The EPA
Drug Initiative

Citizen Petition - Sample Comments

We have faith and trust in the integrity of the FDA and truly believe the agency will make the right decision regarding the ANCHOR Special Protocol Assessment Agreement and the sNDA, as it works to speed innovation and advance / protect public health. We do not envy the task they have before them and thank them for their service.

Below you will find a selection of comments to the Citizen Petitions, that request the FDA overturn their decision to rescind the SPA for Vascepa.

Bob Lyon, MD

As a physician I am very disappointed at the decision to rescind the SPA and the extremely unscientific manner in which the original FDA review was handled. I won't go over the details already stated but to withhold a very safe drug that met all SPA guidelines because of studies of totally unrelated drug classes, looking at normal levels of triglycerides and ignoring the benefit in the high triglyceride sub group analysis is appalling.

Also, you are limiting a completely safe drug to lower triglycerides with few other good alternatives in the market. Niacin has proven to NOT be beneficial, Fibrates data has been borderline and the side effect profile is very bad, Lovaza significantly raises LDL and has Arrhythmia side effects. Vascepa at least has great surrogate marker improvements and the JELIS study to back up it's efficacy. I also want to see the results of the REDUCE-IT trial to assure myself of its CV efficacy. But, in the meantime there are very few alternatives to use for high triglycerides.

There are thousands of drugs approved on the market that have no outcome study benefit but are used because they improve surrogate markers - look at most of the diabetes medications and meds like Zetia.

Vascepa should have at least a modified label to allow in trigs of 200 - 500 with the marketing of the data and JELIS study until REDUCE-IT is completed.

Mary Vafi RN, LPC, Gerontology Specialist

With the recent ruling on the drug Vascepa for the treatment of triglyceride levels of 200 to 500 mg dl range, the FDA sends an unwelcome message to millions of Americans at risk of disability or death due to heart disease.

As an older adult who relies on Medicare for insurance purposes, the failure of the FDA to present a coherent picture of just what constitutes treatable elevated triglyceride levels and how to treat it causes considerable concern. Since the FDA has not approved Vascepa for individuals with triglyceride levels in the 200 to 500 range it will not be considered by Medicare as "medically necessary" and thus will not be covered under Medicare D. What then is the answer? Is the FDA asking Americans to continue to rely on statins for control of high cholesterol levels, when the research is showing that cholesterol is necessarily not the problem, and that treatment of elevated triglycerides is more likely the treatment of choice in cardiovascular risk scenarios? Statins come with a laundry list of side effects, muscular ailments, memory problems, and Diabetes Mellitus to mention a few, and many are unwilling or unable to take these drugs.

At this time, when the issues of health care costs are of such concern, and the need is to get the best bang for the buck, it seems curious that the FDA would rule against a treatment that offers so much potential with a minimum of side effects.

It would likely benefit all Americans if the FDA would revisit this issue with the intent of clarifying their reasoning and research methodology in the case of Vascepa and elevated triglycerides.

The number of errors, inadequacies and outright manipulations orchestrated by FDA personnel in the case of Vascepa is truly shocking. The situation must be rectified. A first step, as this Citizen's Petition requests, is to reinstate the SPA.

Everything stated in the Citizen's Petition is true. FDA's position regarding Amarin Corp. and its product, Vascepa, is unfair, biased and demonstrably wrong. The situation MUST be rectified.

Eric Javel, PhD

I am a retired biomedical research scientist and university professor. I have been a recipient and reviewer of numerous Federal research grants. I have sat on multiple NIH review committees, and I know how the process works. I know how to read and interpret scientific data.

What FDA personnel did in their Advisory Committee meeting of 10/16/2013 was truly scandalous. There was clearly a negative agenda in play, and FDA personnel did their best to promote it. Moreover, the make-up of the panel was sub-par in that it contained no one who could be considered to be an expert on lipid science, and it consisted of several voting members who were clearly in no position to judge the scientific merits of Vascepa. The so-called “expert review” provided by FDA in the briefing documents was highly flawed. As documented in the Citizen's Petition, FDA reviewed existing literature incorrectly, did not consider performance in the appropriate clinical sub-groups, did not cite other relevant studies, and drew conclusions that were unsupported by the evidence. Whoever wrote this incompetent review should be admonished severely, and so should the supervisor who accepted and promoted it.

The applicant, Amarin Corp., was not allowed to rebut the incorrect arguments made by FDA staff during the Advisory Committee meeting. This obviously biased the result. The voting question concocted by FDA did not address the issue at hand, namely Vascepa's safety and efficacy in treating the target mixed-dyslipidemic population. Rather, FDA insisted that panel members predict the results of an ongoing outcome study and base their votes on that. Obviously this is impossible. Recognizing this, the committee asked that the voting question be revised to consider only what Amarin was asking for. FDA personnel rejected this. In the end most panel members did what they thought FDA wanted, namely a negative vote. Was the Advisory Committee meeting a farce? Yes. Were the proceedings unfair to Amarin? Yes. Were the committee members unfairly coerced into voting against Amarin? Yes. Was FDA wrong? You bet.

FDA seems to be taking a hard line defending their highly flawed point of view. Following the Advisory Committee meeting they took the highly unusual action of rescinding the Special Protocol Agreement (SPA) previously entered into with Amarin, citing the appearance of a “substantial scientific issue essential for determining the effectiveness of Vascepa.” This is a joke. Vascepa's safety and efficacy is unquestioned, and Amarin has fulfilled every condition in the SPA. What FDA personnel did was to misinterpret existing data to arrive at an erroneous justification for rescinding the SPA. The arguments against FDA's position are amply documented in the Citizen's Petition, and they are valid.

Many knowledgeable people have taken issue with the way FDA has treated Amarin, as well as the blatantly unfair way the advisory committee meeting was conducted and the inconsistency in drug indications and labeling permitted for Vascepa's competitors. There must a valid reason to provoke such an outcry, and there is. Plain and simple, FDA erred.

Clinical trials have amply demonstrated that Vascepa is safe, produces no significant side-effects, and does what it is intended to do. Several professional societies agree that the physiological response Vascepa elicits represents medically sound treatment. The health of millions of Americans is at stake here. It is likely that thousands of heart attacks and strokes and hundreds of needless deaths would be avoided if Vascepa were approved for use in treating mixed dyslipidemia.

Why, then, is FDA denying Americans at risk for heart attack and other maladies the opportunity to have Vascepa prescribed for them? FDA has an opportunity to rectify their errors, and they should take it.

William Jenkins, MD, JD

I take Vascepa for elevated HDL-C, it also cured my chronic lower back pain and dry eyes. I will not take toxic statins or Lovaza that increases LDL-C. Vascepa has no negative side effects. From the comments at the Adcomm it is apparent Vascepa wasn't approved to supposedly reduce health care costs, but preventive medicine does the opposite. Please approve the truthful labeling for high triglycerides.

Dennis Sapire, PhD

I am astounded that the FDA has not reversed its position on Vascepa's Anchor indication.

It appears the FDA capriciously excluded JELIS (a directly on point study), and included post hoc analyses of confounding groups in three obliquely related studies (which tested totally different meds than EPA and subjects with Trig levels below 200) while failing to tease apart these groups to discover that there were in reality positive outcome benefits for the Anchor population sub-groups when their trigs were lowered (those with trigs above 200). The FDA compared apples with oranges. If apples would have been compared with apples, the direct opposite result would have been achieved using the self-same post hoc data: EPA appears likely to have a positive impact on CV outcomes, consistent with long held belief, the basis for the SPA, current medical practice, the FDA's own website's, and the JELIS study.

Let's not forget, the ANCHOR study succeeded with a stellar safety profile.

The rescission of the SPA was, in fact, the result of a scandalous analytical failure as all evidence (appropriately analyzed) points to the likelihood of substantial benefit!

In addition, the Adcom was forced to answer an impossible and unfair question - "What will Reduce-It show?" (my paraphrase).

If the FDA did not have a solid scientific basis for determining that a new (since execution of the SPA) and significant, scientific issue has been discovered that undermined the assumption that lowering elevated Trigs using EPA will likely have long term benefits for patients, the FDA had no basis for rescinding the SPA.

The SPA was created with a plan to conclude Reduce-It post marketing. There was always uncertainty as to long term CV benefits. But post hocs from two of the three studies (the third could not be teased apart to provide any relevant information) used by the FDA and the JELIS study support the likelihood that Vascepa will have positive long term CV benefit.

There is no basis for claiming a new and significant scientific issue casts doubt on the hypothesis - the opposite is true - new studies support the FDA's long held assumptions!

The FDA is fully aware of its obligations as servant of the American people including the millions of patients with elevated Triglycerides (150 - 499) who would likely benefit from Vascepa.

Everyone makes mistakes.

I urge the FDA to honor its obligations, to correct the error, to resuscitate the SPA, and to approve Vascepa for the Anchor indication without delay.

Tom Hitchcock, Registered Dietitian

On October 16, 2013 the Adcom had recommended that Vascepa approval for mixed dyslipidemia wait until results of the REDUCE-IT trial are completed. The voting question pertained to the level of confidence that considering the data available, what is the likelihood that Vascepa would be successful in treating CHD. I respectfully disagree with the results of this vote. Three studies were presented to the panel which used drugs with different methods of action. Two of the studies cited (ACCORD Lipid and AIM HIGH) both showed a reduction of CVD risks of 28% and 37% respectively in the sub-population covered by the ANCHOR SPA. Omission of this sub-population data in my opinion has unfairly negatively impacted the outcome of this vote. Unlike other treatment options for mixed dyslipidemia, Vascepa has a safety profile that is similar to placebo. Vascepa positively affects numerous biomarkers associated with increased risk of CHD as it decreases triglycerides, non HDL-C, LDL-C, ApoB, LDL particle concentration, Lp-PLA2, hsCRP, Apo C-III, and cholesterol. While some of these biomarkers are considered "exploratory", in my opinion, they should not be written off but considered as improving the odds of an effective treatment. Considerable research on EPA has shown positive correlation on CHD. EPA has been shown to reduce inflammation, improve arterial stiffness, and show significant improvement in plaque area, lumen area, as well as soft plaque volume. According to a study published in 2012 regarding cardiac disease, Japan was found to have a death rate from heart disease 71% lower than America with the major difference being inflammation (measured by the AA/EPA ratio) lower by 76% (refer to uploaded file). Also, the JELIS study showed a reduction in coronary events of approximately 19%, a 53% reduction when looking at patients with a triglyceride level above 150 mg/dl and an HDL level below 40 mg/dl. Average daily consumption of EPA/DHA in the American diet is poor at approximately 125mg; well below the therapeutic 2g and 4g dose used in the ANCHOR trial. Failure to approve Vascepa for the mixed dyslipidemia indication could unnecessarily place many lives at risk, increase future health care costs, and jeopardize the completion of the REDUCE-IT trial which is currently under way. I humbly request Vascepa be approved before completion of the REDUCE-IT trial for the mixed dyslipidemia group. Thank you.

Lucia Carrera

I am extremely concerned the FDA has over stepped its authority by rescinding the SPA with Vascepa. I for one have been suffering with increased CVD risk and all my research indicates Vascepa is the most effective and safe option for me, but this decision by the FDA will remove a safe efficacious drug as an option for me. To make me wait four more years for Vascepa that is safe as placebo is unconscionable. I demand the FDA act immediately to do what is best for the citizens it is charted to protect and reinstate the SPA. I work in the telemetry department of a large metropolitan hospital where I see first hand the effects cardiovascular disease does to the elderly. Our country is in a health crisis with CVD and the financial implications are compounding the deficit. The FDA has made a big mistake in its actions and I have joined this fight to ensure the decision is reversed. A very concerned citizen.

Sidney Idumonyi

Direct from the FDA website:

"What is the approval process for a new prescription drug?

Drug companies seeking FDA approval to sell a new prescription drug in the United States must test it in various ways. First are laboratory and animal tests. Next are tests in humans to see if the drug is safe and effective when used to treat or diagnose a disease.

After testing the drug, the company then sends FDA an application called a New Drug Application (NDA). Some drugs are made out of biologic materials. Instead of an NDA, new biologic drugs are approved using a Biologics License Application (BLA). Whether an NDA or a BLA, the application includes the drug's test results manufacturing information to demonstrate the company can properly manufacture the drug the company's proposed label for the drug. The label provides necessary information about the drug, including uses for which it has been shown to be effective, possible risks, and how to use it.

If a review by FDA physicians and scientists shows the drug's benefits outweigh its known risks and the drug can be manufactured in a way that ensures a quality product, the drug is approved and can be marketed in the United States."

The key point here is "If a review by FDA physicians and scientists shows the drug's benefits outweigh its known risks and the drug can be manufactured in a way that ensures a quality product, the drug is approved and can be marketed in the United States"

Also from the FDA website:

"Triglycerides are another form of fat in your blood that can raise your risk for heart disease. You may need treatment if your triglycerides are:

  • Borderline High (150 - 199 mg/dL)
  • High (200 mg/dL or more)"

Bottomline:

Given its excellent safety profile, the potential benefits of Vascepa (TG lowering and potential for reducing CVD events) clearly outweigh the risks of the drug.

Michael Niziol, MD

I have grave concerns regarding the FDA’S handling of the ADCOM meeting for consideration of VASCEPA in the treatment of triglycerides in the 200 - 500 mg / dl range. Below are a list of occurrences that I believe the FDA and its members and consultants need to take note of:

  • The FDA could not reject Vascepa based on safety or efficacy so most amazingly they rejected existing standards of care indicating that Triglycerides between 200 - 500 mg/dl not be treated. This groundbreaking information was never given to practitioners who continued to prescribe billions of dollars of medication to treat Triglycerides in the 200 – 500 mg dl range. The only public notification of this groundbreaking news was in an SEC Form 8-K to AMARIN investors.
  • Since that time new guidelines have been release regarding the treatment of lipids. However, it should be strongly noted that the guidelines make no mention of any revision of triglyceride treatment parameters. They have neither removed nor changed guidelines with respect to triglyceride treatment. The FDA has removed triglyceride parameters with no evidence as to why.
  • We are all aware that the new guidelines indicate that treatment with statins should occur based upon risk factors alone the implication (as we have known for some time) is that statins do more than lower LDL. Consider if Zetia had presented first to the FDA for the treatment of LDL. Utilizing the same logic that was applied to Vascepa (that since other meds that lower triglycerides do not change CAD incidence therefore Vascepa must not) – statins would never have been approved - millions of life years would have been lost. Of grave concern therefore is the inappropriate inclusion of Vascepa in the same category as other medications that lower triglycerides.
  • The FDA prevented the most compelling evidence regarding lowering of cardiovascular outcomes with EPA (JELIS Study) from being presented to the ADCOM committee. So not only was an inappropriate link made between Vascepa and other medications (as described above) actual evidence regarding the specific drug itself was not allowed to be presented. This would be equivalent to preventing any of the myriad of studies regarding statin benefit from being presented and then saying Statins are the same as Zetia and therefore should not be approved.
  • After meeting all of the agreed upon ANCHOR endpoints the FDA amazingly changed the requirements at the ADCOM meeting and asked the panel to predict the results of a future study.
  • The FDA then indicated to the general public that trans-fatty acids – most of which are converted to Triglycerides in the body should be reduced. In direct contradiction to their statement that triglyceride levels in the 200 - 500 mg / dl range should not be treated (If one wished to argue about inflammatory markers as a result of triglyceride consumption then this makes Vascepa’s position even stronger)
  • The FDA then approved a drug (Antara) and their label, which states that lowering Triglycerides has no effect on cardiovascular outcomes – the very reason they rejected Vascepa!
  • The FDA’s website still indicates that triglyceride > 200 mg / dl be treated
  • The FDA indicates to Amgen and Sanofi that their new PCSK9 drugs do NOT need to prove they prevent heart attacks and death before they’re approved... but Vascepa does!
  • When one views the ADCOM meeting at approximately 22 minutes in starts the confusion – Dr. Coleman advises panel members to use parameters considering Vascepa’s effect on CAD – he then says answer the question without REDUCE–IT (study on CAD occurrence). These are DIRECTLY contradictory! It would be like saying take the test with your calculator but you cannot use it. The fact that no panel member raised a question on this should be of grave concern.

Of course the reason of having meetings such as the ADCOM is to seek input from multiple sources and ultimately arrive at the correct conclusion for the benefit of society in general. I do believe that we can right this wrong and ask all of the dedicated scientists and physicians who have worked on this issue to please seek out what is scientifically correct and do what will benefit humanity the most.

Bruce Holland

The 9-2 vote is evidence of scientific uncertainty - a scientific question mark. How can the FDA state (with certainty) that a substantial change in the science has occurred?

The FDA stated that triglyceride lowering in NORMAL patients didn’t have a cardiovascular outcomes effect. That’s correct and no one should expect that to have an outcome benefit. But Amarin should not be held accountable for no change in normal patients.

Unfortunately, that’s exactly what the FDA has done here, comparing inappropriate groups and drugs to Amarin's clinical data for Vascepa. And in reality, little if anything has changed since the original ANCHOR file was put in place 2009, as there is no new news regarding the triglyceride lowering hypothesis.

Amarin did not seek an indication for CD risk reduction in the sNDA for ANCHOR. It was never the intent of the ANCHOR trial to address the question posed to the panel, nor do we believe it was fair to ask the panel to try to extrapolate such a CV risk reduction conclusion from the ANCHOR results. Based upon how the question was phrased, the panel essentially had no choice but to vote no in advance of the completion of the REDUCE-IT cardiovascular outcome study. Thank you.

Steven Polzin, PhD

I want to express my concerns regarding the FDA actions relating to Amarin. I approach this not as a medical professional but rather as an investor with a PhD in engineering (Northwestern 1986) and 30+ years of analytical research experience. I know how hypotheses should be tested and scientific conclusions reached. The other evening I was listening to a commercial spot for an FDA approved product. After 15 seconds of well-crafted promotion the commercial proceeded with approximately 45 seconds of cautions and qualifiers listing some horrendous potential side effects for an FDA approved noncritical medication. Yet, I recalled FDA staff stumbling and fumbling at the October ADCOM meeting before finally admitting there were no compelling safety issues associated with Vascepa. In the meantime, a growing body of anecdotal evidence, in many cases supported by science, indicate Vascepa’s side effects include such things as improved mood, reduced dry eye, reduced inflammation, improved sleep and energy levels, etc. – with no evidence of safety problems.

After the begrudging acknowledgment that there were not safety issues, the ADCOM meeting stumbled through a virtually incomprehensible discussion of the efficacy of Vascepa. Differences between the special protocol agreement, the FDA voting question language, and the discussion led by the FDA left virtually everybody in the room completely confused or frustrated. While the pursuit of evidence-based justification for expanded application of drugs may be meritorious, the forum for that pursuit should not be an ADCOM meeting with an SPA in effect. If the FDA is inclined to move in that direction it should be done in a transparent manner with a systematically applied strategy with all stakeholders appropriately engaged and with the medical and scientific analyses available that would be appropriate to guide policy and procedural changes to move in that direction. To attempt to change practices in an ad hoc, incremental and nonsystematic fashion was grossly inappropriate and unfair to Amarin. The medical community, both in testimony at the ADCOM and in subsequent communications indicated that they favor expanding the arsenal of products available to treat the target population of the proposed expanded labeling for Vascepa.

Perhaps most troubling was the interpretation of partial results from dated studies of different products, at different dosage levels, and with different target populations, as the basis for implying Vascepa would not be effective in reducing cardiac events. Any research scientist with a modicum of competence would recognize the logic errors in that interpretation. Indeed, the preposterousness of that interpretation coupled with the delayed NCE determination, the clean 74 day letter, the unprecedented post-ADCOM SPA rescission citing “new" science – most of which was available when the SPA was authored, and much of which was preceded and superseded by substantial evidence both empirical and theoretical espousing the role of EPA in improve heart health – have created suspicions regarding the objectivity and/or competency of FDA in this matter. A robust analysis of this issue would have included reviewing hundreds of scientific articles on EPA which is sole component of Vascepa. These articles describe and explain how EPA lowers chronic inflammation. The clinical significance of EPA's importance has been validated by population studies that indicate the EPA/AA ratio in a population is inversely related to the risk of CVD in a population, even when the LDL-C is the same among the populations compared. The FDA and the panelists showed no indication of being aware of any or all this information.

The ADCOM folly was further highlighted when a panel member questioned why an expanded indication was necessary when doctors could prescribe off label. This stunningly naïve statement was oblivious to economics and health practice standards and raised suspicions as to the fundamental competencies for that ADCOM of at least some panel members. The trivialization of the prospect of delayed patient benefits – particularly with the well-known shortcomings of the available treatment options for the target population – and the economic consequences of delay on the prospect of Reduce-it being completed, further undermined confidence that the panelists and FDA staff grasped the full implications of the issues they were impacting. Perhaps most important, the potentially significant precedents regarding evidenced based medicine and the FDA’s implicit engagement in determining the medical need for treatment that would result if subsequent FDA actions for other substances are evaluated consistent with how Amarin’s application, makes one wonder how well the ADCOM voting question and meeting agenda were thought through.

The post ADCOM SPA rescission appeared to be an attempt to use the cover of the ADCOM vote as a rationalization of what should be a very serious science-based decision made after consultation with the applicant and appropriately qualified medical experts. As the “new science” referenced in the SPA recession was available years ago, why wasn’t the SPA rescission discussion held in an appropriate forum in a timely manner so the applicant could plan accordingly?

Obviously, I encourage the FDA to reconsider their previous positions regarding Vascepa and their treatment of Amarin. I realize the natural human tendency is to be defensive when challenged and I recognize there are uncertainties and judgments involved. However, anyone watching the ADCOM with a modicum of objectivity and context would realize the handling of Vascepa by the FDA has been extraordinarily flawed. I encourage you to work toward a much more logical, fact-based and fair path forward.

Again, please reinstate the ANCHOR SPA and approve Vascepa for patients with high triglyceride levels. Thank you.

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