August 12, 1988
Emilio E. Viera, D.V.M.
New Brunswick, New Jersey 08903
Dear Dr. Viera:
This is in response to your submission dated February 29, 1988, pertaining to a public master file which provided for the use of sulfamethazine sustained release tablets for the treatment of bacterial pneumonia caused by Pasteurella spp. and colibacillosis caused by Escherichia coli in sheep. The submission contained animal efficacy and safety data, investigational labeling, human food safety data, environmental data, and a Freedom of Information Summary.
We have reviewed the data and have the following comments:
A. Human Food Safety:
The residue study was not completed properly due to the ineffective dose administered to the sheep. Therefore, a new residue depletion study should be performed. It should contain at least 20 sheep, preferably five groups with four animals per group. We recommend that the animals be slaughtered at 2, 4, 6, 8 and 10 days after cessation of drug administration, instead of 4, 8, 12, 16, and 20 as originally performed. We feel that these sacrifice times will produce more valuable data for determining a withdrawal time. You will be required to measure sulfamethazine residues in liver and kidney only, since your original data shows that these organs retain residues longer than muscle.
In your original residue study, the method was validated adequately at a sensitivity level of 0.1 ppm. However, all results were represented only to one decimal place. In determining the withdrawal time for a drug, we calculate with at least two decimal places (e.g. 0.24 ppm).
The method that you submitted appears to be able to detect levels lower than 0.1 ppm, as indicated in the published method. However, you report only levels greater than or equal to 0.1 ppm. The values that you originally submitted would not have allowed us to use our statistical procedure for determining a withdrawal period. Therefore, if you can quantitate levels below 0.1 ppm, preferably 0.05 ppm, you should validate the data at that concentration and submit all data points greater than 0.05 ppm. Better analytical methodology has been developed for the quantitation of sulfamethazine in cattle and swine, and may be useful in sheep, see reference: Matusik, J.E. et al. L. Assoc. Off. Anal. Chem. 70(3): 546-553, 1987.
B. Environmental Concerns:
Our review has found your submission to be inappropriate for two reasons:
(1) The proposed use of this product is "treatment in a minor species," therefore the appropriate submission would be an abbreviated environmental assessment addressing manufacturing issues from the NADA sponsor (21 CFR 25.31a(b)(4)). An environmental assessment of the use of the product is not required.
(2) Dr. Katz's environmental introduction estimate is based on 100% treatment, suggesting a "control" rather than a "treatment" claim for this product.
In addition,we also found what appears to be an error in your estimate of the environmental introduction of sulfamethazine from the proposed use. Using the information provided by you for the concentration in surface water, we calculate a concentration of 6.1 ug/ml rather than 0.61 ug/ml sulfamethazine, a concentration which you later suggest may result in resistance factor transfer in bacteria.
It would be most appropriate for this portion of the submission to be withdrawn at this time, based on the treatment claim. If the additional claim for control is made, environmental introductions derived from product use could be addressed at that time under 21 CFR 25.31a.
Calfspan (sulfamethazine sustained release) has to be administered every 24 hours for three days to be considered an effective product for use in sheep, thus the sustained release aspect is not valid. Any specific reference to sustained release for sheep would be false and misleading. The "Dosage Section" should read:
Adminster as an oral dose at a rate of one tablet for each 45 pounds body weight per day for three days. If there is no response within 2 to 3 days, reevaluate therapy.
D. Animal Safety and Efficacy:
We have no adverse comments, and consider these data to be adequate for approval of this public master file providing for the use of calfspan in sheep.
E. Freedom of Information Summary:
We reserve the right to comment until you address all the deficiencies cited in this correspondence.
Please feel free to contact us.
Donald A. Gable, D.V.M.
Director, Division of Therapeutic Drugs for Food Animals
New Animal Drug Evaluation
Center for Veterinary Medicine