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Guidance for Industry M4S: The CTD - Safety Appendices[PDF version of this document] U.S. Department of Health and Human Services ICH Appendices Additional copies are available from: Office of Training and Communications or Office of Communication, Training and August 2001 ICH APPENDIX A: EXAMPLES OF TABLES AND FIGURES FOR WRITTEN SUMMARIES The tables and figures in Appendix A are presented merely as examples. Applicants should provide tables and figures using a format appropriate to the product. Study references should be included in the table or text. Tables should include statistics, if appropriate. Table X: Binding of X and Its Major Metabolites and Comparators to Human X2 and X3 Receptors
Ki1 and Ki2 represent the high and low affinity binding sites, respectively (Data from Study Number). Figure X: Blood Pressure Following Chronic Dosing With X to SHRa Blood pressure following chronic dosing with X to SHRa[ref]. Hypotensive effect of saline i.v. infusion over 5 min (s) compared to X, 3 mg/kg i.v. infusion to SHR pretreated twice daily with saline, 1 mL/kg p.o., for 7 (m) or 14 (p) days or X, 25 mg/kg p.o., for 7 (l) or 14 (n) days. Saline pretreated statistical significances: p<0.05, all other points after challenge p<0.01. Values represent mean ± s.e.m. aSHR= spontaneous hypertensive rat (n=5 per group). Table X: Model Independent Pharmacokinetic Parameters for X in Mice Following Single Oral Doses at 2, 10 and 30 mg/kg [ref]
Table X: Excretion of Radioactive Material Following Single Doses of [14C]X to Male Mice [ref]
Table X: Concentrations of Radioactive Material in the Tissues of Male Rats After a Single Intravenous Dose of [14C]X at 1.75 mg/kg [refs]
Table X: Excretion of Radioactive Material Following Single Doses of [14C]X to Male Rats [refs]
Table X: Comparative Pharmacokinetic Data and Systemic Exposure to X Following Oral Administration to Mice, Rats, Dogs, and Patients [ref]
Data presented are for male and female animals and are after daily repeated oral administration (at the end of the 60-day mouse study, 14-day rat study, and 1-year dog study). Data for man are extrapolated from dose normalized data obtained in male and female patients following t.i.d regimen. $ - calculated from the total daily dose assuming a body weight of 50 kg for man. * - Numbers in parentheses represent ratios of exposure in animals to those in patients. Table X: Incidence of Proliferative Interstitial (Leydig) Cell Lesions in Rats [ref]
* Adenoma and/or Hyperplasia. APPENDIX B: THE NONCLINICAL TABULATED SUMMARIES TEMPLATES 2.6.3 Pharmacology 2.6.3.1 Pharmacology: Overview 2.6.3.2 Primary Pharmacodynamics* 2.6.3.3 Secondary Pharmacodynamics* 2.6.3.4 Safety Pharmacology 2.6.3.5 Pharmacodynamic Drug Interactions* 2.6.5 Pharmacokinetics 2.6.5.1 Pharmacokinetics: Overview 2.6.5.2 Analytical Methods and Validation Reports* 2.6.5.3 Pharmacokinetics: Absorption After a Single Dose 2.6.5.4 Pharmacokinetics: Absorption after Repeated Doses 2.6.5.5 Pharmacokinetics: Organ Distribution 2.6.5.6 Pharmacokinetics: Plasma Protein Binding 2.6.5.7 Pharmacokinetics: Study in Pregnant or Nursing Animals 2.6.5.8 Pharmacokinetics: Other Distribution Study 2.6.5.9 Pharmacokinetics: Metabolism In Vivo 2.6.5.10 Pharmacokinetics: Metabolism In Vitro 2.6.5.11 Pharmacokinetics: Possible Metabolic Pathways 2.6.5.12 Pharmacokinetics: Induction/Inhibition of Drug-Metabolizing Enzymes 2.6.5.13 Pharmacokinetics: Excretion 2.6.5.14 Pharmacokinetics: Excretion into Bile 2.6.5.15 Pharmacokinetics: Drug-Drug Interactions 2.6.5.16 Pharmacokinetics: Other 2.6.7 Toxicology 2.6.7.1 Toxicology: Overview 2.6.7.2 Toxicokinetics: Overview of Toxicokinetics Studies 2.6.7.3 Toxicokinetics: Overview of Toxicokinetics Data 2.6.7.4 Toxicology: Drug Substance 2.6.7.5 Single-Dose Toxicity 2.6.7.6 Repeat-Dose Toxicity: Nonpivotal Studies 2.6.7.7 Repeat-Dose Toxicity: Pivotal Studies 2.6.7.8 Genotoxicity: In Vitro 2.6.7.9 Genotoxicity: In Vivo 2.6.7.10 Carcinogenicity 2.6.7.11 Reproductive and Developmental Toxicity: Nonpivotal Studies 2.6.7.12Reproductive and Developmental Toxicity: Fertility and Early Embryonic Development to Implantation (Pivotal) 2.6.7.13Reproductive and Developmental Toxicity: Effects on Embryofetal Development (Pivotal) 2.6.7.14Reproductive and Developmental Toxicity: Effects on Pre- and Postnatal Development, Including Maternal Function (Pivotol) 2.6.7.15 Studies in Juvenile Animalsa (template not provided; see footnote a) 2.6.7.16 Local Tolerance 2.6.7.17 Other Toxicity Studies * : Tabulated summary is optional. It is preferable to include text tables and figures with the Nonclinical Written Summary. a : When a juvenile animal study has been conducted, it should be tabulated using the template appropriate for the type of study and located in Section 2.6.7.15. 2.6.3.1 Pharmacology Overview Test Article: (1)
Notes: (1) International Nonproprietary Name (INN) (2) There should be one line for each pharmacology report, in the same order as the CTD. Reports that contain a GLP Compliance Statement should be identified in a footnote. (3) The location of the Technical Report in the CTD should be indicated. (4) Or Report Number (on all tables). 2.6.3.4 Safety Pharmacology(1) Test Article: (2)
Notes: (1) All safety pharmacology studies should be summarized. (2) International Nonproprietary Name (INN). (3) Or Report Number (on all tables). a - Single dose unless specified otherwise. 2.6.5.1 Pharmacokinetics Overview Test Article: (1)
Notes: (1) International Nonproprietary Name (INN). (2) There should be one line for each pharmacokinetics report, in the same order as the CTD. Reports that contain a GLP Compliance Statement should be identified in a footnote. (3) The location of the Technical Report in the CTD should be indicated. 2.6.5.3 Pharmacokinetics: Absorption After a Single Dose Test Article: (1) Location in CTD: Vol. Page Study No.
2.6.5.4 Pharmacokinetics: Absorption after Repeated Doses Test Article: [Data can be tabulated as in the format of 2.6.5.3 if applicable.] Format A 2.6.5.5 Pharmacokinetics: Organ Distribution Test Article: Location in CTD: Vol. Page Study No.
Alternate Format B 2.6.5.5 Pharmacokinetics: Organ Distribution Test Article: Location in CTD: Vol. Page Study No.
1) [Tissue]/[Plasma] 2.6.5.6 Pharmacokinetics: Plasma Protein Binding Test Article:
2.6.5.7 Pharmacokinetics: Study in Pregnant or Nursing Animals (1) Test Article: (2) Location in CTD: Vol. Page Placental transfer Study No.
Location in CTD: Vol. Page Excretion into milk Study No.
Notes for Table 2.6.5.7 (1) Even if the data are obtained in reproduction toxicology studies, they should be presented in this table. (2) International Nonproprietary Name (INN). (3) The tissue sampled should be described (e.g., plasma for dams, fetal concentrations). 2.6.5.8 Pharmacokinetics: Other Distribution Study Test Article: 2.6.5.9 Pharmacokinetics: Metabolism In Vivo Test Article:
2.6.5.10 Pharmacokinetics: Metabolism In Vitro Test Article: Location in CTD: Vol. Page Study No.
2.6.5.11 Pharmacokinetics: Possible Metabolic Pathways Test Article: (Illustrate possible metabolic map indicating species in which metabolic reactions occur.)
2.6.5.12 Pharmacokinetics: Induction/Inhibition of Drug-Metabolizing Enzymes Test Article: Location in CTD: Vol. Page Study No. Note: Nonclinical studies only.
2.6.5.13 Pharmacokinetics: Excretion Test Article: (1)
2.6.5.14 Pharmacokinetics: Excretion into Bile Test Article: [Data can be tabulated as in the format of 2.6.5.13 if applicable.] 2.6.5.15 Pharmacokinetics: Drug-Drug Interactions Test Article: Location in CTD: Vol. Page Study No.
2.6.5.16 Pharmacokinetics: Other Test Article: Location in CTD: Vol. Page Study No.
2.6.7.1 Toxicology Overview Test Article: (1)
Notes: (1) International Nonproprietary Name (INN). (2) There should be one line for each toxicology report, in the same order as the CTD. (3) The location of the Technical Report in the CTD should be indicated. a - Unless otherwise specified. For Repeat-Dose Toxicity, the highest No Observed Adverse Effect Level (NOAEL) is underlined. 2.6.7.2 Toxicokinetics Overview of Toxicokinetics Studies Test Article: (1)
Notes: (1) International Nonproprietary Name (INN). (2) There should be one line for each toxicokinetics report, in the same order as the CTD (Section 3, Toxicology). (3) The location of the Technical Report in the CTD should be indicated. 2.6.7.3 Toxicokinetics Overview of Toxicokinetics Data Test Article: (1) (2) Notes: (1) International Nonproprietary Name (INN). (2) A one- to three-page summary (tables and/or figures) of steady state toxicokinetic data should be prepared in a format that facilitates comparisons across species, including humans. 2.6.7.4 Toxicology Drug Substance Test Article: (1)
Notes: (1) International Nonproprietary Name (INN). (2) All batches used in the Toxicology studies should be listed in approximate chronological order. (3) The Toxicology studies in which each batch was used should be identified. 2.6.7.5 Single-Dose Toxicity (1) Test Article: (2)
Notes: (1) All single-dose toxicity studies should be summarized, in the same order as the CTD. Footnotes should be used to indicate special features, such as unusual duration, infusion rate, or age of test subjects. (2) International Nonproprietary Name (INN). 2.6.7.6 Repeat-Dose Toxicity Nonpivotal Studies (1) Test Article: (2)
Notes: (1) All repeat-dose toxicity studies (including all range-finding toxicity studies), other than the definitive GLP studies specified by ICH Guidance M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmacaeuticals (November 1997), should be summarized in the same order as the CTD. Footnotes should be used to indicate special features, such as unusual age of test subjects. (2) International Nonproprietary Name (INN). ________ a - No Observed Adverse Effect Level. 2.6.7.7 (1) Repeat-Dose Toxicity (2) Report Title: Test Article: (3) Species/Strain: Duration of Dosing: Study No. Initial Age: Duration of Postdose: Location in CTD: Vol. Page Date of First Dose: Method of Administration: Vehicle/Formulation: GLP Compliance: Special Features: No Observed Adverse Effect Level:
- No noteworthy findings. + Mild ++ Moderate +++ Marked (6) (7) * - p<0.05 ** - p<0.01 a - At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). (Continued) 2.6.7.7 (1) Repeat-Dose Toxicity Study No. (Continued)
- No noteworthy findings. (7) * - p<0.05 ** - p<0.01 a - Both absolute and relative weights differed from controls in the direction indicated. Number indicates percent difference for the absolute organ weights. Notes for Table 2.6.7.7 (1) The tables should be numbered consecutively (e.g., 2.6.7.7A, 2.6.7.7B, 2.6.7.7C). (2) There should be one table for each of the repeat-dose toxicity studies specified by ICH Guidance M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmacaeuticals (November 1997), as well as any other repeat-dose toxicity studies that could be considered pivotal. (3) International Nonproprietary Name (INN). (4) Steady state AUC, Cmax, Css, or other toxicokinetic information supporting the study. If from a separate study, the study number should be given in a footnote. (5) ONLY NOTEWORTHY FINDINGS SHOULD BE PRESENTED. If additional parameters (other than those in the template) showed noteworthy changes, these should be added to the tables. In general, data at end of dosing period can be shown; however, if there were additional noteworthy findings at earlier timepoints, these should be included. Footnotes should be used as needed to provide additional information about the tests or the results. (6) Or other scale, as appropriate. (7) Methods of statistical analyses should be indicated. (8) All parameters that still show drug-related changes should be listed. This section should be deleted if the study does not include a postdose evaluation. (9) When appropriate, information on animals that were necropsied early should be presented separately. 2.6.7.8 (1) Genotoxicity: In Vitro Report Title: Test Article: (2) Test for Induction of: No. of Independent Assays: Study No. Strains: No. of Replicate Cultures: Location in CTD: Vol. Page Metabolizing System: No. of Cells Analyzed/Culture: Vehicles: For Test Article: For Positive Controls: GLP Compliance: Treatment: Date of Treatment: Cytotoxic Effects: Genotoxic Effects:
Notes: (1) The tables should be numbered consecutively (e.g.,2.6.7.8A, 2.6.7.8B). Results of replicate assays should be shown on subsequent pages. (2) International Nonproprietary Name (INN). (3) Units should be inserted. (4) If precipitation is observed, this should be indicated in a footnote. (5) Methods of statistical analyses should be indicated. (5) * - p<0.05 ** - p<0.01 2.6.7.9 (1) Genotoxicity: In Vivo Report Title: Test Article: (2) Test for Induction of: Treatment Schedule: Study No. Species/Strain: Sampling Time: Location in CTD: Vol. Page Age: Method of Administration: Cells Evaluated: Vehicle/Formulation: GLP Compliance: No. of Cells Analyzed/Animal: Date of Dosing: Special Features: Toxic/Cytotoxic Effects: Genotoxic Effects: Evidence of Exposure:
Notes: (1) The tables should be numbered consecutively (e.g.,2.6.7.9A, 2.6.7.9B). (2) International Nonproprietary Name (INN). (3) Methods of statistical analysis should be indicated. (3) * - p<0.05 ** - p<0.01). 2.6.7.10 (1) Carcinogenicity Report Title: Test Article: (2) Species/Strain: Duration of Dosing: Study No. Initial Age: Method of Administration: Location in CTD: Vol. Page Date of First Dose: Vehicle/Formulation: Treatment of Controls: GLP Compliance: Basis for High-Dose Selection: (3) Special Features:
(6) * - p<0.05 ** - p<0.01 a - At 6 months. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). (Continued) 2.6.7.10 (1) Carcinogenicity Study No. (Continued)
- No noteworthy findings. * - p<0.05 ** - p<0.01 Notes for Table 2.6.7.10 (1) Tables should be numbered consecutively (e.g., 2.6.7.10A, 2.6.7.10B). There should be one table for each carcinogenicity study. (2) International Nonproprietary Name (INN). (3) From ICH Guidance S1C Dose Selection for Carcinogenicity Studies of Pharmaceuticals (March 1995). (4) Steady state AUC, Cmax, Css, or other toxicokinetic information supporting the study. If the information is from a separate study, the Study Number should be given in a footnote. (5) If additional parameters showed drug-related changes, these should be added to the tables. Footnotes should be used as needed to provide additional information about the tests or the results. (6) Methods of statistical analysis should be indicated. (7) Drug-related lesions should be listed first. Then other lesions should be listed by alphabetically ordered organs and/or tissues. 2.6.7.11 Reproductive and Developmental Toxicity Nonpivotal Studies (1) Test Article: (2)
Notes: (1) All reproduction toxicity studies (including all relevant range-finding studies), other than the definitive GLP studies specified by M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, November 1997, should be summarized in the same order as the CTD. However, investigative studies should be summarized using a more detailed template. (2) International Nonproprietary Name (INN). 2.6.7.12 (1) Reproductive and Developmental Toxicity - Report Title: Test Article: (2) Fertility and Early Embryonic Development to Implantation (3) Design similar to ICH 4.1.1? Duration of Dosing:M: Study No. Species/Strain: Day of Mating: (8)F: Location in CTD: Vol. Page Initial Age: Day of C-Section: Date of First Dose: Method of Administration: GLP Compliance: Special Features: Vehicle/Formulation: No Observed Adverse Effect Level: F0 Males: F0 Females: F1 Litters:
-No noteworthy findings. + Mild ++Moderate +++Marked (6) (7) *- p<0.05 ** - p<0.01 a - After 4 weeks of dosing. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). (Continued) 2.6.7.12 (1) Reproductive and Developmental Toxicity Study No. (Continued)
-No noteworthy findings. + Mild ++Moderate +++Marked (6) (7)* - p<0.05 ** - p<0.01 a - At end of premating or gestation period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). Notes for Tables 2.6.7.12, 2.6.7.13, and 2.6.7.14 (1) If there are multiple studies of this type, the tables should be numbered consecutively (e.g., 2.6.7.12A, 2.6.7.12B, 2.6.7.13A, 2.6.7.13B). (2) International Nonproprietary Name (INN). (3) If a modified study design is used, tables should be modified accordingly. (4) Steady state AUC, Cmax, or other toxicokinetic information supporting the study. If the information is from a separate study, the study number should be given in a footnote. (5) POSSIBLE PRESENTATIONS OF THE RESULTS ARE SHOWN IN THESE TEMPLATES. DATA PRESENTATION SHOULD BE FLEXIBLE AND APPROPRIATE ACCORDING TO OPTIMAL STATISTICAL ANALYSIS AND THE DESIGN OF THE STUDY. If additional parameters showed drug-related changes, these should be added to the tables. Footnotes should be used as needed to provide additional information about the tests or the results. (6) Or other scale as appropriate. (7) Methods of statistical analysis should be indicated. (8) Day of mating should be indicated (e.g., Day 0 or Day 1). 2.6.7.13 (1) Reproductive and Developmental Toxicity - Report Title: Test Article: (2) Effects on Embryofetal Development (3) Design similar to ICH 4.1.3? Duration of Dosing: Study No. Day of Mating: (8) Species/Strain: Day of C-Section: Location in CTD: Vol. Page Initial Age: Method of Administration: Date of First Dose: Vehicle/Formulation: GLP Compliance: Special Features: No Observed Adverse Effect Level: F0 Females: F1 Litters:
- No noteworthy findings. + Mild ++Moderate +++Marked (6) G = Gestation day (7) * - p<0.05 ** - p<0.01 a- At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). (Continued) 2.6.7.13 (1) Reproductive and Developmental Toxicity Study No. (Continued)
- No noteworthy findings. * - p<0.05 ** - p<0.01 2.6.7.14 (1) Reproductive and Developmental Toxicity - Report Title: Test Article: (2) Effects on Pre- and Postnatal Development, Including Maternal Function (3) Design similar to ICH 4.1.2? Duration of Dosing: Study No. Day of Mating: (8) Species/Strain: Method of Administration: Location in CTD: Vol. Page Initial Age Vehicle/Formulation: Date of First Dose: Litters Culled/Not Culled: GLP Compliance: Special Features: No Observed Adverse Effect Level: F0 Females: F1 Males: F1 Females:
- No noteworthy findings. + Mild ++Moderate +++Marked (6) G = Gestation day L = Lactation day (7) * - p<0.05 ** - p<0.01) a - At end of gestation or lactation. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). (Continued) 2.6.7.14 (1) Reproductive and Developmental Toxicity Study No. (Continued)
- No noteworthy findings. + Mild ++Moderate +++Marked (6) (7)* - p<0.05 ** - p<0.01 a - From birth to weaning. b - From weaning to mating. c - At end of postweaning period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). 2.6.7.14 (1) Reproductive and Developmental Toxicity Study No. (Continued)
- No noteworthy findings. + Mild ++Moderate +++Marked (6) (7)* - p<0.05 ** - p<0.01 a - From weaning to mating b - At end of premating or gestation period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). 2.6.7.14 (1) Reproductive and Developmental Toxicity Study No. (Continued)
- No noteworthy findings. + Mild ++Moderate +++Marked (6) (7)* - p<0.05 ** - p<0.01 a - From birth to mating. b - At end of premating or gestation period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). 2.6.7.16 Local Tolerance (1) Test Article: (2)
Notes: (1) All local tolerance studies should be summarized. (2) International Nonproprietary Name (INN). 2.6.7.17 Other Toxicity Studies (1) Test Article: (2)
Notes: (1) All supplementary toxicity studies should be summarized. (2) International Nonproprietary Name (INN) APPENDIX C: THE NONCLINICAL TABULALTED SUMMARIES - EXAMPLES (The following examples correspond to the templates in Appendix B; examples are not provided for the templates Studies in Juvenile Animals or Local Tolerance) EXAMPLE 2.6.3.1 Pharmacology Overview Test Article: Curitol Sodium
a - Report contains a GLP Compliance Statement. EXAMPLE 2.6.3.4 Safety Pharmacology Test Article: Curitol Sodium
a - Single dose unless specified otherwise. EXAMPLE 2.6.5.1 Pharmacokinetics Overview Test Article: Curitol Sodium
a - Report contains a GLP Compliance Statement. EXAMPLE 2.6.5.3 Pharmacokinetics: Absorption After a Single Dose Test Article: Curitol Sodium Location in CTD Volume 1, Page 258 Study number 95104
EXAMPLE Format A 2.6.5.5 Pharmacokinetics: Organ Distribution Test Article: Curitol Sodium Location in CTD: Vol.21 Page 1 Study No. 95207
EXAMPLE Alternate Format B 2.6.5.5 Pharmacokinetics: Organ Distribution Test Article: Curitol Sodium Location in CTD: Vol. 21 Page 1 Study No. 95207
1) [Tissue]/[Plasma] EXAMPLE 2.6.5.6 Pharmacokinetics: Plasma Protein Binding Test Article: Curitol Sodium
2.6.5.7 Pharmacokinetics: Study in Pregnant or Nursing Animals Test Article: Curitol Sodium EXAMPLE Location in CTD: Vol. 22 Page 1 Placental transfer Study No. 95702
Location in CTD: Vol. 22 Page 102 Excretion into milk Study No. 95703
EXAMPLE 2.6.5.9 Pharmacokinetics: Metabolism In Vivo Test Article: Curitol Sodium Gender (M/F)/Number of animals: Rats: 4M Dogs: 3F Humans: 8M Feeding condition: Fed Vehicle/Formulation: Rats: Solution/water Dogs: Capsules Humans: 75 mg tablets Method of Administration: Rats: Gavage* Dogs: Oral Capsule* Humans: Oral Tablet Dose (mg/kg): Rats: 5 mg/kg Dogs: 5 mg/kg Humans: 75 mg Radionuclide: 14C Specific Activity: 2 x 105 Bq/mg
2.6.5.13 Pharmacokinetics: Excretion Test Article: Curitol Sodium EXAMPLE
2.6.5.14 Pharmacokinetics: Excretion into Bile Test Article: Curitol Sodium EXAMPLE
a - Total radioactivity; percent recovery, 14C 2.6.7.1 Toxicology Overview Test Article: Curitol Sodium EXAMPLE
a - Unless otherwise specified. For Single-Dose Toxicity and Repeat-Dose Toxicity, the highest No Observed Adverse Effect Level (NOAEL) is underlined. (Continued) EXAMPLE 2.6.7.1 Toxicology Overview (Continued) Test Article: Curitol Sodium
________ a - Males: 4 weeks prior to mating. Females - 2 weeks prior to mating through Gestation Day 7. b - G = Gestation Day L = Lactation Day EXAMPLE 2.6.7.2 Toxicokinetics Overview of Toxicokinetics Studies Test Article: Curitol Sodium
EXAMPLE 2.6.7.3 Toxicokinetics Overview of Toxicokinetics Data Test Article: Curitol Sodium Steady State AUC (mcg-hr/ml)
__________ a - In diet. b - By gavage. c - In capsules. Males and females combined. d - Six-month toxicity study. e - Carcinogenicity study. f - Protocol 147-007. EXAMPLE 2.6.7.3 Toxicokinetics Overview of Toxicokinetics Data Test Article : Curitol Sodium AUC24hr (ug x hr/ml) Steady state AUC24hr values of unchanged MM-180801 in humans after repeated oral administration of 1, 2.5, and 5 mg OD, in comparison with those in mice in the carcinogenicity study, rats in the 6-month toxicity study, and dogs in the 9-month toxicity study. EXAMPLE 2.6.7.4 Toxicology Drug Substance Test Article: Curitol Sodium
a - Area percent. EXAMPLE 2.6.7.5 Single-Dose Toxicity Test Article: Curitol Sodium
EXAMPLE 2.6.7.6 Repeat-Dose Toxicity Nonpivotal Studies Test Article: Curitol Sodium
________ a - No Observed Adverse Effect Level. EXAMPLE #1 2.6.7.7A Repeat-Dose Toxicity Report Title: MM-180801: Three--Month Oral Toxicity Study in Rats Test Article: Curitol Sodium Species/Strain: Wistar Rats Duration of Dosing: 3 Months Study No. 94214 Initial Age: 5 Weeks Duration of Postdose: 1 Month Location in CTD: Vol. 4 Page 1 Date of First Dose: 15 Jan 94 Method of Administration: Gavage Vehicle/Formulation: Aqueous Solution GLP Compliance: Yes Special Features: None No Observed Adverse Effect Level: 200 mg/kg
- No noteworthy findings. + Mild ++ Moderate +++ Marked Dunnett's Test: *- p<0.05 ** - p<0.01 a - At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). (Continued) EXAMPLE #1 2.6.7.7A Repeat-Dose Toxicity Study No. 94214 (Continued)
- No noteworthy findings. Dunnett's Test: *- p<0.05 **- p<0.01 (Continued) EXAMPLE #1 2.6.7.7A Repeat-Dose Toxicity Study No. 94214 (Continued)
- No noteworthy findings. Dunnett's Test: * - p<0.05 **- p<0.01 a - At end of postdose recovery period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). b - Both absolute and relative weights differed from controls in the direction indicated. Number indicates percent difference for the absolute organ weights. EXAMPLE #2 2.6.7.7B Repeat-Dose Toxicity Report Title: MM-180801: One-Month Oral Toxicity Study in Dogs Test Article: Curitol Sodium Species/Strain: Beagle Dogs Duration of Dosing: 1 Month Study No. 94020 Initial Age: 5-6 Months Duration of Postdose: None Location in CTD: Vol. 6 Page 1 Date of First Dose: 2 Feb 94 Method of Administration: Oral Vehicle/Formulation: Gelatin Capsules GLP Compliance: Yes Special Features: Hepatic enzyme induction evaluated at termination. No Observed Adverse Effect Level: 10 mg/kg
- No noteworthy findings. + Mild ++ Moderate +++ Marked Dunnett's Test: * - p<0.05 ** - p<0.01 a - At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). (Continued) EXAMPLE #2 2.6.7.7B Repeat-Dose Toxicity Study No. 94020 (Continued)
- No noteworthy findings. Dunnett's Test: * - p<0.05 ** - p<0.01 a - Both absolute and relative weights differed from controls in the direction indicated. Number indicates percent difference for the absolute organ weights. EXAMPLE #1 2.6.7.8A Genotoxicity: In Vitro Report Title: MM-180801: Ames Reverse Mutation Study in Test Article: Curitol Sodium Salmonella and E. Coli Test for Induction of: Reverse mutation in bacterial cells No. of Independent Assays: 2 Study No. 96669 Strains: S. typhimurium and E. coli No. of Replicate Cultures: 3 Location in CTD: Vol. 10 Page211 Metabolizing System: Aroclor-induced rat liver S9, 7.1% No. of Cells Analyzed/Culture: - Vehicles: Test Article: DMSO Positive Controls: DMSO GLP Compliance: Yes Treatment: Plate incorporation for 48 hr. Date of Treatment: Feb. 1996 Cytotoxic Effects: None. Genotoxic Effects: None.
a - Precipitation. EXAMPLE #2 2.6.7.8B Genotoxicity: In Vitro Report Title: MM-180801: Cytogenetics Study in Primary Test Article: Curitol Sodium Human Lymphocytes Test for Induction of: Chromosome aberrations No. of Independent Assays: 1 Study No. 96668 Strains: Primary human lymphocytes No. of Replicate Cultures: 2 Location in CTD: Vol. 10 Page245 Metabolizing System: Aroclor-induced rat liver S9, 5% No. of Cells Analyzed/Culture: 100 Vehicles: Test Article: DMSO Positive Controls: DMSO GLP Compliance: Yes Treatment: Continuous treatment for 24 hrs. without S9; pulse treatment 5 hrs. Date of Treatment: Aug. 1996 and recovery time 24 hrs. with and without S9. Cytotoxic Effects: Dose-related decreases in mitotic indices. Genotoxic Effects: Chromosome aberrations without S9 at 10 and 20 µg/ml, and with S9 at 50 and 200 µg/ml.
Dunnett's Test: * - p<0.05 ** - p<0.01 a - Based on mitotic indices. EXAMPLE #1 2.6.7.9A Genotoxicity: In Vivo Report Title: MM-180801: Oral Micronucleus Study in Rats Test Article: Curitol Solution Test for Induction of: Bone marrow micronuclei Treatment Schedule: Three daily doses. Study No: 96683 Species/Strain: Wistar Rats Sampling Time: 24 hrs. after last dose. Location in CTD: Vol. 10 Page502 Age: 5 Weeks Method of Administration: Gavage. Cells Evaluated: Polychromatic erythrocytes Vehicle/Formulation: Aqueous solution. GLP Compliance: Yes No. of Cells Analyzed/Animal: 2000 Date of Dosing: July 1996 Special Features: None. Toxic/Cytotoxic Effects: At 2000 mg/kg, clinical signs, two deaths, and decreases in bone marrow PCEs. Genotoxic Effects: None. Evidence of Exposure: Overt toxicity at 2000 mg/kg.
Dunnett's Test: * - p<0.05 ** - p<0.01 EXAMPLE #2 2.6.7.9B Genotoxicity: In Vivo Report Title: MM-180801: Oral DNA Repair Study in Rats Test Article: Curitol Solution Test for Induction of: Unscheduled DNA synthesis Treatment Schedule: Single dose. Study No: 51970 Species/Strain: Wistar Rats Sampling Time: 2 and 16 hr. Location in CTD: Vol. 11 Page 2 Age: 5 Weeks Method of Administration: Gavage. Cells Evaluated: Hepatocytes. Vehicle/Formulation: Aqueous solution. GLP Compliance: Yes No. of Cells Analyzed/Animal: 100 Date of Dosing: Jan. 1997 Special Features: None. Toxic/Cytotoxic Effects: None. Genotoxic Effects: None. Evidence of Exposure: Toxicokinetics - See Study No. 94007, Two-Week Oral Toxicity Study in Rats.
Nuclear = Nuclear grain count; the number of grains over the nucleus. Cytoplasm = Cytoplasmic grain count; the highest grain count from 2 nuclear-sized areas adjacent to the nucleus. NG = Net grains/nucleus; the nuclear count minus the cytoplasmic count. % IR = Percentage of cells with at least 5 NG. NGIR = Average net grains/nucleus of cells in repair. EXAMPLE 2.6.7.10 Carcinogenicity Report Title: MM-180801: Dietary Carcinogenicity Study in Mice Test Article: Curitol Sodium Species/Strain: CD-1 Mice Duration of Dosing: 21 months Study No. 95012 Initial Age: 6 Weeks Method of Administration: Diet Location in CTD: Vol. 4 Page 1 Date of First Dose: 20 Sep 95 Vehicle/Formulation: In Diet Treatment of Controls: Drug-Free Diet GLP Compliance: Yes Basis for High-Dose Selection: Toxicity-based endpoint. Special Features: 12 additional males and 12 additional females per drug-treated group bled at 6 months for toxicokinetic monitoring and then removed from the study.
Dunnett's Test: * - p<0.05 ** - p<0.01 a - From Study No. 95013. b - At 6 months. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences) c - One missing mouse could not be evaluated. (Continued) EXAMPLE 2.6.7.10 Carcinogenicity Study No. 95012 (Continued)
a - Trend analysis, p<0.005 b - Trend analysis, p<0.025 (Continued) EXAMPLE 2.6.7.10 Carcinogenicity Study No. 95012 (Continued)
- No noteworthy findings. Fisher Exact Test: * - p<0.05 ** - p<0.01 EXAMPLE 2.6.7.11 Reproductive and Developmental Toxicity Nonpivotal Studies Test Article: Curitol Sodium
G - Gestation day EXAMPLE 2.6.7.12 Reproductive and Developmental Toxicity Report Title: MM-180801: Oral Study of Effects on Fertility Test Article: Curitol Sodium Fertility and Early Embryonic and Early Embryonic Development in Rats Development to Implantation Design similar to ICH 4.1.1? Yes Duration of Dosing: M: 4 weeks prior to mating Study No. 97072 Species/Strain: Wistar Rats F: 2 weeks prior to mating, Location in CTD: Vol. 6 Page 1 Initial Age: 10 Weeks through day 7 of gestation Day of Mating: Day 0 Date of First Dose: 3 Mar 97 Day of C-Section: Day 16 of gestation GLP Compliance: Yes Special Features: None Method of Administration: Gavage No Observed Adverse Effect Level: Vehicle/Formulation: Aqueous solution. F0 Males: 100 mg/kg F0 Females: 100 mg/kg F1 Litters: 1000 mg/kg
- No noteworthy findings. + Mild ++Moderate +++Marked Dunnett's Test * - p<0.05 ** - p<0.01 a -After 4 weeks of dosing. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). b -From Study No. 94220. (Continued) EXAMPLE 2.6.7.12 Reproductive and Developmental Toxicity Study No. 97072 (Continued)
- No noteworthy findings. + Mild ++Moderate +++Marked Dunnett's Test * - p<0.05 ** - p<0.01 a - At end of premating or gestation period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). b - From Study No. 94220. EXAMPLE 2.6.7.13 Reproductive and Developmental Toxicity - Report Title: MM-180801: Oral Study of Effects on Test Article: Curitol Sodium Effects on Embryofetal Embryofetal Development in Rabbits Development Design similar to ICH 4.1.3? Yes Duration of Dosing: G6-G18 Study No. 97028 Day of Mating: Day 0 Species/Strain: NZW Rabbits Day of C-Section: G29 Location in CTD: Vol. 6 Page 200 Initial Age: 5 months Method of Administration: Gavage Date of First Dose: 7 Aug 97 Vehicle/Formulation: Aqueous Solution GLP Compliance: Yes Special Features: None. No Observed Adverse Effect Level: F0 Females: 1 mg/kg F1 Litters: 5 mg/kg
- No noteworthy findings. + Mild ++Moderate +++Marked G = Gestation day Dunnett's Test * - p<0.05 ** - p<0.01 a - At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). b - From Study No. 97231. (Continued) EXAMPLE 2.6.7.13 Reproductive and Developmental Toxicity Study No. 97028 (Continued)
- No noteworthy findings. Fisher Exact Test * - p<0.05 ** - p<0.01 EXAMPLE 2.6.7.14 Reproductive and Developmental Toxicity - Report Title: MM-180801: Oral Study of Effects on Test Article: Curitol Sodium Effects on Pre- and Postnatal Pre- and Postnatal Development in Rats Development, Including Maternal Function Design similar to ICH 4.1.2? Yes Duration of Dosing: G6 - L21 Study No. 95201 Day of Mating: Day 0 Species/Strain: Wistar Rats Method of Administration: Gavage Location in CTD: Vol. 10 Page 1 Initial Age: 9-10 Weeks Vehicle/Formulation: Water Date of First Dose: 8 Oct 95 Litters Culled/Not Culled: Culled to 4/sex/litter GLP Compliance: Yes Special Features: None No Observed AdverseEffect Level: F0 Females: 7.5 mg/kg F1 Males: 75 mg/kg F1 Females: 75 mg/kg
- No noteworthy findings. + Mild ++Moderate +++Marked G = Gestation day Dunnett's Test * - p<0.05 ** - p<0.01 L = Lactation day Kruskal-Wallis with Dunn's procedure + - p<0.05 a -At end of gestation or lactation. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). b -From Study No. 97227 (Continued) EXAMPLE 2.6.7.14 Reproductive and Developmental Toxicity Study No. 95201 (Continued)
- No noteworthy findings. + Mild ++Moderate +++Marked Dunnett's Test * - p<0.05 ** - p<0.01 Kruskal-Wallis with Dunn's procedure + - p<0.05 ++ - p<0.01 a - From birth to weaning. b - From weaning to mating. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences) (Continued) EXAMPLE 2.6.7.14 Reproductive and Developmental Toxicity Study No. 95201 (Continued)
-No noteworthy findings. + Mild ++Moderate +++Marked Dunnett's Test * - p<0.05 ** - p<0.01 a - From weaning to mating. b - During postweaning period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical significance is based on actual data (not on the percent differences). EXAMPLE 2.6.7.17 Other Toxicity Studies Test Article: Curitol Sodium
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