The headlines and newscasts reported Amarin’s success in wining off-label promotion, but behind the scenes, another noteworthy action took place – in a very rare action, the FDA rescinded a special protocol assessment (SPA) that would have enabled Amarin to promote the new indication. In this post, we’ll examine the reasons for FDA’s action and how it may apply to any SPA.

The news about Amarin Pharma, Inc., has centered on the ruling by U.S. District Court for the Southern District of New York, granting a motion for preliminary injunction in favor of Amarin concerning First Amendment protection for a pharmaceutical manufacturer’s off-label promotion (eg, dissemination of information relating to the use of VASCEPA (a purified ethyl ester of eicosapentaenoic acid (EPA) derived from fish oil) in patients with persistently high triglycerides [TG]) of an otherwise approved drug (VASCEPA; NDA 202057).

The First Amendment dispute arose from the FDA’s non-approval of Amarin’s supplemental new drug application (“sNDA”) (submitted on Feb 21, 2013) seeking to expand the treatment population of VASCEPA to include patients with mixed dyslipidemia who are at high risk for coronary heart disease and who are already being treated with HMG-CoA reductase inhibitors (statins). Amarin believed it had satisfied all of FDA’s requirements to obtain approval of VASCEPA for persistently high TG, per the ANCHOR SPA agreement established with the FDA earlier (the ANCHOR study achieved its primary endpoint demonstrating statistically significant reductions in triglyceride levels with VASCEPA, compared to placebo; achieved statistically significant results for its secondary endpoints in the ANCHOR study as well; and Amarin met its enrollment obligations with respect to the REDUCE-IT trial [a cardiovascular (CV) outcomes trial]).

VASCEPA (NDA 202057 approved July 26, 2012), was approved as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (defined as TG ? 500 mg/dL) at a dose of 4 grams per day. This approval of VASCEPA was based on MARINE, a Phase 3, international, double-blind, randomized, placebo (mineral oil)-controlled trial. The primary endpoint was median percent change in TG from baseline. Amarin was pursuing a second indication, “effect of VASCEPA on triglyceride levels among statin-treated patients with “persistently high” TG (? 200 and ? 500 mg/dL)”, based on ANCHOR, a Phase 3, double-blind, placebo (mineral oil)-controlled, parallel-group trial. The primary endpoint was percent change in TG from baseline. Amarin entered into a Special Protocol Assessment (SPA) with FDA (the “ANCHOR SPA”). As part of the ANCHOR SPA, Amarin agreed to conduct a CV outcomes trial (the REDUCE-IT trial) to examine whether VASCEPA would be effective in reducing CV events.  As a condition of the ANCHOR SPA, FDA required that the REDUCE-IT trial would need to be at least 50% enrolled before FDA would accept Amarin’s sNDA for use of VASCEPA in patients with persistently high TG.

After review of the sNDA, FDA acknowledged in a Complete Response Letter, that although VASCEPA yielded a treatment difference showing reduced TG levels compared to placebo in patients treated in the ANCHOR study, the clinical rationale for reducing serum TGs with VASCEPA and modifying other lipid/lipoprotein parameters shown in ANCHOR among statin-treated patients with TGs 200-499 mg/dL is to reduce CV risk. FDA concluded that, for regulatory approval purposes, there were insufficient data at the time to support a drug-induced change in serum TGs as a surrogate for reducing CV risk in the ANCHOR population. FDA rescinded Amarin’s ANCHOR study SPA (an action that is very rare) because the FDA determined that a substantial scientific issue essential to determining the effectiveness of VASCEPA in the studied population was identified after testing began.

A SPA indicates FDA agreement that a study will support the approval of a drug product’s marketing application (or supplement to an approved application) if it is conducted according to the protocol and it achieves its agreed-upon objectives (FDCA § 505(b)(5)(B); FDA, Guidance for Industry: Special Protocol Assessment, (May 2002)).  Once FDA and a sponsor enter into a SPA agreement, there are only two statutory bases for changes to the SPA: 1) written agreement between FDA and the sponsor or 2) where FDA finds a “substantial scientific issue essential to determining the safety or effectiveness of the drug” that is identified after the trial has begun [FDCA § 505(b)(5)(C)].

In the Complete Response Letter to Amarin, FDA indicated the need for data showing a reduction in CV events (i.e., data from the REDUCE-IT trial) prior to approval for persistently high TG. Thus, the FDA stated that it no longer considered a change in serum triglyceride levels as sufficient to establish the effectiveness of a drug intended to reduce CV risk in subjects with serum triglyceride levels below 500 mg/dL.

In the case of Amarin, current scientific knowledge obtained after the ANCHOR trial had begun, impacted the FDA’s decision – this information will be assessed first in this blog. Next, the regulatory precedence that likely played a role in the FDA’s decision will be discussed.

As part of the review of the efficacy supplement to expand the VASCEPA indication, FDA convened an Advisory Committee during which the Agency called into question the benefits of drug-induced changes in lipid/lipoprotein parameters on CV risk in the ANCHOR population.

This was driven by data from several high-profile CV outcomes trials reported after the ANCHOR SPA was entered into by FDA and Amarin. Several CV outcome trials of non-statin lipid-modulating therapy (ACCORD-Lipid¹, AIMHIGH², and HPS2-THRIVE), which were designed to target residual CV risk by improving lipid parameters other than LDL-C (e.g., HDL-C and/or TG) in patients optimally treated with statin therapy, failed to demonstrate unequivocally additional CV benefit of adding non-statin lipid-altering therapy on CV outcomes despite improvements in lipid profiles. Also considered were findings from recent clinical trials and meta-analyses that failed to confirm definitive CV benefit with EPA and DHA supplementation. ^3,4,5

An examination of prior regulatory precedent for similar drug products showed that – although no omega-3 based drug is currently approved for the indication being sought by Amarin’s sNDA – there were historical regulatory examples that were pertinent to the Amarin case. For example, LOVAZA (NDA 021654; GlaxoSmithKline), a prescription product containing high-purity omega-3-acid ethyl esters, is approved by the FDA as an adjunct to diet to reduce very high TG levels (500 mg/dL or higher) in adults based on the add-on to statin therapy trial COMBOS (Combination of Prescription Omega-3 With Simvastatin) – a trial without CV endpoints. These data were strong enough for the FDA to approve the indication for treating that patient population, and Lovaza was approved in the United States in 2005. At the time of the approval of LOVAZA for the treatment of very high TG, the FDA also issued an Approvable Letter citing the requirements for Lovaza to be approved for the treatment of elevated non-HDL-C and TG (200-499 mg/dL) in adult patients concurrently taking a statin at or near LDL-C treatment goal, as an adjunct to diet. The COMBOS study was carried out to address this patient population. It sought to show that Lovaza would not reverse the effect of the statin and that a good overall lowering in non-HDL-C could be achieved. LDL-C and VLDL-C fell by 9.0% in the Lovaza/simvastatin group, and fell by 2.2% in the simvastatin/placebo group, a net difference of about 7%; and, as expected, Lovaza produced a significant fall of 29.5% in TG in these patients whose LDL-C was already well controlled with simvastatin (40 mg). Modest increases in plasma levels of LDL-C were seen with Lovaza monotherapy in people with high TG (? 500 mg/dL), and the FDA wanted to be sure that this did not occur in patients on statins. A clinically insignificant change in LDL-C (an increase of 0.7%) was statistically significant when compared with the 2.8% drop in LDL-C observed in the placebo group. When the results of the study were submitted to the FDA, the FDA issued an Approval Letter permitting the addition of select study data within the clinical studies section of the 2007 label (ie, NDA 021654/S-016; Section 14.2: pg 9 of 15 – Other Clinical Experience) for Lovaza, but it did not approve the additional indication. The COMBOS data information has since been removed from the current labeling. Lovaza’s current approved labeling states: Indications of Use: The effect of LOVAZA on cardiovascular mortality and morbidity has not been determined. No CV outcome study has been conducted with LOVAZA.

In another example, Trilipix (fenofibric acid) capsule (NDA 22224) was approved in 2008 “for use in combination with a statin to reduce TG and increase HDL-C in patients with mixed dyslipidemia and coronary heart disease (CHD) or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-C goal”.   Following the release of ACCORD-Lipid trial results in 2010, the FDA held an advisory committee meeting to discuss the findings of the ACCORD-Lipid trial as they related to the indication granted to Trilipix for coadministration with a statin. Interestingly, in April 2015, NDA 22224 (S-011) provided revisions to the package insert to remove that indication and related labeling statements regarding the combined use of Tripilix and statins and CV risk. Approved labeling now states – Limitations of Use: Fenofibrate at a dose equivalent to 135 mg of Trilipix did not reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus.

From this example – it appears clear that regulatory precedence provides enlightenment into the FDA’s ruling. A thorough assessment of current scientific knowledge and regulatory precedence are common activities that Premier Consulting uses for strategic, streamlined 505(b)(2) regulatory drug development.

In terms of where Amarin stands now, they will continue with the ongoing outcomes study, REDUCE-IT, investigating whether the addition of VASCEPA 4 g daily ameliorates residual CV risk among patients at high CV risk who have moderate hypertriglyceridemia at LDL-C goal on statin therapy. In accordance with the SPA agreement for the REDUCE-IT study, an interim review of the efficacy and safety results of the trial is scheduled to occur upon reaching 60% of the target aggregate number of CV events. Amarin indicated they expect this interim review by the study’s independent data monitoring committee (DMC) to occur during 2016 based on the understanding of the current event rates in the study and expected future event rates.

In terms of First Amendment protection for truthful and non-misleading off-label promotion (dissemination of information relating to the use of VASCEPAVASCEPA in patients with persistently high TG) – Amarin so far has the outcome it wants – the ability to promote to physicians the VASCEPAVASCEPA results in statin-treated patients with persistent high TGs, a large market opportunity (as can be seen in a recent Amarin Investor Presentation).

In conclusion, relevant scientific knowledge and regulatory precedence appear to have played key roles in the FDA decision to rescind the SPA and the request for data showing a reduction in CV events (i.e., data from the REDUCE-IT trial) prior to approval. Premier Consulting is well aware of these factors as they come into play in various regulatory scenarios and can greatly impact the strategy for moving a drug’s development program forward in a successful and time-efficient way. The Amarin case is just another example of many in which the outcome by the FDA appears to be driven by both science and precedence.

[Note: Amarin is not new to divergences with the FDA as described in a previous blog regarding the eligibility of VASCEPA for New Chemical Entity (NCE) exclusivity].

Author:

Stacey Ayres, PhD
Director of Scientific Research Services

References:

1. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. NEJM 2010;362:1563-74.
2. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. NEJM 2011;365:2255-67.
3.  Kotwal S et al. Omega 3 Fatty Acids and Cardiovascular Outcomes: Systematic review and Metaanalysis. Circ Cardiovasc Qual Outcomes 2012;5:808-18.
4. The Risk and Prevention Study Collaborative Group. N-3 Fatty Acids in Patients with Multiple Cardiovascular Risk Factors. NEJM 2013;368:1800-8.
5. Rizos EC et al. Association between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events. JAMA 2012;308 (10):1024-33.