NEJM Issues Safety Correction Vioxx / Consumers International Report Accuses

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[sSRI-Research] NEJM Issues Safety Correction Re: Vioxx /

Consumers International Report Accuses

 

 

 

 

 

 

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

http://www.ahrp.org/cms/

 

FYI

 

Once again, the New England Journal of Medicine (July 13, 2006) has

had to

eat crow after it published false and misleading clinical trial

findings.

The published correction issued by the NEJM to Merck's critical study

of of

its painkiller Vioxx, contradicts the company's position that the drug

doesn't increase risk of heart attacks and strokes for

people who took it for less than 18 months. The unsigned correction

doesn't

specify how soon after starting to take Vioxx the heightened risks

begin but

it advised that references to an 18-month safety threshold in the

study

" should be deleted. " See:

http://content.nejm.org/cgi/reprint/NEJMx060029v1.pdf

 

As in the case of the SSRI antidepressants, the evidence contradicts

pharmaceutical company claims about drug safety revealing instead,

systemic

patterns of deception.

 

According to The Wall Street Journal, Gregory Curfman, executive

editor of

the NEJM said that based on an analysis done by an independent

biostatistician at the behest of the publication,

" the risk could have begun at any point, including time points

earlier than

18 months. "

 

The correction comes about a month after Merck submitted its complete

data

and analysis from the study to the FDA stating it had incorrectly

described

a statistical method used to analyze the Approve data. In an

interview,

Gregory Curfman, executive editor of the journal, said that based on

an

analysis done by biostatistician Stephen W. Lagakos at the behest of

the

publication, " the risk could have begun at any point, including time

points

earlier than 18 months. " See:

http://content.nejm.org/cgi/reprint/NEJMp068137v1.pdf

 

Of note, the Wall Street Journal reports, there are roughly three

months

left before the statute of limitations in some states for filing a

Vioxx

lawsuit runs out.

Thus, plaintiff's attorney, Christopher Seeger, accused Merck of

deliberately falsifying the claimed findings:

" This confirms that all along Merck knew the 18-month hypothesis was

false.

It was simply a litigation strategy. "

 

Steven E. Nissen, M.D. Cleveland Clinic Foundation writes in part:

" The recent public disclosure of data from a 12-month extension study

of the

Adenomatous Polyp Prevention on Vioxx (APPROVe) trial1 provides new

insights

into the effect of rofecoxib on cardiovascular events. These new data

reveal

the full results of both the original study and the extension phase,

including data tables and Kaplan-Meier curves. In the original

article, the

APPROVe investigators reported event rates using an unusual censoring

rule

in which events were excluded if they occurred more than 14 days

after the

study drug was stopped.

 

All data in the new report are assessed by a conventional intention

to-

treat analysis. This new report also provides analysis that uses

several

different end points, including the widely used end point of the

Antiplatelet Trialists' Collaboration (APTC) study.2

 

The original article included a post hoc hypothesis that curves for

confirmed thrombotic events would not begin to diverge until after 18

months

of exposure to rofecoxib.

However, all intention to-treat analyses in the newly released report

show

that the event curves begin to diverge much earlier, generally within

four

to six months. "

[see, Figure 1 and 2]

 

" In the original article, the APPROVe investigators reported event

rates

using an unusual censoring rule in which events were

excluded if they occurred more than 14 days after the study drug was

stopped. All data in the new report are assessed by a conventional

intention

to-treat analysis. "

 

" It is now clear that the approach of censoring events that occurred

more

than 14 days after drug discontinuation had a significant effect

on the results of the APPROVe trial.In a report of a serious drug-

safety

problem, even if the original study design prespecified censoring

of late events, it is particularly important to provide alternative

analyses

if such analyses suggest a substantially different conclusion. "

 

" Since patients who stopped the study drug early are likely to be

people

who had adverse reactions

such as hypertension, heart failure, or renal dysfunction, they

represent a

particularly vulnerable

group. It is now clear that the approach of censoring events that

occurred

more than 14 days

after drug discontinuation had a significant effect on the results of

the

APPROVe trial.

 

In a report of a serious drug-safety problem, even if the original

study

design prespecified censoring

of late events, it is particularly important to provide alternative

analyses

if such analyses

suggest a substantially different conclusion. "

 

Curt D. Furberg, M.D., Ph.D. Wake Forest University School of Medicine

writes:

" An update of the APPROVe trial data is now available. It contains

additional information

about events in the subgroup of participants whose data were censored

if

they had an

event more than 14 days after early discontinuation of the study

medication.

With the addition

of 12 thrombotic events that occurred more than 14 days after the

study drug

was stopped but

within 36 months after randomization, it is now possible to analyze

the

three-year event data according

to the intention-to-treat principle. Eight of the " new " events were

in the

rofecoxib group, and these events

had a clear effect on the published survival curve for rofecoxib

(Fig. 2 of

the original article).

 

The curve is now more linear, and the narrowing of the distance

between the

rofecoxib

and placebo curves at 18 months is almost gone. Statistical analysis

shows

no evidence of deviation

from the proportional hazard over time. The release of the new data

raises

questions. At the time the APPROVe trial was submitted and

published, was the complete data set available to the authors for an

intention-to-treat analysis?

Did they perform a proportionality test of the threeyear event data

before

publication? " cfurberg

 

The unfolding revelations and false claims in published clinical trial

reports confirm the accusations leveled at the drug industry by the

European

Consumers International.

The industry uses unscrupulous, systemic promotional practices to

influence

opinion and prescribing practices. " These include the sponsoring of

patient

lobby groups, funding disease awareness campaigns and use of

hospitality

packages for medical experts. " Industry's claims about the cost of

research

and development are contradicted by industry's spending on marketing:

" The pharmaceutical industry spends nearly twice as much on

marketing as it

does on research and development, yet consumers know next to nothing

about

where [$60 Billion] this money is going. "

 

Contact: Vera Hassner Sharav

212-595-8974

veracare

 

Vioxx Study Correction May Add

Pressure to Merck's Defense

By HEATHER WON TESORIERO

June 27, 2006

 

The New England Journal of Medicine published a correction to a

critical

study of Merck & Co.'s painkiller Vioxx, contradicting the company's

position that the drug doesn't increase risk of heart attacks and

strokes to

people who took it for less than 18 months.

The unsigned correction said key results in the New England Journal of

Medicine's original publication of the study, called Approve, were

reached

by a different statistical method than was described in the article,

and

that when the data were subjected to the stated method, the

contention that

risk

increased only after 18 months didn't hold up. As a result, the

correction

said references to the 18-month threshold in the study " should be

deleted. "

(See the correction1.)

The correction doesn't specify how soon after starting to take Vioxx

the

heightened risks begin. But in an interview, Gregory Curfman,

executive

editor of the journal, said that based on an analysis done by

biostatistician Stephen W. Lagakos at the behest of the

publication, " the

risk could have

begun at any point, including time points earlier than 18 months. "

Dr.Lagakos's analysis also appeared on the journal's Web site.

 

Merck acknowledged it misidentified the statistical methodology that

it used

in its study, which it says it discovered last month and set in motion

events that led to the published correction. But it disputes the

contention

of journal editors and other scientists that the new analysis changes

the

original conclusion. The company said it stands by its assertion

that " the

increased relative risk was observed beginning after 18 months. "

Theodore Mayer, co-lead outside counsel for Merck, said, " We believe

our

position is scientifically sound and we feel comfortable representing

it. "

 

Merck pulled its blockbuster painkiller off the market in September

2004,

after the Approve study linked Vioxx to heart attacks and strokes in

patients taking the drug for 18 months or longer. Since that time,

several

scientists have challenged the 18-month premise, saying the drug could

pose risks much earlier.

 

The correction could be a boon for plaintiffs' attorneys who have

clashed

with Merck on how quickly Vioxx's risks emerge in patients. The

company

faces 11,500 lawsuits from

people alleging Vioxx caused their heart attacks and strokes. A

cornerstone

of Merck's defense in the litigation has been that the drug couldn't

have

had a hand in injuries in people who took the drug for fewer than 18

months.

So far, Merck has won three cases and lost three cases. Juries have

found in

favor of two plaintiffs who took the drug for fewer than 18 months.

There is

a trial under way in Atlantic City and another scheduled to start

tomorrow

in Los Angeles.

 

" This confirms that all along Merck knew the 18-month hypothesis was

false, "

Christopher Seeger, plaintiff's attorney and key player in the Vioxx

litigation, said. " It was simply a litigation strategy. "

 

The New England Journal of Medicine also published letters from two

physicians who have been outspoken critics of the 18-month hypothesis

and

who reiterated what they say is the validity of the

updated analysis. In an interview, Curt D. Furberg, whose letter

appears in

the journal, said, " The whole thing about an 18-month delay is gone.

There

is no support whatsoever for it. "

 

In a response to the letters, Approve authors Robert S. Bresalier and

John

A. Baron wrote that an " indepth analysis of the extended patients in

the

Approve trial " is under way and will include an

independent analysis of the cardiovascular data. The two authors

couldn't be

reached for comment.

 

This is the second time Merck and the journal have differed in Vioxx

study

results. In December 2005, the journal issued an " _Expression of

Concern "

over Merck's reporting of cardiovascular risks in a 2000 study known

as

Vigor. In that study, Merck used different cutoff points for stomach

and

cardiovascular results, which affected the number of reported heart

attacks

and sparked some criticism from outside scientists.

 

The Approve correction comes about a month after Merck submitted its

complete data and analysis from the study to the Food and Drug

Administration. At the time, MercMerck issued a statement saying it

incorrectly described a statistical method used to analyze the

Approve data.

It said that didn't change the results of the study, and that Vioxx

only

appeared to pose risks after 18 months.

There are roughly three months left before the statute of limitations

in

some states for filing a Vioxx lawsuit runs out. It isn't unusual for

there

to be an in increase in cases filed shortly before the statute

deadline. Mr.

Seeger says he estimates there will be 30,000 Vioxx suits.

 

Write to Heather Won Tesoriero at heather.tesoriero

 

URL for this article:

http://online.wsj.com/article/SB115133539472190796.html

 

Hyperlinks in this Article:

(1) NEJM Correction:

http://content.nejm.org/cgi/reprint/NEJMx060029v1.pdf

(2) Stephen W. Lagakos, Ph.D., Time-to-Event Analyses for Long-Term

Treatments -

The APPROVe Trial

http://content.nejm.org/cgi/reprint/NEJMp068137v1.pdf

(3) Letters to the Editor:

http://content.nejm.org/cgi/reprint/NEJMc066260v1.pdf

~~~~~~~~~~

 

http://news.bbc.co.uk/go/pr/fr/-/2/hi/europe/5116312.stm

 

BBC NEWS

June 26, 2006

Drug firms attacked on marketing. Top European pharmaceutical firms

are

using unscrupulous marketing practices to promote their products, a

consumer

report says.

 

The Consumers International lobby group accused drugmakers of using

the

methods to get doctors to prescribe products and persuade consumers

they

need them.

 

It said there was a " shocking " lack of publicity about where the $60bn

(£33bn) annual marketing spend went.

 

Drug firms say that they act within strict guidelines.

 

The Association of the British Pharmaceutical Industry (ABPI) told

the BBC

News website that for UK-based firms there was " a stringent and

transparent

code of practice that goes beyond the requirements of UK law and the

industry regulator " .

 

Sponsorships

Consumers International said it had analysed the selling techniques

of many

leading companies, including Bayer, GlaxoSmithKline and Johnson &

Johnson.

 

The current regulatory framework is clearly insufficient to prevent

systemic violations of marketing regulations

Consumers International

 

Richard Lloyd, the group's director general, said: " The pharmaceutical

industry spends nearly twice as much on marketing as it does on

research and

development, yet consumers know next to nothing about where this

money is

going. "

 

He called for a revision of marketing regulations to achieve " more

transparency from drug companies " .

 

In most Western markets direct advertising to consumers is banned.

But Mr

Lloyd said there were other methods drug companies were using to

influence

opinion.

 

These include the sponsoring of patient lobby groups, funding disease

awareness campaigns and use of hospitality packages for medical

experts.

 

As producers of life-saving medicines it is important that we ensure

doctors

know full details ABPI

 

The report cites sponsorships by such firms as Eli Lilly and Pfizer.

The

latter, the maker of Viagra, sponsored a campaign by the Impotence

Association which sported the Pfizer logo.

 

The report said only one of the firms studied, Orion Pharma, provided

specific marketing budget information.

 

It also pointed to the " large numbers of serious, recent and repeated

breaches of marketing codes " .

 

This showed the " current regulatory framework is clearly insufficient

to

prevent systemic violations of marketing regulations " .

 

However, the ABPI said the number of complaints raised showed the

system,

which had been strengthened this year, was working.

 

It said complaints from drug companies about fellow firms' activities

showed

the self-regulation was effective.

 

But it also said it was vital for doctors to know about products.

 

" There is no point having innovative new medicines if they remain

unused, "

an association spokesman said.

 

Story from BBC NEWS:

http://news.bbc.co.uk/go/pr/fr/-/2/hi/europe/5116312.stm

 

Published: 2006/06/26 10:11:46 GMT

 

© BBC MMVI

 

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