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U.S. Department of Health and Human Services

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PMF 005-637 - Salmonids - Effectiveness Letter

PMF 005-637 C-0003

July 12, 2000

Leslie E. Holland-Bartels, Ph.D.
Center Director
Upper Midwest Environmental Sciences Center
2630 Fanta Reed Road
La Crosse, Wisconsin 54603

Dear Dr. Holland-Bartels:

We refer to your submission dated January 7, 2000, in which you requested our review of studies conducted to demonstrate the effectiveness of chloramine-T for the control of mortality associated with bacterial gill disease (BGD) in apache trout, fall chum salmon, and rainbow trout.

We have completed our review of the submitted studies and offer the following comments.

GENERAL COMMENTS:

1. CVM concurs that the pivotal studies in this submission adequately demonstrate the effectiveness of chloramine-T at a concentration of 12 ppm administered as a 60 minute bath every other day for three treatments for the control of mortality associated with bacterial gill disease in apache trout and fall chum salmon. The data provided in this submission combined with the Final Report submitted into INAD 4000 (H-0071, dated April 17, 2000) are adequate in demonstrating the effectiveness of chloramine-T at a concentration of 12 ppm administered as a 60 minute bath every other day for three treatments for the control of mortality associated with bacterial gill disease (BGD) in freshwater-reared salmonids. Accordingly, the effectiveness technical section is complete for this indication in freshwater-raised salmonids.

2. The draft labeling included in the submission proposes a dose range of 5 to 20 mg/L. In order to include this dose range on the product labeling, effectiveness would need to be demonstrated at the low end of the dose range (in this case 5 ppm), while data would need to be submitted that demonstrates the safety of administration at the high end of the range (20 ppm). Accordingly, to include a dosage level lower than 12 ppm in the labeling for this indication in freshwater-raised salmonids, additional efficacy data would need to be submitted that demonstrate effectiveness at the lower dose.

SPECIFIC COMMENTS:

1. In all three study reports, you state that the null hypothesis tested was H0 : m1 = m2; mortality caused by BGD is equal between fish treated with chloramine-T and untreated fish. T-tests were used to evaluate the null hypotheses. One of the assumptions regarding the use of a t-test is that the data are normally distributed. Based on the information presented in the reports, you analyzed cumulative numbers of dead fish per tank and not cumulative mortality rates. You cannot assume that counts of dead fish are normally distributed. The data should have been analyzed as mortality rates per tank, which are binomially distributed.

2. We also noted that for the apache trout and chum salmon studies, the numbers of fish prior to treatment and number of dead fish per tank presented in the statistical analysis appendices did not correspond to the mortality forms presented for each study.
3. We transformed the mortality rates using an arc sine transformation (sin-1Ö(proportion)) and used the MIXED procedure in SASÒ. We also analyzed the mortality rates using the generalized linear models (GENMOD procedure), using a binomial error distribution and a logit link function. Treatment was included as a fixed effect in both models and an overdispersion parameter was included in the GENMOD procedure. The least-squares means and back-transformed cumulative mortality percentages from the MIXED and GENMOD procedures are presented in the following two tables:

Table 1. The least-squares means and back-transformed cumulative mortality percentages from the MIXED and GENMOD procedures for apache trout

TreatmentMIXED LSMeanMIXED PercentageGENMOD LSMEADGENMOD Percentage 
0 mg/L1.431398.1%3.919498.1%
12 mg/L0.673538.9%-0.451238.9%
p-value<.0001--<.0001--

 

Table 2. The least-squares means and back-transformed cumulative mortality percentages from the MIXED and GENMOD procedures for fall chum salmon

TreatmentMIXED LSMeanMIXED PercentageGENMOD LSMEANGENMOD Percentage
0 mg/L1.517999.7%5.621399.6%
12 mg/L0.27787.5%-2.42858.1%
p-value.0002--<.0001--

 

4. In Table 4 of the summary report (page 20, volume 1), the “Number of Survivors” and “Number of Fish at Initiation of Treatment” columns for rainbow trout (Neosho NFH) do not correspond to the number of fish presented in Figure 1 of Report 4 (page 19, volume 4).

5. The rainbow trout used in Study Number 4000-1-001 had been treated with formalin for ichthyophthiriosis prior to the start of the trial. During the pre-trial fish health examination, it was determined the fish still had a moderate infection (ichthyophthiriosis). The decision was made to proceed with the trial despite the concurrent infection. Due to the concurrent disease, we do not believe that valid conclusions can be drawn from the data generated during this trial. The trial should be considered non-pivotal and should not be summarized in the FOI Summary.

6. The cover letter for this submission refers to INAD 9321, but we believe that the pivotal studies contained in the submission were actually conducted under INAD 4000. INAD 4000 should be referenced in the FOI Summary for the pivotal studies.

7. The following two tables should be included in the FOI Summary.

Table 3. Percent mortality occurring in apache trout during Study No. 4000-1-003 from the initiation of medication through the post-treatment observation period
TreatmentTotal Mortality
No treatment98.1 (6397/6524)
Chloramine-T 12 ppm38.9 (2508/6446)

 

Table 4. Percent mortality occurring in fall chum salmon during Study Number 4000-1 002 from the initiation of medication through the post-treatment observation period
TreatmentTotal Mortality
No treatment99.6 (48067/48241)
Chloramine-T 12 ppm8.1 (3907/48218)

Future correspondence regarding this submission to the PMF should be identified by the date of the submission and our file number, PMF 5637 C 0003, and be addressed to the Document Control Unit, HFV-199. Please include only one request per submission, clearly stating the request in the first paragraph of the submission.

If you have any questions or comments regarding this correspondence, please telephone Dr. Joan Gotthardt, Leader, Aquaculture Drugs Team at 301-827-7571.

Sincerely yours,


/s/
Steven D. Vaughn, D.V.M.
Director, Division of Therapeutic
Drugs for Food Animals
Office of New Animal Drug Evaluation
Center for Veterinary Medicine