The Baltimore Sun
U.S. halts Hopkins research funding
Recent death of drug test subject cited
By Jonathan Bor and Tom Pelton
Sun Staff
Originally published July 20, 2001, 8:09 AM EDT

BALTIMORE -- Seven weeks after the death of a young woman
in an asthma study, the federal government suspended human
medical experiments at the Johns Hopkins University yesterday
because of what regulators characterized as widespread lapses
in safety procedures.

The federal Office for Human Research Protection said Hopkins
conducted the asthma experiment without discovering
and warning patients about reports of sometimes fatal drug
reactions that were readily available on the Internet and
in medical textbooks.

In sweeping and often stinging criticisms, the agency also referred
to a pervasive pattern of safety lapses, saying the review boards
that approve experiments were overwhelmed with work,
didn't adequately warn patients about risks and failed
to rigorously evaluate research proposals.

Discussions of continuing research were "not substantive
nor meaningful," the agency said.

"The bottom line is we found serious problems with their procedures
to protect human lives during trials," said Bill Hall, an agency
spokesman. "This is not a paper-pushing procedure. This is about
protecting people's lives."

The suspension covers 2,400 federally funded human experiments
involving at least 15,000 patients and volunteers. The action affects
the medical school, Hopkins hospital, Bayview Medical Center,
Applied Physics Laboratory and some research at the Kennedy
Krieger Institute.

The federal order does allow some studies - those involving
experimental treatments of patients with life-threatening
illnesses - to continue.

Dr. Edward D. Miller, Hopkins' medical dean and chief executive
officer, appeared before the Hopkins dome on North Broadway
and angrily defended his institution's safety record.

"We are outraged by the actions of the OHRP," said Miller,
referring to the year-old federal agency created to protect
human lives in experiments.

"We find it hard to understand how a new agency would take
a draconian measure against an institution that has been
conducting trials for thousands of patients over many years ... and
providing medical care for more than a century."

In its response to the federal action, Hopkins described the
suspension as "unwarranted, unnecessary, paralyzing
and precipitous."

Miller said he expected that the university would be able
to address criticisms and persuade the federal agency to lift
its ban within three or four days - a time line an agency official
said was possible.

But Miller said he was concerned that during the delay,
patients with life-threatening illnesses would not be able
to enroll in new experimental treatment programs.

"Patients who come here looking for hope will not be able
to receive it," Miller said.

The Hopkins medical institutions received $419 million
in research funding from the National Institutes of Health last
year - the largest sum given to any medical center in the country.
 Of the total, about $277 million is for experiments involving
human subjects, according to an agency official.

The suspension came as a stunning blow to Hopkins,
which is considered to be one of the world's pre-eminent
medical institutions. Walls around campus are plastered
with posters boasting of Johns Hopkins Hospital's recent
selection as the nation's top medical center for the 11th straight
year by U.S. News & World Report.

Earlier this week, an internal panel that investigated the death
of the research subject, Ellen Roche of Reisterstown, criticized
the asthma researchers and the review board that approved
the experiment but said the institution was improving
safety procedures.

It had already added a third review board to evaluate the large
volume of research proposals each month.

The Hopkins investigators concluded that Roche, a 24-year-old lab
technician at Hopkins' Bayview campus, died from inhaling
hexamethonium, a chemical scientists administered to help them
understand how the lungs of healthy people protect against
asthma attacks. It apparently caused Roche to develop
a progressive lung illness.

But the federal agency was far harsher in its criticism
of the flawed experiment.

While Hopkins panel said the principal investigator,
Dr. Alkis Togias, made "a good faith effort" to uncover any
previous injuries linked to the chemical, the federal agency said
the scientist failed to discover published reports of toxic effects
that were readily available on the Internet and in recent textbooks.

It also found fault with the review board for not uncovering
the dangers itself.

In the reports, several patients who had received hexamethonium
for the treatment of hypertension in the 1950s suffered respiratory
failure. Some died.

Also, in the consent form that patients signed, researchers
called hexamethonium a "medication" when, in fact, it was
no longer approved by the Food and Drug Administration,
the agency said. Researchers should have told volunteers
that the chemical, which lost FDA approval in 1972, was being
used experimentally.

Even when hexamethonium was an approved medication,
it was never approved for use in an inhaled form, the agency said.

The federal agency criticized not only the researchers but also
the Institutional Review Board, saying "an adequate evidence
base did not exist for the IRB to be confident that inhaled
hexamethonium was safe for use in research subjects."

But in suspending research, the federal agency said Hopkins
had failed to adequately supervise human experiments throughout
the institution - even after being warned Oct. 3 that problems
existed. Those deficiencies emerged from an agency inspection.

Yesterday, federal officials said many of the same problems
remained. Most involved the supervision given by the
Institutional Review Boards, which are required under federal law
to make sure that experiments protect the safety
of human volunteers.

The federal investigators found "multiple instances" in which
the risks outlined in applications for IRB approval were different
from those in the consent forms shown to volunteers.
The language used in the consent forms was "complex"
and difficult for subjects to understand, the report said.

Miller said his institution responded soon after the critical
October letter, detailing ways it planned to improve its review
process. Yesterday, he complained that the agency had never
responded nor given Hopkins an opportunity to address any
remaining concerns.

Blasting the federal agency for shutting down potentially
life-saving experimental treatments, he characterized many
of the complaints as bureaucratic, such as the length of time
it took Hopkins review boards to type the minutes
of their meetings.

"It's an administrative, bureaucratic nightmare," said Miller.

But Hall said the agency took the rare step of suspending
research at the nation's largest medical research institution
not for trivial reasons, but because widespread safety problems
at Hopkins were putting people's lives at risk.

"We don't do this lightly," Hall said. "In this case, they
[the OHRP investigators] found broad systematic problems
throughout the Hopkins institutions. Because of the potential risk
to human lives, we had to suspend the trials."

U.S. Sens. Barbara A. Mikulski and Paul S. Sarbanes faxed letters
yesterday to the secretary of the Department of Health and Human
Services, Tommy G. Thompson, urging him not to suspend
the Hopkins research projects until officials
could explain themselves.

Last night, Hopkins administrators and doctors were sorting out
how their research and how patients' treatment might be affected.
For example, at the Hopkins Children's Center, physicians were
rushing around, holding emergency meetings to figure out whether
they will be able to continue experimental chemotherapy today
for children with cancer.

"Everyone is very concerned about this," said Emily Burwell,
a lab technician in the unit. "People are wondering if there are kids
in their hospital beds who face the prospect of not getting
their medications."

Meanwhile, Dr. John W. Griffin, director of neurology, said he
and others were reviewing dozens of trials to identify which
patients might be at risk if medications are stopped.

"Right now, all the focus is on identifying patient care issues,"
said Griffin. "A number of trials involve quite ill patients."

The Johns Hopkins School of Public Health was the only
health-related institution within the university that was not covered
by the suspension. Even so, staffers were sorting through
their projects to identify those that were joint projects
with the medical school, and therefore might be stopped.

"This is going to prove extremely disruptive for all concerned:
faculty, patients and study subjects," said Dr. Alfred Sommer,
the school's dean, in an e-mail from Buenos Aires.

Ruth Faden, who heads the Hopkins bioethics institute, said that
hundreds of patients get their medical care through clinical trials.

"There are a lot of people whose medical care is going to be
confused, if not interrupted," Faden said. Even though some
patients will be allowed to stay in their trials, she noted that it's
complicated "who makes the call as to what is life-threatening
and what is life-sustaining."

Faden, who led a national committee six years ago that
investigated problems in human subject research, said she was
stunned by the federal action.

"You don't do this lightly at a place like Hopkins, that has this kind
of volume of ill patients in research," she said. "It's a dramatic action.
It's a huge action. It is very troubling."

Sun staff writers Diana Sugg and Eric Siegel contributed to this article.

SOURCE: The Baltimore Sun
http://www.sunspot.net/features/health/sns-hopkins-research.story?coll=sns%2Dhealth%2Dheadlines

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