Elanco Is Looking Forward to Interacting with EFSA on Technical Questions Regarding Ractopamine Study Design, Objectives and Statistical Aspects*

EFSA FEEDAP Panel concludes that, "ractopamine is not mutagenic and is not likely to present a carcinogenic risk to consumers" Greenfield, IN., April 7, 2009 – Elanco is pleased that the European Food Safety Authority (EFSA) has aligned with 26 other regulatory authorities in determining that "... ractopamine is not mutagenic and is not likely to present a carcinogenic risk to consumers." "The safety of Ractopamine for use in swine and beef has been well established through rigorous scientific studies and regulatory reviews," notes Dr. William Weldon, Senior Director of Research and Development for Elanco.1,2,3 Further, "Elanco looks forward to meeting with EFSA scientific experts to address their technical questions on study design and purpose and statistical aspects," Weldon notes. The FEEDAP Panel under EFSA has been reviewing the human safety data as part of the process toward establishing a Codex international food safety standard for Ractopamine. Normally, the regulatory process involves the exchange of data, questions and responses, but unfortunately due to time constraints the interaction between Elanco and FEEDAP has not been possible. Also, the FEEDAP Panel report notes that, "If the pre-requisites of JECFA [Joint FAO/WHO Expert Committee on Food Additives] of an ADI [Acceptable Daily Intake] value of 0.06 mg/person1 and free ractopamine as the marker residue are taken as a basis, the FEEDAP Panel would reach a similar conclusion that consumer safety would be ensured without applying a withdrawal period to pig and cattle." In their review, the FEEDAP Panel raises a number of technical questions as the reason for not supporting the international food safety standard for Ractopamine determined by JECFA. Elanco recognizes that there can be varying interpretations of scientific data amongst experts. However, Elanco differs with the technical positions of the FEEDAP Panel (See key questions raised by FEEDAP and Elanco's more detailed responses below in Appendix A.). Elanco believes that all these questions can be resolved through scientific interaction with the EFSA and FEEDAP scientists. FEEDAP technical questions and Elanco's response points include:

Whether the relevant effect, which would serve as basis for consumer safety must be a NOAEL (No Observable Adverse Effect Level) verses a NOEL (No Observable Effect Level):

Historically the scientific assessment has been based on adverse effects.

Whether chronic or acute exposure should determine the human safety standard:

Regulatory bodies have traditionally based NOAEL on chronic studies.

Whether the safety standard, i.e. the MRL (maximum residue limit), should be based on toxicological verses pharmacological considerations:

The Codex procedure manual describes the MRL as, "... the type and amount of residue considered to be without any toxicological hazard for human health as expressed by the Acceptable Daily Intake ..." 4

Whether an animal model should be used verses a human study to determine the human safety, and whether the animal model should be based on a dog or a monkey:

Typically animal models are used as surrogates for human studies, and in unique cases where human studies are conducted, the study group is limited.

Monkeys are physiologically more similar to humans than dogs.

Dogs are uniquely sensitive to beta-agonists and have a receptor population different from humans and non human primates.

Whether the statistical power of the population in the human study is sufficiently robust to be determinative:

The six person human study was not designed to be a definitive study.

Whether the human safety assessment should be based on oral verses intravenous (IV) use in food animals:

ADIs and MRLs are developed to determine the safety of residues in food from animals administered a substance that is destined to be used as human food; thus the only route of exposure of consequence to humans is therefore the oral route.

"Elanco is looking forward to working with the EFSA and FEEDAP scientists to resolve all these technical questions," said Dr. Weldon. "With the extensive human safety-record already established for Ractopamine worldwide, we are confident that we will be able to come to a similar assessment outcome with EFSA". For background, ractopamine hydrochloride (Ractopamine) is the compound used in Elanco's brands Paylean® and Optaflexx® that are used as feed ingredients in swine and cattle production.1,2,3 Twenty-six regulatory authorities have extensively reviewed the full Ractopamine data submission and based on a series of stringent human and animal food safety criteria concluded it is safe for use in swine and/or cattle production. It is registered in countries including the United States, Canada, Australia, New Zealand, Mexico, Brazil, South Korea, the Philippines and Hong Kong. Since first approval in 1999 in the United States, the product has been used in well over 300 million swine worldwide producing more of the quality lean meat that consumers desire. Ractopamine has a recommended international food safety standard from the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and is currently at Step 8 in the Codex process.5,6 It has been discussed multiple times during the Codex process and the recommended draft MRLs have been advanced via consensus process and recognized as sound. An international food safety standard is established by Codex for compounds used in food animal production to ensure a common threshold for food safety for consumers around the world. JECFA is the scientific expert review committee that prepares the international food standard assessment before such a standard is determined by Codex.

_____________ *Safety Evaluation of ractopamine. Scientific Opinion of the Panel on Additives and Products or Substances used in Animal Feed. (Question No EFSA-Q-2008-433) Adopted on 2 April 2009 The label contains complete use information including cautions and warnings. Always read, understand and follow the label and use directions. 1Elanco Data on File 2Directions for use in swine: Feed at 4.5 to 9.0 g/ton to finishing swine in a complete ration containing at least 16% crude protein for the last 45 to 90 lbs of gain (group average). Clinical registration studies showed no statistical difference between the effects of 4.5 g/ton and 9 g/ton. Caution: Ractopamine may increase the number of injured or fatigued pigs during marketing. Not for use in breeding swine. 3Directions for use in cattle: Optaflexx is approved for feeding during the last 28 to 42 days prior to harvest to be fed at 8.2 to 24.6 g/ton to provide 70 to 430 mg/hd/d for the last 28 to 42 days on feed. For increased rate of weight gain, improved feed efficiency and increased carcass leanness feed Optaflexx during the last 28 to 42 days prior to harvest at 9.8 to 24.6 g/ton to provide 90 to 430 mg/hd/d. Caution: Not for animals intended for breeding. "http://www.codexalimentarius.net/web/procedural_manual.jsp"> P. 43. 52004 WHO_TRS_925 [1] - 62nd JECFA – Ractopamine Review 6Source: Reports of the 15th, 16th and 17th Sessions of the Codex Committee On Residues Of Veterinary Drugs In Foods and Reports of the 29th, 30th and 31st Session of the Codex Alimentarius Commission. http://www.codexalimentarius.net/web/index_en.jsp Paylean® is a trademark for Elanco's brand of ractopamine hydrochloride used in swine.

Optaflexx® is a trademark for Elanco's brand of ractopamine hydrochloride used in cattle. For more information, click here aquamail.aquariumdigital.com/t/r/l/trdduj/mmdtlyu/y> >

to view Elanco Ractopamine Background and Q&As Regarding EFSA Opinion

Appendix A: FEEDAP's Technical Questions About Ractopamine And Elanco's Responses: NOAEL vs. NOEL:

FEEDAP notes that if an ADI would be derived from pharmacological studies, A NOEL must be taken to consider not only clinically relevant ("adverse") effects in the consumer, but also subjective discomfort even when occurring only for a short time.

Elanco differs with this for the following reasons:

The establishment of a toxicological end point is the primary basis for evaluation of safety. Toxicology by definition is the study of the nature, effects, and detection of poisons and the treatment of poisoning.

Subjective measures are not considered as clinically relevant in toxicological evaluations due to the difficulty in interpretation.

Positive effects by default are not poisonous effects.

Adverse effects are the primary measure of risk.

Effects that are either intended to occur (reduced fat deposition, increased lean deposition) or have a positive impact in the intended species (swine etc.) are not considered to be toxicological, and therefore should not be considered.

Historically the scientific assessment of safety, therefore, has been based on No Observable Adverse Effect Level (NOAEL). Over time this has evolved to just being called No Observed Effect Level (NOEL), but the interpretation has always been meant to discuss and mitigate risk around adverse effects.

Chronic verses acute exposure:

FEEDAP finds that the no effect level should be based on acute exposure, not chronic exposure.

Elanco differs with this for the following reasons:

The NOAEL has historically been based on chronic exposure by all regulatory bodies.

All the data submitted to agencies is based on chronic exposure of indicator species over a statistical lifetime.

ADI and MRL values are developed on the assumption that all food consumed will be from an animal fed the substance at its highest approved level, and that an individual will consume all relevant tissues every day for their lifetime. This is, in essence, impossible to occur, but values are based on this.

Acute exposures, if considered, would need to be measured using totally different criteria, and based on a single tissue exposure in one meal with one tissue, utilizing the full ADI in that single tissue.

All previous substances have been evaluated on chronic exposure.

Toxicological verses pharmacological considerations:

FEEDAP finds that the safety standard, i.e. the MRL (maximum residue limit), should be based on pharmacological considerations not toxicological.

Elanco differs with this for the following reasons:

Safety standards are normally established by finding the No Observed Adverse Effect Level (NOAEL).

The assessment should be the based only on the 'adverse' effects.

The Codex procedure manual describes the MRL as, "... the type and amount of residue considered to be without any toxicological hazard for human health as expressed by the Acceptable Daily Intake..."4

Although the adverse effects are normally toxicological, it is possible for a pharmacological effect to also be an adverse effect.

Positive or expected pharmacological effects should not be used.

An acute pharmacological effect that is both adverse and scientifically measurable (not subjective) should be considered as an Acute Reference Dose, not a toxicological effect, and utilize the full ADI and only one tissue in one day in the consumption calculation.

Animal model based on dog or monkey and animal model verses human model:

FEEDAP wants to base the toxicology assessment on the dog, not the monkey.

Elanco differs with this for the following reasons:

The purpose of evaluating toxicological data is to extrapolate safety from a laboratory model to a human subject.

The closer to human subjects the data is, and the longer the laboratory animal studies run, the more exact a reviewer can be in terms of assessing safety to humans (the lower the safety factor).

It is rare to run actual human studies, but if they are done, safety factors can approach 10X.

Monkeys are physiologically more similar to humans than dogs.

The human study demonstrated a no effect level, even with a small study size.

The human study demonstrated that the response seen in humans is like the response in monkeys, and unlike the response in dogs.

The combination of chronic monkey studies and three human studies gives confidence in the human data being used to assess the NOEL.

The statistical power of the human safety study:

FEEDAP questions the statistical power of the human safety study.

Elanco finds that the human safety study reaffirms the safety of ractopamine:

The single study with six patients was not designed to be the definitive study.

There are two additional studies with butopamine, the active isomer of ractopamine, which support the six subject study.

The human data reaffirms that the monkey is the right chronic species, and allows a safety factor of 50 to be used in the calculation of the MRL.

Subsets of human populations:strong>

FEEDAP finds potential impact on subpopulations which may be at higher risks.

Elanco differs with this for the following reason:

Safety factors built into the residue calculations provide the scientific assurance that subpopulations will not be adversely affected. A safety factor of 50 based on human studies, or 100 based on monkey studies, would assure that all subpopulations are protected. The consumption factors built into the MRL also allow further safety factors.

Oral verses intravenous (IV):

FEEDAP finds that intravenous exposure is a valid route to assess safety of an animal drug.

Elanco differs with this for the following reasons:

ADIs and MRLs are developed to determine the safety of residues in food from animals administered a substance that is destined to be used as human food.

The only route of exposure of consequence to humans is therefore the oral route.

Oral toxicity studies are the only pivotal data that should be used to establish ADI and MRL, as that replicates the exposure risk to humans.

All oral exposure studies in monkeys have NOAEL's of 125 to 250 µg/kg/day, oral exposures in humans are approximately 67 µg/kg/day. A safety factor of 50 as proposed by JECFA will yield the same approximate MRL as a safety factor of 100 applied to the chronic monkey study (NOAEL of 125 µg/kg/day), and will be approximately one half of the MRL allowed if the NOAEL from the six week monkey study (250 µg/kg/day) were used.

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