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NEWS FEATURE
Painful lessons
It is often said that the pharmaceutical industry only adapts in response to a crisis, and Vioxx
might instigate the most dramatic of all changes. The withdrawal of Vioxx has exposed many
scientific, clinical, regulatory and business issues that are fundamental to the industry’s future.
With the integrity of the drug-safety system under scrutiny, companies urgently need to
understand how these problems arose, and how they can be prevented in future. One year on
from Vioxx’s withdrawal, Nature Reviews Drug Discovery asked people closely involved in the
development and use of COX2-selective inhibitors what they think are the biggest lessons that
can be learnt from this debacle.
Dan Simmons,
Brigham Young
University, Utah
Cloned and identified COX2.
From that ecstatic day in 1989 when I saw we
had discovered a new target of aspirin-like
drugs, to my deep concern and worry following Merck’s announcement of the potential
cardiovascular risks with long-term use of
Vioxx, I have experienced a wide range of
emotions about cyclooxygenase-2 (COX2).
This rollercoaster journey, experienced to
some extent by anyone who takes non-steroidal anti-inflammatory drugs (NSAIDs),
re-teaches some lessons that we already knew,
but which had to be re-framed in the modern
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era of media-savvy consumers. Aspirin and
aspirin-like drugs were ideal for re-teaching
these lessons. After all, ‘safe as aspirin’ has been
used to pitch the idea that new drugs were, in
fact, safe. The COX2 saga has re-taught us a
number of things:
• The uses of all drugs are based on risk versus benefit. You take a medication when the
benefits of taking it outweigh its risks;
• Pharmaceutical marketing tactics (remember
Searle’s hype of ‘super-aspirins’?) and mediadriven controversy place pressure on regulatory agencies responsible for determining
drugs with unacceptable risks;
• Because of these pressures and human error,
policy mistakes are occasionally made by
regulatory agencies, but they are usually not
permanent and these agencies do a remarkably
good job of evaluating the data and making the
proper decision;
• The amount of clinical data needed to fully
know all of the risks and benefits of a drug
are prohibitive and cannot be known prior to
marketing a drug;
• Even the oldest and most widely-used drugs
(such as aspirin) are poorly understood and
none are side-effect free;
• We do not yet know the true risks and benefits
of NSAIDs or COX2 inhibitors;
• Many people will still need to take some
form of NSAID therapy (see first point
above);
• Greater post-marketing surveillance will
tell us much about NSAIDs and other
drugs but introduces a new era in which
we will have to deal with the finding that
most or all drugs have adverse effects in
small populations of patients that were not
detected or fully understood before the
drug went to market.
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Identified potential adverse
mechanism for the action of COX2 inhibitors.
It’s clearly exposed the lack of relevant science,
the inattention to clinical pharmacology, the
inappropriate impact of direct-to-consumer
advertising, the power of hubris and the flaws
in the current model of drug development.
On the other hand, although catalysing the
demise of the direct-to-consumer advertisingfuelled blockbuster, the experience might also
accelerate a revision of the business model with
an expansion of Phase II trials at the expense of
Phase III, as drugs are co-marketed with genetic
and biochemical biomarkers which indicate
likely efficacy and safety at the individual level.
Eric Topol,
Cleveland Clinic
Foundation
Detected cardiovascular risk with Vioxx in
clinical studies.
The medical community has learned that it
is imperative to demand data when there are
vital questions left unanswered about the safety
and efficacy of a drug class. For Vioxx, by year
2000, there were three large randomized trials
available that each showed a significant twoto sevenfold increased risk of heart attack
(VIGOR, ADVANTAGE and Study 090). And
no new trials were done to specifically address
this issue.
Other drugs in the COX2 inhibitor class
(for example, Celebrex and Bextra) had to be
considered as a potential liability as well, but
no dedicated trials (in patients with cardiovascular disease, comprising almost 50% of the
patients taking these medicines) were performed. The FDA did nothing to assure that
the proper trials were conducted, but at the
same time allowed mass marketing campaigns
with hundred of millions of dollars supporting
direct-to-consumer advertising.
▼
THE STORY IN STATS
1.5/0.78
The number of cardiovascular events per 100
patient years observed with Vioxx compared
with placebo in the APPROVe trial that led to
Vioxx’s withdrawal.
Source: Bresalier, R. S. et al. NEJM 352, 1092–1102 (2005)
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From now on, if there is a serious question
about a drug/drug class, its use and marketing
should be on hold until the requisite data are
provided and safety/efficacy assured. If Merck
had accepted and disclosed the Vioxx heart risk
to patients and physicians early on, the whole
field would have been different.
John LaMattina,
Pfizer Global
Research and
Development
Vice President of R&D at the manufacturers of
the COX2 inhibitors Celebrex and Bextra.
The most important lesson is that all medicines — whether they are prescription medicines or over-the-counter products — carry
risks in addition to benefits. Moving forward
it will be crucial for all healthcare providers, as
well as patients, to engage in a specific discussion about a medicine’s benefits and risks before
it is prescribed or first used. It is important to
note that these potential risks apply to a very
small minority of patients compared with the
important benefits these medicines bring to a
much broader population.
Philip Needleman,
Prospect Venture
Partners
Co-discoverer of the physiological relevance
of COX2 and Chief Scientist at Searle when
Celebrex was developed.
Since the withdrawal of Vioxx the glare of
publicity, regulatory review and litigation
has led to some hasty conclusions about the
class of COX2-selective inhibitors that are not
supported by actual data.
First, it seems premature to suggest that
strokes and congestive failure induced by
Vioxx are due to inhibition of COX2 in
patients as opposed to side effects caused by
the unique chemical molecule itself. The data
presented at the FDA Advisory Committee
indicated that many of the Vioxx-induced
cardiovascular side effects occurred in
patients taking aspirin, thereby precluding the
notion that there was an imbalance between
prostacyclin and thromboxane as implied by
the FitzGerald hypothesis. In addition, to my
knowledge, there is no direct evidence that
demonstrates that administration of COX2selective inhibitors causes thrombotic events
in experimental animals.
Secondly, it is disturbing that decisions about
benefit/risk ratios are being made without the
presentation and publication of the efficacy
data of the COX2 inhibitors in the colon cancer
trials. There were already compelling data in
precancerous polyps in familial adenomatous
polyposis patients that were predictive of a positive outcome in the much larger population of
spontaneous adenomatous polyposis colon
cancer patients.
Science and medicine should be self-correcting institutions which respond to evolving
data upon rigorous review. There is considerable
room for continuing analysis of the efficacy and
side effects of the numerous oncology trials that
were being conducted with Celebrex, as well as
analysis of the safety and efficacy of the other
COX2 inhibitors (such as Prexige and Arcoxia)
that are in clinical development and undergoing
regulatory review.
THE STORY IN STATS
▼
Garret FitzGerald,
University of
Pennsylvania
16,500/26,000
The estimated number of deaths from NSAIDrelated GI bleeding among arthritis patients in
the US annually, compared with the estimated
minimum number of potential deaths in the US
in the 5 years that Vioxx was on the market.
Source: Wolfe, M. M. et al. NEJM 340, 1888–1899 (1999);
<http://finance.senate.gov/hearings/testimony/2004test/
111804dgtest.pdf> (2004).
Raymond DuBois,
Vanderbilt-Ingram
Cancer Center
Co-discovered link with COX2 and colon
cancer, and carried out cancer trials with
COX2-selective inhibitors .
The lesson that seems to have become buried in
the media hype and litigation over these drugs is
that not all COX2-selective inhibitors behave the
same with regard to side effects. The question is
whether it is possible to design a COX2 inhibitor
that lacks these serious side effects or inhibits
the pathway in a cleverer way.
Given what we know now, other important
lessons to be taken from the COX2 controversy
are these: we have not yet established a rational
approach for determining the proper frequency
of administration or dosages of drugs used in
cancer-prevention studies. Prevention may, in
fact, be achieved with smaller, and therefore less
toxic, amounts. Given that patients will have to
take these drugs for a long period of time, we
must be careful about selecting study subjects
with an appropriate risk profile, which means
that certain clinical trials could take longer,
because fewer patients will qualify for entry.
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Patients at risk for cancer often worry that
they don’t have a lot of time, which raises additional questions. Should the ultimate risk of
each subject developing cancer be taken into
account before exposing them to a drug for 3
years? How many drugs currently on the market
would pass a 3-year safety test in thousands of
patients? Most importantly, we do not have a
post-marketing surveillance system in place that
would enable us to answer these questions with
any degree of confidence.
Alastair Wood,
Vanderbilt University
School of Medicine,
Nashville
Chaired the FDA Advisory Committee meetings
on COX2-selective inhibitors.
Adverse clinical effects occur spontaneously in
the absence of drug, which results in a background rate in the normal drug-free population.
For some adverse effects, that rate is very low in
the normal population; examples would include
rhabdomyolysis with statins and progressive
multifocal leukoencephalopathy with Tysabri
(natalizumab; Biogen Idec/Elan). However,
events such as heart attacks and strokes are
relatively common in the drug-free population,
making it difficult for a physician to associate
any particular event with drug exposure.
▼
THE STORY IN STATS
5/189.8 million
The approximate percentage of patients on
COX2-selective inhibitors who were at highrisk of GI bleeding from traditional NSAIDs.
The amount in US dollars spent on advertising
for Vioxx and Celebrex in 2004.
result in potentially hundreds of thousands of
cases with major public-health implications.
The major lesson from the COX2 debacle is
that a strategy is needed to detect not just an
increase in rare events but, more importantly,
an increase in common events. Such a strategy
needs to avoid impeding drug development.
Source: Dai, C. et al. Arch. Intern. Med. 165, 171–177 (2005);
Nielsen Monitor-Plus
The focus of post-marketing surveillance
in the past has been on the detection of an
increase in the frequency of rare events in
association with drug administration, so that
it was possible to demonstrate that cases of
acute liver failure occurred following Rezulin
(troglitazone; Warner-Lambert) but not after
other hypoglycaemic drugs. Our spontaneous
reporting systems are capable of detecting such
episodes because such events are sufficiently
rare as to attract the reporters’ attention and
a small number of cases easily rise above the
background noise.
However, when a drug increases the risk
of a common effect, such as the increase in
thrombotic events with COX2 inhibitors, we
have no system in place to identify the risk.
This problem is made more serious because,
for example, quadrupling the risk of a very rare
event, although easy to detect, produces very
few actual cases, whereas a similar proportional
increase in the frequency of a common event
such as stroke or myocardial infarction, will
Nancy Olsen,
University of Texas
Southwestern
Medical Center
Academic rheumatologist prescribing COX2
inhibitors to patients with arthritis.
The initial purpose of the COX2 inhibitors
was to provide a treatment option for patients
who did not tolerate traditional NSAIDs due
to gastrointestinal side effects. However, as
more patients requested these new drugs,
in part due to the influence of mass-market
advertising, physicians became less selective
in their use, and as a result lost sight of the
risk-to-benefit ratio.
In reality, there was an important indication for the use of these new drugs, and in
these arthritis patients the risks were probably
justified. However, when these agents became
broadly used, the balance was lost, and risks
were distributed to include patients who were
not deriving specific benefits.
Timeline | The rise and fall of selective COX2 inhibitors
January — Celebrex approved by FDA for
osteoarthritis and adult rheumatoid arthritis.
January — VIGOR study comparing Vioxx and
naproxen in rheumatoid arthritis begins.
January — Studies suggest that selective
COX2 inhibitors affect prostacyclin/
thromboxane ratios (McAdam, B. F. et al. Proc.
Natl Acad. Sci. USA 96, 272–277; 1999).
May — FDA approves Vioxx.
1998
1999
November — Merck submits New
Drug Application for Vioxx to FDA.
February — APPROVe study for Vioxx in colorectal
cancer begins.
March — Preliminary results of VIGOR trial indicate
an increase in CV risk with Vioxx over naproxen.
Merck says this could be due to the cardioprotective
effects of naproxen.
2000
February — FDA approves Merck’s request to
state that Vioxx is safer on the stomach than
other painkillers.
2001
September — CLASS study on celecoxib
(Celebrex; Pfizer) published. A 6-month analysis
shows GI protective effect of drug compared with
NSAIDs. (Silverstein, F. E. et al. JAMA 284,
1247–1255; 2000)
August — Meta-analysis of COX2 inhibitor
trials reinforces CV risk with Vioxx (Mukherjee,
D. et al. JAMA 286, 954–959; 2001). Also
shows that 6-month GI effect with Celebrex
disappears at the 12-month analysis stage.
November — VIGOR study published showing
Vioxx has improved GI safety compared with
naproxen, but has an increased incidence of
myocardial infarction (Bombardier, C. et al. N. Engl.
J. Med. 343, 1520–1528; 2000).
November — Valdecoxib (Bextra; Pfizer)
approved by FDA.
COX2, cyclooxygenase-2; CV, cardiovascular; GI, gastrointestinal; NCI, National Cancer Institute; NIH, National Institutes of Health; NSAID, non-steroidal anti-inflammatory drug; OTC, over the counter.
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Jerry Avorn, Harvard
Medical School,
Boston
Carried out pharmaco-epidemiological analysis
of COX2-selective inhibitors.
The alarm and confusion surrounding the risk/
benefit relationships of the COX2-selective
inhibitors and older NSAIDs are a museum of
inadequacies in drug development, promotion,
regulation and surveillance. The good news is
that we can learn much from each aspect of
the debacle.
• Signals of potential harm detected early in a
drug’s career — whether from basic pharmacological studies or from adverse events in
clinical trials — must be followed up quickly
and rigorously, and not swept under the pharmaceutical rug. Both kinds of signals were
present for Vioxx well before the end of 2000.
• Bad science is bad business: a company that
fails to investigate such potential problems
adequately may reap lucrative sales at first,
but risks losing 40% of its market capitalization and tens of billions of dollars in litigation
costs later.
• FDA must become far more effective in
mandating follow-up clinical trials, postmarketing safety studies and label changes to
address emerging drug safety problems. Its
performance was embarrassingly poor on all
three fronts.
• The glib concept of ‘class effect’ can often
obscure important within-class differences
in risk and benefit, and should not be used to
justify simplistic regulatory decisions hastily
made with insufficient data.
• The advertising of drugs to prescribers and
especially to patients must do a far better job
of conveying benefits without excessive hype,
and safety concerns with greater accuracy and
candour.
Eve Slater, former
Asst. Secretary for
Health, US
Department of HHS
THE STORY IN STATS
Head of Merck Regulatory Affairs from 1990
to January 2001.
It is difficult indeed to reduce this complex issue
to one lesson. If forced, I would say that the
selective COX2 debacle has revealed the gross
253.4 million/4,200
The damages in US dollars awarded to Carol
Ernst in the first Vioxx case and the
approximate number of pending cases
worldwide.
February — FDA Advisory Committees decide that Vioxx,
Celebrex and Bextra all carry serious risks of heart attack
and stroke. The panel narrowly votes in favour of not
withdrawing the drugs from the market, but recommends
that ‘black box’ warnings should be added to the label.
April — FDA makes labelling changes in
light of VIGOR data, stating that CV findings
should be included in the Vioxx label.
April — FDA asks Pfizer to withdraw Bextra because of
adverse CV events and serious and potentially lifethreatening skin reactions, and to include a boxed warning
on the Celebrex label.
April — Study shows that interplay between
prostacyclin and thromboxane could be the
basis of the CV complications observed in
patients taking selective COX2 inhibitors.
(Cheng, Y. et al. Science 296, 539–541; 2002)
2002
inadequacy of our collective ability to monitor
the safety of medicines once they are released to
market. Uncorrected, this deficiency bodes ill
for the future release of all medicines, especially
those intended for chronic indications in large
populations.
It is clear that the existing system of
voluntary reporting, with data residing in a
multiplicity of fragmented safety databases,
was slow to detect a signal which in this case
involved events common in the untreated
population. The clinical trial which eventually revealed risk and attendant labelling
changes came late. Indeed calls for change to
the reporting system, pooling of safety data
and incorporation of more sophisticated computerized signal-detection methods have been
registered pre- and post-hoc (Slater, E. E. N.
Engl. J. Med. 352, 293–297; 2005).
While the media seem focused upon questions of liability, there has been only faint attention paid to better defining the mechanism of
toxicity. Can the vascular and gastrointestinal
risks ultimately be reconciled? Our most
important lesson seems to be that the patient
has been forgotten.
▼
Since the decline in the use of COX2
inhibitors, many patients in fact have returned
to the use of non-selective NSAIDs without
significant problems. The lesson could be a
reminder that drug benefits do not come without risks, and both sides of the equation need
to be taken into consideration when treatment
for an individual patient is prescribed.
May — Merck’s CEO, Ray Gilmartin, steps down to be
succeeded by manufacturing chief Richard Clark.
2004
September — Merck voluntarily withdraws Vioxx from the
market after the APPROVe trial shows increased CV toxicity.
November — An FDA official, David Graham, tells a Congress
hearing on Vioxx that the agency suppressed his study that
estimated that several thousands of heart attacks and strokes
might have been caused by the drug.
2005
July — First court trial of Vioxx begins in Angleton, Texas.
The plaintiff, Carol Ernst, filed suit over the death of her
husband, Robert, who died of arrhythmia, or irregular
heartbeat, after taking Vioxx for about 8 months.
August — Merck found liable in Robert Ernst’s death. Carol
Ernst awarded US$253.4 million in damages.
December— The NCI stops a trial on Celebrex in colon cancer
when a review reveals a greater risk of CV events compared
with placebo.
December— Warnings of CV risks issued to Bextra and
Celebrex. Pfizer suspends advertising of Celebrex.
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