Module 3 - Strategic case studies in practice

When the limit calculated based on ICH M7(R1) principles for a lifetime exposure is exceeded, a thorough benefit/risk assessment performed by the authorities is needed. Such assessment will need to take into consideration the criticality of the medicine (medical need, treatment alternatives, patient risk related to drug shortage etc.) in order to decide on a case by case whether higher limits for N - nitrosamines can be accepted temporarily together with further measures to lower the contamination and potentially control in the long term below the limit calculated based on compound-specific ICH M7 principles for a lifetime exposure. The LTL concept in ICH M7(R1) may be used as a guide for setting temporarily limits in such cases to prevent drug shortages where it would raise a public health issue. ICH M7(R1) may be interpreted in a way that the LTL approach is generally acceptable for all mutagenic carcinogens, including the cohort of concern mutagens. CHMP supports a re-evaluation and clarification whether the LTL concept is relevant for the cohort of concern mutagens. This should be performed as part of interactions with ICH, also taking into account the criticism regarding the LTL approach for cohort of concern mutagens expressed by the Ad-hoc expert group and the CHMP. It should also be noted that some experts of the ad-hoc expert group supported the concept of biological mechanism supporting a practical threshold even for mutagenic carcinogens. Such concepts are being investigated, and the body of knowledge is increasing. These concepts are based on the dose response of key cellular biochemical reactions such as e.g. DNA repair by MGMT and others important in chemical carcinogenesis of small alkylating N-nitrosamines. However, these concepts suggest that risk only starts to increase at exposures where the capacity of defence mechanisms such as DNA- repair is exceeded, but, above this level, may increase overproportionally. Thus, these concepts are not compatible with the assumption of a linear dose-response-relationship underlying the LTL approach, and would lead to particular concerns with nitrosamine doses exceeding individual repair capacities. Although such threshold concepts may appear interesting, defining a threshold is considered extremely difficult due to many unknown factors and interindividual variability, e.g.in terms of nitrosamine intake from other sources and differences in individual repair capacities. Overall, these concepts are not supported by robust scientific evidence at this stage and therefore should not be used as basis for regulatory decisions The TD 50 calculated in the CPDB provides a robust reference value as long as the studies are well described and are multiple dose group studies with a minimum of 3 dose groups and 50 animals per dose per sex. Studies not meeting these requirements need to be assessed for robustness on a case by case basis, e.g. a higher number of dose groups may compensate for fewer animals per dose group. This approach was used for NDBA, NMBA and DIPNA for which the harmonic mean TD 50 values listed in the CPDB were not judged as robust enough because they were derived from one study with one dose group only. The study published for DIPNA was not listed in the CPDB and is assumed not to be reliable enough to calculate any point of departure. CHMP has therefore recommended setting limits for NMBA and DIPNA, NDBA based on SAR considerations for NDMA or NDEA respectively (EMA/351053/2019 rev 1). Therefore, for nitrosamines with insufficient data (e.g. NMEA, NNN, NMA, NDPA, MeNP), a similar approach based on SAR considerations can be used. The TD 50 of the structurally closest related N- nitrosamine for which robust data are available to calculate a reliable TD 50 should be applied. SWP recommends using a class specific TD 50 as default option with the possibility to justify higher limits based on SAR considerations. This approach sets the same TD 50 for all nitrosamines where sufficient data to calculate a substance TD 50 do not exist. Setting of a class specific TD 50 is discussed in 2.5.2. Limits for nitrosamines without sufficient substance specific data

EMA/369136/2020

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