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U.S. Department of Health and Human Services

Animal & Veterinary

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CVM Advisory Committee Reviews Microbial Safety of Pending Veterinary Antimicrobial

FDA Veterinarian Newsletter September/October 2004 Volume XIX, No V

At the October 13 Veterinary Medical Advisory Committee (VMAC) meeting, Pfizer Animal Health presented information about tulathromycin, a new animal drug that the company hopes to market for the treatment of swine and bovine respiratory disease.

The VMAC review is one of the risk management mitigations available under Guidance for Industry #152 (GFI #152), which describes a model qualitative risk assessment that the Center may use in evaluating microbial safety for antimicrobial drugs available for veterinary medicine.

In 1999, CVM officially stated that it would consider the potential risks to human health from the development of bacteria resistant to antimicrobial drugs before approving any antimicrobial for use in food animals. FDA is in the process of reviewing the microbial food safety of all animal drugs and has outlined a recommended process for demonstrating the safety of antimicrobials for use in food-producing animals under GFI #152. Last year, CVM released the final version of GFI #152, in which the Center explained an approach for evaluating whether an antimicrobial new animal drug was safe with respect to public health hazards resulting from the development of antimicrobial resistance.

FDA Review

For antimicrobial drugs, GFI #152 characterizes the hazard as human illness, caused by antimicrobial resistant bacteria. The resistant bacteria must have come from an animal-derived food, and the source of the food must have been an animal treated with an antimicrobial that is also important in human medicine.

Under GFI #152, the risk assessment is made up of three parts.

  • Release assessment, which is an estimate of the probability that the proposed use of the antimicrobial new animal drug in food-producing animals will result in the emergence or selection of resistant -bacteria in the animal treated with the -antimicrobial.
  • Exposure assessment, which describes the likelihood of human exposure to foodborne bacteria of -human health consequence through a particular exposure pathway, in this case animal-derived food products.
  • Consequence assessment, which addresses the human health consequence associated with bacteria that are resistant to antimicrobial drugs. Part of the consequence assessment is the importance of the antimicrobial in human medicine.

According to GFI #152, if an initial assessment indicates that sufficient hazard exists, the next step is a further risk assessment evaluation. Tulathromycin was subject to a qualitative risk assessment process as outlined in GFI #152. Tulathromycin is a member of the macrolides class of antimicrobials and is in the consequence assessment category of “critically important” because macrolides are used for the treatment of infections caused by Campylobacter spp., which is a foodborne human pathogen and associated with food from animals, and because macrolides are important for treating other human diseases, including the potentially fatal “Legionnaire’s Disease.”

Based on the risk assessments, products are put into a low, medium or high risk category. Corresponding risk management strategies can be applied. One of the risk management steps can be a VMAC review of the application and risk management plans. Tulathromycin is the first product reviewed by VMAC under GFI #152.

Pfizer Animal Health’s description of the safety of the drug

At the VMAC meeting, a representative of Pfizer presented information about the drug and the microbial safety steps the product would require.

Pfizer Animal Health said the product should create no microbial safety concerns because the drug would substantially bind to material in the feces and the remaining unbound drug would be sensitive to the pH in the animal’s colon, thus reducing the drug’s activity. The company also said that Campylobacter, which is the bacterium of concern, is more likely to acquire resistance through chromosomal mutation, not gene acquisition, which means tulathromycin is less likely to cause the development of resistance.

Pfizer Animal Health noted that beef and pork typically have Campylobacter contamination rates of 0-5%. And historical data indicate that pork and beef do not pose a significant risk for Campylobacter that can cause human disease.

In addition, Pfizer Animal Health noted that other macrolides have been in use for more than 30 years in humans, pets and food-producing animals, but resistance found in Campylobacter isolates from humans has remained at 3% or lower. (Other animal-use macrolides are erythromycin, tylosin and tilmicosin.)

According to the company, the proposed use of tulathromycin would limit the potential for the development of resistance because the product would be authorized for use only by or on the order of a veterinarian. In addition, the drug is to be used in a single injection, thus further reducing the exposure of bacteria of human health concern to the drug in the treated animals; therefore, the proposed conditions of use (may) minimize the likelihood of resistance development among those bacteria.

CVM concurred with the assessment presented by Pfizer Animal Health.

Role of VMAC

Under GFI #152, FDA has the option of applying several risk management steps involving antimicrobial drugs for food animals, ranging from denying the approval to approving the application under various use conditions that would assure the safe use of the product.

One of risk management options allows FDA to convene an advisory committee to discuss the application before CVM has completed its review of the application. For the review of tulathromycin, CVM convened its VMAC. In addition, this VMAC meeting also included members of the Center for Drug Evaluation and Research’s Anti-Infective Drugs Advisory Committee, who are specialists in human diseases caused by bacteria, including resistant bacteria.

According to its charter, VMAC includes a core of voting members with certain expertise, and FDA can add members as necessary to expand the committee’s level of expertise. The VMAC includes experts in veterinary medicine, microbiology, biometrics, toxicology, pharmacology, chemistry, animal science and public health. Also, the committee includes a consumer representative.

VMAC questions

CVM asked the VMAC whether the members believe that the sponsor’s assessment demonstrated that the product is safe with respect to the potential for transfer of antimicrobial resistant organisms to humans. FDA did not ask the VMAC to decide whether the drug should be approved, but only whether the microbial food safety risk management steps were sufficient to protect public health. CVM will continue to review Pfizer’s application and will ultimately decide on the product’s approvability for the indicated purpose.

CVM made a point of reviewing the microbial food safety of the product in an open and public meeting as a way to allow public access to the process that FDA is using to review antimicrobial animal drugs.