A study in which Chinese children were fed a small amount of genetically modified rice violated university and U.S. federal rules on human research, according to a statement issued yesterday by Tufts University in Boston, whose scientists led the study. Tufts has barred the principal investigator, Guangwen Tang, from doing human research for 2 years and will require her to undergo training in research on human subjects.
In August 2012, Tang and colleagues published a study in The American Journal of Clinical Nutrition showing that golden rice is a promising source of vitamin A in Chinese children aged 6 to 8 years old. The study ignited a media firestorm in China a few weeks later, after Greenpeace issued a statement claiming that the children were used as "guinea pigs" and labeling the study a "scandal of international proportions." Three Chinese collaborators who initially denied involvement in the study, according to media reports, were punished for their participation in December, following an official investigation in China, and parents of the children received generous financial compensation from the Chinese government.
Golden rice contains β-carotene, a compound that is turned into vitamin A inside the body and that gives the rice its trademark yellow hue. It was developed in the 1990s to help fight vitamin A deficiency, a major global health problem estimated to cause blindness in up to half a million children every year, half of whom die within 12 months after losing their eyesight.
The study that has drawn so much opprobrium, carried out in 2008 among 72 children in a primary school in China's Hunan province, was designed to find out how well golden rice is converted into vitamin A inside kids' bodies. The results were good news for supporters of the rice variety: One serving could provide more than half of a child's daily vitamin A needs, the researchers reported.
Tufts launched the investigation in September 2012, shortly after the controversy erupted. A spokesperson says that Tufts won't publish a report about the investigation, but the university e-mailed a brief statement to reporters yesterday. Tufts also sent ScienceInsider a letter from Diane Souvaine, Tufts’ vice provost for research, to the U.S. Department of Agriculture (USDA) with more details about the investigations. (Tang works at the Jean Mayer USDA Human Nutrition Research Center on Aging, a facility operated jointly by Tufts and USDA). ScienceInsider also obtained a letter from Souvaine to Kristina Borror of the U.S. Office for Human Research Protections (OHRP) about the investigation.
The letters show that Tufts' own institutional review board (IRB) investigated the ethical procedures, as did an external panel whose membership has not been made public. In addition, there was a third, internal review to look at whether there was any evidence of scientific fraud or data manipulation.
The reviews found no evidence of health or safety problems in the children fed golden rice; they also concluded that the study’s data were scientifically accurate and valid. Indeed, Souvaine's letter to the USDA stresses that the results "have important public health and nutrition implications, for China and other parts of the world."
But the IRB concluded that there were a number of problems in the way Tang conducted the study. For instance, she provided "insufficient evidence" that the study "was reviewed and approved by an Ethics Review Board in China in accordance with prevailing standards." It also found that some of the consent forms had not been obtained before the trial started, and there was "some evidence that the dates on some consent forms were changed and that other consent forms may have been inappropriately signed."
Tang also made some unauthorized changes to the study protocol after obtaining permission, the IRB concluded; for instance, the participation of research team members from the Chinese Center for Disease Control and Prevention was not described in the protocol, and eight subjects were recruited to an unapproved "placebo" arm. Tufts, in its letter to OHRP, characterized Tang's actions as constituting "serious and continuing non-compliance with federal regulations" and with Tufts IRB policy.
Tang, who was born in China and has been at Tufts since 1987, did not respond to requests for comment from ScienceInsider. Tufts has barred her from doing research on humans for 2 years, during which time she will be "retrained on human subjects research regulations and policies," the university stated; after the training is completed, for a further 2 years she can do human studies only as a supervised co-investigator.
Tang, 64, has decided to close her lab next year as a result of the punishment, says Adrian Dubock, executive secretary of the Golden Rice Humanitarian Board in Switzerland, which was not directly involved in the study. "She did not choose the political controversy thrust upon her altruistic research," Dubock, who has kept in contact with Tang, says in a written statement. "Her retirement and the closure of her laboratory will be a loss to humanity."
Tang is not the only one in the crosshairs. The external panel criticized Tufts' IRB for having failed to verify that there were ethics panels in place in China equipped to review the study, and whether they actually reviewed and approved the trial. The IRB should also have ensured that the informed consent form for parents explicitly stated that the rice is the product of genetic engineering.
U.S. guidelines stipulate that such forms use plain language understandable to lay people, and the IRB agreed to let Tang say that "Golden Rice is a new rice which makes beta-carotene," without using the loaded words "genetically modified." (The consent form for a very similar study by Tang among adults in Boston, published in 2009, didn't use that term either.) Given the sensitivities over transgenic food, which existed in China as well, that was the wrong decision, according to the external panel.
The IRB has taken a number of measures to shore up its reviews, especially of international studies, Tufts says.
The Tufts statement and the letters don't mention the role of Robert Russell, the last author of the paper and a renowned nutrition researcher. Russell, now retired, was the head of the Tufts-USDA lab at the time the study was conducted. Although he helped design the trial, Russell tells ScienceInsider that he had little to do with how it was carried out, was not present at the study site in China, and does not speak Chinese. The paper lists him as "the study physician," but he was only available for "long-distance consultation" if problems emerged, he says.
Russell says that overall, the Tufts statement is "a fair assessment of the problems," but says that Tang, with whom he has been in contact, has different views on a number of issues. In retrospect, Russell says, more than one bilingual researcher from Tufts should have been involved in the study to oversee adherence to the protocol. He says part of the problem was that the researchers relied on their Chinese counterparts. "We thought it was going to be run correctly and at the time had no reason to think it wouldn't be," he says; that was "naive."
Tufts has ordered Tang to write a letter to The American Journal of Clinical Nutrition describing the outcome of the investigations; the journal's editor, Dennis Bier of Baylor College of Medicine, says no decision has been made on what to do with the paper.
In July, China's National Health and Family Planning Commission released new draft guidelines for studies involving humans, which the state news agency Xinhua says were triggered by the golden rice incident. Among the changes is that trials must be registered with the sponsoring institution before they begin, to allow proper oversight.
Cao Xuetao, president of the Chinese Academy of Medical Sciences, says the issue is a reminder that Chinese regulatory authorities haven't kept up with the nation’s burgeoning research enterprise. "Chinese science has expanded so fast in the past few years," he says, and “now there are so many clinical trials."
German plant scientist Ingo Potrykus, who developed the first golden rice variety in the 1990s, says the controversy should not deflect attention from the study's outcome. "The study has shown that golden rice is a very effective source of vitamin A," says Potrykus, who is retired and lives in Switzerland. "That's what's most important."
With reporting by Mara Hvistendahl.