Module 3 - Strategic case studies in practice

As explained above, this is considered a conservative and robust risk-based approach relying on toxicological data. It is based on a lifetime estimate of the theoretical excess risk for patients and considers substance specific data on carcinogenic potency as far as such data are available in contrast to an analytical limit which is based on technical capability of analytics only. This approach also allows a consistent implementation and follow-up for all medicinal products regardless of advances in technical development of analytical methods. It would be in line with the general approach for mutagenic impurities described in ICH M7(R1) and ensures consistent and risk-based regulation of all pharmaceutical products by controlling N -nitrosamines to the same limit in all products. CHMP therefore recommends setting limits for N-nitrosamines in human medicinal products based on ICH M7 principles for substances of the “cohort of concern” and calculated considering a lifetime daily exposure. Non-clinical studies are only meaningful when adding to the weight of evidence for quantitative risk assessment. Further lifetime cancer bioassays in rodents should be avoided due to the long time needed (3 years including evaluation) and high costs. In addition, such studies probably would not add any further scientific value due to the high amount of already available carcinogenicity studies for many N- nitrosamines. Studies measuring mutations in vivo such as the transgenic rodent bioassays (TGR) to determine robust points of departure for mutations as the most important pre-cancerous insult are considered the best choice. However, these studies are relatively insensitive to low dose exposure and extensive studies would be needed to enable a robust calculation of benchmark doses as point of departure for risk calculation. Studies would also be needed for all N- nitrosamines considered relevant. Whether this is ethically acceptable especially with regard to the 3R principle is questionable. Clinical studies under real life conditions to evaluate the risk of endogenous formation of N- nitrosamines from authorised compounds with a suspected potential to form N- nitrosamines endogenously may be helpful to confirm or refute such risk. Although many epidemiological studies already investigated the association between N- nitrosamines and cancer, studies on the association of N- nitrosamine-contaminated medicines and cancer are rare. Due to increasing reporting of N- nitrosamine contamination in medicinal products and the fact that N- nitrosamines are potent mutagenic carcinogens, further studies are required to assess the risk of cancer after exposure to potentially contaminated medicinal products. N- nitrosamines exposure is suspected to increase the risk of several different cancers. Therefore, a composite endpoint may be considered as the primary endpoint in further studies (e.g. any cancer or a combination of cancer types of special interest). However, individual cancer types should always be examined as secondary endpoints. As the liver represents the main target organ of N- nitrosamines toxicity in animals, future studies should in any case investigate the risk of liver cancer more closely. Besides liver cancer, cancers of the upper gastrointestinal tract, the lung and the bladder are also of interest due to biological plausibility and experiences from previous animal and nutrition studies (refer to section 2.4). If possible, outcome identification should be verified by additional procedures and/or medical treatment. 2.6. Consideration for further studies 2.6.1. Consideration for further non-clinical/clinical studies 2.6.2. Consideration for further epidemiological studies

EMA/369136/2020

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