Wednesday, June 3, 2009

Vioxx

Mr. Tom Nesi, a 30 year pharmaceutical industry veteran, recently published a book called, “Poison Pills- The Untold Story of the Vioxx Drug Scandal.” I believe this to be a great book- very informative and interesting.

And I wanted to echo what he likely wrote in this book regarding Vioxx, since I was involved with the promotion of Vioxx when I was a sales representative with Merck some time ago:

Merck brought Vioxx to the market in the Spring of 1999 in the United States, which was six months after the first COX II class drug got approval in the United States, which was G.D. Searle’s Celebrex.

Many remember the shock when Vioxx was pulled from the market in the Fall of 2004. Many called this event unbelievable, if not surreal. The drug was so widely used and had been on the market for about 5 years.

And Merck was…well….MERCK. How could this happen? Over 80 million people had taken the drug worldwide at the time the drug was removed from the market. Sales were approaching 3 billion dollars a year. Why is this happening? To save the cardiovascular function of others who may take Vioxx?

Beginning I believe in 1998, Merck and G.D. Searle, a division of Monsanto, were in a race of sorts to bring to market the first COX-2 inhibitor. It would be a pain and inflammation drug that they speculated would be safe- especially safer on the stomach of the user than any other medication available.

Efficacy would not be compromised. Relief for these patients would occur. The word from both companies heard often was, ‘blockbuster’, when referring to their pending COX-2 inhibitors. This class would be in fact a pain and inflammation panacea, according to these two companies.

Turns out G.D. Searle came out with Celebrex, their COX-2 inhibitor first, towards the end of 1998. Merck was disappointed, but moved on confidently- knowing most likely that their COX-2, Vioxx, would surely get approved soon after Celebrex hit the market.

It had to acquire the lion’s share of the COX II francise. Lipitor was about to be launched, and Parke Davis was convinced it would be the number one statin drug- and would quickly overtake the lead of Merck's Zocor. Merck was very concerned about this viable threat to this franchise they owned with statins. Merck came out with the first statin, Mevacor, in the 1980s.

So, Vioxx was approved in the Spring of 1999. In fact, I launched the drug as a sales rep with Merck at that time along with most other sales representatives employed by Merck. The meeting which thousands of sales reps. attended was at one of San Francisco’s nicer hotels in late May of 1999. David Anstice gave some synthetic cheers, and the obedient soldiers followed. The elation of the sales force was nothing less than what can only be described as complete and disturbing mania. .

Everyone in the various sales teams had some part in the launch of Vioxx. Merck was depending on its success. And a successful launch it was- one of the best drug launches ever for a drug company.

What I did not know at the time I launched this drug is that Vioxx was suspected as having cardiovascular risks associated with this drug as early as 1996- and was confirmed to have this risk in 1998. Also, key opinion leaders (KOLs) increased in number, and their utilization, to further promote Vioxx aggressively and progressively both before and after approval of Vioxx. These speakers who favored Merck’s Vioxx were located within a state, region, or the entire United States.

They were selected by a targeting method utilized that factors in the volume of prescriptions a doctor writes, and how many of these prescriptions favor the products of Merck.

These KOLs were analyzed constantly to make sure they were doing what they were being paid to do- which is sell Vioxx to their peers- their fellow health care providers. Their prescribing analysis is due to the American Medical Association selling prescribing data on individual doctors to pharmaceutical companies- with a third party company as a carrier of this data to them. This earns the AMA about 50 million dollars every year.

I left Merck at the end of 1999- soon after the launch, for another employment opportunity. And I was sad to leave such a well-respected company, yet I felt that the hype of their sales and marketing force was a bit pathological and with an air of desperation within the culture of Merck, it seemed. So at the end of 1999, I wished to explore a new challenge with another company and hope for the best.

In the years after I left, the Merck sales reps. Were forced to acknowledge and address potential obstacles presented to them by prescribers regarding Vioxx, and would play games such as ‘dodgeball’ or some other silly neumonic concept derived from Merck’s marketing department. This was done so Merck could be comforted that their sales force would not engage in a conversation beneficial for the patients of the prescribers, but rather financially beneficial for Merck.

Additional games played by Merck to their sales reps often include comedy skits related to their promoted products, and the hiring of doctors to attend company meetings to hear the sales pitches of Merck reps.- and grade their performance afterwards.

Such ridiculous games enabled Merck sales reps. to hopefully internalize the concept that the cardiovascular risk associated with Vioxx was not a real risk that prescribers need to know. Merck does not want their reps. to think, of course.

Vioxx continued to grow, and it also continued to be studied to reassure others of the safety and efficacy of the drug, as well as possible other uses for the drug besides pain and inflammation.

The much anticipated VIGOR trial results were released in 2001, which compared Vioxx to Naproxen, an older non-steroidal anti-inflammatory drug. During the trial, there was a 4 fold increase in heart attacks with the Vioxx patients vs. Naproxen, which was concerning.

Since Merck controlled and secured all data from this trial for themselves to sculpt to their favor for Vioxx, they had the ability to selectively share data that was incomplete for publication. This is what occurred with the New England Journal of Medicine, who published what they believed was the entire data that was included and acquired from the VIGOR trial.

However, Merck, with deliberate intent, did not report negative data to the NEJM, such as MIs with subjects in the trial taking Vioxx. Merck deleted such data from the VIGOR manuscript before submitting the trial for publication, it has been reported.


Merck said this was due to the natural cardio-protective effects of Naproxen that had been known already. Others attributed the concerning risk of heart attacks and stroke to Vioxx and its undisclosed pro-thrombotic effect which was responsible for the increase in heart attacks and strokes. The debate continues to this day. Many believe Naproxen does not provide any significant cardioprotective effect for one who takes this drug.

Merck has a history of creating with deliberate intent seeding trials. These are trials that are disguised as science-seeking peer-reviewed journals. In actuality, such clinical trials are merely marketing outlets to fulfill marketing objectives.

Created by the marketing divisions of typically large pharmaceutical companies, this division not only handles all data acquired from their jigsaw trial, but also does not disclose the purpose of the trial to the trial participants.

Merck’s ADVANTAGE trial, which began soon after Vioxx got approved was the first documentary evidence that proved the existence of seeding trials, and was published in the Archives of Internal Medicine after its completion.

An editorial from the staff of the journal followed- illustrating that this trial is, in fact, a seeding trial. Merck responded to this editorial expressing shock and disbelief- stating that had only the authors and editors of the clinical trial contacted Merck about the fallacies illustrated in the trial and editorial, then all would see the true benefit and intentions with the ADVANTAGE trial. Yet, according to Merck, these gifted annotators chose not to contact them. Therefore, the study is flawed due to those not as competent as Merck.

Yet the FDA issued a notice to Merck in the Spring of 2002 that a warning would be on the labeling for Vioxx about the increased risk for cardiovascular events for those who take this drug. Also, soon after the results of VIGOR were released, it was discovered that Merck manipulated the data from the VIGOR trial and engaged in scientific misconduct with their deliberate statistical gymnastics they performed with the data from this trial.

When the truth about the complete data was analyzed by others, it was determined that Vioxx caused actually a 5 fold increase in cardiovascular events instead of four. Merck would later claim that this issue with the VIGOR trial was simply an oversight.

Over 100 thousand heart attacks, about 35 percent of them fatal, attributed to those who took Vioxx, and it was an ‘oversight’. Studies now show that one can have a cardiovascular event as soon as two weeks after taking Vioxx, and the risk continues for cardiovascular events up to a year after vioxx is no longer taken by a patient.

In addition, as others analyzed all data about Vioxx they could locate, others determined that Vioxx should have been removed from the Market a year after it was launched for use by patients who were prescribed Vioxx by their health care providers.

Merck, however, moved on with the growth of Vioxx, and appeared to ignore this overt and dangerous risk that likely was associated with their drug.

The APPROVe trial was initiated soon after the VIGOR trial to study the use of Vioxx in treating colon polyps. The trial was terminated early due to increase in adverse thrombitic cardiovascular events, heart attacks and strokes in particular, with those patients taking Vioxx.

In particular, those patients who took Vioxx long term experienced increased cardiovascular events, yet some experienced such events after only 2 months, it has been reported, and this was noted in the VIGOR trial. Vioxx was removed from the market shortly after this trial was halted. Merck minimized if not intentionally eliminated the risks of Vioxx as an etiology for cardiovascular events by skewing research.

Sponsors of their clinical trials have a clear financial interest in their products being studied, as well as a fiduciary duty to shareholders to provide a return on their investment. These particular variables ultimately disqualify the sponsor from other much more important duties, such as assuring clinical trials involving the sponsor’s products are aseptic and void of bias.

Yet since this method frequently occurs, the trust is violated of the human subjects who volunteer for these clinical trials to advance science, medicine, and public health.

The sales reps of Merck were encouraged to strive to increase their income only in all that they did for their employer that they were coerced to do by this source of income for them and the products they now promote that do not include Vioxx as of the Fall of 2004.

Dr. David Graham, Associate Director in the FDA’s Office of Drug Safety, witnessed the FDA trying to discredit him after Dr. Graham told a U.S. Senate Hearing that the FDA had failed to protect the public over Vioxx. Dr. Graham said that the FDA is simply not capable of protecting America against another Vioxx. Dr. Graham went on to mention a few other drugs on the market of concern as well.

Presently, there are warnings with all COX-2 inhibitors that they should not be taken by those patients who have cardiovascular disease, or are at risk for this disease, as it is believed that the cardiovascular events noted with Vioxx are a class effect with all COX-2 inhibitors.

Today, believe it or not, after re-analyzing all the data with Vioxx from all the studies performed on the drug, the FDA has concluded that Vioxx could be returned to the market, as it has been determined that, with certain patients, the benefits outweigh the risks. Other countries feel the same way, and consider COX-2 inhibitors as a class no different than NSAIDS as far as their safety for others is concerned.

Right now, there is a very interesting class action lawsuit occurring in Australia. Since the end of March of this year, often one can read about what tactics implemented by Merck when promoting Vioxx, and the whole world can acquire this very secret information. It is an unusually unexpected window into the aggressive tactics used by international drug companies to market their drugs. This window has been widely opened by Ms. Milanda Rout:


Hi,
I just wanted to say a belated thank you for your lovely comments about my coverage of the Vioxx trial – much appreciated!
I also note with interest that you were once a Merck sales representative – I would love to have a chat with you (off the record if you prefer it) about your experiences at Merck with Vioxx if that would suit you. I am interested in doing a more in-depth piece about the issues that the trial raised after the court process has finished.
Thanks again,

Milanda Rout


Milanda Rout
The Australian
Level 2, West IBM Centre,
60 City Rd, Southbank, Victoria.
Ph: 0414 835 787
Fax: (03) 9292 2803


-----Original Message-----
From: Robyn Clothier [mailto:robyn@healthyskepticism.org]
Sent: Monday, 25 May 2009 10:12 AM
To: Rout, Milanda
Subject: FW: Check out vioxx - The Australian Search

Milanda,

I thought you might be interested in these comments from one of our members – a former pharmaceutical representative in the US.

May I add my congratulations on your excellent work, which we have been following closely.

Robyn Clothier
Administrative Assistant

Healthy Skepticism Inc
34 Methodist St
Willunga SA 5172
Australia
Ph/Fax: +61 8 8557 1040
www.healthyskepticism.org


From: Diohdan@aol.com [mailto:Diohdan@aol.com]
Sent: Wednesday, 20 May 2009 1:05 PM
To: robyn@healthyskepticism.org
Subject: Check out vioxx - The Australian Search

Click here: vioxx - The Australian Search

The Australian has done a wonderful job exposing what were tacit tactics utilized by Merck to promote Vioxx. This would not have happened in the U.S., I'm sad to say, this kind of exposure.

I launched Vioxx as a representative with Merck back in 1999. This drug was very important to Merck for two reasons: One is that Lipitor, which was approved in 1997, rapidly acquired the lion's share of the statin market (Merck has the lion's share of this class of medications with Zocor before this happened). Merck was not prepared for this rapid uptake of Lipitor, and this vexed Merck greatly.

Secondly, Vioxx got approved 6 months after Celebrex, and this concerned Merck. Historically, the drug that is first in class that gains approval first will capture the lion's share of the market, and maintain the lead over the competitors- in this case, the Cox II class of medications.

Celebrex getting approval before Vioxx concerned Merck as well. So the plans implement read almost daily in The Australian are plans that were implemented in the United States as well. Merck was desperate, and clearly was willing to cross ethical lines to assure Vioxx would be the success that Merck needed it to be due to competition.

What we read about this trial that continues is accurate, even though Merck is saying in their defense that most of we read is 'mis-statements', or embellishments. What is now shared with the world are statements that are false, misleading, or lack context.

Merck insists that it has been vigilant in regulating and sharing all cardiovascular issues associated with Vioxx. They say they have acted responsibly and appropriately as it developed and commercialized Vioxx- acting in the best interest of patients always.

What we read is true, and the ethically if not legally corrupt plans of actions implemented by Merck were with deliberate intent and reckless disregard as they continued to strive to gain additional market share with an unsafe drug of theirs.

Dan Abshear

2 comments:

Anonymous said...

I would like t point out an error in you story. The American Medical Association does not have, and has never had, access to physician prescribing data.

Quiact said...

http://content.nejm.org/cgi/content/full/354/26/2745