She speaks!!
I did get your email and I’m working on it.
I’ll be in touch as soon as I can.
Virginia L. Behr
Ombudsman
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
(301) 796-3436
Web page: CDER Ombudsman
Sent: Sunday, December 15, 2013 10:44 AM
To: Behr, Virginia L
Subject: FDA Inconsistencies
Mrs. Behr,
The CDER Ombudsman (aka Ombuds) receives questions and investigates complaints from CDER-regulated industry, law firms, health care providers, and consumers, and informally resolves disputes between those entities and CDER. I am asking you to investigate the FDA's actions towards Amarin Corp. and it's October 16th AdCom and subsequent rescission of the Anchor SPA agreement.
The FDA has a well documented history of unethical behavior and conflicts of interest. In July of 2012, Senator Grassley wrote the FDA questioning the agencies behaviors towards it's own employess who had contacted Congress about unethical behaviors within the FDA. In this letter, Senator Grassley stated, "FDA's misconduct cannot be ignored." Unfortunately we find ourselves questioning the FDA's conduct again. The facts to be presented show clear and concerning misconduct and unethical behavior by the FDA towards Amarin Corp and it's drug Vascepa. The decisions the FDA have made, or refused to make, have become alarmingly inconsistent. Congress enacted SPA provision and the FDA Modernization Act of 1997 to eliminate what was known as the moving target syndrome or repeated changes in FDA’s advice about studies needed to obtain FDA approval. Congress needs to open an investigation to sustain public confidence in, and to reinforce an open and transparent decision making process by the FDA, free of unethical behavior and conflicts of interest.
If you are not aware, Amarin Corp. is studying the effects of EPA on lipid profiles and has an approved drug called Vascepa. Vascepa significantly reduced the TG levels and improved other lipid parameters without significantly increasing the LDL cholesterol levels. Heart attacks, strokes and other cardiovascular events represent the leading cause of death and disability among men and women in western societies. According to the American Heart Association's 2010 At-A-Glance Report, over 831,000 deaths in the United States were caused by heart disease and stroke, substantially more than the approximately 572,000 reported deaths caused by cancer. (American Cancer Society. Cancer Facts & Figures 2011. Atlanta: American Cancer Society, 2011)
FACTS
1. The FDA failed to honor an SPA (Special Protocal Assessment) agreement and later reneged on this agreement to justify it's position.
The FDA approved Vascepa, as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (TG greater than or equal to 500mg/dL) hypertriglyceridemia (very high triglycerides), in July of 2011. In February of this year, Amarin submitted an sNDA (Supplemental New Drug Application), seeking approval for the marketing and sale of Vascepa (icosapent ethyl) capsules for use as an adjunct to diet in the treatment of adult patients with high triglycerides (TG =200 mg/dL and < 500 mg/dL) with mixed dyslipidemia. As part of the agreement with the FDA, Amarin was required to conduct a 12 week efficacy study (Anchor) and substantially enroll a cardiovascular study. Amarin met all obligations set by the SPA agreement with the FDA. On October 16th, the FDA held an AdCom meeting to discuss the efficacy of Vascepa. At this AdCom, the FDA explicitly questioned the efficacy of whether reducing triglycerides in the Anchor Indication would have a positive effect on coronary heart disease or its risk equivalent. Keep in mind that Amarin and the FDA, as part of the Anchor sNDA approval, entered into a SPA (Special Protocol Assessment) agreement for the design of a cardiovascular outcomes study of Vascepa formally titled REDUCE-IT (Reduction of Cardiovascular Events with EPA - Intervention Trial) to answer that exact question. The FDA, with these agreements, led Amarin to believe that once REDUCE-IT was substantially underway, the Company would have met all of the requirements to request approval of Vascepa for treating the mixed dyslipidemia patient population studied in the ANCHOR trial.
Shortly after the AdCom, the FDA rescinded the Anchor SPA, as it had determined that a substantial scientific issue essential to determining the effectiveness of Vascepa in the studied population was identified after testing began. The FDA questioned the efficacy of Vascepa, citing the outcomes results of three studies, (Accord-Lipid, Aim-High and HPS2-Thrive), which according to the FDA failed to support the hypothesis that a triglyceride-lowering drug significantly reduces the risk for cardiovascular events among statin-treated patients with mixed dyslipidemia and residually high serum triglyceride levels (200-499 mg/dL). Because the results of all three of these studies were available to the FDA when Amarin agreed to amend the SPA for the REDUCE-IT study and because these concerns were not raised to Amarin in connection with the FDAs acceptance for review of the sNDA for ANCHOR or at anytime prior to the October 16 AdCom, the FDA failed to timely notify Amarin of these new issues. According to the FDA, "A clinical protocol assessment will no longer be considered binding if the director of the review division determines that a substantial scientific issue essential to determining the safety or efficacy of the drug has been identified after the testing has begun (section 505(b)(4)(C) of the Act). If the director of the review division makes such a determination, (1) the determination should be documented in writing for the administrative record and should be provided to the sponsor, and (2) the sponsor should be given an opportunity for a meeting at which the review division director will discuss the scientific issue involved (section 505(b)(4)(D) of the Act), This meeting will be a Type A meeting under the PDUFA goals for meeting management". There was no mention of this change at any point leading up to the AdCom including the sNDA acceptance letter (Day 74 Letter) for ANCHOR or at any time prior to the AdCom, even though the majority of this outcomes data was available for some time.
2. The studies used by the FDA do not provide substantially new scientific information
The Three studies used by the FDA to question the efficacy of Vascepa were not an apples to apples comparison and should not be used to invalidate the efficacy of Vascepa. The three studies (Accord-Lipid, Aim-High and HPS2-Thrive), did not use the same class of drugs, nor did they involve the patient population Amarin seeks to treat. All three studies, according to the FDA, failed to prove a significant reduction in cardiovascular events. However, all three studies involved patients with triglyceride levels far below that which Vascepa is intended for. None of those outcome studies prospectively enrolled patients who had elevated triglycerides in spite of statin control with LDL cholesterol. In ACCORD, which was a Fenofibrate study, the mean triglyceride level in the overall study was just 162 mg/dL. In the Aim-High, which was a Niacin study, the median triglycerides levels were 161 mg/dL. In HPS2-Thrive, another niacin study, the mean triglycerides were 1.43(0.84) mmol/L. Not one of these studies investigated reduction of triglyceride levels in the 200-500 mg/dL range which Amarin sought approval for. ACCORD and AIM-HIGH proved nothing other than triglyceride lowering has a neutral outcome effect on people with normal baseline triglyceride levels. With respect to the population studies in the ANCHOR trial, the FDA also appears to have entered into an SPA with another company for their drug after the ACCORD and AIM-HIGH data were publicly presented suggesting that these study results were not viewed by the FDA as substantially new scientific information at that time.
3. The FDA approves Antara (fenofibrate) for the treatment of high cholesterol, mixed dyslipidemian and high
triglycerides and allows fenofibrates to continue this treatment despite failed outcomes studies
On October 22nd, the FDA informed drug maker Lupin Limited (Lupin) that it had received final approval for it's fenofibrate drug Antara to treat patients with high cholesterol, mixed dyslipidemia and high triglycerides. The FDA, six days prior, used the failure of a fenofibrate study (Accord-Lipid) to question the efficacy of Vascepa and used this science to rescind the Anchor SPA agreement. The Accord-Lipid study failed to produce a significant reduction in cardiovascular events, yet Antara was approved to treat this patient population. Just recently the FDA and an AdCom panel voted to continue allowing fenofibrates to be prescribed for this patient population despite the failed outcomes trials. Again, no failed studies exist for Vascepa's efficacy in this patient population.
4. The FDA fails to allow Anchor study information on Marine Label
The FDA has failed to allow Amarin to have the ANCHOR data included in the clinical study section of the Vascepa package insert, yet, not become a formal indication for Vascepa. In doing so, the FDA may force Amarain to seek judicial relief to support their efforts, such as the right to use the ANCHOR data in commercial materials based on pre-commercial speech principles by doing the First Amendment, that protect the ability to communicate truthful information such as clinical trials results. As a comparison, the FDA affords Vascepa competitor Lovaza (GlaxoSmithKline) this exact right, which includes information for add-on therapy of Lovaza with a statin. Keep in mind the FDA rejected this study of co-administration of Lovaza with a statin as Lovaza raised LDL cholesterol. The failure of the FDA to allow Amarin to include the Anchor Indication information which is also a co-administrative treatment with a statin has been detrimental to the sales of Vascepa as sales representatives are prohibited in providing the information.
5. The FDA fails to provide Vascepa with an exclusivity designation
Exclusivity designations are made to protect drug makers from generic competition reductions and to create financial incentive for research and development. In 1992, under the Prescription Drug User Act (PDUFA), FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times – Standard Review and Priority Review. A Priority Review designation means FDA’s goal is to take action on an application within 6 months (compared to 10 months under standard review). Vascepa was approved July 26, 2012. Under any timeframe, the FDA has failed to make a ruling to the detriment of Amarin Corp. Additionally, the USPTO requested clarification from the FDA on whether Icosapent Ethyl (Vascepa) had ever been approved prior to July 26, 2013. The FDA failed to respond to the USPTO. Part of the reason for the delay in exclusivity designation was due to a Citizens Petition (known as Lovaza Citizens Petition) filed by John Fuson of Crowell and Moring LLP on February 6, 2013. Mr Fuson, who joined Crowell and Moring LLP May 30, 2012, happened to serve as associate chief counsel at the U.S. Food and Drug Administration (FDA) since 2007, where he worked with the U.S. Department of Justice's Consumer Protection Branch, bringing enforcement actions on behalf of the FDA. The petition was submitted to essentially list Vascepa's active ingredient retroactively for Lovaza, thus preventing NCE for Amarin's Vascepa. Section 505(q)(1)(F) governs the timeframe for final Agency action on a petition. Under this provision, FDA shall take final Agency action on a petition not later than 180 days after the date on which the petition is submitted. The 180-day period is not to be extended for any reason, including any determination made under section 505(q)(1)(A) regarding delay of approval of an application, the submission of comments or supplemental information, or the consent of the petitioner. To date almost 300 days later, a decision has still not been made by the FDA.
6. Sham Citizen Petitions and the anticompetitive effect
In a 95-page decision from the U.S. District Court for the Eastern District of Pennsylvania in In re Wellbutrin XL Antitrust Litigation, the court once again addressed the issues of “sham” citizen petitions, liability under the Sherman Antitrust Act, and Noerr-Pennington immunity. The court previously addressed citizen petitions alleged to be shams in In re Flonase Antitrust Litigation, 795 F. Supp. 2d 300 (E.D. Pa. 2011). When petitioning activity “ostensibly directed toward influencing governmental action[] is a . . . sham to cover what is . . . nothing more than an attempt to interfere directly with the business relationships of a competitor[, then] the application of the Sherman Act would be justified.” Noerr, 365 U.S. at 144. The sham exception requires that a petition be “(i) ‘objectively baseless,’ and (ii) ‘an attempt to interfere directly with the business relationships of a competitor through the use of the governmental process – as opposed to the outcome of that process – as an anticompetitive weapon.’” Primetime 24 Joint Venture v. Nat’l Broad. Co., 219 F.3d 92, 100-01 (quoting Prof’l Real Estate Investors, Inc. v. Columbia Pictures Indus., Inc., 508 U.S. 49, 60 (1993) (“PRE”)). The Lovaza Citizens petition, filed by Crowell & Moring asks "... the Commissioner could adopt a strength for Lovaza based upon the fixed amount of major omega-3-acid ethyl esters specified in the Lovaza reviews and labeling. According to its currently-approved labeling, "at least 900 mg of the ethyl esters of omega-3 fatty acids sourced from fish oils" "are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA - approximately 465 mg) and docosahexaenoic acid (DHA - approximately 375 mg)." By requesting EPA to be listed retroactively, the petition has created uncertainty and delay in the FDA's exclusivity designation of Vascepa. Lovaza maker GSK has opposed each and every request and recommendations made in the petition. GSK refutes the citizens petition by stating that the entire fish-oil based mixture in Lovaza-not just the ethyl esters of omega-3 fatty acids-constitutes the active ingredients. Because this petition interfered directly with the business relationship of a competitor, it needs to be investigated and determined with whom Crowell and Moring are representing. Unsurprisingly, GSK's drug Lovaza has benefited from this citizens petition.
Again, I'm asking you to look into this situation as it seems inconsistent with possible conflicts of interest. This company has done all that has been asked by the FDA and on December 20th the FDA will destroy it. The Science of EPA cannot be ignored forever. However, until it is heard, who will be responsible for the thousands of lives lost. The FDA is flat out wrong. I've included a list of supporting EPA documents and studies. Unlike me, you are in a position to get straight answers to your questions. I have emailed the FDA, DOJ, NIH, NHLBI and many others and at most got a form reply back. I'm asking for more, and I hope you will step up and provide this for me. I truly appreciate your reply and hope to hear from you soon.
