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The "Business" of Drugs: Research Review - Merck's
Withheld Clinical Trial Data Could Have Prevented a
Pharmaceutical Disaster
WINHS Logo World Institute Natural Health Services
    A new research report revealed how withheld clinical trial information, now required by US law to be registered on a clinical-
    trials database, could have identified the cardiovascular risks associated with Merck & Co's COX-2 inhibitor “rofecoxib,”
    marketed as the notorious “Vioxx” wonder drug, as early as four years before it was eventually withdrawn from the market.

    The new report provides a blueprint that emphasizes why it is very important that all data be made available to the public
    following and even preceding FDA approval of any pharmaceutical product. It is hoped that when there is some safety concern
    with a drug we can identify the risks sooner. The report was published this month in the Archives of Internal Medicine.

    This report is unique because it is the first time that all of the placebo-controlled clinical-trial data on rofecoxib (Vioxx) could be
    thoroughly examined, noting that previous independent research was hampered by the fact that only Merck’s “allowed to be
    published” data could be accessed. The study provides insight into what should have been reported about the risks of Vioxx by
    Merck in the first place.

    If we are to detect and identify new pharmaceutical harms early enough to protect the public's health while also ensuring the
    availability of new clinically effective therapeutics then a system must be established that makes full use of all existing
    evidence. Although the recent changes to US legislation go some way toward this goal there is still much room for
    improvement.

    The Answer to a Question

    The tale of rofecoxib (Vioxx) is emblazoned in the pharmaceutical industry’s long and dark history:
  • ·        The drug was introduced in 1999 and feverishly marketed as a safer alternative to traditional non-steroidal anti-
    inflammatory drugs;
  • ·        Its sales soon reached more than $2 billion annually.
  • ·        For four years, from 2000, there were numerous analyses and endless debates about whether the drug actually increased
    cardiovascular risk while Merck forcefully maintaining that it did not.
  • ·        In September of 2004, the last clinical trial was terminated early because of a proven increased risk of cardiovascular
    events and deaths with rofecoxib (Vioxx) compared with placebos used in the trial;
  • ·        Unable to continue to hide the facts, Merck eventually and dramatically pulled the product off the shelves worldwide, the
    biggest withdrawal in pharmaceutical history.

This illustrates how critical it is to make all clinical-trial data available for independent research and confirmation.

All along, Merck insisted there was no evidence that Vioxx increased cardiovascular risk in comparison with placebos, until their own previously
withheld evidence proved the contrary.

Researchers involved in the litigation surrounding Vioxx fortunately obtained access to all of the data on the product, which the judge in the case
allowed to be used for academic purposes.

The researchers set out to answer the question:

'Could we have used all of the unedited clinical-trials data for Vioxx to have identified the risk with the medication before it was withdrawn from the
market?' "

The answer is a resounding YES!

With access to all the data, researchers identified 30 randomized placebo-controlled trials that enrolled 20,152 individuals in trials lasting from four
weeks to four years consuming doses of Vioxx ranging from 12.5 mg to 50.0 mg.

In what researchers described as a "simple, plain analysis," they examined the cumulative results noting that as of December 2000, twenty one (21) of
these trials had been completed and the risk of cardiovascular adverse events or death was already seen to be greater among subjects assigned to
the Vioxx group thereby raising grave concern from a safety standpoint.

Subsequent clinical trial data through June 2001 showed that Vioxx was associated with as much as a 35% increased risk of a cardiovascular
adverse events or death. In fact, the high risk association increased as additional data became available; as of April 2002, the pooled analysis
showed as much as a  39% increased risk and, as of September 2004, a 43% increased risk.

If Merck & Co had done this simple analysis they would have also known the risks. Perhaps they did...

Ideally, going forward, pharmaceutical companies and the FDA should be working in concert to ensure timely and rigorous examination of clinical-trial
data to monitor drug safety, particularly for medications already on the market,

And this is where you come in...

In a statement issued by Merck & Co regarding this report, they stated that they believe the report, "used unreliable methods and reached incorrect
conclusions.”

Oh? Well how is it that they could fall short of reporting the proven increased risk of cardiovascular incidents and even deaths on the Vioxx drug – from
their own (full version) clinical trial information?

No, they chose to withheld the information and thus caused numerous and unnecessary heart attacks and deaths along with one of the largest Legal
and PR nightmares ever faced by the pharmaceutical industry.

US Legislation Falls Short

Currently the only requirement of the recently enacted FDA Amendments Act is to post data on the clinicaltrials.gov website. It does not mandate
analysis, nor does it require that individual patient-level data be made available; the latter is particularly useful for safety assessments.

The availability of this information, in a format that can be used easily, should be prioritized in order to put this substantial amount of clinical-trial data
to use for public-health purposes, allowing external investigators to validate and confirm the findings of companies or the FDA or to evaluate additional
concerns that have not been identified yet.

This is how we can do a better job of pharmaceutical safety surveillance and why it's important to do. \

Let your government representatives know this.

The FDA should ensure that ALL information is obtained from pharmaceutical companies – ALL of the information. When a pharmaceutical company
is found to be withholding clinical research information in order to present their “wonder drugs” in a favourable but undeserved light, they should be
criminally prosecuted and the executives and staff involved in the cover up should be jailed in addition to any financial fines they have already set aside
for in their marketing budgets.

The Vioxx disaster is not the first one that could have been prevented had the drug company been honest with its research findings. Perhaps it won’t
be the last, but hopefully we can put enough pressure on our government representatives to catch the next one.

All the best,

Rudi

Rudi C. Loehwing
Managing Director
World Institute of Natural Health Sciences
www.winhs.org
References
1.      Ross JS, Madigan D, Hill KP, et al. Pooled analysis of rofecoxib placebo-controlled clinical trial data. Lessons for post market pharmaceutical safety surveillance. Arch Intern Med 2009;
169:1976-1984.
2.      Merck statement on article in the Archives of Internal Medicine involving VIOXX®. Available here.
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