Failure to protect? | Science

Science also reviewed versions of the informed consent forms used by Vit-D-Kids, some of which Davidson acquired through a Freedom of Information Act (FOIA) request. Experts in trial design say those forms stressed potential benefits over harms and were overly complex and confusing.

For example, instead of discussing vitamin D deficiency, the forms used the more benign-sounding term “low vitamin D,” says Columbia University cardiologist Raymond Givens, who studies institutional racism in medicine and medical publishing. Ethicist Harriet Washington, whose book Medical Apartheid discusses clinical experiments on Black Americans, also notes parents often misunderstand essential research terms.

The informed consent forms for Vit-D-Kids called rickets, not bone fractures, the primary risk for children who received placebos. But rickets affects infants and very young children—far younger than those enrolled in Vit-D-Kids. The consent form should have clearly stated that any child in the placebo group with insufficient vitamin D would face a higher risk of broken bones, says Boston University medical ethicist George Annas. But if such an explicit concern had been noted, he suspects few parents would have signed the consent form because “it almost sounds like child abuse.”

In his statement, Kiley wrote to Science that the fracture risk from too little vitamin D didn’t apply to the trial’s kids because they used only inhaled steroids, not injected or oral forms, which in adults cause bone to demineralize. But up to 14 children on the placebo took systemic steroids at least twice during the trial—enough to increase the fracture risk, according to an authoritative asthma study.

AFTER LEARNING many details of Vit-D-Kids, Davidson in August 2017 sought advice from Frank Greer, an emeritus professor of pediatrics at the University of Wisconsin, Madison, and member of the Vit-D-Kids DSMB. In an email Davidson gave to Science, Greer expressed alarm about giving a placebo and concerns about possible adverse effects in the high-dose group. (NHLBI recused Greer from discussions of the matter after learning of Davidson’s communication with him.)

Davidson then complained to NHLBI officials. “[Davidson] makes very valid points and … [the investigators] need to address this in a very substantive way,” Kiley subsequently wrote to colleagues in an email Davidson obtained via a FOIA request. “I am inclined to put a clinical hold on this study if we cannot get [a DSMB] review done next week.”

After months of deliberation, the DSMB in early 2018 approved changes to the trial, excluding any future enrollees with vitamin D levels below 14 ng/ml, compared with the prior cutoff of 10 ng/ml, and adding new wording to the consent form. The revised version said, “The risk to bone health is unclear if the vitamin D level is 14–19 ng/ml. However, many doctors would treat with vitamin D at this level.” The board acted “out of an abundance of caution,” Kiley wrote in his recent statement.

Carome calls the revisions a tacit acknowledgment that the consent form used to recruit many of the kids “failed to disclose important information that parents would have needed to make a fully informed decision.” He says the new form continued to obfuscate risk by implying that treating vitamin D deficiency was a gray area. Moreover, parents were never told what their children’s specific vitamin D levels were, either at enrollment or later in the trial. Care decisions, including whether to supplement a kid’s vitamin D on their own, were effectively out of their hands.

WHEN JAMA PUBLISHED the results of Vit-D-Kids in August 2020, it looked like just another failed vitamin supplement trial. The placebo group and treatment groups experienced about the same number of adverse events—mainly asthma-triggered hospitalizations or emergency department visits, according to the paper. JAMA had in 2018 rejected a commentary Davidson submitted criticizing the trial’s use of a placebo arm; after the study’s publication, he sent a letter to the editor outlining that concern and questions about the trial’s racial mix. JAMA rejected that as well.

JAMA‘s editors declined interviews, but wrote in a statement they were “aware” of Davidson’s concerns and that the study was designed to “ensure the safety” of participants. They noted the paper reported that trial investigators stopped giving placebos to several kids, and referred them to an endocrinologist, after their vitamin D levels dropped below the study’s minimum requirement.

But Celedón and colleagues did not report in the JAMA paper, or in results posted to ClinicalTrials.gov, that kids in the trial broke bones. Kiley disclosed that at least nine fractures had occurred only when Representative Lloyd Doggett (D–TX), who chairs an NIH oversight panel and had been contacted by Davidson, asked about the trial.

Five fractures had occurred among kids given vitamin D and four in the placebo group, which is nearly twice the rate expected for asthma sufferers in that age group. But Kiley told Doggett that the trial’s oversight board found no safety issues. (In an interview, DSMB chair Dennis Ownby of Augusta University said his panel was told that the rate of fractures was very low, but does not recall independently verifying that information.) Kiley refused to share details of those fractures with Doggett for unspecified “reasons of patient privacy and scientific integrity.”

Davidson, Natanson, and other trial design experts Science contacted were troubled that Vit-D-Kids failed to report the fractures and their details publicly. Although the comparable number of fractures in each arm might suggest the placebo group was not at greater risk, they note the breaks are impossible to interpret without information on their severity and precipitating events, such as contact sports versus low-stress activities.

“Letting kids spend 48 weeks as low as 10 ng/ml—and doing this primarily to minority kids while warning them about irrelevant rickets instead, then covering up bone fractures—is awful,” Davidson says. “Those kids with the lower vitamin D levels need to be located, carefully assessed, and treated if necessary. They need explanations and oversight for a while to minimize their future risk.”

THE MAKEUP of the 192 trial participants, which included 100 Black kids, intensified the debate. Kiley in his statement defends the trial’s demographics, noting that Black children “are twice as likely as white children to be affected by asthma.” Yet even with higher asthma rates, Black children were vastly overrepresented in the trial, in comparison with their numbers at study sites like Pittsburgh and Boston.

That concerns Givens and others. “[If ] most of [a trial’s] subjects will be nonwhite, and a large proportion low-income and perhaps lacking advanced education among parents, there is a need for heightened attention to the ethics and appropriateness of the trial,” he says, including intensive community outreach before recruitment in poor or minority populations.

Macklin calls it “surprising—if not appalling—that IRBs in these major U.S. medical centers are willing to approve studies in which disadvantaged children are randomly assigned to a placebo group, justified by the argument that they are not being made worse off than they would be if not enrolled in the study.” Annas compares Vit-D-Kids to “no-care as usual care” trials in resource-poor nations, such as NIH-funded trials in African nations in the 1990s. In pregnant women, the antiviral zidovudine, also known as AZT, was tested against a placebo to see whether it blocked mother-to-child HIV transmission. The drug was already the standard of care during pregnancy for HIV-infected women elsewhere.

Washington said she was dismayed to learn the trial protocol and consent forms prominently discussed analyzing kids’ genes for clues connecting low vitamin D to asthma but glossed over obvious inner-city risk factors such as air pollution, stress, and poverty, which could also lead to vitamin deficiency and asthma. The hunt for genetic explanations above social linkages “reinforces the belief that … biological dimorphism drives a lot of illnesses,” she says. “It’s unethical. It’s deeply illogical. And it fits a racist pattern.”

Kiley and Celedón declined to comment on that issue. Ownby says he also sees asthma as a disease “primarily of lower socioeconomic status,” closely linked to disadvantages experienced by Black people and other people of color and to the social issues Washington notes. But he adds that “to try to look at them all at once just isn’t within the scope of most NIH grant studies. There’s just not enough money.” Studying genetic questions, particularly for those most affected by asthma, is also important and ethical, Ownby says.

To Carome, Vit-D-Kids offers new evidence that, overall, “our IRB system is broken.” He doubts that any hospital panel that greenlit the study asked how its own physicians would normally treat asthmatic children deficient in vitamin D. None would fail to give baseline supplements, he says. It’s a sign that IRBs tend to uncritically accept NIH funding as a stamp of approval, Carome adds.

CREDITS: (GRAPHIC) N. DESAI/SCIENCE; (DATA) PCORI/NIH REPORTER

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