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2.4.7.4 Question 7.4

This Q&A relates to the AI of HIV treatment that under Note 7 (Table 2.7) of the M7 guideline falls under the LTL category of a treatment duration of >1–10 years where the AI is defined as 10 μg/day. The HIV disease has now been moved from “treatment duration <10 years” to “lifetime” treatment. The Q&A provides further explanation to this change.

Table 2.7 Examples of clinical use scenarios with different treatment durations for applying AIs.

Scenario^a	Acceptable intake (μg/day)
Treatment duration of ≤1 month: e.g. drugs used in emergency procedures (antidotes, anesthesia, acute ischemic stroke), actinic keratosis, and treatment of lice	120
Treatment duration of >1–12 months: e.g. anti‐infective therapy with maximum up to 12 months treatment (HCV), parenteral nutrients, prophylactic flu drugs (~5 months), peptic ulcer, assisted reproductive technology (ART), preterm labor, preeclampsia, presurgical (hysterectomy) treatment, and fracture healing (these are acute use but with long half‐lives)	20
Treatment duration of >1–10 years: e.g. stage of disease with short life expectancy (severe Alzheimer’s), nongenotoxic anticancer treatment being used in a patient population with longer term survival (breast cancer, CML), drugs specifically labeled for less than 10 years of use, drugs administered intermittently to treat acute recurring symptoms^b (chronic Herpes, gout attacks, substance dependence such as smoking cessation), macular degeneration, and HIV^c	10
Treatment duration of >10 years to lifetime: e.g. chronic use indications with high likelihood for lifetime use across broader age range (hypertension, dyslipidemia, asthma), Alzheimer’s (except severe AD), hormone therapy (e.g. GH, TH, PTH), lipodystrophy, schizophrenia, depression, psoriasis, atopic dermatitis, COPD, cystic fibrosis, and seasonal and perennial allergic rhinitis	1.5

^a This table shows general examples; each example should be examined on a case‐by‐case basis. For example, 10 μg/day may be acceptable in cases where the life expectancy of the patient may be limited, e.g. severe Alzheimer’s disease, even though the drug use could exceed 10‐year duration.

^b Intermittent use over a period >10 years but based on calculated cumulative dose it falls under the >1–10 year category.

^c HIV is considered a chronic indication but resistance develops to the drugs after 5–10 years and the therapy is changed to other HIV drugs.

Question	Answer
Why was HIV disease moved to the “Treatment duration of >10 years to lifetime” in the clinical use scenarios table? How should this change be implemented?	The treatment duration category was changed because of advances in the clinical treatment of HIV disease. To avoid disruption of supply of HIV drugs already on the market, this change would not be applied to currently marketed products. For example, when a new DS supplier is proposed, the AI would remain at 10 μg/day in cases where the DS produced by this supplier, using the same route of synthesis, is a component of an existing DP marketed in the specific region (see ICH M7 Section 4.1). For regulatory submissions 18 months after the date that the M7 Q&A reached Step 4, the 1.5 μg/day or other appropriate AI would be applied in the following situations: New DSs and new DPs during their clinical development and subsequent applications for marketing.Changes to the DS synthesis resulting in new or increased acceptance criteria for existing impurities.Changes in the formulation, composition, or manufacturing process resulting in new degradation products or increased acceptance criteria for existing degradation products.Introduction of a new source of the DS through a drug master file (DMF) from a supplier who has not had a previously accepted DMF in the relevant region.Changes made to a specific synthetic step as described in ICH M7 Section 4.1.A newly discovered Class 1 or Class 2 impurity, a structure in the cohort of concern, or new relevant impurity hazard data, as described in ICH M7 Section 4.4

Question

Answer

Why was HIV disease moved to the “Treatment duration of >10 years to lifetime” in the clinical use scenarios table? How should this change be implemented?

The treatment duration category was changed because of advances in the clinical treatment of HIV disease. To avoid disruption of supply of HIV drugs already on the market, this change would not be applied to currently marketed products. For example, when a new DS supplier is proposed, the AI would remain at 10 μg/day in cases where the DS produced by this supplier, using the same route of synthesis, is a component of an existing DP marketed in the specific region (see ICH M7 Section 4.1). For regulatory submissions 18 months after the date that the M7 Q&A reached Step 4, the 1.5 μg/day or other appropriate AI would be applied in the following situations: New DSs and new DPs during their clinical development and subsequent applications for marketing.Changes to the DS synthesis resulting in new or increased acceptance criteria for existing impurities.Changes in the formulation, composition, or manufacturing process resulting in new degradation products or increased acceptance criteria for existing degradation products.Introduction of a new source of the DS through a drug master file (DMF) from a supplier who has not had a previously accepted DMF in the relevant region.Changes made to a specific synthetic step as described in ICH M7 Section 4.1.A newly discovered Class 1 or Class 2 impurity, a structure in the cohort of concern, or new relevant impurity hazard data, as described in ICH M7 Section 4.4

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