It is becoming more difficult to make new vaccines and drugs available for general use because of increasing governmental controls by the Food and Drug Administration ( FDA), United States Department of Agriculture (USDA) and the Environmental Protection Agency (EPA). The substantial costs involved and the long delays make the economic incentive unattractive to most major pharmaceutical companies who consider the field of aquaculture. However, aquaculture is growing, and the future promises coned and rapid growth. In order to provide the products needed to this promise, the work to satisfy governmental controls must start and it must take the commitment of a major company to sustain the costs needed to complete the process. However, the benefits of this commitment must also be profitable. In this address, I will describe the efforts of one company's attempts to supply the products needed in aquatic animal medicine.

First, Tavolek is a new subsidiary of Johnson & Johnson. Tavolek’s business is the research, development and marketing of vaccines and manceuticals for aquatic animals. In addition, we work very closely Pitman-Moore. This is our base and our source of drugs and biological expertise. The scope of our work is worldwide on the economically important species of fish.

Although we have a broad interest, we are focusing on food fish due to the growing human populations, declining catches due to over fishing, restrictions such as the 200 mile limit, and the increasing need for protein. Because "hunting" of fish is becoming more limited in the ocean, wave of the future has got to be aquaculture. Aquaculture is in its infancy, and there are many associated problems in making it a really flourishing business. What is needed for aquaculture to flourish are better techniques of fish culture, genetics, nutrition, and disease control. I also might add that we need an understanding and helpful government. The political and governmental bureaucracy may limit more cases than the biological problems.  Excessive delays and unrealistic guidelines are problems which significantly limit progress. However, this presentation will focus on methods of disease control.

There are a variety of products needed to assist aquaculture in over coming its disease problems. Among the products being developed are vaccines, antifungal compounds, antibiotics, anesthetics, tranquilizers, endocrine products for spawning induction and growth promotion, parasiticide, disinfectants, diagnostics and new delivery techniques. To make an impact in all these areas at one time is naturally impossible. Priorities must be set, and then one must move into those areas that show most promise. Tavolek, in a little over two years, has developed vaccines for the control of vibriosis and enteric red mouth. Also, two delivery techniques for the mass immunization of fish have been loped: the direct immersion method, and the shower method. Although biologicals and antibiotics are available today, almost all chemicals biologicals used in fisheries must be approved by the government, be he FDA, USDA, or EPA, before they can be used for public use. This he most time consuming and labor intensive aspect of supplying products for aquatic animals. Part of the problem is the unawareness the uninformed officials in the government that deal mostly with "higher" animals do not relate to the problems of aquaculture. Furthermore, the regulations were designed for non-aquatic animals which present some very unique problems. The following will outline the procedures and difficulties in bringing a new product to market, in this case a vaccine. Because my experience is primarily with the USDA, I will briefly outline the process of what it takes to bring a biological to market for use in the fish area.

To develop a vaccine for an infectious disease, we must first ascertain the problem and its current status. For example, how serious is the mortality or morbidity? How easily is it controlled with current procedures such as antibiotics, or is it refractory to treatment? Is it feasible both from a practical and an economic standpoint? Also, ease of treatment is a major concern. Confirmation of the etiological agent and subsequent isolation of the organism must be made.

If we determine that the vaccination is a practical solution, then we must collect as wide a sample of isolates as possible. From this, tests including serological, virulence, biochemical, growth, inactivation curves, preservation studies, relative homology and heterology are made. By putting these results together, a working isolate is selected for vaccine preparations. In order to determine the efficiency and potency of a vaccine, we must have a suitable challenge system. Considerable time may be devoted to this problem, including species, route of administration, environmental factors, and dosage. The development of challenge systems requires a large expenditure of time and facilities, because it must be reproducible, reliable, and useful on several species.

Once a vaccine has been developed, effort is then concentrated on production and a suitable delivery method chosen. Serial lots are produced, followed by stability tests, sterility tests and finally tested for safety and potency. Evaluation of delivery systems includes injection immersion, shower, hyperosmotic infiltration and oral. The data is submitted to the USDA for evaluation. If satisfactory, then you are ready for field tests.

Field tests are primarily safety tests to be sure that problems do not develop when large numbers of fish are vaccinated which cannot be detected under laboratory conditions. If this is not possible, then we bring representative samples of fish back to the laboratory to do experimental challenges. The control and vaccinated groups are carefully monitored, in either instance. Costs and time involved, management acceptance of the procedures, food conversions, mortality are all monitored very closely. Each serial lot is tested at a different location and when the data is completed it is re-submitted to the USDA for review.

If the data is accepted then a final label is submitted and, if approved, a license is granted to market the product. At this point, product marketing begins. However, all further production lots must also be tested for safety and potency, and the products must be released by the USDA before it can be sold. In addition, the research does not stop here, as further improvements may be needed. These can include further application procedures, shelf life, onset and duration of immunity effect on individual species.  Cross-protection and serological tests are also conducted with other vaccine preparations or perhaps studies are made for application to other species of fish. In all cases, these changes must be stated on the label, and the USDA must view and approve all such changes. Any deviation from or additions the approved label could result in the loss of our license.

This completes the process of licensing a product for the USDA. similar but more detailed tests are required by the FDA or EPA.  In these instances, more emphasis is placed on safety -- to the fish, the consuming public, and the environment -- and many more regulations are involved. It is apparent that such processes are time consuming and very costly.

For those interested in further details on the requirements needed to register biologicals and pharmaceuticals for fish, the following references and guidelines are presented:

1. FDA -- This agency is responsible for the clearance of drugs and chemicals that have therapeutic claims.  New Animal Drug applications are reviewed by the director of veterinary medicine which is composed of two divisions -- non-food animals (pets) and food animals -- and the main responsibility is to assure that the sponsor has proven the safety of the drug to the treated animal, and that the drug is effective for the claims being made.  In the case of food animals the Bureau of Foods is also involved, and their responsibility is to assure that no harmful residues are present in edible tissues.
   1. Federal Code of Regulations. 21. Food and Drugs. U.S. Printing Office, Washington, D.C.
   2. Lennon, R. E. 1967. Clearance and Registration of Chemical Tools for Fisheries. Prog. Fish Cult. 29 (4) :87-1 93.
   3. Bureau of Veterinary Medicine (FDA). 1978. Guidelines on Safety and Efficacy in Target Animal on the Minor Use of Drugs. 5600 Fishers Lane, Rockville, Maryland.
2. EPA -- The primary responsibility of this agency is the clearance of pesticides and herbicides. The mission is to protect the environment from harmful chemicals, and chemicals used on fish ultimately are released into the environment. if the primary claim is to disinfect or "treat" the water, this agency reviews the application. However, if the fish is treated, the FDA reviews the application, but the review must contain an Environmental Impact statement to assure that EPA concerns are covered. This review also is to assure that the sponsor has proven safety to the target animal and non-target animals, as well as to prevent accumulation of harmful residues in the water or sediments.
   1. Bureau of Veterinary Medicine (FDA). 1978. Guidelines on Environmental Considerations on Minor Use of Drugs and Environmental Impact Operational Directive of June 1977. 5600 Fishers Lane, Rockville, Maryland.
   2. Environmental Protection Agency. 1975. Guidelines for Registering Pesticides in the United States. Federal Register. 40(123).
   3. Federal Code of Regulations. 40. Pesticides Programs. U.S. Printing Office, Washington, D.C.
3. USDA -- Biologicals sold in interstate commerce must be licensed by the Animal and Plant Health Inspection Service, Bureau of Biologics and Standards. As discussed in this article, the responsibility of this agency is to assure the safety and efficacy of biologicals. Because biologicals are derived from naturally occurring products, residues are not required. However, chemicals used in the processing or manufacture of a biological must comply with the regulations of FDA and EPA.
   1. Antipa, R. G. and T. R. Croy. 1979. Fish Vaccine Development and Testing. Prog. Fish Cult. 41(l):46-48.
   2. Fryer, J. L., D. F. Amend, L. W. Harrell, A. J. Novotny,
   3. J. A. Plumb, J. S. Rohovec, and G. L. Tebbit. 1977.
      Development of Bacterins and Vaccines for Control of
      Infectious Diseases of Fish. Oregon State University.
      Sea Grant Program. Publication ORESU-T-77-012. 10 pp.
   4.  Federal Code of Regulations. 9. Animals and Animal Products. U.S. Printing Office, Washington, D.C. 859 pp.