Science - USA (2020-10-02)

NEWS | FEATURES

26 2 OCTOBER 2020 • VOL 370 ISSUE 6512 sciencemag.org SCIENCE

Science found. Moreover, the agency fre-
quently closed cases on the basis of unveri-
fied claims by those accused.
The apparent neglect appears to be wors-
ening. The agency issued 99 “warning let-
ters” for serious clinical trial transgressions
during Obama’s first 3 years in office, 36 in
his last 3 years, and just 12 during the first
3 years under Trump. “It certainly looks like
FDA is enforcing clinical trial requirements
much less frequently, which is troubling for
protecting subjects’ welfare and ensuring
the validity of data for our medical prod-
ucts,” says Patricia Zettler, a lawyer who
reviewed Science’s findings. She worked for
FDA from 2009 to 2012, rising to associate
chief counsel.
Jill Fisher, a social scientist at the Uni-
versity of North Carolina, Chapel Hill, who
studies clinical trials, is also troubled that
when an FDA inspection exposes apparent
mistakes, recklessness, or fraud in a trial,

neither the agency nor the scientists run-
ning it are obliged to notify participants.
She calls that failure to inform “a travesty.”
At the least, Fisher says, volunteers in a
trial should be told when the integrity of
a research center running the study or its
investigator is in question.

LIGHT ENFORCEMENT
Although best known for overseeing food
safety and evaluating experimental drugs,
vaccines, and medical devices for marketing
approval, FDA performs many other tasks
with its $5.7 billion annual budget (for fis-
cal year 2019). Among them is overseeing
most clinical research in the United States
and some conducted elsewhere for the U.S.
market—including many high-stakes vac-
cine and drug trials for COVID-19. The
agency now deploys 102 inspectors to re-
spond to whistleblower complaints of dan-
gerous operations, conduct routine visits to
trial sites, and review records of those sites
or the institutional review boards (IRBs) that

oversee trials locally. Over the period Science

examined, FDA conducted roughly 6700 in-

spections of clinical researchers or IRBs.

FDA inspections can result in a range of

responses, from “no action” declarations;

to “official action indicated” (OAI) reports,

which require a violator to clean up serious

transgressions; to warning letters, which

threaten further regulatory action unless

corrections are made promptly. In extreme

cases, the agency can even disqualify a scien-

tist from clinical research.

But Science found that FDA rarely levels

sanctions. The agency almost always rules

that no action is warranted or requests vol-

untary corrections, according to documen-

tation on all inspections that drew an OAI

designation or more severe enforcement ac-

tion. Since 2009, FDA has used the OAI des-

ignation to direct only 291 of the inspected

researchers or institutions—about 4%—to

correct serious, illegal, and potentially dan-

gerous clinical trial problems. Furthermore,

FDA officials sometimes downgraded a

problem originally classified by inspectors

as OAI—in which compliance must be con-

firmed by a follow-up inspection or other

actions—to “voluntary action.”

Holly Fernandez Lynch, a lawyer and bio-

ethicist at the University of Pennsylvania

(UPenn), says the agency prefers voluntary

action. “When people fail to comply, it’s hard

to know what to do about it, short of com-

pletely ending a trial or all research at that

institution,” which might deprive patients of

a chance at an effective treatment in trials,

Lynch notes.

Under Trump, the number of FDA inspec-

tions per year has increased significantly,

yet enforcement actions have nosedived

(see graphic, above). About 6% of FDA in-

spections were classified as OAI during

the Obama administration, although the

proportion began to decline in his second

term. During Trump’s first 3 years, however,

OAI reports fell to less than 1% of the total.

Even voluntary action designations declined

sharply under Trump, whereas “no action”

inspections spiked. The agency disqualified

an average of three investigators per year un-

der Obama but just two total during Trump’s

first 3 years.

FDA did not dispute Science’s figures on

OAIs and warning letters—but the agency

said Trump-era policies were not a factor.

“The number of warning letters can ebb and

flow,” the agency wrote in an email.

For extreme problems in a clinical trial,

when patients or data reliability are at imme-

diate and serious risk, FDA can use warning

letters to immediately halt the trial or restrict

an IRB from approving new trials. The agency

did so seven times during Obama’s first term

and not once since Trump took office.

LITTLE FOLLOW-UP

Among the 291 OAI cases Science identi-

fied, only 71 resulted in a clear regulatory

endpoint—such as disqualification,

a “closeout letter” certifying that

corrections were completed, or an-

other formal statement. For the

remaining 220, no clear outcomes

could be found in public documents

or data banks, leaving trial partici-

pants and others in the dark. FDA

can also deem violations “not cor-

rectable,” ending its enforcement

with neither compliance nor any

form of disclosure. From outside the

agency, it’s impossible to know how

often that occurs.

In addition to searching public

documents and FDA databases and

filing FOIA requests for key docu-

ments in nearly all 291 cases, Science

filed additional FOIA requests in 28 of those

cases for every essential document, including

any that described a resolution. After about

10 months, FDA released documents describ-

ing how 16 cases were resolved. Most were

based on written promises from researchers.

In one, the researcher pledged to never again

conduct clinical studies and then violated

that pledge, according to records posted by

drug companies that hired him for clinical

trials—with no apparent FDA response.

In an email, FDA defended its approach,

noting its “strategy to focus inspectional re-

sources on higher-risk facilities.” FDA tries

to address clinical trial problems early in

the process, it also noted, so “an issue that

might warrant a warning letter could be

resolved before the problem rises to that

level.” (Agency officials would not agree to

an interview. Spokespeople instead emailed

selective responses to written questions.)

Yet FDA sometimes issues closeout letters

even when nothing material has changed. In

2016, the agency sent a warning letter to the CREDITS: (GRAPHIC) N. DESAI/

SCIENCE

; (DATA) FOOD AND DRUG ADMINISTRATION

*Combined *scal year budgets for the periods shown, constant 2019 dollars

Obama
First 3 years

Obama

Last 3 years

Warning

letters

Cases classifed

“ofcial action indicated”

Clinical trial enforcement

budget ($ millions)*

Investigator

disqualifcations

Tr u m p
First 3 years
0 10 20 0 40 80 0 40 80 120 160 0 50 100 150

A watchdog loses its bite
Despite a steady or rising enforcement budget, the Food and Drug Administration has wielded its power to enforce laws meant
to safeguard volunteers for clinical trials—and ensure the integrity of testing data—less and less frequently since the beginning
of the Obama administration. Under President Donald Trump, the number of enforcement actions has plummeted.