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Regulatory Focus™ > News Articles > 2020 > 2 > ICH E9(R1) and S5(R3) to Take Effect in EU by End of July

ICH E9(R1) and S5(R3) to Take Effect in EU by End of July

Posted 18 February 2020 | By Michael Mezher 

ICH E9(R1) and S5(R3) to Take Effect in EU by End of July

More than two years after opening public consultations on the guidelines, the European Medicines Agency (EMA) on Tuesday adopted two International Council for Harmonisation (ICH) guidelines, the ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials and ICH S5(R3) on reproductive toxicology, with both guidelines set to take effect on 30 July 2020.
EMA’s move to adopt the guidelines comes after ICH adopted the E9(R1) addendum at its November meeting in Singapore, during which ICH also said the S5(R3) guideline was expected to reach Steps 3 and 4 in early 2020. EMA also adopted ICH’s M9 guideline on biopharmaceutics classification system-based biowaivers last week, which takes effect at the same time as the E9(R1) addendum and S5(R3) guideline.
ICH E9(R1)
The 19-page E9(R1) addendum presents a framework for defining an appropriate estimand for a clinical trial and conducting sensitivity analyses.
The guideline defines an estimand as a “precise description of the treatment effect reflecting the clinical question posted by a given clinical trial objective [and] summarizes at a population level what the outcomes would be in the same patients under different treatment conditions being compared.”
For estimands, the guideline lays out recommendations for handling intercurrent events as they relate to the clinical question of interest, attributes that make up an estimand and considerations for constructing the estimand.
The guideline also discusses the impact of estimands on clinical trial design and conduct. “The design of a trial needs to be aligned to the estimands that reflect trial objectives. A trial design that is suitable for one estimand might not be suitable for other estimands of potential importance,” the guideline states.
Additionally, the guideline discusses the impact of estimands on clinical trial analysis and provides recommendations for conducting sensitivity analyses.
ICH S5(R3)
Within the 127-page S5(R3) guideline, ICH sets recommendations for a harmonized approach to assessing nonclinical developmental and reproductive toxicity (DART) testing used to support clinical trials and drug approvals.
The guideline is the third revision made to the S5 guideline since its introduction in 1993 and has been updated to include discussions on the use of exposure margins in dose level selection and risk assessment. The guideline has also been expanded to cover vaccines and biopharmaceuticals, though it does not apply to cell and gene therapies or tissue-engineered products.
Within the guideline, ICH lays out a framework for assessing drugs for reproductive toxicity, including study design and evaluation; test system selection; and dose level selection, route of administration and schedule.
The two annexes make up the bulk of the guideline, with Annex 1 covering in vivo study designs and Annex 2 discussing the use of qualified alternative assays to support hazard identification and risk assessment.
EMA: ICH E9(R1), ICH S5(R3)


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