The Lancet editorial

Published online
November 5,2004

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4 years before the drug was ?nally withdrawn from the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 over-
sight.In a recent Editorial,we commended Merck for acting
promptly in the face of new ?ndings about the safety of
Vioxx.

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 signi ?cant 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
Journal 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 docu-
ment 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 pro ?le and
its attempt to gloss over these risks in their public state-
ments at the time —it is hard to see how Merck 's chief exec-
utive of ?cer,Raymond Gilmartin,can retain the con ?dence
of the public,his company 's most important constituency.
The FDA 's position is no less comfortable.The public ex-
pects national drug regulators to complete research,such as
that published by Jüni and colleagues,in their ongoing ef-
forts 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 medi-
cines.Once a licensing approval has been made it is natu-
rally in CDER 's own interests to stand by its original
decision.CDER 's reputation would be damaged if its licens-
ing 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 ?aw 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 ".

It did not do so.This refusal to engage with an issue of grave clin-
ical concern illustrates the agency 's in-built paralysis,a
predicament that has to be addressed through fundamen-
tal 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 re ?ect the
of ?cial views of the agency ".The FDA investigators esti-
mate that over 27 000 excess cases of acute myocardial
infarction and sudden cardiac death occurred in the USA be-
tween 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 scienti ?c
peer review.Bypassing independent peer review smacks of
panic in the FDA,which is under intense reputational pres-
sure.And yet its decision to try to undermine the integrity
of this work again shows that the agency 's senior manage-
ment 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 ?nancially
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 con-
tinued erosion of trust that public-health institutions will
suffer.Failure to act decisively on signals of risk might min-
imise short-term political criticism for regulators,or share-
holder 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 compa-
nies 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 sug-
gest that regulators have a nearly impossible job of balanc-
ing harms and bene ?ts.Defenders of our systems of drug
regulation argue that the blame for the Vioxx debacle in-
Vioxx,the implosion of Merck,and aftershocks at the FDA
stead 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 estab-
lished with powerful commercial and governmental institu-
tions.For with Vioxx,Merck and the FDA acted out of
ruthless,short-sighted,and irresponsible self-interest.

Richard Horton

The Lancet ,London NW1 7BY,UK

**************

Now that is strong language.

"ruthless,short-sighted,and irresponsible self-interest"

How many other similarly dangerous "approved" drugs are being
prescribed and taken by millions of unsuspecting patients. What damage
is being done as we speak? Amd Merck has always been seen as one of
the more upstanding pharmaceutical companies. Heads should roll at the
FDA and Merck should be shut down.

TC