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Arsenical Timeline Final Proofed

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Arsenical Timeline Final Proofed Backgrounder: FDA and Pfizer’s Collusion to Downplay Effects of Arsenicals in the U.S. Chicken Supply This document summarizes the FDA’s actions after learning that inorganic arsenic, a human carcinogen, was potentially present in the U.S. chicken supply and the FDA’s eventual decision to conduct its own study. It then discusses FDA’s relationship with Pfizer throughout this process and after the study results were made available. It details how the extremely close working relationship led to considerable collusion between the FDA and Pfizer in delaying the public release of the FDA’s study and in creating a coordinated media strategy, which included Pfizer supplying the actual content of the FDA’s media statements in order to minimize the impact of the announcement. The FDA has approved arsenical drugs for use in chickens, turkeys and pigs. These drugs have been approved for multiple purposes, including growth promotion, improved pigmentation and to treat, control and prevent animal diseases, such as coccidiosis, a parasitic infection of the intestinal track in poultry that can lead to death.1 The FDA has recognized organic arsenic as safe, while inorganic arsenic is considered a carcinogen. Chronic exposure to inorganic arsenic may lead to the development of lung, bladder or skin cancer, and is also associated with 1 Food and Drug Administration (FDA), Questions and Answers Regarding 3-Nitro (Roxarsone) (2011). Available at http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm2583 13.htm. cardiovascular disease.2 Inorganic arsenic exposure may also lead to diabetes, neurological problems in children and adverse pregnancy outcomes.3 Because there are a variety of sources of inorganic arsenic in food (including rice and apple juice), the FDA attempts to monitor these sources.4 Alpharma Inc. (which was purchased by Pfizer and then, along with the rest of its veterinary drug portfolio, spun off as a separate company, Zoetis, beginning in 20125), was a subsidiary of Pfizer that produced one of four arsenical animal drug products, roxarsone. Alpharma sold this product under the brand name “3-Nitro.” Because roxarsone is an organic form of arsenic, it has been approved for use in animal feed since 1944 under the assumption that animals metabolize arsenic and that there was no inorganic residue lingering in the edible tissue.6 Conflicting Study Results For decades, the FDA approved new animal drug applications (NADAs) on the basis that organic arsenic in feed does not significantly metabolize into its inorganic form 2 FDA, Arsenic Foodborne Illness and Contaminants (2013). Available at http://www.fda.gov/food/foodborneillnesscontaminants/metals/ucm280202.htm. 3 U.S. Environmental Protection Agency (EPA), Toxicity and Exposure Assessment for Children’s Health. Available at http://www.epa.gov/teach/chem_summ/Arsenic_summary.pdf. 4 FDA, FDA Statement on Testing and Analysis of Arsenic in Rice and Rice Products (2013). Available at http://www.fda.gov/Food/FoodborneIllnessContaminants/Metals/ucm367263.htm. 5 http://www.zoetis.com/about/history. 6 FDA, Questions and Answers Regarding 3-Nitro (Roxarsone) (2011). Available at http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm2583 13.htm. 2 when consumed by chickens, so there is no inorganic arsenic in the edible tissue.7 Additional NADAs involving roxarsone were approved over the decades without much additional scrutiny. In 2007, John F. Stolz published an article, Biotransformation of 3-nitro-4- hydroxybenzene arsonic acid (roxarsone) and release of inorganic arsenic by Clostridium species, which discussed study results demonstrating the possibility that Clostridium species, a microbe found in the stomachs of chickens, could transform roxarsone into inorganic arsenic.8 In a January 2009 letter (Exhibit A) to Alpharma, the FDA’s Center for Veterinary Medicine (CVM) remarked that “recent evidence, including some information in your submission, calls those assumptions [that there is no increase in inorganic arsenic levels] into question” and requested that Alpharma provide “a demonstration of an insignificant difference in the inorganic arsenic concentrations in control and treated birds . [that] would support our previous conclusions about roxarsone.” By 2009, the FDA had initiated its own study of roxarsone using newly developed analytical testing methods. (See Exhibit B.) The FDA described the new technology as “capable of detecting very low levels of inorganic arsenic in chicken 7 FDA, Questions and Answers Regarding 3-Nitro (Roxarsone) (2011). Available at http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm2583 13.htm. 8 John F. Stolz, Biotransformation of 3-Nitro-4-hydroxybenzene Arsonic Acid (Roxarsone) and Release of Inorganic Arsenic by Clostridium Species, 43(3) Envtl. Sci. Tech. 818 (2007). Available at http://pubs.acs.org/doi/abs/10.1021/es061802i. 3 liver” after the FDA was unable to develop reliable testing methods for the muscle portion of the chicken. (Id.) In December 2009, Alpharma responded to CVM’s January request for more information by stating “[a]lthough at the time of our 2005 submission, we believed the method would provide valid results, subsequent efforts to validate the method proved unsuccessful because the extraction method used did not completely extract total arsenic (i.e., it underestimated the arsenic content)” (Exhibit C.) The letter also made the argument that the Stolz study, which demonstrates that the microbial content of chicken litter and environmental factors provide the conditions necessary to transform roxarsone to inorganic arsenic, that would be unlikely to occur in a real-life scenario.9 (Id.) In June 2010, the FDA responded with a letter stating that the company’s previously submitted information was not adequate to conclude that inorganic arsenic is not present in the edible tissues of roxarsone-fed chickens (Exhibit D.) In November of the same year, the FDA sent a letter to Alpharma indicating that it had written the company three times with concerns regarding roxarsone and nitarsone and Alpharma had “not provided evidence or data resolving our safety concerns regarding inorganic arsenic species resulting from the use of arsenical new animal drugs . CVM is conducting its own scientific investigation . .” (Exhibit E.) The 9 John F. Stolz, Biotransformation of 3-Nitro-4-hydroxybenzene Arsonic Acid (Roxarsone) and Release of Inorganic Arsenic by Clostridium Species, 43(3) Envtl. Sci. Tech. 818 (2007) (arguing that the right conditions can transform roxarsone to release inorganic arsenic). 4 agency issued a 512(l) order compelling Alpharma to submit all information relating to inorganic residue resulting from arsenical new animal drugs. These orders enable the agency to evaluate whether it should revoke approval of the new animal drug approvals. (Id.) Alpharma sent a letter as a preliminary response on December 2010 and contended that all relevant information had already been submitted during the NADA process. (Exhibit F.) Creating Collaborative Media Strategies The FDA’s report on its 2009 study that used new testing methods for arsenical species was finalized in February 2011.10 The report stated that, “[t]he incurred levels of inorganic arsenic species were highly variable in treated chicks but appeared to be significantly greater than that in the untreated control birds.”11 These results were shared with Pfizer representatives soon after they became available, and an email chain was created regarding the “3-Nitro Residue Study” on March 29, 2011 between Bill Flynn at the FDA and Steve Sutherland from Alpharma. (Exhibit G.) Subsequent meeting notes between the FDA and the company would indicate that the FDA had concerns that the inorganic residue from the roxarsone 10 FDA, Final Report on Study 275.30, Provide data on various arsenic species present in broilers treated with roxarsone: Comparison with untreated birds, February 2011. Available at http://www.fda.gov/downloads/AnimalVeterinary/SafetyHealth/ProductSafetyInformatio n/UCM257545.pdf. 11 Id. at 36. 5 was a violation of the Delaney Clause, noting “Pfizer disagrees with our conclusions that our findings violate Delaney and is having an offline conversation with [one of FDA’s attorneys] Nathan Doty.”12 The Delaney Clause gives the FDA the power to refuse approval of any food or chemical additive that is “found to induce cancer in man or animal.”13 However, it makes an exception for animal feed, provided that “no residue of the additive will be found . in any edible portion of such animal after slaughter or in any food yielded by or derived from the living animal.”14 Because the study started in 2009 by the FDA clearly showed higher than natural levels of inorganic arsenic in chicken livers, the FDA was of the opinion that 3-Nitro roxarsone was in violation of the Delaney Clause, which means that its approval should have been withdrawn. Before the FDA study was made public, FDA and Alpharma were already discussing it. (Exhibit G.) And, then, beginning in May 2011 and continuing for several months after, FDA’s Center for Veterinary Medicine and Pfizer traded emails, phone calls and face-to-face meetings, where they coordinated on how to minimize the impact of the study’s results when announcing it to the public. 15 This resulted in a meeting on May 10, 2011 attended by Pfizer’s Dr. Cathy Knupp (VP of R&D), Dr. Scott Brown (Senior Director R&D), Greg Andrews (VP Public Affairs), Heidi Chen (Legal), David 12
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