Backgrounder: FDA and ’s Collusion to Downplay Effects of Arsenicals in the U.S. Chicken Supply

This document summarizes the FDA’s actions after learning that inorganic , 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 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 FDA, Proposals from Pfizer re: Roxarsone 5/18/11. (Exhibit H.) 13 21 U.S.C. § 348(c)(3)(A) (2006). 14 Id. § 348(c)(3)(A)(ii) (2006). 15 An email from CVM’s Bill Flynn to Pfizer’s Heidi Chen indicated the dramatic extent of collaboration: “[J]ust so you know it is extremely unusual (almost never happens) for the agency to engage in the level of discussion we have had to share and obtain input on the specific wording of our planned press materials.” (Exhibit I.)

6 Smith (Assistant General Counsel-Regulatory) and Steve Sutherland (Senior

Director Regulatory Affairs) and FDA-CVN’s Bernadette Dunham, Bill Flynn, Cathy

Beck, Dave White, Jeff Ward, Phil Kijak, Kevin Greenlees, Nadine Steinberg, Nathan

Doty and Sharon Natanblut. (See Exhibit J.)

While the exact discussion that took place during this meeting is unknown, one document (Exhibit H) outlines what the company and agency agreed and disagreed upon at the meeting or shortly thereafter, in terms of the release of the study and the suspension of sales. Pfizer and the FDA are in agreement that the levels of inorganic arsenic in the study did not raise an imminent cause for concern, but

Pfizer disagreed that the FDA’s study was “conclusive in demonstrating the carcinogenic residues in liver are a result of feeding Roxarsone.” (Exhibit H.)

Although Pfizer did agree to suspend sales 3-Nitro after 30 days, the agency was not withdrawing approval of the drug (even though the FDA recognized that this was not the most “definitive action” and this would be recognized by the public). This agreement would not terminate manufacturing, so the company could continue overseas sales. The FDA would perform another study, and only then, if the study’s results were as the FDA expected, Pfizer would withdraw roxarsone from the market. The agreement would not affect other arsenicals, such as nitarsone. The company would work with the FDA attorney who had reached the conclusion that the study’s results indicate a violation of the Delaney clause. (Id.)

7 Moreover, the communications afterward indicate that the FDA and Alpharma agreed to work together and collaborate on a media strategy to minimize the impact of the study results. In a follow up email after a meeting between the company and the agency, Bernadette Dunham of the FDA references the open discussion and an expectation that it would continue, concluding “I look forward to working thru these issues with you, as we have on previous occasions” (Exhibit K.) Pfizer states in the following correspondence, “[b]ased on conversations during the meeting, it is our understanding that CVM will promptly provide responses so that Pfizer can factor this information in to our response to CVM’s request for a plan of action.” (Exhibit

L.) A May 20 to 23, 2011 email chain demonstrates that the agency and Pfizer were having a series of communications about the technical core messages to develop a

“common understanding.” (Exhibit M.) The FDA also indicated that it had pushed back the release of the study and suspension of roxarsone sale until after Memorial

Day. (Id.)

It is clear that Pfizer sent the FDA a set of questions (Exhibit N) to clarify the study results. Pfizer apparently thought that the questions were pointed enough that it would call the FDA’s study into question.16 By May 16, the FDA’s Deputy

Commissioner for Foods and Veterinary Medicine, Mike Taylor, was involved in the close collaboration on message, and in an internal email with FDA personnel, stressed that “these Pfizer questions and requests have important message

16 See email (Exhibit O) from Heidi Chen indicating that Pfizer planned to print its Q and A to provide balance if FDA used “arsenic” in the headline of its press release.

8 implications we should discuss so we can agree on the right strategy for response.”

(Exhibit P.)

This mutually agreed upon plan of attack included strategizing by exchanging and editing the other party’s media materials such as press releases and announcements during interviews, which is well documented in email communications. This was laid out in an email (Exhibit Q) from Pfizer’s Heidi Chen to Nathan Doty, where she protested that FDA was not sharing its drafts: “If we are to be truly collaborative, we propose that the two sides exchange proposed media materials . . . To be collaborative, we are happy to share copies of core messages and media statement.”

They worked closely with their PR departments to ensure that their media strategy was unified and acceptable to the other party.

The FDA even allowed Pfizer to write portions of the agency’s press release, with

Pfizer changing its heading. For example, Pfizer lobbied to convince (Exhibit R) the

FDA to not use the term “arsenic” in the FDA’s press release. The FDA removed the word from the final version, using the subheading “Company takes action in response to FDA data.”17

17 FDA, FDA Press Release, FDA: Pfizer will voluntarily suspend sale of animal drug 3-Nitro, (2011). Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm258342.htm.

9 In the end, FDA and Pfizer’s June 8, 2011 simultaneously released, pre-approved statements reflected a clearly coordinated message.18 Nearly all of Pfizer’s preferred edits were included in the statements. Both statements emphasized two points: 1)

Pfizer was voluntarily suspending 3-Nitro in response to the FDA’s study, but it was not being forced to act by the FDA; and 2) the amount of inorganic arsenic found was minimal and not dangerous. Both announcements stressed that all chicken products sold before and after the 3-Nitro suspension were safe to consume and that the research is ongoing. A draft statement (Exhibit S) and final statement19 from Pfizer describes the potentially higher levels of inorganic arsenic but noticeably makes no mention of carcinogens. The FDA’s statement on the other hand, mentioned the connection between inorganic arsenic levels and cancer twice, but also incorporated many of the emailed suggestions and edits made by Pfizer.20

This can best be demonstrated through the emails from Heidi Chen at Pfizer to Bill

Flynn at the FDA and the draft press release (Exhibit T) and Q & A (Exhibit U). 21

Notably, Pfizer recommended, and FDA obliged, moving up a statement in the agency’s press release about how it did not believe that there was an imminent health risk from consuming chicken treated with the 3-Nitro so that this statement immediately followed one about how inorganic arsenic is a carcinogen.22 FDA also

18 http://www.pfizer.com/files/news/suspending_sale_3nitro_060711.pdf. 19 Id. 20 FDA, FDA Press Release, FDA: Pfizer will voluntarily suspend sale of animal drug 3-Nitro, (2011). Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm258342.htm. 21 The FDA’s final Q & A is available at http://www.fda.gov/AnimalVeterinary/SafetyHealth/ProductSafetyInformation/ucm2583 13.htm. 22 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm258342.htm.

10 inserted into the press release a statement about how arsenic is a naturally occurring element, at Ms. Chen’s request.23

In 2013, after a citizen petition, lawsuit and a subsequent study by the Johns

Hopkins Center for a Livable Future, FDA agreed to withdraw approval of roxarsone, carbarsone and , after it secured letters from the sponsors, including

Zoetis, asking for such withdrawals. FDA continues to not take any action (as it did in 2011) to prevent the sale of nitarsone, instead insisting that the drug needs more study.

23 Id.

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Timeline of Significant Communication

Ø January 6, 2009 – (Exhibit A) letter from FDA CVM to Alpharma requesting more information regarding new research showing that roxarsone consumption could lead to increased levels of inorganic arsenic in edible poultry tissue.

o “recent evidence, including some in your submission, calls those assumptions into question”

o requests “a demonstration of an insignificant difference in the inorganic arsenic concentrations in control and treated birds . . . would support our previous safety conclusions about roxarsone.”

Ø In 2009, FDA initiates a research study intended to determine whether treating chickens with roxarsone results in increased levels of inorganic arsenic in the edible tissues of those chickens, specifically liver, using newly developed analytical testing methods. (See Exhibit B.)

Ø December 7, 2009 – Alpharma argues that the Stolz, et. al., study did not represent conditions that would be naturally found, but CVM wants speciation information on inorganic arsenic in edible tissue that would allow for conclusions to be made regarding the safety of arsenicals. (Exhibit C.)

Ø June 1, 2010 – letter from CVM to Alpharma responding to their argument regarding the Stolz study and asking for speciation data to help understand how organic arsenic works in vivo. (Exhibit D.)

Ø November 16, 2010 – letter from CVM to Alpharma, detailing how CVM has written three times with concerns regarding roxarsone and nitarsone and Alpharma has “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 . . .” Alpharma must also submit all information relating to inorganic arsenic residues from the use of arsenical drugs. (Exhibit E.)

Ø December 10, 2010 – response from Alpharma to CVM that all available information was already submitted during the New Animal Drug process. (Exhibit F.)

Ø The FDA’s study on inorganic arsenic levels in roxarsone-treated chicken livers was completed in December 2010 and the final report (http://www.fda.gov/downloads/AnimalVeterinary/SafetyHealth/ProductSafet yInformation/UCM257545.pdf) was completed February 2011.

12 Ø During early 2011, supplemental approval for 3-Nitro medicated feeds are granted approval without any “reevaluation of the safety or effectiveness data in the original NADA” (See Exhibit V for one of many examples.)

Ø As early as March 29, 2011, there were emails discussing how to handle the results of the 3-Nitro study. (Exhibit G.)

Ø May 10, 2011 – Meeting between FDA and Alpharma, including participants from R&D, Public Affairs and Legal. (Exhibits J, W, X.)

Ø Mid-May, Pfizer and CVM reach agreement on how to release the study results and the suspension of roxarsone sales. (Exhibit H.)

Ø May 16, 2011 – Pfizer reiterates that it has questions that it wants from FDA regarding its study and that it is willing to make them public. (Exhibit L.)

o Mike Taylor gets involved – “These Pfizer questions and requests have important message implications we should discuss so we can agree on the right strategy for response.” (Exhibit P.)

Ø May 20-23, 2011 – email chain regarding collaboration of communications/public announcement discussions and the technical core message so there is “common understanding” between the FDA and Pfizer. (Exhibit M.)

o FDA pushes back release of study and suspension of sale until after Memorial Day.

Ø May 27, 2011 – Pfizer protests not receiving FDA draft press materials via email. (Exhibit Q.)

o “FDA and Pfizer need to resolve the disconnect in the communications in order to move forward in accordance with Pfizer’s proposal and before Bernadette reaches out to USDA.”

Ø May 31, 2011 – FDA sends draft press release and Q & A documents, which are revised to address Pfizer’s concerns. (Exhibit Y.)

Ø June 1-2, 2011 – Discussion of edits to FDA’s press release, including incorporating changes from Pfizer’s Heidi Chen. (Exhibits Z, AA.)

o Edits on FDA’s draft press release (Exhibit T) and Q & A (Exhibit U) documents

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Ø June 3 – Email from Heidi Chen indicating that if the FDA includes the word “arsenic” in the headline of its press release, Pfizer would consider publishing its questions on the FDA’s studies in their Q&A to provide balance. (Exhibit R.)

Ø June 5, 2011- Email about arranging a call between Mike Taylor and animal health president of Pfizer after discussing PR wording and language issues. (Exhibit BB.)

Ø June 8,, 2011 – FDA announces in a press release that Pfizer is voluntarily suspending sale of animal drug 3 -Nitro; Pfizer releases own with subheading, “Action Called a Prudent Step.”24

Ø June 10, 2011 – CVM sends Pfizer its responses to the company’s questions about the agency’s February study. (Exhibit N.)

Ø September 23, 2013 – FDA drafts withdrawal letter for Zoetis asking for regulatory withdrawal of two arsenical drugs, roxarsone and carbarsone. (Exhibit CC.)

24 FDA, FDA Press Release, FDA: Pfizer will voluntarily suspend sale of animal drug 3-Nitro, (2011). Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm258342.htm; Pfizer, Pfizer Press Release. Pfizer to suspend sale of 3-Nitro (Roxarsone) in the United States, (2011). Available at http://www.pfizer.com/files/news/suspending_sale_3nitro_060711.pdf.

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