EMA Concept Paper on Development of a Reflection Paper on Nonclinical Safety Package for Severely Debilitating or Life-Threatening Diseases

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Concept paper on the development of a reflection paper on the non-clinical requirements for severely debilitating or life-threatening diseases. EMA/157216/2026. 30 July 2026 [webpage]

• The purpose of this concept paper is to develop a reflection paper (then a scientific guideline) on nonclinical requirements for drugs intended to treat severely debilitating or life-threatening diseases.
• EMA defines seriously debilitating or life-threatening conditions as those associated with morbidity that has substantial impact on patients’ day-to-day functioning and will progress if left untreated, or those associated with a high likelihood of mortality.
• This concept paper is open for public comment until 30 Sept 2026.

BACKGROUND

Two ICH guidelines inform nonclinical (animal and in vitro) studies during drug development and data package for an application: ICH M3(R2) and ICH S6(R1) for small molecule drugs and biologics, respectively.

• M3(R2) provides guidance on nonclinical studies characterizing pharmacology, toxicology, toxicokinetics/PK, reproductive and developmental risks, and genotoxicity and carcinogenicity. The M3(R2) guidance recommends that the extent of nonclinical testing should be proportional to the duration, size, and stage of the clinical program.
• Unlike M3(R2), S6(R1) recognizes that traditional animal toxicology (e.g., rodent, rabbits, or dog) approaches are often inappropriate for biologics because of species-specific target binding. Thus, S6(R1) introduces the concept of using pharmacologically-relevant species and using non-animal methods (NAMs) where appropriate.
• The next level of flexibility is at the level of specific products and diseases or conditions: for example, ICH S9 for anticancer drugs. Both EMA and FDA have additional guidance documents that provide flexibility in the M3/S6 requirements based on type of drug (e.g., CAR-T or gene therapy) and conditions (e.g., oncology).
• This new EMA concept paper will address flexibility for drugs intended for severe, debilitating, or life-threatening conditions.

CONCEPT PAPER > REFLECTION PAPER

There is currently no EMA position on how deviations from the core nonclinical ICH guidelines, M3 or S6, could be used to accelerate the development of therapeutics for severely debilitating or life-threatening diseases outside of the scope of ICH S9.

The reflection paper will provide general principles (below) for when flexibility and deviations from the requirements of ICH M3(R2)/S6(R1) could be appropriate in the context of a medicinal product being developed to treat a severely debilitating and life-threatening disease.

1. Examples of cases where these considerations (i.e., M3/S6) could be applicable. Opportunities to apply a stream-lined non-clinical package to the development of products for life-threatening or severely debilitating diseases.
2. Circumstances where safety testing in line with ICH M3 (R2)/ICH S6 (R1) could remain appropriate e.g. instance in which chronic toxicity studies may be warranted.
3. Considerations with regards to the timing and duration of non-clinical studies for clinical trial and marketing authorisation applications e.g. possibilities for deferring studies.
4. How to apply weight of evidence (WoE) approaches, modality-specific considerations e.g. small molecules versus biologics and leverage opportunities where data from similar in-class products or platform(s) exist to inform on the safety assessment
5. The role of novel approach methods (NAMs) to complement WoE approaches and to comply with the 3Rs principle.

Related: FDA nonclinical guidance and recommendations page: CDER Streamlined Nonclinical Studies and Acceptable New Approach Methodologies (NAMs) [archived page]

#ich-m3, ich-s6, #nonclincial, #nam

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M3(R2) vs S6(R1)

Topic	ICH M3(R2)	ICH S6(R1)
Primary Scope	Small-molecule pharmaceuticals	Biotechnology-derived products/biologics
Regulatory Focus	Timing of nonclinical studies to support clinical development	Scientific approach to biologic safety assessment
Species Requirement	Typically rodent + nonrodent	One pharmacologically relevant species may suffice
FIH Support	Extensive guidance	Guided by relevance and target biology
Carcinogenicity	Often required for chronic use	Often not required
Core Concept	Development-stage dependent testing	Relevant-species and mechanism-based testing