The Vioxx Hit Squad

"We may need to seek them out and destroy them where they live." The words of a Merck employee regarding people who dared to criticize its bestkilling, er, bestselling painkiller/heart attack inducer Vioxx.

According to The Australian , Merck

...made a hit list of doctors who had to be "neutralised" or discredited because they criticised the anti-arthritis drug the pharmaceutical giant produced. Staff at US company Merck & Co emailed each other about the list of doctors - mainly researchers and academics - who had been negative about the drug Vioxx or Merck and a recommended course of action.

The email, which came out in the Federal Court in Melbourne yesterday as part of a class action against the drug company, included the words "neutralise", "neutralised" or "discredit" against some of the doctors' names.

More about this and similar tales of evil at Before You Take That Pill. You might recall that the superhero team in videos used to train Vioxx sales reps was known as the V-Squad. Perhaps the V-Squad was sent out to "destroy them where they live?" Check out the V-Squad videos here and decide for yourself.

The V-Squad Finale

Here is the final of the 3 training clips for Vioxx salespersons. The first and second clips are also available.

Be The Power:
2 efficacy
2 GI risk (and ZERO cardiovascular risk)

How 'bout a nice dose of data? Oh, this clip is SO rich!

More From the V-Squad

The Superhero team of Merck sales reps continued to work hard to push Vioxx. The ending of this clip is definitely a cliffhanger, so be sure to tune in for the finale tomorrow! See clip 1 in my most recent post.

Meet the V-Squad

How did Merck go about training reps to sell Vioxx? Here's part one of three. Thanks to an anonymous reader for sending me along this trilogy. Part 2 is great and part 3 is outrageously funny. Well, I mean except for the part (not included in the videos) where people were dropping dead from taking this newer, "safer" painkiller. Parts 2 and 3 coming soon.



Go to vioxxdocuments.com for more such goodies.

Sowing the Seeds of Vioxx

A new article in the Annals of Internal Medicine lays bare how research was commandeered by marketing in the promotion of Vioxx, Merck’s former all-star painkiller and personkiller. The article is based on a chunk of internal Merck documents revealed during legal proceedings (not unlike the infamous Zyprexa documents). Merck set up the study known as ADVANTAGE, in which 2785 arthritis patients were given Vioxx and 2772 arthritis patients took naproxen. Physicians across the nation were recruited to enroll patients to participate in the study, which was intiated during the FDA approval process for Vioxx.

The study, however, was conceived and conducted by Merck’s marketing department. Why? As Vioxx was about to come to market, Merck needed to develop a need for their product. By hiring physicians to participate as “investigators” on this trial, Merck was exposing its product to an important group of potential customers. To quote Merck:

The objectives were to provide product trial among a key physician group to accelerate uptake of VIOXX as the second entrant in a highly competitive new class and gather data important to this customer group. The trial was designed and executed in the spirit of the Merck marketing principles.

Other snippets from a Merck marketing memo, with pithy commentary added free of charge:

• "...the trial was targeted to a select group of critical customers.” So the main qualification to be a “research investigator” in this trial was to be a customer that Merck wanted to win over.

• “The sales force nominated potential investigators and completed intake forms, allowing a very large number of sites to be evaluated and enrolled and ensuring equal distribution of investigators across the business groups.” Again, the sales force chose the physicians, apparently based on how easily they could be swayed to prescribe Vioxx as a result of participating in this study.

• “An analysis performed at 6 months post launch demonstrated a significantly higher level of prescribing for VIOXX among primary care ADVANTAGE investigators compared to a control group of VIOXX 99 prescribers (see attached). Feedback from the field has been overwhelmingly positive about their ability to access key customers and the influence that being involved in the trial has had on their perceptions of VIOXX and Merck.” The program apparently had its desired results – more docs prescribing Vioxx as a result of their participation in Merck marketing-designed “research.” As for the patients dying due to taking Vioxx, well, what’s a little collateral damage when there are quarterly sales goals to be met?

The name for such an exercise in marketing is a “seeding trial,” referring to a company planting seeds in physicians to use their product under the guise of research.

II. What about getting the results out?

According to Merck: “Preparations are now underway for analysis and publication of the data, which will utilize key investigators as authors and advisors.” Turns out that worked pretty well – as the lead author on the main ADVANTAGE publication told the New York Times that “Merck designed the trial, paid for the trial, ran the trial. Merck came to me after the study was completed and said, “We want your help to work on the paper. The initial paper was written at Merck, and then it was sent to me for editing.” – it was sent to him to place a veneer of academic credibility on Merck’s marketing-run trial.

Even Merck’s head of research said that trials such as ADVANTAGE are “intellectually redundant” – as they tend to focus on results that are already well-established, such as showing Vioxx to be somewhat easier on the gastrointestinal tract that naproxen.

Harold Sox and Drummond Rennie, also writing in the Annals of Internal Medicine, in a critique of Vioxx’s marketing wrote:

This practice—a seeding trial—is marketing in the guise of science. The apparent purpose is to test a hypothesis. The true purpose is to get physicians in the habit of prescribing a new drug. Why would a drug company go to the expense and bother of conducting a trial involving hundreds of practitioners— each recruiting a few patients—when a study based at a few large medical centers could accomplish the same scientific purposes much more efficiently? The main point of the seeding trial is not to get high-quality scientific information: It is to change the prescribing habits of large numbers of physicians. A secondary purpose is to transform physicians into advocates for the sponsor’s drug. The company flatters a physician by selecting him because he is “an opinion leader” and incorporates him in the research team with the title of “investigator.” Then, it pays him good money: a consulting fee to advise the company on the drug’s use and another fee for each patient he enrolls. The physician becomes invested in the drug’s future and praises its good features to patients and colleagues. Unwittingly, the physician joins the sponsor’s marketing team. Why do companies pursue this expensive tactic? Because it works.

This is hardly the biggest problem with Vioxx, as its tendency to kill people en masse via heart problems is obviously a far more important issue. And we all know at this point that Merck made sure to underplay the risks of Vioxx, and that the medical community was also asleep at the wheel when it came examining published studies on the risks of Vioxx. Nonetheless, using the guise of science to recruit naive (or greedy) physicians to serve as Vioxx pushers is contemptible.

Merck was out pushing how wonderfully safe and well-tolerated was via a “study” designed solely to turn “investigators” into top Vioxx prescribers, while at the same time, more and more people were meeting an early end due to this purportedly safe new drug.

For more hot Vioxx action, check out this site.

Update (8-19-08): Check out an interview with Dr. Kevin Hill, lead author of the investigation of the ADVANTAGE trial, over at the Carlat Psychiatry Blog. As always, Pharmalot also has a good post on the topic.

Key Opinion Leaders, Osteoporosis, Vioxx, Psychiatry, Science, and Patients

Remember Richard Eastell? To summarize briefly, he is a professor at Sheffield University who was lead author on a publication that showed positive results for the osteoporosis drug Actonel. One problem: the data did not actually provide good news for Actonel. In a key graph in the published paper, 40% of patient data was missing. Now that's an interesting form of science: Just eliminate the pesky 40% of the data that don't go along with your hypothesis and POOF!, you get exactly the results you are looking for. An excellent writeup of the situation can be seen in Jennifer Washburn's excellent piece in Slate. Making the plot more interesting, Eastell did not have the raw data; Procter & Gamble's (Actonel's sponsor) statisticians were in charge of the analysis. Hence the missing 40% of the data, which helped to cast Actonel in a more positive light. Read more on the topic here. When all data are included, the analysis does not support Actonel's marketing points. Eastell signed off on the original (misleading) paper saying that he had seen all of the data, which was, of course not true.

I noted in October 2006 that Eastell was chairing a session on osteoporosis, one that charged a hefty registration fee. The website promoting the session at the time mentioned: "This course is suitable for pharmaceutical industry personnel from clinical through to marketing disciplines." I suppose that Eastell is a key opinion leader in his field. Being willing to put one's name on a paper where the key graph knocks out 40% of the data is a good step toward becoming an influential academic these days. I suppose Eastell could at least claim ignorance, since he was unfamiliar with the underlying data.

In psychiatry, Charles Nemeroff, a key opinion leader, put his name on a continuing medical education presentation in which the data don't match with the published article that was based on the same data set. In the CME presentation, the medication (risperidone) outperformed placebo, although the published report indicated that risperidone did not beat a placebo, and in the CME presentation, risperidone was claimed to improve sexual functioning, which was never mentioned in the published article.

Eastell and a colleague recently received a roughly $7.5 million grant. Good for them. I've got nothing against the guy personally; I just find it interesting that he is getting rewarded nicely despite the whole Actonel fiasco. And I've only described a wee bit of that strange saga. The Scientific Misconduct Blog has much, much more. Like the part where he told Blumsohn to stop bothering Procter & Gamble about the data because P & G was a good source of income for the university. I've got no problem with excellence being rewarded. Perhaps Eastell has done many excellent things. However, during the P &G/Actonel fiasco, Eastell was willing to let the sponsors push him around, even if science was being bastardized in the process. Their money meant more than good science. And if patients took Actonel thinking that it was more effective than it actually was, who cares -- they're not the ones providing the research funding, right?

Think about this for a second. Many people have been up in arms about the recently unveiled Vioxx ghostwriting scandal. For a fantastic take on the scandal, see Health Care Renewal or Hooked. Briefly, Merck and its associated medical writers wrote manuscripts that said nice things about Vioxx. Then academic authors/key opinion leaders were found to review the papers and stick their names on as lead authors. Mind you, "reviewing" the papers often meant simply meant making minimal edits, if even putting in that much effort. Did they see the data? They saw tables and figures provided by Merck, but did they see the raw data? In most cases, apparently not. Doesn't that make them information launderers? They take industry data, and clean it up with their academic reputation. Oh, Dr. So-and-So is at Sheffield or Emory or Harvard... -- he must have made sure that the sponsoring drug company is portraying the data accurately. A veneer of credibility. And an extra publication for the key opinion leader, which makes the KOL that much more important in the academic world where publication envy runs rampant.

This system is not exactly set up to benefit patient outcomes, is it?

Vioxx Goes The Way Of Zyprexa

An interesting website (www.vioxxdocuments.com) provides a trove of documents related to controversies surrounding Vioxx. Some of them are hot items, containing statements like this:

The much broader issues, which surfaced at the American College of Rheumatology meetings, were most disturbing and involve suppression of data by Merck and a consistent pattern of intimidation of investigators by Merck staff...

Zyprexa documents, Vioxx documents, Neurontin documents, what's next? If there are any bored researchers, journalists, or bloggers out there, start reading!

Hat Tip: PharmaGossip.

Defending the Hiding of Negative Clinical Trial Data

In the wake of the New England Journal of Medicine study that revealed a sizable discrepancy between the raw data on antidepressants and the data published in medical journals, a few people have jumped to the defense of drug companies. In this post, I will examine their arguments and compare them with evidence. As an extra feature, the DrugWonks' disconcerting love of Vioxx will be discussed toward the end of the post.

"Nathan", who posts frequently on the excellent Pharmalot blog, made several comments. Here's one of them:

For those of you that haven’t written up a scientific article for publication, I’ll make you aware of a few things:
1) Journals don’t accept an article just because it is written. Journal editors scrutinize it and submit it to reviewers who further scrutinize it — very frequently rejecting articles that aren’t conclusive or are poorly written.
2) Scientists write scientific articles — not public relations representatives.
3) Scientists generally don’t waste weeks (or months) of their time writing up articles that don’t prove anything and probably won’t be accepted by the journal. A negative result is generally meaningless in science. Do you think Thomas Edison wrote up articles about the 900 filaments that failed to light a light bulb?

Now I’ll ask again: Is it any surprise that the negative clinical trials were not written up as publications?

Here’s one example: The Paxil trial may have tried doses of 10, 25, and 50 mg. The 10 and 25 mg dose failed to show an effect. The 50 mg dose did show an effect. Why should anyone waste their time writing up a journal article explaining why the 10 and 25 mg dose failed? It’s obvious that drug levels just weren’t high enough to observe an effect.

The problems with the above post:

1. Well, let's face it, peer review does not exactly catch everything. In fact, peer review often results in the publication of very poor studies, like the infamous Paxil Study 329. But it actually appears that Nathan's point is that studies that "aren't conclusive or are poorly written" don't get published. So is he saying that the positive studies of SSRIs were more likely to written better than studies that found negative results? Not sure that makes much sense. Perhaps he is implying that a negative study is not "conclusive" -- well, neither is a positive study, for that matter. When one considers the small benefit of antidepressants over placebo, then even positive studies have not exactly yielded conclusive evidence of anything particularly impressive.

2. Nathan is either naive on this point or is being dishonest. It is well known that ghostwriters are frequently used in the publication process (1, 2, 3, 4, 5). This is not a problem when they are just helping a poor writer piece together a readable manuscript, but this is often a huge problem when one considers that ghostwriters often have a huge conflict of interest in that they are hired by drug companies to pen papers that will paint their product in a favorable light.

3. "A negative result is meaningless in science." That is an amazing comment. Truly amazing. So if 10 trials are conducted on a drug, and one turns up positive, then I suppose everyone should prescribe that drug because the nine negative results were "meaningless." Yeah, that makes a lot of sense.

3.5. The point about dosing would make sense except that it is irrelevant to the case at hand. Remember, Nathan is commenting specifically on the antidepressant studies that did not get published, and he is hypothesizing that the authors of that study included doses that were not approved as effective. Perhaps he missed page 253 of the article, which states:

We included data pertaining only to doses later approved as safe and effective; data pertaining to unapproved dosages were excluded.

Oh, so the authors did not include data for unapproved doses. So much for that critique. Reading a study before offering critiques of it: A good idea.

Nathan in another comment:

I understand how this APPEARS to be a smoking gun. But I’ll state again why I believe it is not: Let’s say I do a clinical trial with Paxil at 10 mg (once per day), 20 mg (once per day), 20 mg (twice per day), and 50 mg (twice per day). That’s a total of 4 trials. Only the 50 mg dose works. Are the other three trials counted as “negative” evidence that the drug doesn’t work? Of course not.

See above for why this critique holds no water.

Nathan:

As Bob pointed out, editors like to accept articles that make their journal look good. NEJM is probably not going to accept a bunch of articles about clinical trials that didn’t work. That doesn’t mean the editors are in some sort of under-the-table deal with the company. It simply means that they are looking out for the best interest of the JOURNAL, not the public.

I think we’re all missing the point. Of course scientists like to publish things that work, not things that fail. The point is that ALL clinical trial data (the good, the bad, and the ugly) is available to the public, the FDA, and anyone else interested. Whether or not the data makes it into a journal is irrelevant.

All clinical trial data is available to the public? Cue the laugh track. Turn it up a little. No, a little more still. Ah, there we go. Who is he kidding? There is absolutely no such thing as a repository for clinical trial data. That is part of the reason why the problem with ghosted science exists in the first place. There are clinical trial registries, but go ahead and check out clinicaltrials.gov. One can outline a study on such a registry then report the results in whatever manner one deems fit, or not at all.

Enter the DrugWonks: And, as you would have guessed, the dependable, fair and balanced DrugWonks weighed in as well. Here are pieces of Robert Goldberg's post:

The NEJM of medicine recycles the old story that many of negative studies about antidepressants were not published. That doesn't affect whether the drugs work or not. It does add to the distortion of what a negative study is and why they are negative. Most of the time they are negative because they simply confirm the hypothesis. Other times they are poorly designed or small studies of little statistical power. They don't prove that the drugs fail. There is a difference. Taken together they can often help guide who responds to what medicines or why not...which again is why we need the Critical Path. To suggest that the failure to publish negative studies is part of a coverup is wrong and leads to fearmongering once again. We have been down this road. And journalists are once again raising unfounded fears about the safety and efficacy of drugs...leading people to die because they stop taking medicines because of the fearmongering the media has engaged in regarding vaccines, SSRIs, Avandia, Vioxx and Vytorin

As for the argument that studies were negative simply because their sample sizes were small, please read the following from the article (page 254):

The difference between the sample sizes for the published studies (median, 153 patients) and the unpublished studies (median, 146 patients) was neither large nor significant.

In other words, Goldberg's analysis is wrong. As I stated above: Reading a study before offering critiques of it: A good idea. As for "Most of the time they are negative because they simply confirm the hypothesis." -- What the hell does that mean? Confirm what hypothesis? This is the sort of seemingly random statement that I have run across frequently on the DrugWonks site. As for the negative studies being poorly designed (so the positive studies are thus designed better?), this seems wrong as well. These studies aren't particularly complex. One group gets drug, the other gets placebo. Participants are assigned to groups randomly. In theory, participants are unaware of if they are receiving drug or placebo. It appears that there were not large differences in how these studies were designed. In any case, Goldberg provides not one single shred of evidence to support his claims. Nathan, mentioned above, also provided no evidence to support his critiques of the NEJM study.

Bring on the Vioxx Love. Goldberg then goes to a new level. He wrote, in part:

And journalists are once again raising unfounded fears about the safety and efficacy of drugs...leading people to die because they stop taking medicines because of the fearmongering the media has engaged in regarding vaccines, SSRIs, Avandia, Vioxx and Vytorin

Let's just focus on one of these medicines: Vioxx. I should mention that as I type this, I am quaking with rage. Goldberg is either incredibly ignorant or incredibly dishonest. For a person who claims expertise in matters of drugs, he should know much better than this. He is claiming that people died because they stopped taking Vioxx. He is apparently serious. Lord Jesus, tell me that this man is joking... First of all, how many people have died because they switched from one minor painkiller to another? Bob, please provide the data. PLEASE.

But (and this is where the rage is coming from), Bob, since you are a Drug Wonk, which would imply at the very least a firm understanding of important and highly publicized findings from the medical literature, how many people died because they did take Vioxx? According to a study by David Graham and colleagues published in the Lancet:

Using the relative risks from the abovementioned randomised clinical trials and the background rates seen in NSAID risk studies, an estimated 88000–140000 excess cases of serious coronary heart disease probably occurred in the USA over the market-life of rofecoxib. [If even a third of these people died, well, you do the math...]

But taking this drug off the market resulted in people dying? Are you *!@! kidding me? Because Graham is a "fearmonger," one of the favorite epithets thrown around on the DrugWonks site, how about we not take his word for it... What have other researchers found? One meta-analysis found an increased risk for heart attacks with COX-2 inhibitors relative to placebo and to some other drugs. Another meta-analysis also found elevated heart attack risk for Vioxx. How about this meta-analysis, which found increased risk for both cardiovascular and renal events on Vioxx? Another meta-analysis found cardiovascular events were related to Vioxx use.

So, Bob, there's my evidence on Vioxx. Where's yours? It's clear that Bob and I differ on a number of points. I think reasonable people can disagree on many items, but Vioxx is not one of them. A drug that has been clearly and repeatedly linked to serious health problems -- and Bob is defending it, while calling those who criticize it "fearmongers." Nice game plan.

A More Reasonable Critique. The Last Psychiatrist offers a more reasonable analysis, suggesting that academic authors did not want to publish the negative studies because publishing negative studies would make them look incompetent -- the mainstream culture of medicine would ask who runs a trial and finds negative results? And even if the studies were submitted to a journal, then they were likely to be rejected by peer reviewers and editors.

This may be true to an extent, but I tend to believe that some negative studies would have been published. There have always been journal editors who have some ability to think critically and publish material that runs counter to that of mainstream medicine. Sure, some of the studies would have been rejected a time or two, but I think they would have been published at some point. While I think his analysis is intelligent (and it thankfully does not involve the term "fearmonger"), I think it only offers a partial explanation.

Missing the Boat. I could certainly have missed something, but I have not even seen a lame attempt to critique part of the study that is quite damning. Remember, the study found that drug companies changed their primary outcome measures and statistical analyses in between submitting to the FDA and submitting for journal publication. This resulted in inflated effect sizes for every antidepressant. Kind of a big deal, as the medical literature ends up suggesting the drugs are more beneficial than they actually are. Not even DrugWonks has mentioned this rather major point.

Oh, and one more thing for Bob Goldberg: Before engaging in a variety of tactics that border on slander regarding Roy Poses of Health Care Renewal (in a recent often nonsensical post that I won't honor by linking to it), you might want to improve your own credibility.

If you missed it, read my post about the NEJM study that some folks are now critiquing.

Outrage Inducer

If reading the following story at PharmaGossip does not make you all sorts of pissed off, you need to have yourself examined. It's about how Merck kept Vioxx on the market through the use of slanted science.