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28 2 OCTOBER 2020 • VOL 370 ISSUE 6512 sciencemag.org SCIENCE
medical director of a Texas research firm.
He had enrolled trial participants who suf-
fered from kidney impairments, an agency
inspection reported, and then overdosed
them with an experimental drug that could
have further damaged their kidneys. The
physician responded with a plan to prevent
future overdoses, but FDA replied that it was
inadequate. Yet on the same day as that re-
ply, the agency sent a letter closing the case.
“The agency should follow through and
complete actions—so they don’t initiate a
process and never resolve it,” says Joshua
Sharfstein, vice dean at the Johns Hopkins
Bloomberg School of Public Health and a
top FDA official under Obama. “And it’s im-
portant for the agency to share information
about its processes, so people can under-
stand what happened.”
When FDA does follow up on the prob-
lems it identifies, the process can be slow.
Agency documents and databases covering
the 291 OAI cases show dozens of cases that
took 10 months to 14 years to be escalated
to a warning letter. Some delays can be
“egregious,” Lynch says.
In 2015, the agency issued an OAI after it
inspected a Pennsylvania hospital IRB that
oversees more than 100 trials annually. The
agency’s findings read like a functional col-
lapse: records glitches, including failure to
keep a list of IRB members and their quali-
fications or record attendance at meetings;
approval of trials without a quorum; sloppy
reviews of trials; a lack of required written
policies on how to determine the risk of de-
vices being tested on patients; neglecting to
promptly inform FDA or the hospital’s own
leaders about trial problems; and poor or
no training for IRB members. According to
FDA documents, the agency waited 4 years
to follow up. In a second inspection, in 2019,
many of the same problems were found, re-
sulting in a warning letter. Only then did the
IRB finally resolve the deficiencies.
A St. Louis IRB received citations about
similar problems in a 2012 warning letter,
which noted that pervasive lapses at the IRB
were also found in 2003 and in 1998. That
IRB finally addressed the issues after the
warning, according to an FDA closeout letter.
That sparse, slow enforcement puts par-
ticipants and the research process itself at
risk, critics say. Given the extremity of vio-
lations that lead to little or no punishment,
Fisher asks: “What would it take for the FDA
to take serious action to ensure that clinical
research is being conducted with the most
integrity possible?”
The secrecy of the process also means trial
participants are kept unaware of possible
harm, violating “a basic human right,” says
Vinay Prasad, a hematologist-oncologist at
the University of California, San Francisco,who studies how drug funding affects re-
search. Steven Joffe, a medical ethicist at
UPenn, agrees, citing an obligation to be
transparent to the people who have volun-
teered their bodies for clinical research: “We
owe that back to them.”“SYSTEMIC PROBLEM” IGNORED
A clinical trial scandal that erupted in Min-
nesota in 2018 illustrates the potential public
health hazards posed by FDA’s lax enforce-
ment. That year, the consumer advocacy
group Public Citizen and more than 60 cli-
nicians and medical ethicists alleged that
a large Minneapolis community hospital
operated by Hennepin Healthcare had vio-
lated informed consent requirements in tri-
als comparing ketamine, a powerful sedative
and anesthetic, with other drugs for people
who came to the emergency room with agi-
tation. The critics said the emergency de-
partment doctors did not obtain informed
consent from trial partici-
pants, even though ketamine
was much more likely to
cause serious breathing prob-
lems and movement disor-
ders. Many patients who
received ketamine developed
such symptoms.
After Public Citizen’s alle-
gations, FDA inspectors con-
firmed the lapses in informed
consent. They concluded that
Hennepin’s IRB had waived
the requirement to obtain
consent and did not institute
additional safeguards “to protect the rights
and welfare of those subjects.” And inspec-
tors said researchers running the trials ne-
glected to properly report serious adverse
events. Nevertheless, the agency did not clas-
sify the inspection as OAI or send a warning
letter. Hennepin rejected most of the FDA
findings, although the health system agreed
to some procedural changes and suspended
one trial for review.
FDA already knew of alleged problems in
Hennepin’s ketamine research at the same
hospital before the Public Citizen allega-
tions, according to new documents obtained
by Science. In 2014, the agency inspected a
Hennepin trial led by Brian Driver, a staff
physician, and James Miner, then and now
chief of emergency medicine at the hospital
where the later trials took place. The trial
compared ketamine with another drug used
to sedate patients who required breathing
tubes. As in the later trials, the agency de-
tailed failures to properly obtain informed
consent from patients.
A 2016 follow-up review by FDA of the
ketamine trial detailed failures by Driver
and Miner to properly report 13 patientdeaths to Hennepin’s IRB—a required prac-
tice to verify that the trial itself does not pose
safety hazards. In a response to FDA, Driver
acknowledged his reporting error in three
of the deaths but did not address the other
10 deaths, and FDA documented no further
information on them. In an email to Science,
Driver wrote that FDA had never discussed
those additional deaths with him, but he ac-
knowledged failing to report the deaths of the
13 FDA initially flagged, as well as 10 others
in the trial that it did not document. Driver
attributed all 23 deaths to acute illnesses or
injuries unrelated to the study drugs, includ-
ing sepsis, stroke, and heart attack.
Driver became a member of the hospital’s
IRB in 2016 and was on it when the group
approved or reviewed the later ketamine tri-
als flagged by Public Citizen. Science showed
the FDA documentation of his earlier ket-
amine trial to Michael Carome, who directs
health research at Public Citizen. “We have
a group of physicians, all in
the emergency department,
over a period of several years
... not complying with FDA
regulations regarding human
subjects protection,” says Car-
ome, a physician himself. The
clinical trial missteps exposed
“a pattern of sloppiness and
carelessness” by Hennepin
researchers and their IRB, he
adds, raising broad doubts
about its oversight of human
subjects research.
The IRB chair, a hospital
spokesperson, Miner, and Driver all declined
to comment about the later clinical trial
problems FDA identified. In a public state-
ment, Hennepin defended the trials while
apologizing for “not involving the commu-
nity in a proactive way” before the studies.
Hennepin said it would increase training for
clinical researchers and improve study mon-
itoring and public disclosure. But the health
system refused to answer questions such as
why—after years of FDA inspections cited
serious problems with ketamine trials—the
IRB and emergency department launched
new trials with no special precautions to
protect patients.
Hennepin’s ketamine controversy also
raises questions about FDA oversight. De-
spite the problems it identified as early
as 2014, FDA never issued a warning let-
ter or otherwise demanded that Hennepin
researchers rectify trial procedures. The
agency imposed no restrictions on the hos-
pital’s clinical research or IRB operations.
FDA never mandated that trial participants
who suffered adverse effects—or their loved
ones—be advised about inspection findings.
FDA declined to comment on Hennepin’s“It certainly looks
like FDA is enforcing
clinical trial
requirements much
less frequently,
which is troubling.”
Patricia Zettler,
former FDA lawyer