S5(R3) - ICH
INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICALREQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USEDRAFT ICH HARMONISED GUIDELINEDETECTION OF TOXICITY TO REPRODUCTION FOR HUMANPHARMACEUTICALSS5(R3)Current Step 2 draft versiondated 5 July 2017At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by theappropriate ICH Expert Working Group, is transmitted by the ICH Assembly to theregulatory authorities of the ICH regions for internal and external consultation,according to national or regional procedures.
TABLE OF CONTENTS12345SCOPE OF THE GUIDELINE .1INTRODUCTION & GENERAL PRINCIPLES .1STRATEGIES FOR REPRODUCTIVE TOXICITY ASSESSMENT .23.1CONSIDERATIONS/PRINCIPLES .23.1.1TARGET PATIENT POPULATION/ THERAPEUTIC INDICATIONCONSIDERATIONS .33.1.2PHARMACOLOGY CONSIDERATIONS .33.1.3TOXICITY CONSIDERATIONS .43.1.4TIMING CONSIDERATIONS .43.1.5OTHER CONSIDERATIONS FOR REPRODUCTIVE TOXICITYSTUDIES .43.2STRATEGY TO ADDRESS FERTILITY AND EARLY EMBRYONICDEVELOPMENT .53.3STRATEGIES TO ADDRESS EMBRYO FETAL DEVELOPMENT(EFD) .63.3.1ROUTINE APPROACH FOR ADDRESSING EFD RISK .63.3.2OPTIONAL APPROACHES FOR ADDRESSING EFD RISK .83.3.2.1Use of Alternative Assays .83.3.2.2In vitro and Non-mammalian Exposure Information.103.3.3POTENTIAL APPROACHES TO DEFER IN VIVO TESTING ASPART OF AN INTEGRATED TESTING STRATEGY .103.4STRATEGY TO ADDRESS EFFECTS ON PPND .113.5TOXICOKINETICS (TK) .11TEST SYSTEM SELECTION .114.1ROUTINE TEST SPECIES .114.1.1RAT AS THE PRIMARY SPECIES FOR REPRODUCTIVETOXICITY TESTING .124.1.2RABBIT AS THE SECONDARY SPECIES FOR EFD STUDIES .124.1.3SPECIES SELECTION FOR PREVENTATIVE ANDTHERAPEUTIC VACCINES .124.2NON-ROUTINE TEST SPECIES .134.3OTHER TEST SYSTEMS .144.3.1USE OF DISEASE MODELS .144.3.2USE OF GENETICALLY MODIFIED MODELS AND USE OFSURROGATE MOLECULES.14DOSE LEVEL SELECTION, ROUTE OF ADMINISTRATION ANDSCHEDULE.155.1DOSE SELECTION COMMON TO ALL PHARMACEUTICALS,INCLUDING BIOTECHNOLOGY-DERIVED PHARMACEUTICALS.162
5.1.15.1.2TOXICITY–BASED ENDPOINTS .16ABSORPTION, DISTRIBUTION, METABOLISM ANDEXCRETION (ADME)-BASED SATURATION OF SYSTEMICEXPOSURE ENDPOINT .175.1.3EXPOSURE-BASED ENDPOINT .175.1.3.1Considerations for Total vs. Fraction Unbound PharmaceuticalExposure .185.1.3.2Exposure-based Approach for Highly Targeted Therapeutics.185.1.4MAXIMUM FEASIBLE DOSE (MFD) ENDPOINT .195.1.5LIMIT DOSE ENDPOINT .195.1.6SELECTION OF LOWER DOSE LEVELS .195.2DOSE SELECTION AND STUDY DESIGNS FOR VACCINES .196DESIGN AND EVALUATION OF IN VIVO MAMMALIAN STUDIES .206.1THREE SEPARATE STUDIES TO ASSESS ALL STAGES (A F) .206.2SINGLE STUDY DESIGN.216.3TWO STUDY DESIGN .216.4COMBINATION DESIGN OF REPEAT-DOSE AND FERTILITYSTUDIES .216.5EVALUATION OF DATA.226.5.1DATA HANDLING/DATA PRESENTATION/STATISTICS FOR INVIVO STUDIES .226.5.2STATISTICS .237PRINCIPLES OF RISK ASSESSMENT.247.1RISK ASSESSMENT FOR REPRODUCTIVE ANDDEVELOPMENTAL TOXICITIES .247.2RISK ASSESSMENT FOR LACTATION.268ENDNOTES.269GLOSSARY.2810 REFERENCES .3011 ANNEX .3111.1 TABLE OF SPECIES ADVANTAGES/DISADVANTAGES .3111.2 IN VIVO STUDY DESIGNS .3411.2.1 FERTILITY AND EARLY EMBRYONIC DEVELOPMENT (FEED)STUDY .3511.2.2 PRE- AND POSTNATAL DEVELOPMENTAL (PPND) TOXICITYSTUDY .3711.2.2.1Optional Modification of Rodent PPND Study to Assess JuvenileToxicity Endpoints .3811.2.2.2Enhanced Pre- and Postnatal Developmental toxicity study(ePPND) in NHP .383
11.2.3 EMBRYO-FETAL DEVELOPMENTAL (EFD) TOXICITY STUDY .3911.2.3.1Dose Range Finding (DRF) Study .3911.2.3.2pEFD Study.4011.2.3.3Definitive Embryo-fetal Developmental Toxicity Study.4011.2.4 COMBINATION STUDIES .4111.2.4.1Fertility and Embryonic Development (FEFD) .4111.2.4.2Fertility and PPND (FPPND).4111.3 QUALIFICATION OF ALTERNATIVE TEST SYSTEMS FORREGULATORY ACCEPTANCE .4211.3.1 SELECTION FACTORS FOR THE ICH REFERENCE COMPOUNDLIST .4211.3.2 PERFORMANCE FACTORS .4311.3.3 ASSAY QUALIFICATION INFORMATION TO BE PROVIDED TOHEALTH AUTHORITIES .4311.3.4 ICH REFERENCE COMPOUND LIST .4511.3.5 EXAMPLES OF EFD TESTING STRATEGIES .5511.3.5.1Scenarios applicable when there are at least 2 relevantmammalian species (crf. Species selection).5611.3.5.2Scenarios applicable in case there is no or only 1 relevantmammalian species (crf. Species selection).594
123456789101SCOPE OF THE GUIDELINEThis guideline applies to pharmaceuticals, including biotechnology-derived pharmaceuticals,vaccines (and their novel constitutive ingredients) for infectious diseases, and novelexcipients that are part of the final pharmaceutical product. It does not apply to cellulartherapies, gene therapies and tissue-engineered products. The methodological principles(e.g., study design, dose selection and species selection) outlined in this guideline can alsoapply to pharmaceuticals intended for the treatment of serious and life threatening diseases,such as advanced malignancies (i.e., see ICH S9 (3)). This guideline should be read inconjunction with ICH M3(R2) (1), ICH S6(R1) (2) and ICH S9 (3) regarding whether andwhen non-clinical reproductive toxicity studies are warranted.1112213141516171819The purpose of this guideline is to provide key considerations for developing a testingstrategy to identify hazard and characterize reproductive risk for human pharmaceuticals.The guidance informs on the use of existing data and identifies potential study designs tosupplement available data to identify, assess, and convey risk. General concepts andrecommendations are provided that should be considered when interpreting study data andmaking an assessment of reproductive risk in support of clinical development and marketingapproval.202122232425To assess a human pharmaceutical’s effects on reproduction and development, theinformation should generally include exposure of adult animals and the impact on all stagesof development from conception to sexual maturity. No guideline can provide sufficientinformation to cover all possible cases, and flexibility in testing strategy is warranted.Regardless of the pharmaceutical modality (see Glossary), key factors to consider whendeveloping an overall integrated testing strategy include:26272829303132333435363738INTRODUCTION & GENERAL PRINCIPLES The anticipated pharmaceutical use in the target population (especially in relation toreproductive potential and severity of disease);The formulation of the pharmaceutical and route(s) of administration intended forhumans;The use of any existing data on toxicity, pharmacodynamics, pharmacokinetics, andsimilarity to other compounds in structure or activity;Selection of specific studies, test species/test system and dose levels.These concepts are discussed in more detail throughout the guideline, which defines athoughtful approach for developing a testing strategy. This guideline recommends the use ofinformation about the pharmaceutical and the patient population in order to perform onlythose studies essential to evaluate the stages (see below) for which there is insufficientknowledge to inform about the risk to reproduction and development.1
3940414243As appropriate, observations through one complete life cycle (i.e., from conception in onegeneration through conception in the following generation) permit detection of immediateand latent adverse effects. For the purposes of this guidance, gestation day 0 (GD 0; seeGlossary) is when positive evidence of mating is detected. The following stages ofreproduction are generally assessed:4445A) Premating to conception (adult male and female reproductive functions, developmentand maturation of gametes, mating behavior, fertilization).4647B) Conception to implantation (adult female reproductive functions, preimplantationdevelopment, implantation).4849C) Implantation to closure of the hard palate (adult female reproductive functions,embryonic development, major organ formation).5051D) Closure of the hard palate to the end of pregnancy (adult female reproductivefunctions, fetal development and growth, organ development and growth).5253E) Birth to weaning (adult female reproductive functions, neonate adaptation toextrauterine life, pre-weaning development and growth).5455F) Weaning to sexual maturity (post-weaning development and growth, adaptation toindependent life, attainment of full sexual function).56575859The stages covered in individual studies are left to the discretion of the Sponsor, althoughthe timing of studies within the pharmaceutical development process is dependent on studypopulations and phase of pharmaceutical development (see ICH M3(R2) (1), ICH S6(R1)(2) and ICH S9 (3)).6061This guideline also provides considerations for interpreting all available nonclinicalinformation as part of the risk he initial step is to determine if reproductive toxicity testing for each of the variousreproductive stages is warranted and, if so, what are the most appropriate studies to conduct.The considerations should include: a) the target patient population and duration of dosing, b)the known pharmacology of the compound, c) the known toxicity of the compound, d) anyexisting knowledge of the impact of the target(s) on reproductive risk (e.g., human and/oranimal genetics, or class effects), and e) data from in vitro and non-mammalian assays(alternative assays, see Glossary) that could be relied upon to identify hazard and/or risk (seeSection 3.3.2). Approaches for qualifying and use of alternative assays in assessingreproductive risk are discussed below (Sections 3.3.2 and 9.5). Generally, most alternativeassays being developed address endpoints related to Embryo-Fetal Development (EFD) andare thus discussed in section 3.3.2. However, as new assays are developed for otherreproductive endpoints, they can be similarly deployed with appropriate qualification.STRATEGIES FOR REPRODUCTIVE TOXICITY ASSESSMENTConsiderations/Principles2
7677787980818283848586878889909192939495969798The experimental strategy to generate the data should consider minimizing the use ofanimals. Alternative assays and/or in vivo studies with fewer animals can be used to identifyhazards in a tiered manner. Reductions in animal use can also be achieved by deferringdefinitive EFD studies (see Section 9.4.3.3) until later in pharmaceutical development (seebelow). Alternative assays can replace definitive assays in some circumstances where as inothers they can be used to defer traditional assays until later in development (see Section3.3). An important component of the overall strategy is the timing for the additionalinformation to support ongoing clinical development (e.g., developmental toxicity (seeGlossary) data to support dosing women of childbearing potential).993.1.1100101Reproductive and developmental studies should in general be conducted according to GoodLaboratory Practice (GLP) as they will contribute to risk assessment. However, if a humandevelopmental or reproductive risk is defined during the conduct of a relevant non-GLPstudy, repetition of the study to confirm the finding(s) under GLP conditions is notwarranted. Preliminary EmbryoFetal Development (pEFD; see Glossary) studies should beconducted under high-quality scientific standards with data collection records readilyavailable or under GLP conditions. It is recognized that GLP compliance is not expected forsome study types, or aspects of some studies, employing specialized test systems or methods,such as disease models or surrogate molecules (see Glossary), or literature. However, highquality scientific standards should be applied, with data collection records readily available.Areas of non-compliance should be identified and their significance evaluated relative to theoverall safety assessment.Target Patient Population/ Therapeutic Indication ConsiderationsThe patient population or therapeutic indication can influence the extent of reproductivetoxicity testing. For example:102103 If the female patient population is post-menopausal there is no utility in evaluatingany of the reproduction stages;104105 A pharmaceutical for use in an elderly male does not warrant conduct of studies toevaluate stages E and F;106107108 If the disease indicates that reproductive toxicity will have minimal impact on theusage of the pharmaceutical in the target population, studies evaluating only stages Cand D can be warranted;109 Short-term therapies under highly controlled settings.1103.1.2111112113114Before testing, it should be determined if the pharmacologic effects are incompatible withfertility, normal EFD, or measurement of endpoints of the study being considered (e.g., ageneral anesthetic and measurement of mating behavior). This assessment could be basedon data with other pharmaceuticals with similar pharmacology on the pathways affected, orPharmacology Considerations3
115116117118119120121on knowledge of effects in humans with related genetic diseases. Based on theseconsiderations, sometimes no testing for a particular reproductive endpoint can bewarranted. In contrast, testing for only off-target effects can be warranted if the expectedpharmacologic effects on reproductive endpoints are non-adverse. Examples includepatients with a condition that mimics the target pharmacology who have normalreproductive capability and healthy offspring; or when other pharmaceuticals have similarpharmacology or pathways affected but have no demonstrated reproductive risk.1223.1.3123124125126127128Repeat–dose toxicity studies with sexually mature animals can provide importantinformation on toxicity to reproductive organs. The existing toxicology data for thecompound should always be considered, taking into account the dose levels, toxicokineticprofile, and dosing duration. For example, the evaluation of fertility effects for apharmaceutical that damages testicular tissue might warrant modifications to the standardfertility study, if such a study would be appropriate.129130Sometimes, toxicity in animals precludes attaining a systemic exposure relevant to thehuman exposure under conditions of use and this should be 2143144General guidance on the timing for conduct of reproductive toxicity studies covering StagesA-F relative to clinical studies is described in the ICH M3(R2) and ICH S9 guidelines (1,3).The timing for when to conduct specific reproductive toxicity assessments should take intoconsideration the points discussed above. Based on these factors, it can sometimes beappropriate to consider altering timing of the assessment of specific reproductive stages. Forexample, if there is an equivocal observation from a preliminary study and other compoundsin the class are without risk, then consideration should be given to accelerating the definitivestudies. In contrast, there can be circumstances for deferring studies. For example, whenother studies have revealed a risk and appropriate precautions in clinical trials have beentaken, the conduct of definitive studies evaluating the relevant reproductive stages can bedeferred to later in development than is recommended in ICH M3(R2) (1). When conductingenhanced Pre- and PostNatal Development (ePPND) studies in NonHuman Primates (NHP)see ICH S6(R1) (2) for timing.145Additional options that include study deferral are di
9 conjunction with ICH M3(R2) (1), ICH S6(R1) (2) and ICH S9 (3) regarding whether and 10 when non-clinical reproductive toxicity studies are warranted. 11 12 2 INTRODUCTION & GENERAL PRINCIPLES 13 The purpose of this guideline is to provide key considerations for developing a testing
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