Points to Consider for nonclinical safety matters when submitting the initial clinical trial notification — PMDA Early Consideration Summary

In Plain Language

The document addresses common questions about nonclinical safety information when a sponsor submits an initial clinical trial notification (CTN). It describes how safety concerns identified in nonclinical studies and other information about the investigational medicinal product (IMP) should be communicated to investigators and participants. It also discusses what to consider about possible light-related toxicity, contraception when pregnancy concerns cannot be ruled out, and participation by lactating women. These points matter because the trial materials and arrangements should make relevant risks and limitations understandable and address participant safety. An attachment provides sample wording for documents such as informed consent forms and the investigator’s brochure, for reference when preparing initial CTN materials.

What This Guidance Covers

The document concerns nonclinical safety matters raised when submitting an initial CTN. It opens by explaining that, during the initial CTN review, a toxicology reviewer checks issues related to the safety of clinical trial participants, mainly using nonclinical study data. The document collects common inquiries raised during recent reviews and presents basic principles on safety information, avoidance of pregnancy, and inclusion of lactating women.

Its four main topics are:

• How to communicate safety concerns about the IMP, including nonclinical toxicity findings, pharmacological effects and class effects.
• Phototoxicity assessment and what to do if the possibility of phototoxicity cannot be ruled out.
• Pregnancy avoidance, including selection of contraceptive methods, how long contraception should continue, and possible follow-up if pregnancy occurs.
• Whether lactating women may participate and, where relevant, what happens if breastfeeding is interrupted.

The attachment gives specific wording examples for initial CTN-related materials. They are examples for reference, not a definitive list: the document says that content should be adjusted to the IMP’s characteristics and risks and to the characteristics of trial participants, such as whether they are healthy adults or patients. The document does not present a single set of wording or contraception arrangements for every trial.

At the outset, PMDA also recommends that sponsors consider using its consultation services before submitting the initial CTN if they have concerns about whether nonclinical safety studies are sufficient to start a trial, or about ensuring participant safety. The stated aim is to support the smooth progress of the 30-day-CTN review.

Why It Matters

The document describes a practical communication and planning problem: a trial’s safety arrangements depend on information from nonclinical studies, but that information needs to be made understandable and usable in trial materials. It notes that safety concerns may be predicted from nonclinical findings, pharmacological effects or class effects, and that the safety margin between the clinical dose and the NOAEL, together with the mechanisms of toxicity findings, may suggest a possibility that the concern could occur in humans.

Some findings can be difficult to monitor in a clinical setting or were irreversible in nonclinical studies. The document therefore says such findings need careful handling, including communicating them even when their relevance to humans is unclear. It also identifies recurring gaps: discussion of phototoxicity is often missing from the investigator’s brochure and other documents, and trial materials need to address pregnancy risks and lactation in a way that reflects the properties of the IMP.

The document also recognizes that a conventional nonclinical safety package may not be available in some situations. For example, biotechnology-derived pharmaceuticals may not have a sufficient period of nonclinical safety studies to justify clinical trials because anti-drug antibodies are produced in animals, or adequate guideline-compliant studies may not have been conducted because of the specificity of the IMP. In these circumstances, the document says the circumstances should be appropriately explained to participants.

Key Recommendations

1. Communicate relevant safety concerns clearly. Information from nonclinical studies should be appropriately provided to investigators and participants so that the trial is conducted properly. Safety concerns to consider include those suggested by nonclinical safety studies, pharmacological effects and class effects, particularly where the clinical dose-to-NOAEL safety margin and toxicity mechanisms suggest possible occurrence in humans. The informed consent document should communicate these concerns clearly and understandably.
2. Take particular care with hard-to-monitor or irreversible findings. Findings that are difficult to monitor in clinical settings, or were irreversible in nonclinical studies, must be handled with care. The document says information on such findings should be provided even when their relevance to humans is not clear.
3. Explain the limits of the available nonclinical safety information where applicable. In those circumstances, trial participants must be appropriately informed. Safety risks related to excipients and other ingredients in the IMP must be appropriately communicated.
4. Address phototoxicity in trial documents. Information on the initial evaluation of phototoxicity potential should be included in accordance with the “Guidelines for the Photosafety Evaluation of Pharmaceuticals” and other guidelines. If phototoxic potential cannot be ruled out, it is necessary either to take appropriate photoprotection measures for participants or to conduct an additional phototoxicity assessment to rule out concern. For IMPs already in clinical use overseas, available clinical study results or other data may be used to discuss phototoxicity potential. When using clinical data, consider the extent of clinical experience, including the number of participants and duration of exposure, whether participants were outpatients or inpatients, and whether photoprotection measures were used. Examples of photoprotection should be adjusted to the IMP’s phototoxic potential.
5. Set contraception provisions when pregnancy concerns cannot be ruled out. This applies where embryo-fetal toxicity was observed in toxicity studies or appropriate reproductive and developmental toxicity studies had not been conducted by the time of CTN submission. The protocol must specify appropriate contraceptive methods for participants who may become pregnant or whose partners may become pregnant. The specific period has to be set in accordance with the named contraception guidance and based on the IMP’s genotoxic potential, reproductive and developmental toxicity risks, pharmacokinetic parameters and other properties.
6. Choose contraception with the product and risk in mind. Evaluate the number and combination of methods in light of the degree of risk and the IMP’s nature; for example, oral contraceptives should be avoided if the IMP is a potent CYP inducer. Strict abstinence (no sexual intercourse) may be selected, but should be adequately explained to participants. The document states that condoms alone do not fall under the category of methods with an annual failure rate of less than 1% when used consistently and correctly, either alone or in combination, as specified in the named nonclinical safety guidance. Depending on the IMP’s properties, contraception may need to be specified for female partners of male participants as well as for the male participants. If contraception is required, specify how long it continues during and after IMP administration.
7. Make participant-facing contraception information specific. It is desirable for the informed consent form to describe acceptable methods—including their approval or certification status in Japan—and the contraception period as specifically as possible. The attachment’s wording examples are not a definitive list; tailor the content to participant characteristics and the IMP’s risks. If pregnancy is discovered in a participant or a participant’s partner during the trial, including a relevant period after treatment depending on product properties, follow-up on the pregnancy outcome may be needed and should be specified as necessary.
8. Consider lactation and explain the arrangements. Decide whether to include lactating women after considering the IMP’s properties and whether it is secreted into breast milk. If lactating women are excluded, specify whether they may participate if breastfeeding is interrupted. If breastfeeding may resume after treatment, specify when. Communicate these provisions clearly in the informed consent form.

Practical Implications

Interpretation: The document’s points can be used as a cross-functional review of whether the initial CTN package explains the safety evidence and translates it into clear participant and investigator information. The points below describe how its recommendations may affect document preparation; they are not additional PMDA requirements.

• For sponsors and regulatory teams: Identify whether the nonclinical safety package has limitations relevant to starting the trial and whether the submission materials explain them. If there are concerns about the sufficiency of studies or participant safety, consider the PMDA consultation services before submitting the initial CTN, as the document recommends.
• For toxicology and safety specialists: Connect findings to the proposed clinical dose, the NOAEL and the mechanisms of toxicity when assessing whether a concern could be relevant to humans. Pay particular attention to findings that are hard to monitor or irreversible, and to safety risks associated with excipients.
• For investigators and medical writers: Check that the investigator’s brochure addresses the initial phototoxicity evaluation. Ensure informed consent materials communicate relevant safety concerns in understandable language, including uncertainty or gaps in nonclinical evaluation when applicable.
• For clinical operations: Where pregnancy concerns cannot be ruled out, ensure the protocol specifies methods and duration that reflect the IMP’s properties, and that participant-facing material explains the arrangements. Consider how pregnancy discovery and any needed outcome follow-up will be handled.
• For teams planning participant eligibility: Make the lactation decision explicit. If breastfeeding interruption could permit participation, state whether that is allowed and when breastfeeding can resume after IMP administration.

The attachment may help teams draft or check wording, but its examples should not be copied as universal provisions. For instance, the sample contraception periods and methods illustrate possible wording; the document says actual content should be based on the IMP’s properties and the trial population.

Technical Details

Terms used in the document. The investigational medicinal product (IMP) is the product administered in the clinical study. The document refers to the NOAEL, the “no observed adverse effect level,” when discussing the safety margin between the clinical dose and nonclinical findings. It does not provide a formula for calculating that margin or specify a numerical threshold for deciding whether a finding may occur in humans.

Phototoxicity. The document calls for information on an initial evaluation in accordance with the named photosafety guidelines. If potential cannot be ruled out, the two approaches it identifies are appropriate photoprotection measures or an additional assessment to rule out concern. Clinical experience with overseas use may inform discussion, but should be interpreted in light of the number of trial participants, exposure duration, inpatient or outpatient status, and photoprotection used. The attachment includes sample investigator’s brochure wording mentioning molar absorptivity greater than 1000 Lmol-1cm-1 within the wavelength range of 290 to 700 nm; this is presented as sample wording, not as a standalone universal decision rule in the main discussion.

Pregnancy prevention. The stated basis for setting a contraception period includes genotoxic potential, reproductive and developmental toxicity risks, pharmacokinetic parameters and other IMP properties, alongside the named guidance. The document does not prescribe one standard period for all products. The attachment’s examples show different kinds of wording, including separate periods for male and female participants, and distinguish methods that are approved or certified in Japan from methods used overseas that are not approved or certified in Japan. These are illustrative examples rather than a universal method list.

Attachment and its sample language. The attachment gives examples covering nonclinical findings and study limitations; photoprotection; contraception for fertile participants; non-fertile participant descriptions; actions when pregnancy is confirmed; and lactation. Some examples contain placeholders such as “●” or describe particular periods and methods. Those details belong to the examples and should not be treated as recommendations for every IMP or trial. The document explicitly says the examples are for reference and should be adjusted to the trial’s participants and the IMP’s risks.

Who Should Read It

This document is relevant to sponsors preparing an initial CTN and to regulatory affairs staff coordinating the submission. It will also be useful to nonclinical toxicologists assessing how findings relate to clinical exposure, statisticians and clinical scientists reviewing the interpretation of safety evidence, and medical writers preparing the investigator’s brochure, protocol or informed consent form. Investigators and clinical operations teams may find its points on participant communication, contraception, pregnancy follow-up and lactation useful when planning trial procedures and eligibility.

Official PMDA Source

• Official title: Points to Consider for nonclinical safety matters when submitting the initial clinical trial notification (Early Consideration)
• Issuing body: Pharmaceuticals and Medical Devices Agency (PMDA), Center for Product Evaluation
• Date on cover: March 25, 2025
• PMDA PDF: Official document PDF
• PMDA list page: PMDA Early Consideration documents

Source: Pharmaceuticals and Medical Devices Agency (PMDA) website, PMDA Early Consideration documents. This page was created by editing and summarising the PMDA document.

Consult the official document for the complete text; this summary does not replace it. PMDA describes Early Consideration documents as reference information reflecting its views at the time of publication, which may change as scientific knowledge develops. PMDA provides the English version for reference, and the Japanese original prevails if there is any inconsistency.

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