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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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June 26, 2006

Vioxx: 18 Months to Trouble?

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Posted by Derek

The latest round in the fit-to-never-end saga of the Vioxx APPROVe trial and the New England Journal of Medicine is here. The journal today released a correction of the orginal paper, perspective article on the statistics of the original study, and some inconclusive correspondence about the (recalculated) risks.

The correction is notable for removing the earlier statements that it appears to take 18 months for risk to develop in the study's Vioxx patient group. And since Merck's made a big deal out of that timing, this has already become the headline story. (I can recommend this overview by Matthew Herper at Forbes).

The perspective article, by Stephen Lagakos of Harvard, may be fairly heavy going for someone who doesn't who isn't statistically inclined. I include in that group - please correct me if I'm wrong here - the great majority of newspaper reporters who might be covering the issue (Herper and a few others excepted). I'm no statistician myself, but I spend more time with the subject than most people do, so I'll extract some highlights from Lagakos's piece.

He has a useful figure where he looks at the two incidence curves for the Vioxx and placebo groups. These are the curves that have been the source of so much controversy: whether or not there was an increased risk after 18 months of Vioxx therapy or not, or if the risk was clear from the outset, and so on. As Lagakos points out, in a slap at Merck's public treatment of the graphs:

"It may then be of interest to assess how the cumulative incidence curves might plausibly differ over time. Doing so by means of post hoc analyses based on visual inspection of the shapes of the Kaplan-Meier curves for the treatment groups can be misleading and should be avoided. A better approach is to create a confidence band for the difference between the cumulative incidence curves in the treatment and placebo groups - that is, for the excess risk in the treatment group."

He does just that, at the 95% confidence level. What it shows is that well past the disputed 18-month point, the 95% confidence band still contains the 0% difference line, and there's room around it on both sides. As he summarizes it:

"The graph shows that there are many plausible differences, including a separation of the curves at times both before and after 18 months, and a consistently higher or lower cumulative incidence in the rofecoxib group, relative to the placebo group, before 18 months."

In other words, the data don't really add much support to anyone's definitive statements about Vioxx risks before 18 months. The 95% band only widens out to a plus or minus 1% difference in cumulative incidence rates at a time between 18 and 24 months. At that point, the upper and lower bounds are both creeping up, though, but the band only rises to an all-positive difference between the two groups at the 30-month mark. By the 36-month point, the last in the study, the 95% confidence band is between a 1% and a 4.5% risk difference for Vioxx therapy compared to placebo.

This doesn't help Merck - in fact, since they've made such a lot of noise about this 18-month threshold, it does them quite a bit of damage. But it doesn't directly help the plaintiffs who are suing them, either - the good news for them is that Merck is looking bad again.

Lagakos goes on to talk about what these demonstrated long-term risks can tell us about short-term ones. Assuming that the risk for, say, 12 months of Vioxx is somewhere between the placebo group and the 36-month figure (a reasonable assumption), these figures will set the upper and lower bounds. The most optimistic outcome, then, is that 12 months of Vioxx does nothing to you at all, compared to placebo, even after another two years of observation. And the most pessimistic outcome is that the Vioxx you took continues to increase your risk the same as if you'd been taking it the whole three years (a damage-is-already-done scenario). Although Lagakos doesn't name these as such, you could call these two boundries the Merck line and the Trial Lawyer line, because they correspond to what each side would fervently like to believe is true.

Combining this with his 95% confidence band plot, you end up with a figure that shows that, within 95% confidence, the excess risk for a 12-month treatment could still range anywhere from zero up to the worst that was seen in the full-term-treatment group. So, because this range still includes the no-effect outcome, you can't conclude that a shorter course of Vioxx was harmful. But because it includes the data of the out-to-three-year group, you can't conclude it's safe, either. And that's really the best you can do. If you're not willing to make those starting assumptions, you can't really say anything about the shorter courses of treatment at all.

This is, I think, a valid way of looking at the controversy, but in the end, it's not going to satisfy anyone. It makes me think that both Merck and the lawyers going after them will either: (a) pick their favorite sections from this article and beat each other with them like pig bladders, or (b) ignore it completely. (I think that the first one is already happening, with the advantage, for now, to the lawyers). If Merck can make a successful counterattack that the data don't show that Vioxx was harmful for shorter doses, either, perhaps they can get something out of this. That depends, of course, on people believing a single word that they say. Which they're making more difficult all the time.

Comments (17) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology


1. John Johnson on June 26, 2006 10:52 PM writes...

And, unfortunately from this statistician's perspective, you've really described the state of the art of drug safety analysis. Basically we generate thousands of lines of adverse event counts and laboratory analysis means and perhaps some vitals and physical exams, and try to graft some p-values on top of some or all of these. Because of the multiple comparisons issue, these p-values are meaningless, and I usually recommend against them. And adjusting your acceptable Type I error rate isn't any good, either, because it's not conservative to say that a drug is safe just because a p-value is greater than 0.05. So essentially we hand it off to an MD and hope they make sense out of it (and usually do so with a lot of time and pain).

We're slowly trying to climb out of this hole by using graphical and Bayesian methods (and the MD's job will never be replaced no matter how fancy we can get), but I don't think we'll be out of it anytime soon.

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2. Still Scared of Dinosaurs on June 27, 2006 9:27 AM writes...

Most of my followup of this issue has come from this blog, so I'm a little hazy on some of the details. That said, however, a few points seem pretty clear. The first is that the results described above are consistent with a real effect that was too weak to detect in the study described. I wonder how this revised interpretation relates to the estimates of 60,000 people dead due to cardio events caused by Vioxx.
JJ is right about the stats of safety, which is why I cringe whenever I see someone post about how some safety endpoint is "not significant". The worst part of safety data for me, though, is the pathetic state of the tools used to handle the data. Meddra is a joke, but one we are obliged to play along with because it's a standard. Clinical lab data NEVER comes through cleanly, and once it's all been fixed in the database there is never a set way of handling the data that maximizes the ability to figure out what's going on. Possibly this is due to the fact that good news almost never comes out of this analysis, but that's not a sufficient excuse especially when it's my time everyone is wasting.
Anywho, the profile of Vioxx, when all is said and done, is one that would support useage in patients with low cardio risk factors who need pain relief but who are are too high a risk of GI complications to support aspirin or ibuprofen. Merck's big failing in the end is that this market wasn't big enough for them.

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3. Jonathan Quince on June 27, 2006 9:28 AM writes...

Combining this with his 95% confidence band plot, you end up with a figure that shows that, within 95% confidence, the excess risk for a 12-month treatment could still range anywhere from zero up to the worst that was seen in the full-term-treatment group.

Doesn't this approach a tautology[*]? After all, I have 100% confidence that Vioxx either is not harmful, is slightly harmful, or is very harmful. (Defining "not harmful" to include negative harm, of course.)

In other words, "we don't know" (at least from this batch of data). This is, after all, the conclusion you essentially reached at the end of your penultimate paragraph.

In a rational world, this should help Merck---since AFAIK, the charge is that they marketed the drug when they knew or should have known it caused harm, including short-term harm; but in the world where we live, it will probably hurt Merck, since evil pharma companies aren't supposed to market anything that isn't absolutely zero per cent risky. (The public evidently labors under the misapprehension that pharmaceutical development is theoretical mathematics.)

[*] Unless we allow that short-term use may cause more harm than long-term use, which is possible but approaches silliness.

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4. Jonathan Quince on June 27, 2006 9:40 AM writes...

Ugh. Looking back, it appears my conclusions belabor a point already well made and well known.

There is nothing new under the sun. Merck is doomed. Carry on your business as usual.

Disclaimer: I take Celebrex. I have informed my relatives that if I die of a sudden heart attack and they sue the manufacturer, I will come back as a ghost and haunt them quite terribly. That I had to do so is worrisome by itself.

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5. tom bartlett on June 27, 2006 9:43 AM writes...

And, gee, if you gave aspirin AT OSTEOARTHRITIS DOSES over 18-24 months, does anyone doubt we wouldn't see MORE adverse events? But, with asprin there's no one to sue.

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6. Daphne L on June 27, 2006 11:46 AM writes...

The below interesting perspective was posted in comment on pharmagossip. The link (given as a conflict) at the bottom is well worth exploring and explains why this is important.

There were seven academic "investigators"
(including first author) on the APPROVE paper.
We hear that Merck cheated the results.

Where were those authors?

Did they see the raw data?

Did they perform statistical analyses themselves?

If not why not?

If statistically incompetent did any authors think
to send data to a third party statistician for

If not, why not?

If they did, how is it possible that this
could have escaped undetected?

Is this research misconduct?

Merck used these investigators to give
research a veneer of University respectability.
All seemingly accepted what the company said with
blind faith (as do the regulators).

How long before Seeger and Lanier name one of
these paid "academic" authors or a University as chief respondent in a case? This might usefully sharpen some minds out there.

Aubrey Blumsohn

Conflicts of interest:

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7. James Powell on June 27, 2006 12:05 PM writes...

The whole thing to me smacks of stupidity on the behalf of trial lawyers, who see $$$ because their clients were too stupid to read the full instruction sheet for the drug.

I am reasonably sure that ALL drugs have side effects. Even Caffeine. They have the desired effect, and then there are risks associated with each and every drug.

If Merck knew about the side effects and they were signifigant, then they are at fault if they did not disclose them in the entries and the safety/effectiveness/side effect sheets.

If however, the science of statistics cannot reasonably (call it 66% certain) that events are the result of the drug in what is a relatively small scale usage, then it is reasonable to assume the drug is safe ENOUGH to continue on with trials or usage. If there are concerns that an event may be happening, but is being hidden by the dataset available, then it is prudent to select and follow a dataset that will allow a yes or no answer to the question. (this is science in action, no?). If the data requires 36+ months to get the answer, and the answer is not a large statistical event (which I tend to think in Vioxx's case is true), then it is a risk judgement as to if to release the product without the further testing being complete. In the case of drugs, this decision is made by several organizations with the data available to them (FDA and the company).

If it was disclosed, then it is too bad, at some point we (all people) have to take responsibility for our choices. There are risks associated with life. The prime one is death. It is GOING to happen...accept it, get over it...If you want to be pain free from arthritis, then you may be shortening your life to make it more enjoyable... If you don't want to shorten your life, then you have to deal with the pain and loss of movement...Choice is yours.

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8. Hap on June 27, 2006 12:34 PM writes...

Do I have this right?

Good news: there doesn't appear to be a significant efect of Vioxx on heart attacks over a substantial period of time.

Bad news: it's not clear that people can trust Merck on its handling of Vioxx.

This doesn't seem to be a good outcome - it seems a lot like the public confidence issues that chemical companies and the nuclear power industry have had in their history, and which have not been successful solved by either. Even if you do people lots of good, if people don't feel they can trust you they're not going to like you. Lawyers feed on mistrust like sharks on chum.

Also, while people should inform themselves about the safety of a drug, if doctors, scientists, and statisticians can't agree on whether risks exist for Vioxx, how do you expect the average person (or doctor) with less information and time to understand those risks and account for them? This sounds too much like my dentist and dental plan expecting me to know more about their procedures and coverage than they do - a way to offload costs and risk onto consumers.

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9. Derek Lowe on June 27, 2006 12:42 PM writes...

Not quite right. We can't say yet if there's an effect on cardiac risks for short-term Vioxx use. Can't say it's good, can't say it's bad, can't even say that it's the same. The data won't let us draw that conclusion.

But Merck has been trying to make that statement, so you're right, this does undermind confidence in them and their statements, which is something they really can't afford.

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10. OnceAChemist on June 27, 2006 2:52 PM writes...

Is the discussed Lagakos data only hypothetical? See his Fig. 1 - "Hypothetical 95 Percent Confidence Band...Constructed from the Results..."

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11. Morten on June 28, 2006 12:00 AM writes...

If people really think pharma companies are evil then they should do 40 minutes of good cardio, 3-4 times a week. Now that would really hurt pharma's income...

I still don't get why it isn't a problem for the FDA if Merck loses the majority of these trials though?

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12. Insider on June 28, 2006 9:07 AM writes...

The risk doesn't begin after 18 months.

This would be analogous to saying that daily sunbathing for 18 months poses no risk for melanoma if no melanomas are detected during that time, and that the risk doesn't begin until the melanomas are first discovered.

The risk is present from the beginning but only evident at 18 months.

This analogy comes from a piece by Robert Burton MD.

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13. tgibbs on June 29, 2006 10:04 AM writes...

Depends upon your risk model. For something like melanoma, the damage is done when the first cancer cell is produced, but it may take months or years for the harm to be apparent at a clinical level. If the cardiovascular risk of Vioxx is due to something like effects on blood clotting, then the risk would presumably vanish pretty soon after the drug left your system--if you didn't have a heart attack while you were taking the drug, you dodged the bullet. This would lead to a constant risk per unit exposure time model, in which case the risk/benefit ratio might be substantially more favorable for short-term use than long-term. However, if Vioxx did something like affect the deposition of cholesterol in arteries, then it might be more like the cancer model, with a risk that persists long after treatment is terminated. One could also imagine a cumulative damage model, in which risk increases more than linearly with time. Or a model in which the risk is high initially and declines later on, as that Canadian study suggests.

Basically, what the revised analysis indicates is that the evidence simply does not provide a strong basis for favoring one risk model or another.

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14. tgibbs on June 29, 2006 4:36 PM writes...

One odd thing about Vioxx is the number of people I've met who insist that Vioxx is a miracle drug (often using those very words). The story is always the same--they had severe joint or back pain that nothing would touch, they took Vioxx for a week or two and the pain went away and never came back. I've never heard such testimonials other NSAIDs, not even other COX-2 drugs like Celebrex or Bextra (which shares with Vioxx the cachet of now being unobtainable). I've had people tell me that they are hoarding their last few Vioxx pills. Nothing I've seen in any of the studies on Vioxx seems to support such a dramatic effect--it seemed to be just another NSAID with a lower bleeding risk. But after hearing such anecdotal accounts from a number of people, I start to wonder if their is a subpopulation for which Vioxx works particularly well.

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15. Still Scared of Dinosaurs on June 30, 2006 12:27 AM writes...

Even with a risk model where there is a very high risk for a short time followed by a long period of equal risk it could take a long time for enough events to appear. It's possible to think of drug effects that would produce this pattern if tolerance develops, but I have to admit I've never actually worked on a drug that did it.
This effect would be easier to spot in the Kaplan-Meier plots, or even with simple freqs of events per time window, than the increasing risk with time scenario, but both would violate the assumption that the risk ratio of the groups is constant over time.

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16. michael on July 3, 2006 1:31 AM writes...

Interesting comments from people at heartwire (I will post here because it is behind a password):

"They overinterpreted survival curves to conclude there was an 18-month delay in cardiovascular risk," Dr Curt Furberg (Wake Forest University School of Medicine, Winston-Salem, NC) told heartwire. "In their test for proportionality, they used the wrong p value and the data do not include an intention-to-treat analysis. But that is being corrected now," Furberg, who has served on Food and Drug Administration committees evaluating coxibs, said. "The error is troubling, and I don't know why it happened."

This is not the first time the journal has issued a correction on rofecoxib data. In December, editors recommended changes to cardiovascular data in the largest rofecoxib study—the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial. Now problems appear in the publication of the Adenomatous Polyp Prevention on Vioxx (APPROVE) trial.

"This latest correction is not something that could have been picked up by a review panel," executive editor Dr Gregory Curfman told heartwire. "Our editing procedures are rigorous, tight, and vigilant." He says that short of recalculating results, many details have to be left to the integrity of study authors. Curfman and managing editor Dr Stephen Morrissey did not speculate as to whether or not they were misled, but they note that the researchers report having made an honest mistake.

"At present, these investigators and the company don't look very good in the eyes of the medical community," Furberg said. "This illustrates the difficulty for reviewers. It demonstrates how authors have total control over what is reported, and reviewers and journals are at a disadvantage."

"I'm losing some trust in industry-sponsored trials, and I think we have to be very careful," Furberg said. "There are more data to come, and we will also be looking at drugs such as celecoxib [Celebrex, Pfizer]; so far, the data there are suggesting it is not very different."

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17. Dennis Harrison on November 28, 2007 8:29 AM writes...

VIOXX – Should there be a ROUND 2?
What about alleged bone/spine healing problems?

Sources for the following quotes are towards the end of this writing:

... Cox-2 inhibitors effect fracture healing and spine fusion… should never be used in spinal fusion…
... impair fracture healing… due to the inhibition of Cox-2 and not COX-1! Vioxx is a Cox-2 inhibitor…
..."It's time to tell the public," concludes Dr. Thomas Einhorn…
... It could affect the billions of dollars in sales of the COX-2 inhibitors if people knew they…
…cox-2, which causes pain and inflammation, also appears to play a crucial role in bone healing…
..."a prudent approach" is to temporarily quit using either NSAIDS, Vioxx or Celebrex if you break a bone…
... calls for targeted research on broken-bone sufferers…

While the emphasis has been on heart and stoke (alleged) issues; one may be quite surprised that there is, as researched and (allegedly) experienced by this writer, bone and spine healing issues that have not (allegedly) been addressed by Merck. It is NOT a small issue, and potentially impacts tens of thousands of people who, even today, don’t know why their spine operation did not heal correctly, or why after many months a leg would not heal. This writer feels very strongly that Merck (allegedly) knew, or should have known, that there were bone and spine healing issues which should have been addressed. If you are interested in some related, and in general consistent enough to be compelling enough to scream a warning, do some Google searches on the following:

vioxx bone spine healing
cox-2 bone spine healing
fracture bone spine healing Vioxx

and remember this:

1 – there are over 1 million fractures per year requiring hospitalization (United States Bone and Joint Decade, NFP
6300 N. River Road, Rosemont, IL 60018).

2 – with the sales of Vioxx having been so high (approximately 20 million users), it is not hard to interpolate tens of thousands of individuals have been severely impacted by Vioxx – and they don’t even know how it might (allegedly) have happened! Furthermore, consider that there is still a cox-2 inhibitor on the market (Celebrex); AND others drugs in the same class have attempted to get to the market (ARCOXCIA/Merck; PREXIGE/Novartis). These “newer� Cox-2 inhibitors are likely to attempt approval again as the Vioxx settlement works its way through..

Bone and Spine healing (alleged) problems with Vioxx – time for Round 2?

Just one Independent Research (IR) snippet - more follow: there are hundreds representing many studies PLUS a quite logical analysis (also called the Science of Vioxx) of the bone/spine healing process by so many well respected surgeons (who also do research) and professional researchers, etc. This writer just cannot understand how Merck could (allegedly) just blithely ignore the (alleged) issues without even formally establishing a position on them or doing their own research. After all, Merck, with all of its development on arthtiris and bone medications (Vioxx, Arcoxcia, Fosamax) should be considered – one would think – subject matter experts on the bone and spine healing and regeneration process. Unfortunately for the public – Merck has (allegedly) successfully swept the issue(s) under the rug and radar; with severe consequences for many people, but with many benefits (allegedly) for Merck.

In fact, the 2003 Merck Manual very well describes the healing process – certainly a good enough description to logically assume that they (Merck) allegedly would (and should) have been at least wary of the cox-2 inhibitors! I may be wrong; but it seems that the Merck description of the bone/healing process seems to have worked its way out of the manual – if I am right, seems like interesting timing…

Just one of the hundreds of Google “hits� that may be of interest…

MAY 21, 2002 - JOURNAL OF BONE AND MINERAL RESEARCH - COX-2 DECREASES BONE HEALING? - mechanical testing revealed that COX-2 inhibitors…reduce bone strength ((in healing) – note by this BLOG’s author))…expression of COX-2 is critical for bone healing…essential for fracture healing…the inhibition of prostaglandin synthesis stops normal fracture healing;

I maintain that the responsible action would have been to announce the (alleged) bone/spine concerns when Vioxx was taken off of the market. (Allegedly) Merck knew, or should have known, enough to have at least more than a passing interest in the problem and should have taken a position. Instead, “this muddy picture," (as termed by Dr. Scott Reuben of Baystate Medical Center in Springfield, Mass. (and of which one of my own surgeons referred to in a similar way), was allegedly maintained by Merck rather than provide any kind of caution, warning(s), consumer or physician education, etc. Nope – this was one issue that apparently and allegedly was better just to keep “muddy� as long as possible….delay creates confusion and allows red herrings to become a strategic tool for profits.

The Public needs to demand that Merck acknowledge the (alleged) bone/spine healing issues, NOW, and that the STATUTE OF LIMITATIONS clock be reset for potential bone/spine litigants. Because this was not done when Vioxx was taken off of the market, Merck (allegedly) most likely avoided many (thousands) more lawsuits. This also would have made their general publicity much worse, and perhaps juries would have seen (allegedly) not one, but a pattern of alleged neglect and deceit by active concealment, as well as the other charges. If this had happened, the value of the heart/cv/stroke “settlement� quite likely would have been higher. But let’s get back to the bone/spine (alleged) problems – ROUND 2. I have made some initial, and conservative, estimates of how much Merck’s liability could be on the bone/spine problem(s), and it is not a pretty sight for Merck – perhaps that is why Merck has (allegedly) been successful in the past of (allegedly) concealing the issue.

I have become versed and researched on many of the issues as I continue to pursue my own, “pro se� litigation (attorney’s ONLY wanted to take cases which were heart/CV/stroke oriented – I better not get started on that subject also but I have come to understand why – and it’s not what you would be told…). I continue to work to have the public, and attorneys across the land, become aware (and motivated) of the bone/spine healing problems, but it is a slow process. After all - it has been much easier (for an attorney) and offers much less risk submitting a lawsuit and letting the PSC within the MDL do the “heavy lifting Discovery� of “common issues�, than actually do original DISCOVERY and conduct a jury trial. As of yet, I have not reached the critical mass (of Public awareness) needed for logical and responsible actions to be put into motion (i.e. Merck – Round 2), I look to make significant progress in 2008.

How about this idea – if indeed the “settlement� is approved with its 85% threshold, the legal community (esp. the Plaintiff’s BAR) should now tackle the bone/spine alleged problems, at least a solid, and sxxxxxx preliminary investigation to understand the issue(s) and the potential number of impacted individuals. In this case (vs the heart) the causation issues would seem a bit more direct to understand and prove on a case by case basis. And while they are at it, perhaps it is appropriate for a review of Celebrex (another Cox-2 inhibitor) along the same lines

As mentioned above, it is (allegedly) likely that (tens of thousands of) people, in the past (Vioxx) and CURRENTLY (Celebrex), were (are) being adversely impacted. It is about time that both Merck (and Pfizer/Celebrex) finally takes a comprehensive, cohesive, position on Cox-2 inhibitors and their (alleged) bone/spine healing problems.

…there were, and are, other factors that should have caused responsible actions but allegedly failed to - thus the issue(s) would remain in never never land! It certainly would seem that even just the general industry “wariness� (of Cox-1 inhibitor concerns) SHOULD have motivated Merck to address the matter with Vioxx (as well as its new proposed Cox-2 inhibitor entry – Arcoxia). Wouldn’t you think that they would be the SUBJECT MATTER EXPERTS! There seems to be no reasonable explanation as to why Merck did not tackle the mounting Independent Research (IR), the very scientific explanations, and general industry wariness of early generation of Cox-1 inhibitors (which also, by the way, were(allegedly) not treated in an open or fair manner.

Back to Vioxx, just a small sample of the Independent Research (IR) that Merck (allegedly) just simply ignored and (allegedly) apparently hoped would just fade away. By the way, (allegedly) there were NO warnings, nor public or physician education on the bone/spine healing issue(s)…

REPRINTED FROM: WWW.USATODAY.COM/NEWS - "It's time to tell the public," concludes Dr. Thomas Einhorn, Boston University's orthopedic surgery chairman (Einhorn, A PAID CONSULTANT for Vioxx maker Merck & Co. and Celebrex maker Pharmacia Corp)….New research suggests some of the most widely used painkillers may delay healing of a broken bone… "If it were my fracture ... to me every day counts," he says. Vioxx and Celebrex are among the culprits…. the makers of Vioxx and Celebrex deny any link. Comment by author – a paid consultant’s for Merck and Pharmacia (at the time) is apparently not even followed up with….apparently his results were not what they wanted to see…

Copyright 2002 The Associated Press. All rights reserved. …O'Connor says his findings prompted some colleagues to withhold cox-2 inhibitors from broken-bone patients … Arthritis Foundation… urges more research... surgeons made the surprise discovery a few years ago that high doses of the intravenous NSAID Toradol delays spinal surgery healing… a recent British study concluded using NSAIDS was the biggest factor in delayed healing of a broken leg. …"It is confusing. ... You see this muddy picture," says Dr. Scott Reuben of Baystate Medical Center in Springfield, Mass., who conducted that study -- and calls for targeted research on broken-bone sufferers… It's an important question, as more Americans regularly use Vioxx, Celebrex and other anti-inflammatory painkillers called NSAIDS… Doctors increasingly offer bone surgery or fracture patients higher and higher doses of such painkillers in place of narcotics… At issue is the discovery that an enzyme called cox-2, which causes pain and inflammation, also appears to play a crucial role in bone healing. …Einhorn, a paid consultant for Vioxx maker Merck & Co. and Celebrex maker Pharmacia Corp (at the time)….despite the companies displeasure…concludes "a prudent approach" is to temporarily quit using either NSAIDS, Vioxx or Celebrex if you break a bone.

"If you don't know, you should err on the side of caution." – (my comment – apparently and allegedly, Merck decided not to err on the side of caution!).

COX-2: WHERE ARE WE IN 2003? - THE ROLE OF CYCLOOXYGENASE-2 IN BONE REPAIR - EINHORN TA. PROFESSOR AND CHAIRMAN, DEPARTMENT OF ORTHOPEDIC SURGERY, BOSTON UNIVERSITY MEDICAL CENTER, BOSTON, MASSACHUSETTS - both non-specific and specific inhibitors of cyclooxygenases impair fracture healing - but that this is due to the inhibition of Cox-2 and not COX-1! Vioxx is a Cox-2 inhibitor. "It's time to tell the public," concludes Dr. Thomas Einhorn;

“Somehow, this study flew under the radar,� SAYS JASON THEODOSAKIS, MD, MS, MPH., AUTHOR OF THE ARTHRITIS CURE (ST. MARTIN’S PRESS 2004). This information is unlikely to be broadcast by pharmaceutical companies, he explains: “It could affect the billions of dollars in sales of the COX-2 inhibitors if people knew they might be destroying cartilage while they’re trying to relieve their pain.�;

FEBRUARY 02, 2005 - HSS PHYSICIANS REVIEW LITERATURE ON THE SAFETY OF COX-2 INHIBITORS - COX-2 inhibitors effect fracture healing and spine fusion… should never be used in spinal fusion;

The unnecessary victimized (including myself!) who's bones and/or spines didn't heal correctly, or even at all, never even knew what hit them! We didn’t even have a warning – not even a chance to make an informed decision on the pros and cons ourselves. Pathetic, on our backs (and the heart victims) we carried the weight of Merck’s (alleged) ill-gotten gains. Certainly I would have not taken Vioxx if I were to at least have been warned! Especially sad is that the period in question generally revolves around the first three or four weeks of healing – not really a very long time.

POSSIBLE OTHER PUBLIC CONERNS! – taken from a Vioxx Blog…
You may or not know it, but there are also emerging (alleged) issues and litigation with bio-phosphates, such as FOSAMAX and how it impacts the natural, healthy process of bone regeneration. The process of bone/spine healing, as well as natural, healthy bone regeneration is not hard to understand. It has already been alleged, and there are active lawsuits, that FOSAMAX can prevent the jaw from healing after a tooth extraction (bone dies - the issue is called “Dead Jaw�). This should cause one to ask this question - what about FOSAMAX's relation to other bones? Furthermore, what if some one took VIOXX, or another Cox-2 inhibitor, and FOSAMAX at the same time? Since both work basically by interfering with the body’s natural reaction of bone repair and healthy regeneration - could the problem be even worse with concurrent use – which did and does exist?

Take the time to understand the process and I believe that you would shutter at taking a Cox-2 inhibitor (not only Vioxx – but how about Celebrex and the other “proposed� Cox-2 inhibitors) and something like FOSAMAX concurrently – especially since FOSAMAX can stay in the bones for about 10 years!

This is (potentially) an explosive issue that should be addressed now, not later after the (potential) massive damage. A little bit of “preventive medicine� is certainly due here – and wouldn’t you think that Merck and Pfizer (and by the way – Novartis), being the “bone experts� should have already have had position(s) on this? Also, any degree of reasonableness and safety concerns would cry out for post-marketing monitoring. My gosh, it is only common sense and what you would expect of “world class� organizations!

VIOXX, and all COX-2 inhibitor drugs, work by inhibiting the body's natural response to inflammation and bone repair. FOSAMAX works by interfering with the natural, healthy process of bone regeneration. Doesn’t that sound like a potentially dangerous combination? It begs other questions. (1) What might be the impact of FOSAMAX (also produced by Merck!) on bone healing and what about the concurrent use of VIOXX and FOSAMAX? Incredibly, both drugs have been produced by Merck! Shouldn’t Merck (allegedly) have a formal opinion on concurrent usage, especially during the bone/spine healing process by now?Also, how about some kind of testing and Post Marketing follow-up? Also, since Celebrex exists today and it is also a Cox-2 inhibitor, what about current concurrent use (Celebrex and Fosamax)? Shouldn’t the maker of Celebrex (allegedly) also have a formal opinion about this, as well as some kind of testing and Post Marketing follow-up?

And remember when you see a person, deformed and suffering (allegedly) because he/she was not warned (and nor were the physicians) of using Vioxx during bone/spine healing....

"there but for the Grace of God, go I".....

Dennis Harrison
Pro Se – Bone/Spine healing
Harrison v Merck & Co, Inc. case, Civil Action No. 07-905

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