PROBLEMS ENCOUNTERED IN CONDUCTING PIVOTAL CLINICAL EFFICACY 
STUDIES AT FISH CULTURE FACILITIES

Jeff J. Rach* and Mark P. Gaikowski

      U.S. Geological Survey, Upper Midwest Environmental Sciences Center
      2630 Fanta Reed Road, La Crosse, Wisconsin, 54603.	
      jeff_rach@usgs.gov

The approval of new therapeutic drugs for aquaculture use is regulated by the U.S. 
Food and Drug Administration’s Center for Veterinary Medicine.  An important 
requirement for obtaining a new animal drug approval is to document the clinical 
efficacy of the new animal drug’s effectiveness to control an epizootic(s).  Often these 
pivotal efficacy trials are conducted at a fish culture facility during a natural disease 
outbreak. 

Epizootic results from complex interactions between the fish, the pathogen and the environment. 
 Within these interactions, numerous variables are continually changing and may complicate or 
reduce the efficacy of a specific therapeutic treatment.  The presence or absence of the disease 
organism in the culture water supply, health status of individual fish, and the severity of the 
pathogen infection/infestation on the fish often determines how quickly the disease spreads to 
uninfected fish.  Within the fish population, changes occur in the host population as the disease 
progresses.  Initially, there may be a large “at-risk” population within the culture unit as most 
hatcheries intentionally crowd fish at higher than natural densities.  As the disease progresses, 
significant mortalities may occur that may result in improved environmental conditions as fish 
densities decline (dead fish removed reduce the pathogen density); these circumstance may lead 
to the remission of the epizootic.  Pathogens also provide their own variability to epizootics, with 
differences in virulence from outbreak to outbreak.

These difficult to control biological factors are further complicated by the dynamic culture 
conditions in which the fish are treated.  Changes in water chemistry (dissolved oxygen, 
temperature, and pH), loading in the culture tank, etc., may result in spontaneous remissions or 
further the progression of the disease.  The timing of administering therapeutic treatments during 
an epizootic are critical in obtaining an efficacious treatment of the pathogen.  Treatments 
administered after the disease entry into an exponential growth/infection phase are likely to be 
drastically less effective relative to treatments applied early after discovery of the infection.  
Also, as more fish become infected with a pathogen and fish health diminishes there is an 
increased possibility of therapeutic toxicity to the fish.  Interactions of the aforementioned factors 
frequently result in highly variable survival of control and treated fish. 



Pivotal clinical efficacy studies often delay therapeutic treatments, due to complex study 
procedures (randomization, blinding, and disease identification), until the disease is well 
established in the fish population.  Ideally, an efficacy trial should be conducted with uniformly 
infected/infested fish that are in a similar health condition; a nearly impossible scenario to 
achieve under normal fish culture efficacy trials.  The effects of numerous variables often impact 
the outcome of clinical trials and every effort must be taken to minimize the number of variables.