The
makers of the blood-thinning drug Pradaxa were so worried that an
internal research paper would damage drug sales that some employees not
only pressured the author to revise it, but suggested it should be
quashed altogether, according to newly unsealed legal documents.
The
documents were made public last week by a federal judge in Illinois who
is overseeing thousands of lawsuits filed by patients and their
families, who say that Pradaxa’s manufacturer, the German company
Boehringer Ingelheim, failed to properly warn them about the risks of
taking the drug.
Since its approval in 2010, the drug, which can cause fatal bleeding, has brought in more than $2 billion in sales in the United States, according to the research firm IMS Health.
It has been prescribed to 850,000 patients, but has also been linked to more than 1,000 deaths.
Boehringer
Ingelheim has stood by the drug, noting that the Food and Drug
Administration has upheld its safety and that its value has been proved
in clinical trials.
Many
of the documents released by Chief Judge David R. Herndon of the United
States District Court in East St. Louis, which included emails, memos
and internal presentations, centered on whether a coming research paper
would undercut one of Pradaxa’s main selling points: that it does not
require regular blood tests to ensure it is working.
The
issue has been hotly debated among heart and stroke specialists, in
part because not all people — especially older patients — metabolize the
drug the same way, and because there are fewer dose options as well as
no tests available for Pradaxa in the United States to monitor those who
might be most at risk. An additional dose and a test are available in
Europe.
Testing
is a critical issue because Pradaxa and two other recently approved
drugs, Xarelto and Eliquis, are in a race to gain market share from
warfarin, a generic drug that for decades has been the standard
treatment for preventing blood clots and strokes.
Many patients viewed
the older warfarin as a nuisance because it requires frequent blood
tests and careful attention to diet and other drugs.
The
new drugs do not require such monitoring, yet claim to be as good, or
better, at preventing strokes and blood clots in patients with a
heart-rhythm disorder known as atrial fibrillation.
The
documents show that Boehringer Ingelheim employees openly fretted when
it appeared that the results of the research paper, written by Paul A.
Reilly, a clinical program director at the company, indicated that some
patients could benefit from monitoring of their blood. A certain segment
of patients, the paper found, absorb too little of the drug to
effectively prevent strokes, while another group absorbs so much that
they are at a higher risk for bleeding.
In
a draft version of the paper included in the court records, Dr. Reilly
and his co-authors detailed specific levels of how much Pradaxa should
be in a patient’s bloodstream, and said that keeping some patients
within that range would help prevent strokes and bleeding.
As
Dr. Reilly’s draft paper circulated within the company, some employees
questioned what the marketing implications of such a conclusion would
be.
One
company supervisor, Dr. Jutta Heinrich-Nols, wrote in an email to other
employees that she could not believe the company was planning to
publish research that would negate a decade’s worth of work proving that
patients taking Pradaxa would not need regular tests.
Publishing
the research results, she warned, could make it “extremely difficult”
for the company to defend its long-held position to regulators that
Pradaxa did not require testing.
And,
Dr. Heinrich-Nols added in the email, the research, if known, would
“undermine” the company’s efforts to compete with other new
anticoagulants, such as Xarelto and Eliquis.
“I would like to ask you to check again whether this is really wanted,” she wrote about publishing the research.
Another
company leader, Dr. Andreas Clemens, questioned whether legal
repercussions would arise if Dr. Reilly’s paper detailed a specific
range where the drug worked best. “Maybe I am phobic, but I am not happy
with the conclusion,” he wrote.
Still,
some of the same employees acknowledged that Dr. Reilly’s paper
addressed serious concerns that doctors were raising outside the
company. “The world is crying for this information — but the tricky part
is that we have to tailor the messages smart,” Dr. Clemens wrote in a
separate email.
In
emails, Dr. Reilly defended his conclusions, saying the research showed
that a minority of patients might benefit from blood testing. “I think
we just need to make the message clear,” he said. Dr. Reilly declined to
comment, referring questions to the company’s public relations
department.
The
documents highlight how much information about drug safety is in the
hands of people with a financial interest in the outcome, some drug
industry observers said.
“With
these drugs, this is a really tough call,” said Dr. Lisa M. Schwartz, a
professor of medicine at the Dartmouth Institute for Health Policy and
Clinical Practice.
“In
these situations, where the stakes are really high, how crazy is it
that it’s in the hands of people who are so conflicted?” she asked.
Dr. Reilly’s paper was published Tuesday
in the Journal of the American College of Cardiology, and although many
of the conclusions in the draft version remained, references to a
patient’s optimal blood-level range no longer appear in the article.
In
a statement, representatives for Boehringer Ingelheim said the recently
unsealed documents “represent small fragments of the robust discussion
and debate that is a vital component in all scientific inquiry, and in
the research and development of any important medication such as
Pradaxa.” The company said the changes to the manuscript were made as
the scientists’ thinking evolved, and they ultimately concluded that no
single blood-level range is ideal for all patients.
Lawyers for the plaintiffs declined to comment.
Pradaxa
is approved in a 150-milligram dose, as well as a lower 75-milligram
dose for patients with low kidney function. But unlike European
regulators, the F.D.A. did not approve a 110-milligram dose because the agency felt the lower dose would not benefit most patients.
Boehringer
Ingelheim continued to pursue the approval of the 110-milligram dose
even after the higher dose was approved, but the company said it
abandoned the effort after concluding that a proposed study and other
analyses were not feasible.
Some
doctors applauded Boehringer Ingelheim for finally addressing an area
of intense interest among cardiologists. Dr. Hugo ten Cate, a professor
of medicine at Maastricht University Medical Center in the Netherlands
who has called for more monitoring of patients on the new blood
thinners, said there had been a “lively discussion” about this issue.
“The
company was initially reluctant to recommend anything about monitoring,
because they were claiming you no longer have to monitor anymore,” said
Dr. ten Cate, who said he had received payments from Boehringer
Ingelheim and other companies to speak on such issues, and who also
heads a Dutch association of warfarin-testing clinics. “But now, they’ve
gradually come back a little bit.”
Others
said the newly released documents show that drug makers and regulators
had been too eager to approve such powerful drugs without more careful
monitoring.
“The
one-size-fits-all was a mistake for a drug with this kind of risk,”
said Thomas J. Moore, a senior scientist at the Institute for Safe
Medication Practices, which keeps track of safety reports
submitted to the F.D.A. He rated anticoagulants — including warfarin
and Pradaxa — as the most serious safety problem in 2011 and 2012. He
said Pradaxa has been cited in more than 1,000 deaths reported to the
agency through the end of 2012.
No comments:
Post a Comment