ronova BioPharma Norge AS BY HAND DELIVERY CITIZEN PETITION Statement of Grounds Lysaker, February 25, 2011

Transcription

1 Lysaker, BY HAND DELIVERY 2011 FEB 28 P 2 : 45 Division of Dockets Management Food and Drug Administration Department of Health and Human Services 5630 Fishers Lane, Room 1061 Rockville, Maryland USA CITIZEN PETITION Pronova BioPharma Norge AS ("Pronova") submits this Citizen Petition pursuant to the Federal Food, Drug, and Cosmetic Act ("FDC Act") and the Food and Drug Administration's ("FDA's" or the "Agency's") implementing regulations at 21 C.F.R to request the Commissioner of Food and Drugs to make available the information in this Petition as described below, to help ensure the safety of products containing fish oils. I. Actions Requested This Citizen Petition requests that FDA make the information discussed in this document available to the appropriate scientific reviewers within the Agency with responsibility for products containing fish oils (including omega-3-acid ethyl esters and related components). This Petition provides a discussion of scientific information that may not be readily known by or available to Agency personnel, but which may be important to consider when assessing the safety of fish oil-containing products. Statement of Grounds A. Factual Background On November 10, 2004, FDA approved NDA for Lovaza (omega-3-acid ethyl esters) Capsules.' Lovaza is indicated for use as an adjunct to diet, for the reduction of very high triglyceride levels (hypertriglyceridemia) in patients. 2 Lovaza is a mixture of 2 Although GlaxoSmithKline (GSK) is the NDA holder, GSK licensed certain rights to Lovaza R from Pronova, which (as has been publicly disclosed) supplies the primary raw material for the drug product. Lovazat Package Insert, approved by FDA on December 22, 2010, available at Hypertriglyceridemia is a serious disease associated with risk for pancreatitis which can lead to chronic pancreatic exocrine and endocrine deficiency and death. Hypertriglyceridernia has been implicated in the development of atherosclerotic vascular disease that may lead to lifethreatening complications. ronova BioPharma Norge AS Mail address Visiting address Contact pronova@pronova.com Invoice address P.0 Box 420 Vollsveien 6 Telephone Web P.0 Box 2109 NO-1327 Lysaker NO-1366 Lysaker Fax Org.no NO VAT NO-3202 Sandefjord Norway Norway Norway FDA `doil Aolgo 80

2 Page 2 of 8 P;',01**410\01, endogenously available omega-3-acid ethyl esters and other components obtained from the body oil of specific species of fish. Each Lovazat capsule contains one gram of purified fish oil comprised of % w/w purified eicosapentaenoic acid ethyl ester ("EPA") and approximately % w/w docosahexaenoic acid ethyl ester ("DHA"). Other omega-3- acid ethyl esters contained in Lovazak, include docosapentaenoic acid ethyl ester ("DPA"), stearidonic acid ethyl ester (-SDA"), heneicosapentaenoic acid ethyl ester (-HPA"), eicosatetraenoic acid (-ETA -), and alpha-linolenic acid (-ALA-).3 The fish oil starting material from which Lovazat is manufactured also contains other biologically active ingredients including cholesterol, saturated fats and omega-6-acid ethyl esters, such as arachidonic acid ethyl ester ("AA"). This starting material further contains various persistant environmental organic pollutants such as dichlorodiphenyltrichlorothane (-DDT"), dioxins, and polychlorinated biphenyls (-PCBs"). In addition, a more recent public concern has been the accumulation of brominated flame retardants ("BFRs -) in the environment and living organisms (including fish). These substances are used to reduce the flammability of a wide range of consumer and industrial products and materials. BFRs have been studied in more detail in recent years because of their persistent nature and increasing prevalence in humans and animals. It is important to note that the Lovaza manufacturing process includes various steps such as stripping that are specifically proven to reduce the concentration of dioxins, PCBs, BFRs, and several other known persistent organic pollutants in fish, to very low levels. According to the present release specification, a 4 g dose of fish-oil could potentially expose patients to daily intakes that approach or exceed the U.S.-EPA suggested daily exposure limits. However, as a result of the manufacturing process which includes specific purification steps, actual batch testing demonstrates that the impurity limits in Lovaza are substantially below the permitted maximum levels in the approved specifications. Thus, Lovaza users are exposed to actual impurity levels that are below the U.S.-EPA suggested limits. Pronova is in the process of revising the Lovazat active pharmaceutical ingredient ("API") release specification for PCBs and other impurities to better reflect the very low levels actually present at the conclusion of all manufacturing steps. B. New Scientific Developments Since the approval of Lovazat in 2004, a considerable amount of new information has been published in the scientific literature concerning the potential health effects of exposure to PCBs and BFRs. Pronova does not believe that much of this information has been reviewed in a comprehensive fashion, despite the potential importance of these impurities to the safe consumption of products containing fish oils. 3 These omega-3-acid ethyl esters are known by various names in the NDA and in the literature. DPA (C22:5 n-3) is also called clupanodonic acid. SDA (C18:4 n-3) is also called moroctic acid. HPA is C21:5 n-3, ETA is C20:4 n-3, and ALA is C18:3 n-3.

3 Page 3 of 8 PRONION/11. In light of these concerns, this Citizen Petition provides an objective review of the relevant scientific literature on the potential health effects of exposure to PCBs and BFRs. The following sections present a summary of the findings. A more detailed discussion is presented in the attached reports, which were prepared by appropriately-qualified toxicology experts. C. Summary: Polychlorinated biphenyls (PCBs) - Biological Effects and Risk Assessment Background. Polychlorinated biphenyls cover a group of environmental pollutants that are highly persistent and may be globally circulated by atmospheric transport. Because of their lipid solubility and their resistance to degradation in nature, PCBs tend to biomagnify in the food chain and may persist in the human body for a life-time. The production and use were banned in late 1970s and the levels of PCBs in the environment and human tissues are now declining. However, the downward trend is slow and considerable levels are still detected in biological samples. PCBs occur at highest concentration in fatty foods which contribute to more than 90% of the daily intake for the general population. Fish and fish products have the uppermost levels of PCBs and it is therefore appreciated that these products are the main source for human exposure. Present hazard systems. The TEF system. PCBs consist of 209 different chemicals (congeners) that exhibit different physiochemical properties and biological activities resulting in diverse environmental distribution and toxic properties. To simplify hazard characterization and risk assessment, PCBs are divided into two main classes; the dioxin-like and the non-dioxin-like PCBs based on the mode of actions. For the 12 dioxin-like PCBs the toxic equivalency system is available (WHO-TEFs) as they exert the toxicity via the same receptor as dioxin. The TEF system gives the opportunity to quantify the health risk when the intake of these PCBs is known. However, for non-dioxin-like PCBs, even though they occur at the highest levels in human tissues and the toxic potential is extensively documented, no similar hazard system exists, and they lack international regulation. The mixture approach. As an alternative approach to evaluate the risks posed by PCB exposure, data from studies on the PCB mixtures most commonly used in industry may be used. Although the composition of exposures from food, water and air is not identical to the commercial mixtures, studies of environmental relevant mixtures (as breast milk) have been found to have comparable toxicity. Present regulation. Health risk assessment is based on the evaluation of current available toxicological exposure data, and it is set to protect all human subpopulations. A tolerable daily intake (TDI) is based on the assumption there exists a threshold dose for toxicity and it is expressed as the dose on a body weight basis that can be ingested daily over a lifetime without considerable health risk. TEQ. Risk assessment authorities around the world have used different approaches resulting in various TDIs for PCBs within the range of 1-10 pg TEQ/kg bw/day. It is noteworthy that the tolerable weekly intake (TWI) set by the EU in 2001 (14 pg/kg bw) was based on selected studies rather than all available data. Therefore, the German Environment Agency suggests that TDI for dioxin and dioxin-like PCBs should be reassessed by including all the relevant scientific data.

4 Page 4 of 8 P.CD IA OVAL For a typical PCB mixture (Aroclor 1254), a TDI for humans of 20 ng/kg bw/day has been determined based on the lowest level of PCBs that gave rise to adverse effects in a particular animal species (rhesus monkeys). Present exposure. Human daily intake has been estimated by combining consumption data with the concentration of pollutants in the different food items. The estimated European intake of dioxin-like PCBs and dioxin are pg WHO TEQ/kg, while the intake of nondioxin-like PCB is ng/kg/ day. The concentrations in US and Japanese inhabitants are comparable with the European levels while people from traditionally less industrialized countries have substantially lower concentrations of PCBs (Huan-yun et al. 2010). Breast-fed infants may be exposed to levels up to orders of magnitude higher than adults. Fish contribute substantially to the intake of dioxin and dioxin-like PCBs. In a study from the UK, PCB levels were measured in salmon available on the British market and it was estimated that 3 portions/week resulted in a mean intake of 3.93 TEQ/kg bw/day which exceed the TDI set by EU and WHO (2 pg/kg bw/day). Furthermore, studies on dioxins and dioxin-like PCBs from various fish oil supplements have demonstrated that intake at manufactured recommended doses alone would give exposure in excess of the TDI. In UK the levels of PCBs were measured in 33 fish oil supplements. Twelve of the 33 products contained PCB and dioxin levels that exceeded the maximum limit of 2 pg/g TEQ. Based on this study the UK FSA recommended a withdrawal of the polluted batches from the market (Fernandes et al., 2006). Health effects. Numerous reports have documented potential toxicological effects in top predators and human populations exposed to high levels of PCBs. Until recently the major endpoints associated with PCB exposure included endocrine disruption, cancer and adverse effects on the development and functioning of the brain, reproductive system and immunity. However, new data suggest that the study of PCB toxicity should extend to additional endpoints as cardiovascular diseases, diabetes and obesity. Highlights of recent relevant studies. Effects on the central nervous system (CNS): Because of the high lipid content the brain receives a large portion of the accumulated PCBs. Furthermore, PCBs and their metabolites cross the placenta, exposing vulnerable fetus to the PCB circulating in maternal blood. A recent analysis of studies on children cognition from different parts of the world show that all studies, except one, conclude with a clear negative effect on PCB exposure on cognitions in children (Schantz et al., 2003). A new report also finds an association between low level prenatal PCB exposure and ADHD-like behaviors in childhood (Sagiv et al., 2010). Malignancy: For many years PCBs were concerned as etiologic agents for several cancer forms, including breast cancer, whereas several studies showed no positive correlation between PCB exposure and cancer development, or possible positive correlation to some specific congeners or among particular populations. However, mounting new evidence suggest that PCB exposure contributes to the aggressiveness and metastases of breast cancer. A recent scientific publication showed that PCB may activate intracellular motor proteins thereby increasing cell motility and potentially metastasis (Liu 2010).

5 Page 5 of 8 451{5624p Cardiovascular disease: Exposure to environmental pollutants has been shown to play a critical role in the pathology of cardiovascular diseases, and new research (2008) has shown that PCB through the release of inflammatory mediators may promote development of obesity and obesity-related atherosclerosis. Using National Health and Nutrition Examination Study (NHANES) a recent publication (2008) also found that elevated PCB serum levels in Americans were significantly associated with hypertension, even when adjusted for age, gender, smoking status, body mass index, total cholesterol, and more. Diabetes. The prevalance of type 2 diabetes and insulin resistance syndrome have increased at a globally alarming rate. A recent study on a random sample of the general American population has showed that the prevalence of diabetes was more than five times higher in groups with higher concentration of PCB than in those with lower concentrations. Furthermore, the prevalence of diabetes was quite low in subjects with low PCB levels and high body mass index (BMI), suggesting that obesity was a risk factor for diabetes only when combined with high PCB levels (Lee et al., 2007).This finding is in accordance with the results from Ruzzin and co-workers (2010) which showed that rats exposed to crude, but not refined salmon oil, developed insulin resistance, abdominal obesity and elevated serum cholesterol through the dysregulation of lipid and glucose metabolism. Conclusion. PCBs are documented to induce cancer and disrupt normal functioning of the central nervous, immune and reproductive systems. Recent data suggest that the increasing prevalence of cardiovascular diseases, diabetes and obesity observed worldwide may also be associated with PCB exposure. Fish and fish oils for human consumption contain substantial levels of PCBs and it is estimated that people consuming these products regularly may exceed the tolerable daily intake suggesting that fish and fish oil alone represent a serious risk to human health. This intake comes in addition to exposure from other sources thereby increasing the risk. Because potential harmful concentrations of PCBs and other toxicants are frequently detected in fish and fish products, research on a wider range of products are warranted, including analyses of multiple lots to draw firm conclusions regarding the contamination of fish and fish products for human consume available worldwide. Moreover, detailed information from the manufacturer regarding quality control and purification procedures will be required in order to evaluate their impact on product quality. A more complete discussion of the toxicology data of PCBs is presented in the attached Appendices A and B. D. Summary: Exposure and effects assessment of brominated flame retardants Introduction. Brominated flame retardants (BFRs) consist of different groups of chemicals with a range of physiochemical properties. At present, three groups of compounds are used in large volumes; polybrominated diphenyls ethers (PBDEs), hexabromocyclododecane (HBCD) and tretrabromobisphenol A (TBBP A). BFRs are successfully used to protect the public from fires by reducing the flammability of materials like electronic equipment, furniture, textiles, plastics, and insulating materials from which they leak to the surrounding environment. BFRs are persistent and accumulate in living organisms including humans. Increasing levels have been observed in wildlife and human populations during the past decades. The rising trends in humans correlate with the increased

6 Page 6 of 8 world production of PBDEs. For the general population, food of animal origin is suggested as the main source of exposure, and because most BFRs are highly lipid soluble, fatty fish and fish oils are important sources and contribute to 75% of the human contamination. Other exposure routes, such as inhalation /ingestion of dust, have also been suggested to contribute significantly to the contamination of babies and toddlers but are less important in adults. Present regulation. To limit the occurrence, and protect health and environment from BFRs a number of voluntary and governmental actions has been made in EU and US. Current safe (lifelong) daily intake for human has been set to 0.1 lug/kg/day (RfD) in USA. Human exposure. Recent toxicological risk assessments suggest that the present human exposure of BFRs is close to and may also exceed the safe level set by US EPA (114/kg/day) The concentrations of BFRs in environment and people are considerably higher in USA and Canada than in European and Japanese people, and in contrast to the leveling off observed in Norway and Sweden the concentration is still rising in US breast milk (Darnerud, 2008; Thomsen et al., 2010; Hites, 2004). The highest levels of BFRs are detected in infants and toddlers, as a result of exposure from breast milk and house dust and it has been estimated that the daily intake via breast milk exceed the US reference dose (RfD) in 10% of US infants. Health effects. The widespread contamination of the environment and the detection in wildlife and humans has raised concerns on possible adverse health effects. In animal studies, exposure to BFRs has induced endocrine-, reproductive and behavior effects at doses not far from human exposure. Recent studies have reported a significant correlation between BFRs and thyroid hormone concentration and adverse neuro-development effects. Furthermore, human epidemiological studies have reported an association between exposure to BFRs and similar adverse effects as observed in animal studies. Conclusion. The widespread use of BFRs in consumer products and their persistent nature leads to ubiquitous exposure of humans and wildlife from fetal life to adulthood. Fish and fish oils for human consumption contain substantial levels of BFRs and infants and toddlers consuming these products on a daily basis may exceed the tolerable daily intake suggesting that fish and fish oil alone represent a risk to human health. This intake comes in addition to exposure from other sources thereby increasing the risk. Because potential harmful concentrations of BFRs and other toxicants are frequently detected in fish and fish products, research on a wider range of products is warranted, including analyses of multiple lots to draw firm conclusions regarding the contamination of fish and fish products for human consumption available worldwide. Moreover, detailed information from manufacturers regarding quality control and purification procedures will be required in order to evaluate their impact on product quality. A more complete discussion of the toxicology data of BFRs is presented in attached Appendix C. E. Conclusion Developments in the recent scientific literature suggest concerns over the potential health effects of exposure to various impurities in fish oils. Pronova requests that FDA make

7 Page 7 of 8 this information available to the appropriate scientific reviewers to help ensure the safety of these types of products. III. Environmental Impact Pursuant to 21 C.F.R. Part 25, Subpart C, Pronova claims a categorical exclusion from the need to prepare an environmental impact statement or an environmental assessment because the action requested by this Citizen Petition would not significantly affect the quality of the human environment. To Pronova's knowledge, no extraordinary circumstances exist. IV. Economic Impact Information on the economic impact of the action requested in this Citizen Petition will be submitted if requested by FDA. V. Certification Pursuant to FDC Act section 505(q)(1)(H), Pronova makes the following certification: I certify that, to the best of my knowledge and belief: (a) this petition includes all information and views upon which the petition relies; (b) this petition includes representative data and/or information known to the petitioner which are unfavorable to the petition; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me. I further certify that the information upon which I have based the action requested herein first became known to the party on whose behalf this petition is submitted on or about the following dates: August 4, 2009 through. If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations: Pronova. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition. Respectf Ily sub 'tt d, orten Chief E cutive Officer Prono BioPharma Norge AS

8 Page 8 of 8 PRO ploy& Appendices: [A] "Biological effects of polychlorinated biphenyls (PCBs) a review of recent relevant literature." [B] "Risk and exposure assessment of PCB in food and supplements - [C] "Exposure and effects assessment of brominated flame retardants" [D] Complete list of all references (numbered for convenience) References: (contained in 5 total separate volumes) Vol. 1 of 5: Appendix A: References 1 50 Vol. 2 of 5: Appendix A: References Vol. 3 of 5: Appendix B: References Vol. 4 of 5: Appendix C: References Vol. 5 of 5: Appendix C: References