S5(R3) DETECTION OF TOXICITY TO REPRODUCTION FOR HUMAN PHARMACEUTICALS This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page. For questions regarding this draft document, contact (CDER) Abigail Jacobs 301-796-0174. 1 2 INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL 3 REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE 4 5 6 DRAFT ICH HARMONISED GUIDELINE 7 8 DETECTION OF TOXICITY TO REPRODUCTION FOR HUMAN 9 PHARMACEUTICALS 10 S5(R3) 11 12 13 Current Step 1 draft version 14 dated 5 July 2017 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the 30 appropriate ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory 31 authorities of the ICH regions for internal and external consultation, according to national 32 or regional procedures. 33 TABLE OF CONTENTS 34 1 SCOPE OF THE GUIDELINE ......................................................................................4 35 2 INTRODUCTION & GENERAL PRINCIPLES .........................................................4 36 3 STRATEGIES FOR REPRODUCTIVE TOXICITY ASSESSMENT ......................3 37 3.1 CONSIDERATIONS/PRINCIPLES ....................................................................3 38 3.1.1 TARGET PATIENT POPULATION/ THERAPEUTIC INDICATION 39 CONSIDERATIONS .....................................................................................4 40 3.1.2 PHARMACOLOGY CONSIDERATIONS ..................................................4 41 3.1.3 TOXICITY CONSIDERATIONS .................................................................4 42 3.1.4 TIMING CONSIDERATIONS .....................................................................4 43 3.1.5 OTHER CONSIDERATIONS FOR REPRODUCTIVE TOXICITY 44 STUDIES .......................................................................................................5 45 3.2 STRATEGY TO ADDRESS FERTILITY AND EARLY EMBRYONIC 46 DEVELOPMENT ..................................................................................................5 47 3.3 STRATEGIES TO ADDRESS EMBRYO FETAL DEVELOPMENT (EFD) 6 48 3.3.1 ROUTINE APPROACH FOR ADDRESSING EFD RISK ..........................6 49 3.3.2 OPTIONAL APPROACHES FOR ADDRESSING EFD RISK ...................8 50 3.3.2.1 Use of Alternative Assays ....................................................................8 51 3.3.2.2 In vitro and Non-mammalian Exposure Information .........................10 52 3.3.3 POTENTIAL APPROACHES TO DEFER IN VIVO TESTING AS PART 53 OF AN INTEGRATED TESTING STRATEGY ........................................10 54 3.4 STRATEGY TO ADDRESS EFFECTS ON PPND .........................................11 55 3.5 TOXICOKINETICS (TK) ..................................................................................11 56 4 TEST SYSTEM SELECTION .....................................................................................11 57 4.1 ROUTINE TEST SPECIES ................................................................................11 58 4.1.1 RAT AS THE PRIMARY SPECIES FOR REPRODUCTIVE TOXICITY 59 TESTING .....................................................................................................12 60 4.1.2 RABBIT AS THE SECONDARY SPECIES FOR EFD STUDIES ...........12 61 4.1.3 SPECIES SELECTION FOR PREVENTATIVE AND THERAPEUTIC 62 VACCINES..................................................................................................12 63 4.2 NON-ROUTINE TEST SPECIES ......................................................................13 64 4.3 OTHER TEST SYSTEMS ..................................................................................14 65 4.3.1 USE OF DISEASE MODELS .....................................................................14 66 4.3.2 USE OF GENETICALLY MODIFIED MODELS AND USE OF 67 SURROGATE MOLECULES.....................................................................14 68 5 DOSE LEVEL SELECTION, ROUTE OF ADMINISTRATION AND 69 SCHEDULE....................................................................................................................15 70 5.1 DOSE SELECTION COMMON TO ALL PHARMACEUTICALS, 71 INCLUDING BIOTECHNOLOGY-DERIVED PHARMACEUTICALS .....16 2 72 5.1.1 TOXICITY–BASED ENDPOINTS ............................................................16 73 5.1.2 ABSORPTION, DISTRIBUTION, METABOLISM AND EXCRETION 74 (ADME)-BASED SATURATION OF SYSTEMIC EXPOSURE 75 ENDPOINT..................................................................................................16 76 5.1.3 EXPOSURE-BASED ENDPOINT .............................................................17 77 5.1.3.1 Considerations for Total vs. Fraction Unbound Pharmaceutical 78 Exposure ............................................................................................17 79 5.1.3.2 Exposure-based Approach for Highly Targeted Therapeutics ...........18 80 5.1.4 MAXIMUM FEASIBLE DOSE (MFD) ENDPOINT ................................18 81 5.1.5 LIMIT DOSE ENDPOINT ..........................................................................19 82 5.1.6 SELECTION OF LOWER DOSE LEVELS ...............................................19 83 5.2 DOSE SELECTION AND STUDY DESIGNS FOR VACCINES ..................19 84 6 DESIGN AND EVALUATION OF IN VIVO MAMMALIAN STUDIES .................20 85 6.1 THREE SEPARATE STUDIES TO ASSESS ALL STAGES (A F) .............20 86 6.2 SINGLE STUDY DESIGN..................................................................................20 87 6.3 TWO STUDY DESIGN .......................................................................................21 88 6.4 COMBINATION DESIGN OF REPEAT-DOSE AND FERTILITY 89 STUDIES ..............................................................................................................21 90 6.5 EVALUATION OF DATA..................................................................................22 91 6.5.1 DATA HANDLING/DATA PRESENTATION/STATISTICS FOR IN 92 VIVO STUDIES ..........................................................................................22 93 6.5.2 STATISTICS ...............................................................................................23 94 7 PRINCIPLES OF RISK ASSESSMENT.....................................................................23 95 7.1 RISK ASSESSMENT FOR REPRODUCTIVE AND DEVELOPMENTAL 96 TOXICITIES ........................................................................................................24 97 7.2 RISK ASSESSMENT FOR LACTATION ........................................................25 98 8 ENDNOTES....................................................................................................................26 99 9 GLOSSARY....................................................................................................................27 100 10 REFERENCES ...............................................................................................................30 101 11 ANNEX ...........................................................................................................................30 102 11.1 TABLE OF SPECIES ADVANTAGES/DISADVANTAGES .........................30 103 11.2 IN VIVO STUDY DESIGNS ...............................................................................34 104 11.2.1 FERTILITY AND EARLY EMBRYONIC DEVELOPMENT (FEED) 105 STUDY ........................................................................................................35 106 11.2.2 PRE- AND POSTNATAL DEVELOPMENTAL (PPND) TOXICITY 107 STUDY ........................................................................................................37 108 11.2.2.1 Optional Modification of Rodent PPND Study to Assess Juvenile 109 Toxicity Endpoints .............................................................................38 110 11.2.2.2 Enhanced Pre- and Postnatal Developmental toxicity study (ePPND) 111 in NHP ...............................................................................................38 3 112 11.2.3 EMBRYO-FETAL DEVELOPMENTAL (EFD) TOXICITY STUDY .....39 113 11.2.3.1 Dose Range Finding (DRF) Study .....................................................39 114 11.2.3.2 pEFD Study ........................................................................................40 115 11.2.3.3 Definitive Embryo-fetal Developmental Toxicity Study ...................40 116 11.2.4 COMBINATION STUDIES ........................................................................41 117 11.2.4.1 Fertility and Embryonic Development (FEFD) .................................41 118 11.2.4.2 Fertility and PPND (FPPND).............................................................41 119 11.3 QUALIFICATION OF ALTERNATIVE TEST SYSTEMS FOR 120 REGULATORY ACCEPTANCE ......................................................................42 121 11.3.1 SELECTION FACTORS FOR THE ICH REFERENCE COMPOUND 122 LIST .............................................................................................................42 123 11.3.2 PERFORMANCE FACTORS .....................................................................43 124 11.3.3 ASSAY QUALIFICATION INFORMATION TO BE PROVIDED TO 125 HEALTH