Bureaucratic Malpractice by the FDA?

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1 Bureaucratic Malpractice by the FDA? As an ad hoc (but rapidly growing and organizing) group of informed and expert citizens and individuals from other countries, we are writing to inform you of a rather urgent matter of public policy related directly to cardiovascular disease, one of the most pressing issues of American public health. We sincerely request your full possible attention and assistance in this matter as in our view, your constituents deserve much better. More specifically, we are deeply concerned by the review conducted by the US Food and drug Administration (FDA) in relation to a drug called Vascepa and sponsored by Amarin Corp, and the hereto unprecedented decision by the FDA to rescind a Special Protocol Assessment. The evidence to date suggests that: The FDA has used flawed, selective and inconsistent scientific data; The FDA has violated its own policies and procedures and/or adopted inconsistent application of them; The decisions and actions are inconsistent or questionable based upon the views of other leading expert groups; A number of other irregularities may be indicative of antitrust violations; and More importantly, the American public is being denied a drug with an abundance of good scientific evidence that it is of great potential benefit for reducing pathogenic factors that contribute to cardiovascular disease (CVD) and improving outcomes. Furthermore, Vascepa is safe and well- tolerated, has no adverse side effects and could significantly reduce overall healthcare costs (even beyond CVD). Following a highly irregular set of circumstances leading up to an Advisory Committee (AdCom) meeting on October 16, the Endocrinologic and Metabolic Drugs Advisory Committee voted 9 to 2 against recommending approval for Vascepa. The circumstances are, frankly, so bizarre that the sponsor has requested a Type A meeting with the FDA. Time is of the essence for both the imminent Type A meeting and the PDUFA date of December 20, Cardiovascular Disease in the United States Before proceeding further, we want to provide you with the most recent statistics in relation to CVD as provided by the American Heart Association: Approximately 84 million people in this country suffer from some form of cardiovascular disease, causing about 2,200 deaths a day, averaging one death every 40 seconds. Almost one out of every three deaths results from cardiovascular disease. 1

2 The direct and indirect costs of cardiovascular disease and stroke are about $300 billion. This figure is increasing every year. On average, someone in the U.S. suffers a stroke every 40 seconds. Stroke is a leading cause of serious, long- term disability that accounts for more than half of all patients hospitalized for a neurological disease. Cardiovascular disease is the cause of more deaths than cancer, chronic lower respiratory diseases, and accidents combined. Clearly, we have a very serious and urgent problem; so, why are we in this mess? A Little Bit About Vascepa and Amarin Corp Amarin Corp, (Amarin) an advanced clinical- stage pharmaceutical company with US headquarters in Bedminster, NJ. The company s focus is on reducing cardiovascular issues through lipid management. Vascepa, known chemically as Eicosapentaenoic acid (EPA), is an omega- 3 fatty acid derivative protected by over 16 patents in the United States, and is Amarin Corp s primary product. Vascepa was approved by the FDA in July of 2012 for treatment of high triglyceride levels (serum blood concentration of greater than 500 mg/dl), known as the MARINE indication. Approximately four million US citizens are afflicted with this health problem. Amarin s most significant competitor is the pharmaceutical giant GlaxoSmithKline (GSK) with its product, Lovaza. A significant problem faced by GSK (and others) is the pending expiration of intellectual property protection starting within the next 12 months. In addition to the patent protection, Vascepa has a number of clinical benefits over the products of competitors. The company s longer- term plans have included obtaining approval for the use of treating individuals with mixed dislipidemia (more than one lipid disorder) and mid- level triglyceride levels of greater than 200 mg/dl but less than 500 mg/dl, known as the ANCHOR indication. There are an estimated 40 million US citizens with this disorder. To date, no other pharmaceutical company has had a product approved to treat such individuals. Both of the MARINE and ANCHOR clinical trials were developed under Special Protocol Assessments (SPAs) in SPAs, as you may well know, are effectively contracts between the FDA and the sponsor that significantly enhance the prospects for approval if clinical endpoints are met, no safety issues are identified and there are no new substantial scientific issue essential to determining the effectiveness or safety of the drug. When MARINE and ANCHOR were negotiated, it was recognized that our collective knowledge and hard evidence of the precise nature of the relationship between triglycerides and CVD was lacking. For this reason, Amarin agreed to undertake the REDUCE- IT trial, also under SPA. REDUCE- IT is a significant undertaking for a small company like Amarin. The costs involved are in excess of $150 million and the trial involving over 8,000 individuals to develop hard outcomes data as to the link between CVD and triglyceride levels will is not expected to have results until As a side note to the REDUCE- IT trial, there has been an implicit expectation that Amarin s application for New Chemical Entity (NCE) status, which would further extend intellectual property protection, would be granted because of the costs incurred. 2

3 As a final key comment, preliminary and meta- analysis of other scholarly and scientific research provides a strong body of evidence that Vascepa has tremendous potential for other afflictions and conditions with some being related to pain and inflammation, memory and mood as well as dermatology. Where We Find Ourselves at Present The preliminary review of the ANHOR application found no matters of concern and a PDUFA date of December 20, 2013 was assigned. In the summer of 2013, many people were surprised that the FDA scheduled an Advisory Committee meeting for October 16, 2013, especially given the safety profile of the drug and that no concerns were identified in the review and that the drug had met all end points of the Special Protocol Assessment (SPA) agreed to by the FDA with flying colors. Despite being involved in and approving the design of the clinical trials, many people were horrified when FDA staff provided their briefing book to the AdCom and general public before the meeting of October 16. Two days before the meeting, the FDA moved the goal posts by suggesting a delay in the approval of ANCHOR with the REDUCE- IT results that will not be available for four more years. At the conclusion of the Advisory Committee meeting and, under circumstances that many would argue to be bizarre (discussed below), the Committee voted 9 to 2 not to approve the application. Later, on October 29, 2013, in an unprecedented move, the FDA rescinded the ANCHOR study SPA with Amarin Corporation. An excerpt of the FDA s communication to Amarin is below. a substantial scientific issue essential to determining the effectiveness of Vascepa in the studied population was identified after testing began. Specifically, the FDA cited results from other studies (the ACCORD- Lipid and AIM- HIGH outcome trials, as well as the publicly presented results from the HPS2- THRIVE outcome trial, which the FDA stated in its notice to Amarin), fail 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 ( mg/dl). Thus, the FDA stated that it no longer considers a change in serum triglyceride levels as sufficient to establish the effectiveness of a drug intended to reduce cardiovascular risk in subjects with serum triglyceride levels below 500 mg/dl. (Amarin Corp. Form 8- K announcement, 2013) This surprising and controversial and categorically unprecedented action by the FDA has created a great deal of confusion and concern, and question as to whether such action was justified. The FDA unilateral dissolving of a binding SPA sets a troubling precedence and could have important negative consequences for both the FDA and the pharmaceutical industry. OK, Fine but Mal Practice, Really? In a word, YES! While we can only provide an overview in this memorandum, we stand by our more detailed comments, videos, articles and notes found at our website: 3

4 Here s what we know and it s pretty shocking in our view. Use of Flawed, Selective, Inconsistent and Inappropriate Data The Executive Summary of the FDA Briefing Book refers to three outcomes trials completed subsequent to the ANCHOR SPA as supporting substantial scientific issue as the basis for rescinding the SPA: ACCORD- Lipid; AIM- HIGH; and HPS2- THRIVE. A brief overview of each study is presented in the following table. Summary of Study Objectives Study ACCORD- Lipid AIM- HIGH HPS2- THRIVE Primary Objective whether addition of fibrate to statin therapy compared with statin monotherapy alone reduces the risk of cardiovascular disease in patients with type 2 diabetes mellitus who are at high risk for cardiovascular disease whether treatment with extended- release niacin leads to a reduction in CVD complications in high risk patients with CVD. The CVD complication was defined as death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome or symptom- driven coronary or cerebral revascularization. to assess the effects of niacin (2 g) in reducing CVD risk in patients with occlusive arterial disease. The occlusive vascular disease was defined as history of myocardial infarction, cerebral vascular disease, peripheral artery disease, and diabetes mellitus with any of the above three vascular conditions. CVD risk was defined as coronary death, nonfatal MI, stroke, or coronary revascularization. To even a casual observer, it is apparent that the objectives of the studies differ widely from those of ANCHOR. When one reviews the studies in more detail and examines matters such as the comparability of the individuals, and other study flaws, the FDA s logic is an incredulous leap of faith. The FDA has refused to consider other and more recent studies that would question the logic and science used or to recognize post hoc sub- group analysis of the three studies that would be an apples to apples comparison and strongly support Amarin s case. Violation of Policies and Procedures The FDA rightly has strict policies and procedures for the conduct of meetings. Among other things, FDA's advisory committee program is governed by a number of Federal laws and regulations that set forth standards for convening advisory committees and reviewing potential conflicts of interest, among other things. FDA also has developed guidance documents that describe FDA's recommendations and policy related to advisory committees and matters such as briefing books and voting questions. In this instance, among other things: A single voting question (when there should have been several) that ignored safety issues and the effectiveness of Vascepa for the indication sought was leading and biased and structured to foster a no vote. 4

5 There was considerable confusion regarding the voting question and FDA staff were not forthcoming in answering questions or addressing concerns from committee members. The response of Dr Mary Parks was [paraphrasing] look, we ve considered this a lot but I m not going to get into specifics right now. (Approximately three weeks later, the American Heart Association produces new guidelines for treating cardiovascular issues.) Amarin staff and consultants were abruptly cut off when attempting to speak to issues and concerns raised by the FDA (which were unexpected). Please reference the video or transcripts of the meeting, in particular the last 90 or so minutes to garner the full context of the meeting. We make these laws, regulations, and guidance documents available through our web site to provide ready access to the statutory and regulatory framework that FDA advisory committees operate within and to describe the steps that FDA has taken to enhance decision making, increase transparency, and strengthen public confidence in our advisory committee program. Some Unsavory Lingering Thoughts and Doubts That Need Resolution Setting aside the forgone health and treatment benefits and potentially billions in savings that are now at risk, something is just not right and, while it is not possible to get into details in this note, we are left to wonder: Was the FDA s position and harsh treatment of Amarin to save face or avoid embarrassment of being out of step with the new AHA guidelines, notwithstanding that they are noted to be controversial and based upon older data? Is it easier for a large Federal Agencies to neutralize a small company rather than deal with controversial issues of a large association with industry ties? Heaven forbid is there some interest in not having Amarin succeed? Does Amarin present a disruptive influence to the business model of big pharma given the potential of Vacepa and the intellectual property issues faced by the industry? Why has the company been subject to a seemingly unending barrage of negative attacks from sections of the media? Have there been leaks of data? We can point to irregularities in the trading and share price of Amarin, and in hindsight statements made by individuals with timing that causes serious doubt in this regard. Has Amarin been thrown under the bus or forced to abide by a standard that is considerably higher than for the rest of industry? The FDA s current position that the results of REDUCE- IT are needed for before approval is hugely unfair. Notwithstanding that the company s revenue stream from the expanded indicated (expected to help to cover the cost of REDUCE- IT) is crippled and the viability of the company is challenged, there is a bigger injustice if Amarin attempts to complete the study. A number of other companies are attempting to obtain approval for the highly sought after 200 to 500 mg/dl indication. To date, none has been successful, and many are known to have programs under development. Amarin is the first to satisfy all of the requirements of the FDA according to a SPA. We are now faced with the 5

6 outrageous situation whereby Amarin will have done all of the heavy lifting and endured extreme costs (well over $100 million) to provide the data to link cardiovascular disease with triglycerides. It seems that they will now all get a free pass when their trials are completed in the next few years. If the FDA does not approve Vascepa for the indication requested by Amarin, then the Federal Government MUST assume the full cost of the REDUCE- IT trial. As a society, we have a desperate need for the answers that it will provide. Conclusion As we have noted, it is impractical or impossible to provide all of the details to the matters of which we speak in this letter. We are a small group taking on a large problem. We need your assistance to get the FDA to reconsider their position and would welcome your support, advice and kind consideration of time to allow us to provide you with additional details before it is too late. 6