Issues Regarding the Use of Sedatives in Fisheries and the Need for Immediate-Release Options

The lack of an immediate-release sedative (i.e., one for which no postsedation holding or withdrawal period is required) jeopardizes fish and fisheries research and poses considerable risk to those involved in aquatic resource *Corresponding author: [email protected] Received March 29, 2012; accepted September 14, 2012 Published online December 12, 2012 156 D ow nl oa de d by [ C ol le ge o f W ill ia m & M ar y] a t 0 8: 59 0 1 A ug us t 2 01 3 SEDATIVE OPTIONS IN FISHERIES 157 management and the operation of public hatcheries and commercial fish farms. Carbon dioxide may be used as an immediate-release sedative, but it is slow-acting and difficult to apply uniformly and effectively. Tricaine methanesulfonate (MS-222) is easier to apply but requires a 21-d withdrawal period. The lack of an immediate-release sedative approved by the U.S. Food and Drug Administration (FDA) is a consequence of numerous factors, including the complexities of the approval process, the substantial human and monetary resources involved, and the specialized nature of the work. Efforts are currently underway to demonstrate the safety and effectiveness of benzocaineand eugenol-based products as immediate-release sedatives. However, pursuing approvals within the current framework will consume an exorbitant amount of public and private resources and will take years to complete, even though both compounds are “generally recognized as safe” for certain applications by the FDA. We recommend using risk management–based approaches to increase the efficiency of the drug approval process and the availability of safe and effective drugs, including immediate-release sedatives, for use in the fisheries and aquaculture disciplines. Access to safe and effective fish sedatives is a critical need of fisheries researchers, managers, and culturists. Federal, state, private, tribal, and academic fisheries professionals routinely sedate1 fish for transport (e.g., moving them to a captive holding facility, stocking site, or to market), the collection of tissue samples (e.g., scales, spines, gametes, and fin clips) or morphometric data (e.g., length and weight), and the surgical implantation of tags or tracking devices (e.g., for monitoring movement, spawning behavior, or survival). Ideally, a fish sedative will be easy to administer, safe to use, and effective at low doses; provide quick and predictable sedation; offer some analgesia; elicit a state of sedation that is easily managed; have a reasonable margin of safety with respect to oversedation; be usable over a broad range of water chemistries; allow for rapid recovery from sedation and the physiological responses to the sedative; and be inexpensive. Additionally, it is often desirable that the sedative have no withdrawal period, meaning that sedated fish can be immediately released into the wild or taken to market upon recovery (typically referred to as “zero withdrawal” or “immediate release”). Unfortunately, there are few fish sedatives that possess all of these qualities, and at this time there are none that can be legally used in North America without a lengthy withdrawal period. Our objectives were to review the need for immediate-release sedatives, describe the current regulatory process for making such compounds available to fisheries professionals in North America, assess the relative risks associated with the use of two candidate immediate-release sedatives (a benzocaine-based product and a eugenol-based product), and provide recommendations to increase “regulatory efficiency” in 1As discussed by Trushenski et al. (2012), the terms “anesthesia,” “sedation,” and “immobilization” are used somewhat interchangeably in fisheries science, but they actually have distinct definitions. Anesthesia is “a reversible, generalized loss of sensory perception accompanied by a sleep-like state induced by drugs or by physical means”; sedation is “a preliminary level of anesthesia, in which the response to stimulation is greatly reduced and some analgesia is achieved but sensory abilities are generally intact and loss of equilibrium does not occur”; and immobilization generally means the prevention of movement only (Ross and Ross 2008). Although these different definitions may be appropriate under different circumstances, most of the scenarios described herein are best described by the terms “sedate,” “sedation,” and “sedative”; for simplicity, we have used these terms throughout. the area of aquatic animal drug approvals as they pertain to fish sedatives. Specifically, we recommend a risk management– based approach to regulating the candidate immediate-release sedatives and outline a semiquantitative risk assessment which indicates that the proposed uses of these compounds have negligible risk. GENERAL NEED FOR SEDATION WHEN HANDLING FISH Unlike most terrestrial vertebrates, which can be handled without causing significant mechanical damage, fish are particularly vulnerable to external and internal injury during physical restraint. Compared with the epithelium of terrestrial vertebrates, that of most fishes is delicate and prone to damage. The epithelium can be damaged by simply disrupting the protective mucus layer, potentially compromising osmoregulation and predisposing the fish to infection or infestation (Shephard 1994). Fish are innately difficult to handle, and when they actively resist restraint, epithelial damage or other physical injury to the fish or the handler is more likely. If fish are sedated prior to handling, the risk to both fish and handler is greatly minimized. In addition to suffering mechanical damage, fish handled without proper sedation may be physiologically compromised as a result of stress. Stress may be defined as a natural reaction to a negative stimulus culminating in the mobilization and redirection of energy to support the “fight or flight” response (Selye 1950). During the stress response, the maintenance of important but not immediately critical functions is often sacrificed as a consequence of stress hormone release (Barton and Iwama 1991; Barton 2002). In fish, noncritical functions can include osmoregulation, reproduction, feeding, and particularly the exclusion and/or clearance of pathogens (Tort et al. 2004). As a result, stressed individuals may become homeostatically compromised and suffer tertiary consequences of stress, such as increased vulnerability to disease, reduced reproductive performance, and reduced growth (Barton and Iwama 1991; Wendelaar Bonga 1997; Barton 2002; Tort et al. 2004). Beyond the readily quantified physiological consequences of handling unsedated fish, fisheries professionals must consider D ow nl oa de d by [ C ol le ge o f W ill ia m & M ar y] a t 0 8: 59 0 1 A ug us t 2 01 3 158 TRUSHENSKI ET AL. TABLE 1. Attributes of currently available sedatives. Sedative Approved? Limitations Benzocaine No, but can be used under INADa authorization 3-d withdrawal period CO2 No, but FDAb unlikely to use regulatory authority Cumbersome and not all fish respond well Eugenol No, but can be used under INAD authorization 3-d withdrawal period MS-222 Yes for temporary immobilization 21-d withdrawal period aInvestigational New Animal Drug. bU.S. Food and Drug Administration. animal welfare (Huntingford et al. 2006). There is considerable scientific debate as to whether fish are capable of feeling pain or only exhibit nociception2 (e.g., Rose 2002, 2003; Chandroo et al. 2004; Sneddon 2006); the specifics of this debate and its resolution are largely outside the scope of the present review. Regardless of whether fish perceive pain in the same manner as higher vertebrates, with respect to fisheries research, relevant guidelines advise that “investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals” (USPHS 1986; CCAC 2005), “prolonged stressful restraint [without appropriate sedation or anesthesia] should be avoided” (UFR 2004), and “procedures with animals that may cause more than momentary or slight pain or distress should be performed with appropriate sedation, analgesia, or anesthesia” (USPHS 1986). CURRENTLY AVAILABLE SEDATIVES AND THEIR LIMITATIONS Currently, there are few sedative options available to fisheries professionals that are safe, effective, and practical to use (Table 1). Perhaps more importantly, MS-222 (tricaine methanesulfonate [3-aminobenzoic acid ethyl ester methanesulfonate]) is the only compound approved by the U.S. Food and Drug Administration (FDA) and Health Canada for such use in these countries. Two MS-222 products (Tricaine-S and Finquel) are approved in the United States for the temporary immobilization of fish and other aquatic, cold-blooded animals, and one MS-222 product (Aqualife TMS) is approved in Canada for veterinary use only for anesthesia or the sedation of salmonids. Like other local anesthetics, MS-222 is rapidly absorbed through the gills and believed to exert its sedative effect by preventing the generation and conduction of nerve impulses (Frazier and Narahashi 1975), though there is some uncertainty regarding this (Popovic et al. 2012). MS-222 has direct actions on the central nervous system, cardiovascular system, neuro2As discussed by Sneddon (2009), the generally accepted definition of “pain” involves two elements: (1) the perception of stimuli associated with actual or potential tissue damage, referred to as nociception; and (2) awareness of an associated negative emotional experience, sometimes described as discomfort or suffering. It is relatively easy to demonstrate nociception in fish. However, it is impossible to demonstrate what a fish “feels” and therefore whether it can experience pain as it is defined. muscular junctions, and ganglion synapses. Lower doses induce tranquilization and sedation, and higher doses result in general/surgical anesthetic planes (Alpharma 2001). In fish, brief tachycardia (elevated heart rate) occurs within 30 s of exposure, followed by prolonged bradycardia (depressed heart rate; Popovic et al. 2012). MS-222 also causes vasoconstriction in the gills, which slows down the uptake of waterborne materials across the gill membrane (Hunn and Allen 1974). Other effects of prolonged exposure include hypoxia (inadequate oxygen supply at the tissue or whole-body level), increased plasma lactate concentrations, hyperglycemia (elevated blood glucose levels), increased urinary output, and electrolyte loss. MS-222 is continually absorbed throughout immersion in spite of gill vasoconstriction and therefore can lead to a lethal overdose (Treves-Brown 2000). Additionally, unbuffered MS-222 acidifies water, and without sufficient buffering it may be stressful to fish (Popovic et al. 2012). Use of any pH buffering compound (e.g., sodium bicarbonate), however, adds an additional unapproved substance to the sedative solution. Despite its acidifying property, MS-222 is generally considered to be a safe and effective fish sedative and is widely used by fisheries professionals for a variety of purposes. According to the FDA product label instructions, the use of MS-222 should be restricted to fish in the ictalurid, salmonid, esocid, and percid families at water temperatures exceeding 10◦C. In addition, a 21-d withdrawal period is required for use on fish intended for human consumption or fish that may be captured and consumed. The use of MS-222 is similarly restricted in Canada, including a provision that treated fish cannot be slaughtered until 5 d after the last exposure. Also, during this holding period, fish must be held in water warmer than 10◦C (Health Canada 2010). For many applications, holding fish for 5 d postsedation is not practical or seriously compromises the objectives of management or research activities. In field settings, it can be extremely problematic to hold fish for as little as 1–2 h posttreatment without utilizing specialized equipment and allotting additional time to complete such field procedures. Most severely affected are fisheries professionals collecting population morphometric data or gametes from wild-caught fish and those involved in surgically implanting devices (e.g., electronic or acoustic tags) in catchable-sized fish. To avoid the complications of holding fish in field settings, an approved immediate-release sedative is critically needed. Currently, the only immediate-release sedative compound available in the United States is CO2, which is considered a D ow nl oa de d by [ C ol le ge o f W ill ia m & M ar y] a t 0 8: 59 0 1 A ug us t 2 01 3 SEDATIVE OPTIONS IN FISHERIES 159 low regulatory priority (LRP) drug by the FDA3. Although CO2 gas has been characterized by some as an effective sedative (primarily for freshwater fishes), it is generally not considered safe for target animals because it is slow-acting and difficult to apply uniformly and often results in adverse outcomes, including presedation hyperactivity and postsedation morbidity and mortality. There is a large body of research on the physiological consequences of hypercapnia in fish (e.g., Tufts and Perry 1998) indicating that CO2 gas is not an ideal sedative. Sedative concentrations of CO2 can be established in two primary ways: CO2 gas can be bubbled into the water until the desired concentration is achieved, or CO2 can be produced by the addition of sodium bicarbonate to acidified water. In each of these cases, the concentration of CO2 must be closely monitored to achieve and maintain the target concentrations (e.g., Trushenski et al. 2012). Compared with other sedatives, CO2 can be logistically difficult to use because it requires continuous monitoring and the adjustment of concentrations and it may require the use of heavy, bulky, and potentially hazardous pressurized gas cylinders. The effectiveness of CO2 as a sedative is based on its interference with normal respiratory exchange. Under normal conditions, CO2 produced by a fish’s tissues is transported via the circulatory system to the gill, where it is excreted via diffusion down the blood–water tension gradient. When environmental concentrations of CO2 are high, this process is slowed or reversed, causing CO2 to build up in the bloodstream and tissues (Perry et al. 2009). When CO2 is applied as a sedative, respiratory levels of the gas build in the central nervous system, interfering with the normal metabolism and function of these cells. Gradually, widespread central nervous system depression occurs, resulting in the loss of consciousness and voluntary motor function, though involuntary movements may occur in CO2-sedated fish (Iwama and Ackerman 1994). Induction times for CO2 are usually long (Trushenski et al. 2012) and are typically accompanied by a period of intense hyperactivity. A short period of hyperactivity is commonly observed during the induction phase of sedation, likely due to the presence and irritating nature of sedatives (Ross and Ross 2008). However, the hyperactive response to CO2 may be more pronounced in some species, which exhibit strong avoidance behaviors upon exposure to sedative concentrations of CO2 (e.g., Bernier and Randall [1998] observed fish “violently struggling”) and may remain agitated for extended periods of time (minutes) before passing into the early stages of sedation. Recovery times following CO2 sedation are also typically extended, greatly exceeding the ideal time frames for fish sedatives. To sedate fish with CO2, hypercapnia must be induced. Although this achieves the desired result in terms of sedation, 3For the drugs in this category, the FDA has determined that regulatory action is unlikely as long as an appropriate grade is used, they are used for the listed indication at the prescribed levels, good management practices are followed, and local environmental requirements are met (USFDA 2011c). hypercapnia affects all major organ systems and considerable time is needed to fully compensate for the resulting acidosis. It is perhaps not surprising that exposure to elevated environmental CO2 also induces the generalized stress response in fish and can result in direct or delayed mortality if exposure concentrations or durations are excessive. Thus, depending on the duration and severity of the response, exposed fish will experience the consequences of corticosteroid or catecholamine release (Barton and Iwama 1991). The direct and indirect (via actions of corticosteroid/catecholamine release) effects of CO2 exposure include acid–base disruption and lactate accumulation, osmoregulatory dysfunction, and elevated plasma glucose (Trushenski et al. 2012). Depending on exposure conditions, full recovery from these disturbances can take hours or days (Wagner et al. 2002; Pirhonen and Schreck 2003). Although the sedative application of CO2 can be problematic, if it is applied correctly, exposure often results in the light sedation and immobilization of many freshwater species. The same cannot be said for marine species, however; because of the high concentration of ions in the marine environment, the solubility of CO2 is reduced, making it more difficult to achieve sedative concentrations of CO2 in brackish or saltwater. Additionally, CO2 excretion occurs more readily in marine environs, making it difficult to induce hypercapnia in marine species. In some situations, achieving the desired levels of sedation in marine species with CO2 requires decreasing water pH to 5–6, which can have unintended negative consequences (e.g., morbidity and mortality; R. P. Yanong, unpublished data); in a recent study assessing the light sedation of Cobia Rachycentron canadum, we demonstrated that CO2 decreased the pH of brackish water (20‰) with 88 mg CaCO3/L alkalinity by more than one unit (Trushenski et al., in press); similar results were reported for high-alkalinity (>200 mg CaCO3/L) seawater CO2 sedation baths used in the harvest and slaughter of Atlantic Salmon Salmo salar (Erikson 2008). Because CO2 can be impractical for field use, typically allows for only light sedation, can induce long-term physiological disruptions, and is not fully appropriate for marine species, it is not considered a suitable sedative by the majority of fisheries professionals. Neither MS-222 nor CO2 is a viable option for broad use as a fish sedative in field situations. Similarly, hatchery personnel who wish to lightly sedate fish to improve the poststocking survival of catchable-size fish by reducing stress during transport have no reasonable options. As a result, fisheries professionals are often faced with a difficult choice—to use MS-222 off-label (i.e., disregarding the 21-d withdrawal period), to use unapproved sedative compounds, or to use nothing at all. In the United States, off-label drug use and the use of unapproved drugs are both illegal. Although the Animal Medicinal Drug Use Clarification Act (AMDUCA) allows some extra-label drug use with veterinary oversight, such use is limited to circumstances “when the health of an animal is threatened or suffering or death may result from failure to treat” (USOFR 2002a). D ow nl oa de d by [ C ol le ge o f W ill ia m & M ar y] a t 0 8: 59 0 1 A ug us t 2 01 3 160 TRUSHENSKI ET AL. Although sedatives are often associated with applications focusing on animal health and well-being, these uses are likely outside the intended scope of AMDUCA. Hence, the lack of an approved immediate-release sedative that is safe and effective presents fisheries professionals with both a legal and an ethical dilemma: They must (1) adhere to their individual ethics and the guidelines established for the fisheries profession and treat fish humanely with safe and effective (albeit unapproved) sedatives prior to procedures causing distress, (2) use FDA-approved or LRP drugs according to the label instructions and be severely constrained by impractical withdrawal periods or the risk of harming fish during sedation, or (3) use nothing and defy the spirit of all relevant animal welfare regulations and guidance documents. A widely used set of guidelines for the use of fish in research published jointly by the American Fisheries Society (AFS), the American Institute of Fishery Research Biologists, and the American Society of Ichthyologists and Herpetologists (UFR 2004) states that “prolonged stressful restraint [without appropriate sedation or anesthesia] should be avoided” but also stipulates that the full range of potential effects on the subject fish, not just the sedative qualities, must be considered. The sedative chosen should be one that permits a rapid return to normal physiological and behavioral status and is a low risk compound for humans as well as fish. The use of sedatives in fisheries work is also described in two seminal AFS publications, Fisheries Techniques (Murphy and Willis 1996) and Methods for Fish Biology (Schreck and Moyle 1990), which advocate using sedatives as a routine part of fish care and handling (Kelsch and Shields 1996) and provide detailed explanations of sedatives and their use (Summerfelt and Smith 1990). It is imperative that a practical, safe, effective, and approved sedative be available to conform to the guidance provided by such documents, but the options are severely limited. Conducting procedures that cause distress without proper sedation/anesthesia is not appropriate from the perspective of animal welfare; poses risk to personnel (particularly in the case of large fish or fish that are otherwise hazardous when handled without restraint) and the animals themselves; and is not consistent with the spirit and recommendations of any of the aforementioned guidance documents. PROCESS FOR GAINING AQUATIC ANIMAL DRUG APPROVALS AND THE CURRENT REGULATORY ENVIRONMENT: THE U.S. EXPERIENCE The pursuit of FDA approval of an immediate-release sedative has been long and, to date, fruitless. This is a consequence of numerous factors, including the complexities of the drug approval process, the substantial human and monetary resources which must be expended in pursuit of an approval, the low potential for return on investment by pharmaceutical firms, the specialized nature of the work, and the limited number of personnel and institutions engaged in drug approval research and support activities. Under authority of the Federal Food, Drug, and Cosmetic Act (FFDCA), the FDA’s Center for Veterinary Medicine (CVM) regulates the manufacture, distribution, approval, and use of animal drugs. This regulatory authority includes drugs for use in food-producing animals such as fish as well as pets/companion animals. With respect to drugs that are used in food-producing animals, the CVM is responsible for ensuring that the drugs are safe and effective and that the food products derived from treated animals are free from potentially harmful drug residues. What Qualifies as a Drug? A drug is defined by FDA as any article that is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; any article (other than food) intended to affect the structure or function of the body of man or other animals; or any article that is recognized in official drug compendia (USC 2010). This definition is extremely broad and would apply to any substance other than the unadulterated food fed to a fish and the unadulterated water in which fish live, including virtually any compound administered to fish via immersion, feed, injection, or any other method. The breadth of this definition is clearly exemplified by the CVM’s List of Drugs of Low Regulatory Priority, which includes, among other compounds, onion and garlic to control or reduce infestations of some ectoparasites, salt (NaCl) for osmoregulation or as a parasiticide, ice to reduce the metabolic rate of fish during transport, and fuller’s earth to reduce the adhesiveness of fish eggs. More recently, the CVM has suggested that preor probiotics derived from the natural gut microflora of fish may be classified as drugs if advertised (or promoted) as such, i.e., to control or reduce an infectious fish pathogen, disease symptom, or mortality. What Qualifies as a Food Fish? Although the CVM has not clearly defined food fish in laws or regulations, the general consensus is that the agency considers any fish that is potentially available for human consumption to be a food fish—a very broad definition (USFDA 2008). Obviously, fish raised commercially for sale as live, in-the-round, filleted, or otherwise processed products are considered food fish. Less obvious is the fact that fish released for restoration/recovery, stock enhancement, mitigation, recreational fishing, or other management purposes are also generally considered food fish. The rationale is that if at any point in time hatchery-raised fish are available for legal harvest (i.e., angling or commercial fishing), they are potentially available for human consumption and are therefore food fish. Threatened or endangered species which cannot be legally harvested are not considered food fish by the CVM; however, it is unclear whether this rationale extends to sublegal life stages of game fishes or nongame fishes. Although common sense suggests that sublegal and nongame D ow nl oa de d by [ C ol le ge o f W ill ia m & M ar y] a t 0 8: 59 0 1 A ug us t 2 01 3 SEDATIVE OPTIONS IN FISHERIES 161 fishes would not be considered harvestable or consumable, this does not appear to be the case. Even more ambiguous is the status of baitfish, which may be indirectly incorporated into the food chain via the absorption by game fish of drug residues from baitfish consumed naturally or as a result of angling activity. Although the CVM has published a guidance regarding this issue, it is relatively vague and does not agree with some recent decisions (USFDA 2008). For example, the CVM has determined that “feeder” goldfish (i.e., goldfish sold to hobbyists, aquariums, zoos, and others as live food for other animals) are considered food fish. Until more definitive guidance is issued, it would seem prudent to assume that all nonimperiled fish species are considered food fish, with the possible exception of certain “ornamental and aquarium fish” strictly associated with the aquarium trade (USFDA 2008). Data Requirements and Other Challenges to Gaining Approvals The CVM approves new animal drugs based on review of the data submitted by the pharmaceutical or chemical company drug sponsor. In the case of aquaculture drugs, for which the economic incentives for pharmaceutical sponsors to seek a new approval are typically extremely low, sponsor-submitted data are augmented by data generated by public sector entities (e.g., the U.S. Fish and Wildlife Service [USFWS], the U.S. Geological Survey [USGS], the Agricultural Research Service of the U.S. Department of Agriculture [USDA–ARS], the CVM’s Office of Research, and several universities). When all data have been accepted by the CVM, the sponsor requests a new drug approval via a new animal drug application (NADA). The data required for approval must demonstrate that the drug is effective as claimed on the label and safe when used as directed for (1) the treated animals, (2) the people administering the treatment, (3) the environment, including nontarget organisms, and (4) consumers. To demonstrate the efficacy and safety of a specific drug, a drug sponsor must adequately address eight NADA technical sections (information categories): (1) chemistry, manufacturing, and controls, (2) human food safety, (3) effectiveness, (4) target animal safety, (5) environmental safety, (6) labeling, (7) freedom of information summary, and (8) all other information. For any animal species, the successful completion of all NADA technical section requirements is time-consuming and expensive. Previous reports have suggested that getting a new aquaculture drug approved required a minimum investment of $3.5 million (Schnick et al. 1996) over the course of a decade. More recent estimates indicate that new drug approvals may cost in excess of $40 million, and label expansions to include new species or claims may cost as much as $8 million (Storey 2005). In some respects, new drug approvals for fish are more difficult to obtain than new drug approvals for virtually any terrestrial animal. Unlike companion animals, fish are considered a potential source of food for humans, and fish drug approvals require completion of the full tier of studies to satisfy the human food safety technical section. Of all the data requirements, the human food safety technical section is typically the most expensive to complete. Completion of this section is also required for terrestrial livestock drugs, but with respect to NADA data requirements the CVM views fish differently than it does other food or companion animals. Although the CVM considers all breeds of a single species to represent the species, it does not consider any fish species to be representative of fish collectively or categorically. Although the CVM will accept studies conducted on a single cattle or dog breed as sufficient to complete the NADA technical sections for all cattle or dog breeds, studies conducted on a single fish species generally apply to that species only. Hundreds of freshwater fish species and varieties are currently raised in the United States, resulting in significant implications of this “species-by-species” approach to data requirements. Although the CVM has allowed species grouping for drug approvals for freshwater fish (i.e., data from two or more species within a group of fish are considered sufficient for all group members, e.g., all freshwater salmonid species), the data requirements for “all fish” label claims remain significantly greater than similar claims for other animal groups. The additional NADA data requirements associated with marine fish drug approvals have not yet been fully explored, but given the potential differences between marine and freshwater species and the conditions in marine and freshwater environments, it is anticipated that the data requirements for label expansion to marine species will be significant. Because of low economic incentives and high regulatory requirements for aquaculture drugs, drug sponsors have relied heavily on assistance from public entities to complete NADA requirements. Public data-generating partners comprise a small but dedicated cadre of member agencies constituting the Federal–State Drug Approval Partnership Project (PROJECT) under the direction of the Association of Fish and Wildlife Agencies (AFWA). The PROJECT was established in 1995 to work collaboratively toward the approval of eight priority aquaculture drugs and continues such efforts today. Oversight of the PROJECT is provided by the Drug Approval Working Group (DAWG), which was formed in 1997 under the Fisheries and Water Resources Policy Committee of the AFWA. In addition to the members representing the AFWA (the 50 state fish and game agencies), DAWG members from the USFWS, USGS, and USDA–ARS help to coordinate aquatic drug approval activities and set PROJECT priorities. While initial approvals for four of the PROJECT drugs have been obtained, these approvals have been restricted to use in certain species (or species groups) and/or to control mortality caused by specific pathogens. Seventeen years after the PROJECT was formed, the other priority drugs still await initial approvals. Obtaining an initial approval for an immediate-release field sedative remains the DAWG’s highest priority, with approval for all freshwater finfish as the principal goal. D ow nl oa de d by [ C ol le ge o f W ill ia m & M ar y] a t 0 8: 59 0 1 A ug us t 2 01 3 162 TRUSHENSKI ET AL. While the DAWG and its technical partners have made significant progress and are committed to pursuing new and/or expanded aquatic species drug approvals, progress has been slow. Dedicated resources (i.e., funding and staff with sufficient expertise to develop study protocols acceptable to the CVM and conduct studies according to good clinical practices or in compliance with good laboratory practices [GLP] regulations) are simply insufficient to accomplish the work in a timely manner. This situation has been exacerbated by changing program priorities among the public data-generating partners that have resulted in erosion of the resources dedicated to the fish drug approval process. For example, in 2011 the USGS eliminated all drug approval research funding from its budget. Today the USFWS’s Aquatic Animal Drug Approval Program is the only program comprising more than one senior scientist with a fulltime commitment to aquatic species drug approval efforts. Other entities continue to contribute to the process (e.g., the CVM’s Office of Research, National Research Support Program-7, Mississippi State University, the University of Idaho, Auburn University, and others), but the available resources simply do not meet needs. However, current difficulties are not solely related to the lack of sufficient financial resources. The limited number of institutions and individuals capable of, and interested in, completing the needed work is an equally important constraint. Many of the studies required to gain FDA approval of a drug require that the testing be conducted at facilities that comply with GLP regulations; few fisheries institutions are capable of meeting these standards or are willing to do so. The regulatory process for aquatic species drug approvals is inherently arduous—as it should be—to ensure public health and safety; however, the current regulatory process and atmosphere may be more restrictive than necessary or appropriate. In short, aquatic species drug approval efforts are challenged by low economic incentives for sponsors (often small chemical companies with minimal budgets for research and development), a relatively small group of active participants, and a very expensive and arduous regulatory process. Previous Attempts to Gain Approval for an Immediate-Release Sedative In the past, several compounds have been considered as candidate immediate-release sedatives, including MS-222, benzocaine, and isoeugenol. Originally, it was thought that expanding the current MS-222 approval to reduce the 21-d withdrawal period (which, to the best of our knowledge, was somewhat arbitrarily defined by the CVM) or obtaining new animal drug approvals for the other two products would occur in a timely manner. However, pursuit of an immediate-release approval reached an impasse for each of these compounds. The sponsors for MS-222 do not wish to devote the necessary resources to provide the FDA with data to support the immediate-release label claims for their products. Furthermore, these sponsors were justifiably concerned that efforts to modify current labels might jeopardize their existing approvals. Requests for label expansions allow the CVM to revisit and reassess previously submitted data. Given the changes to the regulatory landscape, it is plausible that CVM reviewers would deem previously accepted data insufficient to meet current requirements, rendering existing approvals invalid. This concern, whether real or perceived, is warranted because over time the FDA has significantly “raised the bar” relative to the data required to support approvals. The approval guidelines and criteria in place when MS-222 was approved were significantly less rigorous than those used for multispecies drug approvals today. Thus, without sponsor support, it was concluded that MS-222 is a nonstarter for immediate-release uses. In 1994, benzocaine was identified as an immediate-release fish sedative candidate. Unfortunately, the approval process for benzocaine was not pursued because no drug company was willing to sponsor such efforts. As a result, in 1996, the focus of approval efforts shifted to AQUI-S (50% isoeugenol [4-propenyl-2-methoxyphenol]), which had existing immediate-release approvals in several other countries (Australia, Chile, New Zealand, and others), and a committed sponsor (AQUI-S New Zealand, Ltd., Lower Hutt, New Zealand) willing to pursue FDA approval. During the ensuing 10 years, significant progress was made toward assembling an AQUI-S NADA package in support of an immediate-release claim for all freshwater finfish. AQUI-S was on the home stretch for an initial FDA approval, but due to unforeseen potential human health concerns all research was permanently derailed in April–May 2007. Reviewers of a 2-year cancer study on rats and mice (conducted by the National Toxicology Program [NTP]) concluded that isoeugenol demonstrated “some” level of carcinogenicity, and the FDA subsequently terminated further review of the data in support of an approval for AQUI-S (in accordance with the Delaney Clause of the FFDCA). Despite being generally recognized as safe and approved by the FDA for direct use in human foods (NTP 1991), the use of isoeugenol as a fish sedative was deemed to pose an unacceptable human food safety risk. Thus, in the United States, isoeugenol-based products (such as AQUIS) or clove oil (which contains some isoeugenol) will likely never be approved for use as fish sedatives (USDHHS 2007). However, this finding will not affect previous FDA approvals for the use of isoeugenol in foods. Interestingly, the European Medicines Agency (EMA), which regulates the use of animal drugs in the European Union (EU), reviewed the NTP isoeugenol carcinogenicity report and nonetheless licensed the product as a sedative in fishes (EMA 2008). More specifically, data from the report have been used to establish an allowable dietary intake of 0.0075 mg isoeugenol/kg body weight (∼45 mg isoeugenol/person) based on a maximum residue level of 6,000 μg isoeugenol/kg fish tissue (muscle and skin in natural proportions; EMA 2011). This development will allow isoeugenol products to be registered in the EU. Additionally, in the EU a sponsor that wishes to market a new drug need only submit a single application to the EMA for a “marketing authorization” (license) that is valid in all EU member states as well as Iceland, Liechtenstein, and Norway. D ow nl oa de d by [ C ol le ge o f W ill ia m & M ar y] a t 0 8: 59 0 1 A ug us t 2 01 3 SEDATIVE OPTIONS IN FISHERIES 163 CANDIDATE IMMEDIATE-RELEASE SEDATIVES AND THEIR EFFECTS Efforts spearheaded and prioritized by the DAWG are currently underway to evaluate the safety and effectiveness of other candidate immediate-release fish sedatives. Currently, Benzoak (a benzocaine-based product) and AQUI-S 20E (a eugenolbased product manufactured by the producer of AQUI-S [which is isoeugenol based]) are the top candidates with engaged sponsors willing to pursue approvals.