S5(R3)
1 INTRODUCTION & GENERAL PRINCIPLES
This document aims to promote harmonization and establish global standards for evaluating nonclinical developmental and reproductive toxicity (DART) testing. This is essential for supporting human clinical trials and pharmaceutical marketing authorization. It outlines potential approaches and methodologies for risk detection and evaluation, while also providing general ideas and suggestions for analyzing study data.
This is a revision of the ICH guideline “S5 Detection of Toxicity to Reproduction for Medicinal Products” that was originally published in 1993. This revision brings the guideline into alignment with other ICH guidelines, elaborates on the use of exposure margins in dose level selection, incorporates a section on risk assessment, and expands the scope to include vaccines and biopharmaceuticals. It also describes qualification of alternative assays, potential scenarios of use, and provides options for deferral of developmental toxicity studies.
To evaluate a human pharmaceutical’s impact on reproduction and development, information regarding the effects of the drug and its metabolites on all developmental stages is essential. Guidelines may not cover every scenario, necessitating flexible testing strategies.
- Aim of Studies
The DART studies aim to assess the impact of pharmaceuticals on mammalian reproduction, relevant for human risk assessment. These studies should cover a complete life cycle, from conception in one generation to the next, and allow for the detection of both immediate and latent adverse effects. Key reproductive stages are typically evaluated:
A) Premating to conception (adult male and female reproductive functions, development and maturation of gametes, mating behavior, fertilization).
B) Conception to implantation (adult female reproductive functions, preimplantation development, implantation).
C) Implantation to closure of the hard palate (adult female reproductive functions, embryonic development, major organ formation).
D) Closure of the hard palate to the end of pregnancy (adult female reproductive functions, fetal development and growth, organ development and growth).
E) Birth to weaning (parturition and lactation, neonate adaptation to extrauterine life, pre-weaning development and growth).
F) Weaning to sexual maturity (post-weaning development and growth, adaptation to independent life, onset of puberty and attainment of full sexual function, and effects on second generation).
The risks to all stages should be assessed, unless the stage is not relevant to the intended population. The stages covered in individual studies are left to the discretion of the Sponsor, although the timing of studies within the pharmaceutical development process is dependent on study populationsand phase of pharmaceutical development (see ICH M3, ICH S6 and ICH S9.
2. SCOPE OF THE GUIDELINE
This guideline addresses all pharmaceuticals, including biopharmaceuticals and vaccines for infectious diseases, while excluding cellular and gene therapies. The outlined methodological principles apply to compounds needing reproductive and/or developmental toxicity studies. It should be read alongside ICH M3, ICH S6, and ICH S9 for guidance on nonclinical DART studies.
3. GENERAL CONSIDERATIONS ON REPRODUCTIVE TOXICITY ASSESSMENT
The majority of pharmaceuticals under development should undergo evaluation throughout all stages of the reproductive cycle, except in justified cases. Typically, this assessment is conducted through three in vivo study types: a fertility and early embryonic development study (FEED), embryo-fetal development studies in two species (EFD), and a pre- and postnatal development study (PPND). For each compound, it’s crucial to determine which stages will be evaluated and the appropriate studies to conduct, while considering key factors for an integrated testing strategy on reproduction and development.
• The targeted patient population and conditions of use (especially in relation to reproductive potential and severity of disease);
• The formulation of the pharmaceutical and route(s) of administration intended for humans;
• Relevant data on toxicity (which can also include data from in vitro, ex vivo and non-mammalian studies, and structure-activity relationships), pharmacodynamics, pharmacokinetics, and pharmacological similarity to other pharmaceuticals;
• Aspects of the general biology of the pharmaceutical target, or known roles of the target in reproduction or development.
These ideas are covered in further detail throughout the guideline.
The experimental strategy should minimise the use of animals to the extent that it does not compromise the overall risk assessment. Conducting studies that integrate typical study types (see Section 7) and using suitably qualified alternative assays for risk assessment (see Annex 2) are two ways to achieve this goal. According to ICH M3, animal use can also be decreased by appropriately timing studies to support ongoing clinical development (e.g., embryo-fetal developmental toxicity data to support enrolment of women of childbearing potential). This is because many clinical development programs end before Phase 3.
Since DART studies will aid in the risk assessment, they should generally be carried out in accordance with Good Laboratory Practice (GLP) guidelines. Replicating the study to confirm the findings under GLP settings is not always necessary, though, if a pertinent DART risk is found in a non-GLP study. A risk that arises at or close to planned clinical exposures and is of a type that is likely to affect people is considered relevant (see Section 9). It is acknowledged that certain study types or parts of certain studies using specialised test equipment or methodologies are not anticipated to comply with GLP.
Nonetheless, data collecting records should be easily accessible and high-quality scientific criteria should be applied. In the study report, non-compliance areas should be noted, and their effects on the study’s findings and data interpretation should be evaluated in light of the overall safety evaluation.
3.1 Target Patient Population/ Therapeutic Indication Considerations
The scope of DART testing may vary depending on the target patient population or treatment indication. If the disease suggests that DART will have little effect on the pharmaceutical’s risk in the target population, then studies assessing every stage of development and reproduction are not necessary. For instance, research encompassing all stages may not be suitable for use in paediatric or juvenile pre-pubescent populations, for patient populations in hospital settings where pregnancy may be ruled out, or for a patient group that is only post-menopausal.
3.2 Pharmacology Considerations
It is important to ascertain whether the targeted pharmacologic effects of a medication are known to be incompatible with normal EFD, fertility, or the evaluation of specific endpoints (e.g., a general anaesthetic and study of mating behaviour) before developing a testing plan. Data from other medications with comparable pharmacology, established target engagement effects, or information on impacts in people with relevant genetic illnesses can all be used to make this assessment. For a drug designed to prevent preterm labour, for instance, it would be reasonable to alter the design of a PPND research. Testing for a specific reproductive objective is not justified if the planned pharmacologic effects are incompatible with the research endpoints.
3.3 Toxicity Considerations
Repeated–dose toxicity studies with sexually mature animals can provide important
information on toxicity to reproductive organs that can affect the design of a DART study.. The dose levels, toxicokinetic profile, and duration of treatment should always be taken into account when evaluating the compound’s current toxicology data. For a substance that affects testicular tissue, for instance, the duration of dosing or the beginning of cohabitation can be changed using the normal fertility research design.
3.4 Timing Considerations
ICH M3, ICH S6, and ICH S9 provide general guidelines on when to perform research evaluating reproductive and developmental objectives. The necessity for these data to support the safe use of the medication in clinical trials or the target patient group should be taken into account when determining when to do particular DART assessments. As a result, it may be reasonable to think about changing when certain reproductive phases are evaluated. Sections 4.2.2 and 4.2 describe other choices.
3.5 Toxicokinetics (TK)
Exposure data for pharmaceuticals can be generated through reproductive (dose range finding (DRF) or pivotal) or repeated-dose toxicity studies. It’s essential to assess if pregnancy affects exposure due to potential changes in toxicokinetic (TK) parameters. For dose selection based on exposure ratio, Good Laboratory Practice (GLP)-compliant TK data from pregnant animals is required, with justified sampling days. To clarify developmental hazards, determining the drug concentration in embryos or fetuses may be necessary, though direct comparisons to human conceptus levels are inappropriate. Evidence of lactational excretion can be gathered by sampling milk or assessing offspring exposure pre-weaning. General TK data collection principles are outlined in ICH S3A (4).
The entire text of ICH S5 (R3) could not be presented in this article due to space constraints. To properly grasp, DETECTION OF REPRODUCTIVE AND DEVELOPMENTAL TOXICITY FOR HUMAN PHARMACEUTICALS, it is advised that you read the entire guideline. The link is provided below:
Reference:
https://database.ich.org/sites/default/files/S5-R3_Step4_Guideline_2020_0218_1.pdf
-Dr. Subramanian S Iyer
