and Dindigul studies, adequate information on the studies and cervical cancer was provided to all participants in the local language. ‘In addition, women in the control group were advised where to seek cervical screening, diagnosis and treatment services and were given adequate information to [help them] seek screening [at] their local healthcare facility, including our collaborating institutions,’ he says over email.

Since 2012, researchers on the NCI- study have started offering VIA screening to those in the control group. According to Dr Shastri, this was provided because they had already been able to establish VIA’s efficacy and has nothing to do with OHRP’s findings. Dr R Sankaranarayanan claims VIA screening was provided to the control group between 2007 and 2011 and HPV screening to the control group in Osmanabad since 2010. He also states that those who were diagnosed with cervical cancer in the control group received free treatment.

Claiming that study participants are often poor, illiterate and unaware of their rights, Amulya Nidhi, co-convener of the Swasthya Adhikar Manch (SAM), a health rights forum that has filed a writ petition in the Supreme Court (SC) asking for stricter regulation in clinical trials in India, says, “The studies may or may not have been essential to science and India. But the rights of the human subjects are paramount. Absolute informed consent is a must.” The SAM plans to mention the 254 deaths, the women who died in the three control groups, at the next SC hearing.

Critics of the three studies question the need to judge the efficacy of a screening agent by forming a control group that receives no screening and then monitoring how many die without it. In 2009, Sujit Rathod, an epidemiologist of the London School of Hygiene and Tropical Medicine, wrote in IJME: ‘It is of particular interest why cervical cancer mortality was a necessary endpoint… A non-mortality endpoint has been found acceptable in another low-resource setting trial… It is questionable, then, whether human experimentation is required to demonstrate a mortality benefit from cervical cancer screening.’

Says Dr Suba over email, ‘The death- rate measurements used by Drs Sankar and Shastri are scientifically unnecessary and scientifically pointless.’ He wrote in IJME, ‘Randomised trials that compare cervical screening to no-screening to confirm that cervical screening prevents cervical cancer are as scientifically pointless as randomised trials that compare smoking to no-smoking to confirm that no- smoking prevents lung cancer.’

Dr Shastri, however, claims that studying mortality over a long period is necessary because it most effectively proves the efficacy of a novel approach. He says in his defence, “The internal review boards of Tata Memorial Hospital and NCI have looked carefully into the ethics of this study. This [study] can immensely benefit the country. Now armchair ethicists with no experience of healthcare in developing countries are trying to find fault with it.” Making a similar argument, Dr Sankaranarayanan claims the most rigorous assessment of a new method calls for measuring cancer-specific mortality reduction. According to Dr Shastri, some Pap-smear advocates are worried that the efficacy of alternate screening methods may soon be proven. Besides, he argues, the standard care protocol in India for cervical cancer, unlike in the West, involves no screening.

All three studies, however, run afoul of the Declaration of Helsinki’s ethical guidelines on medical research, which state that the benefits, risks, burdens and effectiveness of any new intervention must be compared with those of the best current proven interventions. Pointing this out, Sandhya Srinivasan, consulting editor of IJME, says, “There are at least three proven screening methods—the Pap smear, VIA, and testing for HPV. And the women in the control arms of these trials were denied any proven intervention. They were subjected to the risk of serious and irreversible harm and this clearly violated the guidelines of the Declaration of Helsinki.” She also points out that the three studies paid scant respect to the principle of clinical equipoise. By this principle, a clinical trial should be undertaken only on the assumption that there is genuine uncertainty over whether a certain intervention is superior to others. “None of these studies would have been permitted in the US, the country of the organisations funding these trials,” she adds.

Pointing out that VIA and other methods of cancer detection have been known for several years now, Suba writes in the journal, ‘You can’t let people die to show something you already know.’

cervical cancerclinical trialsvinegar test