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PORTSIDE  December 2011, Week 3

PORTSIDE December 2011, Week 3

Subject:

Troubled Study at Heart of Therapy Debate

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Sun, 18 Dec 2011 21:58:35 -0500

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Troubled Study at Heart of Therapy Debate
Disciplined doctors, potentially deadly drug marred 
study of questionable treatment that cost taxpayers 
$30 million
By Trine Tsouderos
Chicago Tribune
December 12, 2011
http://www.chicagotribune.com/health/ct-met-nccam-tact-trial-20111212,0,1974124.story

With $30 million of taxpayer money, researchers set out
to conduct one of the largest studies ever of an
alternative medical treatment, a controversial therapy
for coronary artery disease.

The project was marred with problems from beginning to
end.

Because the treatment was so out of step with mainstream
medicine, it was difficult to find enough patients to
take part.

The researchers failed to inform the subjects that one
risk of the treatment was death. In consent form
documents, they made a confusing statement about the
study drug, implying it was safer than it was.

The researchers overseeing the study stepped up
background checks on the doctors involved after some
physicians ran into disciplinary problems unrelated to
the chelation trial. Two doctors consulting on the trial
have been convicted of crimes.

The troubles with the study, called the Trial to Assess
Chelation Therapy or TACT, are emblematic of the
difficulties faced by the National Center for
Complementary and Alternative Medicine as it tries to
study alternative treatments in a scientific way.

In its 12 years of existence, NCCAM has found itself
funding clinical trials of therapies with weak
scientific foundations, from distant prayer as a
treatment for AIDS to a risky regimen for pancreatic
cancer involving coffee enemas.

The chelation study was one of the center's biggest
projects, launched about a decade ago with support from
a powerful congressman. Funding came from NCCAM and a
second organization within the federal National
Institutes of Health, the National Heart, Lung, and
Blood Institute.

The project was designed to assess whether intravenous
chelation therapy, which helps expel metals from the
body, can treat coronary artery disease. Tens of
thousands of Americans are choosing to undergo such
treatments, even though using chelating drugs as heart
medicine originated in decades-old ideas about arterial
plaques that have never been proved.

Chelating drugs also carry risks. In fact, the drug
being studied, edetate disodium, turned out to be so
risky that the U.S. Food and Drug Administration later
withdrew its approval. Yet the study was not halted, and
the volunteers were not immediately told.

"To subject human subjects to risks for no plausible
benefit is really unethical," said Dr. Kimball Atwood,
an anesthesiologist at the Newton-Wellesley Hospital in
Newton, Mass., and first author of a lengthy critique of
the study published in The Medscape Journal of Medicine
in 2008.

A co-author of the critique, Liz Woeckner, said the
trial is a black eye for the National Institutes of
Health.

"(The NIH) is the nation's premier medical research
facility. We look up to them. We put our hopes in them.
We trust them," said Woeckner, president of Circare, a
nonprofit that advocates for people enrolled in clinical
trials. "For them to conduct a trial that is unethical
and unscientific - and continue to conduct it? It is
just mind-boggling."

The Medscape paper also questioned whether the results
of the study would be valid, citing flaws that included
wrong or incomplete information given to subjects and
the tarnished professional records of some researchers.

"The trial's outcome will be unreliable and almost
certainly equivocal, thus defeating its stated purpose,"
Atwood wrote in the paper. In an interview, he called
the project "rotten to the core."

Dr. Josephine Briggs, head of NCCAM since 2008, declined
to discuss the study in detail, saying her center no
longer oversees it. She did say such research is
difficult to conduct. "It has been hard to complete
because of the fact that physicians are highly polarized
in what they believe," Briggs said.

She referred questions to the National Heart, Lung, and
Blood Institute, which was handed oversight of the trial
in 2006. Dr. Susan Shurin, its acting director, said in
a written statement that a well-designed, sufficiently
large clinical trial was needed because so many people
were choosing to receive the therapy.

"The lack of compelling evidence to support a widely
practiced therapy is an argument FOR doing a randomized
trial, not against it," wrote Shurin, who is board-
certified in pediatric hematology-oncology.

TACT's principal investigator, cardiologist Gervasio
Lamas, defended the project in a written statement and
said researchers are committed to ensuring the highest
level of patient safety. Lamas is chairman of medicine
at Mount Sinai Medical Center in Miami Beach, Fla.

Lamas emphasized that the study operates under extensive
oversight by multiple groups. "We are serious scientists
trying to provide needed evidence to define whether
chelation therapy for coronary heart disease should be
part of the standard clinical armamentarium, or whether
the risks of chelation outweigh any possible benefit,"
he wrote.

'Considered obsolete'

Problems with TACT start with the most basic of all:
There was little scientific reason to believe the study
drug, edetate disodium, could help treat coronary artery
disease.

In fact, far from helping, edetate disodium can rapidly
strip calcium from the body, which can cause an
electrolyte imbalance and interfere with the beating of
the heart, sometimes fatally.

In the 1950s, doctors hypothesized that the drug could
yank calcium from the plaques that clog arteries,
helping break them down, like Drano for blood vessels.
The therapy has been promoted over the years in books
like "Bypassing Bypass: The New Technique of Chelation
Therapy" and on practitioners' websites.

But in a document submitted as part of the grant
application, Lamas acknowledged there was "little data
to support the decalcifying hypothesis." He listed six
other possible explanations for how chelation therapy
could help, but none had been proved.

Scientists say it's fine to study a potential treatment
without knowing exactly how it works - but there needs
to be compelling evidence to suggest that it does work.

Chelation to treat coronary artery disease didn't have
that either. Three randomized, double-blind clinical
trials found no meaningful difference between chelation
therapy and a placebo.

Dr. Edzard Ernst, a retired professor of complementary
and alternative medicine at University of Exeter, summed
up the evidence in a 2000 review published in the
American Heart Journal. "The most striking finding is
the almost total lack of convincing evidence for
efficacy," Ernst wrote. "Given the potential of
chelation therapy to cause severe adverse effects, this
treatment should now be considered obsolete."

Lamas wrote in an email that the study had a plausible
hypothesis that deserved to be tested. "TACT was
supported by Congress, reviewed by multiple peer-review
committees and approved," he wrote.

Dr. Clyde W. Yancy, chief of the cardiology division at
the Northwestern University Feinberg School of Medicine,
agreed with Lamas. "It's time to either prove this to be
a reasonable treatment or put it to rest," Yancy wrote
in an email.

Yet this is a question cardiac researchers were not
clamoring to answer. Over a period of 30 years, the
NIH's National Heart, Lung, and Blood Institute received
just three chelation-related research grant applications
amid tens of thousands, according to congressional
testimony. They were not funded.

"If the science is invalid," said Woeckner, who
advocates for the rights of clinical trial patients, "it
is unethical to expose human beings to any risk
whatsoever."

Congressional push

With scant compelling evidence that chelation therapy
might be safe and effective for coronary artery disease,
why did the government spend $30 million of taxpayer
money studying it?

The answer begins with a powerful politician.

In 1999, Rep. Dan Burton, R-Ind., held a congressional
hearing titled "Cardiovascular Disease: Is the
Government Doing More Harm Than Good? EDTA Chelation
Therapy."

An advocate of alternative medicine, Burton wanted to
know why NIH wasn't spending more of its taxpayer
dollars studying such treatments.

He brought the director of the National Heart, Lung, and
Blood Institute, Dr. Claude Lenfant, before the
committee and pressed him to explain why the institute
had not yet studied chelation therapy for coronary
artery disease.

Then he asked proponents of chelation therapy to talk
about how effective it was and how the therapy had not
been given a fair shake.

One who spoke was Dr. Theodore Rozema, president-elect
of the American College for Advancement in Medicine, the
largest organization advocating for chelation therapy.

In 1978, the state Board of Medical Examiners in North
Carolina disciplined Rozema's medical license after
learning that in 1976 in Massachusetts, Rozema had
pleaded guilty to and was convicted of the charge that
he "did knowingly, willfully and feloniously extort by
the use of force, violence and fear money," according to
board records.

Medical boards in Illinois, South Carolina and
Pennsylvania also disciplined his medical license,
according to the North Carolina board. Rozema did not
respond to requests for comment.

After Rozema and others spoke, Burton left officials
with the NIH and other agencies in charge of medicine
with an unambiguous message: "We are going to be hauling
them before this committee on a regular basis - they
will get sick of seeing my face before this is over - to
make sure that we are not blocking something that is
going to save lives."

In 2001, NCCAM and NHLBI issued a joint request for
applications for a maximum $30 million federally funded
grant to study chelation in people suffering from
coronary artery disease. Lamas submitted an application
that passed review by various NIH panels. TACT was a go.

More than 2,300 heart attack survivors older than 50
were sought, according to Lamas' 2003 protocol. Patients
would be assigned randomly to one of four groups. Some
would receive 40 infusions of the chelation solution
recommended by the American College for Advancement in
Medicine, plus either high or low doses of supplements.
Others would receive 40 infusions of a placebo with
either high or low doses of supplements. The study would
be double-blinded, meaning neither volunteers nor
researchers would know who got the treatment and who got
the placebo.

"Welcome to the Trial To Assess Chelation Therapy!"
Lamas wrote in a newsletter sent to study sites in 2003.
"I am proud to welcome you to an elite group of
physicians and coordinators who are committed to
answering an important clinical question."

This group included many fine doctors who enrolled
volunteers and ran study sites out of their own clinics.

But 13 of them have run afoul of state medical boards or
health departments for actions unrelated to the
chelation study, the Tribune found. Two physicians had
their medical licenses revoked. Two others paid fines
for placing misleading ads about the benefits of
chelation therapy. One was issued two administrative
complaints this year for allegedly running a clinic with
unsanitary conditions linked to a hepatitis C outbreak.

Meanwhile, both consultants to the trial - each was paid
more than $19,000 in taxpayer money, according to study
records - were convicted of federal crimes, government
records show.

One was Rozema, who also ran a study site and was among
the first to enroll volunteers. The other was Dr. Martin
Dayton. In 1986, a jury found Dayton guilty of mail
fraud and conspiracy for his role in helping a family
defraud an insurance company, according to U.S. Court of
Appeals records. Dayton appealed, arguing, among other
issues, that he had poor legal representation.

Today in a clinic in Sunny Isles Beach, Fla., Dayton
offers several unproven remedies, including chelation
and treatments with cell extracts made from pig fetuses
and embryos, according to his website. His book "The
Case for Intravenous EDTA Chelation Therapy" is
available as a free download.

Dayton called his legal history "a distraction to your
readership" and declined to discuss it further.

Lamas wrote in an email that only a small number of the
physicians who participated in the study have troubled
histories. "When these physicians joined the study, all
had unrestricted licenses to practice medicine, granted
by their state medical boards," he wrote.

Informed consent?

One of the most critical parts of a trial is a process
known as informed consent. The aim is to ensure that
patients who agree to enter a clinical trial understand
what they are getting into, including the potential
benefits and risks.

But the consent form for TACT was misleading and omitted
important information. For example, it failed to tell
volunteers that edetate disodium was never meant to
treat coronary artery disease and that one risk of the
drug is death, according to a 2009 letter from the
federal Office for Human Research Protections, which
looks out for the welfare of subjects in federally
funded studies.

The form also included the information that "EDTA," or
edetate, had been approved as a treatment for lead
poisoning, according to the letter.

That's true of edetate calcium disodium. But the drug
used in the study, edetate disodium, is a different
medication not used for lead poisoning.

The FDA issued a public health advisory in 2008 to warn
that children and adults had died because the two drugs
had been confused or because edetate disodium had been
used to treat conditions for which it wasn't approved.

After the FDA announced it would review edetate
disodium's safety and efficacy, its manufacturers
voluntarily recalled the drug in 2007 and 2008. The FDA
removed it from the agency's list of approved drugs in
2008.

Yet the chelation study continued, and subjects were not
immediately told that the FDA had delisted the drug over
safety concerns.

After the Medscape critique came out in 2008, the Office
for Human Research Protections told study coordinators
they would have to change the consent form for new
subjects and tell patients already enrolled what
information had been left out.

The federal office said it was "concerning" that
"several of the TACT study investigators have been
accused of substandard practices by state medical
boards, involved in insurance fraud, and at least three
are convicted felons" but concluded that didn't
necessarily mean subjects were put at risk.

The office recommended that institutional review boards
overseeing the study re-examine the way they evaluate
researchers signing on to the project.

Shurin, of the National Heart, Lung, and Blood
Institute, told the Tribune that trial leaders have
closed clinic sites or changed investigators at sites
where concerns exist over medical licensing. In 2007,
Lamas initiated a policy of checking regularly with
medical boards for any concerns about active TACT
investigators, she wrote.

In an email, Lamas wrote that researchers did not
consider death to be a potential side effect of the
therapy because the safety of clinical trials is closely
monitored. "NIH, FDA and dozens of independent
institutional review boards agreed and approved the
form," he wrote. "In 2009, in an abundance of caution,
OHRP asked us to revise the consent form, and, of
course, we did."

The study continues, Lamas noted, despite scrutiny by
the Office of Human Research Protections, the FDA, the
NIH and other groups. A data safety monitoring board
looks at data from TACT every six months, he wrote. "At
every meeting, they have recommended continuing the
trial," he wrote.

Shurin wrote that in the setting of a well-monitored
trial, in which the infusion rate is tightly controlled,
the disodium form of EDTA is very safe. "Our experience
in TACT has reinforced our confidence in the safety of
this drug in the setting of a well-conducted trial," she
wrote.

In Melbourne, Fla., cardiologist Rajiv Chandra said he
welcomes evidence that will help him decide whether to
offer chelation therapy to heart patients or not.

Chandra, one of the most successful recruiters for TACT,
had offered chelation therapy to some patients before
the study began but suspended treatments until the
results of the research come in.

"If it comes back negative, we ought to stop," he said.

But negative results may not sway heart patients who
strongly believe chelation therapy helped them.

One is Chet Jenkins, a 76-year-old Korean War veteran
who volunteered for TACT through Chandra's practice.
Several years before joining TACT, Jenkins had undergone
chelation and said he felt improvement.

"I don't know if it was psychological or not," he said.
"But I am a believer."

Atwood, first author of the critique of TACT, said the
Office of Human Research Protections and other oversight
groups have let down volunteers like Jenkins and allowed
a flawed study to continue even though the results will
mean little or nothing. "They agreed with our points and
then let everyone off the hook," he said.

"You still have criminals," he said. "You have the vast
majority of subjects enrolled up to this point based on
wildly inaccurate statements in the consent form, and
you think it can proceed? . If you already have data
from, say, 1,000 subjects and they all came in under
false pretenses, that is it. It's over."

___________________________________________

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