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articolo da the Lancet. se quattro anni vi sembran pochi.....
Today we publish results from a cumulative meta-analysis which show
that the unacceptable cardiovascular risks of Vioxx (rofecoxib) were
evident as early as 2000--a full 4 years before the drug was finally
withdrawn from the market by its manufacturer, Merck. This discovery
points to astonishing failures in Merck's internal systems of
post-marketing surveillance, as well as to lethal weaknesses in the US
Food and Drug Administration's regulatory oversight. In a recent
Editorial, we commended Merck for acting promptly in the face of new
findings about the safety of Vioxx.1
Our praise was premature. The evidence showing that Vioxx caused
significant adverse events was apparent well before data from the
APPROVe trial triggered Merck's overdue intervention. This week's
report by Peter
Jüni and colleagues will add significant weight to ongoing
litigation against Merck by patients who believe they were harmed by
this drug.
These findings also come in the wake of new disclosures that suggest
Merck was indeed fully aware of Vioxx's potential risks by 2000.
Investigations by the Wall Street Journal2
have revealed e-mails that confirm Merck executives' knowledge of their
drug's adverse cardiovascular profile--the risk was "clearly there",
according to one senior researcher. Merck's marketing literature
included a document intended for its sales representatives which
discussed how to respond to questions about Vioxx--it was labelled
"Dodge Ball Vioxx". Given this disturbing contradiction-- Merck's own
understanding of Vioxx's true risk profile and its attempt to gloss
over these risks in their public statements at the time--it is hard to
see how Merck's chief executive officer, Raymond Gilmartin, can retain
the confidence of the public, his company's most important
constituency.
The FDA's position is no less comfortable. The public expects
national drug regulators to complete research, such as that published
by Jüni and colleagues, in their ongoing efforts to protect patients
from undue harm. But, too often, the FDA saw and continues to see the
pharmaceutical industry as its customer--a vital source of funding for
its activities--and not as a sector of society in need of strong
regulation.
Worse still, the FDA's Office of Drug Safety co-exists in the
same centre--the Centre for Drug Evaluation and Research (CDER)--as the
Office of New Drugs, the part of the agency that works most closely
with industry to license new medicines. Once a licensing approval has
been made it is naturally in CDER's own interests to stand by its
original decision. CDER's reputation would be damaged if its licensing
judgments were constantly challenged by its own staff. This
understandable but dangerous tendency to discourage dissent makes the
Office of Drug Safety, which sits lower in the hierarchy of CDER than
the Office of New Drugs, weak and ineffective. The inherent precedence
that licensing of new drugs takes over safety evaluation is a serious
flaw in FDA's complex regulatory structure.
In the case of Vioxx, FDA was urged to mandate further clinical
safety testing after a 2001 analysis suggested a "clear-cut excess
number of myocardial infarctions".3
It did not do so. This refusal to engage with an issue of grave
clinical concern illustrates the agency's in-built paralysis, a
predicament that has to be addressed through fundamental organisational
reform.
On Nov 2, 2004, the FDA tried to shore up its tarnished
reputation by posting on its website an early version of a recently
completed observational study into the safety of Vioxx. The report
comes with a warning that it has "not been fully evaluated by the FDA
and may not reflect the official views of the agency". The FDA
investigators estimate that over 27 000 excess cases of acute
myocardial infarction and sudden cardiac death occurred in the USA
between 1999 and 2003. "These cases", they write, "would have been
avoided had celecoxib been used instead of rofecoxib". This study is
presently under review at The Lancet.
It is unclear why the FDA could not have waited for the fully evaluated
report to have been scrutinised, revised, and published according to
the norms of scientific peer review. Bypassing independent peer review
smacks of panic in the FDA, which is under intense reputational
pressure. And yet its decision to try to undermine the integrity of
this work again shows that the agency's senior management is more
concerned with external appearance than rigorous science.
The licensing of Vioxx and its continued use in the face of
unambiguous evidence of harm have been public-health catastrophes. This
controversy will not end with the drug's withdrawal. Merck's likely
litigation bill is put at between US$10 and $15 billion. The company
has seen its revenues and market capitalisation slashed. It has been
financially disabled and its reputation lies in ruins. It is not at all
clear that Merck will survive this growing scandal.
But the most important legacy of this episode is the continued
erosion of trust that public-health institutions will suffer. Failure
to act decisively on signals of risk might minimise short-term
political criticism for regulators, or shareholder unrest for company
chief executives. But the long-term consequence of prevarication is a
tide of public scepticism about just whose interests drug makers and
regulators truly represent.
It is no good saying, as some academic physicians have said to
me, that one must expect pharmaceutical companies to do all they can to
protect their products, even in the face of clear evidence of risk. And
it is of little help to suggest that regulators have a nearly
impossible job of balancing harms and benefits. Defenders of our
systems of drug regulation argue that the blame for the Vioxx debacle
instead rests on allegedly credulous specialists who should have asked
tougher questions about the drug they were prescribing. Why clinical
investigators studying Vioxx did not do more to raise concerns is a
fair question that needs to be answered. But in doing so, we must not
diminish the importance of the covenant of trust that society has
established with powerful commercial and governmental institutions. For
with Vioxx, Merck and the FDA acted out of ruthless, short-sighted, and
irresponsible self-interest.
Richard Horton |
-- www.e-laser.org [EMAIL PROTECTED]
