Changes from plenary report to adopted text

Added— Genotoxicity

Added— In vitro

Added— In vivo (including supportive toxico-kinetics evaluations)

Added— Carcinogenicity

Added— Long-term studies

Added— Short- or medium-term studies

Added— Other studies

Added— Reproductive and Developmental Toxicity

Added— Fertility and early embryonic development

Added— Embryo-fetal development

Added— Prenatal and postnatal development

Added— Studies in which the offspring (juvenile animals) are dosed and/or further evaluated

Added— Local Tolerance

Added— Other Toxicity Studies

Added— Antigenicity

Added— Immuno-toxicity

Added— Mechanistic studies

Added— Dependence

Added— Metabolites

Added— Impurities

Added— Other

Added— Literature references

Added4.2. Content: basic principles and requirements

AddedSpecial attention shall be paid to the following selected elements.

Added(1) The pharmacological and toxicological tests must show:

Addeda) the potential toxicity of the product and any dangerous or undesirable toxic effects that may occur under the proposed conditions of use in human beings; these should be evaluated in relation to the pathological condition concerned;

Addedb) the pharmacological properties of the product, in both qualitative and quantitative relationship to the proposed use in human beings. All results must be reliable and of general applicability. Whenever appropriate, mathematical and statistical procedures shall be used in designing the experimental methods and in evaluating the results.

AddedAdditionally, it is necessary for clinicians to be given information about the therapeutic and toxicological potential of the product.

Added(2) For biological medicinal products such as immunological medicinal products and medicinal products derived from human blood or plasma, the requirements of this Module may have to be adapted for individual products; therefore the testing program carried out shall be justified by the applicant.

AddedIn establishing the testing program, the following shall be taken into consideration:

Addedall tests requiring repeated administration of the product shall be designed to take account of the possible induction of, and interference by, antibodies;

Addedexamination of reproductive function, of embryo/foetal and peri-natal toxicity, of mutagenic potential and of carcinogenic potential shall be considered. Where constituents other than the active substance(s) are incriminated, validation of their removal may replace the study.

Added(3) The toxicology and pharmaco-kinetics of an excipient used for the first time in the pharmaceutical field shall be investigated.

Added(4) Where there is a possibility of significant degradation during storage of the medicinal product, the toxicology of degradation products must be considered.

Added4.2.1. Pharmacology

AddedPharmacology study shall follow two distinct lines of approach.

Added— Firstly, the actions relating to the proposed therapeutic use shall be adequately investigated and described. Where possible, recognised and validated assays, both in vivo and in vitro, shall be used. Novel experimental techniques must be described in such detail as to allow them to be reproduced. The results shall be expressed in quantitative terms using, for example, dose-effect curves, time-effect curves, etc. Wherever possible, comparisons shall be made with data relating to a substance or substances with a similar therapeutic action.

Added— Secondly, the applicant shall investigate the potential undesirable pharmaco-dynamic effects of the substance on physiological functions. These investigations shall be performed at exposures in the anticipated therapeutic range and above. The experimental techniques, unless they are standard procedures, must be described in such detail as to allow them to be reproduced, and the investigator must establish their validity. Any suspected modification of responses resulting from repeated administration of the substance shall be investigated.

AddedFor the pharmaco-dynamic medicinal product interaction, tests on combinations of active substances may be prompted either by pharmacological premises or by indications of therapeutic effect. In the first case, the pharmaco-dynamic study shall demonstrate those interactions, which might make the combination of value in therapeutic use. In the second case, where scientific justification for the combination is sought through therapeutic experimentation, the investigation shall determine whether the effects expected from the combination can be demonstrated in animals, and the importance of any collateral effects shall at least be investigated.

Added4.2.2. Pharmaco-kinetics

AddedPharmaco-kinetics means the study of the fate of the active substance, and its metabolites, within the organism, and covers the study of the absorption, distribution, metabolism (bio-transformation) and excretion of these substances.

AddedThe study of these different phases may be carried mainly by means of physical, chemical or possibly by biological methods, and by observation of the actual pharmaco-dynamic activity of the substance itself.

AddedInformation on distribution and elimination shall be necessary in all cases where such data are indispensable to determine the dosage for humans, and in respect of chemo-therapeutic substances (antibiotics, etc.) and substances whose use depends on their non-pharmaco-dynamic effects (e.g. numerous diagnostic agents, etc.).

AddedIn vitro studies also can be carried out with the advantage of using human material for comparison with animal material (i.e. protein binding, metabolism, drug-drug interaction).

AddedPharmaco-kinetic investigation of all pharmacologically active substances is necessary. In the case of new combinations of known substances, which have been investigated in accordance with the provisions of this Directive, pharmaco-kinetic studies may not be required, if the toxicity tests and therapeutic experimentation justify their omission.

AddedThe pharmaco-kinetic program shall be design to allow comparison and extrapolation between animal and human.

Added4.2.3. Toxicology

Addeda) Single-dose toxicity

AddedA single-dose toxicity test shall mean a qualitative and quantitative study of the toxic reactions, which may result from a single administration of the active substance or substances contained in the medicinal product, in the proportions and physico-chemical state in which they are present in the actual product.

AddedThe single-dose toxicity test must be carried out in accordance with the relevant guidelines published by the Agency.

Addedb) Repeat-dose toxicity

AddedRepeated dose toxicity tests are intended to reveal any physiological and/or anatomo-pathological changes induced by repeated administration of the active substance or combination of active substances under examination, and to determine how these changes are related to dosage.

AddedGenerally, it is desirable that two tests be performed: one short term, lasting two to four weeks, the other long-term. The duration of the latter shall depend on the conditions of clinical use. Its purpose is to describe potential adverse effects to which attention should be paid in clinical studies. The duration is defined in the relevant guidelines published by the Agency.

Addedc) Geno-toxicity

AddedThe purposes of the study of mutagenic and clastogenic potential is to reveal the changes which a substance may cause in the genetic material of individuals or cells. Mutagenic substances may present a hazard to health since exposure to a mutagen carries the risk of inducing germ-line mutation, with the possibility of inherited disorders, and the risk of somatic mutations including those leading to cancer. These studies are obligatory for any new substance.

Addedd) Carcino-genicity

AddedTests to reveal carcinogenic effects shall normally be required:

Added1. These studies shall be performed for any medicinal product whose expected clinical use is for a prolonged period of a patient's life, either continuously or repeatedly in an intermittent manner.

Added2. These studies are recommended for some medicinal products if there is concern about their carcinogenic potential, e.g. from product of the same class or similar structure, or from evidence in repeated dose toxicity studies.

Added3. Studies with unequivocally geno-toxic compounds are not needed, as they are presumed to be trans-species carcinogens, implying a hazard to humans. If such a medicinal product is intended to be administered chronically to humans a chronic study may be necessary to detect early tumorigenic effects.