[e-drug] FDA, paracetamol and 450 deaths a year

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E-DRUG: FDA, paracetamol and 450 deaths a year
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[Copied as fair use; WB]

BMJ 2002;325:678 ( 28 September )

FDA fails to reduce accessibility of paracetamol despite 450 deaths a year

Confidential documents from the US Food and Drug Administration suggest
that the agency has avoided a debate on tough new measures to reduce
overdoses from painkillersto avoid offending the pharmaceutical industry.
Ray Moynihan reports from Washington, DC

FDA fails to reduce accessibility of paracetamol despite 450 deaths a year
Confidential documents from the US Food and Drug Administration suggest
that the agency has avoided a debate on tough new measures to reduce
overdoses from painkillersto avoid offending the pharmaceutical industry.
Ray Moynihan reports from Washington, DC

Staff at the Food and Drug Administration's Office of Drug Safety wanted
the United States to consider following the United Kingdom's policy of
reducing the public's ease of access to paracetamol to try to reduce the
number of deaths from overdose, a concern in both these countries.

But the office's views never reached the FDA's non-prescription drugs
advisory committee, which met last week to consider the drug's safety. The
result was that the advisory committee recommended only that the drug,
known as acetaminophen in the United States, carry expanded safety
warnings. No change was recommended in how it is sold.

Drug company executives were delighted with the committee's decision. "I
felt really very good," said Dr Anthony Temple, a vice president of the
Johnson & Johnson company McNeil, which dominates the market in paracetamol
products, taken by almost 50 million Americans a week. "I'm pleased the
panel came up with the same concepts we've come up with already."

The advisory committee was looking at the drug, which is contained in many
combination products, in an effort to reduce the accidental liver damage it
can cause when taken in overdose. In the United States paracetamol is
associated with more than 100000 calls a year to poison control centres, as
well as 56000 visits to emergency departments, 26000 hospitalisations, and
450 deaths.

The FDA appoints outside expert members to its advisory committees, and
before meetings it provides them with background documents and lists of
questions, in an effort to seek informed recommendations on important
decisions about drug approval or regulation.

In the case of last week's hearing, after eight hours of what were at times
confused, uncertain, and vague deliberations, the FDA advisory committee
simply recommended changes to labelling and better consumer education about
paracetamol (marketed in the United States as Tylenol). These are
initiatives in which the manufacturer is already engaged. Asked whether the
recommendations could have been worse, Dr Temple responded instantly:
"Absolutelyit could have been a lot worse."

The FDA advisers did not seriously consider following the lead of the
United Kingdom and some other countries, which have introduced measures to
restrict the numbers of tablets per pack and replacing bottles full of
loose pills with "blister packs." The option was not even suggested for
consideration by FDA officers appearing before the advisory committee
despite the fact that tentative evidence indicates that such reforms in the
United Kingdom may have significantly reduced the number of drug related
poisonings, liver transplantations, and deaths (BMJ
2001;322:1203-7)[Abstract/Full Text].

The reforms in the United Kingdom have also led to a substantial reduction
in annual sales of tablets containing paracetamol and paracetamol
compounds, from 123 billion to 84 billion.

Behind the closed doors of the FDA, in the lead up to the meeting, staff
from the Office of Drug Safety had suggested that the advisory committee
should consider the measures that the United Kingdom took. A confidential
draft document reveals that the Office of Drug Safety also wanted the
advisory panel to discuss whether the "maximum tablet strength should be
decreased," whether "combination products be reformulated without
acetaminophen," and whether there was "a need to standardize the various
paediatric formulations."

The advisers never saw that draft, however, and none of these key options
ended up being clearly presented to the committee by the FDA in the final
list of questions they were to consider.

Acknowledging an unusual level of confusion throughout the hearings, the
advisory committee's chairman, Dr Lou Cantilena, said in an interview
afterwards that the questions supplied by the FDA were too vague. "The
committee would have preferred more focused questions," he said.

According to one FDA insider, the draft questions were dropped because
senior FDA managers saw them as too offensive to Johnson & Johnson. Asked
about this alleged corporate influence within the FDA, Dr Cantilena smiled
and said he did not want to speculate.

In an interview last Friday, FDA spokesman Dr John Jenkins said he was not
aware of the draft questions from the Office of Drug Safety but said that
FDA managers had opted to give the advisory committee more open ended,
rather than yes/no-type, questions.
At one point, when the committee's deliberations drifted towards
consideration of the United Kingdom changes, another FDA manager, Dr
Charles Ganley, effectively cut off debate by strongly cautioning advisers
against such action. "It's very difficult to impose these things," he
warned. Dr Ganley is understood to have been actively involved in rejecting
the draft questions before they got to the advisory committee.

More than 200 people attended last week's two day hearing, which focused
first on paracetamol and then on aspirin and non-steroidal
anti-inflammatory drugs, said to be associated with more than 16000 deaths
in the United States every year as a result of gastrointestinal bleeding.
As on day 1, the recommendations on day 2 were for minor changes to labels
and more education.

Although liver damage from paracetamol is rare, its effects can be
devastating. Ms Kate Trunk told the committee meeting that her healthy 23
year old son Marcus had died after an accidental overdose, because he had
inadvertently taken several products containing the same drug. "Death is
not an acceptable side effect," she said.

The FDA's apparent timidity over reforming the marketing of the
multibillion dollar paracetamol will only add to concerns that the
regulatory agency may be too close to the companies that by law now fund
half of its drug review work. Rejecting those concerns, Dr Temple said the
manufacturer had "shared data with the FDA, worked with them, and talked
back and forth" in the lead up to last week's meeting, but the FDA had been
"pretty arm's length on this."

The FDA refused a request by the BMJ for an interview with Dr Ganley.


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