E-drug: Lancet editorial: The statin wars and AstraZeneca
---------------------------------------------------------------------
[Please also read response of AstraZenica Chief Executive below this
editorial. HH]
The statin wars: why AstraZeneca must retreat
Editorial
Lancet 362 (9393):1341 (25 October 2003)
Tom McKillop is chief executive of AstraZeneca. He is widely
respected across the drug industry. The UK's Academy of Medical
Sciences elected him to its Fellowship in 2002, the same year that he
received a knighthood. Yet this glittering arc of success is now cast
into shadow. For AstraZeneca's tactics in marketing its
cholesterol-lowering drug, rosuvastatin, raise disturbing questions
about how drugs enter clinical practice and what measures exist to
protect patients from inadequately investigated medicines.
The statin market is vast. Pfizer's atorvastatin the world's
best-selling drug had sales in 2002 of US$ 8 billion. AstraZeneca
predicts that it can take a 20% share of this global market. It needs
to. The company reported a 17% drop in pre-tax profits in the second
quarter of this year. After a damaging delay over safety concerns,
rosuvastatin finally won US FDA approval in August and was
launched last month, winning a 2% market share after only three
weeks. McKillop has pledged to do whatever it takes to persuade
doctors to prescribe rosuvastatin, including launching an estimated $1
billion first-year promotional campaign. "We've got to drive the
momentum", he said at a recent investors meeting. "You get one shot
at launching a major new product. This is our shot."
The sales strategy for rosuvastatin is based around the Galaxy
programme. Galaxy is the contrived umbrella name for at least 16
clinical trials of wide-ranging quality designed to investigate the
efficacy of rosuvastatin in various clinical settings. The trials within
Galaxy have names to match the company's cosmic intentions
Mercury, Stellar, Orbital, Asteroid, Meteor, Jupiter, etc. With no
clinical end-point trial yet completed, the company has chosen to
market rosuvastatin by applying adventurous statistics to an
overinterpreted syllogism. The argument is familiar and seems
compelling. First premise: atherogenic lipid profiles cause
atherosclerosis. Second premise: atherosclerosis causes
cardiovascular disease. Conclusion: reversing atherogenic lipid
profiles will reduce the risk of heart disease. But AstraZeneca has
proceeded to push Galaxy into the realms of astrological rather than
astronomical logic.
Take one example. Stellar was a six-week, open-label dose
comparison in 2268 patients with primary hypercholesterolaemia.
Results were recently reported in Current Medical Research and
Opinions (2003; 19: P1-P10). Rosuvastatin was compared with
atorvastatin, simvastatin, and pravastatin. AstraZeneca's drug was,
dose for dose, more effective at achieving national guideline targets
for lipid concentrations than its competitors. Based on these tentative
surrogate findings, one Stellar investigator, Peter Jones, commented
that, "If I have the option of achieving goals at a lower comparable
dose, I would choose that". This kind of gloss does little to foster
sensible, let alone critical, appraisal of weak data.
Similar twists in the statistical wind were reported in a promotional
supplement to the American Journal of Cardiology in March this year
by James Blasetto and colleagues. Blasetto, who works for
AstraZeneca in Wilmington, Delaware, combined soft end-point data
from five small 12-week trials to conclude with astonishing certainty
that rosuvastatin "can be of considerable value". It is difficult to
understand how such blatant marketing dressed up as research can
appear under the name of a respected peer-reviewed medical journal.
Why does the quality of debate about statins matter? First, because
safety cannot be assured. Bayer withdrew cerivastatin in August,
2001, after the occurrence of unexpected cases of fatal
rhabdomyolysis. The 80 mg dose of rosuvastatin was withdrawn by
AstraZeneca because of safety concerns. Some critics are even
anxious about the 40 mg dose. The finding of proteinuria and
microscopic haematuria associated with rosuvastatin use are
additional worries. Second, talking up the efficacy of statins subverts
efforts to conduct large-scale outcome trials where they matter most
eg, in heart failure. And third, given the beneficial results of
mortality end-point trials for other statins, what possible clinical
justification can there be for licensing an unproven statin?
Since there are no reliable data about efficacy and safety--and
AstraZeneca is facing unusually acute commercial pressure to force
rosuvastatin into the market doctors should pause before
prescribing this drug. Physicians must tell their patients the truth
about rosuvastatin that, compared with its competitors, rosuvastatin
has an inferior evidence base supporting its safe use. AstraZeneca
has pushed its marketing machine too hard and too fast. It is time for
McKillop to desist from this unprincipled campaign.
---
Astra's response:
Lancet 362 (9394):1498 (1 November 2003)
Correspondence
The statin wars
Sir--In your Oct 25 Editorial,1 you write that "Physicians must tell their
patients the truth about Crestor (rosuvastatin)". Readers of The
Lancet are entitled to no less from their Editor.
Your readers should know the following. Crestor is an extensively
studied and well tolerated drug with a safety profile comparable to
other marketed statins combined with a greater ability to get patients
to their cholesterol goals than any other single product. More than
80% of patients reach their LDL cholesterol goals on the starting dose
of 10 mg which also significantly increases HDL cholesterol--a profile
unmatched by competitor drugs.
AstraZeneca developed and submitted for regulatory approval the
largest clinical database for any statin with more than 10 000 patients
studied in clinical trials. Eight full primary publications of Crestor data
have appeared in prestigious peer review journals including the
American Heart Journal, American Journal of Cardiology, and the
Journal of Cardiovascular Risk.
All of the safety and efficacy data on Crestor have been reviewed in
great depth by regulatory authorities globally, who have assessed the
benefit-risk profile of the product and approved it in a very demanding
regulatory climate. For example, the whole database was publicly
scrutinised at a meeting of the Food and Drug Administration
Advisory Committee, with all nine members unanimously supporting
the recommendation for approval of Crestor 5-40 mg for long-term
lipid control.
More than 30 regulatory authorities worldwide have approved Crestor
to date and more approvals are pending. Over 200 000 patients
worldwide have now been treated with Crestor. Post-marketing
surveillance confirms its safety profile to be similar to that of other
marketed products in the statin class.
Outcome data are rarely available for any new medicine at the time of
launch, and have never been available for cholesterol-lowering and
hypertensive drugs at this stage. Mandating outcomes data for any
drug before approval would stifle innovation and needlessly delay the
introduction of new therapeutic advances. External clinical opinion
leaders were so impressed by the Crestor clinical trial data that
AstraZeneca started a comprehensive outcomes programme before
approval. However these studies, including trials in heart failure, are
long-term and it will be a number of years before they reach maturity.
Lipid surrogate endpoints are necessary, widely accepted, and form
the basis of clinical decision making. Large studies have established
that an increased concentration of LDL cholesterol is a risk factor for
the development of atherosclerosis. In turn, atherosclerosis is a major
cause of cardiovascular mortality and morbidity. Crestor has an
impressive, reproducible, and reliable effect on these surrogates, and
this evidence is the basis for the Crestor GALAXY Programme.
Millions of people are at risk of cardiovascular disease because they
are either untreated or not being effectively treated with current
lipid-lowering therapies. With this compelling medical need, it is
unthinkable that we should desist from our efforts to make this
medicine more widely available to physicians and patients.
Regulators, doctors, and patients as well as AstraZeneca have been
poorly served by your flawed and incorrect editorial. I deplore the fact
that a respected scientific journal such as The Lancet should make
such an outrageous critique of a serious, well studied, and important
medicine.
Tom McKillop
Chief Executive, AstraZeneca PLC
--
To send a message to E-Drug, write to: e-drug@healthnet.org
To subscribe or unsubscribe, write to: majordomo@healthnet.org
in the body of the message type: subscribe e-drug OR unsubscribe e-drug
To contact a person, send a message to: e-drug-help@healthnet.org
Information and archives: http://www.essentialdrugs.org/edrug