PMF 5590 A-0000

Dr. Meg Oeller
FDA Liaison to NRSP 7
FDA Center for Veterinary Medicine
Office of New Animal Drug Evaluation (HFV 130)
7500 Standish Place
Rockville, Maryland 20855

Dear Dr. Oeller:

We refer to your Public Master File (PMF 5590) and your submission dated June 3, 1997, regarding the use of copper sulfate as a broad spectrum microbicide on fish. The submission contains a request of CVM to review a final report comprising three series of studies, each documenting the efficacy of copper sulfate as either a parasiticide, fungicide or anti-columnaris drug. The final report was assembled by Dr. Billy R. Griffin, USDA, Stuttgart National Aquaculture Research Center, Stuttgart, Arkansas. The CVM has reviewed your submission and has the following comments.

TECHNICAL SECTION COMPLETE

Based on the information in this submission, the Division of Therapeutic Drugs for Food Animals considers the effectiveness technical section complete for purposes of recommending approval of a New Animal Drug Application (NADA). However, our consideration of completeness is limited to only the effectiveness of copper sulfate as a parasiticide for the prevention and treatment of Ichthyophthiriosis (Ich) in all fish susceptible to this disease (caused by the ectoparasite Ichthyophthirius multifiliis). A final decision on the FEDERAL REGISTER publication of availability of data in PMF 5590 will be made when all the data for all technical sections have been completed and it has been determined that the information contained in these technical sections would support an approval.

COMMENTS

As noted in the first paragraph, your submission comprised study reports intended to support effectiveness claims for copper sulfate as a parasiticide, fungicide and anti columnaris drug for all susceptible fish. Our review of the submission found the claims, beyond that for the prevention and treatment of Ich, to be unsupported. The following comments address specific inadequacies as they pertain to the three broad claims.

1. Parasiticide Claims:

a. Relevant Evidence – Of the six studies submitted for review, only five were considered to contain relevant information that could be applied to the claim or a subset of the claim. The study by Byran and Allen (1969) was considered to be not acceptable, for it only contained implicit information about copper sulfate and did not document any copper sulfate/Ich (or other parasite) studies.

b. Limited Evidence – Of the five acceptable studies, none provided any evidence for copper sulfate’s effectiveness against any parasite other than that causing Ich.

c. Label Directions – The directions for use are flexible, but require that the total alkalinity (TA) of the culture water to be known; TA directly affects the bioavailability, and hence toxicity, of copper. Please see attached suggested draft label, which includes the following “Directions for Use”.

DIRECTIONS FOR USE: Apply copper (cupric) sulfate pentahydrate to water at a rate directly proportional to the total alkalinity (TA) of the culture water. Due to the inherent toxicity of copper sulfate to fish, the rate of application should not exceed 1 part per million (ppm) copper sulfate per 100 ppm TA (as CaCO3). Typical application rates (based on documented effectiveness research) vary from as high as 1 ppm copper sulfate per 240 ppm TA to as low as 1 ppm copper sulfate per 610 ppm TA. A concentration of 1 ppm is achieved by applying 2.72 pounds of copper sulfate per acre foot of water.

2. Anti Columnaris Claims:

a. Limited Evidence – The single submitted study intended to support the claim of copper sulfate’s effectiveness to control or prevent columnaris disease in fish was considered to contain relevant information that could be applied to an anti columnaris claim for copper sulfate. However, this study alone, conducted on striped bass, was considered to be insufficient documentation to support the claim that copper sulfate is effective for the control and prevention of columnaris in striped bass, let alone effective for the same in ALL fish susceptible to columnaris disease.

3. Fungicide Claims:

a. Relevant Evidence – Of the two studies submitted for review, only one was considered to contain relevant information that could be applied to the claim or a subset of the claim. The study by Bly, et al. (1996) was considered to be not acceptable, for it contained only the results of investigations in very soft water in which copper sulfate is highly toxic, and hence the data are of little value and applicability.

b. Limited Evidence – The single acceptable study (Li, et al., 1996) intended to support the claim of copper sulfate’s effectiveness to control or prevent winter saprolegniosis (or winter kill) in channel catfish was considered to contain relevant information that could be applied to a fungicide claim for copper sulfate. However, this study alone was considered to be insufficient documentation to support the claim that copper sulfate is effective for the control and prevention of the fungal disease saprolegniosis in channel catfish, let alone effective for the same in ALL fish susceptible to saprolegniosis.

In addition to the claim specific comments noted above, we believe that one other point should be brought to your attention, that may assist you in future submissions.

4. We found the 1 to 2 page summary sheet and the enumeration of the study’s conformance to a defined series of data quality criteria, all of which preceded each submitted study, to be of significant potential value. Unfortunately, we found several cases in which it was falsely claimed in the summary sheets that the study included at least one of the data quality criteria, when close examination of the respective study refuted that claim. As an example, Criteria #8 is the inclusion of documentation to support that analytical tests were accomplished to validate or confirm that the actual concentration of copper sulfate in the culture water matched that nominal concentration added to the water. Relative to this criterion, of the eight studies submitted, the summary reports indicated that in seven of the studies, concentration analysis had been accomplished. However, close examination of those seven studies revealed that such analytical validation had been conducted in only three of the studies.

The summaries did not serve to help reduce the review time, but had quite the opposite effect. Instead of using the summaries to allow for some spot checking, they interjected sufficient doubt as to the summaries’ value, and caused a complete word by word review.

One final point should be made to help in your preparation of an NADA for copper sulfate.

5. It is assumed that your intent was to provide documentation to support an exceptionally broad and flexible claim for the use of copper sulfate. The breadth and flexibility was to be not only from the perspective of the species indicated for treatment, but also for the disease claims. We remind you that such a broad and flexible approved label can be gained by two routes. The first by seeking the entire broad and flexible claim in one NADA technical section (as you were attempting). The second by seeking a limited claim (e.g., for the treatment and control of Ich in susceptible fish) in an NADA, to be followed by supplement(s) to the NADA, which would add the additional disease claims.

We would like to express our sincere appreciation for the willingness of Dr. Griffin to assist the entire aquaculture industry, and CVM, by compiling and submitting technical section components.

Future correspondence regarding this submission to the PMF should be identified by this submission's correspondence date and our file numbers, PMF 5590 A0000 and be submitted 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, regarding this correspondence, please contact Thomas A. Bell, Group Leader, Aquaculture Drugs, 301-594-1649.

Sincerely yours,

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