August 2, 2013
W. Robert Dodemaide, BVSc, BSc, MS
Director, Regulatory Affairs & Compliance
ECO LLC doing business as ECO Animal Health
344 Nassau Street
Princeton, New Jersey 08540
RE: NADA 141-336, Aivlosin® Water Soluble Granules (62.5% w/w tylvalosin as tylvalosin tartrate) promotional labeling and advertisements
- PRODUCT PROFILE – Novel therapeutic antibiotic
- INFORMATION BROCHURE – Gold Standard
- TECHNICAL BRIEF – Efficacy
- TECHNICAL BRIEF – Mixing & Administration
- TECHNICAL BRIEF – Judicious Use - 1009-1012
- PharmGate Animal Health website. http://pharmgateah.com/products.html
Dear Dr. Dodemaide:
The U.S. Food and Drug Administration (FDA), Center for Veterinary Medicine (CVM), Division of Surveillance has reviewed the above-noted promotional materials for Aivlosin® Water soluble Granules (62.5% w/w tylvalosin as tylvalosin tartrate), NADA 141-336, which were submitted on July 5, 2012, and November 27, 2012. We have also reviewed PharmGate Animal Health’s website for Aivlosin® Water Soluble Granules (http://pharmgateah.com/products.html).
As explained in more detail below, these promotional materials are misleading because they contain incomplete and inadequate information about the approved indication for Aivlosin®. For this reason, these materials cause Aivlosin® to be misbranded within the meaning of sections 502(a), 201(n), and 502(n) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) [21 U.S.C. §§ 352(a), 321(n), and 352(n)].
Aivlosin® is a macrolide antibiotic that is indicated for the control of porcine proliferative enteropathy (PPE) associated with Lawsonia intracellularis infection in groups of swine in buildings experiencing an outbreak of PPE. The approved indication for Aivlosin® contains important antimicrobial resistance and human food safety risk mitigation language, specifically: “in groups of swine in buildings experiencing an outbreak of PPE”. The intention of this language is to limit use of Aivlosin® to treatment only of groups of swine in specific buildings that are exposed to Lawsonia intracellularis.
FDA Guidance for Industry #152, “Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern,” describes how new animal drug sponsors can conduct a qualitative risk assessment to evaluate the risk that a new animal drug poses to human food safety with respect to the development of antimicrobial resistance. The guidance categorizes classes of antimicrobial drugs in terms of their importance to human medicine, which serves as one component of a risk estimation that FDA uses to determine whether the drug can be approved with specific management conditions to mitigate the risks of using the drug.
Macrolide antibiotics are considered critically important to human medicine under Guidance 152, which is the highest level of risk under the guidance. Therefore, based on the qualitative risk assessment submitted in support of the new animal drug application, FDA concluded that Aivlosin® Water Soluble Granules poses a high risk for antimicrobial resistance and, thus, a threat to human food safety. Because the product poses a high risk for antimicrobial resistance, it was approved with the “extent of use” limitation described above: “in groups of swine in buildings experiencing an outbreak of PPE.” FDA’s decision to approve Aivlosin® Water Soluble Granules (NADA 141-336) with a restriction is explained in the Microbial Food Safety (Antimicrobial Resistance) section of the Freedom of Information (FOI) Summary for Aivlosin® Water Soluble Granules (NADA 141-336):
“Macrolides are ranked as critically important drugs in human medicine; therefore, by default, the consequence assessment yields a high ranking. The overall risk estimation is derived to be high. The conditions of use and restriction of use to only groups of swine in buildings experiencing an outbreak of PPE are compatible with the Agency’s risk management strategies associated with a product having an overall risk estimation of high.”
Inadequate Communication of Indication
Under section 502(a) of the FD&C Act, a drug is misbranded if its labeling is false or misleading in any particular. Section 201(n) of the FD&C Act (21 U.S.C. § 321(n)) provides that in determining whether a drug’s labeling or advertising is misleading, “there shall be taken into account … not only representations made or suggested … but also the extent to which the labeling or advertising fails to reveal facts material in light of such representations or material with respect to consequences which may result from the use of the article.” As noted above, the approved indication for Aivlosin® Water Soluble Granules (NADA 141-336) includes the phrase “in groups of swine in buildings experiencing an outbreak of PPE.” However, the product website and the submitted promotional materials cited above feature a truncated version of the approved indication statement, which reads: “control of Porcine Proliferative Enteropathy (PPE/ilieitis) associated with Lawsonia intracellularis in pigs.” This truncated version of the approved indication excludes the phrase “in groups of swine in buildings experiencing an outbreak of PPE,” which is an essential and critical part of the approved indication. These promotional materials are misleading because they fail to reveal material facts within the meaning of section 201(n) of the FD&C Act relating to the restrictions on the use of this product that are necessary to mitigate the high risk that the product poses for antimicrobial resistance, and therefore your products are misbranded under section 502(a) of the FD&C Act (21 U.S.C. §§ 352(a) and 321(n)).
In addition, under section 502(n) of the FD&C Act, prescription drug advertisements must contain a true statement of information in brief summary relating to the drug’s side effects, contraindications, and effectiveness as required by regulation, or the product is considered misbranded. 21 U.S.C. 352(n). FDA’s prescription drug advertising regulations clarify that this requirement may not be met if the summary omits certain information. Specifically, the regulations state: “An advertisement does not satisfy the requirement that it present a ‘true statement’ of information in brief summary relating to side effects, contraindications, and effectiveness if…[i]t fails to reveal facts material in the light of its representations or material with respect to consequences that may result from the use of the drug as recommended or suggested in the advertisement.” 21 CFR 202.1(e)(5)(iii)(italics added). The use limitation specified by the phrase “in groups of swine in buildings experiencing an outbreak of PPE” is a material fact regarding the use of the drug. By omitting this phrase from the indications statement in your promotional materials and on the website, you fail to communicate important information to users regarding restrictions on the use of the product that reduce the likelihood of development of antimicrobial resistance when using Aivlosin®. The omission of this information results in your product being misbranded within the meaning of section 502(n) of the FD&C Act (21 U.S.C.§ 352(n)).
Additionally, the prescription drug advertising regulations state: “An advertisement for a prescription drug is false, lacking in fair balance, or otherwise misleading, or otherwise violative of section 502(n) of the act, among other reasons, if it: (i) Contains a representation or suggestion, not approved or permitted for use in the labeling, that a drug is …. safer …. than has been demonstrated by substantial evidence or substantial clinical experience.” 21 CFR 202.1(e)(6)(i). By using a truncated version of the approved indication, the materials cited above suggest that the drug is safe for use without the “extent of use” restriction. We are not aware of any evidence that this broader use of the product is safe from the perspective of antibiotic resistance and human food safety.
In summary, these promotional materials are misleading because they omit pertinent information relating to the mitigation of antimicrobial resistance and human food safety risks and represent that the product is safer than has been demonstrated.
Conclusion and Requested Action
The misleading statements in your materials and website cause Aivlosin® to be misbranded within the meaning of sections 502(a), 201(n), and 502(n) of the FD&C Act [21 U.S.C. 352(a), 321(n), and 352(n)].
CVM requests that ECO Animal Health and PharmGate Animal Health immediately cease the dissemination of the Aivlosin® promotional items described above, and any other materials that may contain similar exclusions of important antimicrobial resistance risk mitigation language from the indication.
Please submit a written response within thirty calendar days of receipt of this letter describing whether you intend to comply with this request. Please direct your response to Dr. Neal Bataller at the Food and Drug Administration, Center for Veterinary Medicine, Division of Surveillance, HFV-216, 7519 Standish Place, Rockville, Maryland 20855.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that all promotion and advertisement materials for Aivlosin® comply with the requirements of the FD&C Act and applicable FDA regulations.
If you have any questions, please contact Dr. Dorothy McAdams at the address above, or by phone at (240) 453-6802.
Neal Bataller, ME, DVM
Director, Division of Surveillance
Office of Surveillance & Compliance
Center for Veterinary Medicine
Dr. Liz Abbott
Global Director Product Development & Regulatory Affairs
ECO Animal Health
78 Coombe Road,
New Malden, Surrey KT3 4QS