4.2.3.6 — Local Tolerance

Local tolerance assessment relevant to route of administration

Requirements by Phase

IND Phase 1: conditional IND Phase 2: conditional IND Phase 3: conditional NDA: required

Content Requirements

• Local tolerance studies summarized by species, route, methodology, findings
• Relevant to intended route of administration
• Assessment of irritation, sensitization potential
• Histopathological evaluation of injection/application sites

Expected Deliverables

• Local tolerance study report
• Summary table of local tolerance findings by species/route

ICH Guidelines: M3(R2)

Regulatory Requirements (ICH M3R2)

• [Phase 1] If a novel i.v. vehicle is employed in a microdose study, local tolerance of the vehicle should be assessed.
• Local tolerance should preferably be evaluated by the intended therapeutic route as part of general toxicity studies; stand-alone studies are generally not recommended.
• [Phase 1] A single-dose local tolerance study in a single species is appropriate for limited human administration by non-therapeutic routes.
• [Phase 1] If systemic exposure from non-therapeutic administration is covered by existing toxicology, local tolerance study endpoints can be confined to clinical signs and macroscopic/microscopic examination of application site.
• [Phase 1] For i.v. microdose studies supported by an oral toxicology package, local tolerance of the drug substance is not warranted.
• [before Phase 3] For parenteral products, local tolerance at unintended injection sites should be conducted before exposure of large numbers of patients (e.g., Phase III clinical trials), when appropriate.
• Other parenteral routes should be evaluated on a case-by-case basis for local tolerance.

Regulatory Requirements (ICH S1A)

• [Pre-marketing approval] Carcinogenicity studies should only be performed when human exposure warrants the need for information from life-time studies in animals in order to assess carcinogenic potential.
• [Pre-marketing approval] Carcinogenicity studies should be conducted to avoid the unnecessary use of animals in testing and to provide consistency in worldwide regulatory assessments of applications.
• [Pre-marketing approval] Carcinogenicity studies should be performed for any pharmaceutical whose expected clinical use is continuous for at least 6 months.
• [Pre-marketing approval] For pharmaceuticals used frequently in an intermittent manner in the treatment of chronic or recurrent conditions, carcinogenicity studies are generally needed.
• [Pre-marketing approval] Carcinogenicity studies may also need to be considered for certain delivery systems which may result in prolonged exposures.
• [Pre-marketing approval] Pharmaceuticals administered infrequently or for short duration of exposure (e.g., anaesthetics and radiolabelled imaging agents) do not need carcinogenicity studies unless there is cause for concern.
• [Pre-marketing approval] Carcinogenicity studies may be recommended for some pharmaceuticals if there is concern about their carcinogenic potential.
• [Pre-marketing approval] Unequivocally genotoxic compounds need not be subjected to long-term carcinogenicity studies.
• [Pre-marketing approval] If an unequivocally genotoxic drug is intended to be administered chronically to humans, a chronic toxicity study (up to one year) may be necessary to detect early tumorigenic effects.
• [Pre-marketing approval] Assessment of the genotoxic potential of a compound should take into account the totality of the findings and acknowledge the intrinsic value and limitations of both in vitro and in vivo tests.
• [Pre-marketing approval] When carcinogenicity studies are required, they usually need to be completed before application for marketing approval.
• [Clinical development] Completed rodent carcinogenicity studies are not needed in advance of the conduct of large scale clinical trials, unless there is special concern for the patient population.
• [Pre-marketing approval] For pharmaceuticals developed to treat certain serious diseases, carcinogenicity testing need not be conducted before market approval, although these studies should be conducted post-approval.
• [Pre-marketing approval] In instances where the life-expectancy in the indicated population is short (i.e., less than 2 - 3 years), no long-term carcinogenicity studies may be required.
• [Pre-marketing approval] Oncolytic agents intended for treatment of advanced systemic disease do not generally need carcinogenicity studies.

Note: If relevant for route of administration

Source: ICH M3(R2) Section 9