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ICH S9 – Nonclinical evaluation for anticancer pharmaceuticals reached Step 4 in late 2009 [19]. This, as the title suggests, aims to provide guidance relating to the level of safety evaluation required to support the use of anticancer pharmaceuticals particularly in the context of the stage of disease. It suggests a reduced package of testing where treatment is associated with advanced disease, recognizing the inconsequential impact any toxicity‐related issues would have in terms of patient risk/benefit.

ICH S9 contains the specific statement:

It is recognised that impurities are not expected to have any therapeutic benefit, that impurity standards have been based on a negligible risk (e.g. an increase in lifetime risk of cancer of one in 10⁵ or 10⁶ for genotoxic impurities) and that such standards might not be appropriate for anticancer pharmaceuticals intended to treat advanced stage patients.

In 2018 ICH S9 was augmented by a Q&A document [20]. Within this specifically in relation to ICH M7 the following is tabulated (Table 1.4).

Table 1.4 Extracted text from ICH S9, Q&A document relating to MIs.

4.12	Should impurities exceeding the established qualification limits in ICH Q3A/B be assessed in genotoxicity studies? When the API is genotoxic? When the API is non‐genotoxic?	API genotoxic?	Impurity exceeds 3A/B qualification threshold?	Proposed action
Yes	No	None
Yes	Yes	None
No	No	None
No	Yes	Genotoxicity assessment of impurities should be conducted.
4.13	Is ICH M7, giving guidance for the management of MIs, applicable to the patient population covered in the scope of ICH S9?	The scope of ICH M7 specifically states that the guidance does not apply to “drug substances and drug products intended for advanced cancer indications as defined in the scope of ICH S9.” Therefore, MIs in products used for treatment of indications under the scope of ICH S9 should be considered for management consistent with the concepts outlined in ICH Q3A/B (see Question 4.12).

Unlike the earlier EMA guideline, which simply stated that factors such as limited life expectancy and seriousness of disease can be used as the basis for establishing alternative limits, ICH M7 explicitly states that this guideline does not apply to drug substances and drug products intended for advanced cancer indications as defined in the scope of ICH S9.

Another interesting aspect of this is the question as to whether the oncology therapy area is a “special case” or whether the same logic applies to other treatments of life‐threatening conditions. To date experience has been that extrapolation to other life‐limiting conditions has been difficult in terms of regulatory acceptance.