GENERAL NEWS
last updated:
6 January 2009

Now order your free AFS-AADAP Aquaculture Drug-use Guidance Poster on-line: It's now even easier to obtain your free poster or posters. Click here for the on-line order form.

New AADAP news release series: AADAP just instituted an information series entitled "Aquaculture Drug Updates" to be placed online and distributed via email. It will be published as new substantive aquaculture drug information becomes available. Click here to view the inaugural Update and all Updates as they are published. A permanent link for the Aquaculture Drug Updates is provided above under the 'What's Shakin' button.

17α-methyltestosterone efficacy technical section complete for sex-reversal in tilapia: In a 10 December 2008 letter, the Center for Veterinary Medicine informed AADAP that all effectiveness studies submitted have been accepted and they now consider the efficacy technical section of the NADA to be complete. For detailed information click here and scroll down to the 17α-methyltestosterone section.

15^th Annual Whirling Disease and Aquatic Invasive Species Symposium scheduled for 5-6 February 2009 in Denver, Colorado: This year’s symposium will integrate whirling disease research with findings of other aquatic invasive species of concern. For more information click here for the Symposium website and click here for a presentation submission form and Symposium deadlines.

2009 Eastern Fish Health Workshop; Lake Placid, New York 27 April - 1 May 2009: This year's 34^th annual workshop is being held at the High Peaks Resort in Lake Placid, New York. Numerous sessions are scheduled as well as an exceptional full social schedule. For more information, including deadlines, etc. please click here.

40^th Annual International Association for Aquatic Animal Medicine Meeting and Conference; 2-6 May 2009; San Antonio, Texas: This year's meeting is being held at the Hliton Hill Country Resort and Spa. For more information, including abstract instructions and on-line submission click here for the Conference Website.

The 2009 Combined Fish Health Section & Western Fish Disease Conference scheduled for Park City Utah, USA: The 2009 joint meeting of the American Fisheries Society's Fish Health Section and the Western Fish Disease Conference is scheduled to take place on 8-10 June 2009 in Park City, Utah, USA. Detailed information, when it becomes available, can be accessed at the following AFS website:
http://www.fisheries.org/units/
fhs/meeting.htm

The 2009 14^th International Conference on Diseases of Fish and Shellfish planned for Prague, Czech Republic: Next year's conference, organised by the European Association of Fish Pathologists (EAFP) will be held at the Clarion Congress Hotel in Prague, Czech Republic on the 14^th through the 19^th of September. Scientific and technical sessions consisting of poster presentations, invited talks, keynotes, oral presentations, workshops and an EAFP General Assembly will take place during the Conference. The EAFP will welcome suggestions for potential topics for scientific sessions and workshops. Planned social events include a Welcome Cocktail, Civic Reception and the traditional Conference Banquet. For more information visit the official conference website:
http://eafp2009.org/.

2009 INAD Sign-up Forms are now available: Once again it is that time of year for renewal of your facility‘s INADs for Calendar Year 2009. Please send in the completed sign-up forms to the AADAP Office by 31 December 2008. Invoices will be mailed out the end of February. All 2009 sign-up forms are available on our website, click here to access.

End of the Year INAD Forms due: If you have not already done so, please send in all Form 2‘s (Drug Inventory Form) and Form 3‘s (Results Report Form) for each of the INADs that were used at your facilities for INAD Year 2008. For the 17-α methyltestosterone medicated feed participants, Form 6 (Year End Efficacy Report) will also need to be submitted.

Examples of completed INAD forms are now available on the AADAP website: A completed example of every INAD Form is now available on the appropriate INAD drug fact sheet. These forms have been "mocked up" in order to aid Investigators in completing their INAD paperwork. Please use these forms as a guideline, and if you have any questions do not hesitate to contact Bonnie Johnson at 406-994-9905.

Just a heads up to all of you participating in the National INAD Program: Bonnie Johnson will be on leave for 3 months starting around mid-October 2008. Please fax study worksheets to the AADAP Office instead of emailing or mailing them during this time. Please note if you have any pressing matters during this three month period to call Dave Erdahl at 406-994-9904.

14^th Annual Aquaculture Drug Approval Coordination Workshop: This year's workshop was once again held in Bozeman, Montana, and by all accounts was another very successful meeting focused on wide-ranging and collaborative drug approval efforts. It also appears to have been a "record breaker" with 89 registered workshop attendees. Not only was it a record-breaker for total attendance, but FDA's Center for Veterinary Medicine also broke a personal participation record by sending 13 members of their staff. CVMer's attending covered a broad spectrum of experience and Center expertise - all the way from a summer student intern (Ms. Courtney Coddington) to two Office Directors (Dr. Steve Vaughn, Office of New Animal Drug Evaluation and Dr. Meg Oeller, Office of Minor Use and Minor Species).

A special thanks goes out to the many folks that provided presentations/updates on completed, planned, and ongoing work. Special appreciation is also expressed to representatives of senior management of FDA's Center for Veterinary Medicine, U.S. Geological Survey, U.S. Fish & Wildlife Service and the Association of Fish and Wildlife Agencies for providing keynotes addresses detailing their respective agency‘s role in overall collaborative drug approval efforts. As we are all very well aware, the aquatic species drug approval "game" is most definitely a "team sport."

This year's Workshop would not have been possible if it were not for the generous monetary assistance provided by a number of the chemical, pharmaceutical and feed companies attending. Our hats go off to Aquatic Life Sciences, Inc., Axcentive SARL, Bimeda USA, BioOregon/Skretting, Carus Chemical, Eka Chemical, Frontier Scientific Inc., Intervet/Schering-Plough Animal Health and Novartis Animal Health. We can't say THANK YOU enough!!!

For more information on the workshop, including viewing many of the presentations given at the Workshop, click here.

17MT mini-meeting: This year‘s Drug Approval Coordination Workshop also provided the venue for researchers and regulators to meet and strategize about the studies remaining to be completed to fulfill the requirements for a 17α-methyltestosterone New Animal Drug Application (NADA) for sex-reversal in tilapia. About a dozen folks met Monday afternoon (28 July 2008) and were able to provide the information necessary to update a master progress table. Additionally, attendees worked together to plan the best course of action given available funds and limited personnel. If all studies currently scheduled to be conducted go as planned and are accepted by CVM, the sponsor should be able to submit a complete NADA in December 2010. The master progress table can be viewed by clicking here.

Update from the 7^th meeting of the National Aquaculture Drug Research Forum (NADRF): The most recent meeting of the NADRF was also held in conjunction with the 14^th Annual Drug Approval Coordination Workshop. Thirty individuals interested in helping to resolve issues faced by researchers conducting studies in support of aquaculture drug approvals met on 1 August 2008 to discuss the following: 1) status of a survey to identify protozoan ectoparasites of primary importance, 2) overview of a parasite round table discussion that was held prior to the Workshop on 28 July 2008 (see below); 3) a proposal for an NADRF white paper review process; 4) the value of round-table discussions such as the below noted parasite discussion; 5) finding a new home for the NADRF (based on the anticipated termination of the JSA Drugs, Biologics, and Pesticides Working Group), and 6) providing statements of aquaculture drug needs to the JSA National Research and Technology Task Force. To view the notes from this meeting, click here.

Round table discussion on parasite-studies and the National Parasite Survey — research on the horizon: Over the past year or two, there has been considerable discussion about how to design field trials to evaluate the effectiveness of therapeutants to control ectoparasite infestations in fish. To more clearly articulate some of the issues and to try to resolve them, a "Parasite Round Table Discussion" was held (28 July 2008) in conjunction with the 14^th Annual Aquaculture Drug Approval Coordination Workshop. Attending were approximately 40 individuals representing various research agencies, fish health experts, professional associations, drug and chemical companies, and representatives from various CVM Teams (e.g., Aquaculture Drugs, Biometrics, and Environmental).

Starting off the session was a presentation by Ms. Courtney Coddington (a CVM summer intern). Ms. Coddington provided an excellent overview of the issues, including challenges relative to protocol development and maintaining sample collection and evaluation consistency.

Following Ms. Coddington‘s presentation, the group launched into discussions that were more brain-storming in nature and (of course) led to even more questions. Although little was resolved during this first meeting, there was considerable constructive discussion relative to 1) the level of pathogen identification preferred by CVM (i.e., identify the parasite to the genus/species level); 2) different procedures that may be used to enumerate pathogens; 3) how such data should be analyzed; 4) whether to pursue a claim(s) for control of level of parasite infestation or control of mortality caused by parasite infestation; 5) how to deal with secondary pathogens; 6) whether we should pursue approvals for a disease complex, i.e., when more than one pathogen is present (e.g., ectoparasite and columnaris bacteria); and 7) how much of the "process" was used to successfully gain an approval for formalin.

In the relatively short time available to the group, it proved to be rather difficult to address in much detail many of the issues discussed. However, it was fortuitous that Mark Gaikowski (USGS - UMESC) was able to provide an overview of a survey recently submitted by the National Aquaculture Drug Research Forum through the AFWA Drug Approval Working Group, soliciting information relative to freshwater fish ectoparasites of concern to fish health professionals throughout the USA. Results from this survey should help identify ectoparasites of primary concern in freshwater aquaculture, and in general, assist the group to better focus future discussions.

Coincidentally, CVM had previously arranged a webinar dealing with quantification of parasites in clinical studies. On 28 August 2008, instructor Sarah L. Poynton Ph.D., Associate Professor of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine lectured on "Enumeration of Fish Parasites." Material covered included: 1) basic principals of parasite population quantitative descriptors; 2) calculation of parasite prevalence, intensity, and density; 3) statistical approaches commonly used by fish pathologists; and 4) practical considerations when choosing an enumeration technique(s). In summary, the information covered by Dr. Poynton should be extremely helpful to those developing protocols and conducting studies to evaluate the effectiveness of therapeutants to control ectoparasite infestations in fish.

Status/Establishment of the National Aquaculture Industry – Therapeutic Agent Program (NAI-TAP): The establishment of a new national aquaculture drug working group, comprising private and public sector members, was first considered during a meeting of the Joint Subcommittee on Aquaculture‘s Working Group on Aquaculture Drugs, Biologics and Pesticides (WGADBP) at the 2008 World Aquaculture Conference. At this meeting, WGADBP attendees were informed (for the first time) that it was likely the WGADBP would soon be terminated. Several meeting attendees recognized that if such action was indeed to occur, a need would likely still exist for an aquaculture group to perform at least a portion of the activities of the WGADBP. Thus, an organizational meeting was held on 1 August 2008 (in conjunction with the 14^th Annual Drug Approval Coordination Workshop in Bozeman, Montana) to determine the direction, mission, scope, types of membership, and to set a focus for moving forward. As a first step, the group was tentatively given the name—the National Aquaculture Industry – Therapeutic Agent Program or NAI-TAP.

Since the NAI-TAP was being designed to specifically address the needs and provide input for private aquaculture, and the fact that very few private industry representatives attended the 1 August meeting, a new focus was deemed to be in order. By consensus, it was noted that 1) the private sector was already represented on most issues of concern by the National Aquaculture Association, 2) drug approvals and the drug approval processes has advanced considerably since the formation of the WGADBP in November 1990, and 3) USDA‘s Cooperative State Research, Education and Extension Service (CSREES) works at the national program level to address private aquaculture sector needs and issues.

During the August 1^st meeting, a possible solution to address the need for the continuation of some of the objectives and goals of the WGADBP was proposed. The Aquaculture Chemical Subcommittee (ACS) of the American Fisheries Society (AFS) Task Force on Fishery Chemicals was considered as a potential 'home' for this new group, in particular to selectively address any unmet objectives and goals of the WGADBP. However, since the AFS president reappoints the ACS members annually, this would prove to be difficult since there are 170+ members on the current WGADBP‘s roster.

AFS resolved the issue by suggesting forming a new working group that would be under the Fish Culture Section (FCS), or possibly, under a joint FCS and Fish Health Section agreement. Based on further discussion it was decided that a working group under one section was the better alternative, and thus the FCS was selected as the governing body. The primary reason for FCS‘s selection was the fact that its members are the most directly impacted by drug approvals and biologic licensing. Additionally, this decision received strong support from Dr. Curry Woods, the 2008-2009 President of FCS, who attended the meeting and provided valuable input. Dr. Woods is not only very familiar with the drug approval process, but has also been a member of the WGADBP since 1990.

Group consensus determined that all past WGADBP members should be encouraged to become members of the new group, and that this new group will be called the Working Group on Aquaculture Chemicals (WGAC). Dr. Woods appointed Mark Gaikowski (USGS‘s Upper Midwest Environmental Sciences Center) to be chair of the WGAC. Mr. Gaikowski will preside over the WGAC at all meetings, including the inaugural meeting being held at Aquaculture America 2009 (AA 09), scheduled for 15-18 February 2009 in Seattle, Washington. Any- and-all folks who are planning on attending AA 09 and may be interested in participating in WGAC are encouraged to attend!

Text provided by: Rosalie (Roz) Schnick, National Coordinator for Aquaculture New Animal Drug Applications, Michigan State University, La Crosse, Wisconsin.

Update on the 15^th Annual Aquaculture Drug Approval Coordination Workshop (2009) planned for Little Rock, Arkansas: June 9^th through 11^th are the dates set for next year‘s Workshop. It will be held at the La Quinta Little Rock Downtown Conference Center. The meeting will be hosted by USDA/ARS‘s Stuttgart National Aquaculture Research Center, and will highlight regional aquaculture, including industry tours to a catfish hatchery, a baitfish farm and a hybrid striped bass production facility. There will also be an opening mixer at a local brew-pub to get things started and allow everyone to become acquainted or reacquainted. Hope you‘all can make this meeting and experience some Southern Hospitality! Keep checking the AADAP Workshop Webpage for updated information.

Text provided by Dave Straus, Disease & Drug Approval Section, Harry K. Dupree – Stuttgart National Aquaculture Research Center, Agricultural Research Service, U.S. Dept. of Agriculture, Stuttgart, Arkansas, USA.

Update on the planned 16^th Annual Aquaculture Drug Approval Coordination Workshop to be held in Bozeman, Montana: Although it may be a long way off, for those of you who like to plan ahead the Workshop will be returning home to Bozeman, Montana in 2010. As has always been the case when it takes place in Bozeman, the Drug Approval Coordination Workshop will be scheduled for the last week in July or the first week in August, or more accurately, the week immediately before the Sweet Pea Festival weekend. So mark it on your 2010 calendar (if you have one) or just don‘t forget to check the AADAP website for news of upcoming workshops.

Update on the search for a new candidate zero-withdrawal anesthetic: Activities to select a new anesthetic (sedative) drug continues. At the request of the Association of Fish and Wildlife Agencies‘ Drug Approval Working Group (DAWG), AADAP requested a pre-submission conference meeting with CVM to discuss all NADA technical section requirements for three drugs – benzocaine, eugenol and tricaine methanesulfonate. Representatives of the DAWG, as well as a number of interested drug sponsors, attended the meeting that was held on 20 August 2008 at CVM in Rockville, Maryland.

So where are we with respect to the sedative issue presently? The initial focus of the DAWG centers on a sedative use-pattern appropriate for short-term handling in natural resource management field activities. After an informative review of the technical section requirements at the pre-submission conference, the candidate list was narrowed to benzocaine and eugenol. It was also agreed by all parties to change the claim from "zero withdrawal" to "immediate-release," which better defines the time frame after a fish is sedated to the initial opportunity for capture. In the near future the official CVM Memorandum of Conference from the meeting will be publically available on the AADAP website.

At the annual Association of Fish and Wildlife Agencies (AFWA) Conference in September2008, the DAWG received approval to allocate remaining Multi-State Conservation Grant Program funding (originally dedicated to AQUI-S^®) for additional assessment of both eugenol and benzocaine until the "best candidate" can be determined. DAWG members are now developing grant objectives for submission by 15 November 2008. These objectives tentatively include the following.

• Developing study criteria to establish a postsedation catchability timeframe for each drug. Such criteria are essential to determine if either drug will potentially meet requirements for an immediate release claim. Opportunities for academic-based and government studies exist, but study guidelines etc. need to be first developed and vetted.
  
  
• Finalize highest priority funding objectives needed to better define the label claim process for each drug, and work with potential sponsors.

The AFWA grant funding will definitely provide a "jump start" for a new immediate-release fisheries sedative. The overall approval process is just starting and will take considerable time, effort, commitment and funding. The DAWG is committed to work with sponsors to seek approval for this initial label claim. The possibility of having two anesthetic/sedative drugs available for the fisheries toolbox is an interesting opportunity to explore. Stay tuned...

Text provided by Steve Sharon; Chair, Association of Fish and Wildlife Agencies’ Drug Approval Working Group; Wyoming Game & Fish; Casper, Wyoming.

Good Laboratory Practices (GLP) inspection of AADAP facilities and studies: During the week of 18-22 August 2008, an Investigator from the FDA's Seattle District Office - Investigations Branch paid the AADAP group a little visit. The purpose of the visit was to use a "fine-toothed comb" to inspect our facilities and one of the target animal safety (TAS) studies we had conducted since a previous inspection in 2006. The Investigator performed his inspection according to Compliance Program Guidance Manual 7348.808 for Bioresearch Monitoring (or BiMo for those familiar with the lingo). He spent the first 2.5 days inspecting our facilities and the various processes/protocols we use to launch and conduct TAS studies. He paid particular attention to:
1) development and revisions of study protocols and standard operating procedures,
2) maintenance of training records, 3) use of lab equipment and instrument logs, and
4) maintenance of active, archived, and historical records and documents.

The FDA Investigator then moved on to an in-depth inspection of a study conducted to evaluate the safety of AQUI-S^® as a sedative for use on fingerling cutthroat trout. Following the inspection, a short debriefing meeting was held to discuss the Investigator‘s findings. Overall, the he concluded that "no action was Indicated," and that: 1) he was happy that the data were as complete as it was; 2) he found no data errors, i.e., all data were transposed correctly; 3) data were attributable (signed) and contemporary (dated), 4) he was please with the data inspection and that data were 100% inspected;
5) all SOPs were signed and dated; 6) the historical SOP file (archive file) was complete; 7) training records were up to date; 8) he was impressed with the traceability of wet tissues, tissue blocks, and slides; and 9) the facility inspection was good, all equipment was in working order, log books were all signed and dated, all entry information was complete, and that training records indicated who was currently trained to operate each piece of equipment. Although the above-described inspection findings are technically unofficial, we are confident that the official inspection report will indicate GLP-compliance.

Although we had a pretty good feeling going into this inspection, due primarily to the efforts of Ms. Molly Bowman and Ms. Miranda Dotson, it was a huge relief to "pass" another inspection. An additional reason we felt pretty good going into the inspection was due to the help provided over the years by Dr. David Kennedy, QA Officer at USGS‘s UMESC — many thanks David! Although we‘ll keep up our "GLP Attitude," it is quite a relief knowing that we won‘t be inspected for another two years.

AFS-AADAP "Aquaculture Drug-use Guidance" Poster: As many of you are aware, AADAP and the American Fisheries Society‘s Fish Health and Fish Culture Sections recently published, in limited quantities and for limited distribution, an "Aquaculture Drug-use Guidance" poster. The large-format laminated poster outlines the aquaculture drugs approved for use in the USA, and describes permitted aquatic species, diseases or conditions, and treatment regimens. Interest in the poster has been overwhelming and in very short order we‘ve run out of copies to distribute. But help is on the way; FDA‘s Center for Veterinary Medicine has committed to assisting us in publishing a new batch of posters, which should become available within a month or so. This new printing will be modified slightly to include very recent new approvals or label expansions, and will be printed with a different background color to allow one to quickly distinguish it from the earlier version. As soon as the new poster becomes available, we will announce it on our website, along with information on how to obtain copies.

FDA launches new public-access database of animal drug approvals: The FDA‘s Center for Veterinary Medicine (CVM) recently (1 October 2008) announced the availability of a new database of approved animal drugs. The database, called "Animal Drugs @ FDA," is a publicly-accessible web-based application available through the CVM home page.

"Animal Drugs @ FDA" replaces the "Database of Approved Animal Drug Products," or "Green Book," a database that was previously developed and managed by the Virginia-Maryland Regional College of Veterinary Medicine Drug Information Laboratory at Virginia Tech University.

This new application allows users to search for detailed descriptions of all FDA-approved new animal drugs. The search tool not only allows users to conduct simple word searches, but is also capable of more complex searches through the following eight specific search criteria: NADA/ANADA, Sponsor, Ingredients, Proprietary, Dose Form, Route, Species and Indication.

Under the Generic Animal Drug and Patent Term Restoration Act, CVM will continue to make available electronic files of listed drugs previously provided through the Green Book on its web site. Click here to access the FDA‘s new searchable database.

AADAP establishes three Public Master Files - an update: A Public Master File, or PMF, is a type of master file recognized and held on file by FDA‘s Center for Veterinary Medicine (CVM) for the purpose of making data and information generated with public funds available to the public. The submission or establishment of a PMF is voluntary and not required by law or by FDA regulations. It is created to serve as a repository for information and data that supports the completion of a technical section(s) for a particular drug compound and associated claim. In AADAP‘s case, they serve primarily as a repository for efficacy and target animal safety data that are required to support a New Animal Drug Application (NADA). A PMF is not a substitute for an Investigational New Animal Drug (INAD) exemption or an NADA. The submission is not approved or disapproved by CVM, but rather simply found to be acceptable or not. CVM asks that all data submitted to a PMF be previously approved, i.e., the PMF's sponsor has received a "Technical Section complete" letter(s). The existence of a PMF is made known through a notice of availability published in the U.S. Federal Register. PMFs (and all associated correspondence) established by AADAP are now available on the AADAP website (click here to access). PMFs are retained in CVM‘s files and reviewed at the time it is referenced in support of a sponsor‘s NADA.

So now that you have a little background on the what, why and how a PMF comes to be, let‘s fill you in on what AADAP has done to date…

• On 24 May 2007 AADAP requested the establishment of a PMF for the use of chloramine-T as an immersion treatment to control mortality caused by external bacterial pathogens in a variety of fish species. CVM quickly acknowledged receipt of our submission and assigned it Public Master File # PMF 005-893. On 28 July 2008 CVM granted our request and concluded that the data was satisfactory to support the following label claim: "...for use to control mortality caused by bacterial gill disease in freshwater-reared salmonids. Treat fish one time per day at 12 – 20 mg per L for 60 min in a static or flow-through bath on three alternate or consecutive days." On 21 August 2008 the availability of these data were announced in the Federal Register. Great news!
  
  
• To continue on the PMF trail, AADAP requested the establishment of a PMF for the use of oxytetracycline-medicated fish feed on 13 August 2008. All data submitted is anticipated to support the label claim: "...for use to control mortality caused by coldwater disease associated with Flavobacterium psychrophilum in freshwater-reared salmonids and columnaris disease associated with Flavobacterium columnare in freshwater-reared Oncorhynchus mykiss. Treat fish one time per day at 3.75g per 100 lbs of fish for 10 consecutive days.” Again, CVM quickly acknowledged receipt of our submission and assigned it Public Master File # PMF 005-927.
  
  
• On 1 October 2008 AADAP requested the establishment of a third PMF, this one for the use of florfenicol as a medicated feed treatment in a variety of fish species. All data submitted for this PMF is anticipated to support several label claims: "...for use to control mortality caused by furunculosis associated with Aeromonas salmonicida in freshwater-reared salmonids; for use to control mortality caused by coldwater disease associated with Flavobacterium psychrophilum in freshwater-reared salmonids; and for use to control mortality caused by streptococcal septicemia associated with Streptococcus iniae in hybrid striped bass. Treat fish one time per day at 10 mg/kg of fish for 10 consecutive days." CVM acknowledged receipt of our submission on 3 October 2008 and assigned it Public Master File # PMF 005-932.

To date, we are still awaiting word as to whether CVM will grant our request for these two new PMF submissions. Watch our PMF webpage for new information.

Update on the proposed temperature classification strategy for finfish: In the last edition of the Newsletter we described a document submitted to CVM by AADAP in which four temperature-based groups of finfish were proposed for consideration. This proposal was based on the rearing- water temperatures of millions of finfish, and represented data on over 100 species that are included in the 2005 Public Aquaculture Production Database. CVM responded on 19 August 2008 with a letter in which they discussed their perceived shortcomings of the proposal and their current thinking on finfish classification based on temperature. CVM noted that traditionally they have considered that there are three categories: coldwater, coolwater and warmwater finfish. As discussed in their letter, CVM identifies the following in the three categories:

• Coldwater: Family Salmonidae (e.g., salmon, trout, char, grayling, whitefish).
  
  
• Coolwater: Walleye, sauger, saugeye, yellow perch, northern pike, muskellunge, tiger muskellunge, June and razorback suckers, and shovelnose, pallid and white sturgeon.
  
  
• Warmwater: Ictalurid catfish, tilapia, hybrid striped bass, tropical ornamental finfish and species commonly reared above 26°C that have been identified as coolwater species.

Although traditional-thinking is somewhat of a rarity in the data-oriented and ever-evolving drug approval regulatory process, it appears to work in this case. The submitted proposal and CVM‘s response letter can be found by clicking here.

Just the Stats, Man...Just the Stats; or The Statsman (with apologies to George Harrison): In aquaculture drug approval work, the term "pivotal" is often used to describe target animal safety or efficacy studies that are both biologically sound and statistically defensible. What constitutes "sound and defensible" is usually clarified and codified during study protocol writing and the CVM study protocol review-and-revision process. For AADAP, one of the biggest challenges in pivotal work has been, and continues to be, statistical data analysis. As such, during the past few years, we have worked closely with CVM, our contracted statistician, and the U.S. Geological Survey (USGS) Upper Midwest Environmental Sciences Center (UMESC) when designing and statistically analyzing pivotal studies (AADAP Newsletter Vol. 3-3, October 2007).

In this issue, we thank Mark Gaikowski (Acting Branch Manager and Research Physiologist, UMESC) for the pivotal efficacy data sets he has analyzed for us during the past year. Mark used a SAS PROC GLIMMIX-based model, co-developed by CVM (Dr. Todd Blessinger, Mathematical Statistician, Biometrics Team) and UMESC (Mark), to analyze mortality data generated in several pivotal efficacy studies conducted to evaluate the efficacy of 35% PEROX-AID^® (hydrogen peroxide), Halamid^® (chloramine-T), or AQUAFLOR^® (florfenicol) to control mortality in a variety of fish species due to a variety of fish diseases associated with specific fish pathogens. Mark‘s efforts have helped us submit our 2008 pivotal efficacy final study reports to CVM in a timely manner and have helped facilitate CVM‘s reviews of those reports. Again, thanks much Mark, you‘re the Statsman!!

DRUG UPDATES
last updated:
7 November 2008

Copper sulfate (Triangle Brand Copper Sulfate^®) update:

Report on channel catfish egg studies: The following is an abbreviated write-up of recent studies conducted on channel catfish eggs provided by Dr. Dave Straus (USDA—Stuttgart National Aquaculture Research Center; Stuttgart, Arkansas).

The safety and effectiveness of CuSO₄ to control fungus on intact egg masses in channel catfish hatcheries.

David L. Straus, Andrew J. Mitchell,
Ray R. Carter, Matthew E. McEntire, Andrew A. Radomski and
James A. Steeby.

Harry K. Dupree – Stuttgart National Aquaculture Research Center, Agricultural Research Service,
U.S. Dept. of Agriculture,
Stuttgart, Arkansas, USA.

Copper sulfate (CuSO₄) is widely used by the catfish industry as an economical treatment to control fungus (Saprolegnia spp.) on channel catfish eggs. This is an overview of our effectiveness and safety studies for the proposed indication “...to control egg mortality associated with Saprolegniasis infecting channel catfish eggs."

Channel catfish were spawned on-site and spawns were moved to the hatching lab within 24 - 48 hrs. Similar portions of a single spawn were placed into mesh baskets of individual compartments of a customized hatching trough and acclimated for 1 hr in 23.5°C well water. Egg counts on smaller samples were also determined for each spawn to estimate number of eggs in each compartment. The effectiveness range-finding study consisted of five CuSO₄ concentrations (2.5, 5, 10, 20, and 40 ppm) and an untreated control. Eggs were treated daily until the embryos developed eyes. Chemistry of the well water was pH 7.5, 220 ppm alkalinity, and 90 ppm hardness. When hatching was complete for all viable eggs, fry were siphoned into individual jars containing 70% ethanol and counted within a few days to determine the percent of fry that hatched in each treatment. Fungus was severe in the untreated controls (2% survival) and the most effective treatment of 10 ppm CuSO₄ controlled fungus (63% survival). Very little fungus was present in treatments receiving 10 ppm CuSO₄ or higher except in 1 replication (1 spawn) that had numerous unfertilized eggs. Two dose-confirmation studies have been completed to verify the optimum dose of 10 ppm both in the lab and at a commercial hatchery.

The purpose of this second study was to access the safety of CuSO₄ to channel catfish eggs when treated at the therapeutic rate (10 ppm) determined in the above noted effectiveness study, and also at 30 (3x the therapeutic dose) and 50 ppm (5X) CuSO₄. Channel catfish were obtained as described above and eggs were treated daily until the embryos developed eyes; exchange rate of the 26ºC water was 90 minutes (3X the normal rate) during treatments. When hatching was complete, the percent hatch in each treatment was determined. Some fungus developed in the controls at this temperature and mean percent hatch was 40.8%. The percent hatch of the 10, 30, and 50 ppm CuSO₄ was 80.1, 64.2 and 80.2%, respectively. The difference between the 10 and 30 ppm CuSO₄ treatments was statistically significant, while the difference was not significant between the 10 and 50 ppm CuSO₄ treatments. The lower hatch-rate of the 30 ppm treatment is attributed to the random sampling within the original egg masses and the range of hatching rates that are common in the industry. A separate experiment looked at the hatching success when eggs were treated daily until the embryos developed eyes with 100 ppm CuSO₄. The water temperature was 24ºC and the exchange rate during the treatment was 30 minutes. The individual percent hatch of each replication was 62.7, 94.9, 59.7 and 64.8%.

Florfenicol (Aquaflor^®) update:

Rainbow trout/systemic columnaris study: AADAP‘s long-awaited pivotal field efficacy trial to confirm that florfenicol is effective in controlling mortality due to systemic columnaris in a salmonid species, other than coho salmon, has finally been completed! With help from our good friends Dr. Jed Varney and Kevin Clark (Washington Department of Fish and Wildlife), along with on-site assistance from two students from the Bellingham Technical College (Jason Radany and Faith Sandretzky), a study was conducted at the Bellingham FH (Bellingham, Washingto, USA) using rainbow trout as the test species. Moribund fish from each test tank were diagnosed with columnaris by Dr. Varney, the 10-d treatment period began, and after the 14-d posttreatment period mean percent cumulative mortality in treated tanks (18.4%) was lower than that in control tanks (30.4%).

We anticipate that CVM will accept this study. The Final Study Report was submitted to CVM in late October along with a letter requesting that the effectiveness technical section for the following claim be considered complete: “...to administer Aquaflor^® in feed at a concentration of 10 mg florfenicol per kg fish body weight for 10 consecutive days to control mortality due to columnaris disease in all freshwater-reared salmonids."

If CVM agrees with this request, the expanded label claim for Aquaflor^® will cover use to control mortality in freshwater-reared salmonids due to coldwater disease, furunculosis, and columnaris disease. Check the AADAP website for updates.

Largemouth bass/systemic columnaris study: In our world, too sick is not necessarily a bad thing. Mike Matthews (Richloam Fish Hatchery, Florida, USA) experienced a columnaris outbreak in some largemouth bass that quickly became systemic. He called and asked us if we would mind if he tried to conduct a field effectiveness trial using Aquaflor^® to control mortality. How could we refuse?

With assistance from Dr. Roy Yanong (University of Florida‘s Tropical Aquaculture Lab; Ruskin, Florida, USA), the crew at Richloam successfully completed a study to demonstrate the effectiveness of Aquaflor^® when administered at a dose of 10 mg florfenicol per kg fish body weight per day for 10 days to control mortality due to columnaris disease in largemouth bass.

At the end of the 14-d posttreatment period, mean percent cumulative mortality in treated tanks (6.6%) was significantly lower (P = 0.0171) than that in control tanks (14.3%). The Final Study Report was submitted to CVM in September requesting review, and we anticipate that it will be accepted (at a minimum) as providing supportive evidence for this effectiveness claim.

Target Animal Safety Research Study Protocols: AADAP recently submitted two research study protocols to CVM for review. The protocols were developed to describe procedures to evaluate the safety of Aquaflor^® to 1) yellow perch, and 2) sunshine bass. Although the protocols are very similar, the study on yellow perch will be conducted in its entirety at AADAP‘s GLP lab in Bozeman, Montana, USA and the in-life phase of the sunshine bass study will be conducted at USDA-ARS‘s Stuttgart National Aquaculture Research Center (SNARC; Stuttgart, Arkansas, USA).

AADAP staff will travel to SNARC to help launch the sunshine bass study, and return again to assist with study termination and the collection of fish tissues for histological evaluation. During AADAP‘s absence during the remainder of the in-life phase of the study, Dr. Dave Straus (SNARC) will be responsible for all day-to-day study activities. We anticipate that successful completion of these two studies, along with "data-mining" of existing TAS data on freshwater-reared salmonids, will satisfy all target animal safety data requirements to allow for the use of Aquaflor^® at a concentration of
15 mg florfenicol per kg fish body weight in all freshwater-reared finfish.

Key researcher moving on: Dr. Vaughn Ostland, the current Director of Aquatic Pathology at Kent SeaTech Corp., has for many years played a key role in adding to the aquatic animal health knowledge base. In particular, Dr. Ostland has focused considerable attention and effort on the development of finfish biologics and effectiveness testing of prospective drugs. Although not an official member of AADAP, Dr. Ostland (OK….let‘s just call him Vaughn) is probably about as close as one could (or would choose to?) get. Vaughn is practically a founding principal of the FWS/AADAP‘s Annual Aquaculture Drug Approval Coordination Workshop, having attended 12 out of 14 Workshops. During the last 10 years or so, AADAP and Vaughn have "hooked-up" numerous times on a plethora of drug approval-related ventures (also known as pivotal studies). Some worked, and some didn‘t. None-the-less, Vaughn always gave the best he, and Kent SeaTech, had to offer...and together we accomplished a lot! Most recently, AADAP and Vaughn were laying the groundwork necessary to conduct a pivotal Aquaflor^® target animal safety study on hybrid striped bass. Unfortunately for all of us, Kent SeaTech Corp. is undergoing significant restructuring and Vaughn will soon be leaving their employ. Hence, part of the reason for the aforementioned sunshine base target animal safety study being now planned for SNARC. AADAP would like to take this opportunity to express our sincere gratitude to Vaughn for his valuable contributions to the field of aquatic animal drug approval research. We also thank him for his friendship. Although there has been no word as to where Vaughn will hang his hat next, we are certain our community of researchers will continue to gain from his contributions. Good luck Vaughn!

Halamid^® (chloramine-T) update:

Largemouth bass/external columnaris efficacy study #2: With the help of the crew at Richloam Fish Hatchery (Webster, Florida, USA), a study was conducted in which chloramine-T was administered on three consecutive days to control mortality due to external columnaris in fingerling largemouth bass. After review by CVM, we were asked to revise the Final Study Report and address one issue that had not been adequately described in the original submission, and to reanalyze the data using a "worst-case scenario" approach. With the help of CVM‘s Biometrics Team, we were able to revise our fish mortality database and reanalyze the data. The revised FSR was submitted to CVM on
11 July 2008 with a request to consider the effectiveness technical section for the following claim to be complete “...to administer chloramine-T at a concentration of 20 mg per L in a flow through or static bath for 60 min per day on three consecutive days to control mortality due to external columnaris in largemouth bass.” We await a response from CVM.

Bluegill/external columnaris study: Again, with the help of the crew at Richloam FH (thanks Mike Matthews, Kathy Childress, Josh Sakmar, and Justin Elkins), another chloramine-T study was successfully completed. After sampling moribund bluegills from the reference population, columnaris was presumptively diagnosed as causing the mortality and morbidity. Fish were transferred to test tanks, and fish in three tanks received 20 mg per L chloramine-T for 60 min per day on three alternate days, and fish in three control tanks received a sham water treatment. At the end of the 14-d posttreatment period, mean percent cumulative mortality in treated tanks (12.9%) was significantly lower (P = 0.0304) than that in control tanks (26.9%). The ensuing Final Study Report was submitted to CVM in July 2008 summarizing the study conduct and results. We anticipate that CVM will agree that results from this study demonstrate the effectiveness of chloramine-T to control mortality due to external columnaris in bluegill when administered on three alternate days. However, official CVM review is still outstanding.

Largemouth bass/external columnaris study #3: With very little prodding, the gang at Richloam FH conducted one more study with chloramine-T to control mortality due to external columnaris in fingerling largemouth bass. This time, treatments were administered on three alternate days. At the end of the 14-d posttreatment period, mean percent cumulative mortality in treated tanks (45.5%) was significantly lower (P = 0.0034) than that in control tanks (62.3%). All other study parameters were considered acceptable, and we anticipate that CVM will agree that results from this study demonstrate the effectiveness of chloramine-T to control mortality due to external columnaris in largemouth bass when administered on three alternate days.

The Final Study Report was submitted to CVM in early October 2008 along with a letter requesting that the effectiveness technical section be considered complete for the following claim be considered complete “… to administer chloramine-T at a concentration of 20 mg per L in a flow through or static bath for 60 min per day on three alternate days to control mortality due to external columnaris in all warmwater finfish.”

If CVM agrees with this request, the initial label claim for chloramine-T will cover use to control mortality due to 1) bacterial gill disease in all freshwater-reared salmonids, and 2) external columnaris in walleye and all warmwater finfish. Stay tuned.

Oxytetracycline (OTC) update:

OTC medicated feed for marking pivotal study scheduled: In previous AADAP Newsletters, we‘ve discussed our efforts, using INAD-generated data, to expand the current OTC skeletal-marking label claim from Pacific salmon to all freshwater-reared salmonids. CVM‘s response to our original submission basically stated that the INAD data were acceptable as supportive, but one pivotal effectiveness study on a representative freshwater-reared salmonid would be required to expand the label to all salmonids. AADAP, in coordination with the drug‘s sponsor Phibro Animal Health, has begun the work to complete the required study.

This fall, AADAP will submit to CVM for review a pivotal study protocol designed to evaluate the efficacy of Terramycin^® 200 for Fish (oxytetracycline dihydrate) Type A Medicated Article (TM200; 200 g OTC per lb) for the following new indication “… to administer TM200 orally in feed at 2.5 to 3.75 g OTC per 100 lbs fish per day for 10 consecutive days for the skeletal marking of all freshwater-reared salmonids for subsequent identification."

If the review process goes smoothly (i.e., few substantive changes), AADAP will conduct a single study in which TM200-treated feed will be administered to test tanks of large fingerling/small juvenile rainbow trout (a representative salmonid) using the above-described treatment regimen. The in-life phase will comprise a 1-d acclimation period, 10-d treatment period, and 21-d posttreatment period. During the
10-d treatment period, TM200-treated feed will be administered to treated tanks and control feed (nontreated) will be administered to control tanks. During the 21-d posttreatment period, control feed will be administered to all tanks. On posttreatment day 21, test fish will be euthanized and vertebrae will be removed for OTC mark evaluation.

Evaluation of OTC marks (absence/presence and quality of a yellow fluorescent ring on a vertebral centrum) will be conducted in partnership with Montana Fish, Wildlife and Parks, and accomplished by viewing vertebrae under ultraviolet light and a dissecting scope. The null hypothesis to be tested is that the mean percentage of fish with marked vertebrae in Terramycin^® 200-treated test tanks is equal to the mean percentage of fish with marked vertebrae in control test tanks. The alternative hypothesis to be tested is that the mean percentage of fish with marked vertebrae in Terramycin^® 200-treated test tanks is not equal to the mean percentage of fish with marked vertebrae in control test tanks. The difference between treated and control tanks will be considered significant if P < 0.05.

35% PEROX-AID^® (hydrogen peroxide) update:

Successful studies conducted on largemouth bass and bluegill: Not being able to keep the Richloam FH (Florida, USA) gang from forging ahead, two pivotal field efficacy studies were successfully conducted that will assist to complete the data requirements needed to fulfill the following label claim “...administer 35% PEROX-AID^® at a concentration of 50–75 mg per L in a flow through or static bath for 60 min per day on three alternate days to control mortality due to external columnaris in all warmwater finfish fingerling and adults (50 mg per L for fry)."

The first study was conducted on largemouth bass, and at the end of the 14-d posttreatment period mean percent cumulative mortality in treated tanks (49.0%) was significantly lower (P = 0.0085) than that in the control tanks (74.1%).

The second study was conducted on bluegill, and at the end of the
14-d posttreatment period mean percent cumulative mortality in treated tanks was lower (10.3%) than mortality in control tanks (20.0%). Preliminary analysis indicates that a significant difference will be detected.

If CVM agrees with this request, the expanded label claim for 35% PEROX-AID^® will cover use to control mortality due to 1) bacterial gill disease in all freshwater-reared salmonids, and 2) external columnaris in all cool- and warmwater finfish. Stay tuned.

FINS & TAILS, BITS & BOBBERS
last updated:
7 November 2008

2009 INAD Sign-up Forms are now available: Once again it is that time of year for renewal of your facility‘s INADs for Calendar Year 2009. Please send in the completed sign-up forms to the AADAP Office by 31 December 2008. Invoices will be mailed out the end of February. All 2009 sign-up forms are available on our website, click here to access.

Examples of completed INAD forms are now available on the AADAP website: A completed example of every INAD Form is now available on the appropriate INAD drug fact sheet. These forms have been "mocked up" in order to aid Investigators in completing their INAD paperwork. Please use these forms as a guideline, and if you have any questions do not hesitate to contact Bonnie Johnson at 406-994-9905.

End of the Year INAD Forms due: If you have not already done so, please send in all Form 2‘s (Drug Inventory Form) and Form 3‘s (Results Report Form) for each of the INADs that were used at your facilities for INAD Year 2008. For the 17-α methyltestosterone medicated feed participants, Form 6 (Year End Efficacy Report) will also need to be submitted.

AFS-AADAP "Aquaculture Drug-use Guidance" Poster statistics and its use in the field: Earlier this summer, the AADAP Program, in coordination with American Fisheries Society (AFS) Fish Culture and Fish Health Section, produced and distributed a quick reference guide poster "Approved Drugs for Use in Aquaculture." The request for this outreach tool was deemed a huge success. A total of 485 posters were distributed nationwide. Provided below is a breakdown of distribution:

• 44 states, 3 foreign countries (Brazil, England, Spain)
  
  
• 73% were requested by state/federal employees
  
  
• 15% were requested by private entities
  
  
• 12% were requested by private sector organizations, students, and retirees

As noted in the 'What‘s Shakin‘ section of this edition of the AADAP Newsletter (as well as above), plans are already underway for the printing of an updated version of the Poster. Check AADAP‘s website for news of its publication and information on how to obtain copies.

Just a heads up to all of you participating in the National INAD Program: Bonnie Johnson will be on leave for 3 months starting around mid-October 2008. Please fax study worksheets to the AADAP Office instead of emailing or mailing them during this time. Please note if you have any pressing matters during this three month period to call Dave Erdahl at 406-994-9904.