Directive 2001/83/EC of the European Parliament and of the CouncilShow full title

[F1 4. MODULE 4: NON-CLINICAL REPORTS U.K.

4.1. Format and Presentation U.K.

The general outline of Module 4 is as follows:

• Table of contents

• Study reports

  • Pharmacology

    • Primary Pharmaco-dynamics

    • Secondary Pharmaco-dynamics

    • Safety Pharmacology

    • Pharmaco-dynamic Interactions

  • Pharmaco-kinetics

    • Analytical Methods and Validation Reports

    • Absorption

    • Distribution

    • Metabolism

    • Excretion

    • Pharmaco-kinetic Interactions (non-clinical)

    • Other Pharmaco-kinetic Studies

  • Toxicology

    • Single-Dose Toxicity

    • Repeat-Dose Toxicity

    • Genotoxicity

      • In vitro

      • In vivo (including supportive toxico-kinetics evaluations)

    • Carcinogenicity

      • Long-term studies

      • Short- or medium-term studies

      • Other studies

    • Reproductive and Developmental Toxicity

      • Fertility and early embryonic development

      • Embryo-fetal development

      • Prenatal and postnatal development

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

    • Local Tolerance

  • Other Toxicity Studies

    • Antigenicity

    • Immuno-toxicity

    • Mechanistic studies

    • Dependence

    • Metabolites

    • Impurities

    • Other

• Literature references

4.2. Content: basic principles and requirements U.K.

Special attention shall be paid to the following selected elements.

(1)

The pharmacological and toxicological tests must show:

a)

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;

b)

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.

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

(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.

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

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

examination 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.

(3)

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

(4)

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

4.2.1. Pharmacology U.K.

Pharmacology study shall follow two distinct lines of approach.

• 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.

• 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.

For 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.

4.2.2. Pharmaco-kinetics U.K.

Pharmaco-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.

The 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.

Information 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.).

In 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).

Pharmaco-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.

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

4.2.3. Toxicology U.K.

a)

Single-dose toxicity

A 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.

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

b)

Repeat-dose toxicity

Repeated 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.

Generally, 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.

c)

Geno-toxicity

The 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.

d)

Carcino-genicity

Tests to reveal carcinogenic effects shall normally be required:

1.

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.

2.

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.

3.

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.

e)

Reproductive and developmental toxicity

Investigation of possible impairment of male or female reproductive function as well as harmful effects on progeny shall be performed by appropriate tests.

These tests comprise studies of effect on adult male or female reproductive function, studies of the toxic and teratogenic effects at all stages of development from conception to sexual maturity as well as latent effects, when the medicinal product under investigation has been administered to the female during pregnancy.

Omission of these tests must be adequately justified.

Depending on the indicated use of the medicinal product, additional studies addressing development when administering the medicinal product of the offspring may be warranted.

Embryo/foetal toxicity studies shall normally be conducted on two mammalian species, one of which shall be other than a rodent. Peri- and postnatal studies shall be conducted in at least one species. If the metabolism of a medicinal product in particular species is known to be similar to that in man, it is desirable to include this species. It is also desirable that one of the species is the same as in the repeated dose toxicity studies.

The state of scientific knowledge at the time when the application is lodged shall be taken into account when determining the study design.

f)

Local tolerance

The purpose of local tolerance studies is to ascertain whether medicinal products (both active substances and excipients) are tolerated at sites in the body, which may come into contact with the medicinal product as a result of its administration in clinical use. The testing strategy shall be such that any mechanical effects of administration or purely physico-chemical actions of the product can be distinguished from toxicological or pharmaco-dynamic ones.

Local tolerance testing shall be conducted with the preparation being developed for human use, using the vehicle and/or excipients in treating the control group(s). Positive controls/reference substances shall be included where necessary.

The design of local tolerance tests (choice of species, duration, frequency and route of administration, doses) will depend upon the problem to be investigated and the proposed conditions of administration in clinical use. Reversibility of local lesions shall be performed where relevant.

Studies in animals can be substituted by validated in vitro tests provided that the test results are of comparable quality and usefulness for the purpose of safety evaluation.

For chemicals applied to the skin (e.g. dermal, rectal, vaginal) the sensitising potential shall be evaluated in at least one of the test systems currently available (the guinea pig assay or the local lymph node assay).]

Textual Amendments

F1 Substituted by Commission directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (Text with EEA relevance).