Wednesday, April 30, 2008

Remember the January 23, 2008 FDA-Mandates (Ordering REVISIONS to the Zetia/Vytorin Advertising Materials)?


Or. . . . Your 90 days are. . . . over!

Well, in the last few days, the Schering/Merck website has begun to implement the FDA January 23, 2008 mandates (click on the small FDA letter image, below right, to read those mandates) -- The quote below is from the last line, on the first page, of the NEWLY-REVISED Vytorin web-advertising; the second paragraph (in blue, below) is from the Zetia page, on that same site [Emphasis below, is as it appears in the original]:

". . . .VYTORIN contains two cholesterol medicines, Zetia (ezetimibe) and Zocor (simvastatin), in a single tablet. VYTORIN has not been shown to reduce heart attacks or strokes more than Zocor alone. . . .

[Ed. Note -- And, from the new Zetia page:]

The most common cholesterol-lowering medicines, known as statins, work mainly with the liver. ZETIA works in the digestive tract, as do some other cholesterol-lowering medicines. Statins are a good option. As you can see in the animation above, ZETIA works differently. Now there are some other medicines, such as fibrates, bile acid sequestrants, and niacin, that work in the digestive tract to help lower cholesterol, but ZETIA is unique in the way it helps block the absorption of cholesterol that comes from food. Unlike some statins, ZETIA has not been shown to prevent heart disease or heart attacks. . . .
"


Wow. I'm going to pay up to four-times more, at least here, in the U.S. (where about 80 percent of the sales of Vytorin/Zetia were generated, last year), for Vytorin/Zetia, but Schering's website tells me that, unlike statins, it "has NOT been shown to prevent heart disease." Note particularly this sentence, as well:

"Statins are a good option." Wow.

Then, on the Vytorin page aimed at "people already taking Zocor", we read this, right near the top of the very first page:
"VYTORIN contains two cholesterol medicines, Zetia (ezetimibe) and Zocor (simvastatin), in a single tablet. VYTORIN has not been shown to reduce heart attacks or strokes more than Zocor alone. . . ."

[The same language (immediately above, with the same emphasis) appears on the page aimed at people taking Lipitor or Crestor -- and it even still refers to "Zocor" -- hmmm -- that seems like a typo, no?]

These revisions are almost word-for-word, what FDA earlier wrote it would expect Schering/Merck to say, in order to avoid "misleading" the public, post ENHANCE. And now -- the object-lesson, here? When the regulator holds your license-to-sell in its hands -- it has quite a bit of negotiating ju-ju, no?

I am, quite frankly, uncertain as to how a salesperson for the Joint Venture product(s) would go about handling any doctor who, during a sales-call, took even one moment to point these web-pages out, to that sales representative [shivers!]. Said another way, it would seem a very tall-order to "talk around" these recitations, in one's own marketing materials -- especially that the competitors' products (at a fraction of the price!) are a "good option."

And, of course, it remains a largely-open question as to whether, and for what purposes, these now very-public changes and revisions will be admissable as evidence in the various RICO/consumer fraud lawsuits now pending against Schering, and Merck, and the joint venture each helps operate.

8 comments:

Anonymous said...

The new language pointed out in web ads are truthful but more data points are needed: Condemning Zetia because "it has not been shown to prevent heart disease or heart attacks" is like saying, "Mary jumped in the pool and forgot to bring her jumprope."

Say you measure the temperature for two days in May and two days in July and compare them. By chance, the two days in May are hotter than two days in July. This is very possible. The authors conclude that May is a hotter month than July. Would you agree? Wouldn't you need more days to be examined for a more thorough picture? Wouldn't you be quite certain that July is hotter? The authors did not look at enough data to convince you. What they were looking for evades your understanding. More data points are needed for clarification.

Your arguments do not reflect a complete understanding of the issues. Enhance is a very low resolution JPEG. Another picture is needed with higher resolution to make sweeping generalizations about the ability or lack thereof of Zetia in generating plaque regression.

There are certain quirks with the study design and results that make it difficult to understand. The patient population, by virtue of their severe condition can not be associated to the general population. The P values of the IMT results were P=.29. (Remember your P values?) The patients started with normal IMT and ended with normal IMT. (How do you do better than normal?)

Consider this: Enhance was not an "outcomes" trial. There were not enough patients to predict morbidity and mortality. 720 patients does not an outcomes trial make. On the other hand, Simvastatin - Zocor has 25,000+ patients in trials spanning many years and has shown "outcomes" or direct reductions in cardiac events. Zetia has not been marketed to "reduce plaque" but to reduce LDL.

The primary target for reduction of cardiac events (morbidity and mortality) is lower LDL. This standard is set via years of study and exhaustive review by many researchers whose results are compared and analyzed as evidenced in the ATPIII guidelines from the NCEP.

From www.NHLBI.nih.gov/about/ncep: The National Heart, Lung, and Blood Institute (NHLBI) launched the National Cholesterol Education Program (NCEP) in November 1985. The goal of the NCEP is to contribute to reducing illness and death from coronary heart disease (CHD) in the United States by reducing the percent of Americans with high blood cholesterol. Through educational efforts directed at health professionals and the public, the NCEP aims to raise awareness and understanding about high blood cholesterol as a risk factor for CHD and the benefits of lowering cholesterol levels as a means of preventing CHD.

Zetia lowers LDL and it does it extremely well in the combination with Zocor called Vytorin. Lower LDL has been shown to reduce events. Its about LDL. Drugs that lower LDL probably lower cardiac events even though outcomes data has not been generated. Ask this question: Did physicians use Lipitor or Crestor before there were outcomes data? (Of course they did because lowering LDL is directly related to lower cardiac events. Until Lipitor had its own "outcomes" data, it had not been shown to prevent heart disease or heart attacks either. Crestor is just now getting "outcomes" data yet no one is pointing out that until that data is reflected in their marketing materials, Crestor "has not been shown to prevent heart disease or heart attacks".) Lower LDL using statins appears to be a "class effect" ie, all statins lower LDL and by association, lower Cardiac events.)

(There are other so called "pleiotropic" effects that may contribute to lowering cardiac events. These are related to the role of inflamation in the vessels and measures like Crp among others. Zetia lowered Crp in the Enhance trial)

There may, in fact, be a sweet spot with the whole Enhance fiasco. Patients who were extensively pre-treated with statins before starting Enhance, may provide a clue as to how the whole plaque regression model works.

Questions are legitimate but they must be meaningful correct questions. The usefulness of discourse can not be ignored and Enhance is creating a climate where these questions will be asked. To criticize Vytorin based on price as if it provides no added benefit, when it in fact lowers LDL better than the generic alone, is unwarranted.

The value of Enhance is being ignored in the face of media toxicity. Zetia may not have been "shown" to prevent heart disease or heart attacks but it has been shown to lower LDL and lower LDL is related to lower events. It is never a good idea to throw the baby out with the bath water.

Take a look at Evan Stein's perspective in Clinical Chemistry. "After Enhance - is more LDL cholesterol lowering still better?' www.clinchem.org/cgi/reprint/clinchem.2008.104893v1.pdf or www.ncbi.nlm.nih.gov/pubmed/18403568

Mary may have forgotten her jumprope but the important thing is whether or not she learned to swim.

Best Regards.

the condor said...

This is truly an excellent comment. Thank you, Anon. no. 1! It is well-thought-out, and carefully-stated. I may, later today, feature it in a separate post -- but for now, let me offer a few thoughts. First, you wrote:

". . .Zetia lowers LDL and it does it extremely well in the combination with Zocor called Vytorin. Lower LDL has been shown to reduce events. It[']s about LDL. . . ."

I think the main source of our quarrel here, is that the data thus far adduced would suggest that the WAY Vytorin/Zetia lowers LDL, through the gut -- may, emphasis MAY -- not have any salutory effect on outcomes. What is plain, from numerous outcomes studies, is that removing LDL from the liver (the older, statins', mechanism) DOES have a salutory effect on outcomes (lowered heart attack risks). And yet, it seems, statins do NOT lower the patient's LDL number, per se, nearly as much, on an absolute scale, as Vytorin/Zetia does. [A puzzle, that.]

But what good is a lower LDL reading, generated by Vytorin/Zetia therapy (a pure numbers-game, that!), if my heart-attack risk RISES, albeit only very-slightly? That is what I'd like an answer for. We both concede that is an open question.

Similarly, now, from yours:

". . .To criticize Vytorin based on price as if it provides no added benefit, when it in fact lowers LDL better than the generic alone, is unwarranted. . . ."

As discussed above, what we do not know -- what is an open question -- is whether the WAY Vytorin/Zetia lowers LDL actually provides any incremental benefit as to outcomes. That is what IMPROVE-IT will show (or not show) sometime in 2012. So, between now and then (2012), I think it entirely appropriate, and "FAIR", to evaluate these competing drugs on their relative costs -- where one does have favorable outcomes-data for its LDL lowering mechanism (statins -- liver) and one does not (Vytorin?Zetia -- gut).

That seems fair to me. The central error, on the part of Schering and Merck, it seems to me, was launching this product (Vytorin) without any outcomes data.

History has proved statins work -- so launching them, without the benefit of favorable outcomes studies, turned out to be a good bet. But once they got the outcomes data, the playing field shifted -- and, now we won't know until 2012 whether Vytorin was a good bet, for certain, but we do NOW know it PRESENTLY costs a lot, especially compared to these generics.

And the generics seem to work.

QED.

Please do return to point me to my errors, and thanks again for such a thoughtful, and thought-provoking, comment.

Anonymous said...

I wonder what SP would have said about ENHANCE if the result had gone their way

the condor said...

Hey Anon. No. 2 -- Schering would probably have said that Vytorin could cure cancer and AIDS. . . .

Wait, didn't they already make those claims, here?

Heh! More seriously, though -- you are right -- the Schering marketing gurus would be beating the drums without cessation, on TV -- at the Super Bowl, the NBA Finals, and the World Series, next fall. To say nothing of the NASCAR track -- Wait! -- Claritin is already all over that venue, just like a shiny cheap suit. Yep.

Thanks for the comment! Do stop back by, from time to time.

Anonymous said...

Ahhh, polite discourse. Delightful.

Yours: I think the main source of our quarrel here, is that the data thus far adduced would suggest that the WAY Vytorin/Zetia lowers LDL, through the gut -- may, emphasis MAY -- not have any salutory effect on outcomes.

Absolutely correct, but do not leave out the other half of the equation. The addition of ezetimibe to a statin MAY have a positive effect on outcomes. It certainly has a positive effect on LDL so it is logical to wonder whether the same relationship exists with this combination as exists in twenty years of study of statins alone. It will be interesting to find whether an alternate lowering mechanism does the job.

Enhance patients were not statin naive. Is this an important clue? This fact may well have played a roll in the FLAT IMT measurements. We will, as you point out, have to wait until IMPROVIT comes out.

In the mean time, look into the SANDS trial: Stop Atherosclerosis in Native Diabetics Study - www.jama.com Jama 2008: 299(14): 1678-1689. Zetia was added to some regimens. Although not an outcomes trial, regression via IMT was seen. (Have you seen Ms. Couric discuss this study? Why not? Who will ask what are the politics of Mr. Nissen appearing with Ms. Couric the day after Enhance was released?)

In a normal research world, this study would have been ignored (P values again), reviewed and analyzed by peers (not analyzed in public by people who do not care to delve into this great detail, but desire only to slash the feather pillow with a knife, shake it and leave the room) and published with all the data in a proper journal. Do not be misled by the hidden agendas that may be lurking, unseen (admittedly by both sides).

Yours: But what good is a lower LDL reading, generated by Vytorin/Zetia therapy (a pure numbers-game, that!), if my heart-attack risk RISES, albeit only very-slightly? That is what I'd like an answer for. We both concede that is an open question.

Did your risk really rise? Why do you dismiss the importance of the P value? The IMT changes are not significant. Again, how do you do better than normal?

From www.lipid.org: Although no significant CIMT regression was seen in the selected population of 720, the majority of whom (over 80%) had previously been treated for FH with statin therapy, no adverse outcomes were seen, either.

Also: Although this trial showed no benefit in reducing carotid IMT by the combination of simvastatin and ezetemibe, it did show that ezetimibe lowered LDL-C and apo B as expected. The ENHANCE trial demonstrated a 16% greater reduction in LDL-C in the combination group compared to the simvastatin-alone group over the 24-month period as well as an 18% greater reduction in hs-CRP.

Remember Enhance was NOT powered as an outcomes trial and no outcomes can be claimed by the manufacturer. If you play by the rules, you can not make reverse outcomes complaints either. Serious researchers will look for more information and not jump to conclusions. It is premature to insist that your risk is rising.

Yours: I think it entirely appropriate, and "FAIR", to evaluate these competing drugs on their relative costs.

Fair enough. Zocor is less expensive, Vytorin is more expensive. Zocor treatment gives you less LDL reduction. Vytorin gives you more LDL reduction. You get what you pay for.

Yours: The central error, on the part of Schering and Merck, it seems to me, was launching this product (Vytorin) without any outcomes data.

Research the costs of bringing a new drug to market. Add the additional costs of outcomes data. Question whether this incredible outlay would result in the drug ever being sold. Outcomes take time and money. Lots of money. Once the drugs pass FDA processes confirming efficacy and safety and receive approval, the scientific community continues the research process. Statins have traditionally been approved for efficacy and safety. Subsequently, years are taken to measure outcomes. It is simply not done the way you suggest. It is a continuum of investigation and building of knowledge one study at a time.

Yours: we won't know until 2012 whether Vytorin was a good bet, for certain, but we do NOW know it PRESENTLY costs a lot, especially compared to these generics.

Precisely. Vytorin costs more and achieves more LDL reduction than generics. One can not dismiss the mountain of evidence that more LDL lowering results in less events.

(Question: Having taken on the responsibility for the entire world to research and develop medicines with monumental risk and enormous cost; which drugs unquestionably save millions of lives, is it fair to measure big pharma solely in terms of cost while ignoring beneficial effects?) (Does pharma have the responsibility to provide drugs for free? Why? How does their incredible investment get rewarded if so?) (Why do we not challenge top executives in every industry to bring their pay scale into line at 100x the lowest paid employee? Reference your examination of the $30 Million dollar package for Mr. Hassan and other top Schering executives in 2007.)

This author will play the odds and opt for lower LDL any day until data shows the fallacy of that approach. If cost is used as the sole yardstick, why doesn't every patient with high LDL drive a YUGO?

Best regards and Thank you.

condor said...

Thanks for another very cmplete reply, Anon.

You wrote:

". . . .The addition of ezetimibe to a statin MAY have a positive effect on outcomes. . . ."

True. It might. But will the insurers pay for four times as much -- for a "might"?

Now, didn't the SANDS trial only involve about 80 patients (at least as to the "inflamation-treating leading to better outcomes" data suggestion)?

I think it did. That SANDS data would then be vulnerable to "the law of small numbers" attack. That is likely why Ms. Couric isn't all over that story. It is likely no story, at all. Reasonable people may differ on this, but it seems possible, if not likely, that data are just an anomaly, at this point.

Let me also apologize, now: I knew that the increases found in wall thickness during ENHANCE were not statistically-significant. It was unnecessary to "pile-on" like that -- as there is so much (else) wrong with that data. So, forgive me -- that wasn't called for.

I have no untoward interest in seeing any one drug "win-out" over any other drug -- I am just interested in letting the science decide -- not the pharma-marketeers -- so, now we will wait unitl 2012.

As luck would have it, the CafePharma boards, for Merck, suggest that Merck sales-people are hearing that the Joint Venture may fold well before then -- at year-end 2008.

Thank you, again, for the civil discourse.

And, do check back in here!

-- condor

condor said...

Note: I've taken a stab at some more complete answers, to your parenthetical posers, above.

That is, as you will see -- in my view -- a wider, and deeper, topic than the commentary in this thread permits. So I decided to share it on the front page, as it were. I trust you won't mind -- after all, you are simply listed as "Anonymous" -- no attachment to that handle, I'd presume. Heh!

Take a look.

Thanks, sincerely -- as ever -- for your thoughts! Do stop back.

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