Science - USA (2020-01-17)

NEWS

SCIENCE sciencemag.org

CREDITS: (GRAPHIC) N. DESAI/

SCIENCE

; (DATA) CLINICALTRIALS.GOV/TRIALSTRACKER

institutions as the Harvard University–

affiliated Boston Children’s Hospital, the

University of Minnesota, and Baylor College

of Medicine—all among the top 50 recipi-

ents of NIH grants in 2019.

The violations cover trials in virtually all

fields of medicine, and the missing or late

results offer potentially vital information

for the most desperate patients. For exam-

ple, in one long-overdue trial, researchers

compared the efficacy of different chemo-

therapy regimens in 200 patients with ad-

vanced lymphoma; another—nearly 2 years

late—tests immunotherapy against conven-

tional chemotherapy in about 600 people

with late-stage lung cancer.

Other leading NIH grantees did only

slightly better in Science’s analysis based

on data collected from the TrialsTracker

website of the University of Oxford, which

automatically mines ClinicalTrials.gov in-

formation. The University of Texas MD An-

derson Cancer Center and the Mayo Clinic

both failed to report results on time, or at

all, in about two-thirds of their trials. Yale

University failed to do so in 84% of its trials.

NIH’s own institutes also had a bad record.

They are directly responsible for reporting

results when they sponsor studies done by

agency staff or some grantees, and the top

four NIH institute sponsors, taken together,

reported results late or not at all in more

than six of every 10 trials Science looked at.

Contacted for comment, none of the insti-

tutions disputed the findings of this inves-

tigation. In all 4768 trials Science checked,

sponsors violated the reporting law more

than 55% of the time. And in hundreds of

cases where the sponsors got credit for re-

porting trial results, they have yet to be pub-

licly posted because of quality lapses flagged

by ClinicalTrials.gov staff (see sidebar, p. 243).

Although the 2017 rule, and officials’

statements at the time, promised aggres-

sive enforcement and stiff penalties, nei-

ther NIH nor FDA has cracked down. FDA

now says it won’t brandish its big stick—

penalties of up to $12,103 a day for failing

to report a trial’s results—

until after the agency is-

sues further “guidance” on

how it will exercise that

power. It has not set a date.

NIH said at a 2016 brief-

ing on the final rule that

it would cut off grants to

those who ignore the trial

reporting requirements, as

authorized in the 2007 law,

but so far has not done so.

Many scientists who con-

duct clinical trials, and their

sponsors or funders, have

downplayed concerns about

late or missing results in ClinicalTrials.gov.

Researchers, doctors, and patients can

instead learn about trial outcomes from

peer-reviewed publications, they say. But

thousands of trials are never published,

particularly when they find treatments

ineffective, history has shown.

ClinicalTrials.gov also uses a common for-

mat, allowing comparisons of results across

trials that journal articles rarely make pos-

sible. Doctors, researchers, and potential

trial participants rely on the site, to judge

from its 215 million monthly page views.

Deborah Zarin, a physician at Brigham

and Women’s Hospital and Harvard who

headed ClinicalTrials.gov between 2005

and 2018, says the Science findings show

failures of the research culture, FDA, and

NIH. “If this was a priority for the leader-

ship of NIH, then they could ensure that

high-quality, timely reporting happened

all of the time,” says Zarin, an NIH-paid

research consultant for the database. “You

can set up processes so trial reporting is an

expectation. You can’t pass ‘go’ and collect

$200 until this is done.”

Zarin, who works in a program to advance

clinical research, adds that the problem

persists because “reporting to ClinicalTrials.

gov is frequently seen by sponsors, funders,

and trialists as an annoying administrative

and perhaps legal burden, not a scientific

imperative. Human nature being what it is,

people follow the requirements when forced

to do so.”

NIH and FDA officials do not seem inclined

to apply that pressure. Lyric Jorgenson, NIH

deputy director for science policy, says her

agency has been “trying to change the cul-

ture of how clinical trial results are reported

and disseminated; not so much on the ‘aha,

we caught you,’ as much as getting people to

understand the value, and making it as easy

as possible to share and disseminate results.”

To that end, she says, ClinicalTrials.gov staff

have educated researchers about the website

and improved its usability.

As for FDA, Patrick McNeilly, an official

at the agency who handles

trial enforcement matters,

recently told an indus-

try conference session on

ClinicalTrials.gov that “FDA

has limited resources, and

we encourage voluntary

compliance.” He said the

agency also reviews re-

porting of information

on ClinicalTrials.gov as

part of inspections of trial

sites, or when it receives

complaints.

McNeilly declined an in-

terview request, but at the

conference he discounted violations of Clini-

calTrials.gov reporting requirements found

by journalists and watchdog groups. “We’re

not going to blanketly accept an entire list

of trials that people say are noncompliant,”

he said. Such determinations require “non-

public information” submitted to the agency

by trial sponsors. In response to Science’s

findings, a spokesperson said an absence of

posted results on ClinicalTrials.gov did not

mean a trial sponsor has broken the 2007 law.

Yet that law and the 2017 final rule de-

tail only a few exemptions that would allow

trial sponsors to withhold results on the

basis of nonpublic information. The very

few registered trials that qualify for those

exemptions are not flagged as violators by

TrialsTracker or in Science’s analysis.

CONGRESS APPROVED the creation of

ClinicalTrials.gov in 1997, after allegations

that patients were harmed because compa-

nies withheld evidence showing their medi-

cines were ineffective or hazardous. A widely

cited case involved the GlaxoSmithKline anti-

depressant Paxil (paroxetine). According to

legal filings and a report in The BMJ, the firm

held secret data showing that in clinical trials

Missed deadlines

Among more than 4700 clinical

trials examined by Science, less

than 45% had their results reported

early or on time to ClinicalTrials.gov.

1506

31.6%

Not reported

1132

23.7%

Reported late

2130

44.7%

Reported on

time or early

17 JANUARY 2020 • VOL 367 ISSUE 6475 241

Published by AAAS