Local tolerance assessments

Local tolerance assessments are usually incorporated into repeat-dose toxicity studies. Specific assessments include clinical observations (e.g.,Draize scoring) and macroscopic and microscopic evaluations of the injection site. These types of studies may also be used to test formulation changes during the course of clinical development. 

Both irritation and local tolerance studies assess the short-term hazard of pharmaceutical agents in the immediate region of their application or installation. In particular, these studies are done (expected) to assess topically or parenterally administered drugs. 

Recent guidelines entitled Non-clinical Local Tolerance Testing of Medicinal Product from the CPMP refer to the murine local l)unph node assay as a method for the assessment of the induction phase of skin sensitisation. This method measures the ability of compoimds to induce proliferative responses in skin-draining lymph nodes. This method uses fewer animals than alternative in vivo methods and reduces the trauma to which animals are potentially subjected. ... 

Adequate evaluation of patient acceptability and compliance of buccal patches should include a clinical examination to observe local tolerance, and the incidence and degree of irritation. Trials should also involve the use of questionnaires, in order to determine a subject assessment of such factors as ... 

Assess local tolerance (infusion toxicity, implant site reaction, local microenvironment, release of paracrine factors). 

As a result of these unique delivery routes, there is an increased potential for toxicity to tissues at or near the injection site. Assessment of local tolerance and tissue compatibility of the clinical formulation is usually evaluated as part of the animal model of efficacy and/or general toxicity study, thus obviating the need for separate local tolerance studies. There may be additional concerns in cases where analogous products are used including potential differences in formulation, stability, and so forth. 

CRITICAL ASSESSMENT OF THE METHOD In case of drugs which are administered i.m., the pre-clinical i.m. toxicological is an important assay in the early phases of development. Often sings of i.m. local intolerance can be avoided or local tolerance can be improved by changes of the vehicle. 

Before human clinical trials are initiated, a number of toxicology studies need to be completed and documented in the IND submission. In addition to the studies listed above for toxicology developability assessment, preclinical toxicology studies include local tolerance, genotoxicity, safety pharmacology, and subchronic tests. 

An ICH guideline [8] indicates that local tolerance evaluations are to be conducted in animals using the route of administration proposed for human clinical testing and that these evaluations are to be performed before human exposure. The assessment of local tolerance may be part of other toxicity studies. 

Good local tolerability as assessed by low risk of injection site reactions and antibody formation... 

The ointments were applied daily for a maximum of 3 weeks, according to summary of product characteristics. After assessment of the infected nail debridement, topical antifxmgal bifonazole cream was applied daily in both groups for 8 weeks. A total of 102 patients were evaluated, i.e. 51 in the 40% urea ointment with plastic dressing group and 51 in the bifonazole urea group. The primary end point was complete removal of the nail plate at day 21. Secondary end points were complete cure and mycological cure evaluated at day 105. Ease of use and local tolerability were also assessed. 

Mazzitelli M, Brega G, Dirani D, Andalo A Antidiarrhoeal effectiveness and tolerance in man of a local antibiotic Rifaximin. Comparative assessment using a control drug. Eur Rev Med Pharmacol Sci 1984 6 301-306. 

IRRITATION AND LOCAL TISSUE TOLERANCE IN PHARMACEUTICAL SAFETY ASSESSMENT... 

TISSUE TOLERANCE IN PHARMACEUTICAL SAFETY ASSESSMENT TABLE 11.1. Evaluation of Local Tissue Reactions in Tissue Irritation Studies... 

Few, if any, products are administered via the vagina that are intended for systemic absorption. Thus, this route has not been as widely studied and characterized as others. On the other hand, large numbers of different products (douches, spermicides, antiyeast agents, etc.) have been developed that require introduction into the vagina in order to assert their localized effects. Increased research into different birth control and antiviral prophylaxis will result in more vaginal products in the future. All these must be assessed for vaginal irritation potential, and this serves as an example of the other tissue tolerance issues. 

Treatment with DNA alone, MVA alone, and in combination was well tolerated in mice. Some of the local reactions observed were considered to be related to the injection procedure rather than to the vaccine components. Other hndings were considered to be incidental in nature and not related to the vaccine treatment. Persistence was assessed by PCR, and results showed that positive signals were observed at the injection sites on both days 46 and 78. Equivocal positive results were observed in some mice (including vehicle controls) in a few other tissues, and these were most likely due to contamination and the high sensitivity of the PCR method. Since there was no persistence in any other tissue except for the injection site, no integration assays were carried out. 

Nonclinical PK/IA Minimal toxicity data were needed on recombinant HGH (rHGH) itself, since the clinical effects of HGH excess are well established and understood and are extensively documented in published literature. Sandoz performed toxicity studies to appropriately qualify impurities specific to Omnitrope, that is, a subacute 14-day rat study and a local (skin) tolerance study in rabbits. Further, the bioactivity of Omnitrope was assessed using a validated weight gain bioassay using a hypophysectomized (growth-hormone-deficient) rats. 

Safety of the product itself for the target organism, the user (who applies it) or the environment is addressed by a range of preclinical and clinical assessments which depend on the product and its use pattern. The range of safety features to be assessed includes local and systemic tolerance, acute and chronic toxicity, mutagenicity and tumorigenicity, reproductive toxicity, immunotoxicity and, for veterinary medicinal products, also the ecotoxicity. The safety tests will be described in more detail in a separate chapter below on preclinical pharmacological and safety test procedures. 

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