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WARNING LETTER

ECO LLC, DBA ECO Animal Health

Product:
Animal & Veterinary

Recipient:
ECO LLC, DBA ECO Animal Health


United States

Issuing Office:
Center for Veterinary Medicine

United States


   

Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  Rockville, MD 20857 

DEC 23, 2014

OVERNIGHT DELIVERY
 
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
 
Collin Gray
President & CEO, Pharmgate Animal Health, LLC
161 N. Franklin Turnpike, Suite 2C
Ramsey, New Jersey 07446
 
 
RE:     NADA 141-336
Aivlosin®(62.5% w/w tylvalosin as tylvalosin tartrate) Water Soluble Granules – promotional labeling and advertisements
 
WARNING LETTER
 
Dear Dr. Dodemaide and Mr. Gray:
 
The U.S. Food and Drug Administration (FDA), Center for Veterinary Medicine, Division of Surveillance (DS), has reviewed promotional materials for Aivlosin® (62.5% w/w tylvalosin as tylvalosin tartrate) Water Soluble Granules (WSG), which are available on the website http://www.aivlosin.com/aivlosin/ as of November 2014 and/or were distributed at the 45th Annual Meeting of the American Association of Swine Veterinarians (AASV) held on March 1-4, in Dallas, Texas. These materials distributed at the 2014 AASV meeting included: (1) An ECO Animal Health and Pharmgate Animal Health-produced white paper: “Recent experiences with tylvalosin (Aivlosin®) intervention for the eradication of Mycoplasma hyopneumoniae in commercial swine operations”, (2) INFORMATION BROCHURE – The Powerful New Gold Standard – Pharmgate Animal Health, and (3) PRODUCT PROFILE– Aivlosin Water Soluble Granules – Pharmgate Animal Health.  
 
These promotional materials provide evidence that Aivlosin® WSG is intended for new uses for which it lacks approval and for which its labeling does not provide adequate directions for use, which renders Aivlosin® WSG misbranded under section 502(f) [21 U.S.C. 352(f)], and unsafe within the meaning of section 512 of the FD&C Act [21 USC § 360b] and therefore adulterated under section 501(a)(5) of the FD&C Act [21 USC § 351(a)(5)]. The introduction of an adulterated or misbranded drug into interstate commerce is a violation of section 301(a) of the Act [21 USC § 331(a)].  
 
We also note that the promotional materials cited in this letter are false or misleading in that they omit important risk information for Aivlosin® WSG, suggest that the drug is useful in a broader range of species or conditions than has been substantiated, omit material facts, and make unsubstantiated efficacy claims.
 
Background
 
According to the FDA-approved product labeling (PI), Aivlosin® WSG 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 [emphasis added]. This approved indication for Aivlosin® WSG contains important antimicrobial resistance and human food safety risk mitigation language. The intent of this language is to limit use of Aivlosin® WSG to treatment only of groups of swine in specific buildings that are exposed to Lawsonia intracellularis.
 
Under CVM’s Guidance for Industry #152, “Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern, ® WSG 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.”  This “extent of use” limitation is explained in the Microbial Food Safety (Antimicrobial Resistance) section of the Freedom of Information (FOI) Summary for Aivlosin® WSG (NADA 141-336): macrolide antibiotics are considered critically important to human medicine, which is the highest level of risk as described in the guidance. On the basis of the qualitative risk assessment submitted in support of the new animal drug application, FDA concluded that Aivlosin
 
“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.”
 
Prior Communications
 
We note that DS expressed concerns regarding similar violative promotional activities in August of 2013. On August 2, 2013, DS sent ECO Animal Health, sponsor of Aivlosin® WSG and parent company of Pharmgate Animal Health, an Untitled Letter that explained why omission of the risk mitigation language in its promotional materials and website cause Aivlosin® to be misbranded within the meaning of sections 502(a), 502(n) and 201(n) of the FD&C Act [21 USC §§ 352(a) and (n), and § 321(n)].
 
Omission of Risk Information
 
Promotional materials are misleading if they fail to reveal facts that are material in light of the representations made or with respect to consequences that may result from the use of the drug as recommended or suggested in the materials.
 
The promotional materials cited above are misleading because they omit the important “extent of use” limitation from the indication statement. In addition, the product website and the promotional materials also omit the following risk information contained in the “User Safety Warnings” section of the approved label:
 
“May cause skin irritation.” “When handling Aivlosin® Water Soluble Granules and preparing medicated drinking water, avoid direct contact with the eyes and skin. Wear a dust mask, coveralls and impervious gloves when mixing and handling this product. Eye protection is recommended.”
 
Omission of the limitation “in groups of swine in buildings experiencing an outbreak of PPE,” from the indications statement, and other important risk information is misleading because it does not communicate material facts relating to restrictions on the use of this product that are necessary to mitigate the high risk that the product poses for antimicrobial resistance and user skin irritation, and therefore causes the product to be misbranded. See FD&C Act section 21 U.S.C. §§ 352(a) and 321(n).
 
Unsubstantiated Efficacy Claims and Broadening of Patient Population or Condition
 
Your promotional materials contain representations or suggestions that Aivlosin® WSG is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The Aivlosin® WSG website (http://www.aivlosin.com/aivlosin) includes the following claim:
  • “Aivlosin® contains the innovative antibiotic tylvalosin, which is rapidly absorbed and concentrates in target tissues to provide proven control of major respiratory and enteric disease in both pigs and poultry.”
 
Further, your promotional materials contain representations or suggestions that Aivlosin® WSG is useful in a broader range of species or conditions than has been substantiated. The Aivlosin® WSG website (http://www.aivlosin.com/aivlosin) includes the following claims:
  • The section “In pigs – Swine Dysentery” states that infected pigs with this disease “need to be treated as soon as possible with Aivlosin®.”
  • The section “In pigs – Enzootic Pneumonia” states that Aivlosin® meets the key components of effective therapy and prevention of the disease [enzootic pneumonia].”
  • The section “In poultry” states “Aivlosin® contains the innovative antibiotic tylvalosin, which is rapidly absorbed and concentrated in target tissues to provide proven control of major respiratory and enteric diseases in poultry, in particular: Mycoplasmosis, Necrotic Enteritis, and Ornithobacterium rhinotracheale (ORT) in poultry.”
 
In addition, an ECO Animal Health and Pharmgate Animal Health-produced white paper designated “Poster 94,” entitled “Recent experiences with tylvalosin (Aivlosin®) intervention for the eradication of Mycoplasma hyopneumoniae in commercial swine operations” that was distributed by Pharmgate Animal Health in the commercial exhibit hall at the 45th Annual Meeting of the American Association of Swine Veterinarians held on March 1-4, 2014, in Dallas, Texas, presents the following:
 
“The eradication programs summarized have shown that it is possible to eradicate Mycoplasma hyopneumoniae with tylvalosin (Aivlosin®) using customized protocols, even with young animals on site.”
 
Aivlosin® WSG is not currently approved in the U.S. for any type of respiratory disease in swine, and is not currently approved for any use in chickens. We are not aware of scientific data to substantiate the Mycoplasma eradication claim. For example, the data presented in “Poster 94” does not provide adequate evidence to support the suggestion that Aivlosin® WSG is safe or effective for Mycoplasma eradication. Furthermore, Poster 94 describes treatment of pigs using either medicated feed containing tylvalosin, or a water soluble formulation; however, Aivlosin® WSG is not indicated for use in medicated feed.
 
Unsubstantiated Superiority Claim
 
Your promotional materials contain representations or suggestions that Aivlosin® WSG is safer or more effective than other antimicrobial drugs when it has not been demonstrated to be safer or more effective by substantial evidence or substantial clinical experience. The INFORMATION BROCHURE distributed by Pharmgate Animal Health at the 45th Annual Meeting of the American Association of Swine Veterinarians contains a boldly emphasized statement: “the powerful new Gold Standard for ileitis control.” Such reference to Aivlosin® WSG as a “Gold Standard” suggests that the product is superior to other antimicrobial products with similar indications. This promotional material contains four citations including two publications (2007 & 2010), and two unpublished internal reports. However, these references fail to provide substantive evidence that Aivlosin® WSG is superior to other similar antimicrobial products.
 
Conclusion and Requested Action
 
The Division of Surveillance requests that ECO Animal Health immediately cease misbranding Aivlosin® WSG and/or cease introducing the adulterated and misbranded drug into interstate commerce.
 
The violations cited in this letter do not necessarily constitute an exhaustive list. It is your responsibility to assure that your promotional materials for Aivlosin® WSG comply with all the requirements of the FD&C Act and its implementing regulations. You should take prompt action to correct the violations cited in this letter. Failure to correct the violations discussed above may result in enforcement action by FDA without further notice, including seizure and injunction.
 
Please submit a written response within fifteen (15) calendar days of receipt of this letter describing how you intend to comply with this request, listing any promotional materials for Aivlosin® WSG that contain statements such as those described above, and explaining your plan for discontinuing use of such materials or, in the alternative, your plan to cease distribution of Aivlosin® WSG. If you cannot complete corrective action within 15 calendar days, state the reason for the delay and the time within which you will complete the correction. Please direct your response to Dorothy R. McAdams, VMD, at the Food and Drug Administration, Center for Veterinary Medicine, Division of Surveillance, 7519 Standish Place, Rockville, Maryland, 20855 or by facsimile at (240) 276-9193.
 
To ensure timely delivery of your submissions, please use the full address above and include a prominent directional notation (e.g., a sticker to indicate that the submission is intended for the Division of Surveillance). Please refer to the NADA number in all future correspondence relating to this particular matter. All correspondence should include a subject line that clearly identifies the submission as a response to warning letter. Please note that only written communications are considered official.
 
 
Sincerely,
/S/ 
Neal Bataller, ME, DVM
Director, Division of Surveillance
Office of Surveillance & Compliance
Center for Veterinary Medicine 
 
 
cc:       Dr. Liz Abbott           
            Global Director Product Development & Regulatory Affairs
            ECO Animal Health
            78 Coombe Road,
            New Malden, Surrey KT3 4QS
            United Kingdom