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long-debated study aimed at validating a low-cost way to screen for cervical cancer in India has come under fire again, based on new evidence of ethical lapses contained in documents obtained through the U.S. Freedom of Information Act.

Critics of the 18-year trial said that U.S.-funded Indian researchers used ineffective screening that endangered thousands of poor women in Mumbai. They were told the test could help prevent cancer, but far fewer pre-cancerous lesions were found than expected, suggesting that some lesions were missed — possibly leading to an unknown number of deaths.

The trial should have been stopped years earlier for another reason, critics said: Other research had already shown that the screening method worked when properly applied, making it unethical to use an unscreened control group.

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A paper detailing the new evidence was briefly published by BMJ Global Health. But in an odd twist, the U.K. science journal withdrew the paper from its website in May before it attracted much notice — not out of concern about its scholarship, the BMJ journal group’s editor said, but because its legal advisers warned that the accused researchers might sue.

Dr. Eric Suba, a pathologist at Kaiser Permanente Medical Center in San Francisco and co-author of the paper, provided STAT with a copy and links to supporting documents. In an interview, he described the Mumbai study, which ended in 2015, in stark terms: “catastrophic,” “monumentally unethical,” and a “radical departure from normal scientific procedures.”

But the principal investigator of the trial, Dr. Surendra Shastri of Mumbai’s Tata Memorial Hospital, rejected the criticisms as “gibberish” and “lies and distortions.” In an email to STAT, Shastri accused Suba of unspecified ulterior motives, and said he would have sued except for the difficulties of doing so in India.

The Mumbai trial tested whether lay community health workers could identify precancerous cells through visual examination of cervixes painted with dilute acetic acid, the active ingredient in vinegar. If so, the patient was referred for further tests and possible treatment before invasive cancer developed. The vinegar method, which turns problem cells white before they become malignant, is an alternative to Pap smears, a standard test in rich nations that is not widely used in India due to its higher cost.

The study detected only 44 cases of precancerous cells among more than 129,000 screenings — far fewer than seen in similar trials that relied on either trained lay health workers or nurses — and showed no reduction in the incidence of cervical cancer. The visual exams, however, allowed the Mumbai lay health workers and their expert supervisors to find actual cancers at earlier, more treatable stages, reducing deaths by 31 percent among women in the screened group compared to those in the control group — a key finding of the study.

But Suba’s paper contends, based on a review of the new documents, that the researchers might have engaged in “data falsification” to support their claims that cancers were caught earlier and deaths reduced. Suba and his colleagues cited sharp differences between the data submitted to the funder, the National Cancer Institute, on the stages when cancers were detected, and the data later published by the Indian researchers. They also noted that staging data were missing for many trial participants — another reason to doubt the results.

Dr. Amar Jesani, editor of the Indian Journal of Medical Ethics, said via email that the Suba paper casts “reasonable doubts on both the science and the ethics of the Mumbai trial.” He called for a review by the National Cancer Institute.

In 2015, Suba asked the Department of Health and Human Services Office of Research Integrity to examine his data concerns. According to letters he obtained under the Freedom of Information Act, the agency criticized the Mumbai researchers for confusing descriptions and for omissions — which were redacted from the release. But it accepted their explanations that “many factors” — whose specifics also were redacted — “were responsible for the changes.”

In the interview, Suba called the Office of Research Integrity assessment “meaningless” because it didn’t release any specific information about the causes of the data discrepancies.

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Dr. Edward Trimble, who directs global health programs for the National Cancer Institute, said the Mumbai study’s success was demonstrated by its reduction of cervical cancer mortality in a cost-effective way for a developing nation. He declined to comment on Suba’s data concerns.

Dr. Fiona Godlee, chief editor of the BMJ group of journals, said in an interview that the Suba article had been peer-reviewed and approved by editors, but inadvertently published before legal review. Suba said he has appealed the decision to the BMJ ethics committee. The paper’s withdrawal was first reported by Retraction Watch.

Longstanding dispute

The allegations followed years of controversy about the Mumbai study and two similar cervical cancer trials testing visual inspection with vinegar to prevent cancer, funded by the Bill and Melinda Gates Foundation.

Suba and others have objected in the past, and in the most recent paper, to the design of the Mumbai study and those Gates-funded trials because the women randomly assigned to control groups received no routine cancer screening. They argued that if women fully understood that available tests can help detect abnormal cells and prevent cancer, they wouldn’t have agreed to participate. The Suba paper cited studies showing that vinegar-aided exams and Pap smears had already been shown as cost-effective in underserved areas of poor nations, including India.

“A randomized trial that includes an unscreened control group and mortality endpoints is incompatible with the concept of informed consent,” Suba said in an interview.

In a letter to the researchers of the Mumbai trial, the U.S. Office for Human Research Protections partly supported the concern. “[S]ubjects were not adequately informed of the alternative procedures or courses of treatment regarding screening for … cervical cancer, namely … Pap testing,” the office wrote in 2012, 15 years into the study. It ordered the researchers to improve their verbal and written informed consent process.

Shastri and Trimble insisted that Pap smears are unavailable to most Indian women. Trimble said the informed-consent concerns raised by U.S. authorities mainly involved improving paperwork, and that members of the control group could have requested free screenings. “This was a study approved by the relevant ethical review committee in India, and they are obviously closer to understanding what are the relevant clinical questions, what are the relevant community concerns,” he said.

Suba objected to what he called a misguided assumption by the researchers — that “no screening” was the accepted norm for poor women in India, and therefore suitable for the control group.

“Where the number of preventable deaths becomes astronomical is when you start thinking about the opportunity costs that were baked into the Mumbai trial,” which was viewed as a benchmark for Indian clinical practice, Suba said. “That trial made India assume that ‘no screening’ was the standard of care throughout the 18 years. … We’ll never know how much screening India would have done if they hadn’t been committed to this Mumbai trial.”

Jesani, the medical ethicist, called the three trials, all of which included poor women in unscreened control groups, the “21st century’s biggest ethics dumping in clinical research by the U.S.A.” Ethics dumping refers to studies in poor nations that would violate accepted research norms in funder nations.

A representative of the Gates Foundation declined to comment.

In 2007, a large and influential Gates-funded trial was terminated early after it proved the preventive vinegar test effective in a community setting after a single screening. Yet the Mumbai trial, with its four sets of screenings, continued for eight more years.

Shastri said his trial and that Gates study differed in an essential way. In Mumbai, lay health workers conducted the exams, although their work was spot-checked by experts to ensure accuracy. In the Gates study, nurses conducted the exams.

The Mumbai trial did not prevent cancers, and vinegar plays no role in detecting the stage of a cancerous lesion. But the study still strongly supported the idea that low-cost visual exams by lay health workers could significantly reduce mortality, Shastri said, calling it “unimaginable” that India would have enough nurses to perform such exams nationwide. He added, “We are most gratified that the government of India has introduced countrywide [vinegar-based] cervical screening since August 2016.”

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