Sunday, November 25, 2007

Are Merck and Schering-Plough "enhancing" the ENHANCE data?

I'm from Missouri, "The Show-Me State," and like many others, I'd like Merck and Schering-Plough to show me the ENHANCE trial results. I'd like them raw and unenhanced, please. This expose in the NYT last week is priceless:

I just learned that Matthew Herper at Forbes reported it first in an equally priceless article:

In a nutshell: Sinvastatin (misspelling intentional) recently lost patent protection. Sinvastatin (Zocor) has been combined with ezetimibe (Zetia) to yield combination drug Vytorin. This combination holds the promise of rescuing Sinvastatin, a multi-billion dollar drug, from generic death if doctors continue to prescribe it in combination with ezetimibe as a branded product. There's only one problem: unlike sinvastatin, ezetimibe has never been shown to do anyting but lower LDL cholesterol, a surrogate endpoint. That's right, just like Torcetrapib, we don't know what ezetimibe does to clinically meaningful outcomes, the ones that patients and doctors care about. (The drug compaines care about surrogate outcomes because some of them are sufficient for FDA approval - that subject is a blog post or two in itself.)

So Merck and Schering-Plough designed the ENHANCE trial, which compares 80 mg of simvastatin to 80 mg of simvastatin + 10 mg of ezetimibe on the primary outcomes of carotid intima-media thickness and femoral artery (IMT). Note that we still don't have a clinically meaningful endpoint as a primary outcome, but we're getting there. A trial assessing the combination's effects on meaningful outcomes isn't due to be completed until 2010. Of course a big worry here is that ezetimibe is like torcetrapib and that in spite of creating a more favorable cholesterol profile, there is no clinically meaningful outcome improvement; i.e., the cholesterol panel is a merely cosmetic result of ezetimibe.

(Regarding the ongoing trials evaluating clinical outcomes: Schering-Plough is up to some tricks there too to rescue Sinvastatin from generic death. The improve-it study [they need a study to "prove-it" before they embark on a mission to "improve-it," don't you think?] design can be seen here:
In this study, ezetimibe is not being compared to maximum dose sinvastatin, nor is a combination of ezetimibe and sinvastatin being compared to maximum sinvastatin alone. If one of those comparisons were done, important information could be gleaned - doctors would know, for example, if ezetimibe is superior to an alternative (one that is now available in generic, mind you) at maximum dose, or if its addition to maximum dose sinvastatin has any additional yield. But such trials are too risky for the company - they may show that there is no point to prescribing ezetimibe because it is either less potent than max dose sinvastatin, or that it has no incremental value over max dose sinvastatin. So, instead, sinvastatin 40mg+ ezetimibe 10mg is being compared to sinvastatin 40mg alone. The main outcomes are hard clinical endpoints - death, stroke, MI, etc. Supposing that this trial is "positive" - that the combination (Vytorin) is superior to sinvastatin 40mg. Should patients now be on Vytorin (sinvastatin 40mg+ ezetimibe =patent-protected=expensive) instead of sinvastatin 80 mg (=generic=cheap)? Well, there will be no way to know based on this trial, which is exactly the way Schering-Plough wants it. You see, this trial was designed primarily for the purpose of securing patent protection for simvastatin in the combination pill. Its potential contribution to science and patient care is negligible. So much so in fact, that I think this trial is unethical. It is unethical because patients volunteer for research mainly out of altruism (although in this case you could argue it's for free drugs). The result of such altruism is expected to be a contribution to science and patient care in the future. But in this case, the science sucks and the main contribution patients are making goes to the coffers of Schering-Plough. Physicians should stop allowing their patients to participate in such trials, so that their altruism is not violated.)

The NYT article makes some suspicious and concerning observations:

  • The data, expected to be available 6 months ago (the trial was completed almost 2 years ago!), will not be released until some time next year, and then only a partial dataset analysis, not complete data analysis.
  • The primary endpoint was changed after the trial was concluded! (Originally it was going to be carotid IMT at three places, now only at one place - a change that is rich fodder for conspiracy theorists, regardless if an outside consulting agency suggested the change.)
  • Data on femoral artery IMT are not going to be released at all now

Matthew Herper's Forbes article also notes that the trial was not listed on until Forbes asked why it was not there!

For the a priori trial design and pre-specified analyses, see pubmed ID # 15846260 at . In that report of the study's design, I do not see mention of monitoring of safety endpoints such as mortality and cardiovascular outcomes. But I presume these are being monitored for safety reasons. And Merck and Schering-Plough, who have claimed that they have not released the IMT data because it's taking longer than anticipated to analyze it, could certainly allay some of our concerns by releasing the data on mortality and safety endpoints, couldn't they? It doesn't take very long to add up deaths.

The problem with pre-specifying all these analyses (carotid IMT at 3 locations and femoral IMT) is that now you have multiple endpoints, and your chances of meeting one of them by chance alone is increased. That's why the primary endpoint holds such a hallowed position in the heirarchy of endpoints - it forces you to call your shot. I liken this to billiards where it doesn't matter how many balls you put down unless you call them. And none of them counts unless you first put down your first pre-specified ball - if you fail that, you lose your turn. In this case, if you check a bunch of IMTs, one of them might be significantly different based on chance alone - so if you change the primary endpoint after the study is done, we will rightly be suspicious that you changed it to the one that you saw was positive. That's bad science, and we and the editors of the journals should not let people get away with it.

I have a proposal: When you register a trial at , you should have to list a date of data/analysis release and a summary of the data/analyses that will be released. Should you not release the data/analysis by that pre-specified date, your ability to list or publish future trials, and your ability to seek or pursue regulatory approval for that or any other drug you have is suspended until you release the data. Moreover, you are forbidden from releasing the data/analyses prior to the pre-specified date - to prevent shenanigans with pre-specified list dates in the remote future, followed by premature release.


  1. Pssst, it's "siMvastatin," not "siNvaststin," unless you're making some sort of pun. This is an interesting story, but I can't bother reading your take on it if you can't spell the name of the drug correctly.

  2. Yes, it is an intentional pun. And besides, misspellings and typos don't undermine story lines or logic.

  3. Regarding your suggestion re:, Section 801 of Public Law 110-85, enacted on Sept 27, 2007, enhances this NIH-operated clinical trials registry and adds a mandatory summary results reporting provision, which would require posting of summary data from clinical trials testing FDA-approved drugs -- such as Zetia, Zocor, and Vytorin -- and FDA-approved or cleared medical devices within a year of completion (or up to two years if the trial will be used to support a "new use"). Data to be reported include demographic and baseline characteristics of patient sample, primary and secondary outcomes, and serious and frequent adverse events. Failure to comply could result in civil monetary penalties or withholding of Federal grant funds. When the new law is implemented, it should increase transparency in clinical research and mitigate common data reporting issues, such as the ENHANCE case. (See for more information.)

    NOTE: The primary outcome measure listed in the ENHANCE trial registration (, which was only submitted recently (Oct 31, 2007) is: "Change in ultrasound-determined average carotid artery intima-media thickness (IMT) on a per subject basis between baseline and endpoint. [ Time Frame: 24 months ]" The other three endpoints are listed at as secondary outcome measures.

    According to the Forbes article, "Schering and Merck did not list the trial on the government Web site, ... until asked by about its absence."

    However, the International Committee of Medical Journal Editors (ICMJE) , which include NEJM, JAMA, Annals of Internal Medicine, BMJ, and Lancet issued a Clinical Trials Registration Policy in 2004 that requires, "as a condition for consideration for publication," that clinical trials to be registered "at or before the onset of patient enrollment." The ICMJE stated in a subsequent editorial that it would "consider for publication ongoing trials that are registered before September 13, 2005." According to its registration record at, ENHANCE was initiated in June 2002 and completed in April 2006, but was registered in October 2007. Were the sponsors ever intending to publish the full results in a peer-reviewed journal article?

  4. Sir or Madam - that is an excellent comment. Very informative! Thank you!

  5. Echoing the anonymous comment above is this perspective in this week's NEJM:
    Which also focuses on this newly passed legislation.


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