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Council Directive 75/318/EEC of 20 May 1975 on the approximation of the
laws of Member States relating to analytical, pharmaco-toxicological and
clinical standards and protocols in respect of the testing of proprietary
medicinal products
Official Journal L 147 , 09/06/1975 p. 0001 - 0012
Greek special edition ....: Chapter 13 Volume 3 p. 54
Spanish special edition...: Chapter 13 Volume 4 p. 80
Portuguese special edition Chapter 13 Volume 4 p. 80
Finnish special edition....: Chapter 13 Volume 4 p. 86
Swedish special edition...: Chapter 13 Volume 4 p. 86
Amendments:
Amended by 383L0570
(OJ L 332 28.11.1983 p.1)
Amended by 387L0019
(OJ L 015 17.01.1987 p.31)
Amended by 389L0341
(OJ L 142 25.05.1989 p.11)
Amended by 391L0507
(OJ L 270 26.09.1991 p.32)
Amended by 393L0039
(OJ L 214 24.08.1993 p.22)
Incorporated by 294A0103(52)
(OJ L 001 03.01.1994 p.263)
Amended by 399L0082
(OJ L 243 15.09.1999 p.7)
Amended by 399L0083
(OJ L 243 15.09.1999 p.9)
Text:
COUNCIL DIRECTIVE of 20 May 1975 on the approximation of the laws of Member
States relating to analytical, pharmaco-toxicological and clinical standards and
protocols in respect of the testing of proprietary medicinal products
(75/318/EEC)
THE COUNCIL OF THE EUROPEAN COMMUNITIES,
Having regard to the Treaty establishing the European Economic Community, and in
particular Article 100 thereof;
Having regard to the proposal from the Commission;
Whereas the approximation begun by Council Directive 65/65/EEC (1) of 26 January
1965 on the approximation of provisions laid down by law, regulation or
administrative action relating to proprietary medicinal products should be
continued and the implementation of the principles laid down in that Directive
should be ensured;
Whereas among existing disparities those relating to the control of proprietary
medicinal products are of fundamental importance and point 8 of Article 4,
second paragraph of the said Directive requires that applications for
authorization to place a proprietary medicinal product on the market should be
accompanied by particulars and documents relating to the results of tests and
trials carried out on the product concerned;
Whereas standards and protocols for the performance of tests and trials on
proprietary medicinal products are an effective means of control of these
products and hence of protecting public health and can facilitate the movement
of these products by laying down uniform rules applicable to tests and trials,
the compilation of dossiers and the examination of applications;
Whereas the adoption of the same standards and protocols by all the Member
States will enable the competent authorities to arrive at their decisions on the
basis of uniform tests and by reference to uniform criteria and will therefore
help to avoid differences in evaluation;
Whereas the physico-chemical, biological or microbiological tests provided for
in point 8 of Article 4, second paragraph, of Directive 65/65/EEC are closely
related to points 3, 4, 6 and 7 of the same paragraph and it is therefore
necessary to specify the data to be provided pursuant to these points;
Whereas the quality of the tests is the essential consideration ; whereas
therefore tests carried out in accordance with these provisions must be taken
into consideration irrespective of the nationality of the experts who perform
them or the country in which they are carried out;
Whereas the concepts of "harmfulness" and "therapeutic efficacy"
referred to in Article 5 of Directive 65/65/EEC can only be examined in relation
to each other and have only a relative significance depending on the progress of
scientific knowledge and the use for which the proprietary medicinal product is
(1)OJ No 22, 9.2.1965, p. 369/65.
intended ; whereas the particulars and documents which must accompany an
application for authorization to place a proprietary medicinal product on the
market demonstrate that potential risks are outweighed by the therapeutic
efficacy of the product ; whereas failing such demonstration, the application
must be rejected;
Whereas the evaluation of "harmfulness" and "therapeutic efficacy"
may be modified in the light of new discoveries and standards and protocols must
be amended periodically to take account of scientific progress,
HAS ADOPTED THIS DIRECTIVE:
Article 1
Member States shall take all appropriate measures to ensure that the particulars
and documents which must accompany applications for authorization to place a
proprietary medicinal product on the market (marketing authorization), pursuant
to points 3, 4, 6, 7 and 8 of Article 4, second paragraph, of Directive
65/65/EEC, are submitted by the persons concerned in accordance with the Annex
to this Directive.
Where, pursuant to point 8 (a) and (b) of Article 4, second paragraph, of the
abovementioned Directive, references to published data are submitted, the
provisions of this Directive shall apply in like manner.
Article 2
Notwithstanding the provisions of other Directives on proprietary medicinal
products, Member States shall take all appropriate measures to ensure that the
competent authorities examine the particulars and documents submitted in support
of applications for marketing authorization in accordance with the criteria of
the Annex to this Directive.
Article 3
Member States shall bring into force the provisions needed in order to comply
with this Directive within 18 months of its notification and shall forthwith
inform the Commission thereof.
Member States shall ensure that they communicate to the Commission the text of
the main provisions of national law which they adopt in the field covered by
this Directive.
Article 4
This Directive is addressed to the Member States.
Done at Brussels, 20 May 1975.
For the Council
The President
R. RYAN
ANNEX
PART 1 PHYSICO-CHEMICAL, BIOLOGICAL OR MICROBIOLOGICAL TESTS OF PROPRIETARY
MEDICINAL PRODUCTS
A. QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS
The particulars and documents which must accompany applications for marketing
authorization, pursuant to point 3 of Article 4, second paragraph, of Directive
65/65/EEC shall be submitted in accordance with the following requirements. 1.
"Qualitative particulars" of all the constituents of the proprietary
medicinal product shall mean the designation or description of: - the active
ingredient(s);
- the constituent(s) of the excipients, whatever their nature or the quantity
used, including colouring matter, preservatives, stabilizers, thickeners,
emulsifiers, flavouring and aromatic substances, etc.;
- the constituents, intended to be ingested or otherwise administered to the
patient, of the outer covering of the proprietary medicinal products - capsules,
gelatine capsules, cachet shells, rectal capsules, etc.
These particulars shall be supplemented by any relevant data concerning the
container and, where appropriate, its manner of closure.
2. The "usual terminology", to be used in describing the constituents
of proprietary medicinal products, shall mean, notwithstanding the application
of the other provisions of point 3 of Article 4, second paragraph, of Directive
65/65/EEC: - in respect of substances which appear in the European Pharmacopoeia
or, failing this, in the national pharmacopoeia of one of the Member States, the
main title at the head of the monograph in question, with reference to the
pharmacopoeia concerned;
- in respect of other substances, the international non-proprietary name
recommended by the World Health Organization, which may be accompanied by
another non-proprietary name, or, failing these, the exact scientific
designation ; substances not having an international non-proprietary name or an
exact scientific designation shall be described by a statement of how and from
what they were prepared, supplemented, where appropriate, by any other relevant
details;
- in respect of colouring matter, designation by the "E" code assigned
to them in a future Council Directive on the approximation of the rules of the
Member States concerning the colouring matters authorized for use in proprietary
medicinal products.
3. In order to give "quantitative particulars" of the active
constituents of the proprietary medicinal products, it is necessary, depending
on the pharmaceutical form concerned, to specify the weight, or the number of
international units, either per dosage-unit or per unit of weight or volume, of
each active ingredient.
This information shall be supplemented: - in respect of injectable preparations,
by the weight of each active ingredient in the unit container, taking into
account the usable volume of the product;
- in respect of proprietary medicinal products to be administered by drops, by
the weight of each active ingredient contained in the number of drops
corresponding to an average dose;
- in respect of syrups, emulsions, granular preparations and other
pharmaceutical forms to be administered in measured quantities, by the weight of
each active ingredient per measured quantity.
Active ingredients present in the form of compounds or derivatives shall be
described quantitatively by their total weight, and if necessary or relevant, by
the weight of the active moiety or moieties of the molecule (in the case of
chloramphenicol palmitate, for example, the weight of the ester and that of the
corresponding chloramphenicol shall be given).
The biological units of activity of substances which have not been defined
chemically, and on which there is insufficient bibliographical information,
shall be expressed in such a way as to provide unambiguous information on the
activity of the substances.
B. DESCRIPTION OF METHOD OF PREPARATION
The "brief description of the method of preparation" accompanying the
application for marketing authorization pursuant to point 4 of Article 4, second
paragraph, of Directive 65/65/EEC, shall be drafted in such a way as to give an
adequate synopsis of the nature of the operations employed.
For this purpose it shall include at least: - mention of the various stages of
manufacture, so that an assessment can be made of whether the processes employed
in producing the pharmaceutical form might have produced an adverse change in
the constituents;
- in the case of continuous manufacture, full details concerning precautions
taken to ensure the homogeneity of the final product;
- the actual manufacturing formula, with the quantitative particulars of all the
substances used, the quantities of excipients, however, being given in
approximate terms in so far as the pharmaceutical form makes this necessary ;
mention shall be made of any substances that may disappear in the course of
manufacture;
- a statement of the stages of manufacture at which sampling is carried out for
in-process control tests, where other data in the documents supporting the
application show such texts to be necessary for the quality control of the
proprietary medicinal product.
C. CONTROL OF STARTING MATERIALS
For the puposes of this paragraph, "starting materials" shall mean all
the constituents of the proprietary medicinal product and, if necessary, of its
container, as referred to in paragraph A point 1, above.
The particulars and documents accompanying the application for marketing
authorization pursuant to points 7 and 8 of Article 4, second paragraph, of
Directive 65/65/EEC shall include the results of the tests relating to quality
control of all the constituents used. These shall be submitted in accordance
with the following provisions.
1. Starting materials listed in pharmacopoeias
The monographs of the European Pharmacopoeia shall be applicable to all
substances appearing in it.
In respect of other substances, each Member State may require observance of its
own national pharmacopoeia with regard to products manufactured in its territory.
Constituents fulfilling the requirements of the European Pharmacopoeia or the
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently
with point 7 of Article 4, second paragraph, of Directive 65/65/EEC. In this
case the description of the analytical methods may be replaced by a detailed
reference to the pharmacopoeia in question.
However, where a starting material in the European Pharmacopoeia or in the
pharmacopoeia of a Member State has been prepared by a method liable to leave
impurities not mentioned in the pharmacopoeia monograph these impurities and
their maximum tolerance levels must be declared and a suitable test method
advanced.
Reference to pharmacopoeias of third countries may be permitted in cases where
the substance is described neither in the European Pharmacopoeia nor in the
national pharmacopoeia concerned ; in that case the monograph shall be submitted,
accompanied where necessary by a translation for which the applicant will be
responsible.
Colouring matter shall, in all cases, satisfy the requirements of a future
Council Directive on the approximation of the rules of the Member States
concerning the colouring matters authorized for use in proprietary medicinal
products.
For routine tests on each batch of starting material, only that part of the
pharmacopoeia relating to control tests (purity and strengths) shall be
mandatory ; the full range of identity tests need not necessarily be performed
where those that have been performed permit an unambiguous characterization. In
this case, the reference to the monograph of the pharmacopoeia mentioned above
shall include details relating to this aspect.
In cases where a specification contained in a monograph of the European
Pharmacopoeia or in the national pharmacopoeia of a Member State might be
insufficient to ensure the quality of the substance, the competent authorities
may request more appropriate specifications from the person responsible for
placing the product on the market.
2. Starting materials not in a pharmacopoeia
Constituents which are not given in any pharmacopoeia shall be described in the
form of a monograph under the following headings: (a) The name of the substance,
meeting the requirements of paragraph A, point 2, shall be supplemented by any
trade or scientific synonyms;
(b) the description of the substance, set down in a form similar to that used in
a descriptive item in the European Pharmacopoeia, shall be accompanied by any
necessary explanatory evidence, especially concerning the molecular structure
where appropriate ; it must in such a case be accompanied by a brief indication
of the method of synthetic preparation. Where substances can only be described
by their method of preparation, the description should be sufficiently detailed
to characterize a substance which is constant both in its composition and in its
effects;
(c) methods of indentification may be described in the form of complete
techniques as used for production of the substance, and in the form of tests
which ought to be carried out as a routine matter;
(d) purity tests shall be described in relation to the sum total of predictable
impurities, especially those which may have a harmful effect, and, if necessary,
those which, having regard to the combination of substances to which the
application refers, might adversely affect the stability of the proprietary
medicinal product or distort analytical results;
(e) the assay technique(s) must be described in sufficiently precise detail so
as to be reproducible in control tests, carried out at the request of the
competent authority ; any special apparatus and equipment which may be used
shall be described in adequate detail, possibly accompanied by a diagram. The
formulae of the laboratory reagents shall be supplemented, if necessary, by the
method of preparation.
The standard error of the method, its reliability and the acceptability limits
of the results shall be specified and, if necessary, explained.
With regard to complex substances of plant or animal origin, a distinction must
be made between the case where multiple pharmacological effects render chemical,
physical or biological control of the principal constituents necessary, and the
case of substances containing one or more groups of principles having similar
activity, in respect of which an overall method of assay may be accepted;
(f) any special precautions that may be necessary during storage of the starting
material and, if necessary, its storage life shall be given.
D. CONTROL TESTS CARRIED OUT AT AN INTERMEDIATE STAGE OF THE MANUFACTURING
PROCESS
The particulars and documents accompanying an application for marketing
authorization ; pursuant to points 7 and 8 of Article 4, second paragraph, of
Directive 65/65/EEC, shall include particulars relating to the product control
tests that may be carried out at an intermediate stage of the manufacturing
process, with a view to ensuring the consistency of the technical
characteristics and the production process.
These tests are essential for checking the conformity of the proprietary
medicinal product with the formula when, exceptionally, an applicant proposes an
analytical technique for testing the finished product which does not include the
assay of all the active ingredients (or of all the excipient constituents
subject to the same requirements as the active ingredients).
The same applies where the quality control of the finished product depends on
in-process control tests, particularly if the substance is essentially defined
by its method of preparation.
E. CONTROL TESTS ON THE FINISHED PRODUCT
The particulars and documents accompanying the application for marketing
authorization pursuant to points 7 and 8 of Article 4, second paragraph, of
Directive 65/65/EEC, shall include particulars relating to control tests on the
finished product. They shall be submitted in accordance with the following
requirements.
1. General characteristics of the various pharmaceutical forms
Certain tests of the general characteristics of a product which can be carried
out in the course of the manufacturing process shall always be included among
the tests on the finished product.
As a guideline, and subject to the possible future requirements of the European
Pharmacopoeia or the national pharmacopoeias of Member States, the general
characteristics which are to be verified for various pharmaceutical forms are
given at point 5 below.
These tests shall, wherever applicable, relate to the control of average weights
and maximum deviations, to mechanical, physical, or microbiological tests,
organoleptic characteristics, such as clarity, colour, taste, physical
characteristics such as density, pH, refractive index, etc. For each of these
characteristics, standards and tolerances must be specified by the applicant in
each particular case.
2. Identification and assay of active ingredient(s)
The description of the techniques for analyzing the finished product shall set
out in sufficiently precise detail, so that they can be reproduced readily, the
methods used for identification and assay of the active ingredient(s) either in
a representative sample from the production batch or in a number of dosage-units
analyzed individually.
In every case, the methods must correspond to the state of scientific progress
at the time and give details and explanations of the standard errors and
reliability of the analytical method and also of maximum acceptable deviations.
In certain exceptional cases of particularly complex mixtures, where assay of
active ingredients which are very numerous or present in very low amounts would
necessitate an intricate investigation difficult to carry out in respect of each
production batch, the assay of one or more active ingredients in the finished
product may be omitted, on the express condition that such assays are made at
intermediate stages in the production process. This relaxation may not be
extended to the characterization of the substances concerned. This simplified
technique shall be supplemented by a method of quantitative evaluation, enabling
the competent authority to have the conformity of the proprietary medicinal
product with its formula verified after it has been placed on the market.
An assay of biological activity shall be obligatory when physico-chemical
methods cannot provide adequate information on the quality of the product.
Where the particulars given in paragraph B show that a significant overage of an
active ingredient was employed in the manufacture of the proprietary medicinal
product, the description of the control tests on the finished product shall
include, where appropriate, the chemical and, if necessary, the
toxico-pharmacological investigation of the changes that this substance has
undergone, and possibly the characterization or assay of the degradation
products.
3. Identification and assay of excipient constituents
In so far as is necessary, the constituents of the excipient shall be subject at
least to characterization tests.
The method proposed for identifying colouring matters must enable a verification
to be made that such matters appear in the list to be annexed to a future
Council Directive on the approximation of the rules of the Member States
concerning the colouring matters authorized for use in proprietary medicinal
products.
An upper limit test shall be obligatory in respect of excipient constituents
which are subject to rules relating to toxic substances or which are being used
as preservatives, while an assay shall be obligatory in respect of constituents
liable to affect physiological functions.
4. Safety tests
Apart from the toxico-pharmacological tests submitted with the application for
marketing authorization, particulars of safety tests (abnormal toxicity) or
local tolerance in animals shall be included in the analytical particulars
wherever such tests must be undertaken as a matter of routine in order to verify
the quality of the product.
5. General characteristics of finished products to be verified systematically,
depending on the pharmaceutical form of each product
The following requirements are given as an indication and without prejudice to
any future requirements of the European Pharmacopoeia or national pharmacopoeias
of Member States ; for example, microbiological control tests of preparations
for oral administration shall be performed in accordance with the requirements
of the European Pharmacopoeia.
Tablets and pills : colour, weight and acceptable variations in unit weight ; if
necessary, disintegration time with the method used to determine this.
Coated tablets : colour, disintegration time with the method used to determine
this ; weight of finished tablet ; weight of core and acceptable variations in
unit weight.
Capsules and gelatine capsules : colour, disintegration time with the method
used to determine this ; appearance and weight of content with acceptable
variations in unit weight.
Enteric-coated preparations (tablets, capsules, gelatine capsules, granular
preparations) : in addition to the requirements of the particular pharmaceutical
form, resistance time in an artificial gastric medium, with the method used to
determine this ; disintegration time in an artificial intestinal medium, with
the method used to determine this.
Preparations with special protective coating (tablets, capsules, gelatine
capsules, granular preparations) : in addition to the requirements of the
particular pharmaceutical form, verification of the effectiveness of the coating
for the desired purpose.
Preparations with gradual release of the active principle : in addition to the
requirements of the particular pharmaceutical form, requirements relating to
gradual release, with the method used to determine this.
Cachets, packets and sachets : nature and weight of contents and acceptable
variations in unit weight.
Injectable preparations : colour, volume of contents and acceptable variations
of this volume ; pH, clarity of solution, size limit of particulate matter in
the case of suspensions ; sterility tests, with description of test methods ;
except in special cases, in respect of preparations to be administered in single
doses of 10 ml or more, a pyrogen test with description of method.
Ampoules with solid content : quantity of product per ampoule and permitted
variations in weight ; sterility requirements and tests.
Ampoules to be taken orally : colour, appearance, volume of content and
acceptable variations.
Ointments, creams, etc. : colour and consistency ; weight and acceptable margin
of variation ; nature of container ; in certain cases microbiological control
tests.
Suspensions : colour ; where settlement occurs, the ease of re-suspendability.
Emulsions : colour, type, stability.
Suppositories and pessaries : colour, weight and acceptable variations in unit
weight ; melting temperature or disintegration time, with the methods used to
determine these.
Aerosols : description of container and valve with details of output ; particle
size-limit, where the product is intended to be inhaled.
Collyria, eye ointments, eye lotions : colour, appearance, sterility controls,
with description of the method used ; where appropriate, clarity and size limit
of particulate matter in the case of suspensions, pH determination.
Syrups, solutions, etc : colour, appearance.
F. STABILITY TESTS
The particulars and documents accompanying the application for marketing
authorization pursuant to points 6 and 7 of Article 4, second paragraph, of
Directive 65/65/EEC shall be submitted in accordance with the following
requirements: A description shall be given of the investigations by which the
shelf life proposed by the applicant has been determined.
Where a finished product is liable to give rise to toxic degradation products
the applicant must declare these and indicate characterization and assay methods.
The conclusions shall contain the results of analyses, justifying the proposed
shelf life under normal, or, where appropriate, under special storage conditions.
A study of the interaction between product and container shall be submitted
wherever the risk of such interaction is regarded as possible, especially where
injectable preparations or aerosols for internal use are concerned.
PART 2 TOXICOLOGICAL AND PHARMACOLOGICAL TESTS
The particulars and documents accompanying the application for marketing
authorization pursuant to point 8 of Article 4, second paragraph, of Directive
65/65/EEC shall be given in accordance with the requirements of Chapters I and
II below.
CHAPTER I PERFORMANCE OF TESTS
A. INTRODUCTION
The toxicological and pharmacological tests must show: 1. 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 gravity of the pathological condition concerned;
2. 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 potential of the product.
B. TOXICITY
1. Single dose toxicity (acute toxicity)
Acute toxicity test means 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 proprietary medicinal product, in the proportions
in which they are present in the actual product.
Wherever practicable, the product in its actual pharmaceutical form shall be
subjected to an acute toxicity test.
This study will cover the symptoms observed, including local reactions. Where
possible, the LD50 value with its fiducial limits (95 %) will be determined. The
period during which the test animals are oberserved shall be fixed by the
investigator and shall not be less than one week.
The acute toxicity test must be carried out on at least two mammalian species of
known strain, and at least two different routes of administration shall normally
be used : one being indentical with or similar to that proposed for use in human
beings and the other ensuring systemic absorption of the substance. This
determination must be carried out on equal numbers of male and female animals.
In the case of active substances in combination, the study must be carried out
in such a way as to check whether or not potentiation or novel toxic effects
occur.
2. Repeated dose toxicity (sub-acute or chronic toxicity)
Repeated dose toxicity tests are intended to reveal any physiological and/or
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 shall be to determine by
experiment the non-toxic dose range of the product and normally it shall last
three to six months.
In respect of proprietary medicinal products to be administered once only to
humans, a single test lasting two to four weeks shall be performed.
If, however, having regard to the proposed duration of use in human beings, the
investigator sees fit to carry out experiments of greater or lesser duration
than indicated above, he must give adequate reasons for doing so.
Reasons should also be given for the dosages chosen.
Repeated dose toxicity tests shall be carried out on two species of mammals one
of which must be a non-rodent. The choice of route(s) of administration employed
shall depend on the intended therapeutic use and the possibilities of systemic
absorption. The method and frequency of dosage shall be clearly stated.
The maximum dose should be chosen so as to bring harmful effects to light. The
lower doses will then enable the animal's tolerance of the product to be
determined.
Wherever possible, and always in experiments on small rodents, the design of the
experiment and the control procedures must be suited to the scale of the problem
being tackled and enable fiducial limits to be determined.
The evaluation of the toxic effects shall be based on observation of behaviour,
growth, haematological and biochemical tests, especially those relating to the
excretory mechanism, and also on autopsy reports and accompanying histological
data. The choice and range of each group of tests will depend on the species of
animal used and the state of scientific knowledge at the time.
In the case of new combinations of known substances that have been investigated
in accordance with the provisions of this Directive, the long-term tests may,
except where acute and subacute toxicity tests have demonstrated potentiation or
novel toxic effects, be suitably modified by the investigator who shall submit
his reasons for such modification. Substances that have been shown to be safe by
wide usage over at least three years in clinical treatment of human beings, and
by the result of controlled trials shall be treated in the same way as known
substances which have already been investigated in accordance with these
standards and protocols.
An excipient used for the first time in the pharmaceutical field shall be
treated like an active ingredient.
C. FOETAL TOXICITY
This investigation comprises a demonstration of the toxic and especially the
teratogenic effects observed in the issue of conception when the substance under
investigation has been administered to the female during pregnancy.
Although up to the present these tests have had only a limited predictive value
in regard to the application of the results to human beings, they are thought to
provide important information where the results show effects such as resorptions
and other anomalies.
Omission of these tests, either because the proprietary medicinal product will
not normally be used by women capable of childbearing or for other reasons, must
be adequately justified.
The tests in question shall be carried out on at least two animal species : a
breed of rabbits sensitive to known teratogenic substances and rats or mice
(specifying the strain) or, if appropriate, in some other animal species.
The details of the test (number of animals, amounts administered, timing of
administration and criteria for evaluation of results) shall depend on the state
of scientific knowledge at the time when the application is lodged, and the
level of statistical significance that the results must attain.
D. EXAMINATION OF REPRODUCTIVE FUNCTION
If the results of other tests reveal anything suggesting harmful effects on
progeny or impairment of male or female reproductive function, this shall be
investigated by appropriate tests.
E. CARCINOGENICITY
Tests to reveal carcinogenic effects shall be essential: 1. in respect of
substances having a close chemical analogy with known carcinogenic or
cocarcinogenic compounds;
2. in respect of substances which have given rise to suspicious changes during
the long term toxicological tests.
Such tests may also be required in respect of substances to be included in
proprietary medicinal products likely to be administered regularly over a
prolonged period of a patient's life.
F. PHARMACODYNAMICS
This heading covers the variations caused by the substance in the functions of
the physiological systems, whether these functions are normal or experimentally
modified.
This study shall follow two distinct lines of approach.
Firstly, the actions on which the recommended application in therapeutic
practice is based shall be adequately described. The results shall be expressed
in quantitative terms using, for example, dose-effect curves, time-effect curves
etc., and wherever possible, compared with data relating to a substance whose
activity is known. Where a higher therapeutic potency is being claimed for a
substance, the difference shall be demonstrated and shown to be statistically
significant.
Secondly, the investigator shall provide a general pharmacological
characterization of the substance, with special reference to collateral effects.
In general, the main functions of the physiological systems should be
investigated. The depth of this investigation must be increased as the doses
liable to produce side-effects approach those producing the main effect for
which the substance is being proposed.
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. The experimental results shall be set out clearly
and, when relevant to the test, their statistical significance quoted.
Unless good reasons are given to the contrary, any quantitative modification of
responses resulting from repeated administration of the substance shall be
investigated.
Tests on combinations of active substances may be promoted either by
pharmacological premises or by indications of therapeutic effect.
In the first case, the pharmacodynamic 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.
If a combination includes a novel active substance, the latter must previously
have been studied in depth.
G. PHARMACOKINETICS
Pharmacokinetics means the study of the fate of the active substance within the
organism, and covers the study of the absorption, distribution,
biotransformation and elimination of the substance.
The study of these different phases may be carried out both by means of
physical, chemical or biological methods, and by observation of the actual
pharmacodynamic 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 chemotherapeutic substances (antibiotics, etc.) and substances whose
use depends on their non-pharmacodynamic effects (e.g. numerous diagnostic
agents etc.)
Pharmacokinetic investigation of pharmacologically active substances is
desirable.
In the case of new combinations of known substances which have been investigated
in accordance with the provisions of this Directive pharmacokinetic studies
shall not be required, if the toxicity tests and therapeutic experimentation
justify their omission. The same applies to substances that have been shown to
be efficaceous and safe by wide usage over a period of at least three years in
the clinical treatment of human beings and by controlled trials.
H. PRODUCTS FOR TOPICAL USE
Where a proprietary medicinal product is intended for topical use systemic
absorption must be investigated, due account also being taken of the possible
use of the product on broken skin. Only if it is proved that systemic absorption
under these conditions is negligible may repeated dose systemic toxicity tests,
foetal toxicity tests and studies of reproductive function be omitted.
If, however, systemic absorption is demonstrated during therapeutic
experimentation, toxicity tests shall be carried out on animals, and where
necessary, foetal toxicity tests.
In all cases tests of local tolerance after repeated application shall be
carried out with particular care and include histological examinations ; the
possibility of sensitization shall be investigated and any carcinogenic
potential investigated in the cases referred to in paragraph E.
CHAPTER II PRESENTATION OF PARTICULARS AND DOCUMENTS
As in all scientific work, the dossier of toxicological and pharmacological
tests shall be arranged as follows: (a) an introduction defining the subject
accompanied possibly by references to published data;
(b) a detailed experimental protocol giving a description of the methods,
apparatus and materials used, details of the species, and the breed and strain
of animals, where they were obtained, their number and the conditions under
which they were housed and fed, stating, inter alia, whether they were specific
pathogen-free (SPF) or not ; omission of any of the tests listed above shall be
explained;
(c) all the important results obtained, whether favourable or unfavourable. The
original data should be described in sufficient detail to allow the results to
be critically evaluated independently of their interpretation by the author. By
way of explanation and illustration, the results may be accompanied by
reproductions of kymographic charts, microphotographs, etc.;
(d) a statistical analysis of the results, where such is called for by the test
programme, and variance within the data;
(e) an objective discussion of the results obtained, leading to conclusions on
the toxicological and pharmacological properties of the substance, on its safety
margins in the animal and its possible side-effects, on its fields of
application, on its active dose levels and any possible incompatibilities;
(f) all information necessary to acquaint the clinician as fully as possible
with the potential of the proposed proprietary medicinal product. The discussion
shall be supplemented by suggestions as to possible treatment for acute toxic
reactions and any side-effects that may occur in human beings;
(g) a summary together with precise references to published data.
PART 3 CLINICAL TRIALS
The particulars and documents accompanying applications for marketing
authorizations pursuant to point 8 of Article 4, second paragraph, of Directive
65/65/EEC shall be submitted in accordance with the provisions of Chapters I and
II below.
CHAPTER I CONDUCT OF TRIALS
1. Clinical trials must always be preceded by adequate pharmacological and
toxicological tests, carried out on animals in accordance with the requirements
of this Directive relevant to such tests. The clinician must acquaint himself
with the conclusions drawn from the pharmacological and toxicological studies
and hence the applicant must provide him with the complete pharmacological and
toxicological reports.
2. Clinical trials must be carried out in the form of "controlled clinical
trials". The design of the trials will vary from case to case and also will
depend on ethical considerations ; thus it may, in some instances, be more
pertinent to compare the therapeutic effect of a new proprietary medicinal
product with that of an established medicinal product of proven therapeutic
value rather than with the effect of a placebo.
3. As far as possible, and particularly in trials where the effect of the
product cannot be objectively measured, the "double blind" method of
controlled study should be used.
4. If statistical methods are necessary to determine the therapeutic effect, the
criteria upon which the trial is based must be sufficiently precise to permit a
statistical analysis to be undertaken. Inclusion of a large number of patients
in a trial must not be regarded as an adequate substitute for a properly
controlled trial.
CHAPTER II PRESENTATION OF PARTICULARS AND DOCUMENTS
1. The clinical particulars to be provided pursuant to point 8 of Article 4,
second paragraph, of Directive 65/65/EEC must enable a sufficiently well-founded
and scientifically valid opinion to be formed as to whether the proprietary
medicinal product satisfies the criteria governing the granting of a marketing
authorization. Consequently, an essential requirement is that the results of all
clinical trials should be communicated, both favourable and unfavourable.
2. The results of the trials shall be presented in accordance with the following
scheme:
A. PHARMACOLOGICAL PARTICULARS (Clinical pharmacology)
1. Wherever possible particulars shall be-given of the results of: (a) tests
demonstrating pharmacological actions;
(b) tests demonstrating the pharmacodynamic mechanisms underlying the
therapeutic effect;
(c) tests demonstrating biotransformation and the main pharmacokinetic
processes.
Total or partial omission of these data must be explained.
Should unexpected results occur during the course of the tests, further
preliminary toxicological and pharmacological tests on animals must be
undertaken and reviewed.
2. If the proprietary medicinal product is intended for long-term
administration, particulars shall be given of any modification of the
pharmacological action following repeated administration.
3. If the product is normally to be administered concomitantly with other
medicinal products, particulars shall be given of joint administration tests
performed to demonstrate possible modification of the pharmacological action.
4. All side-effects noted during the tests shall be described individually.
B. CLINICAL PARTICULARS
1. Individual case histories - Clinical records
Particulars of clinical trials must contain sufficient detail to allow an
objective judgment to be made. As a general rule, these trials should be carried
out in a medical care establishment.
The aim of the trials shall be stated, together with the criteria, both
favourable and unfavourable, for evaluating the results.
Each investigator shall give his name, address, appointments, university
qualifications and clinical duties, state where the trial was carried out and
assemble the following information in respect of each patient individually: 1.
identification of the patient (e.g., by reference to the number of his medical
file);
2. criteria determining admission of the patient to the trials;
3. patient's age;
4. patient's sex;
5. diagnosis and indication for which the product was administered and the
patient's history ; relevant particulars of any previous illnesses shall be
given;
6. dosage and method of administration of the product;
7. frequency of administration and any precautions taken at the time of
administration;
8. duration of treatment and of the subsequent observation period;
9. details of medicinal products administered previously or concomitantly, i.e.
at any time during the period covered by the investigation;
10. dietary regime, if pertinent;
11. all results of the clinical trials (including unfavourable or negative
results) with a full statement of clinical observations and results of clinical
investigations (such as X-rays, electroencephalograms, electrocardiograms,
laboratory analyses, physiological tests etc.), required to evaluate the
application. The techniques used must be specified, and the significance of any
variations in the results explained (for example, variance in method, variance
between individuals or the effects of treatment);
12. all particulars of the observed side-effects, whether harmful or not, and
any measures taken in consequence. Relation of cause and effect must be
investigated with the same care normally accorded to identifying therapeutic
action;
13. an opinion concerning each individual case.
Omission of one or more of items 1 to 13 must be explained.
The information referred to above must be forwarded to the competent
authorities.
The competent authorities may waive this requirement in whole or in part if the
documentation is very extensive or if there are other adequate reasons of the
same order, subject, however, to there being no doubt as to the sound basis of
the summary and conclusions referred to in point 2 below.
The person responsible for placing the proprietary medicinal product on the
market must make arrangements to ensure that the original documents which formed
the basis of the data supplied, including the codes for associating those
documents with the patients in question, are kept for at least five years
following transmission of the dossier to the competent authority.
2. Summary and conclusions
1. The clinical observations referred to in items 1 to 13 of paragraph 1 above,
shall be summarized in a synopsis of the trials and their results, indicating:
(a) the number and sex of patients treated;
(b) the selection and age-distribution of the groups of patients being
investigated and the control groups;
(c) the number of patients withdrawn prematurely from the trials and the reasons
for such withdrawal;
(d) where controlled trials were carried out under the above conditions, whether
the control group: - received no treatment,
- received a placebo,
- received another medicinal product of known effect;
(e) the frequency of observed side-effects;
(f) details concerning patients who may be at increased risk, e.g. elderly
people, children, women during pregnancy or menstruation, or whose physiological
or pathological condition requires special consideration;
(g) a statistical evaluation of the results when this is called for by the
design of the trials and the variable factors involved.
2. Finally the investigator shall, in the general conclusions on the
experimental evidence, express an opinion on the safety of the product under
normal conditions of use, its compatibility, its therapeutic efficacy and any
useful information relating to indications and contraindications, dosage and
average duration of treatment as well as any special precautions to be taken
during treatment and the clinical symptoms of overdosage.
C. GENERAL CONSIDERATIONS
1. The clinician shall always indicate his observations on: (a) any signs of
habituation, addiction or difficulty in weaning patients from the medicinal
product;
(b) any interactions that have been observed with other medicinal products
administered concomitantly;
(c) the criteria determining exclusion of certain patients from the trials.
2. Particulars concerning a new combination of medicinal substances must be
identical to those required for new medicinal products and must substantiate the
safety and therapeutic efficacy of the combination.
CHAPTER III EXAMINATION OF APPLICATIONS FOR AUTHORIZATION TO PLACE A PROPRIETARY
MEDICINAL PRODUCT ON THE MARKET
In examining any application submitted pursuant to Article 4 of Directive
65/65/EEC, the competent authorities of Member States shall apply the following
principles. 1. Evaluation of the application for marketing authorization shall
be based on clinical trials or clinical pharmacological experiments designed to
determine the therapeutic efficacy and safety of the product under normal
conditions of use, having regard to the therapeutic indications for use in human
beings. Therapeutic advantages must outweigh potential risks.
2. Clinical statements concerning the therapeutic efficacy or safety of a
proprietary medicinal product under normal conditions of use which are not
scientifically substantiated cannot be accepted as valid evidence.
3. Demonstration of pharmacodynamic effects in human beings shall not in itself
be sufficient to justify conclusions regarding any particular potential
therapeutic effect.
4. The value of data on the therapeutic efficacy and safety of a proprietary
medicinal product under normal conditions of use will be very greatly enhanced
if such data come from several competent investigators working independently.
5. When, in respect of particular therapeutic indications, the applicant can
show that he is unable to provide comprehensive data on therapeutic efficacy and
safety under normal conditions of use, because: (a) the indications for which
the product in question is intended are encountered so rarely that the applicant
cannot reasonably be expected to provide comprehensive evidence, or
(b) in the present state of scientific knowledge comprehensive information
cannot be provided, or
(c) it would be contrary to generally accepted principles of medical ethics to
collect such information,
marketing authorization may be granted on the following conditions: (a) the
proprietary medicinal product in question may be supplied on medical
prescription only and may in certain cases be administered only under strict
medical supervision, possibly in a hospital;
(b) the package leaflet and any medical information shall draw the attention of
the medical practitioner to the fact that the particulars available concerning
the proprietary medicinal product in question is as yet inadequate in certain
specified respects.
Source: EUR-Lex
Community Legislation in force-Document 37
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Anthroposophic
Medicine