Bob Ortega, The Arizona Republic
PHOENIX -- For more than 12 years, as part of two massive U.S-funded studies in India, researchers tracked a large group of women for cervical cancer but didn't screen them, instead monitoring them as their cancers progressed. At least 79 of the women died.
One study, funded by the National Cancer Institute, did not adequately inform more than 76,000 women taking part about their alternatives for getting cervical-cancer screening; and those women did not give adequate informed consent, according to the Office of Human Research Protection, part of the U.S. Department of Health and Human Services.
The other study, funded by the Gates Foundation, is under review by the Food and Drug Administration, according to Kristina Borror, the OHRP's director of compliance oversight. That study has raised similar concerns regarding 31,000 women who were tracked but not routinely screened or treated for cervical cancer.
Both studies continue today, though researchers for both told The Arizona Republicthey have begun to offer screening to the women.
While the two studies differ in important respects, both included large numbers of women placed in "control groups" who were offered free visits with health care workers, but who, until recently, were not screened for cervical cancer. Instead, researchers met with and tracked these women to monitor how many would develop cervical cancer and die, so their death rates could be compared with those of women who were being screened and treated for free.
Researchers for both studies said they told women in the control groups they would not be screened or treated, but they were given health care information and told they could seek screening on their own. The women signed consent forms; but it's unclear how many of them fully understood. Very few acted on their own to seek screening.
As of 2009, according to data published by the two studies, 15 women in the control group of the NCI-funded study had died of cervical cancer, and 64 women in the control group of the Gates-funded study. Researchers have declined to say how many more women in their control groups have died since then.
Daniel Wikler, a professor of ethics at the Harvard School of Public Health, said the types of issues raised in these studies are among the most difficult and hotly disputed related to doing research in developing countries.
Such issues include what constitutes informed consent and when or whether unscreened control groups are necessary or appropriate. But to Wikler, there is a bottom line.
"When you recruit research subjects," he said, "you take on a responsibility that can't be ignored. ... You have to do the best you can for (each person in) your control" groups."
The NCI-funded study, which began in 1997, recruited more than 151,000 uneducated women from the slums of Mumbai. It looked to study the effectiveness of a low-tech approach in which a doctor or trained health worker applies diluted acetic acid --- vinegar -- to a woman's cervix, and looks for color changes, because abnormal tissue will temporarily turn white.
Roughly half of the women were screened using this method, known as visual screening with acetic acid; the rest went into the control group.
Researchers say the control-group women were provided with health education and told verbally that they could seek screening on their own. Women in the screening group, meanwhile, were provided with free treatment if cancer or precancerous lesions were detected.
In 2009, the NCI-funded study's lead researcher reported to the institute that the data showed a significant difference: screening turned up cancers and potential cancers much earlier, when they hadn't progressed as far. But a review board, with NCI support, decided to continue the study, and not to start screening the more than 76,000 women in the control group.
Sarah Kobrin, NCI's program director, explained that decision, saying the point of the study was to see if the chosen screening -- visual inspection using acetic acid -- could save the lives of women living in the slums.
Just showing the screening detected cancers earlier "wasn't sufficient," she said: "It needed to continue until we could see a statistically significant difference" in cancer mortality between the control group and the group being screened.
But that approach -- using women's deaths as a yardstick -- has been excoriated as needless by some critics.
Health care workers collected consent forms from the women -- though the forms also would prove problematic because of language and literacy issues.
Of the 142 women who sought screening, 50 already had full-blown cervical cancer, and 15 of them had died by 2009.
The lead researcher for the NCI-funded study is Dr. Surendra Shastri, head of the department of preventive oncology at Tata Memorial Hospital, in Mumbai. Dr. Shastri declined to discuss the OHRP findings, but said that he believes his hospital's review board adequately answered the questions they raised.
The Gates-funded study, conducted in poverty-stricken rural areas, recruited 131,746 women who were divided into four groups. Three of the groups would be screened for cervical cancer: one using Pap smears, one using visual screening with acetic acid, and one using DNA tests for human papillomavirus, which causes cervical cancer. And 31,488 women were put into the control group. Researchers say the control-group women were provided with health education and told they could seek screening on their own.
In the Gates-funded study, 64 women in the control group had died of cervical cancer by 2009. Researchers said 6.2 percent of the women in their control group of 31,488 sought screening independently. Their published results state that 58 percent of the women in their study had no formal education, an even higher percentage than in the NCI study, which suggests a comparably low literacy rate.
The Gates Foundation did not comment to The Republic on the study. Dr. Rengaswamy Sankaranarayanan, whom Western colleagues refer to as Dr. Sankar, for short, is the lead investigator on the Gates-funded study. He said the women were adequately informed and gave proper consent.
Screening process continues
The Presidential Commission for the Study of Bioethical Issues and the Office of Human Research Protection are tasked with preventing the unethical use of human subjects in research experiments. The OHRP oversees any studies funded by the National Institutes of Health, which includes the National Cancer Institute.
Last July, the OHRP, in response to a May 2011 complaint by a physician about both studies, determined that the NCI-funded study had not adequately informed the women about their alternatives, and hadn't gained their adequate informed consent -- in violation of federal regulations.
After months of back-and-forth between Borror, the NCI, and doctors at Tata Memorial Hospital in Mumbai, which is conducting the NCI-funded study, researchers there wrote to Borror in November saying they agreed to offer cervical cancer screening to the more than 76,000 women in their control group.
But, the lead investigator, Dr. Shastri, denied Thursday that the move has anything to do with the OHRP findings. Offering screening now to the control-group women was "part of the previously decided study plan and this decision had nothing to do with anything else," he said.
Sankar said Thursday that the Gates-funded study began screening the 31,488 women in their control group in January 2011, using tests for the human papillomavirus. Sankar said they've screened nearly half of the women so far, and plan to complete their screening by the end of August, offering free treatment to any women diagnosed with precancerous lesions.
In India, an estimated 77,000 women died from cervical cancer in 2010, according to the World Health Organization. Half of Indian women who develop cervical cancer die within five years, according to WHO, largely because, historically, relatively few women in India have undergone cervical-cancer screening, for cost reasons. In the United States, about 4,000 women die from cervical cancer annually. The rate of deaths from cervical cancer in India is more than seven times higher.
Disagreements over the studies reflect a larger debate.
"There is a profound and deep disagreement within the community of scientists and ethicists who debate these issues," said Wikler, the Harvard bioethicist.
On one side are researchers in developing countries who accuse critics of "ethical imperialism" for trying to impose ethical standard, often from countries with more advanced economies, on studies conducted in countries like India, which have different needs.
On the other side, critics sometimes question whether those researchers' decisions are affected by the lure of research funding, and accuse them of "ethical relativism."
That's the view that ethical standards depend on the culture or situation, which critics argue leaves the door open to potential exploitation.
Responding to one critic, for example, Sankar wrote: "Informed consent in studies in developing countries may be portrayed as contentious by researchers who have limited understanding of the prevailing socio-cultural context," adding that "it is presumptuous to think rural women with no formal education are incapable of understanding and comprehending what is being offered to them and making a decision to participate or not or to withdraw from the study at any given time during its course."
For his part, Suba said "ethical imperialism is a legitimate concern, but science is the same everywhere."
To date, the presidential bioethics commission has not acted on Suba's complaint.
The OHRP investigation and FDA review continue.
"The history of all this stuff," Austin said, "has been that there have been lapses and stricter regulations. My guess is that the regulations that exist in the future will be stricter than they are today."
Both Shastri and Sankar said they expect to publish updates on their study data later this year.
That will include information on how many more women in the control groups have developed cancer, and how many more have died.