Has Vytorin Created New FDA Approval Hurdles?
14 CommentsBy Ed Silverman // April 28th, 2008 // 9:20 am
Last Friday, Genzyme and Isis Pharmaceuticals disclosed that the FDA wants them to gather more data in order to win approval for a novel cholesterol drug. Specifically, the agency indicated that lowering cholesterol is an “acceptable surrogate endpoint” for using their mipomersen in patients with a rare, inherited form of high cholesterol. But an outcomes trial will be needed to win approval for other patients with high cholesterol. Such a trial can prove valuable if the outcome is achieved, but it’s also expensive and time-consuming because many more patients are needed to enroll.
Interestingly, Zetia was approved six years ago on its ability to lower cholesterol, but actual outcomes data for Vytorin still isn’t available. We mention both drugs in the same breath because Zetia, of course, is one part of the Vytorin cholesterol combo sold by Merck and Schering-Plough; the other part is Zocor. And the results of a study that is designed to show that Vytorin can outperform Zocor alone in preventing deaths, heart attacks and strokes won’t be released until 2012, at the earliest.
You may recall that the controversial Enhance study used a surrogate endpoint - carotid intima-media thickness (IMT) - because people with thicker IMT in the carotid artery have a higher risk of cardiovascular events. But the Enhance trial found that Vytorin failed to show any benefit over the much cheaper Zocor in reducing the plaque in the carotid artery, and even showed a statistically insignificant buildup, although it did a better job of lowering LDL in a small group of patients with inherited high cholesterol.
In a recent commentary in the Journal of the American Medical Association, Bruce Psaty and Tom Lumley of the University of Washington wrote that “the public health advantages of rapid approval for drugs that turn out to be safe and effective need to be balanced against harms that might occur when drugs approved on the basis of surrogate end points turn out later either to have significant safety problems or to lack efficacy.”
Given the concerns over how widely marketed Vytorin and Zetia were over the past few years, the FDA response to Genzyme and Isis raises an interesting thought - whether the agency is no longer willing to approve new drugs for wide use based solely on the ability to improve cholesterol. What do you think?
Is the FDA overreacting with Black Box warnings?
- Yes (57%, 83 Votes)
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condor
In a recent commentary in the Journal of the American Medical Association, Bruce Psaty and Tom Lumley. . . .
The link to that PDF references your email box at the moment, Ed — should be very easy to fix the anchor.
It is such a good read — it would be a shame for the readers to miss it. Great work, as ever!
Sincerely,
– the Condor
Nathan
In my opinion, if the FDA is going to start requiring long-term outcome studies (rather than shorter term biomarker studies), then they are going to have to extent the period of exclusivity. It just isn’t going to be cost-effective to study a drug for 5-10 year “outcome” studies and, in the end, only have 3-5 years of patent life remaining on the drug. The resulting drugs will either become exponentially more expensive or they will simply not be developed.
Lipid Guy
They should grant approval based upon LDL-C lowering, as it is a validated surrogate, but require an outcomes trial be started during Phase 3 (but not necessarily completed prior to approval). this would have avoided the current situation with Vytorin- they did not start the outcomes trial until well after approval. Remember, there was no signal of harm with ENHANCE, and therefore the FDA position should not change.
However, I also wonder if an Antisense compound, i.e. Isis’ Mipomersen, shouldn’t require additional hurdles as we simply don’t know what such a compound will do. Especially since mipomersen is so long acting.
Common Sense
The ISIS compound is intended for use in Homozygous Familial Hypercholesterolemia. I think that the FDA is being way too demanding by expecting them to perform a clinical outcomes trial before approval. It could take them 5-10 years or more to enroll! This disorder occurs in only 1 in 500 people in the general population. Given that these individuals are at very high risk and few options to really lower their cholesterol into acceptable range, the FDA should consider fast track if there are no major safety issues. Have ISIS make a Phase IV commitment to track a group of patients long-term, but don’t bankrupt them!
Paul
Just to be clear, unless I completely missed it, there were no “later safety” issues found with Zetia or Vytorin as a result of the Enhance study. What happened is that they tried a small trial on something that in itself is a surrogate endpoint (people don’t die of carotid intimate narrowing, it’s only an indicator). The trial didn’t work for who knows what reasons, but the product still works for what was indicated and the safety is the same as before.
Vince
The point of this study is that it showed no improvement in the surrogate endpoint and in fact the changed noted in the study pointed in the wrong direction. This combination could in fact decrease or increase events.The fact that previous drugs used to reduce LDL in fact did not reduce mortality must in fact be considered. If the LDL hypothesis is indeed correct. than why did this data not support it?
Response to Paul
ENHANCE wasn’t a small trial that MSP tried, but designed as a definitive trial intended for a regulatory submission requesting approval for a new indication for reducing the progression of atherosclerosis. Additionally, thickening of carotid IMT is associated with increased risk for CV events. It is a failed trial.
The big fallour from ENHANCE appears to have been created by the companies themselves as they delayed releasing results until almost 2 years after the study completed. In addition, it seems that several top individuals make have taken advantage by selling large blocks of stock. This doesn’t please anybody, particulalry other shareholders!
MKM
response to Common Sense:
The FDA is allowing accelerated approval for homozygous FH (hoFH) based on LDL-lowering. HoFH occurs in 1 out of a million people. The outcomes trial is to support full approval for hoFH and for other indications (heterozygous FH (heFH) and other high-risk individuals with high cholesterol).
People with hoFH generally need to be treated with LDL apheresis. However, people with heFH (1/500 people) can usually be managed with medication.
I think the FDA is being sensible here, because the long-term effects of antisense drugs are not known. This is a first-in-class drug, and there are other treatments available.
www.worldpharmanews.net
Pharmalot » Has Vytorin Created New FDA Approval Hurdles?…
Given the concerns over how widely marketed Vytorin and Zetia were over the past few years, the FDA response to Genzyme and Isis raises an interesting thought - whether the agency is no longer willing to approve new drugs for wide use based solely on t…
Common Sense
Hi MKM,
Thanks for the clarification. When I first heard about this item, I was surprised. can you imagine a clinical outcomes trial in HoFH? Talk about difficult. How about impossible? I agree that the plan sounds sensible given your points.
riv
People who have heterozygous do not need to be on meds.
Lowering cholesterol doesn’t do anything for mortality rates. Why take cholesterol lowering drugs when the only proven benefit is to pharma? There is risk of rhabdomyolysis, myopathy, myositis, transient global amnesia, aphasia, memory loss, language loss, strokes, pancreatic disease including pancreatic cancer, ALS and Parkinson’s syndrome. (Syndrome: the weasel word pharma is now using for the thousands of the latter two cases showing up).
Justice in Michigan
I wouldn’t agree with the opening part of Riv’s post, but I would add neuropathies to her list. I have personal experience with that one, confirmed by neurologist on retrial. It certainly appears to be rare, but, in the best summary I’ve found, each of the statins is associated with hundreds of confirmed cases that are not explicable in other ways (pts. not diabetic, etc.)
riv
“her” ???
I have a TC of 480. No cardiovascular disease. What is FH anyway but some artificial ceiling over which pharma decides we have a deficit of statins.
http://www.spacedoc.net
John Osborne, MD, PhD
Dear riv:
With a TC of 480 (and I suspect it’s not with an HDL of 200!), i’d be happy to do a free Cardiac CTA on you to see if you really don’t have coronary artery disease!
John Osborne, MD, PhD
State of the Heart Cardiology