FDA’s recent decision to add the results of the SHARP study in chronic kidney disease patients to the labeling for Merck & Co. Inc.’s Vytorin (ezetimibe/simvastatin), but not to allow a claim for cardiovascular risk reduction based upon those results, begs the regulatory question of what constitutes an “approval.”

The regulatory action on Vytorin, which was preceded by an advisory committee review of the SHARP data and Merck’s request for a new indication, would appear to challenge the traditional notion of an approval.

Following the committee’s 16-0 vote in favor of approval of Vytorin for reducing the risk of major vascular events in pre-dialysis chronic kidney patients, the cholesterol-lowering combination drug appeared to be on track to add a new indication. Such a claim would have been the first directly linking ezetimibe with a CV outcomes benefit.

Yet, FDA opted against a new indication for Vytorin because the SHARP trial did not assess the independent contributions of ezetimibe and simvastatin on the observed effect.

FDA’s apparent invocation of the combination rule took some observers by surprise, because there was almost no discussion of the issue at the day-long advisory committee meeting.

The agency’s invocation of the “combination rule” took some observers by surprise; there was almost no discussion of the issue at the day-long advisory committee meeting and no hint that it could serve as a roadblock to approval.

Yet, apparently in FDA’s mind, when it asked the committee whether “approval” was supported, it wasn’t considering just a new claim but, rather, a range of possibilities for labeling changes.

Ultimately, it may not matter very much that Merck failed to get the indication it wanted. The SHARP data showing a CV benefit in CKD patients are now reflected in the label and can be included in promotional materials and freely discussed by sales reps. The data also should provide some confidence in the CV benefits of ezetimibe, which have been in dispute since the highly publicized failure of the ENHANCE trial.

Nevertheless, the Vytorin experience should make sponsors and advisory committee members think twice about the agency’s view of its regulatory options when deciding whether an “approval” is warranted.

Invoking The Combination Rule

FDA convened its Endocrinologic and Metabolic Drugs Advisory Committee on Nov. 2 to discuss Merck’s sNDA for a new indication for Vytorin to reduce the risk of major CV events in CKD patients. Merck sought a similar indication for Zetia (ezetimibe), when used in combination with simvastatin (Merck’s Zocor and generics).

In the 9,000-patient, placebo-controlled SHARP study, the ezetimibe/simvastatin combination was associated with a significant 16% reduced risk of major vascular events among renally impaired patients.

A key focus of the meeting was the divergent results between the pre-dialysis and end-stage renal disease populations in SHARP. While patients in the pre-dialysis group had a 23% reduced risk of MVE, there was only a 6% reduced risk among patients on dialysis. The combination also did not reduce the risk of pre-dialysis patients progressing to dialysis during the course of the trial. FDA asked the committee to analyze the results against a backdrop of two earlier statin studies, both of which failed to show a CV benefit in dialysis patients.

The agency asked the panel to discuss the primary efficacy results, treatment effects for individual components of the MVE endpoint and efficacy in the pre-dialysis versus dialysis subgroups. FDA also requested discussion about the study’s inclusion criteria and safety data.

The fifth and final question was a two-parter, asking whether the available efficacy and safety data “provide substantial evidence to support approval of Vytorin 10/20 mg for the prevention of major vascular events” in patients with (1) pre-dialysis chronic kidney disease, and (2) end-stage renal disease receiving dialysis. The committee voted 16-0 in favor of approval for CV risk reduction in the pre-dialysis population, but 10-6 against approval in the dialysis population Also see "Merck's Vytorin/Zetia Headed For CV Outcomes Claim, But Will Dialysis Patients Be Off-Limits?" - Pink Sheet, 2 November, 2011..

Based upon the panel’s discussions and vote, it seemed as though a CV outcomes claim was headed Vytorin’s way, though potentially one that was limited to the pre-dialysis setting.

On Jan. 25, Merck announced that FDA had approved a Vytorin labeling update to include the SHARP efficacy results in the Clinical Trials section. However, the agency did not approve the CV risk reduction claim because the study did not assess the independent contributions of each drug to the observed effect Also see "Vytorin/Zetia Affirmation Continues To Elude Merck With Denied CKD Indication" - Pink Sheet, 25 January, 2012.. The agency similarly rejected a risk reduction claim for Zetia but went a step further for the single-agent compound, declining to add the SHARP efficacy results to the drug’s label.

FDA apparently invoked the combination rule, under which a sponsor must show that each component of a fixed-dose combination makes a contribution to the claimed effects. However, the possibility that FDA would decline to approve a new indication on this basis got almost no discussion at the advisory committee meeting, the focus of which was clearly on the combination’s performance among pre-dialysis versus dialysis patients.

Little Advisory Committee Discussion

It was no secret that data on the CV benefit provided by ezetimibe/simvastatin over simvastatin alone were lacking.

At the meeting, FDA clinical reviewer James Smith pointed out that the Vytorin label states that no incremental benefit of the cholesterol-lowering combination drug on CV mortality and morbidity over and above that demonstrated for simvastatin has been demonstrated. Zetia’s label contains similar language. “This lack of cardiovascular outcomes data for Vytorin and Zetia has been the subject of a great deal of controversy that was further fueled by some recent ezetimibe/simvastatin clinical trials,” Smith said, citing the failed ENHANCE and SEAS studies.

In ENHANCE, the combination failed to demonstrate a statistically significant benefit on an imaging endpoint, carotid-artery intima-media thickness, compared to simvastatin alone. In the SEAS study, the combination was not associated with a statistically significant reduction in major CV events compared with placebo among patients with mild to moderate asymptomatic aortic stenosis.

SHARP was the first study to supply evidence for use of ezetimibe to improve clinical outcomes. However, the study was not designed to compare the efficacy of the combination versus simvastatin alone, Smith said, adding that the ongoing IMPROVE-IT study is aimed at answering this question. IMPROVE-IT is a randomized, double-blind study of subjects with acute coronary syndrome who are being treated with ezetimibe/simvastatin or simvastatin alone. The primary outcome is CV death, nonfatal coronary events and nonfatal stroke.

One-year data from SHARP “are the only unblinded, head-to-head data we have with regard to cardiovascular outcomes in ezetimibe/simvastatin against simvastatin,” FDA’s clinical reviewer told the advisory committee.

In SHARP, subjects initially were randomized 4:4:1 to Vytorin, placebo or simvastatin alone. After one year, the simvastatin-only group was re-randomized to either Vytorin or placebo. Smith presented data on the number of MVEs and major atherosclerotic events at the end of the first year in the three initial treatment arms. “At present … these are the only unblinded, head-to-head data we have with regard to cardiovascular outcomes in ezetimibe/simvastatin against simvastatin,” he said. The combination arm had the lowest rate of MVEs and MAEs among the three arms.

Committee member Erica Brittain, National Institute of Allergy and Infectious Diseases, asked how, from a regulatory perspective, FDA viewed the fact that SHARP was not designed to assess the independent contributions of ezetimibe and simvastatin in the CKD population. “If we can just forget about it, that’s fine,” she said.

FDA Metabolism and Endocrinology Products Division Deputy Director Eric Colman responded that at the time SHARP was designed, there was no good evidence that lipid-lowering reduces CV risk in CKD patients. “I think if you were to say that they should have had a third arm, which was simvastatin alone, you’d really be asking them to take a very large shot in the dark because no one knew at that point if lipid lowering had an effect in this population,” Colman said.

Temporary voting member William Hiatt, University of Colorado, said that while the body of evidence for statins’ benefit on CV outcomes is pretty clear, the same cannot be said for other drugs that lower LDL cholesterol through different mechanisms of action, and it remains unclear whether simvastatin alone would have the same effect as was seen with the simvastatin/ezetimibe combination. “We just don’t know that, and I can understand why it was not a big topic on the table” for the meeting, Hiatt said at the time.

An Explanation From FDA

It is not out of the ordinary for FDA to take a regulatory action on a drug application unrelated to issues under discussion at an advisory committee meeting. As was the case with the Vytorin meeting, the agency generally includes a disclaimer in background briefing materials stating that they may not include all issues relevant to final regulatory recommendation, and that final action may be affected by issues not discussed at the meeting.

Examples of the types of issues that can prove to be stumbling blocks for an application’s approval, but which are not discussed at a public advisory committee meeting, include ongoing agency investigations into manufacturing violations, data integrity and clinical trial conduct.

In the case of Vytorin, it seems a discussion about the combination rule and the implications for a new CV outcomes indication was purposely avoided.

In response to questions from Elsevier Business Intelligence’s RPM Report as to why the issue of the Vytorin individual ingredients’ contributory effects was not discussed in greater depth at the advisory committee meeting, FDA said it did not believe such discussion would have been useful.

“In planning for the advisory committee meeting for SHARP, FDA was well aware of the limitations of the trial design and that SHARP would not inform us of the contribution to CV risk reduction by each of the components in the combination therapy of ezetimibe and simvastatin,” the agency replied. “FDA did not feel discussions would be productive if the meeting focused on or even asked members specifically about the effects of each of these two drugs in patients with chronic kidney disease, as no rigorous scientific discussion could be held in the absence of clinical data.

“However, FDA recognized that this issue might be considered by some members; therefore, the FDA presentation mentioned this limitation and presented the first-year data from SHARP, which compared ezetimibe/simvastatin, simvastatin and placebo. FDA cautioned against making definitive conclusions based on this exploratory analysis of only a subset of events.”

The agency said it believed the meeting needed to focus on the pre-specified objectives of SHARP, the study outcomes and the pre-dialysis and dialysis patient subgroups “because there were not only clinical data from SHARP to thoroughly vet but also data from two large clinical trials with statins in the population of patients with end-stage renal disease. FDA believes the discussion and recommendations provided by the members helped inform us on appropriate labeling for the safe and effective use of Vytorin in patients with chronic kidney disease, since the addition of SHARP to labeling allows Merck to disseminate the trial's results to the medical community and their patients.”

Although FDA asked the committee whether the data supported approval for CV risk reduction, “the term ‘approval’ covers a range of regulatory options,” the agency said.

“The Pink Sheet” subsequently asked FDA why, given the inherent limitations of the SHARP trial design, the committee was asked to vote on whether the data supported approval of Vytorin for prevention of MVE in pre-dialysis and dialysis patients. “The term ‘approval’ covers a range of regulatory options, including approval of changes to the Clinical Studies section of the labeling, as was done with SHARP,” the agency responded.

One of the SHARP trial investigators said the agency’s decision not to award a new indication came as a big surprise, particularly because the issue of the ingredients’ separate effects was not flagged by FDA as being a concern at the advisory committee meeting.

When experts from Oxford University, which conducted SHARP, met with FDA about the study design in 2002, they asked whether the design was appropriate given FDA’s combination rule, but the agency raised no concerns at that time, the researcher said.

The investigator called FDA’s decision not to approve a new indication regrettable because although SHARP produced clear results, it has resulted in “equivocal labeling” which could limit the drug’s use in the U.S. CKD population.

No Indication, But Does It Matter?

It remains to be seen whether the lack of a CV outcomes claim in the CKD population really matters to Merck or to the use of Vytorin/Zetia in renally impaired patients.

While Merck did not get the indication it wanted, the SHARP efficacy results are now reflected in the Vytorin label, and this may be viewed within the medical community as a seal of approval that ezetimibe does, in fact, have a positive impact on CV outcomes.

However, an actual indication likely would have given the data more gravitas (not to mention more prominence in promotional materials), and it’s unclear how reimbursement will be affected, if at all, by FDA’s decision not to award an outcomes claim in the CKD population.

National Kidney Foundation Chief Medical Officer Joseph Vassalotti said he was surprised FDA declined to add a new indication, particularly given the advisory committee’s unanimous vote in favor of approval in the pre-dialysis population. He expects the SHARP efficacy results, combined with the new labeling language reflecting the data, will provide a “modest” uptake in Vytorin use among CKD patients.

The labeling change adding the SHARP data is “a positive step forward, [but] maybe not the leap we thought it would be” had a new indication been granted, he said.

Merck said the company looks forward to discussing the SHARP results with health care providers “in a manner consistent with the updated label for Vytorin.”

All Eyes On IMPROVE-IT

The issues surrounding the recent Vytorin labeling change will surely shine an even brighter spotlight on the IMPROVE-IT study, which Merck is hoping will be the “holy grail” when it comes to showing the cardiovascular outcomes benefit of adding ezetimibe to simvastatin.

The 18,000-patient trial is targeted for completion in June 2013, according to the ClinicalTrials.gov database. During Merck’s year-end earnings call on Feb. 2, company officials said a pre-specified interim look at the data is scheduled for the end of the current quarter, and they expressed confidence that the final study would prove positive for their ezetimibe franchise.

The SHARP “Approval”: Merck Gets Vytorin Labeling Change, But Not The CV Outcomes Claim It Sought

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