• ICH Safety Guidance Documents (Toxicology)
• ICH Multi-Discipline Guidance Documents
• ICH Draft Safety and Multi-Discipline Guidance Documents
• ICH Quality Guidance Documents (Impurities)
• European Adopted Guidelines
• European Draft Guidelines
• FDA Guidance on INDs
• FDA Pharmacology/Toxicology Guidance
• FDA Pharmacology/Toxicology Draft Guidance
• EU Toxicity Test Methods

Links to ICH, FDA and EMEA / CPMP guidelines on nonclinical safety testing for pharmaceutical products.  Users of this page may also be interested in:

 Regulatory Safety Assessment Links and Spreadsheet Calculators.

This page was updated 21 November 2009

ICH Safety (Toxicology) Guidance Documents

• S1A The Need for Carcinogenicity Studies of Pharmaceuticals
• S1B Testing for Carcinogenicity of Pharmaceuticals
• S1C(R2) Guidance on Dose Selection for Carcinogenicity Studies of Pharmaceuticals
• S2A Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals
• S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals
• S3A Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies
• S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies
• S4A Duration of Chronic Toxicity Testing in Animals (Rodent and Nonrodent Toxicity Testing)
• S5(R2) Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility
• S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
• S7A Safety Pharmacology Studies for Human Pharmaceuticals
• S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals
• S8 Immunotoxicity Studies for Human Pharmaceuticals

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ICH Draft Safety and Multi-Discipline Guidance Documents

• S2(R1) Final Concept Paper, September 2006 (revision of S2A and S2B)
• S2(R1) DRAFT Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use
• Revision of S6 Guideline: S6(R1) Concept Paper, June 2008
• S9 DRAFT Nonclinical Evaluation for Anticancer Pharmaceuticals
• M3(R2) Final Concept Paper, September 2006 (revision of M3(R1))
• M3(R2) DRAFT Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals

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ICH Joint Safety/Efficacy Guidance Documents (Multidisciplinary)

• M3(R2): Guideline on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals
• M4: Common Technical Document for the Registration of Pharmaceuticals for Human Use
  • M4(R3): Organization of the CTD
  • M4S(R2) Safety -- The Nonclinical Sections (including appendices and table templates)
  • M4: The CTD - Safety Questions and Answers

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ICH Quality Guidance Documents (Impurities)

• Q3A(R2) Impurities in New Drug Substances
• Q3B(R2) Impurities in New Drug Products
• Q3C(R4) Impurities: Residual Solvents
  • Q3C Tables and list
  • Appendix 4: Toxicological data for Class 1 Solvents (Solvents to avoid)
  • Appendix 5: Toxicological data for Class 2 Solvents (Solvents limited by toxicity)
  • Appendix 6: Toxicological data for Class 3 Solvents (Low toxicity solvents)
  • Maintenance Procedures for Updating

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European Adopted Guidelines

• Pharmacokinetics and metabolic studies in the safety evaluation of new medicinal products in animals - [3BS11A] - Apr 1994
• Replacement of animal studies by in-vitro models - [CPMP/SWP/728/95] - Feb 1997
• Investigation of chiral active substances - [3CC29A] - Jun 1997
• Pre-clinical pharmacological and toxicological testing of vaccines - [CPMP/SWP/465/95] - Dec 1997
• Pre-clinical evaluation of anti- cancer medicinal products - [CPMP/SWP/997/96] - Jul 1998
• Repeated dose toxicity - [CPMP/SWP/1042/99] - Jul 2000
• Non-clinical local tolerance testing of medicinal products - [CPMP/SWP/2145/00] - Feb 2001
• Single dose toxicity - [3BS1A] - Apr 2001
• Points to consider on the Non-clinical assessment of the carcinogenic potential of human insulin analogues - [CPMP/SWP/372/01] - Nov 2001
• Points to consider on the Need for assessment of reproduction toxicity of human insulin analogues - [CPMP/SWP/2600/01] - Mar 2002
• Photosafety testing - [CPMP/SWP/398/01] - Jun 2002
• Carcinogenic potential - [CPMP/SWP/2877/00] - Jul 2002
• Position Paper on the non-clinical safety studies to support clinical trials with a single micro dose - [CPMP/SWP/2599/02] - Jun 2004
• CHMP SWP Conclusions and recommendations on the use of genetically modified animal models for carcinogenicity assessment - [CPMP/SWP/2592/02] - Rev 1 Jun 2004
• Reflection Paper on the assessment of the Genotoxic Potential of Antisense Oligodeoxynucleotides - [CHMP/SWP/199726/04] - Jan 2005
• Evaluation of Control Samples for Non - clinical Safety Studies: Checking for Contamination with the Test Substance - [CPMP/SWP/1094/04] - Mar 2005
• Non-Clinical Investigation of the Dependence Potential of Medicinal Products - [CHMP/SWP/94227/04] - Mar 2006
• Limits of genotoxic impurities - [CPMP/SWP/5199/02] - Jun 2006
• Strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products - [CHMP/SWP/28367/07] - Jul 2007
• Need for Non-Clinical Testing in Juvenile Animals on Human Pharmaceuticals for Paediatric Indications - [CHMP/SWP/169215/05] - Jan 2008
• Risk Assessment of Medicinal Products on Human Reproduction and Lactation: From Data to Labelling - [EMEA/CHMP/203927/05] - Jan 2008
• Specification Limits for Residues of Metal Catalysts - [CPMP/SWP/QWP/4446/00] - Jan 2008
• Guideline on Summary of Product Characteristics Rev. 2 Sept 2009
  

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European Draft Guidelines

• Non-Clinical Development of Fixed Combinations of Medicinal Products - [CHMP/SWP/258498/05] - Oct 2005
• Detection of Early signals of Drug-Induced Hepatotoxicity in Non-clinical Studies - [CHMP/SWP/150115/06] - Jun 2006
• Carcinogenicity Evaluation of Medicinal Products for the Treatment of HIV Infection - [EMEA/194898/2006] - Jul 2006
• Non-clinical studies required before first clinical use of gene therapy medicinal products - [EMEA/CHMP/GTWP/125459/2006] - March 2007
• Guideline on Repeated dose toxicity CHMP/SWP/488313/07 - Feb 2008

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FDA Investigational New Drug Applications

• Format and Content of the Nonclinical Pharmacology/Toxicology Section of an Application; Feb 1987
• Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs; Nov 1995
• Q&A - Content and Format of INDs for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products; Oct 2000
• Pharmacology/Toxicology Review Format; May 2001
• Exploratory IND Studies; Jan 2006

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FDA Pharmacology/Toxicology Guidance

• Single Dose Acute Toxicity Testing for Pharmaceuticals; 8/1996
• Reference Guide for the Nonclinical Toxicity Studies of Antivial Drugs Indicated for the Treatment of Non-Life Threatening Disease Evaluation of Drug Toxicity Prior to Phase I Clinical Studies; 3/2/1998
• Content and Format of INDs for Phase 1 Studies of Drugs,
  Including Well-Characterized, Therapeutic, Biotechnology-Derived Products; 10/2000
• Carcinogenicity Study Protocol Submissions; 5/22/2002
• Immunotoxicology Evaluation of Investigational New Drugs 10/2002
• Photosafety Testing; 5/7/2003
• Developing Medical Imaging Drug and Biological Products Part 1: Conducting Safety Assessments;6/17/2004
• Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients; 05/18/2005
• Nonclinical Pharmacology/Toxicology Development of Topical Drugs Intended to Prevent the Transmission of Sexually Transmitted Diseases (STD) and/or for the Development of Drugs Intended to Act as Vaginal Contraceptives; 7/2005
• Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers; 7/21/2005
• Recommended Approaches to Integration of Genetic Toxicology Study Results; 1/3/2006
• Exploratory IND Studies; 1/12/2006
• Nonclinical Safety Evaluation of Pediatric Drug Products; 2/14/2006
• Nonclinical Safety Evaluation of Drug or Biologic Combinations; 3/14/2006
• Safety Testing of Drug Metabolites; 2/14/2008

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FDA Draft Pharmacology/Toxicology Guidance

• Statistical Aspects of the Design, Analysis, and Interpretation of Chronic Rodent Carcinogenicity Studies of Pharmaceuticals; 5/2001
• Integration of Study Results to Assess Concerns about Human Reproductive and Developmental Toxicities; 11/2001
• Nonclinical Evaluation of Late Radiation Toxicity of Therapeutic Radiopharmaceuticals; 6/17/2005
• Nonclinical Safety Evaluation of Reformulated Drug Products and Products Intended for Administration by an Alternate Route; 3/7/2008
• Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches; 12/15/2008
• Animal Models — Essential Elements to Address Efficacy Under the Animal Rue; 1/16/2009

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Annex V to Directive 67/548/EEC
Methods for the Determination of Toxicity

• General Introduction
• B.1bis Acute Oral Toxicity - Fixed Dose Procedure
• B.1tris Acute Oral Toxicity - Acute Toxic Class Method
• B.2 Acute Toxicity (Inhalation)
• B.3 Acute Toxicity (Dermal)
• B.4 Acute Toxicity: Dermal Irritation/Corrosion
• B.5 Acute Toxicity: Eye Irritation/Corrosion
• B.6 Skin Sensitisation
• B.7 Repeated Dose (28 Days) Toxicity (Oral)
• B.8 Repeated Dose (28 Days) Toxicity (Inhalation)
• B.9 Repeated Dose (28 Days) Toxicity (Dermal)
• B.10 Mutagenicity - In Vitro Mammalian Chromosome Aberration Test)
• B.11 Mutagenicity - In Vivo Mammalian Bone-Marrow Chromosome Aberration Test
• B.12 Mutagenicity Mammalian Erythrocyte Micronucleus Test
• B.13/14 Mutagenicity - Reverse Mutation Test Using Bacteria
• B.15 Gene Mutation - Saccharomyces Cerevisae
• B.16 Mitotic Recombination - Saccharomyces Cerevisae
• B.17 Mutagenicity - In Vitro Mammalian Cell Gene Mutation Test
• B.18 DNA Damage And Repair - Unscheduled Dna Synthesis - Mammalian Cells In Vitro
• B.19 Sister Chromatid Exchange Assay In Vitro
• B.20 Sex-Linked Recessive Lethal Test In Drosophila Melanogaster
• B.21In Vitro Mammalian Cell Transformation Test
• B.22 Rodent Dominant Lethal Test
• B.23 Mammalian Spermatogonial Chromosome Aberration Test
• B.24 Mouse Spot Test
• B.25 Mouse Heritable Translocation
• B.26 Sub-Chronic Oral Toxicity Test. Repeated Dose 90 - Day Toxicity Study In Rodents
• B.27 Sub-Chronic Oral Toxicity Test: Repeated Dose 90 - Day Toxicity Study In Non-Rodents
• B.28 Sub-Chronic Dermal Toxicity Test: 90-Day Repeated Dermal Dose Study Using Rodent Species
• B.29 Sub-Chronic Inhalation Toxicity Test: 90-Day Repeated Inhalation Dose Study Using Rodent Species
• B.30 Chronic Toxicity Test
• B.31 Teratogenicity Test – Rodent And Non-Rodent
• B.32 Carcinogenicity Test
• B.33 Combined Chronic Toxicity/Carcinogenicity Test
• B.34 One-Generation Reproduction Toxicity Test
• B.35 Two Generation Reproduction Toxicity Test
• B.36 Toxicokinetics
• B.37 Delayed Neurotoxicity Of Organophosphorus Substances Following Acute Exposure
• B.38 Delayed Neurotoxicity Of Organophosphorus Substances 28 Day Repeated Dose Study
• B.39 Unscheduled DNA Synthesis (UDS) Test With Mammalian Liver Cells In Vivo
• B.40 Skin Corrosion (In Vitro)
• B.41 Phototoxicity - In Vitro 3T3 NRU Phototoxicity Test
• B.42 Skin Sensitisation: Local Lymph Node Assay
• B.43 Neurotoxicity Study In Rodents

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