10- Year University Cover-Up: Unethical BleedingExperiment_Huffington Post

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Oct 26, 2009, 10:44:34 AM10/26/09
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ALLIANCE FOR HUMAN RESEARCH PROTECTION
A Catalyst for Public Debate: Promoting Openness, Full Disclosure, and
Accountability
http://www.ahrp.org

FYI

Recent reports about fraudulent research, tainted medicines, gross
violations that put patient-subjects at risk of death--underscore the
failure of the current medical research protections system. The outmoded
system meant to ensure patient-subject safety and the integrity of the
scientific process relies on misplaced trust, which has repeatedly been
shown to be betrayed. Institutional review boards (IRBs) have inherent
conflicts of interest: IRB members are beholden to the institution that
employs them. The problems are exacerbated by the lackadaisical oversight
by federal agencies the FDA, NIH, and OHRP who fail to inspect and enforce
federally mandated safeguards. Federally licensed academic medical centers
have institutional financial stakes in the research enterprise: their
failure to take action when ethical /scientific violations are reported-as
is their responsibility--has been shielded by a "don't ask, don't tell"
culture. The issues, however, are gathering momentum.

1. A report by the Government Accountability Office (GAO-09-807,
http://www.gao.gov/new.items/d09807.pdf September 25, 2009) "Oversight of
Clinical Investigators: Action Needed." documents numerous cases of rogue
researchers who continue to conduct medical experiments on human subjects
despite being found to have committed fraud. For example, The New York
Times cites the case of one researcher who "helped conduct more than 170
drug studies for nearly every major drug maker in the world and routinely
falsified data and patient records while doing so." Yet, the FDA failed to
disbar him.

The New York Times reports that the GAO found that it took the FDA between 1
and 11 years to complete it process to ban rogue researchers. "This means
that many who were convicted of fraud remained eligible to conduct
experiments for years."
http://www.nytimes.com/2009/10/22/health/policy/22fda.html

The GAO report prompted senior Republican Congressman, Joe Barton, on the
House Energy and Commerce Committee to announce that he would introduce
legislation to ban researchers convicted of fraud from later participating
in any kind of human research to "ensure that American families will be
safe."

2. The Office of Human Research Protections (OHRP) the federal
oversight office of human subject research that is conducted (at least
partially) with taxpayer funding, has cited more than 40 hospitals and
academic medical centers in the past two decades for violating federal
research safeguards-many of who are flagrant repeat offenders.

We bring to your attention the first of two recent reports of unethical,
scientifically dubious medical experiments conducted on American patients at
high volume medical research centers that are federally licensed to conduct
human medical research in compliance with federal research regulations.

The experiments violated both ethical and scientific standards, for some
patients resulting in "medical disasters." Yet, they had been approved by
hospital institutional review boards (IRB). They were brought to the
attention of the federal oversight agency, OHRP by conscientious
physicians-turned-whistleblowers.

Case 1: An investigative report by Jeanne Lenzer and Shannon Brownlee
(below), focuses on a 10-year cover-up by Columbia University Medical Center
which is the recipient of more than $1 Billion in federal research funds.
The unethical experiment conducted on more than 200 heart surgery patients
who were put at high risk to test an Abbot Lab blood expansion product
(hetastarch) without being informed about the nature of the experiment or
the potentially fatal risks involved in the test product--i.e.,
hemorrhaging.

The experiment resulted in the death of "at least two patients" and "more
than two dozen others required transfusions." The chart of one such
victimized patient acknowledged that this was a "medical disaster."

In the past decade-the same period during which dubious HIV-AIDS drugs and
vaccines were tested in foster children-the "bleeding" experiment had
undergone three internal reviews that raised serious questions about the
trial's design, management and oversight. However, those internal reviews
were submerged by the university's legal defense team which shielded the
researchers and the institution, baldly claiming that "there was no evidence
that the fluid caused deaths or other medical problems for patients and that
there was no need to provide the patients with additional information about
the study."

That self-serving conclusion, crafted by the University's legal arm, is
belied by the federal Office of Human Research Protections (OHRP) whose
letter (June 8, 2009) to Columbia, obtained by the Huffington Post
Investigative Fund ,shows that "at least some of the subjects appear to have
suffered harms that were a function of the design and procedures of the
study."

The case is so egregious that OHRP officials have taken the rare action of
demanding that Columbia track down the patients involved in the experiment
and their families, and acknowledge that they never were informed about the
"true nature" of the drug study, the risks they faced or the consequences of
their participation.

Of note: as is often the case, when unethical, harm producing human
experiments are uncovered, the subjects were disadvantaged, therefore,
vulnerable to exploitation: "Some of the subjects were Spanish-speaking
patients who lived in low-income neighborhoods near the hospital and were
admitted through the emergency room, according to people who worked at the
hospital at the time."

The researcher, Elliott Bennett-Guerrero, an anesthesiologist, was 34 in
1999, when he was recruited to serve as clinical director of Columbia's
division of cardiothoracic anesthesiology. The Huffington Post reports that
"within two years, records show, he was simultaneously running 25 clinical
trials. He received approximately $150,000 in the form of an unrestricted
grant from Abbott Laboratories as reimbursement for the comparative study of
blood expanders."

The trial appears to have been designed strictly to increase profits for
Abbott, while putting patients at increased risk of bleeding:
"Several previous studies had shown that the original hetastarch product
could sometimes trigger excessive bleeding during surgery. If Abbott's new
formulation of hetastarch - called Hextend -- turned out to be safer in high
doses, anesthesiologists might be persuaded to switch, even though Abbott's
price was about 40 percent higher."

Dr. Bennett-Guerrero subsequently filed a lawsuit against the hospital and
its officials, vigorously challenging their claims and decision. The lawsuit
ended with a confidential settlement in 2003.

A yet to be publicly disclosed letter (June 8, 2009) to Columbia University,
OHRP states: there was "a statistically significant higher rate" of
"negative clinical outcomes, including bleeding events (requiring use of
transfusions) and decreases in renal [kidney] function among study
participants who received hetastarch. Beyond that, there was the trend
toward increased need for re-operation."

After the settlement, Bennett-Guerrero left Columbia in 2003 for
Duke-another of the nation's elite medical research centers.

The Alliance for Human Research Protection will be filing Freedom of
Information requests with for the documents and correspondence relating to
this case. We urge others to make such requests as well.

FOIA Contact:
Department of Health and Human Services FOIA Office
Freedom of Information Officer
Mary E. Switzer Building, Room 2221
330 C Street, S.W.
Washington, D.C. 20201
Phone: 202-690-7453
Fax: 202-690-8320
FOIA Officer: Robert Eckert
FOIA Public Liaison: Michael J. Robinson

Case 2: Unethical cancer trials at the Carle Clinic / Carle Foundation
Hospital will be the subject of a follow-up Infomail.

Contact: Vera Hassner Sharav
vera...@ahrp.org
212-595-8974
~~~~~~~~~~~~~~

http://huffpostfund.org/stories/2009/10/government-orders-columbia-tell-pati
ents-true-nature-drug-study
Government Orders Columbia to Tell Patients 'True Nature' of Drug Study
Officials Say Research May Have Caused Harm to People Who Had Heart Surgery
By Jeanne Lenzer and Shannon Brownlee
Special to Huffington Post Investigative Fund
7 Oct 2009

NEW YORK -- The man who would be known as Patient No. 1 emerged from routine
open-heart surgery at Columbia University Medical Center in stable
condition. Then he began to bleed uncontrollably. Surgeons rushed him back
to the operating room to reopen his chest, but by the time they could stop
the hemorrhaging, Patient No. 1 was barely breathing and in a coma.

On Aug. 15, 2000, shortly before he was discharged on his way to a nursing
home, a physician wrote a terse final diagnosis in his chart: "Medical
disaster."

Patient No. 1, along with more than 200 other open-heart surgery patients,
was part of a two-year medical study at Columbia that government regulators
now say was carried out with ethical and regulatory mistakes and may have
caused harm to some patients. The study was testing a commonly used
intravenous surgical fluid that previous studies had shown could cause
hemorrhaging at high doses. At least two patients in the study died shortly
after receiving the fluid and more than two dozen others required
transfusions, according to documents submitted to the federal government by
the hospital and obtained by the Huffington Post Investigative Fund.

In the past decade, Columbia has conducted three separate internal reviews
of the study. The reviews raised serious questions about the drug trial's
design, management and oversight. But they concluded that there was no
evidence that the fluid caused deaths or other medical problems for the
patients and that there was no need to provide the patients with additional
information about the study.

Now federal regulators have decided not to accept that conclusion. They have
taken the rare action of demanding that Columbia track down the patients and
their families, and acknowledge that they never were informed about the
"true nature" of the drug study, the risks they faced or the consequences of
their participation.

New information shows that "at least some of the subjects appear to have
suffered harms that were a function of the design and procedures of the
study," the federal Office of Human Research Protections wrote to the
hospital in a June 8, 2009, letter obtained by the Investigative Fund.

Federal officials also demanded that Columbia turn over a newly completed
internal analysis of how the patients fared in the study.

The issues raised by the Columbia study, which was indirectly funded by a
pharmaceutical company, reflect the ongoing national debate over flaws in
the system designed to protect people who participate in medical research.
The federal oversight office has cited more than 40 hospitals and academic
medical centers in the past two decades for falling short. The Columbia case
stands out for the bitter controversy it has engendered for years inside the
hospital, the courts and the federal government - reported here for the
first time - and for the hospital's failure to contact patients even after
federal investigators recommended it do so in 2003.

The study, conducted between December 1999 and February 2001 in the famed
heart surgery unit at what is now called New York-Presbyterian
Hospital/Columbia University Medical Center, involved four blood expanders
approved by the U.S. Food and Drug Administration. The fluids are generally
administered by anesthesiologists and combat medics when patients or
soldiers have lost significant quantities of blood.

Two of the blood expanders in the study contained a substance known as
hetastarch, a clear fluid made of a starch and salt solution. Published
studies dating back to 1981 showed that hetastarch can prevent blood from
clotting properly, especially when used at higher doses. According to
documents filed by the hospital in New York state court, one purpose of the
Columbia trial was to test whether a new formulation of hetastarch,
manufactured by Abbott Laboratories, was less likely to trigger serious
bleeding at high doses than the other fluids. It was largely funded from a
$150,000 unrestricted grant given by the drug company to the hospital and
lead researcher, records show.

In the consent form used in the study, patients were told that they would
receive one of four fluids approved by the FDA and routinely "used to
replace blood and fluid lost during surgery." The consent form stated that
the researchers would extract a few tablespoons of blood from the patient to
test a machine that monitors clotting. Patients were not told that they
could be given high doses of the fluids or that they faced a risk of serious
bleeding, according to a copy of the consent form obtained by the
Investigative Fund.

Documents later filed in court show that about half of the 215 people who
agreed to participate were given hetastarch, and some received up to three
times the level recommended by the manufacturers. Some of the subjects were
Spanish-speaking patients who lived in low-income neighborhoods near the
hospital and were admitted through the emergency room, according to people
who worked at the hospital at the time. The names of the patients and
details about their cases have not been made public because of medical
privacy rules.

Two hospital doctors raised concerns about the study with hospital
authorities in 2000, triggering the internal Columbia reviews. The hospital
decided in 2002 to discipline the study's lead researcher because, Columbia
alleged, he had not properly disclosed the nature of the drug study to the
hospital or the patients and had failed to report promptly a "substantial
number" of medical complications among the participants, according to court
papers. The researcher, Elliott Bennett-Guerrero, an anesthesiologist,
subsequently filed a lawsuit against the hospital and its officials that
vigorously challenged their claims and decision. The lawsuit ended with a
confidential settlement in 2003, court records show, and Bennett-Guerrero
left Columbia for another hospital.

Columbia hospital officials declined requests for interviews and would not
discuss the recent findings by federal regulators that some patients appear
to have been harmed or the government's demand that the hospital notify the
study's participants.

In a statement to the Investigative Fund, Columbia said its internal reviews
had concluded that neither patients nor the hospital board that approves
clinical trials "were adequately informed of the risks posed by one of the
treatments in the study." Nevertheless, the hospital said, its most recent
review completed in 2008 -- which included outside experts -- analyzed
patient records and concluded that the medical outcomes did not meet the
definition of "harm."

Columbia also said that as a result of its investigations it had made
"substantial improvements" in its procedures for overseeing research on
humans.

KEY DOCUMENTS Inside Columbia University's investigation of the drug study.

In the lawsuit he filed against Columbia in 2003, Bennett-Guerrero said that
proper consent was obtained from all the patients in the study. He said
there was no misrepresentation of the study's design or purpose, that
hospital officials had been fully informed and had approved every aspect. He
contended that their actions against him were meant to hide weaknesses in
their own hospital procedures.

Bennett-Guerrero, who joined Duke University Health System in 2003, declined
a request for an interview. He said in e-mails: "It is hard to imagine that
an unbiased expert in cardiac surgery clinical trials could conclude that
subjects were harmed in this study, since with only 50 patients per group
the study was not designed or powered to prove any differences in major
complications including death."

Bennett-Guerrero wrote that the study proposal and consent form "were
approved by Columbia's Institutional Review Board. The Columbia IRB sought
comments from members of the Departments of Surgery, Anesthesiology, and
Medicine and the IRB had before it the package inserts for each of the four
FDA approved fluids, as well as the protocol and the consent form."

He added: "Please understand that I am, and have throughout my entire
professional career been, committed to patient safety and improving patient
outcomes. Indeed, as a practicing anesthesiologist who takes care of high
risk patients, my primary focus in the operating room is patient safety and
reducing pain and suffering."

An Unrestricted Grant

The Columbia study came at a time when Abbott Laboratories, the manufacturer
of one of the blood expanders, was looking to boost its share of the
business. The fluids were often needed during more than half a million
cardiac surgeries each year and in the late 1990s the market for blood
expanders containing hetastarch was growing due to a shortage of albumin,
one of the older, more commonly-used products.

In 1999, Bennett-Guerrero, then 34, was recruited to serve as clinical
director of Columbia's division of cardiothoracic anesthesiology. Within two
years, records show, he was simultaneously running 25 clinical trials. He
received approximately $150,000 in the form of an unrestricted grant from
Abbott Laboratories as reimbursement for the comparative study of blood
expanders, according to his statements in his lawsuit against the hospital.
Medical centers welcome such grants, since they typically can take a portion
for overhead.

Several previous studies had shown that the original hetastarch product
could sometimes trigger excessive bleeding during surgery. If Abbott's new
formulation of hetastarch - called Hextend -- turned out to be safer in high
doses, anesthesiologists might be persuaded to switch, even though Abbott's
price was about 40 percent higher.

Before the study could begin, it had to pass muster inside the hospital.
Under federal regulations, every clinical trial must be approved by an
institutional review board, or IRB -- a panel of doctors, other medical
professionals and at least one non-medical professional from outside the
hospital -- that is charged with protecting human test subjects and ensuring
that they are fully informed of the potential risks. The board must also
ensure that studies are properly designed.

According to court documents, half of the open-heart patients in the study
were slated to receive one of the two hetastarch solutions. The other half
would get either albumin or a salt solution.

The original proposal requested a waiver from the standard requirement of
obtaining written patient consent, on the grounds that participation in the
trial "will not increase the likelihood of patients requiring blood
transfusions . . . [or] any additional discomfort or risk."

The study proposal and request for a waiver was reviewed in 1999 by the IRB,
whose approximately 12 members met once a month. But there was no expert in
blood expanders on the board and no member examined the published studies
about the risks of high levels of hetastarch, according to court documents.

The review board did insist that patients sign a written consent form.
Columbia investigators later concluded that the consent form failed to
inform patients of the risk of bleeding. They also found that the IRB was
unaware of those risks, in part because the panel "failed to adequately use
data provided" by the hospital's departments of surgery and anesthesia,
which also reviewed the proposed study. A surgeon on the review board told
the investigators that the board's members, 11 of whom had other full-time
duties in the hospital, didn't have enough time to probe. "When we do these
reviews we are presented with the investigator's stack of IRB stuff," he
said, according to the court papers. "Most of us barely get to read the
birthday cards from our kids . . ."

'A Very Common Deficiency'

In November 2000, two Columbia anesthesiologists - Marc Dickstein and Mark
Heath- sought out the head of the institutional review board, Paul Papagni,
a lawyer. They told Papagni that they had been in the operating room when a
number of patients had hemorrhaged. They feared the study's design virtually
guaranteed that there would be more who would suffer hemorrhaging, according
to Heath's statements to hospital investigators, included in court filings.

Dickstein would later tell Columbia investigators that he and Heath assumed
the study would be suspended and reviewed since they had alerted the board.
In court documents, he said, "We were two reasonably senior members of the
cardiac anesthesia team coming in saying patients are being harmed. . . .
[we thought] anyone who actually would look at the literature [on blood
expanders] . . . would come to the same conclusion." But the IRB did not
suspend the study.

Heath and Dickstein declined to comment for this article. Attempts to
contact Papagni were unsuccessful.

Court records show that Bennett-Guerrero and his department head, Margaret
Wood, disagreed with the assessments of Heath and Dickstein. Columbia
investigators later suggested that the concerns raised by Heath and
Dickstein may have been initially cast aside as rooted in professional
rivalry with Bennett-Guerrero.

Five months after the study ended, Heath and Dickstein wrote to Gerald
Fischbach, dean of Columbia's medical school, with their concerns. According
to court documents, Fischbach soon ordered Bennett-Guerrero to stop
enrolling patients in studies, pending the results of an investigation.

Fischbach later removed Bennett-Guerrero as clinical director of the
division of cardiothoracic anesthesiology, according to court records. The
university took him off tenure track in 2002, barred him from conducting
research, and told him in a letter that he could not publish the results of
the blood expander study.

In September 2002 Columbia sent a letter about the matter to the federal
Office of Human Research Protections, part of the Department of Health and
Human Services. The letter, obtained through the Freedom of Information Act,
affirmed the chief complaints that Dickstein and Heath had raised. Columbia
alleged that Bennett-Guerrero "failed to convey" the purpose of the study to
the review board and patients, had not informed the patients of the risks
and did not appropriately report serious medical complications. The letter
also faulted the manner in which fluids were prepared for the study (they
were allegedly mixed in an unsanitary, blood-spattered room). Columbia also
assured federal regulators in the letter that it was overhauling its review
process.

But hospital officials stated that patients had not suffered harm as a
result of participating in the study. Columbia's investigation, said the
letter, "failed to show a causal relationship" between the fluids and the
two deaths. It also added that there was "no evidence of harm to any
particular patient that could be attributed to the study."

What the letter did not say was how Columbia investigators calculated harm.
Columbia reviewed only 14 patient charts of the more than 200 in the study,
according to court documents. The investigators looked for kidney damage,
another potential side-effect of blood expanders, but at that point did not
report on bleeding.

Fischbach, who retired as dean in 2006, declined requests for an interview.

Federal officials responded to Columbia in a letter dated January 2003. They
suggested that the university "re-consent patients," which meant finding
them or their survivors and informing them that the study may have put them
at greater risk than they had been told when they gave informed consent. But
the federal regulators didn't force the issue. Columbia decided, as it had
the year before, that there was no need to tell the patients.

That same month, Bennett-Guerrero filed suit against Columbia and Fischbach
in New York Supreme Court, claiming the university had harmed his reputation
and wrongly stripped him of his ability to conduct and publish research.
Bennett-Guerrero attacked the university's findings about the study and
denied that he acted improperly in any way. The settlement, reached in June
2003, is confidential but the court file remains public.

E-mails obtained through a public records request from the Office of Human
Research Protections show that Heath and Dickstein continued to ask the
government to re-examine the study and its outcomes. In July 2006, a
compliance officer responded that the federal agency would not challenge
Columbia again. Failing to disclose risks to subjects in completed research
was "a very common deficiency,"the officer wrote in an e-mail, adding that
the agency "is not inclined, at this time, to investigate this matter
further."

Then in early 2007, for reasons that are not apparent from any documents,
Columbia initiated yet another internal examination of the blood expander
study. It was completed in the fall of 2008 and the hospital contacted
federal regulators and acknowledged some deficiencies in a letter dated
March 31, 2009. In the letter, the hospital again concluded that "the
conditions necessary for a finding of patient harm had not been met."

This time, federal regulators balked. In its letter to Columbia on June 8,
the oversight office wrote that "new information" provided by the hospital
now showed that among study participants who received hetastarch there was
"a statistically significant higher rate" of "negative clinical outcomes,
including bleeding events (requiring use of transfusions) and decreases in
renal [kidney] function. Beyond that, there was the trend toward increased
need for re-operation." The letter said that the analysis "supports the
hypothesis" that patients who received hetastarch did worse than the others.

The federal office instructed the hospital to draft a letter explaining the
study to its former patients. Regulators also asked Columbia to hand over a
full accounting of what happened to the patients who agreed to be part of
its study. The federal agency has issued such a directive only three other
times since 2000. Although the office has no direct authority to enforce its
demands, it can cut off federal research funding to institutions that fail
to comply.

This week, neither Columbia nor the federal government would say when the
patients and families will learn the whole story behind the heart operations
they underwent 10 years ago.

Jeanne Lenzer is an independent medical investigative journalist and a
frequent contributor to the BMJ (formerly the British Medical Journal). She
can be reached at jeanne...@gmail.com. Shannon Brownlee is a senior
research fellow at the New America Foundation and the author of Overtreated:
Why Too Much Medicine is Making Us Sicker and Poorer. She can be reached at
shannon....@comcast.net.

***
Do you have additional information about the drug trial involving heart
patients at Columbia University Medical Center? Have you participated in
similar medical research? Tell us about your experience and we may publish
the results.

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