FDA Will Take A ‘Balanced’ View Of Enhance: Analyst
10 CommentsBy Ed Silverman // April 4th, 2008 // 12:21 pm
Despite the flogging that Vytorin and Zetia have received in recent days, one wag remains somewhat optimistic about their longer term prospects. In a research note to investors this morning, Tim Anderson of Sanford Bernstein writes that the cholesterol meds - which are being questioned as useful treatments for cholesterol - cites comments by FDA officials that could be interpreted as suggesting little or no change to product labeling.
“There are several assumptions that are key to our less pessimistic view of future Vytorin/Zetia sales: 1 - We don’t believe FDA will do much with ENHANCE in terms of making material adverse changes to the product labels; 2 - Subsequently, we don’t believe that there will be significant movement by payers away from Tier 2 coverage of the products in the US (some traction will be lost, however); 3 -We think the Enhance trial will continue to be mostly a US issue, with less of a negative impact internationally; and 4 - We ultimately think the Improve-It trial has good odds of showing a much-needed mortality benefit.” These are the FDA statements to which he referred….
“What people allege the Enhance trial showed is lack of expected benefit, which to me seems a questionable assertion,” Bob Temple, who heads the Office of Medical Policy at the FDA’s CDER, tells FDAWebview, while noting that his comments do not necessarily reflect FDA’s position on the surrogate itself.
“The only ‘finding’ I’m aware of is failure to show an added effect on carotid plaques, a surrogate endpoint at best, and one that rates, as a surrogate for predicting coronary events, in my book below LDL cholesterol, in a study that was far too small to be an outcome study…Of course, we do not yet have actual outcome data so we cannot know that ezetimibe will add to the effect of the simvastatin in Vytorin. I don’t, however, see any reason to doubt that Vytorin will have an effect at least equal to its simvastatin component alone.”
In any event, it will take six months to absorb the compete Enhance trial. “As we also said in January, we believe that it is premature based on this single study to alter our approach to the approval of lipid-lowering drugs,” John Jenkins, who heads the FDA’s Office of New Drugs. “The NEJM publications spelled out a number of potential reasons why the Enhance study failed to meet its primary endpoint and the results of the ongoing Improve-It study should help to clarify whether there is an incremental benefit on CV risk reduction for Vytorin over simvastatin alone, as would be predicted by the increased LDL lowering seen with Vytorin in the Enhance study.”
After seeing their comments, Anderson believes the FDA will take a more balanced approach. By this, he means “recognizing the possible reasons for why Enhance showed what it did, and not ignoring the wealth of prior data that says that lowering LDL is what matters - and there is a fair bit of evidence showing that it doesn’t really matter how that LDL is lowered. This would imply that Vvytorin will, in the end, indeed likely show a benefit from Improve-It. The balanced assessment of Enhance seems to have gotten lost by the likes of Drs. Nissen and Krumholz. FDA seems to be taking a more rationale view of the totality of the data, which is refreshing.”
Paul
Finally a sensible opinion.
G MD
Tim Anderson does not understand how the Part D providers work and set Tiers. He is a typical sell side analyst humping a theme. His personal agenda trumps the truth. Rah rah. Cheerlead that stock…..fool
Grieving
Bob Temple? Is that the same Bob Temple that agreed with me at last June’s Medguide Hearing that Zyprexa (especially) but also the other atypical antipsychotics met all the criteria for having Medguides - another underutilized and overpoliticized drug safety tool - should have Medguides, as I testified?
And then, of course, did nothing……
Justice in Michigan
Bob Temple has a talent for talking in whatever direction appears convenient to him at the time.
If carotid plaque was not a particularly informative surrogate endpoint, why does anyone suppose MSP chose it?
And if Enhance had come out differently, does anyone think that MSP would also be in any way downplaying its significance?
I would suggest it would be all carotid, all the time.
And Temple would be saying …………. zilch.
Steven Walker
I rarely agree with Bob Temple, but in this case, he is right. The word is still out on Vytorin, and he is doing what the FDA should do when individuals in medicine, and many in the press, over-react to a single clinical trial finding. Randomized trials are not nearly as definitive as the clinical trialing community (and sometimes the FDA)would like us to believe, nor did the Enhance trial ask or answer the question some seem to think was asked and answered. Everyone should take a deep breath on this one. The outocome of a trial designed to measure plaque buildup using an unvalidated measurement technique with accuracy and precision problems in heavily-treated patients with a genetic predisposition for high cholesterol and accelerated formation of plaque proves only that Vytorin is not in highlky obvious fashion the miracle drug its sponsor and many others hoped it would be. It is still a drug that has a dramatic effect on a valdiated endpoint, cholesterol lowering (and perhaps C-reactive protein), and there is no evidence anyone is being directly harmed by it. Our clunky, archaic staistical clinical trials system produces usable information at an agonizingly slow rate, so we will simply have to wait to find out how Vytorin will fit into the treatment scheme long term. Isn’t this really a reflection of just how insane the drug safety hysteria moevement has become when a drug that everyone agrees is safe and positively effects a well-validated endpoint for prevention and control of heart disease, becomes the center of a “scandal” for showing no discernible effect on something we are not even sure matters in a very difficult to treat population? Where is the scandal here? Why are people being told to stop taking this drug? We actually have no good reason to think that anyone should stop taking Vytorin. What I think we do know is that there are docs out there who know that creating and pumping up drug “scandals” boosts their careers, and media outlets who know that hyping them at the sound bite level sells their news product. Isn’t it time to get back to thinking about medicine and medical progress in a more rational and measured manner?
Mike M
Let’s all keep in mind that IMPROVE it will still fail to answer the real question, that is, does adding ezetimibe improve relevant outcomes when added to a statin alone, as Merck and Schering Plough are failing to include a cohort of patients who would receive 80 mg of simvastatin. By omitting the maximum dose of the statin, you are not truly assessing whether another agent needs to be added, you can still double the dose. When you see an inherent design flaw in a drug company study, it makes you wonder if it was placed there for a reason. Just throwing that out there.
CVMD
Temple needs to speak to the Metabolic/Endpcrine Division as they have been allowing companies to use Carotid Ultrasound IMT as one of their “gold standard” endpoints for years. All of the statin development programs have used this approach to try to obtain a “reduced progression of atherosclerosis” claim for their products. He should remember that ENHANCE was reviewed and negotiated with the FDA before it was ever started. he should also be reminded that MSP chose CUS IMT as their only study because they thought they could show a positive result in their stacked population. I’m sure they chose this route over Coronary IVUS, which would have been a much better choice. They made mistakes and that’s why they’re where they are. Particularly, since they apparently delayed the delivery of the negative results and profited by doing so.
TALL16
After ENHANCE the FDA has to make a decision if they want lower LDL or not.
Paul
We all have to recognize:
- LDL is the current accepted surrogate marker because it has been demonstrated over and over — and regardless of method — to be a modifiable risk factor, i.e. the high higher the number, the higher the risk AND if you lower it, you lower the risk - with now “J curve”, meaning it has not been show how low is low
- Carotid IMT is an interesting marker of plaque formation BUT is not necessarily correlated to MI’s or mortality. It simply offers the best window into what may be going on in the artery wall. But there is a lot more to events, including inflammatory responses and other stuff.
- Vytorin claims that it lowers cholesterol. They don’t claim that it reduces hospitalization or mortality — even if it’s main component is the well-proven simvastatin.
All of this means that Temple is correct in his assertions. Nothing has changed.
If you need your LDL to come down a lot, then you can get high doses of Zocor, Lipitor or Crestor with risks of Rhabdomyalisis, or you can lower it with Vytorin. I’ll stay on Vytorin.
BWP MD
Paul,
Thanks for the perspective from MSP Marketing & Sales. As for Carotid IMT, you should look it up. This method has been used for two decades. There are innumerable studies correlating IMT thickness with CV risk, and big ones at that.