Guideline No. 185
Draft Guidance for Industry - Target Animal Safety for Veterinary Pharmaceutical Products (VICH GL43)
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE
Contains Non-Binding Recommendations
Draft—Not for Implementation
185
Guidance for Industry
Target Animal Safety for Veterinary
Pharmaceutical Products
VICH GL 43
DRAFT GUIDANCE
May 17, 2007
This guidance document is being distributed for comment purposes only
This guidance document is intended to cover target animal safety (TAS) studies for any Investigational Veterinary Pharmaceutical Product (IVPP) used in the following species: bovine, ovine, caprine, feline, canine, porcine, equine, and poultry (chickens and turkeys). The guidance does not provide recommendations for the design of TAS studies in other species, including aquatic animals. This VICH document, when finalized, will supersede FDA Guidance No. 33, Target Animal Safety Guidelines for New Animal Drugs.
Comments and suggestions regarding the document should be submitted to Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments. All comments should be identified with the Docket No. 2007D-0166.
For questions regarding this document, contact Laura Hungerford, Center for Veterinary Medicine, (HFV-100), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, 301-827-6439, e-mail: laura.hungerford@fda.hhs.gov.
VICH GL 43 (TARGET ANIMAL SAFETY) - PHARMACEUTICALS
December 2006
For consultation at Step 4
TARGET ANIMAL SAFETY FOR VETERINARY PHARMACEUTICAL PRODUCTS
Recommended for Consultation
at Step 4 of the VICH Process
on 10 December 2006
by the VICH Steering Committee
This Guidance has been developed by the appropriate VICH Expert Working Group and is subject to consultation by the parties, in accordance with the VICH Process. At Step 7 of the Process, the final draft will be recommended for adoption by the regulatory bodies of the European Union, Japan, and USA.
Table of Contents
1. INTRODUCTION
1.1. Objective
1.2. Background
1.3. Scope
2. GENERAL SAFETY STUDIES
2.1. Standards
2.2. Animals
2.3. Investigational Veterinary Pharmaceutical Product and Route of Administration
2.4. Dose, Frequency and Duration of Administration
2.5. Study Design
2.6. Variables Used in Margin of Safety Studies
2.7. Statistical Analysis
2.8. Study Reports
3. OTHER LABORATORY SAFETY STUDY DESIGNS
3.1. Injection Site Safety Studies
3.2. Administration Site Safety Studies for Dermally Applied Topical Product
3.3. Reproductive Safety Studies
3.4. Mammary Gland Safety Studies
4. TARGET ANIMAL SAFETY DATA FROM FIELD STUDIES
5. RISK ASSESSMENT IN ANIMAL SAFETY EVALUATION
6. GLOSSARY
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word “should” in Agency guidances means that something is suggested or recommended, but not required.
The purpose of this harmonized guidance is to provide recommendations regarding TAS evaluation for regulatory submission of an Investigational Veterinary Pharmaceutical Product (IVPP), which is appropriate for determining the safety of an IVPP in the target animal, including identification of target organs, where possible, and confirmation of margin of safety, using the minimum number of animals appropriate for the studies.
The VICH was initiated to develop internationally harmonized guidance that outlines regulatory recommendations for the registration of an IVPP in the regions participating in the program. By their nature, guidance documents cannot address all possibilities. The TAS Expert Working Group has developed the general principles included in this guidance document to aid in the development and conduct of TAS studies and to support the monitoring of potential adverse events in field studies. For more specific recommendations, review of the study protocol by the relevant regulatory authorities prior to the initiation of the study is encouraged.
If in a particular circumstance an alternative approach is deemed more fitting, preparation of a reasoned explanation by the sponsor and discussion with the regulatory authorities is encouraged before work is initiated.
This guidance document is intended to cover TAS studies for any IVPP used in the following species: bovine, ovine, caprine, feline, canine, porcine, equine, and poultry (chickens and turkeys). The recommendations in this guidance may not be appropriate for minor species or minor uses for local registration. The guidance does not provide recommendations for the design of TAS studies in other species, including aquatic animals. For other species, TAS studies should be designed following local guidance.
This guidance contributes to the international harmonization of methods used for evaluation of IVPP. The guidance is provided to aid sponsors in preparing and conducting TAS studies under laboratory conditions and in the field. All recommendations in this document may not be necessary for every IVPP. For other IVPP, additional information not specified in this document may be important to show target animal safety.
The aim of TAS studies is to provide information on the safety of an IVPP in the intended species under the proposed conditions of use. The margin of safety study is indispensable in the approval of an IVPP. Furthermore, adverse effects associated with overdoses and increased duration of administration of the IVPP should be identified, if possible. Dose confirmation and field studies conducted to confirm the effectiveness of the IVPP provide further information on safety in the target species. Depending on the known or suspected properties of the IVPP, it may be necessary to conduct additional toxicologic or specialized tests.
The margin of safety may be documented if the study includes both the recommended dose and overdoses, given for the proposed and longer treatment periods. Generally, the margin of safety study should examine the response of the animal to two or three non-zero multiples of the recommended dose (X). The selection of dose levels and duration of treatment should always be justified by the sponsor, taking into account the proposed use of the product and the known pharmacological and toxicologic properties of the pharmacologically active substance. Where usage or formulation involves a greater risk or consequence of overdose, then a separate study, or inclusion of a higher dose level in the margin of safety study, is recommended for IVPP. This may include cases where a dose calculation error may be likely, such as a mistake in decimal point identification during addition to feed.
The design of the TAS evaluation and the prediction of potential adverse effects that may occur in the target species should be assisted by reference to data including published literature and preliminary studies, including pharmacokinetics, pharmacodynamics, and toxicology from target and non-target laboratory animal studies. The specific information used to evaluate the safety of an IVPP depends on factors such as proposed usage regimen and dose, type of drug, chemistry and manufacturing considerations, claims, previous use history of similar products, and animal species including class and breed. Appropriate observations, physical examinations, clinical pathology tests (hematology, blood chemistry, urinalysis, fecal analysis, etc.), necropsy, and histopathology should be conducted to identify possible adverse effects of IVPP.
Margin of safety studies are generally recommended for new salts of the pharmacologically active substance or formulations of an IVPP. Exceptions should be justified, for example, on the basis of known toxicology and target animal safety profiles for the pharmacologically active substance, widespread clinical use of existing products, and/or where the systemic or local exposure (as applicable) of the new product is proven to be equivalent to or less than that of the existing product.
If systemic exposure to the active ingredient is negligible and based on pre-existing knowledge in pharmacology and toxicology there is no safety concern, then the margin of safety study may not be important. This should, however, be justified by the sponsor, and safety study at the site of administration (see 3.1 to 3.4) is recommended.
Target animal safety studies (margin of safety and other laboratory safety studies) must be performed in conformity with the principles of Good Laboratory Practices (GLP; 21 CFR Part 58). The principles of Current Good Manufacturing Practice (CGMP) must be applied to the IVPP, as appropriate, for new animal drugs intended for investigational use (21 U.S.C. § 352(a); 21 CFR Parts 210 and 211).
Healthy animals, representative of the species and class in which the IVPP will be used, should generally be used in TAS studies. The age of animals should be considered carefully; if the product is intended for use in young, immature animals then the animals in the TAS studies should generally be the youngest age for which product approval is sought. Otherwise, healthy young mature animals should be used. Studies should include members of potentially sensitive subpopulations, if such groups have been identified in the intended target population. This guidance makes no specific recommendation regarding the use of diseased animals in TAS studies.
Acclimatization of the animals to the study conditions is recommended. Treated and control animals should be managed identically and prophylactic treatments completed before the baseline period of the study, where possible. Use of concurrent therapy with other products during the study may make it more difficult to identify safety concerns due to the IVPP and is not recommended. Studies should be carefully planned to provide adequate information while minimizing the number of animals used. Housing and husbandry should be adequate for the purpose of the study as well as conforming to local animal welfare regulations. Environmental conditions, diet, and water should be controlled throughout the study as appropriate to the species, physiological state, and age. It is recommended that quality and composition of diet and water are monitored throughout the study. Reduction or elimination of suffering during the study is essential. Euthanasia and necropsy of moribund animals is recommended.
The IVPP to be evaluated should be identical to the product intended to be marketed in terms of qualitative and quantitative composition, and should have a similar profile of impurities. If the market formulation is not used, comparative studies may be necessary, e.g., the relevance of TAS data for one formulation of an IVPP to another formulation can be demonstrated by the use of bioequivalence data between the two formulations. The IVPP should be evaluated by comparison to a placebo (e.g., saline) or untreated control. The formulation details, generic or trade name, and batch number should be documented. Packaging, storage conditions, and preparations for administration should be clearly identified. The site of administration is to be identified. Dosing should follow the use conditions suggested in the proposed labeling. If food affects pharmacologically active substance bioavailability, animals should be fed or fasted before administration to provide the highest likelihood of showing adverse effects. If volume or palatability becomes a limiting factor for higher dose levels, alternative techniques (for example, multiple sites, gavage, or increased frequency of administration) may be considered. If multiple routes of administration are proposed by the sponsor, the route that is most likely to cause adverse effects should be selected as the basis for safety studies. Additional studies on local tolerance (see 3.1 or 3.2) should be conducted, as appropriate.
The general design for margin of safety studies uses multiples of the proposed use dose and duration of administration of the IVPP. Specific dose, frequency, and duration combinations for use in TAS studies should be selected and justified based on the pharmacology and toxicology of the IVPP.
Unless otherwise justified by the pharmacological-toxicologic properties of the active substance and the proposed use of the product, the design of the margin of safety study should include a control, the highest recommended dose level (1X), and two multiples of this use dose (in most cases three times (3X) and five times (5X)) for a period of time in excess of the recommended maximum duration of use. In some regions, alternative designs based on the pharmacology and toxicology may be acceptable, for example, the administration of the product in excess of the recommended maximum duration of treatment given only in the highest recommended dose level (1X). Regardless of design, a negative control should always be included.
In general, it is recommended that each group be treated for at least 3 times the proposed duration up to a maximum of 90 days (for example, for a proposed single use IVPP, treatments should be administered on 3 consecutive days; a proposed daily dosing for 7 days should be given for 21 consecutive days). If short-term, intermittent use is intended, treatments should be administered 3 times at the recommended interval (for example, proposed weekly treatments should be administered for 3 consecutive weeks). Where product use is expected to exceed 3 consecutive months in individual animals then, depending on pharmacology and toxicology, longer duration studies may be recommended up to a maximum of 6 months or longer, if appropriate (e.g., where drug accumulation may increase over time or where duration of drug activity following a single dose exceeds 2 months).
The most important techniques for avoiding bias in studies are randomization and masking (blinding). A randomization plan should be used to allocate animals to treatment groups. Blocking may be used to control, as far as possible, the distribution of the one or two most important factors, such as sex, age, stage of lactation, or body weight to ensure balance between treatments.
Target animal safety studies typically include relatively small numbers of experimental units (often only 8 per treatment) and assess large numbers of variables. Both males (4 per treatment) and females (4 per treatment) should be included unless the product is only intended for use in one sex. Medical, animal welfare and statistical considerations are generally used to determine the total number of animals used to evaluate for potential safety concerns. When interim sacrifice or withdrawals of animals for other reasons are anticipated, the number of experimental units should be increased accordingly. Although there is strong interest in the null hypothesis of no difference between treatments, study design constraints limit the statistical power and discriminatory ability of these studies. Under these conditions, statistical analysis alone may not detect potential adverse effects and thus provide assurance of safety. Results should be evaluated and interpreted based on a combination of medical, toxicologic, and statistical principles with consideration of biological significance and plausibility.
Where group housing is needed to provide appropriate animal welfare and allow for adequate experimental conditions, certain variables, such as diarrhea, vomiting, or feed or water consumption may be difficult to measure on an individual animal basis. In addition, even measurements that can be accurately made for individual animals from the same cage or pen may be influenced by the presence of the other animals in the group. For example, presence of a dominant animal in a pen may be a contributing factor in weight loss among other animals in the pen. Potential influence of group housing should be taken into consideration in interpreting drug effects from a study, even if statistical analyses are not used. Failure to consider this information might lead to incorrect attribution of effect to the IVPP.
The planned times for measuring each variable should be described in the study protocol. Often this schedule includes daily observations of animals throughout the study period, with more detailed measurements at several time points, including the beginning and end of the study. Pretreatment measurements should be made to identify baseline levels. Measurement at time points during the proposed label duration of IVPP use may help characterize the time course of potential safety issues. Equally-spaced measurement intervals may facilitate statistical modeling. For longer studies, data collection may be planned in designated phases, with different frequencies of data collection.
Data should be collected in a manner that minimizes bias. For example, when examinations are needed on a subgroup from each treatment, animals should be randomly designated before study initiation. Personnel collecting data, including gross post mortem results, should be masked to treatment. Histopathology data should be evaluated by recognized procedures (e.g., Crissman et al., Toxicologic Pathology, 32 (1), 126-131, 2004).
Many variables are measured during an animal safety study. The types of observations, examinations, and tests for safety depend on the nature of the IVPP, proposed use, target animal, and potential for adverse effects. In general, there are four types of variables that should be considered in margin of safety studies: physical examinations and observations, clinical pathology tests, necropsy, and histopathology examinations.
A detailed physical examination by qualified personnel (generally a veterinarian) should be conducted at several time points during the study, including the beginning and end. Baseline observations of other variables should be made by qualified personnel at the beginning of the study. Observations relating to general health and behavior by trained personnel (not generally a veterinarian) should be recorded on all animals daily, seven days a week, or at pre-determined intervals appropriate for the purpose of the study, during the entire period. Food and water consumption should be monitored at appropriate intervals. Body weights should be measured at the beginning, end, and several other appropriate times. Generally, the following should be considered and measured depending on the nature of the IVPP:
General Physical Examination (these generally should be done by a veterinarian)
| Ocular system | Nervous system |
| Musculoskeletal system | Integumentary system |
| Cardiovascular system | Respiratory system |
| Reproductive system | Urinary system |
| Lymphatic system | Gastrointestinal system |
| Behavior |
Specific Examination of Injection/Application Site (semi-quantitative or quantitative assessment should be used wherever possible)
Appearance (e.g. erythema, eschar formation, hair loss, scaling, pigmentation)
Swelling
Pain
Heat
Observations (these should be done by appropriately trained staff)
Feed intake
Water intake
Weight
Behavior
Body temperature
Signs of illness
Feces (consistency, color and mucus, blood)
Hematology, blood chemistry, and urinalysis should be conducted at several points during the study, including at the beginning and end of the study. Other specialty tests to monitor appropriate physiologic parameters may be appropriate, depending on the IVPP. A standardized feeding schedule prior to sample collection should be followed. Tests should be conducted on all animals or on randomly pre-selected animals. These tests are subject to influence by the conditions under which the samples are collected such as feeding or fasting, and sedation or anaesthesia, and therefore it is critical that samples are collected in the same manner from concurrent control and treatment groups of animals. Blood samples from multiple animals should not be pooled. For animals showing adverse events, additional clinical pathology and other diagnostic tests to address causality may be appropriate. Collection of clinical pathology data twice during the pre-treatment stage can be helpful in providing reliable baseline data for interpretation of study results. Typical measured variables include (units should be appropriate for regions):
Hematology
Erythrocytes: Total and differential counts, reticulocyte count
Leukocytes: Total and differential counts
Packed cell volume, (PCV)
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin (MCH) and Mean corpuscular hemoglobin concentration (MCHC)
Hemoglobin
Prothrombin time
Platelet count
Activated partial thromboplastin time
Whole blood clotting time or bleeding time
Fibrinogen
Acute phase protein, as applicable
Blood Chemistry
| Sodium | Urea nitrogen |
| Potassium | Creatinine |
| Chloride | Alanine aminotransferase (ALT) |
| Calcium | Aspartate aminotransferase (AST) |
| Phosphate | Lactate dehydrogenase (LDH) |
| Magnesium | Gamma-glutamyltransferase (GGT) |
| Total protein | Alkaline phosphatase (AP) |
| Albumin | Creatine kinase (CK) |
| Globulin | Total bile acids |
| Glucose | Cholesterol |
| Amylase |
Urinalysis
Color Protein pH Ketone bodies Specific gravity (e.g. by refractometer) Bilirubin Glucose Urobilinogen Microscopic examination of sediment (crystals, casts, RBCs, WBCs, epithelial cells)
As a minimum, tissues from all animals in the highest dose group and control group should be examined grossly and microscopically (for recommended procedures, see Crissman et al. Toxicologic Pathology, 32 (1), 126-131, 2004). Where the toxicity of the IVPP is anticipated to be relatively high, different necropsy schemes may be recommended, to include gross and microscopic examinations for all animals or for randomly pre-selected animals. If lesions are found in any tissue from the highest dose group, then samples from animals in the next lowest dose group of the IVPP should be examined grossly and microscopically, until a no-observable-adverse-effect-level is determined. In addition, tissues from all animals showing systemic clinical signs should normally be examined grossly and microscopically.
Organ weights, where appropriate, and gross lesions should be recorded. Tissue samples should be preserved for microscopic evaluation. The types of organs selected for gross and microscopic examination will depend upon animal species and target tissues. Histopathology should be conducted on organs/tissues, with particular attention given to organs/tissues showing macroscopic lesions, including at the injection site, where applicable. Generally, it is recommended that the following organs/tissues be considered in gross and microscopic examinations, as appropriate:
Organs/tissues considered for gross and microscopic examination:
| Pituitary gland | Brain | Bone & marrow |
| Thyroid gland | Spinal cord | Marrow smear |
| Parathyroid gland | Eyes | Spleen |
| Adrenal gland | Lung | Stomach |
| Pancreas | Muscle | Duodenum |
| Ovaries | Mammary gland | Jejunum |
| Uterus | Liver | Ileum |
| Testes | Gall bladder | Colon |
| Prostate | Kidneys | Cecum |
| Epididymis | Urinary bladder | Thymus |
| Heart | Lymph nodes | Injection site: Muscle, subcutaneous tissue |
| Crop | Proventriculus | Bursa of Fabricius |
| Ventriculus | Skin |
In most studies, the safety implications are best addressed by applying descriptive statistical methods to the data. Tables and descriptive text are common methods of data summarization; however, it is also valuable to make use of graphical presentations in which patterns of adverse events are displayed both within treatments and within individual animals. Selection of the general form for a statistical model and the factors to be included in the model will depend on the nature of the response variable being analyzed and the study design. Regardless of the methods chosen, the process and steps used to conduct any statistical evaluations should be described. The outcomes of the data analysis should be clearly presented to facilitate evaluation of potential safety concerns. The terminology and methods of presentation should be chosen to clarify the results and expedite interpretation.
Tables may be used to present the data from individual animals and summary statistics from treatments. For quantitative variables, useful descriptive statistics include the number of animals in each treatment, median, mean, standard deviation, maximum, minimum, and the number and percentage of cases with values falling outside a recognized reference range. For some quantitative variables, categorization of animals with values that fall within different ranges may help to identify patterns. For qualitative variables, useful descriptive statistics include the total number of animals evaluated and the number and percentage of experimental units within each response category. Other events, such as adverse events, mortalities and early terminations may also be tabulated.
Graphs may be very helpful in depicting the data and identifying potential safety concerns, including possible dose trends, time-related patterns, and values that fall outside reference ranges. Plots, that show responses over time, both within treatment groups and within individuals, may illustrate consistency of responses between animals, sex, age, or dose levels. These graphs may show trends or time-related patterns in adverse effects of treatment.
Statistical models should represent the study design. When animals that are housed together are all assigned to the same treatment, the housing unit is typically the experimental unit. If animals from different treatments can be housed together, then the individual animal may be considered the experimental unit. In addition to test group, other blocking factors, such as housing units or sex and pretreatment covariates should be included in the models, as appropriate. A useful approach is to include the fewest number of terms that adequately represent the underlying process that generated the safety data, and to represent the longitudinal nature (repeated measurements) of the design (if applicable). Choice of model form should be driven by the nature of the response variable being analyzed. The potential impact of any missing data on the results should be considered.
Analysis results from statistical modeling include statements of significance levels for terms included in the model. The calculation of p-values is sometimes useful either as an aid to evaluating a specific difference of interest, or as a ‘flagging’ device applied to a large number of safety variables to highlight differences worth further attention. This is particularly useful for clinical pathology data, which otherwise can be difficult to summarize appropriately. It is recommended that clinical pathology data be subjected to both a quantitative analysis, e.g. evaluation of treatment means, and a qualitative analysis where counts of numbers above or below certain thresholds are calculated. While p-values are one indication of a substantial difference that should receive clinical appraisal, the small size of safety studies makes it crucial that clinical judgment be used to evaluate all differences, irrespective of the p-value observed. A statistically significant test does not necessarily indicate the presence of a safety concern. Similarly, a non-significant test does not necessarily indicate the absence of a safety concern. Statistical adjustments for multiplicity can be counterproductive for considerations of safety; the importance and plausibility of results will depend on prior knowledge of the pharmacology of the drug and this evaluation should be made by clinicians or scientists with appropriate experience and training in interpreting the biological relevance of the results.
A study report is a document describing the objectives, material and methods, any amendments or deviations from the protocol, results (including individual animal data, data summaries, and any analyses), and conclusions of a TAS study. Content of final study reports must conform to principles of GLP (21 CFR Part 58). In some regions, additional provision of raw data may be required (21 CFR 514.1(b)(8)).
Additional safety studies may be important for particular IVPP, depending on the conditions of use and the characteristics of the IVPP. When appropriate, such studies may be combined with the margin of safety evaluation and, in food producing animals, residue studies. These specialized studies should be designed according to the general principles outlined below and follow any official local guidance. It is recommended that the specific types of studies to be conducted be determined by communication between the sponsor and the regulatory agency.
The basic study design should consider dose (1X), duration, route(s), vehicle, and maximum volume of the injection. The study should include a saline control of the same volume as the complete and final formulation of the IVPP. In the case of non-liquid IVPP, an alternative suitable control should be used. The location and timing of each injection should be specifically noted to facilitate determination of time to resolution. The study should consider site lesions that may be produced by administration by syringe or other applicator by intravascular, intradermal, intramuscular, and/or subcutaneous routes. If intravascular administration is the only route proposed, consideration should be given to the effects of extravascular administration of the IVPP. For formulations where intravascular use is not intended and there is a potential risk associated with intravascular injection (e.g., ear) the safety in the event of intravascular injection should be considered.
Evaluation of safety data from injection site studies may include the following:
- Clinical signs including changes in behavior or locomotion.
- Appearance, inflammation, edema, or other changes at the injection site.
- Measuring creatine kinase and aspartate transaminase levels.
- Gross pathology and histopathology of lesions at appropriate times.
If there is inflammation at the injection site that has not resolved on visual examination or by palpation by the end of the planned study, then the time required for return to clinically acceptable resolution at the injection site should be determined. Where clinical signs indicative of injection site effects are evident, it may be necessary to conduct histopathology of the lesions.
Local adverse reactions to topically applied IVPP should be evaluated at the dosage proposed on the label unless the pharmacology and toxicology of the product warrants multiples of dose and/or duration. For systemically absorbed topical IVPP, it is recommended that evaluation of topical administration sites be included in studies of systemic TAS outcomes. The variables measured will depend upon of the type of formulation. In general, the site should be examined for swelling, pain, heat, erythema, and other clinical signs. Changes in animal movement or behavior should be noted. If there are inflammation or other clinical signs at the topical application site that have not resolved on visual examination or by palpation by the end of the planned study, then the time required for return to clinically acceptable resolution at the topical application site should be determined. Where clinical signs indicative of administration site effects are evident, it may be necessary to conduct histopathology of the lesions.
Oral dosing, at the maximum proposed dose of the topical formulation, may be important to examine the safety of the IVPP if accidental ingestion is likely to occur after treatment (e.g., by licking). If based on pharmacology and toxicology, there are no significant safety concerns with oral exposure, then this study may not be appropriate.
Reproductive safety studies are recommended for systemically absorbed pharmacologically active substances intended for use in breeding animals. The goal of reproductive safety studies is to identify any adverse effects of the IVPP on male or female reproduction or on offspring viability. These studies generally focus on reproductive variables, although safety data on other body systems may be collected. These studies do not usually extend to considering viability of offspring beyond weaning unless there is specific evidence of possible effects on, for example sexual maturity, based on pharmacology and toxicology of the pharmacologically active substance.
Healthy, intact, reproductively-sound males and females should be selected that are representative of the species, age and class in which the drug will be used. In general, it is recommended that a minimum of eight animals per sex be included per treatment. Males and females may be evaluated in the same or separate studies. Dose and frequency of administration should be selected and justified based on the pharmacology and toxicology of the IVPP. Generally, males should be treated with a 3X dose of the IVPP during a minimum of one spermatogenic cycle. Generally, females should be treated with a 3X dose of the IVPP prior to breeding (covering the follicular phase of reproduction), throughout the gestational period (embryonic phase, fetal phase, natal phase), and after parturition for an appropriate time covering the main lactation period. It is not necessary to administer the IVPP at or around parturition, unless the IVPP is specifically indicated for use at that time.
Reproductive safety studies should evaluate, as appropriate:
- in the male, spermatogenesis, semen quality, and mating behavior.
- in the female, estrous cycle, mating behavior, conception rates, length of gestation, parturition, and lactation.
- in the offspring from treated males and/or females, developmental toxicology (including teratogenicity, fetotoxicity), fetal development, number of offspring, viability and growth, health and development to weaning.
- in poultry, also, egg weight, shell thickness, egg-laying curve of a hen, egg fertility, hatchability, and chick viability.
Ideally, reproductive safety studies are conducted in the target species; however, data obtained from reproductive studies in laboratory animals may be considered, provided that the pharmacokinetic profiles of the pharmacologically active substance are comparable in laboratory animals and in all species in which the IVPP is intended for use. Depending on the results of such evaluation, appropriate information should be included on the labeling. However, if reproductive safety studies have not been conducted in the target species, labeling should reflect this and state that safety has not been determined in breeding, pregnant, or lactating animals or their offspring.
Mammary gland safety studies should be conducted to evaluate the safety of IVPP intended for intramammary use in lactating or non-lactating animals. It is recommended that safety evaluation of an IVPP intended for use in non-lactating animals include both an objective evaluation of acute inflammatory effects in lactating animals (data collected in conformity with the principles of GLP, see 21 CFR Part 58) and clinical evaluation of chronic inflammatory effects in non-lactating animals (data collected in conformity with the principles of GCP or GLP; 21 CFR Part 58).
For a study to see acute inflammatory effects, study animals should be in early to mid-lactation for a lactating claim. The animals should be free of subclinical or clinical mastitis. The IVPP should be administered to each teat. The conditions of use, dose (1X), and frequency of administrations should be those proposed. Alternatives should be justified by the sponsor.
For both lactating and non-lactating claims, it is preferred that a one-group, comparative design be used to evaluate similarity of values from pre-treatment and post-treatment periods within each animal. A two-group design may also be used, with treated animals compared to negative control animals. A minimum of 8 lactating animals, including a minimum of 4 in their first lactation, should be assigned to each treatment in either study design for both lactating and non-lactating claims.
For either study design in lactating animals (both lactating and non-lactating claims), data on all relevant variables associated with tissue irritation and milk production should be collected pre-treatment, at treatment, and post-treatment until return to control values. Physical examination, including palpation, should be done to determine swelling, erythema, pain, or heat. Samples for quantitative somatic cell count and bacterial culture should be collected from each teat prior to milking. Daily milk yield, composition (e.g., fat, protein, lactose, and non-fat solids), and appearance should be recorded.
Key variables for safety assessment generally include signs of mammary gland irritation, elevated SCC and changed milk production. Very high post-treatment SCC may not be acceptable and should be explained by the sponsor. Any elevated SCC following treatment should return to control values within the proposed milk withdrawal period.
Field studies intended to evaluate effectiveness of an IVPP also provide essential TAS data under conditions of intended use. These studies should be conducted in accordance with the principles of good clinical practice (GCP).
Field studies are typically conducted under conditions representative of the target population and provide an evaluation of potential adverse effects at the intended use dosage in a much larger number of animals. Field studies use the target population which, if applicable, includes diseased animals. Where disease and husbandry are similar between regions, international data may be used for field studies, as long as a minimum proportion of the data acceptable to the region is generated within the region where approval is being sought. Including a relatively large number of animals in the study improves the ability to detect relatively low frequency adverse events. Animals should be representative of the age range, class, breed, and sex for which the IVPP is intended. The study should be designed with an appropriate control group. In each study, health observations should be performed by appropriate masked (blinded) personnel before, during, and after treatment, with specific evaluation of potential adverse effects (e.g., physical examination and clinical pathology tests). The appropriate variables for evaluation may be based on results of pharmacodynamic studies in laboratory animals or studies in the target species. Adverse events should be reported and determination of causality for the adverse event attempted.
For some IVPP, laboratory and field safety data may not alone provide sufficient information to determine if an acceptable safety profile exists in relation to IVPP benefits. In these instances, risk assessment methodologies may provide a means to supplement or augment evaluation of target animal safety. Risk assessment uses the available body of evidence to weigh the severity of an adverse effect (harm) and the probability that it will occur.
Adverse Effect: Adverse event suspected to be related to IVPP.
Adverse Event: Any observation in animals that is unfavorable and unintended and occurs after the use of an IVPP, whether or not considered to be product related.
Baseline Data: Information collected after the acclimatization period and before the administration of the IVPP.
Breeding Animal: Any animal that is actively breeding, intended for breeding, or pregnant.
Class: Subset of target animal species which is characterized by factors such as reproductive status and/or use (dairy vs. beef, broiler vs. layer)
Control for Target Animal Safety Studies: Any substance used as a reference treatment for comparison with the IVPP under investigation.
Experimental Unit: The smallest, independent grouping of animals that could receive a different treatment during the study, given the methods of allocation and treatment administration.
Good Clinical Practices (GCP): A standard for the design, conduct, monitoring, recording, auditing, analysis, and reporting of clinical studies. Adherence to the standard provides assurance that the data and reported results are complete, correct and accurate, that the welfare of the study animals and the safety of the study personnel involved in the study are ensured, and that the environment and the human and animal food chains are protected.
Good Laboratory Practices (GLP): A standard for the design, conduct, monitoring, recording, auditing, analysis, and reporting of non-clinical studies. Adherence to the standard provides assurance that the data and reported results are complete, correct and accurate, that the welfare of the study animals and the safety of the study personnel involved in the study are ensured, and that the environment and the human and animal food chains are protected.
Investigational Veterinary Pharmaceutical Product (IVPP): Any pharmaceutical form of, or any animal feed containing one or more active substances being evaluated in a clinical or non-clinical study, to investigate any protective, therapeutic, diagnostic, or physiological effect when administered or applied to an animal.
Margin of Safety Study: Well-controlled study designed to show if an IVPP is safe for the intended species. It is generally conducted by treating healthy target animals with two or three non-zero multiples of the proposed dosage followed by clinical evaluation, clinical pathology, necropsy and histopathology of tissues to detect adverse effects.
Masking/Blinding: A procedure to reduce potential study bias in which designated study personnel are kept uninformed of the treatment assignment(s).
Phases of Reproduction: Follicular Phase (includes follicular development, follicular recruitment, follicular selection, follicular maturation, ovulation, and fertilization), Embryonic Phase (from conception through completion of organogenesis), Fetal Phase (from beginning of fetal activity, through development of allantoic sac and umbilical cord, ending with the first stage of parturition. Placentation and fetal gonad development are also included in this phase), Natal Phase (parturition) and Neonatal Phase (from birth through weaning).
Reference range (clinical pathology or blood chemistry): The range of usual values found in healthy animals of a given class.
Target Animal: The specific animal species, class, and breed identified as the animal for which the IVPP is intended for use.
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