A study of asthmatic children, most of them Black, shows how a common clinical trial design can expose vulnerable participants to serious risks.
ILLUSTRATION: STEPHAN SCHMITZ
Juan Celedón, a respected pulmonary researcher at the University of Pittsburgh, wanted to address an urgent national problem. Severe asthma attacks send hundreds of thousands of U.S. children to the hospital every year. For decades, researchers have suspected extra vitamin D—essential for bone growth and healthy development, and also an immune modulator in children and adults—might help them. In 2016, Celedón and colleagues launched a major trial to test that premise.
With $4.3 million in funding from the National Heart, Lung, and Blood Institute (NHLBI) and support from a vitamin company and a drug firm, they enrolled asthmatic kids who had low or deficient levels of vitamin D—many from urban, minority communities; most were Black. Half of the 400 planned participants would receive a daily high-dose vitamin D supplement for about 1 year. The other half would serve as controls. The researchers also made a decision that cast a shadow over the trial—and inflamed a controversy confronting many other trials of similar design. Instead of treating the randomly chosen control group with a more modest dose of vitamin D—as many medical authorities advise for children with a deficiency of the vitamin—the researchers chose to give them a placebo.
When Seattle physician Bruce Davidson, a pulmonary specialist who has studied vitamin D and asthma, heard about the “Vit-D-Kids” trial, he was stunned. The children, as asthmatics treated with corticosteroids, already faced possible bone health problems and diminished growth, and any vitamin D deficiency would place them at greater risk for fractures. Yet Davidson discovered that informed consent forms posted online failed to inform parents of enrolled children about those dangers.
Davidson, who had worked on a comparable vitamin D trial that rejected a placebo arm as unethical, repeatedly voiced his concerns about Vit-D-Kids to the scientists running it, institutional review boards (IRBs) that approved it, and NHLBI. But trial researchers called the risks minimal. The placebo was justified because vitamin D testing is not routine, they argued. If not for the trial, the kids’ vitamin deficiency probably wouldn’t have been detected, so they were no worse off in the study.
Davidson’s objections drew some media attention during the trial and led to small changes to its enrollment criteria and consent forms, but Vit-D-Kids pressed ahead. It wasn’t a success. Trial enrollment grew to nearly 200 children but was halted early for “futility” in 2019 after a data safety monitoring board (DSMB) concluded during an interim review of results that vitamin D supplementation had failed to prevent asthma attacks. Yet the researchers kept an unspecified number of kids, even if very deficient in the vitamin, on a placebo for up to six more months—to ensure “an orderly closeout,” James Kiley, director of NHLBI’s Division of Lung Diseases, later told a U.S. politician who asked about the decision.
“That approach was stunning and callous,” Davidson says. And possibly harmful. At least nine kids, across both arms of the trial, broke bones during the trial—nearly double the number expected among asthmatic children over a comparable period. The fractures were neither disclosed as possible adverse events when the study was published in JAMA last year nor noted in another public summary of the trial results.
A Science investigation of Vit-D-Kids reviewed thousands of pages of trial protocols and consent forms; previously undisclosed DSMB deliberations; emails from the trial’s principal investigator, NHLBI officials, and JAMA editors; and letters between National Institutes of Health (NIH) officials and a concerned member of Congress. Those documents and others reveal new aspects of the trial that concern asthma researchers like Davidson, medical ethicists, and specialists in clinical trial design who reviewed the materials at Science‘s request.
“The advantages to society of this trial, because of the poor design, were likely none. And the risks did outweigh the benefits,” says Charles Natanson, a physician and expert on trial design at the NIH Clinical Center. “This trial did not, in my opinion, meet the standards set forth in The Belmont Report,” which in 1979 established ethical guidelines, adopted by the U.S. government, for protecting human subjects. Keeping children on a placebo after the trial was stopped for futility stood out as an “unconscionable” error, adds Ruth Macklin, a medical ethicist at Albert Einstein College of Medicine.
Davidson and others suggest the study’s focus on minority children—which Kiley called “appropriate” in a statement to Science—only elevates their concerns about using a placebo. Jill Fisher of the University of North Carolina, Chapel Hill, who wrote a book on racial inequality in clinical trials, says Vit-D-Kids ignored the ethical imperative to treat children at known risk from vitamin D deficiency because of inadequate diet, poverty, and a lack of Sun exposure in inner cities. “We shouldn’t say, ‘It’s unfortunate that there are these health and nutritional disparities, but it serves the interests of science to have placebo-controlled trials,’” she says. It is “structural racism” to scientifically exploit such inequalities, Fisher adds.
CREDITS: (GRAPHIC) N. DESAI/SCIENCE; (DATA) E. FORNO ET AL., JAMA, 324(8):752 (2020;) 10.1001/JAMA.2020.12384
Kiley and Celedón declined to be interviewed but provided statements after being sent a list of questions. The trial, its protocol, and consent forms “underwent rigorous review before and after it was funded,” Celedón wrote in a brief note emailed to Science, adding: “All regulatory bodies, including a [DSMB] and [IRBs] at seven pediatric hospitals, stated that the trial was both safe and ethical.” In NHLBI’s statement to Science, Kiley wrote, “The highest priority was to keep every child in the study safe.”
Vit-D-Kids could easily be dismissed as a controversial outlier, but Natanson and others suggest it instead exemplifies the growing number of studies in humans that inappropriately reject control groups receiving “usual care”—current best practice treatments used by doctors. In a hunt for compelling results, many researchers favor using sharply divergent treatment arms in a trial. But such extreme comparisons mean doctors can’t learn whether a new treatment is better or worse than usual care, says Natanson, who has analyzed the issue in trials involving critically ill patients. He has found that many such trials mislabel one or more arms as “usual care,” sometimes endangering participants and misinforming physicians, which he calls “a big problem.”
MORE THAN A DECADE AGO, NIH supported an ambitious trial that foreshadowed the usual-care issue in Vit-D-Kids. The study’s researchers meant to solve a life-and-death medical conundrum affecting premature infants: They depend on supplemental oxygen to stay alive, but too much can cause blindness. The trial aimed to identify an oxygen level that would save lives with the fewest side effects.
It assigned more than 1300 preemies to be maintained at a relatively low blood oxygen range (85% to 89%) or a higher range (91% to 95%). Most consent forms said either range represented “usual” or “standard” care and that babies in both groups had the same likelihood of dying. Prominent supporters, including NIH Director Francis Collins, argued that both infant groups met the standard of care as practiced at trial sites.
But in a 2016 analysis in PLOS ONE, whose authors included Natanson, researchers examined other trials of oxygen management in preemies and concluded the bottom of the trial’s low-oxygen range was not considered usual care in multiple countries. The trial departed from usual care in another respect, not noted on the consent forms: By design, the oxygen monitors displayed inaccurate readings to prevent caregivers from knowing a baby’s study group.
Scores of bioethicists and clinicians—and the federal Office for Human Research Protections (OHRP)—said the informed consent forms inadequately described the risks. About 20% of babies in the low-oxygen range died, compared with 16% in the high-oxygen group.
Several other U.S. trials (see table, below) also became magnets for criticism that they violated usual-care safeguards seen as crucial, even if sometimes complex to define. Each trial had eminent backers who said accepted practices can be ambiguous, fueling divisive debates. “Usual care in Seattle may differ from usual care in San Antonio. This applies particularly to uses of technology and high-cost interventions,” said Edward Campion, an editor at The New England Journal of Medicine when it published the infant oxygen study, at a public hearing.
Trials that compare alternate treatments but lack a usual-care group reflecting standard medical practice have grown increasingly common—and drawn a backlash from ethicists and clinical research experts. They say the approach sometimes endangers trial participants and may not offer clear clinical guidance. The trials below are among those that drew scrutiny.
Trial: Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial, 2005–09
Sponsor: National Institute of Child Health and Human Development
Goal: Determine the optimum oxygen level for premature infants.
Controversy: Critics charged that the trial paired high levels of oxygen with levels below usual care and set oxygen monitors to provide false results—misleading parents and clinicians about the risk of death. Supporters argued that evidence to define usual care was unclear and both groups fell within that standard.
Trial: Established Status Epilepticus Treatment Trial, 2016–19
Sponsor: National Institute of Neurological Disorders and Stroke
Goal: Determine which of three anticonvulsant drugs most effectively treats seizures lasting more than 5 minutes.
Controversy: Critics said the study endangered subjects by randomly assigning them to a drug, when under usual care each patient’s history would be a key consideration. Because the researchers were initially blinded as to which drug was given, it was difficult for them to adjust treatment if patients did not respond. Researchers argued the trial was essential to determine objectively which drug worked best.
Trial: Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis Trial, ongoing
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Goal: Determine optimal treatment—drugs that constrict blood vessels plus limited fluids, or a larger volume of fluids alone—for people with life-threatening septic shock.
Controversy: Critics said both treatments deviated sharply from usual care for septic patients, increasing participants’ risk of death. Trial sponsors said they fell within the accepted range of care.
Trial: Myocardial Ischemia and Transfusion, ongoing
Goal: Determine the optimal blood transfusion strategy for heart attack patients with anemia, using red blood cell levels to decide when more blood is needed.
Controversy: Critics said informed consent forms misled participants and the trial placed those in the more restricted transfusion group at greater risk. Supporters said the trial would help resolve uncertainty about the best approach.
Those issues came to a head again in Vit-D-Kids. Vitamin D supplementation has long been contentious. It is said to be a remedy for diabetes, cancer, heart disease, and other ailments, but clinical trials often failed to show such benefits, particularly for the high-dose pills touted by the supplement industry. How much vitamin D a growing child needs also is debated, but most authorities say kids need levels in the blood of 20 to 29 nanograms per milliliter (ng/ml) to minimize risks of bone fractures and impaired immune response, and to protect lifelong skeletal health. Guidelines from the American Academy of Pediatrics and Pediatric Endocrine Society call anything below that threshold “deficient” or “insufficient” and recommend supplements. The Vit-D-Kids protocol also cites an Institute of Medicine report that agrees with those assessments. And NIH labels 20 ng/ml “inadequate” and below 12 ng/ml “deficient.”
With sites at big-city hospitals, Vit-D-Kids originally recruited asthmatic kids, ages 6 to 16, who had vitamin D levels between 10 and 29 ng/ml. Many kids were below 20 ng/ml—levels the study itself, in its protocol, deemed “deficient” and inadequate for musculoskeletal health. Yet that protocol, posted publicly online and included with the JAMA publication, also described the risk of leaving those children untreated as “no greater than encountered in daily life by healthy community-dwelling children.” But the kids participating in the study, afflicted with asthma and receiving powerful steroid drugs to treat it, were far from healthy.
In his statement to Science, Kiley defended Vit-D-Kids by saying vitamin D–deficient children were excluded in favor of those with “vitamin D levels in the low to low-normal range, who normally would not be treated with supplemental vitamin D.” He cited a 2016 global consensus report on rickets, a condition linked to vitamin D deficiency that causes soft bones and bow legs. Yet even the rickets report defined vitamin D levels of 12 to 20 ng/ml as “insufficient.”
Vit-D-Kids compared inadequate treatment and overtreatment, according to Natanson. Kids in the treatment arm were given daily vitamin D supplements of 4000 international units, or seven times their recommended daily allowance, and some reached serum levels above 100 ng/ml. NIH guidelines say anything above 50 ng/ml is potentially hazardous; studies have suggested such levels encourage some cancers and cardiovascular problems or increase risk of death overall.
The trial protocol noted the high-dose supplement was tested against a placebo to avoid a “false negative” outcome. “They wanted to maximize their chances of finding a difference,” says physician Michael Carome, a former top regulator at OHRP who directs health research for the consumer advocacy group Public Citizen.