Guideline No. 50
Draft Guideline for Target Animal and Human Food Safety, Drug Efficacy, Environmental and Manufacturing Studies for Teat Antiseptic Products
Revised February 1,1993
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE
The Food and Drug Administration Center for Veterinary Medicine (CVM) has Developed a GUIDELINE FOR TEAT ANTISEPTIC PRODUCT DEVELOPMENT. This guideline refers to the regulatory requirements and outlines general procedures for conducting evaluations for a drug product being considered for approval. This guideline does not preclude alternative procedures which document animal safety and effectiveness of a drug product.
This Guideline represents the agency's position on a procedure or practice at the time of its issuance. This Guideline is not a legal requirement. A person may follow the Guideline or may choose to follow alternative procedures or practices. If a person chooses to use alternate procedures or practices that person may wish to discuss the matter further with the FDA/CVM to prevent an expenditure of money and effort on activities that may later be determined to be unacceptable. This Guideline does not bind the agency, and it does not create or confer any rights, privileges, immunities, or benefits for or on any person. When a Guideline states a requirement imposed by statute or regulation, however, the requirement is law and its force and effect are not changed in any way by virtue of its inclusion in the guideline.
Table of Contents
ABSTRACT FOREWORD I. ANIMAL SAFETY STUDY II. DRUG EFFICACY STUDIES III. HUMAN FOOD SAFETY IV. MANUFACTURING V. ENVIRONMENTAL REQUIREMENTS VI. GLOSSARY OF TERMS FOREWORD Introduction: This guideline has been assembled to inform the drug Industry of the types of data that will demonstrate that a teat antiseptic product: 1) is safe for the cow, 2) is effective. and 3) fulfills human food safety, manufacturing and environmental requirements. This guideline is by no means compete: it deals with the product-specific issues listed above. Other useful general information may be found in CVM guidelines for Human Food Safety, Drug Stability, etc., which are available from [he Communications and Education Branch (HFV- 12), FDA/Center for Veterinary Medicine, 7500 Standish Place, Rockville. MD 20855. Regulations: Before the approval of a new animal drug is published in the FEDERAL REGISTER, the drug's sponsor must demonstrate, among other relevant factors, that the proposed drug is safe and effective for use as recommended in the proposed labeling. The authority upon which these requirements are based can be found in Section 512 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360b). Applicable Federal regulations are Title 21 of the Code of Federal Regulations, Part 514 which covers New Animal Drug Applications. Products Covered by this Guideline: This guideline pertains to pre and postmilking teat dips and sprays, teat barriers, udder washes, and related entities which claim antimicrobial properties. I. ANIMAL SAFETY STUDY The sponsor should demonstrate that the product which it proposes for marketing is safe to the target animal. In addition to the safety study listed below any adverse drug reactions occurring during efficacy trials should be reported. A. IRRITATION STUDY: 1. Animal Selection: Select 6 normal multiparous cows and 6 normal primiparous cows. Half (3) of each group should have daily milk production ABOVE 60 lb (early lactation) and half (3) BELOW 35 lb (late lactation). A description of each test animal should be submitted stating the animal's age, lactation stage, and number and dally milk production. Cows entered into the study should not be treated for a period of one month in order to eliminate the possible irritating effects of the previous teat antiseptic. 2. Data Collection: Information to be documented for the pretreatment (one week), treatment (four weeks), and post treatment periods (one week), should include animal identification, farm site, trial number, date, test day and hour, milk production, and body temperature. 3. Evaluations: a. Skin Reactions i) Erythema and Eschar Formation No erythema 0 Very slight erythema (barely noticed) 1 Well-defined erythema 2 Moderate to severe erythema 3 Severe erythema 4 (beet redness to slight eschar formation) ii) Edema Formation No Edema 0 Very ,slight edema (barely noticed) 1 Slight edema 2 (edges or area well defined by definite raising) Moderate edema 3 (raised approximately 1 mm) Severe edema 4 (raised more than 1 mm and extending beyond the area of exposure) Severe eschar and /or corrosion Note occurrence b. Milk Quality Somatic cell counts should be determined by quantitative count methods. For example, "Direct Microscopic Somatic Cell Count in Milk" reported in Journal of Milk and Food Technology, Vol. 31. No. 11 November 1968 and "Design of Eyepiece Reticules for Use in the Direct Microscopic Somatic Cell Count Method" reported in the same volume. Electronic cell counting may also be used. It is advised that somatic cell counts be consistently determined in aliquot samples taken from the total milk production of each quarter. Animal data sheets should include a copy of the laboratory analyses (QSCCs) with the technician's signature and the dates of the analyses. 4. Treatment Periods: a. The PRE-TREATMENT period includes one week before drug product is administered. Baseline observations are made during this time to establish that all test animals are normal. During this period, consecutive milk samples, 24-hours apart should be taken for culture from all four quarters. This procedure will help to distinguish udder irritation due to a pathogenic organism from that caused by the drug product. b. The TREATMENT period begins at the second week and lasts for four weeks. The labeled dose schedule should be followed, and all four quarters are to be treated at the same time with test product. c. The POST-TREATMENT period begins at the sixth week and lasts for one week. B. FIELD TRIALS: All barn sheets used in the following drug efficacy studies (clinical field trials) should include a section for further animal safety observations. Winter and summer animal safety observations should be made in actual field trials. II. DRUG EFFICACY STUDIES Label claim- For the reduction in the herd incidence of infectious mastitis caused by... A. IN-VITRO TRIALS (ANTISEPTIC DETERMINATION): The proposed drug product should qualify as a antiseptic by in vitro testing. The following tests are recommended for the appropriate products. 1. The Phenol Coefficient Method for phenolic compounds. 2. The Use-Dilution Methods for disinfectants miscible with water to determine maximum dilution that kills test organisms. 3. Available Chlorine Germicidal Equivalent Concentration Method for water-miscible chlorine disinfectants. Note: These three methods are complete end-point methods which require, within the experimental error, a 100% kill of the test organism. The above methods are found in the Official Methods of Analysis of the Association of Official Analytical Chemists 15th Edition, 1990. 4. The in vitro antimicrobial activity of the antiseptic ingredient, the vehicle, and the formulated product should be characterized by the determination of their antimicrobial spectrum with minimal inhibitory concentration (MIC) determinations performed against common infectious mastitis pathogens. Note: Sponsors should demonstrate that concentrated drug products are not inactivated by acidic or hard water. B. CLINICAL FIELD TRIAL: Efficacy data is to be collected on each pathogen for which a claim is made. The PIVOTAL PARAMETER for the effectiveness of the drug product are the results of the bacteriological cultures. CVM encourages discussion of protocols and studies in advance for data requirements pertaining to infectious bovine mastitis caused by environmental pathogens. 1. Experimental Design: A split herd design is recommended. Under this design, all teats of half of the cows are treated after milking with the final teat antiseptic formulation, with the remaining half serving as untreated controls. Determine the number of new infections that occur in all quarters of all cows both treated and control (untreated) quarters. The experimental unit is the individual lactating quarter. 2. Selection of Herds, Cows, and Quarters: Data should be collected in a minimum of six herds in two geographical locations with two independent investigators (the investigator is defined as that individual receiving the drug shipment and supervising the trial). It is recommended that 20% of the animals in the herds selected be infected in at least one quarter with infectious mastitis. All lactating cows and quarters should be enrolled in the study. Cows should be concurrently enrolled in no other experiment. Injured quarters should be recorded and excluded before and during the study. Any concurrent antibiotic or non-antibiotic therapy administered to a study animal or herd should be described, grouped, and filed according to the herd and its investigator for the NADA purposes. A pre-trial culture/somatic cell survey is recommended for clinical and subclinical infectious mastitis studies. The survey should include milk samples from all lactating quarters on all cows in a herd. This data will establish the baseline incidence of mastitis in the herd. The data collected from this survey are to be submitted in the NADA. All infected and non- infected quarters of cows in the herd should be included in the study. General herd/cow descriptive data should be submitted including herd size, number of cows currently lactating, percentage of lactating cows sampled in the herd, percentage of lactating cows affected by infectious mastitis, approximate age of each cow, stage of lactation and vaccination history. 3. Trial Duration: A minimum of one year. The starting and termination dates should be declared before the study begins. 4. Treatment Procedure: As a standard dairy farm procedure each teat should be treated immediately before or after milking depending upon the claim (pre- or post-treatment). 5. Pre-trial Culturing: Herd surveys should take place within one week prior to the initiation of the trial. 6. Trial Culturing:Culture single quarter milk samples monthly or duplicate/consecutive bimonthly during the entire trial. Individual cow somatic cell records should be submitted with the bi-monthly cultures. Dairy Herd Improvement Association (DHIA) records are acceptable. Investigators should culture all quarters for the common infectious mastitis pathogens and should record the type of clinical infectious mastitis encountered. Appropriate bacteriologic culture methods are described in the Microbiological Procedures for the Diagnosis of Bovine Mastitis, National Mastitis Council (NMC), 1990. Milk from each quarter should be examined grossly at the time of sampling for signs of clinical mastitis. The diagnosis of clinical mastitis is made at sampling time by the investigator, and at other times by the dairyman. Results should be recorded on the barn data records. 7. Criteria for Diagnosing Infections: a. The same pathogen is isolated from both the duplicate or two single consecutive samples taken bimonthly. b. Clinical infections should be accompanied by the cardinal signs of inflammation, a high somatic cell count and an attempted milk culture. A bacteriologically negative clinical case occurs when duplicate samples don't agree. 8. Data Presentation and Statistical Analysis: a. For each pathogen for which a claim is to be made, the incidence of infectious mastitis caused by these individual pathogens should be sorted, summarized, and submitted by herd for each investigator. b. Due to anticipated large variations between herds in treatment response, the statistical analysis should be conducted using statistical method (Mantel Haenszel test) for discrete data that accounts for differences due to herds and investigators. If herd and investigator differences are not accounted for in the statistical analysis, the true treatment effect can be confounded with treatment sample sizes in the various herds tested. 9. Data Reporting: a. Collected data for each trial should include the numbers of quarters in the trial at the beginning of the herd survey; the number of infected and non-infected quarters in the initial survey; the number of new or recurrent infections detected monthly or bi-monthly with somatic cell counts in the control and treated groups; the percentage differences in new infections from each pathogen species and type of mastitis. b. The overall reduction in the incidence of infectious mastitis types (clinical vs subclinical etc.) should be reported for each experimental herd. For specific types of infectious mastitis with known etiologies, adequate efficacy will be demonstrated when incidence of infectious mastitis is reduced by 50%. c. The study protocol, together with barn sheets, laboratory report forms, and data summary sheets should be submitted to CVM as part of the final study report. III. HUMAN FOOD SAFETY: A. TOXICOLOGY: Toxicity studies for establishing safe concentrations of residues for teat antiseptics in milk and edible tissues of treated cows are presented in the Guideline II of the "General Principles for Evaluating the Safety of Compounds Used in Food-Producing Animals", 1986. B. RESIDUE CHEMISTRY: For teat antiseptics products, an initial evaluation will be made of the active component and also of the excipients. For certain products using iodine, chlorine or citric acid, for example, the oral residue requirement will likely be waived. However, most teat antiseptics will be evaluated based on the guidelines in GENERAL PRINCIPLES FOR EVALUATING THE SAFETY OF COMPOUNDS USED IN FOOD-PRODUCING ANIMALS. For the New Animal Drug Application (NADA), CVM recommends that a minimum of five cows be treated with the teat antiseptic containing radiolabeled drug until total residues in milk reach a steady-state concentration. Sponsors should demonstrate that the total residue in milk present at steady-state is below the safe concentration. This is essential since teat antiseptics will be used under no- discard conditions. If the residue exceeds the safe concentration the teat antiseptic will not be considered as a viable product. If the teat antiseptic can be used under no-discard conditions, CVM suggests that the five animals treated with radiolabeled teat antiseptics in the milk study above be serially sacrificed to afford 'pilot' study information regarding tissue depletion curves. In addition, sponsors should conduct a total tissue residue depletion and metabolism study and, if necessary, a second depletion study in which the regulatory assay has been used to obtain data to establish the withdrawal period. The sponsors should follow the guidelines for these studies as presented in FDA's "Guideline for Metabolism Studies and for Selection of Residues for Toxicological Testing" and "Guideline for Establishing Withdrawal Periods." IV. MANUFACTURING CHEMISTRY: A. INTRODUCTION: Products to be marketed must be manufactured according the cGMP regulations (21 CFR Part 211) for pharmaceutical dosage forms under the approved NADA process. B. PATHOGEN CONTENT OF FINISHED PRODUCT: The finished product dosage form should be free of potential mammary pathogens or endotoxins. Pathogens to be tested for include the following: Staphylococcus aureus Salmonella spp. Streptococci spp. Mycoplasma spp. Escherichia coli Pseudomonas aeruginosa Corynebacteria pyogenes Nocardia Yeast Samples that are positive for any microorganism should be subjected to bacterial or fungal identification to confirm that it is not one of the above pathogens, nor is it any other microorganism with the potential to induce infection. C. REFORMULATED PRODUCTS: Significant formulation changes for teat antiseptic drugs may necessitate a new milk-out study. Sponsors are encouraged to discuss this issue with CVM. D. REVISED MANUFACTURING PROCESS: Significant manufacturing process changes for teat antiseptic drugs may necessitate a new milk-out study. Sponsors are encouraged to discuss this issue with CVM. E. NEW OR ALTERNATE MANUFACTURING SITES: Approved products that will be manufactured at a new or alternate manufacturing site may necessitate a new milk-out study. Sponsors are encouraged to discuss this issue with CVM. F. NEW BULK DRUG SOURCE: A new source of bulk drug material used in the manufacture of mastitis products may necessitate a new milk-out study. Sponsors are encouraged to discuss the issue with CVM. V. ENVIRONMENTAL REQUIREMENTS The National Environmental Policy Act (NEPA) was enacted by Congress in 1969. The Act is to assure that all Federal Agencies consider the potential environmental impacts of their actions. The Food and Drug Administration first published NEPA-implementing regulations in 1973. The regulations were amended in 1985. FDA's NEPA implementing regulations are contained in 21 CFR Part 25 Environmental Impact Considerations. Two of the major actions that FDA takes that require review under NEPA for potential environmental impacts are the exemptions under INADs to conduct investigations and approvals of new animal drugs under NADAs under the Federal Food, Drug and Cosmetic Act. For investigations and approvals, the sponsor of an INAD or NADA may either request a categorical exclusion from providing an environmental assessment (EA) or provide an EA. A. FILING REQUIREMENTS: 1. The procedures under 21 CFR Part 25 require that each INAD, NADA or NADA supplement filed with CVM must address the environmental impacts of the requested action. In general, this is done by submitting either: a. A claim for categorical exclusion under the appropriate subparagraph of 21 CFR 25.24 or b. An Environmental Assessment (EA) under the appropriate subparagraph of 21 CFR 25.31a. 2. A categorical exclusion from the need to prepare an EA is possible for certain actions, provided that an appropriate exclusion is claimed under 21 CFR 25.24. A categorical exclusion will be allowed only if all the criteria for the claimed exclusion under section 25.24 are met. It is expected that most investigations conducted under an INAD may be categorically excluded from preparing an EA. 3. Preparation of an adequate EA by the applicant or petitioner is required so that CVM can identify and address the potential environmental impact of a requested or contemplated action. Relevant EA information is intended to do the following: a. identify and estimate the quantities and concentrations of chemicals that could be introduced into the environment through production, use and disposal. b. assure that a manufacturing facility is in compliance with all applicable Federal, state and local environmental requirements. c. estimate the fate of those emitted chemicals by evaluating their mobility (in air, soil and water) - chemical degradatlon, biological transformation or subsequent accumulation (or persistence). d. determine the ecotoxicological effects resulting from exposure (including occupational) to those emitted chemicals. e. predict any potential effects upon natural resources, endangered species or historical places. f. identify methods to eliminate any potential effects. 4. Adequate EAs filed with CVM are used as the basis for determining whether a proposed action requires the preparation of a Finding of No Significant Impact (FONSI) or an Environmental Impact Statement (EIS) and for the public to understand the Center's decision. a. A FONSI is prepared by the Environmental Sciences Staff for actions determined not to require an EIS. The Environmental Sciences Staff must prepare, at the minimum, a (FONSI) for every adequate EA filed with the Center. b. An EIS is prepared by the Environmental Sciences Staff only for major actions significantly affecting the quality of the human environment. 5. An NADA is not considered acceptable for filing if the applicant fails to submit a complete environmental assessment addressing each of the items listed in Section 25.31 or fails to provide sufficient information to establish that the requested action is subject to categorical exclusion under Section 25.24. (21 CFR Section 514.110 (b) (10)). INADs shall contain either a claim for categorical exclusion or an environmental assessment. (21 CFR Section 511.1 (b)(10)). B. ENVIRONMENTAL ASSESSMENT TECHNICAL HANDBOOK: FDA has made available (52 FR 37372. October 6, 1987) an Environmental Assessment Technical HandbooK. The Handbook is intended to improve the quality and consistency of NEPA documents and to save time and resources for preparers and reviewers of the documents. The handbook also provides assistance on the types of information necessary for NEPA documents. Copies of the handbook may be obtained from the National Technical Information Service (NTIS), 5285 Port Royal Rd., Springfield, VA 22161 (703-487-4650). The NTIS order number is PB 87-175345. VI. GLOSSARY OF TERMS Mastitis - Inflammatory condition of the mammary gland generally caused by one or more pathogenic microorganisms. It is characterized by pathological changes of the udder epithelium, followed by inflammatory reactions and secretional changes. Evidence of leukocytosis is found in the milk of affected quarters. Clinical Mastitis - A form of mastitis characterized by signs including: a) grossly abnormal milk and presence of flakes, clots and/or discoloration. b) evidence of inflammation with apparent clinical tissue changes, swelling, heat and/or pain in the affected quarters. c) evidence of leukocytosis in milk. d) isolation of pathogenic microorganism in pure culture from fresh plating of milk sample is generally possible. e) drop in milk production. f) fever (especially in cases of peracute mastitis) Infectious Mastitis (Subclinical) - A form of mastitis without clinical signs of udder changes. Visibly normal milk with an abnormal mastitis screening test value and pathogenic microorganism found on bacteriological culture. Appropriate dose of drug - That level of drug (administered at its proper regimen) beyond which any further incremental increase in drug level produces no meaningful improvement in desired efficacy, or if further drug does provide increased efficacy, the benefit is outweighed by increased risks in terms of human and/or animal safety. Quantitative Somatic Cell Count (QSCC) - Coulter counters or electronic somatic cell counting techniques which determine the number of somatic cells in milk. Consecutive Milk Samples - Milk samples collected at sequential milkings.
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