[A study of asthmatic children, most of them Black, shows how a
common clinical trial design can expose vulnerable participants to
serious risks] [[link removed]]

FAILURE TO PROTECT?  
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Charles Piller
August 12, 2021
Science
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_ A study of asthmatic children, most of them Black, shows how a
common clinical trial design can expose vulnerable participants to
serious risks _

, 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.

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 sidebar, below
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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.

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.

_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.

_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 inwhich
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 green-lit
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.

Critics of Vit-D-Kids say the study, though an extreme case, also
points to troubling trends amid an explosion of comparative
effectiveness research (CER) trials, which examine the benefits and
harms of treatments. U.S. funding for CER clinical trials and related
trial support rocketed from an annual average of about $34 million
between 2009 and 2011 to $284 million since then—largely because of
the government-created nonprofit Patient-Centered Outcomes Research
Institute (PCORI), which specializes in assessing treatments side by
side.

Meanwhile, criticisms of such studies have mounted. In 2018 Public
Citizen challenged what it called “reckless” flaws in an
NIH-backed study of treatments for septic shock, a life-threatening
effect of infection. The group said the trial randomly assigned
subjects to combinations of fluids and drugs in ways that departed
sharply from usual care tailored to each patient’s condition. In a
public statement, Carome called patients in the ongoing trial
“unwitting guinea pigs in a physiology experiment that will not
advance medical care for sepsis and likely will harm many.”

Trial organizers challenged that verdict but last year OHRP and NHLBI
forced changes in the trial’s protocol to allow individualized
care—improvements Public Citizen commended but called insufficient.
(At the time, NIH barred Natanson and another NIH scientist from
commenting on the sepsis trial.)

Natanson recently analyzed CER trials of critically ill people
published over 1 year in three “high-impact journals with a
reputation for a rigorous review process—the best clinical trial
journals in the country.” The yet-unpublished study examined roughly
50 trials, identifying those that improperly excluded a usual-care
arm. He estimates that “up to half of the [CER] trials done in
critically ill subjects have this problem.” A huge proportion of
trials of nonemergency interventions, like Vit-D-Kids, also excludes a
usual-care arm, including more than 70% of PCORI’s CER trials.
Natanson says scientific results, patient safety, and the informed
consent process all suffer when a usual-care comparator is absent. But
he acknowledges that trial funders and IRBs struggle when no bright
line differentiates experimental interventions from usual care. Making
those distinctions can require laborious observational studies and
surveys.

PCORI itself says usual-care comparators are often important or
necessary. But given frequent challenges in defining standard
practice, the group actively discourages usual-care arms—“unless
they represent legitimate and coherent clinical options.” That’s
an abdication, Natanson says. “It’s much easier to say, ‘I have
two ideas, two strategies.’ … It’s much more difficult to say,
‘What is usual care? How is it practiced? How can I design the trial
so that … at least one arm is receiving usual care?’”

A real-world benchmark can be essential to evidence-based
medicine—whether a trial examines oxygen levels for preemies or
vitamin D for asthmatic kids, Natanson adds. “It’s just common
sense. Why study two things inside of a trial that nobody does outside
of the trial?”

This story was supported by the Science Fund for Investigative
Reporting
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_Charles Piller
[[link removed]] is a
contributing correspondent based in Oakland, California._

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