August 6, 2012
U.S. Fish & Wildlife Service
Aquatic Animal Drug Approval Partnership Program
Attention: David Erdahl, Ph.D.
Branch Chief, AADAP
4050 Bridger Canyon Road
Bozeman, MT 59715
Re: Effectiveness technical section complete
Dear Dr. Erdahl:
Based upon the information you submitted on February 1, 2012, and amended on February 8, 2012 (T-0036) and the information contained in the investigational new animal drug (INAD) files I-010023 and I-011669, we consider the Effectiveness technical section to be complete. The technical section is complete for the use of 35% PEROX-AID (hydrogen peroxide) for the treatment and control of Gyrodactylus spp. in freshwater-reared salmonids when administered at 50 mg/L for 60 minutes or 100 mg/L for 30 minutes once per day on alternate days for three treatments in a continuous flow water supply or as a static bath.
JUSTIFICATION FOR THE EXPANDED LABEL CLAIM
The justification of a genus level claim is based on information which demonstrates that Gyrodactylus salmonis is the most prevalent and pathogenic species of Gyrodactylus infesting freshwater-reared salmonids in the US, and subsequently, that the effectiveness data submitted for G. salmonis infestations is representative of an overwhelming majority of the expected use pattern for an approved product.
The non-specific nature of hydrogen peroxide treatment, physiological similarities among gyrodactylids, and literature reports of hydrogen peroxide sensitivity in other Gyrodactylus species provide additional support for the expansion of the labeled claim by supporting the likelihood that similar effectiveness will be observed in untested Gyrodactylus species. However, these justifications would not be sufficient to support the proposed label expansion in the absence of the epidemiological information regarding the prevalence and pathogenicity of gyrodactylid species in US salmonid culture.
- We recognize that your general interest in pursuing broader indications for aquatic ectoparasites is based on concerns regarding the usefulness of the final labeled product to fish culturists. In order to expand the claim for the treatment of “Gyrodactylus spp.” to other groups of fish, additional information and effectiveness testing will be required. For each additional group of fish, we suggest that you utilize any existing epidemiological information, scientific literature, and/or conduct a survey similar to the one submitted for salmonids in order to identify the most relevant species of pathogen for use in your clinical effectiveness trials.
- In addition to the many similarities noted in your submission, your referenced reports also describe important biological differences between closely related and physiologically similar species of Gyrodactylus. These differences include preference for host species (Bakke et al., 2002), attachment location (Cone and Cusack 1988), tegument thickness and composition (Cable et al., 1996), ability to cause disease (Dalgaard et al., 2004), and tolerance of environmental conditions (Schelkle et al., 2011). It is worth noting that reactive oxygen species are part of the normal anti-parasitic arsenal of host organisms, and that many parasites produce enzymes (ex. peroxidases) which are capable of neutralizing reactive oxygen species1,2.
Because of the potential for important biological differences to exist between apparently similar species, we are not likely to consider the general similarities among species to be sufficient justification for a broad label claim. It is important that you continue to include effectiveness data and epidemiological information along with supporting biological information, as part of any future requests for a broad label claim.
- You provided reports of effective hydrogen peroxide treatment of two additional Gyrodactylus species. These studies provide indirect support for your request but are not directly relevant to the current technical section because they used either a different drug formulation, longer exposure time, or both (Montgomery-Brock et al., 2004; Buchmann and Kristensson 2003, see above).
Thank you for submitting potential warning language for an approved product.
Because the effectiveness of hydrogen peroxide at the proposed dose has not been tested against other species of Gyrodactylus, and because it is understood that even G. salmonis may not be susceptible to treatment under all conditions of use, it may be appropriate for a warning to be placed on the label which states that the drug is expected to be safe and effective when used according to the label, but that it has not been tested for all pathogen and fish species covered by the labeled claim, and recommending that the user monitor safety and effectiveness and report any adverse events.
In the future, please include draft labeling language with each major technical section.
FREEDOM OF INFORMATION (FOI) SUMMARY
We have revised the Effectiveness section of the FOI Summary and a copy is enclosed. Please review the FOI Summary for accuracy and notify us if you find errors.
Include a copy of this technical section complete letter when you submit your new animal drug application. Please contact us if there are changes in the product development plan (e.g., indication, dosage, duration of use) or you become aware of any issues that may impact the status of this technical section or your application. We will make a final decision on whether we can approve your application after we have reviewed all of the data for all applicable technical sections and any other information available to us, as a whole, and determined whether the requirements for approval described in the Federal Food, Drug, and Cosmetic Act have been met.
If you submit correspondence relating to this letter, your correspondence should reference the date and the principal submission identifier found at the top of this letter. If you have any questions or comments, please contact me at (240) 276-8341. You may also contact Dr. Jennifer Matysczak, Leader, Aquaculture Drugs Team, at (240) 276-8338.
Cindy L. Burnsteel, DVM
Director, Division of Therapeutic
Drugs for Food Animals
Office of New Animal Drug Evaluation
Center for Veterinary Medicine
Draft Section of FOI Summary: Effectiveness
1 Leid et al. 1987. Parasite Defense-mechanisims for evasion of host attack – A review. Veterinary Parasitology 25: 147-162
2 Lindenstrom et al. 2004. Expression of immune response genes in rainbow trout skin induced by G. derjavini infections. Veterinary Immunology and Immunopathology 97: 137-148