No C 293/8 Official Journal of the European Communities 5. 11. 84 
with the principles of good laboratory prac­
tice recognized by Community law in the 
field of tests on dangerous substances or, in 
the absence thereof, with those recom­
mended by the Organization for Economic 
Cooperation and Development.' 
(b) In Chapter I (B) (1) the fourth subparagraph 
is replaced by the following: 
'This study will cover the signs observed, 
including local reactions. The period during 
which the test animals are observed shall be 
fixed by the investigator as being adequate 
to reveal tissue or organ damage or recov­
ery, usually for a period of 14 days but not 
less than seven days, but without exposing 
the animals to prolonged suffering. Animals 
dying during the observation period should 
be subject to autopsy as also should all ani­
mals surviving to the end of the observation 
period. Histopathological examination 
should be considered on any organ showing 
macroscopic changes at autopsy. The maxi­
mum amount of information should be obtained from the animals used in the 
study. The single dose toxicity tests should 
be conducted in such a way that signs of 
acute toxicity are revealed and the mode of 
death assessed as far as reaspnably possible. 
In suitable species a quantitative evaluation 
of the approximate lethal dose and informa­
tion on the dose-effect relationship should 
be obtained, but a high level of precision is 
not required.' 
Article 2 
Member States shall take the measures necessary to 
comply with this Directive no later than 1 January 
1986. They shall forthwith inform the Commission 
thereof. 
Article 3 
This Directive is addressed to the Member States. 
Proposal for a Council recommendation concerning tests relating to the placing on the 
market of proprietary medicinal products 
COM(84) 437final 
(Submitted by the Commission to the Council on 3 October 1984) 
(84/C 293/04) 
THE COUNCIL OF THE EUROPEAN 
COMMUNITIES, 
Having regard to the Treaty establishing the Euro­
pean Economic Community, 
Having regard to the proposal from the Commis­
sion, 
Having regard to the opinion of the European Par­
liament, products ('), the Council adopted a first series of 
notes for guidance intended to prevent differences 
of interpretation in the implementation of the stan­
dards and protocols for the testing of proprietary 
medicinal products provided for by Council Direc­
tive 75/318/EEC of 20 May 1975 on the approxima­
tion of the laws of the Member States relating to 
analytical, pharmaco-toxicological and clinical stan­
dards and protocols in respect of the testing of pro­
prietary medicinal products (2), as amended by 
Directive 83/570/EEC (3); 
Having regard to the opinion of the Economic and 
Social Committee, 
Whereas in Council recommendation 83/571/EEC 
of 26 October 1983 concerning tests relating to the 
placing on the market of proprietary medicinal Whereas the adoption of new notes for guidance, 
supplementing those annexed to recommendation 
83/571/EEC, will help to promote the free move­
ment of proprietary medicinal products by facilitat-
(') OJ No L 332, 28. 11. 1983, p. 11. (2) OJ No L 147, 9. 6. 1975, p. 1. 
(3) OJNoL332, 28. 11. 1983, p. 1. 
5. 11. 84 Official Journal of the European Communities No C 293/9 
ing the taking into consideration by Member States 
of marketing authorizations already granted by 
other Member States; 
Whereas the Pharmaceutical Committee and the 
Committee for Proprietary Medicinal Products have 
been consulted on the measures contained in this 
recommendation, 
HEREBY RECOMMENDS THE MEMBER STATES 
TO: Ensure that, in the conduct of tests and in the 
presentation of results, applicants for authoriza­
tion to place proprietary medicinal products on 
the market comply with the principles and 
adhere to the methodology set out in the notes 
for guidance annexed hereto. 
Examine and evaluate, in accordance with the 
notes for guidance, all applications for market­
ing authorization. 
ANNEX I 
SINGLE DOSE TOXICITY 
Note for guidance concerning the application of the Annex to Directive 75/318/EEC, part 2, 
chapter I, paragraph B, point 1, with a view to the granting of a marketing authorization for a 
new drug. 
1. INTRODUCTION 
These guidelines deal with the qualitative and quantitative study of toxic phenomena and 
their occurrence related to time after a single administration of the substance, or combina­
tion of substances. 
These studies may give some indication of the likely effects of acute overdosage in man and 
may be useful for the design of toxicity studies requiring repeated dosing on the relevant 
animal species. 
The single dose toxicity tests should be conducted in such a way that signs of acute toxicity 
are revealed and the mode of death determined. In suitable species a quantitative evaluation 
of the approximate lethal dose and information on the dose-effect relationship should be 
made, but a high level of precision is not required. 
Toxicologists should use their best judgements in designing the studies so that the maximal 
amount of relevant information is obtained from the smallest number of animals. 
PRODUCT SPECIFICATION 
(a) Drug substance 
The active substance should have the same pattern of impurities as the product to be 
marketed, when possible. Should the final dosage form be shown to have impurities sig­
nificantly different either in quantity or quality from those in the test batch then further 
steps should be taken to ascertain their possible toxicity. Consideration should be given 
to the physical characteristics of the drug substances in relation to the route of adminis­
tration, e. g. the particle size of a compound given orally. 
(b) Finished product 
When large animals are used in the acute toxicity study, it may be possible to conduct a 
study with the pharmaceutical formulation intended to be marketed. This is particularly 
desirable when the pharmaceutical formulation is likely to lead to major changes in the 
bioavailability of the active ingredient(s). 
(c) Excipients 
Where a new excipient is used for the first time it should be evaluated as a new active 
substance. 
No C 293/10 Official Journal of the European Communities 5. 11.84 
(d) Products containing a combination of active substances 
In the case of combination of active substances it is necessary to make a study of each 
active substance separately and of the combination of active substances in the same 
proportions as in the proposed final product in order to check whether or not there is 
enhancement of toxicity or if novel toxic effects occur. Deviations from this protocol 
should depend on documented pharmacokinetic or pharmacodynamic differences 
between the animal species studied and man. 
(e) Degradation products 
Where degradation products occur under conditions of storage, consideration should be 
given to their possible toxicity and this might be best evaluated initially by an acute tox­
icity study. 
3. ANIMALS 
(a) Single dose toxicity tests must be conducted on at least two mammalian species of 
known strain using equal numbers of both sexes. Rodents such as the mouse, rat and 
hamster are suitable for the qualitative study of toxic signs and the quantitative determi­
nation of the approximate lethal dose. If no difference in response is observed between 
the animals of the two sexes of the first rodent species, then only animals of one sex 
need be used in the other acute toxicity studies. Toxic signs should also be observed and 
recorded in detail for each animal used in the case of other mammals. 
(b) Whatever species or strain of animals are selected it is essential that the following infor­
mation should be provided: age, sex, weight, origin and the time in the laboratory 
before test, whether or not the animals are classified as being free of specific pathogens, 
whether or not the animals have been vaccinated or submitted to any other procedure. 
Details of housing and environmental conditions should be given. Access to and the 
nature of the diet and the availability of water should be stated. All the above factors 
are known to affect the acute toxicity of substances. 
4. ADMINISTRATION 
(a) Route of administration 
In the case of rodents in general, two routes should be used and when possible should 
include those routes proposed for man and at least one should ensure full access of 
unchanged drug into the circulation. If the proposed route of administration to man is 
intravenous, then use of this route alone in animal testing is acceptable. 
(b) Conditions of administration 
Details of administration of the product should be provided and include particulars of 
the vehicle or adjuvants used, method of preparing the suspension in the case of insolu­
ble products, concentration of the solution used and the volume administered. The 
route and the method of administration should be clearly given. The formulation to be 
administered should be as bland and as close as possible to physiological pH and osmo­
lality. 
Special attention should be paid if the formulation is alkaline, acid or potentially corro­
sive. Exceeding the tolerable volume should be avoided. If the intravenous route is used 
the rate of infusion (ml/min) and the pH and temperature of the solution administered 
should be provided. 
If it is necessary to use more than one injection site for parenteral administration, this 
should be stated. 
(c) Dose levels 
In all species used the number of dose levels should be such that the spectrum of toxic­
ity is revealed. In rodents a quantitative estimate of the approximate lethality and the 
dose-effect relationship should be obtained. 
5. 11.84 Official Journal of the European Communities No C 293/11 
5. OBSERVATIONS 
Animals should be observed at regular intervals and all signs of toxicity and the time of their 
first occurrence and their severity, duration and progression recorded. The time and mode of 
any death should be documented, any signs of toxicity should be presented separately for 
each animal. 
Observation should usually be for 14 days, but should continue so long as signs of toxicity 
are apparent, e.g. progressive loss of weight or inhibition of growth. 
6. AUTOPSY 
All animals surviving to the end of the study and all animals dying during the period of 
observation should be subjected to autopsy. Any organ showing macroscopic changes (other 
then agonal changes) should be subjected to histopathological examination unless these 
changes are well documented and adequate explanation for them can be given on the basis 
of previous experience in the strain of animal used. 
7. PRESENTATION OF DATA 
The results from which any calculations have been made should be given in detail, the meth­
ods of calculation used should be stated. 
The toxic effects including assessment of morbidity should be described in each species and 
for each route of administration at all dose levels. 
The investigator should draw all relevant conclusions from the data obtained in these stu­
dies. 
Any significant deviations from these guidelines should be justified. 
ANNEX II 
TESTING OF MEDICINAL PRODUCTS FOR THEIR MUTAGENIC POTENTIAL 
I. INTRODUCTION 
Mutagenesis refers to those changes in the genetic material in individuals or cells brought 
about spontaneously or by chemical or physical means whereby their successors differ in a 
permanent and heritable way from their predecessors. Current scientific knowledge over­
whelmingly supports the concept that many chemicals possess mutagenic properties which 
present a potential genetic hazard to future generations as well as a potential cancer risk to 
the present one. Therefore there is a necessity to identify chemicals with such properties and 
to limit human exposure. Positive evidence of mutagenicity must be taken into consideration 
when evaluating the risk of carcinogenicity (Directive 75/318/EEC, as amended by Direc­
tive 83/570/EEC). The primary object of these guidelines, however, is to determine the pos­
sible existence of a mutagenic hazard. 
Damage to the genetic apparatus may be at the level of individual genes (point mutations) or 
the interference may be of a grosser type in which the structure of the chromosomes (chro­
mosome mutations) or their numer (genome mutations) is altered. If the structural alteration 
is small and results in the deletion of one or a few genes the net effect can be difficult to 
distinguish from a point mutation. A wide variety of procedures has been devised to test the 
ability of a chemical to induce these various kinds of mutations in organisms ranging from 
those with the simplest arrangement of the deoxyribonucleic acid molecule (DNA) in bac­
teria (prokaryotes) to those in which the DNA is arranged in a most complex association 
No C 293/12 Official Journal of the European Communities 5. 11.84 
with proteins and enzyme systems (chromatin) to form the chromosomal system found in 
eukaryotes ranging from simple organisms such as fungi to insects and finally mammals. 
2. OBJECTIVES OF A MUTAGENICITY TESTING PROCEDURE 
Directive 75/318/EEC, as amended by Directive 83/570/EEC, states that any new sub­
stance for use in medicinal products prior to being marketed has to be investigated for muta­
genic properties. The objective of these notes is to provide some guidance on how to con­
duct such investigations. In designing a mutagenicity testing procedure the following points 
are of primary importance: 
(a) The procedure should be able to identify chemicals with mutagenic properties, with 
maximum accuracy and at reasonable cost. Therefore, from the wide variety of available 
tests a deliberate choice has to be made. 
(b) The procedure should be capable of detecting the main classes of relevant genetic dam­
age, notably gene mutation, chromosome mutation and — when possible — genome 
mutation. 
(c) Although DNA is universal to both prokaryotes and eukaryotes, the organization of the 
genetic material is very different in these two types of organisms. The procedure should 
take this into account. 
(d) The capacities to metabolize xenobiotic compounds differ widely between organisms 
and between test systems. In in vitro procedures mammalian metabolism is simulated by 
the addition of one or more extrinsic metabolic activation systems. However, these may 
fail to mimic the in vivo situation at critical points. Therefore it is necessary to include 
one in v/'votest. In all tests the characteristics of the metabolism of the substance should 
be taken into account. 
3. PROPOSED MUTAGENICITY TESTS FOR MEDICINAL PRODUCTS 
It is generally acknowledged that the above requirements and considerations are not met by 
any single test but only by a well-selected combination of procedures. However the combi­
nation of tests applied should in each case depend on the specific characteristics of the 
substance to be tested. 
Based on current knowledge, a system using four categories of tests is proposed as an appro­
priate approach to meet the conditions set out in paragraph 2 (a) to (d). This is not to imply, 
however, that other tests are inappropriate, or that evidence from other tests would not be 
acceptable as alternatives to part of the package. Deviations from these procedures could be 
indicated, for instance, by particular characteristics of the compound under study, or a parti­
cular feature of its metabolism. For example it may be considered inappropriate to evaluate 
a potent antibacterial agent in a bacterial test. Conversely, when toxicity studies have 
revealed an effect on the reproductive system, the use of germ cells under 3 (d) may be indi­
cated. In any event, the responsibility will be on the applicant to justify the reasons for the 
selection of individual tests used, as well as explaining the overall strategy used in the sys­
tem of tests chosen. Normally one test from each of the following four categories should be 
selected. 
(a) Test for gene mutations in bacteria 
These are the most widely used tests for assessing the mutagenic properties of chemi­
cals. Tests are carried out using several well-established bacterial strains designed to 
detect various types of genetic change, including frame shift and base change muta­
tions. Tests are carried out with and without extrinsic metabolic activation. 
(b) Test for chromosomal aberrations in mammalian cells in vitro 
For this procedure human lymphocytes can be used as well as several mammalian cell 
lines. The damage is scored by microscopic examination of chromosomes at mitotic 
metaphase. Tests are carried out with and without extrinsic metabolic activation. 
5. 11. 84 Official Journal of the European Communities No C 293/13 
(c) Test for gene mutation in eukaryotic system 
The relevance of this test is that a positive result found in bacteria can be additionally 
studied in a system which has the complex eukaryotic chromosomal structure. This 
structural complexity also allows the possibility of detection of mutations arising 
through mechanisms that cannot occur in the simple bacterial genome. Suitable tests 
include those using mammalian cells designed to detect the induction of mutations at 
specific loci such as the ones coding for the enzymes hypoxanthine-guanine-phosphori-
bosyl-transferase or thymidine kinase. Other eukaryotes, such as fungi and insects, may 
be considered. As appropriate, extrinsic metabolic activation may be incorporated into 
this test. 
(d) In vivo test for genetic damage 
The main role of the in vivo test in the four categories of tests is to ascertain if a muta­
genic compound has been missed by the in vitro tests because of inappropriate meta­
bolic activation systems having been used. The best validated tests are those which have 
end points of chromosomal damage e.g. bone marrow metaphase and micronucleus 
tests and the dominant lethal test. As an in vivo test for somatic gene mutations the 
mouse spot test is becoming more widely used. 
All tests used should be well validated and conducted in line with established procedures set 
out in the current international literature. 
There is one notable omission in the recommended test package as described above in that it 
does not include a test primarily designed for the detection of genome mutation (non-dis­
junction, aneuploidy). Specific methods presently under development are not sufficiently 
validated to incorporate them. 
These notes for guidance were prepared in the light of current knowledge. It is to be 
expected that in the future, new and modified test procedures may be evolved, and will be 
applied in practice. In order to accommodate such future developments, these notes for 
guidance need to be periodically updated. 
4. INTERPRETATION OF THE RESULTS 
The objective of the mutagenicity testing procedures is to establish with reasonable certainty 
whether a substance possesses mutagenic properties or not. Following from this is a second 
quite separate issue which is the significance of the obtained results in terms of genetic 
hazard to man. If all results indicate convincingly that a substance has no effect in any of the 
tests then it would seem reasonable to conclude that the possibility of mutagenic hazard is of 
an acceptable low order (although it may be considered insufficient evidence of absence of 
carcinogenic potential). If all results both in vitro and in vivo indicate that the compound has 
mutagenic properties this would argue strongly for the existence of a risk for humans. An 
often occurring situation is that the results are non-uniform. This is to be expected since the 
tests are designed to have different end points and/or different characteristics for metabolic 
activation. In such cases the significance of positive and negative results is to be judged not 
by their number but by their nature. For instance, in the above package a positive result in 
an in vivo test deserves more weight than a positive bacterial test. This difference does not 
apply to negative results, implying that one negative in vivo test does not necessarily invali­
date a series of positive results obtained in vitro. A better understanding of the genotoxic 
potential of the substance may be gained by carrying out supplementary investigations. The 
manufacturer should decide whether supplementary tests should be carried out and which 
ones should be selected. This selection should be based on the results already obtained as 
well as on other properties of the compound and its intended use. Consultation with the 
regulatory authorities may be appropriate. 
5. RISK/BENEFIT CONSIDERATIONS 
When a compound has been shown to possess mutagenic properties this indicates the poten­
tial of the substance to present a genetic hazard to man (and at the same time to constitute a 
possible risk for tumour induction). 
Mammalian tests, such as the heritable translocation test or the specific locus test may occa­
sionally be useful for such assessment of the genetic risk in humans. These tests are expen-
No C 293/14 Official Journal of the European Communities 5. 11.84 
sive and require large numbers of animals; their application is justified only in well-founded 
cases. 
The overall risk/benefit assessment of a mutagen should take into consideration not only the 
results of mutagenicity testing, but also the pharmacokinetics, metabolism, and the whole 
toxicity profile. In addition, the intended use of the medicinal product, its degree of expo­
sure, the age and reproductive status of the patient, as well as the aspect of the potential risk 
of alternatively available substances have to be taken into consideration. 
ANNEX III 
CARDIAC GLYCOSIDES 
1. GENERAL 
The following notes are designed with a view to clinical evaluation of cardiac glycosides and 
may also apply to other drugs which share the same pharmacological actions on the heart, 
i. e. positive inotropic and negative chronotropic and dromotropic effects.. 
These notes for guidance should be read in the light of the norms and protocols (Directive 
75/318/EEC) and are intended solely to assist applicants in the interpretation of the latter 
with respect to the specific problems presented by cardiac glycosides and analogous drugs. 
Management of cardiac disease in clinical practice using these drugs (and hence the evalua­
tion of such drugs for use in this situation) is fraught with difficulties, resulting for example 
from: 
— the low therapeutic/toxic dose ratio of these compounds, 
— problems with respect to their pharmacokinetics, such as a tendency to accumulation, 
— bioavailability problems, 
— the multitude of extrinsic and intrinsic factors which influence their therapeutic effi­
cacy, 
— the fact that studies of such drugs inevitably involve critically ill patients with unstable 
disease patterns of varying aetiology. 
2. PROBLEMS ARISING FROM THE LOW THERAPEUTIC/TOXIC DOSE RATIO 
(a) General remarks 
Not infrequently a modest overdose causes extracardiac symptoms of toxicity without 
evidence of cardiac toxicity. In addition undertreatment may be difficult to define. 
Assay methods of plasma concentrations have provided some insight, though the rela­
tionships between pharmacokinetics, pharmacodynamics and therapeutic and toxic 
effects are not as yet fully understood. 
(b) Recommendations 
Notwithstanding the problems concerning plasma concentration assays, as mentioned 
above, such assays should be performed since they can provide valuable information as 
to whether unexpected side effects are related to toxic concentrations of the drug or its 
metabolites at the receptor site or other target organs, and whether failure of treatment is 
linked to unexpectedly low values. It will be useful to provide, if possible, quantitative 
information on the therapeutic/toxic plasma concentration ratio and its correlation with 
5. 11. 84 Official Journal of the European Communities No C 293/15 
3. TENDENCY TO ACCUMULATION 
(a) General remarks 
Cardiac glycosides are commonly characterized by a relatively slow tissue uptake, 
extensive tissue binding and a prolonged half-life with a long duration of action. Such 
pharmacokinetic and pharmacodynamic factors must therefore be well defined. 
(b) Recommendations 
Clear evidence should be obtained as to the limits of dosage if excessive accumulation 
is to be avoided; clinical, and if possible pharmacokinetic, data should be available jus­
tifying dosage regimens during chronic treatment both with (if judged necessary) and 
without loading dose(s) in patients in whom the use of such drugs is indicated, together 
with data concerning the time which is expected to elapse between starting therapy and 
the first signs of a clinical effect. Even initial clinical studies of the effect of the drug 
should thus continue longer than the time necessary to obtain steady-state plasma lev­
els; the duration of the basic investigation hence depends on the pharmacokinetics of 
the individual glycoside. In addition, as with other drugs for long-term use, the efficacy, 
adverse effects and particularly possible clinical evidence of accumulation should be 
studied for a longer period, and during such studies further evidence to exclude the risk 
of accumulation should be sought. Clinical factors such as are listed under paragraph 4, 
which may profoundly alter the pharmacokinetic behaviour of the drug, should be taken 
into account in analyzing data. 
4. PROBLEMS RELATING TO BIOAVAILABILITY 
(a) General remarks 
Relatively slight differences in pharmaceutical formulation can result in marked varia­
tions in plasma concentrations between individuals due to differences in the rate and 
extent of absorption of cardiac glycosides after oral absorption. In view of their narrow 
therapeutic index such variations in plasma concentrations can be hazardous. It has 
been shown clearly that this factor is of paramount importance for most cardiac glyco­
sides; every possible degree of bioavailability varying from approximately 3 % for oral 
ouabain to about 90 % in the case of digitoxin may be encountered in clinical practice. 
Individual and intersubject variations in plasma concentration increase as bioavailabil­
ity decreases. 
The oral absorption depends on the pharmacochemical properties of the glycoside and 
its pharmaceutical formulation. 
(b) Recommendations 
If the drug is available both in an intravenous form and as an oral form the percentage 
bioavailability of the oral tablet, capsule or solution should ideally be assessed by com­
paring the pharmacokinetic data after oral administration with that obtained after 
intravenous administration. A full description of radiochemical or other biochemical 
methods used in such studies to assay plasma or urine concentrations of the drug and/ 
or its metabolites should be given, and the accuracy, sensivity and specificity of the 
method stated. In calculating the area under the curve (AUC) the relatively long distri­
bution phase of cardiac glycosides should be taken into account and the area calculated 
by extrapolation of the elimination phase to infinity. 
Bioavailability below the order of magnitude of 50 % is unlikely to be acceptable for 
any cardiac glycoside. Individual variations should be defined and should be as small 
as possible. 
For every new glycoside the in vitro dissolution rate should be determined. Any sub­
sequent alterations in the pharmaceutical formulation or processing create the need to 
submit new and adequate in vitro dissolution rate studies. In some such instances, 
depending on the in vitro findings and the extent of the modification, in vivo compari­
son of the rate and extent of the absorption of the new formulation with the old one 
No C 293/16 Official Journal of the European Communities 5. 11.84 
should be furnished, using either single-dose or multiple-dose plasma concentration stu­
dies. 
It is advisable to submit studies of steady-state plasma concentrations during chronic 
oral administration (multiple-dose studies). 
If it has been demonstrated that a known and substantial proportion of the drug is 
excreted unmetabolized in the urine, urinary assays may be acceptable for comparative 
bioavailability studies. 
5. CLINICAL INVESTIGATIONS AND FACTORS AFFECTING EFFICACY AND 
SAFETY 
(a) General remarks 
The clinical efficacy of a glycoside has to be demonstrated in patient groups of suffi­
cient size, with clinical syndromes forming the principal indication for using cardiac 
glycosides, e. g. left ventricular failure and rapid atrial fibrillation. The clinical efficacy 
and safety depend on many individual patient factors and data obtained in healthy vol­
unteers may not apply in the presence of one or more of these factors. Whereas the 
influence of factors like youth and old age, and disturbed renal and hepatic function 
may usually be reasonably well assessed by pharmacokinetic studies, such will not be 
the case with factors influencing the pharmacodynamics such as hypokalaemia and thy­
roid dysfunction. 
(b) Recommendations 
It is necessary to provide a full assessment of the clinically relevant effects of the glyco­
side on patients with atrial fibrillation along with estimates of the plasma concentra­
tions. 
Although it is more difficult, it is highly desirable and may even be essential to have 
quantitative data on cardiac function (e. g. cardiac index) in at least some patients with 
heart failure and regular sinus rhythm in whom cardiac glycosides are used to produce a 
positive inotropic effect or to prevent the occurrence of tachyarrhythmias. Plasma con­
centration data, if obtainable, should be recorded. For new drugs it is to know whether 
there is a correlation between plasma levels and the appearance of undesired effects. 
Adverse reactions occuring during these studies should be carefully monitored; though 
most adverse reactions to cardiac glycosides are symptoms of overdosage, both the 
extracardiac and the possible cardiac adverse reactions (arrhythmias) should be clearly 
described. The number of patients so studied need not necessarily be large, but the 
investigations should be carefully designed, executed and recorded. Clinical studies 
should preferably be done in patients without the complicating factors mentioned above 
(5 (a)) but data obtained in patients with complications will not be excluded per se. 
6. DIFFICULTIES IN DEVELOPING ADEQUATE DOSAGE RECOMMENDATIONS 
Recommendations on dose (including loading doses) should be based on sound pharmaco­
kinetic evidence. Claims for dosage regimens which are at variance with normal usage 
should be based on well-documented observations in appropriate clinical syndromes such as 
rapid atrial fibrillation, abnormal renal, hepatic, or thyroid function, or during cardiac sur­
gery and cardioversion. If specific claims are made concerning safety or efficacy in certain 
clinical conditions, appropriate pharmacokinetic and pharmacodynamic studies must have 
been carried out. 
7. RECOMMENDATIONS WITH RESPECT TO DATA SHEETS AND DIRECTIONS 
FOLDERS 
(a) Dosage recommendations 
Recommendations for dosage in children, elderly patients an,d other groups requiring 
special dosage regimens should always be given. Since a multitude of intrinsic and 
extrinsic, pharmacokinetic and pharmacodynamic factors may affect the therapeutic 
efficacy of cardiac glycosides, and most of these occur in serious clinical situations, dos-
Official Journal of the European Communities No C 293/17 
age recommendations (changes in dose or dose interval or other therapeutic measures), 
whether or not based on clinical data, should be given for the following conditions: 
— diminished renal function, 
— hepatic failure, 
— hypo- and hyperthyroidism, 
— youth and old age. 
Proper warnings should be given concerning the use of the cardiac glycoside in the fol­
lowing conditions: 
— hypokalaemia, 
— hypercalcaemia, 
— hypomagnesaemia, 
— cardiversion, , 
— cardiac surgery. 
(b) Interactions 
If there are indications that interactions may occur and that they may be clinically rel­
evant they should be studied in detail and mentioned in the directions folder. 
(c) Precautions 
All available information concerning therapeutic measures in accidental overdosage or 
deliberate (self-) poisoning should be provided. 
8. FIXED COMBINATIONS 
In view of the narrow therapeutic index of the cardiac glycosides and the need for careful 
individual titration of dosage, fixed combinations of cardiac glycosides with other drugs are 
extremely unlikely to meet the standards set by the norms and protocols (see the notes for 
guidance on fixed combination products). 
ANNEX IV 
CLINICAL INVESTIGATION OF ORAL CONTRACEPTIVES 
1. GENERAL 
These notes for guidance should be read in the light of the norms and protocols (Directive 
75/318/EEC) as well as the First Directive (65/65/EEC) and are intended solely to assist 
applicants in the interpretation of these documents with respect to the specific clinical prob­
lems involved in establishing the safety and efficacy of oral contraceptives. 
The present notes have been compiled primarily with those contraceptives in mind which 
have hormonal activity and are administered orally to women. It is evident that for other 
contraceptive products subject to medicines legislation the investigational approach required 
to assess efficacy and safety will be analogous but not necessarily identical. 
A contraceptive preparation consisting of two or more components should also be investi­
gated so as to elucidate the points listed in the notes for guidance on fixed combination 
products, i.e. the properties of the individual components and their contribution to the total 
effect should be known. 
Where a new contraceptive can be considered as a modification of one already recognized as 
being efficaceous and safe (particularly where there is merely a minor change in dosage, or 
No C 293/18 Official Journal of the European Communities 5. 11.84 
where one oestrogen is replaced by another accepted oestrogen) it may be possible to sim­
plify the investigations provided the theoretical basis for the new formulation appears to be 
sound. 
2. CLINICAL-PHARMACOLOGICAL STUDIES 
Clinical-pharmacological studies performed with an oral contraceptive (and in the case of a 
fixed combination also with its components) are most likely to meet the standards set by the 
norms and protocols section, part 3, chapter IIA, paragraphs 1 to 4 if they are designed to 
provide data on: 
(a) the pharmacological action or actions in man by virtue of which a contraceptive effect is 
attained; 
(b) other pharmacological effects on the reproductive system and process, including those 
on hypothalamic and pituitary activity, ovarian endocrine secretion, ovulation, endome­
trial histology and biochemical activity, cervical mucus and vaginal cytology and secre­
tion. Effects on tubal function, which cannot currently be studied in human subjects, 
can be investigated in animals; 
(c) the degree of progestogenic, oestrogenic, androgenic, corticosteroid and other hormonal 
or anti-hormonal activity of the product and its components in man. It is appreciated 
that the quantitative study of some of these effects (particularly androgenicity and anti-
androgenicity) in the clinical-pharmacological phase may be difficult, but conclusions 
on these points may also be drawn from animal studies and from side effects occurring 
during efficacy investigations; 
(d) the nature and hormonal activity of the principal metabolites; 
(e) suspected drug interactions likely to impair the efficacy of the product; 
(0 those adverse effects likely to be detectable with products of this type even in a limited 
population, including those involving liver function, adrenal activity, lipid and carbohy­
drate metabolism, the thyroid and haemostatic mechanisms. 
3. CLINICAL INVESTIGATIONS OF EFFICACY AND SAFETY 
Clinical studies with an oral contraceptive are most likely to meet the standards set by the 
norms and protocols, part 3, chapter IIB if the following principles are borne in mind: 
(a) Trial population 
The population studied should be reasonably comparable to that in the country or coun­
tries in which it is proposed to introduce the product. It should be realized that dietary 
habits, endemic diseases, body weight, illiteracy, etc. can substantially affect the results 
obtained with a given contraceptive method. 
(b) Scope of trials 
The clinical investigation should be sufficiently large to render possible a reliable calcu­
lation of efficacy (in terms of the Pearl Index and the Life Table method) and of the 
incidence of adverse reactions. In practice it generally proves desirable for an entirely 
new contraceptive product (e.g. one incorporating a new progestagen) to study some 
20 000 cycles of treatment. Where a modification of an existing product is investigated, 
valid conclusions may sometimes be drawn from more limited material. 
Since both the effect of the product and the degree of precision with which it is used 
may alter during long-term use, a substantial part of the total population studied should 
have used the contraceptive for a period of not less than 12 months, e.g. about a quarter 
of the total data available should relate to prolonged use. 
Although any large-scale study of an oral contraceptive will as a rule have to be con­
ducted on a multi-centre basis, only data from those centres which have gained substan­
tial experience with the product should be included in the total analysis. 
5. 11.84 Official Journal of the European Communities No C 293/19 
(c) Studies on admission 
History taking and clinical examination at the time of admission to the trial should pro­
vide a detailed record of any risk factors, relative contra-indications or other elements 
which may subsequently be relevant to the assessment of efficacy and supposed adverse 
effects, e.g.: 
— age, 
— obesity, 
— smoking habits, 
— alcoholism, 
— cardiovascular disease, 
— psychic disorders or symptoms, 
— migraine, 
— endocrine and metabolic disorders, 
— epilepsy, 
— anaemia, 
— disorders of the haemostatic system, 
— renal disorders, 
— hepatic disorders, 
— tumours. 
The prior obstetric, gynaecological and contraceptive history should be known and 
recent and current drug intake recorded. The findings on certain of the above points will 
clearly lead to the exclusion of some subjects from the trial. 
(d) Recording of data 
It is recommended that in a contraceptive study individual patient data be recorded on 
a well-recognized form, such as that advocated by the World Health Organization. Trial 
"subjects should be seen by investigators at intervals of not more than three months. 
In all subjects taking part in such studies there should be a periodic gynaecological 
examination including cervical smear, as well as examination of the breast, weight and 
blood pressure, a test for glycosuria, and a close record of the menstrual history and any 
suspected adverse reactions. Intercurrent illness as well as adverse events noted by the 
patient should be recorded and any change in libido registered. 
In a subgroup detailed laboratory examinations should be performed to detect any 
change in the normal endometrium, hepatic function, lipid metabolism, haematological 
parameters, protein spectrum, serum electrolytes, urine composition, adrenal activity, 
carbohydrate metabolism, and any parameter an effect on which might be anticipated in 
view of the pharmacological and toxicological findings. Where clear abnormalities are 
detected, the patient should be examined clinically and the findings recorded, irrespec­
tive of whether the subject continues to take part in the trial or not. 
Any patients admitted to the study despite the presence of certain risk factors or func­
tional disorders at the time of admission, should undergo regular re-examination in 
these respects during the trial. 
In cases of contraceptive failure, data on the pregnancy and the condition of the neo­
nate or embryo should be recorded and the possibility of patient failure assessed. 
Where a subject withdraws from the study the reasons for withdrawal should be 
recorded and where possible the subject should be followed up to determine the time of 
resumption of menstruation and fertility and any possible effect on subsequent preg­
nancy. 
No C 293/20 Official Journal of the European Communities 5. 11. 84 
Follow up. Any subject who has shown significant variation in metabolic functions 
should be followed up to determine if and when these return to normal after termina­
tion of the trial. 
(e) Analysis of data 
(i) General 
Data relating to efficacy, cycle control, adverse reactions and laboratory findings 
should be presented for the investigational programme as a whole and for the indi­
vidual studies and also analyzed to try and find correlations with factors likely to 
be capable of affecting the findings. 
(ii) Efficacy 
If pregnancies have occurred during the study, a detailed analysis of each indivi­
dual case should be presented. 
(iii) Cycle control 
Data on cycle control should be recorded and presented in such a manner that the 
incidence and severity of menstrual irregularity, spotting, breakthrough bleeding 
and amenorrhoea are clear, and so that any variation therein between individuals 
or over a period of time can be discerned. It is useful to indicate to what extent 
such events have been regarded as acceptable by the trial subjects and the investi­
gators. 
(iv) Laboratory findings 
Abnormal laboratory findings should be analyzed inter alia with respect to any pos­
sible correlations with clinical findings in the subjects concerned. 
(f) Absolute and relative efficacy and safety 
An oral contraceptive is likely to be regarded as effective if the degree of contraceptive 
efficacy attained when the product is employed under field conditions by a normal 
population is not less than that currently attained with other contraceptive methods 
which have obtained wide acceptance. Some lesser degree of efficacy may be acceptable 
if it is outweighed by advantages in terms of safety and tolerance, and provided the 
chances of contraceptive failure can be quantified and are clearly explained in the texts 
made available to the user. 
An oral contraceptive is likely to be regarded as not harmful if its adverse effects are not 
more severe or prolonged than those of oral contraceptives in current use, and provided 
that it does not result in persistent derangement of the menstrual bleeding pattern 
during long-term use or persistent changes after withdrawal. 
(g) Post-marketing studies 
Whilst Directives 65/65/EEC and 75/318/EEC impose no requirement that post-mar­
keting studies be conducted, applicants proposing to market oral contraceptives of a 
new type are urged to consider the possibility of continuing long-term clinical investiga­
tions and monitoring subsequent to introduction of the products concerned; this will 
greatly facilitate the assessment of reports on supposed adverse reactions. 
ANNEX V 
USER INFORMATION ON ORAL CONTRACEPTIVES 
1. GENERAL 
The following text is intended to indicate the information on oral contraceptives which 
should be provided for users of these products, for example in the packaging leaflet 
(Article 6 of Directive 75/319/EEC). It should be noted that: 
5. 11. 84 Official Journal of the European Communities No C 293/21 
(a) The present text is directed exclusively to the woman using the product, and is therefore 
selective and written in non-technical language. If a packaging leaflet is also supposed 
to provide information to the physician or pharmacist it will have to be considerably 
more extensive; in that case it will be advisable to separate this technical information 
from that directed to the user. 
(b) The text is drawn up in the light of current knowledge and relates to oral contraceptives 
containing progestagens and oestrogens, employed to inhibit ovulation. For contracep­
tives of other types some adaptation of this text may be required. 
(c) The text represents only a general standard; in some situations it may be considered 
more appropriate to provide more detailed or extensive information, or to omit points 
which in the national situation are irrelevant. 
(d) The text should be presented in a manner which can be readily understood by the aver­
age user. 
(e) The order in which the information is given need not necessarily follow that of the pres­
ent notes for guidance. 
2. NATURE OF THE PRODUCT 
The nature of the product and the purpose(s) for which it is intended should be indicated. 
This means that where a product is destined both for use as an oral contraceptive and in 
gynaecological treatment this should be made clear. 
3. CONSULTING YOUR DOCTOR 
This section should include statements of the following type: 
(a) 'You should consult a doctor before starting to take this preparation; only he can deter­
mine whether it is suitable for you. You should also consult your doctor before chang­
ing from one oral contraceptive to another. 
(b) There are some conditions in which it is generally inadvisable to take oral contracep­
tives. It is particularly important to tell your doctor if you have ever suffered from any 
of these illnesses: 
— clots in the legs or lungs, 
— strokes, heart attacks or angina pectoris, 
— known or suspected cancer or tumours, 
— unusual vagina bleeding, the cause of which has not been found, 
— jaundice. 
For the same reason you should also tell your doctor if there is any reason to think you 
may already be pregnant. 
(c) In some conditions the doctor may wish to take special precautions or may advise you 
to use another type of contraception. Be sure that he knows if you have been found to 
be suffering at any time from: 
— any disorder of the breast, or discharge from the breast, 
— diabetes, 
— high blood pressure, 
— high blood fat levels, 
— migraine, 
— heart disease, 
— kidney disease, 
— epilepsy, 
— deafness, 
— mental depressions, 
— fibroids of the uterus, 
— gall bladder disease. 
For the same reason you should tell the doctor about your smoking habits, (particulary 
since heavy smoking can increase the chance of certain side effects), and about any 
medicines which you often need to take, including pain relievers.' 
No C 293/22 Official Journal of the European Communities 5. 11. 84 
4. HOW TO USE THIS PRODUCT 
This section should include: 
(a) Clear instruction as to: 
— the day when the first tablet is taken, 
— the time of day when the tablet is to be taken (if relevant), 
— the duration of ingestion in each cycle, 
— the order in which the tablets are to be used (if these are arranged in a fixed order 
in the package), 
— the day when the second and subsequent cycles of treatment should start. 
(b) Clear advice as to how the user should act: 
— if a tablet (or more than one tablet) has been forgotten, 
— if no withdrawal bleeding occurs. 
(c) Warnings as to conditions under which the reliability of the preparation may be 
impaired should be indicated. These will vary with the nature and dosage of the product 
but may include the first cycle of treatment (particularly if. a preparation with a higher 
dose has previously been used), the simultaneous use of certain other drugs, and the 
occurrence of vomiting and severe diarrhoea. 
5. GENERAL INFORMATION AND ADVICE 
(a) The degree of reliability of the preparation should be indicated in general terms. 
(b) The user should be advised to inform any other doctor or surgeon whom she consults 
for any reason that she is taking oral contraceptives, since this may be important in 
diagnosis or Jreatment. 
(c) The user should be recommended to consult once more the doctor who has prescribed 
the product at regular intervals, as agreed with him, and in addition: 
— if any severe symptoms occur whilst using it, 
— if she has any reason to think that she has become pregnant, 
— before restarting treatment after interruption, 
— before restarting treatment after pregnancy or during lactation. 
(d) The user should be informed as to the likely course of events if she stops taking the 
product (e.g. the time of onset of the next period and the resumption of fertility) and 
advised to see the doctor again if anything unusual happens at this time. 
(e) A woman who wishes to become pregnant should be advised not to do so for three 
months after stopping the product, so that reproductive function can return completely 
to its previous pattern. 
6. ADVERSE REACTIONS 
(a) Commonly occuring adverse reactions should be listed, with some indication as to 
whether or not they are more common at the start of treatment. Effects listed here 
should include gastrointestinal symptoms, mild headache, mammary discomfort or 
swelling, some increase in weight, chloasma and mild depression. The effects on the 
menstrual cycle should be described in terms appropriate to the product concerned. 
(b) Less common but severe adverse reactions should be mentioned, particularly throm­
bosis and cholestasis, and a list provided of those warning signs which justify consulting 
the doctor at once, such as: 
— mammary discharge and nodule formation, 
— severe changes in the monthly bleeding pattern, 
— marked vaginal secretion, 
5. 11. 84 Official Journal of the European Communities No C 293/23 
— vertigo, faintness, 
— jaundice, 
— sudden impairment of vision, 
— sudden pain in the chest or abdomen, 
— pain or swelling in the legs, 
— severe headache or migraine, 
— any other unexpected symptom. 
ANNEX VI 
DATA SHEETS FOR ANTIMICROBIAL DRUGS 
1. GENERAL REMARKS 
Because of the wide range of antimicrobial products available and the complexity of the 
information on each of them, which is required if the most suitable product for a given case 
is to be selected and optimally employed, it is advantageous to standardize to some extent 
the presentation of technical information on products of this type. 
The present document is not intended to replace or modify any existing or future national or 
international guideline for the presentation of 'data sheets', 'fiches techniques' or 'package 
inserts', but merely suggests the topics to which particular attention should be paid when 
such documents for antimicrobial drugs are drawn up and how the information can best be 
worded. 
These notes for guidance are for all antimicrobial drugs irrespective of the mode of adminis­
tration or the pharmaceutical form. 
In the presentation of information on an antimicrobial drug, comparisons with other anti­
microbial agents, which should be mentioned by generic name, are defensible only when 
they constitute an essential element in understanding the proper use of the product. 
In view of the possibility of changes in resistance of micro-organisms, data sheets for anti­
microbial agents should be dated, and should be revised whenever necessary. 
2. GENERAL FORMAT 
The text should contain the following sections, arranged and headed in accordance with 
Article 4 A of Directive 65/65/EEC: 
— composition, 
— microbiology, 
— pharmacokinetics, 
— indications, 
— contra-indications, 
— use during pregnancy, 
— use during lactation, 
— warnings, 
— precautions, 
— interactions, 
— dosage and other instructions for use, 
— adverse reactions, 
— human toxicology and treatment of overdosage, 
No C 293/24 Official Journal of the European Communities 5. 11. 84 
— storage and stability, 
— packaging form. 
Not all the sections of this document will apply strictly to every type or presentation of 
antimicrobial agent. For some externally or orally applied drugs which are poorly absorbed it 
will for example be sufficient to mention this fact, instead of including detailed pharmaco­
kinetics, though if the absorption of this kind of drug is considerably increased in such cir­
cumstances as damage to the skin or intestine this should be stated. 
The following sections are particularly relevant for antimicrobial agents: 
(a) Microbiology 
The classification, nature and mode of action of the drug should be indicated. The 
groups of micro-organisms sensitive to the drug should be indicated. These data should 
be based on tests using multiple recently isolated epidemiologically unrelated strains of 
each species for which an effect is claimed. Special attention should be devoted to 
micro-organisms which are particularly sensitive or insensitive, especially when this is 
unexpected having regard to the nature of the drug. The text should indicate to what 
extent resistance can develop and how rapidly and under what conditions this occurs. 
The occurrence of cross-resistance to other antimicrobial agents should be mentioned. 
Break points should be indicated if possible. 
If MIC (Minimum Inhibitory Concentration) data are included, such information 
should, in order to be meaningful, meet the following standards: 
— the sensitive micro-organisms should be listed in groups in a table in order of 
increasing MIC values, 
— specifications should be given briefly with respect to the microbiological methods 
employed for the determination of the MIC values, for example the size of the ino­
culum, the origin of the organisms and the number of strains tested, the medium 
and the date of study, 
— if the difference between MIC and MBC (Minimum Bacteriocidal Concentration) 
values is very narrow or very large this should be stated. When, during therapeutics 
use, concentrations are attained which are bacteriocidal in vitro this can be men­
tioned provided it is clinically relevant; the micro-organisms concerned and the site 
at which the concentrations are attained should be specified. 
If a significant degree of synergism or antagonism with other antimicrobial drugs has 
been found this should be specified. 
(b) Pharmacokinetics 
It is advisable to group the information on human pharmacokinetics in subsections con­
cerning absorption, distribution, biotransformation and excretion. 
(i) Bioavailability and absorption 
The bioavailability of the active drug should be indicated. 
Factors which influence to an important extent the degree and rate of absorption 
should be listed. 
(ii) Distribution and plasma levels 
For antimicrobial drugs clinically relevant information in regard to distribution 
should be given. 
The following points are of particular importance: 
— The average maximum and trough serum or plasma concentrations after 
administration in the appropriate way should be given, specifying the dose 
administered, the dosage regimen and the time intervals at which a maximum 
concentration is attained. When the individual variation in drug concentration 
is large this should be specified. 
— Half-life in plasma. 
5. 11. 84 Official Journal of the European Communities No C 293/25 
— Penetration into other body fluids in so far as relevant to the indications and/ 
or toxicity. 
— Where the drug penetrates intracellularly this should be stated. 
— When the distribution is predominantly extracellular it is sufficient to indicate 
the free drug concentration in plasma. 
— In so far as it is relevant to the therapeutic use, the organs or tissues into which 
the drug penetrates poorly (e.g. eye, prostate, CNS) should be listed. 
— Where animal studies indicate that the drug accumulates in particular organs 
or tissues and this is clinically or toxicologically relevant, this should be stated. 
(iii) Bio-transformation 
The pattern of bio-transformation should be indicated; for antimicrobial drugs it is 
particularly important to include available data on any metabolites which have rel­
evant antimicrobial or toxic effects. 
(iv) Excretion 
The excretion patterns of the drug and its important metabolites should be indi­
cated. Excretion into the urine, bile and faeces should be given as a percentage of 
the total dose administered and, where this is clinically relevant, the concentrations 
likely to be attained should be listed. In so far as relevant to the indications the 
excretion into sputum should be given. 
(c) Indications 
It should be made clear that the drug is only indicated for diseases caused by micro­
organisms which are sensitive to it. Even within this field it is desirable to restrict the 
indications of a new antimicrobial drug in order to preserve its usefulness for as long a 
period as possible. 
It is acceptable to give a summary of the organs and tissues, microbial disorders of 
which can be treated effectively. It is not desirable to mention specific diseases, except 
where the clinical usefulness of a drug can only be defined in terms of a particular dis­
ease, or where it is necessary to point out that the drug is unsuitable for treating a parti­
cular condition. When prophylactic indications are listed it will be proper to mention 
the diseases concerned in general or specific terms, provided the value of the drug for 
this purpose has been adequately demonstrated. 
General fields of indication (e.g. 'surgical infections', 'paediatric infections') are inad­
missible. 
When in certain situations it is better to use another form of administration of the drug 
this should be stated. 
(d) Use during lactation 
It should be stated if the drug is excreted in the milk and if there is any risk of sensitiza­
tion of the infant. 
(e) Warnings 
Other antimicrobial drugs to which cross-hypersensitivity and/or cross-resistance may 
occur should be listed. 
If relevant, the-possibility of superinfection with insensitive micro-organisms should be 
mentioned. 
(f) Dosage and other instructions for use 
The usual doses in the various clinical situations in which the drug is useful, which may 
differ substantially, should be listed. 
It should be specifically stated whether adaptation of dosage is necessary in renal fail­
ure or the presence of other concomitant disease, and whether the drug can be used in 
the very young and the very old. 
If the drug can be used in children, neonates and premature infants, then a dosage 
schedule for children under the age of three must be provided in which the dose is 
expressed per kilogram or m2 per day. For older children and adults a total dose may be 
indicated. 
No C 293/26 Official Journal of the European Communities 5. 11. 84 
If relevant, a special dose regimen for aged persons should be indicated, particularly 
where the physiological decline in renal function renders this necessary. 
Maximum safe total doses for the entire course of therapy should be listed wherever 
they are known. 
Compatibility with infusions should be specified where the drug is likely to be used in 
this way. 
ANNEX VII 
CLINICAL TESTING REQUIREMENTS FOR DRUGS FOR LONG-TERM USE 
INTRODUCTION 
The general requirements for clinical trials are given in Directive 75/318/EEC, part. 3. These 
notes for guidance advise on those clinical trials likely to be demanded for long-term use. The 
planning and design of pre-marketing long-term studies should take into account specific prob­
lems raised by each type of drug and disease; the following are general guidelines and do not 
exlude specific recommendations for particular therapeutic classes. 
1. DEFINITION OF LONG-TERM USE 
(a) The CPMP has already defined long-term use in its carcinogenicity guidelines as 'where 
the medicine is likely to be administered regularly over a substantial period of life, i.e., 
continuously during a minimum period of six months or frequently in an intermittent 
manner so that the total exposure is similar'. 
(b) Drug therapy may therefore be classified as: 
(i) occasional, e.g., the infrequent use of an analgesic for occasional toothache or hea­
dache, the prescription of an antibiotic unlikely to be repeated, or an anaesthetic 
gas. This is not long-term use. 
(ii) intermittent use, e.g. an antibiotic regularly prescribed for chronic bronchitis, or 
regular use of an analgesic for dysmenorrhoea. 
(iii) prolonged use 
, e.g., treatment of epilepsy, hypertension, rheumatoid arthritis, or 
heart failure. 
(iv) life-long use 
Categories (iii) and (iv) are considered as long-term use and will be applied to drug 
when current medical practice is likely to bring the drug into one of these categories, 
irrespective of any particular recommendation of the company concerned. Whether (ii) 
constitutes long-term use in the sense of the present notes for guidance will depend 
upon the circumstances of the case, especially the nature of the disorder, but also the 
risks thought to be involved and the novelty of the compound. The examples given are 
illustrative and not meant to be an exclusive list. 
INVESTIGATION OF EFFICACY IN LONG-TERM STUDIES 
(a) The need for evidence of long-term efficacy generally assumes that efficacy in short-
term use has been established for each proposed use by properly controlled studies with 
5. 11. 84 Official Journal of the European Communities No C 293/27 
the formulation and dosage proposed. Evidence should also be provided that efficacy is 
maintained in long-term or repeated-interrupted use. 
(b) Where relevant objective criteria of efficacy are available these should be used rather 
than subjective criteria. 
(c) Patients entering trials should be well defined with respect to diagnosis and presence of 
risk factors and should be as representative as possible of the population which will be 
later treated by the drug. Particularly, the extreme age groups (elderly, children) should 
be appropriately included. 
As with efficacy generally, evidence for each proposed use should be presented from 
well-controlled studies, each with an adequate number of comparable patients for scien­
tific validity, with appropriate and well-defined endpoints as criteria of efficacy. 
The sample size must be sufficient to demonstrate adequate significant differences. In 
case of non-significant differences from control drugs, it is necessary to demonstrate 
through calculation of power or confidence intervals that the sensitivity of the trial 
would have been sufficient to show relevant differences. 
Randomized controlled trials should normally be carried out, placebo being employed 
in appropriate cases. 
Other types of study, if carefully designed and executed, can contribute supplementary 
evidence of efficacy. 
The duration of the studies may vary depending on the purpose of the trials and the 
nature of the drug. It should be sufficient to take into account any spontaneous varia­
tions in the course of the disease, possible effects of the drug on the course of the disor­
der and changes in compliance which are likely to occur. 
If seasonal variations are believed to influence the course of the disease or response to 
therapy, this must be taken into account in arranging the trials and interpreting the 
results. 
Evaluation of results should always include at least one analysis of all the patients allo­
cated to treatment and control groups, including all withdrawals for whatever reason. 
The reasons why patients have failed to complete the study period should wherever pos­
sible be recorded. Description, fully documented, of all critical events, even those occur­
ring after withdrawal from therapy, is required. 
(d) Where efficacy has been established in short-term studies at dose levels higher than pro­
posed in the long-term studies, evidence for efficacy needs to be based on adequate 
numbers studied at the actual dose or within the dose range proposed. 
3. INVESTIGATION OF SAFETY IN LONG-TERM STUDIES 
(a) As with drugs for short-term use, it is important that evidence should be provided that 
an adequate number of patients have been monitored to rule out the occurrence of fre­
quent serious adverse reactions and to define the frequency of less-serious complica­
tions. Claims as to a relatively low frequency of adverse reactions will have to be 
supported by comparative studies. 
The total clinical experience must generally include data on a large and representative 
group of patients (e.g. 100) exposed to the drug for at least 12 months, irrespective of the 
indications. In certain cases the applicant may be able to justify investigating a larger 
number of patients (200 to 300) for a shorter period of time (six months). This may be 
relevant particularly when dealing with drugs for intermittent use. When the drug's sole 
indication is a rare disease a smaller number of patients may be accepted. 
These patients should be fully monitored for clinical, biochemical and haematological 
adverse reactions. Moreover, "for certain drugs it would be useful to know the effect on 
the immune system. The exact requirements will necessarily vary with the nature of the 
drug and the disorder and the known adverse effects of related compounds. Naturally, 
No C 293/28 Official Journal of the European Communities 5. 11.84 
this fully monitored group will, as a rule, only comprise part of the total clinical experi­
ence relating to long-term use. Data on individual patients who have received the drug 
for longer periods should be presented if available. 
(b) The following specific points also need attention in any drug proposed for long-term 
use. 
(i) No pre-marketing study is likely to provide a complete picture of long-term adverse 
reactions, and manufacturers are urged to undertake adequate post-marketing mon­
itoring. 
(ii) Evidence is needed on accumulation of the drug at the proposed dosage schedule, 
and that this schedule is safe and appropriate. Such evidence needs to be supple­
mented by clinical evidence of safety. 
(iii) With long-term use there is obviously an increased likelihood of concurrent use of 
other drugs, and particular attention should be paid to the problem of drug interac­
tions. 
(iv) Where there may be adverse reactions with a seasonal occurrence, e.g., photosensi­
tivity, evidence of safety needs to be demonstrated accordingly. Where adverse 
reactions may occur in particular categories of patients (e.g. elderly, children) who 
are likely to receive the drug, then evidence for safety for such patients needs to be 
established. 
(v) Where adverse effects occur in a particular category of patient, and where it is pro­
posed that the drug is safe for use in categories excluding such patients, then the 
evidence for safety needs to be based on adequate numbers studied in the subset 
for whom the use of the drug is proposed. 
(vi) Investigations should, where appropriate, be performed to determine whether with­
drawal symptoms or a rebound effect occur when the drug is stopped. Such effects 
should where possible be distinguished from mere recrudescence of the original 
symptoms. 
(vii) Where adverse effects have occurred at a higher dose than that proposed, evidence 
for safety must be based on adequate numbers studied at the proposed dose range. 
4. FIXED COMBINATIONS 
(see EEC Notes for Guidance on Fixed Combination Products) 
In principle the present notes for guidance apply to new fixed combinations as well as to 
entirely new compounds. However, requirements in the individual case will depend upon 
the nature of the compounds and the originality of the fixed combination and its proposed 
use. 
5. 11. 84 Official Journal of the European Communities No C 293/29 
ANNEX VIII 
NON-STEROIDAL ANTI-INFLAMMATORY COMPOUNDS FOR THE TREATMENT 
OF CHRONIC DISORDERS 
INTRODUCTION 
These notes for guidance should be read in the light of the general requirements set by the norms 
and protocols (Directive 75/318/EEC). 
1. DEFINITION 
This document relates to applications for registration of non-steroidal anti-inflammatory 
products intended primarily for symptomatic long-term treatment of such disorders as rheu­
matoid arthritis and osteoarthrosis and other disorders of joints, muscles and tendons. Such 
terms as 'anti-rheumatic' and 'anti-phlogistic' are commonly used in various languages to 
characterize these drugs. 
These notes are not primarily intended to apply to drugs used to produce remission. 
2. STAGES OF CLINICAL INVESTIGATION 
(a) Initial short-term studies in patients (3 to 14 days) 
The initial clinical studies undertaken in patients will serve to define the anti-inflamma­
tory effect of the preparation and some adverse reactions occuring in short-term use, as 
well as to estimate the approximate dosage range. At least, some of these studies should 
be conducted against placebo. 
(b) Medium-term studies in patients (2 to 8 weeks) 
In subsequent controlled studies it is advisable to compare the anti-inflammatory pro­
perties of the product at various dose levels with those of at least one other well-studied 
drug of similar type given in fully-effective doses. 
(c) Long-term clinical investigations (see also notes for guidance on 'drugs for long-term use') 
The fact that these products are intended to be used over very long periods at least for 
some indications means that it is of the greatest importance both from the point of view 
of efficacy and safety to study their effects during prolonged use. 
(i) Efficacy 
The pattern of long-term efficacy for drugs of this type can generally be adequately 
defined in controlled studies of up to six months in each of the major indications 
claimed. 
Where drugs of this type are indicated primarily in rheumatoid arthritis, such a 
long-term study should relate to that condition. The known seasonal variations in 
rheumatoid arthritis should be taken into account in arranging these trials and 
interpreting the results. 
Where osteoarthrosis or ankylosing spondylitis are claimed as indications, long-
term investigations should also have been performed in these conditions, but the 
extent and duration of this work will depend upon the totality of clinical evidence 
available on the drug, e.g. the availability of similar studies in rheumatoid arthritis. 
In long-term clinical investigations, particular attention must be devoted to all 
other factors which might influence the results, e.g. other forms of treatment. 
Because of the prolonged nature of this phase, most patients will be on some con­
comitant therapy which should be noted. In particular and irrespective of the type 
of trial (points (b) and (c), an analgesic drug which has no material anti-inflamma-
No C 293/30 Official Journal of the European Communities 5. 11.84 
tory effect, may be used as supplementary therapy if the need arises. Such treat­
ment should be reported separately. 
(ii) Safety 
With respect to numbers of patients and duration of treatment see notes for guid­
ance on 'drugs for long-term use'. The exact requirements are bound to vary to 
some extent from one country to another, because of climate variations; in more 
temperate climates these drugs are generally given throughout the year, whereas in 
warmer climates treatment tends to be suspended during the summer. Nevertheless, 
trials should be designed to take into account possible seasonal variations of 
adverse effects. 
The dosage and pattern of use should be that which is likely to be employed in 
practice. The trial patients should include substantial numbers of the elderly. 
3. ANALGESIC AND ANTIPYRETIC ACTIVITY 
Where specific analgesic or antipyretic activity is claimed or implied, this must have been 
investigated directly in controlled studies which include short-term double-blind comparison 
against placebo and comparisons with other compounds. 
4. CLINICAL PARAMETERS 
The clinical parameters in all studies must be such that they give a clear picture of the extent 
to which the disorder, the symptoms and physical function are influenced. Existing sets of 
criteria for the diagnosis and grading of rheumatoid arthritis may be regarded as a basis. 
5. EXTRAPOLATION OF RESULTS 
Since the various disorders of the joints, tendons, bursae, etc. which are usually treated with 
anti-inflammatory and analgesic drugs differ pathologically, it is important to study the ther­
apeutic effects of a drug in various types of well-defined and carefully diagnosed clinical 
conditions. Extrapolation of the results to another disorder is only permissible where the two 
are pathologically and clinically closely allied. When juvenile rheumatoid arthritis is claimed 
to be an indication for the drug, this must be justified by studies conducted in children suf­
fering from this disease. 
6. SIDE EFFECTS 
A careful study of adverse effects (their nature, frequency and severity) is necessary. Any 
claim that the frequency of certain adverse effects is lower than with other products of this 
type must be supported by adequate evidence obtained with administration in fully effective 
doses. In the assessment of this material, particular attention will be devoted to the question 
of gastro-intestinal tolerance, effects on blood and haemopoiesis, effects on platelet aggrega­
tion, to those adverse reactions which might be anticipated in the light of the animal phar­
macology and toxicology, and to the extent to which the major adverse reactions are dose 
related. 
Data on the reasons for drop-outs in clinical studies should be available since they may 
throw light on the severity of adverse effects. 
Where the pharmacological and/or toxicological data suggest that a drug may stimulate or 
suppress the immune response or interfere significantly with the immune system, work 
should be undertaken using therapeutic doses, to determine whether these effects are of clin­
ical importance. 
7. INTERACTIONS 
Interactions with other drugs prescribed concurrently, as is often the case in the elderly, 
should be looked for during clinical trials and a careful record kept of all concurrent medica­
tion. 
5. 11.84 Official Journal of the European Communities No C 293/31 
Specific studies of possible interactions with particular drugs likely to be used concurrently 
should be undertaken where there is reason to think that they are present. 
ANNEX IX 
ANTI-EPILEPTIC/ANTICONVULSANT DRUGS 
1. GENERAL 
The following notes are concerned primarily with the clinical evaluation of medicines 
intended for long-term use in epileptic disorders. Properly designed long-term clinical stu­
dies are essential, and should be submitted together with short-term studies of special 
aspects of efficacy, tolerance and safety. Experience to date shows that manufacturers and 
physicians would be well-advised, irrespective of any legal obligation, to continue to study 
drugs of this type after they have been registered and marketed, in order to detect unusual 
effects, long-term adverse reactions or alterations in the therapeutic effect over a long 
period (see also notes for guidance on 'drugs for long-term use'). 
2. INVESTIGATORS 
Except for the very earliest phase of tolerance studies it is generally desirable that clinical 
assessment of anti-epileptic drugs is performed by clinicians experienced in the medical 
evaluation and management of epilepsy. 
3. SELECTION OF PATIENTS 
Particularly in the early stages of therapeutic studies it is advisable to select individuals suf­
fering from one or more types of seizures which are well-defined and of known frequency. 
Patients selected for the main therapeutic studies should preferably have a stable form of 
epilepsy, and if they have received drugs already, their therapeutic response to previous 
therapy must be known. Some studies should also include investigations of the therapeutic 
outcome in patients with various degrees of severity of epilepsy. 
It is recognized that in the interest of the patient new anti-epileptic drugs often have to be 
evaluated while combined with other, established drug treatments and during the earlier 
phases of evaluation this approach will generally be essential. Patients who are incom­
pletely controlled on existing drugs constitute an important subgroup for study with a view 
to defining the spectrum of activity of the new drug. In such cases, it is essential that the 
previous drugs have been prescribed for a sufficiently long period to attain a steady state. 
The blood levels of these previous treatments must be known and stable and they should 
continue to be studied after the new compound is administered. Once the efficacy of the 
new compound in combination with others has been determined, it is equally important to 
assess the efficacy of the drug when given alone. While initial therapeutic studies usually 
will be performed on hospitalized patients only, it is essential in the later phases also to 
study the effectiveness and safety of the test drug when used on out-patients, including 
those engaged in normal daily activity. 
4. PHARMACOKINETICS AND BIOAVAILABILITY 
Among existing anti-epileptic drugs several examples are present of kinetic problems which 
are of significance for therapeutic control (non-linear kinetics, alterations in protein-bind­
ing, active metabolites, etc.). Thorough kinetic exploration is therefore particularly needed 
No C 293/32 Official Journal of the European Communities 5. 11.84 
for such drugs, and should include information on the degree of individual variation in 
clinically relevant kinetic parameters. For this reason data on such parameters should be 
submitted for an adequate number of patients. These investigations are often closely related 
to those concerned with drug interactions (see below). Existing anti-epileptic drugs have 
certain characteristics (such as a narrow therapeutic margin and/or complex relationships 
between dose and serum level) which raise problems of bioavailability: if the new sub­
stance is chemically similar to existing drugs, particular attention to these problems will be 
necessary (see notes for guidance on bioavailability). 
5. CRITERIA OF EFFICACY 
In early studies continuous observation is desirable. At this stage and subsequently, reduc­
tion in the frequency of seizures is the main clinical parameter of efficacy. In assessing 
ambulant and in particular petit-mal cases use of telemetry may be advisable. Effects on 
the EEG and on behaviour should be recorded systematically at least in some studies, irres­
pective of whether or not they correlate with the anticonvulsant potential of the drug. In 
subsequent work, reduction in both frequency and severity of seizures should be measured 
and quantified under controlled conditions. It is important to assess social and working 
capacity at the same time. As a measure of benefit, decrease in adverse reactions should 
also be kept in mind. It is recommended that data be obtained on the effects of more than 
one dose level and that serum level monitoring be employed (see 7 below). 
6. COMPARATIVE STUDIES 
The use of placebo alone in patients with convulsions should be avoided, but the use of 
placebo comparisons should be possible (and is of value) when assessing the benefit of a 
new drug as an addition to a known but inadequate regimen. In assessing the effect on 
some other forms of epilepsy (e.g. petit-mal) a new drug may also be tested againt placebo. 
Since a full placebo comparison will not often be feasible or ethically acceptable in convul­
sive epilepsy, it is important in the later phases of evaluation to carry out controlled (ran­
domized) clinical trials in which the drug is compared with other drugs or other combina­
tions of drugs usually employed for the seizures in question. 
7. SERUM LEVELS 
Dose/response evaluation (both effect and dose-related side effects) should not be consid­
ered complete until a clear impression has been gained of the drug's therapeutic and toxic 
range, including serum level studies. The latter are particularly important in determining 
whether or not serum concentration monitoring in the therapeutic situation is meaningful 
and advisable in practice. 
If other monitoring parameters are proposed, for example salivary levels, their significance 
and reliability must be adequately studied. 
8. ADVERSE REACTIONS 
Events occurring during the course of treatment should be carefully recorded, with parti­
cular regard to neurological and psychological changes (e.g. those involving thought pro­
cesses, gait, speech, cooordination, nystagmus or lethargy), and any problems which may 
arise in long-term use, and clinical observations supplemented by appropriate laboratory 
tests. 
9. INTERACTIONS 
Anti-epileptic pharmacotherapy is not infrequently performed with a combination of two or 
more drugs and it is therefore of particular significance that studies to detect clinically 
important drug interactions be carried out. Such studies should include those anti-epileptic 
5. 11.84 Official Journal of the European Communities No C 293/33 
drug combinations which are likely to be used in practice and those which seem likely to 
give rise to interactions. 
Many existing anti-epileptic drugs (e.g. phenytoin, barbiturates, carbamazepine) are also 
well known for their interference with the metabolism of other types of drug, involving 
enzyme induction or inhibition; it is therefore advisable to conduct studies to detect effects 
of this type, particularly if they involve drugs the dosage of which is critical (e.g. cardiac 
glycosides, anticoagulants, oral contraceptives) or interactions with alcohol. 
10. DURATION OF TRIALS 
The principles set out in the notes for guidance on 'drugs for long-term use' will clearly be 
applicable to anti-epileptic/anticonvulsant drugs. Well-documented observations on 
patients treated for 12 months should be available in order to assess the safety and efficacy 
of these drugs in long-term use. Data relating to safety should be available on at least 100 
of such patients. 
11. SPECIAL CLAIMS 
New anti-epileptics are sometimes claimed to have special properties, e.g. psychostimulat-
ing effects. Such claims must be substantiated in controlled clinical trials, specially 
designed for such purpose. 
12. FIXED COMBINATIONS 
Some epileptic patients are treated with two or more anticonvulsants. However, initial indi­
vidual adjustment of the dose of each drug is particularly important in such cases because 
of individual variations in their dose/response curves, their varying kinetics and their some­
times narrow therapeutic margin. Unless there is a special rationale, fixed combinations of 
drugs used for convulsive disorders are generally undesirable and are unlikely to be accept­
able until or unless extensive field experience over some years has indicated that a parti­
cular mixture is in fact of value and well tolerated in practice (see notes for guidance on 
'fixed combination products'). 
13. CHILDREN 
In the light of Directive 75/318/EEC, part 3, chapter III, final paragraph, an epileptic drug 
is unlikely to be acceptable for unrestricted use in children until sufficient experience has 
been gained in various groups and patient types (e.g. infantile spasms, akinetic seizures) to 
determine dosage, serum levels and effectiveness. If possible, long-term studies should be 
designed to detect any possible effects on learning, intelligence, growth and puberty. As 
pointed out in paragraph 1, such studies may need to be conducted subsequent to market­
ing. 
ANNEX X 
INVESTIGATION OF BIOAVAILABILITY 
1. GENERAL REMARKS 
Bioavailability studies evaluate the performances in vivo of dosage forms. They require 
generally a knowledge of the pharmacokinetics of the drug. Broadly, there are two types of 
bioavailability studies: 
No C 293/34 Official Journal of the European Communities 5. 11.84 
(a) studies done during the development of a new product, 
(b) comparisons between existing and new formulations. 
It will be noted that Directive 75/318/EEC, whilst referring both in the pharmacological 
(part 2, chapter 1, section G) and clinical pharmacoligical (part 3, chapter II, paragraphs 2A, 
lc) sections to the need for pharmacokinetic studies, does not set requirements with respect 
to the study of bioavailability. This reflects the fact that when a medicinal product has been 
subjected to the various pharmacological, pharmacokinetic and therapeutic studies specified 
in the Directive, the reports on these studies will generally include precise data on the 
absorption and fate of the drug, from which it will be possible to draw clear conclusions as 
to the adequacy and reliability of its bioavailability from the form which is to be marketed. 
However, a number of specific situations do arise in which the question of bioavailability 
assumes especial importance, and may have to be studied more extensively and more expli­
citly. Some of these situations are indicated in the present notes. 
It should be noted that a number of topics commonly dealt with as aspects of bioavailability 
in fact relate to pharmacokinetics; for these matters reference should be made to the separate 
notes for guidance on human pharmacokinetic studies. 
2. DEFINITIONS 
For the present purpose, bioavailability means the rate and extent of delivery to the site of 
action of an active drug ingredient or therapeutic moiety when a drug is administered in a 
particular pharmaceutical form. Bioavailability is a characteristic of this form and does not 
necessarily run parallel to particular pharmacological or therapeutic effects. Bioavailability 
is generally determined by the extent and rate of absorption of a drug from its pharmaceuti­
cal form, but there may be other important determinants such as first-pass metabolism. It 
may be usefull to distinguish between the 'absolute' bioavailability of a given pharmaceuti­
cal form when compared with that (100%) following intravenous administration, and the 
'relative' bioavailability as compared with another form administered by any route other 
than intravenous (e.g. tablets versus capsules). Clearly the concentration at the site of action 
will rarely be directly measurable and indirect parameters will often have to be employed 
(see paragraph 'Parameters'). 
3 PARAMETERS 
Questions of bioavailability most commonly arise with products administered by the oral 
route, and the present notes are formulated with such products in mind. In these cases, the 
most convenient measure of bioavailability is as a rule the concentration/time curve in the 
blood of the active component and/or its active moiety or metabolites, since this will pres­
umably reflect the concentration attained at the site of action. However, administration by 
other routes will obviously sometimes raise analogous problems, requiring a comparable 
(though different) approach. Studies of blood concentrations are sometimes not feasible, and 
in other instances they are not directly relevant to the effects of a drug; in such cases the 
measurement of concentrations elsewhere (e.g. in urine), of pharmacological effects or thera­
peutic efficacy, using sensitive and reproducible methods, may be acceptable and occasion­
ally more realistic. 
It is felt to be undesirable to lay down here detailed rules as to the method of studying bio­
availability, but some general points may be made: 
(a) The absorption of a medicine in different individuals may be influenced by genetic, 
environmental, dietary and nutritional factors, as well as by age and previous exposure 
to the same drug; in order to eliminate or at least minimize those factors not related to 
the formulations, it is necessary to conduct comparative studies in well-defined and 
controlled conditions. Such studies are generally performed using a crossover design 
which requires fewer subjects than parallel studies. The approach using stable isotope-
labelled and unlabelled drug permits simultaneous administration by different routes 
and thus simplifies the protocol. 
5. 11. 84 Official Journal of the European Communities No C 293/35 
(b) Alongside bioavailability studies which will normally be conducted on an empty 
stomach there will sometimes be a reason to perform kinetic studies designed to deter­
mine the fate of a drug when the stomach is filled, as it will often be when the drug is 
: employed in practice. 
4. APPLICATIONS WITH FULL CLINICAL DOCUMENTATION 
For medicines based on new chemical substances and new forms of administration of 
known substances it may be assumed that all the material specified in Directive 75/318/ 
EEC will be submitted. As pointed out above, this may well provide all the information on 
the bioavailability from the final pharmaceutical form which is required in order to draw 
conclusions. More explicit and extensive investigations of bioavailability are likely, however, 
to be needed in some situations, examples of which are give below: 
(a) Where the results of any studies conducted in animals or man are highly variable, and 
the possibility exists that this variation may be due to a particularly marked effect of 
pharmaceutical processing on absorption. 
(b) Where it is particularly important to ensure exact dosage e.g. because the drug has a 
steep dose/response curve or a narrow margin between therapeutic and toxic dosage, 
and/or where there is a hazard to the patient in the event of inefficacy. 
(c) Where the substance is closely related to one which is known to raise problems of bio­
availability. 
(d) Where the physico-chemical or pharmacokinetic properties of a drug are such that any 
subsequent change in pharmaceutical formulation or processing is likely to alter bio­
availability. 
(e) Where the pharmaceutical process employed is unusual, or such that constancy of bio­
availability is difficult to foresee. This may, for example, be the case where tablets have 
a protective coating, where a slow-release form is involved, or where the active subst­
ance comprises only a very small part of the total formulation. 
(f) Where the product contains more than one active component, in so far as there are theo­
retical or experimental grounds for anticipating that one of these may increase or 
decrease the bioavailability of the other(s). 
5. APPLICATIONS WITHOUT FULL DOCUMENTATION 
Certain applications relate to new specialities which are very similar or even identical in 
their composition to existing specialities. Other applications relate to modifications in exist­
ing products. It is evident that in such cases it will not be necessary to repeat all the studies 
performed with the original speciality. The essential question to be answered is whether the 
older and the newer formulation are bioequivalent (see Appendix) and whether any differ­
ences in bioavailability between them are likely to induce significant change with regards to 
efficacy and/or safety. 
The following principles are applicable: 
(a) Where a substantial departure from the original formulation is involved, or where prob­
lems such as those listed under 'Applications with full clinical documentation' are 
known to exist with respect to the medicine, clinically and statistically adequate bio­
availability studies, comprising direct comparison of the two formulations in man, will 
be required in order to draw conclusions. They may be usefully complemented by phar­
macokinetic studies or therapeutic trials. 
(b) In those other cases where only a very minor modification to an existing product is 
being made, there should be an appropriate in vitro comparison between the older and 
the newer formulation, e.g. with respect to their dissolution time profile or the release of 
the active component. 
6. SITUATIONS IN WHICH BIOLOGICAL AVAILABILITY NEED NOT BE 
STUDIED 
Studies of bioavailability are generally not required: 
(a) when the drug is intended solely for i.v. use; 
No C 293/36 Official Journal of the European Communities 5. 11.84 
(b) when the drug is destined for local therapeutic use (though this does not necessarily 
exclude the need for studies of its passage into the general circulation); 
(c) when the drug is an oral product not required to be absorbed (though this does not 
necessarily exclude the need for studies of its passage into the general circulation); 
(d) when the drug differs only as regards the quantity of active substance from another hav­
ing the same pharmaceutical form, the same proportion of active component and exci-
pients, made by the same manufacturer, provided the bioavailability of the latter has 
been demonstrated and the two products meet the requirements of an appropriate in 
vitro test; 
(e) when the drug has been reformulated but remains an identical (except as regards the 
colorant, sweetener or preservative), to the drug previously prepared by the same manu­
facturer, provided the bioavailability of the latter is known and the two versions meet 
the requirements of an appropriate in vitro test. 
Appendix 
FDA definition of bioequivalence (Federal Register, vol. 42, No 5, 7 January 1977) 
'Bioequivalent drug products' means pharmaceutical equivalents or pharmaceutical alternatives 
whose rate and extent of absoprtion do not show a significant difference when administered at 
the same molar dose of the therapeutic moiety under similar experimental conditions, either sin­
gle dose or multiple dose. Some pharmaceutical equivalents or pharmaceutical alternatives may 
be equivalent in the extent of their absorption but not in their rate of absorption and yet may be 
considered bioequivalent because such differences in the rate of absorption are intentional and 
are reflected in the labelling, are not essential to the attainment of effective body drug concentra­
tions on chronic use, or are considered medically insignificant for the particular drug product 
studied. 
ANNEX XI 
CLINICAL INVESTIGATION OF DRUGS FOR THE TREATMENT OF CHRONIC 
PERIPHERAL ARTERIAL DISEASES 
1. INTRODUCTION 
Drugs influencing peripheral haemodynamics, whether acting on the vessel wall, the blood 
itself or in other ways, are commonly marketed for the relief of intermittent claudication, rest 
pain or symptoms related to vasospasm. The value of the drugs available for this purpose is 
disputed and the reliability or relevance of much clinical investigation performed with these 
products is questionable. 
2. GENERAL PRINCIPLES 
The clinical section of submissions relating to drugs of this type should meet the standards 
generally considered applicable to good investigational practice. 
In particular: 
(a) indications claimed should be based on studies demonstrating directly a clinically rel­
evant and statistically significant effect on the patients' symptoms or the course of the 
disease, and not on pharmacodynamic findings or laboratory data alone; 
(b) results relating to specific pathological entities, types of patient or forms of administra­
tion should not without justification be extrapolated to other situations; 
(c) the reasons why patients have failed to complete the study period should wherever pos­
sible be recorded; 
5. 11. 84 Official Journal of the European Communities No C 293/37 
(d) attention should be devoted to the long-term efficacy and safety of these products and 
to any effect which may follow their withdrawal. 
3. SPECIFIC RECOMMENDATIONS 
In planning and analyzing clinical studies which are intended to form part of a submission, 
applicants are particularly urged to bear the following points in mind. They are listed pri­
marily with respect to studies in intermittent claudication, but certain points are also appli­
cable to studies of other peripheral ischaemic conditions. 
(a) Definition of patients 
In order to make valid comparisons and constitute homogenous sub-groups for ana­
lysis, it is vital to characterize trial subjects at the time of admission with respect to a 
number of variables, particularly: 
(i) the nature, site and extent of the peripheral vascular disorder, which should be 
determined as objectively as possible. Angiography, which is often performed in 
this type of patient, will be of great value in this respect; 
(ii) the duration and severity of the clinical symptoms. In studies involving the lower 
limbs, only patients who display a pronounced reduction of the ability to walk are 
eligible for the trial; 
(iii) relevant dietary habits and body weight; 
(iv) intake of alcohol, smoking habits; 
(v) use of other drugs; 
(vi) the presence of any relevant concurrent disease (e.g. diabetes, hypertension); 
(vii) the usual degree of physical activity. 
Changes relating to (iii), (iv), (v), (vi) and (vii) during the study should be recorded. 
(b) Use of controls 
Because the course of symptoms due to peripheral ischaemia can fluctuate sponta­
neously and can be very strongly influenced by factors such as training and other 
behavioural measures, etc., treated patients must be compared with a contemporaneous 
control group. Since the merits of all existing drugs in this field are widely disputed, no 
valid reference compound can be proposed, i.e. the comparison should at the present 
time include a placebo. 
(c) Patient selection 
Alert, ambulatory outpatients with stable intermittent claudication, generally at a non-
advanced stage of the chronic arterial disease, will be selected. In this document, stable 
should be defined as having no significant change in severity of symptoms during a pre­
vious three months period. 
A long observation period is necessary to characterize the fluctuation of the symptoms 
and for the patients to reach stability under general measures such as exercise, limita­
tion of use of tobacco and alcohol, appropriate diet, and treatment of concomitant dis­
eases; these measures should be kept as constant as possible during the whole trial. 
Before the actual study begins, patients considered to be stable under the above condi­
tions will enter a placebo run-in period intended to check their stability and to assess 
their base-line. During this pretreatment period, appropriate standardized exercise tests 
should be carried out at intervals (e.g. two weeks) until sufficiently reproducible results 
are obtained. Experience has shown that a period of four to six weeks will often be suf­
ficient for this purpose. 
Random allocation of patients to the treatment or placebo groups should be made after 
this run-in period. 
No C 293/38 Official Journal of the European Communities 5. 11. 84 
(d) Parameters 
The most essential parameters are those reflecting measurement of the clinical effect 
claimed. 
Any effect claimed on intermittent claudication should be studied in standardized exer­
cise tolerance tests, e.g. using a treadmill. Such tests should be performed under con­
trolled temperature conditions and with a prolonged period of acclimatization. These 
studies may be supplemented by scoring the patients' own assessment of the improve­
ment attained. 
Whilst drugs developed in this field may affect the outcome of various types of purely 
objective study (e.g.) involving venous occlusion, plethysmography, xenon clearance as 
a measure of blood flow in the muscles, Doppler blood pressure measurements, oscillo­
metry, calorimetry, muscular p 02), there appears as yet to be no such method available 
which is both entirely dependable and correlates to any useful extent with the effects 
desired clinically. Such methods may be of some value in screening new products, but if 
an applicant wishes to claim that such a technique actually demonstrates the clinical 
usefulness of a product its relevance must be proven. 
(e) Comparative studies 
(i) In order to allow for spontaneous fluctuations in the course of the disease and to 
detect the possible development of tolerance and some delayed adverse effects, the 
double-blind phase of treatment should last for prolonged periods (6 to 12 months). 
(ii) Enrolment of patients should take into account the seasonal influences on the evo­
lution of such disorders and occurrence of adverse effects. 
(iii) Any relevant even occurring after treatment withdrawal during or after the trial 
should be taken into account. 
(f) Analysis of results 
Any clinical effect obtained is unlikely to extend to all the types of patient treated and 
in order to obtain a clear impression a careful analysis of the results obtained in prede­
fined sub-groups (see (a) above) will be required. 
ANNEX XII 
PHARMACOKINETIC STUDIES IN MAN 
GENERAL 
/ 
The present notes are designed to provide guidance on, and assist applicants in the interpretation 
of, preclinical and clinical pharmacokinetic investigations of a new drug, irrespective of the 
nature, mode of action or route of administration. 
These notes for guidance should be read in the light of the norms and protocols (Directive 75/ 
318/EEC) and are intended solely to assist applicants in the interpretation of the latter with res­
pect to the specific problems of pharmacokinetic studies, including drug metabolism, in healthy 
volunteers and patients. 
These notes only consider general rules; all the points mentioned do not necessarily apply to 
each substance; therefore each study should be planned and designed taking into account the 
properties and indications of the drug concerned. 
5. 11. 84 Official Journal of the European Communities No C 293/39 
The relation between dose, plasma concentrations and therapeutic or toxic effects, where this is 
feasible, should be studied. Pharmacokinetic studies are as a rule necessary in order to employ 
drugs under the best conditions of efficacy and safety. They are essential to establish therapeutic 
schedules, to evaluate their relevance or to proceed to dosage adjustments in particular patients. 
This particularly applies to drugs with a narrow therapeutic range and to those for which a close 
relation between plasma concentrations and therapeutic and/or toxic effects can be demon­
strated or expected. 
In some instances, pharmacokinetic studies may be impossible or limited, e.g. where their provi­
sion raises insuperable difficulties or would create risks for test subjects; in these cases, the use of 
drug is partly or completely based upon pharmacodynamic and clinical studies. 
The present notes consist of two sections: 
I. Pharmacokinetic factors to be studied 
which deals with: 
1. absorption, 
2. distribution, 
3. elimination, 
as well as with interactions and adverse reactions, 
II. Methodology and conditions of study 
which deals with: 
1. choice of administration (route, dosage, dosage intervals), 
2. choice of subject (healthy volunteers, patients with relevant disorders, patients with 
other interfering conditions), 
3. choice of methodology: sampling and analysis, data processing and statistics. 
I. PHARMACOKINETIC FACTORS TO BE STUDIED 
1. ABSORPTION 
Both the rate and extent to which the active drug ingredient or therapeutic moiety are 
absorbed should be known 
Data on bioavailability, which is referred to in the EEC notes for guidance on investiga­
tion of bioavailability, should be provided. 
(a) Substances intended to produce systemic effects 
Whatever the route of administration (e.g. buccal, sublingual, parenteral, rectal, 
percutaneous, pulmonary), direct or indirect data on the extent of absorption 
should be submitted; whenever possible, comparison with an intravenous dose 
should be made. Preferably a precise pharmacokinetic analysis of the entire plasma 
profile, including absorption, distribution and elimination, should be given since 
these various steps may be interrelated to a great extent. This applies particularly to 
special dosage forms for which delayed release of the active substance or a pro­
longed duration of action is claimed. Failing this, at least data on drug concentra­
tion at peak (Cmax), time to reach peak (tmax) and area under the concentration/time 
curve (AUC) should be provided. 
If there is reason to suspect that certain physiological or pathological factors, such 
as the presence of food or certain food constituents (e.g. dairy products) in the sto­
mach, or certain functional or anatomical disorders of the gastrointestinal tract 
might substantially alter absorption, separate pharmacokinetic studies in suitable 
volunteers or patients should be performed. 
(b) Substances not intended to produce systemic effects 
In the case of drugs with a high intrinsic activity (i.e. topical corticosteroids, some 
aerosols for respiratory disease), it is often desirable to study the passage into the 
No C 293/40 Official Journal of the European Communities 5. 11. 84 
circulation, since pronounced systemic effects can be produced. The same principle 
holds good for topical application of drugs in patients suffering from- disorders of 
the skin or mucous membranes. Data on systemic effects should therefore be sub­
mitted or direct pharmacokinetic data otherwise. 
2. DISTRIBUTION 
Data on adequate mathematical analysis (descriptive and/or interpretative analysis or 
models) including data on model independent parameters should be provided. 
The percentage and characteristics of binding to serum proteins should be studied using 
appropriate ex vivo or in vitro methods. Particularly in the case of drugs or their active 
metabolites of which a high percentage is bound to plasma proteins, factors which 
might alter protein binding and so alter therapeutic response should be studied. Binding 
to red blood cells and other blood components should also be known. 
Some disease states may significantly alter the distribution pattern of a drug. If such 
changes (e.g. decreased volume of distribution in renal insufficiency, changes in pene­
tration of antibiotics into csf in meningitis, changes in the concentrations of individual 
proteins to which a drug is bound, etc.) could lead to alterations in dosage schemes or 
indications, they should be studied in suitable patients. 
In so far as relevant to the claims, distribution to accessible body fluids (csf, synovial 
fluid) should be investigated. 
Actual drug concentrations in tissues can rarely be measured; nevertheless, such data 
should be submitted when they are particularly desirable or even necessary to solve 
some important problems related to efficacy or safety and when such measurements are 
feasible. 
3. ELIMINATION 
The elimination rate for the parent compound (e.g. total body clearance, elimination 
half-life) should be studied in volunteers with normal elimination mechanisms, and 
whenever possible also in patients with functional disturbances of these elimination 
mechanisms. The nature of the main routes of elimination and their relative importance 
in regard to total elimination should be known. 
(a) Metabolism 
With few exceptions drugs are to a greater or lesser extent subject to metabolic 
breakdown within the human body. Pharmacokinetic studies should indicate 
whether the rate of biotransformation may be substantially modified in case of 
genetic enzymatic deficiency and whether within the dosage levels normally used, 
saturation of metabolism may occur, thereby inducing non-linear kinetics. The pos­
sibility of enzymatic induction should also be studied if metabolic clearance as a 
fraction of the systemic clearance is relatively high. If there is an indication that 
pharmacologically active metabolites (the qualitative activity of which may also 
occasionally differ from that of the parent drug) are formed, this should be ascer­
tained and, if there is reason to suspect that they contribute to a significant extent 
to the therapeutic activity and/or adverse reactions in man, they should be exam­
ined in suitable animal models or if necessary in appropriate human clinical-phar­
macological studies. The pharmacokinetic data on such metabolites, the rate of 
their formation and elimination and their distribution and clearance characteristics 
should be known. 
(b) Excretion 
The urinary excretion should be defined by parameters such as: 
— total cumulated amounts of unchanged and metabolized drug found in the 
urine following a single dose, 
— renal clearance of the drug. 
5. 11.84 Official Journal of the European Communities No C 293/41 
The excretion half-life and the extent of variation between individuals should be 
determined. In drugs which show a high renal clearance or form pharmacologically 
active metabolites to a significant level with a predominantly renal clearance and 
are liable to be used in patients with renal insufficiency, the elimination and accu­
mulation characteristics in patients with varying degrees of reduction of glomerular 
filtration rate should, when possible, be examined. Further quantitative data on the 
relation between the elimination rate constant and the glomerular filtration rate 
should be provided, or evidence be presented that such data can be derived from 
the measurement of the fraction of the absorbed dose excreted in unchanged form 
in the urine of patients or healthy volunteers with normal renal function. 
If renal clearance constitutes a substantial proportion of systemic clearance (e.g. 
more than 30 %), the existence of tubular secretion and/or reabsorption and pH 
dependency of secretion should be investigated. In so far as relevant to the claims 
(i.e., prolonged duration of action caused by enterohepatic recirculation), other 
routes of excretion (bile, milk) should be investigated. It may be useful to know if 
the substance is dialyzable and/or can be removed by haemoperfusion. 
4. INTERACTIONS AND ADVERSE REACTIONS 
Pharmacokinetic interactions may occur during the absorption phase, as well as during 
the distribution and the elimination phase. If such interactions are suspected on the 
basis of animal data, expected on the basis of the physico-chemical or pharmacological 
properties of the drug or similar compounds (i.e., protein binding, enzyme induction), or 
observed during (pre-)clinical studies, the pharmacokinetic changes due to such interac­
tions should be measured and, whenever possible, the mechanisms elucidated (e.g. 
enzyme induction, competition for renal elimination sites, etc.). 
Certain types of adverse reactions are due to unusual genetic pharmacokinetic varia­
tions; though it will rarely be possible to study such aberrant behaviour in a prospective 
manner every effort must be put into elucidating the pharmacokinetic mechanism(s) if 
there is any reason to suspect that the adverse reaction is caused by the altered pharma­
cokinetics of the drug. 
II. METHODOLOGY AND CONDITIONS OF STUDY 
1. SCHEME OF ADMINISTRATION 
Both single dose and multiple dose studies should be performed within the recom­
mended dose range and dose intervals. 
Multiple dose studies should be, whenever possible, continued long enough to establish 
steady-state concentrations of the drug, and for such steady-state levels, their dose-
dependence and variability should be determined. Accumulation kinetics of the drug 
predicted from the kinetic constants obtained from single dose studies should be veri­
fied experimentally: different doses should be included in one study to determine dose 
dependence and to decide whether changes from linearity to non-linearity occur at dos­
age levels which are normally used. After discontinuation of a prolonged treatment, the 
possibility of a very slow terminal decrease in plasma concentrations, which can reflect 
the existence of a deep compartment, should be investigated. This might explain the dis­
crepancy between the long action of the substance and the apparent short elimination 
half-life as measured after a single dose administration. 
Though these principles should normally be followed in detail, it is acknowledged that 
this is not always feasible. 
2. SUBJECTS 
(a) Initial studies 
Initial studies are generally performed in a restricted number of fasting, healthy, 
adult volunteers, in well-defined and controlled conditions. When the substance 
No C 293/42 Official Journal of the European Communities 5. 11.84 
carries too serious a risk to healthy volunteers (e.g. cytostatics), they are conducted 
in patients suffering from diseases for which the drug is considered to be indicated. 
(b) Further studies in patients 
Further studies should be conducted in patients suffering from diseases for which 
the drug is claimed to be indicated. The relation between dose, plasma concentra­
tion and therapeutic effect, where this is feasible, should be studied. Particularly, it 
should be established that the pharmacokinetic behaviour of the drug in patients 
corresponds to that in healthy subjects. The full range of kinetic studies needs only 
be repeated in patients if studies indicate that the pharmacokinetics in this group 
differ from those in healthy volunteers. 
(c) Influence of various patho-physiological states 
It is very useful to know the kinetics of drugs in a very large number of patho-phy­
siological situations; however, it is clear that this knowledge requires multiple, long 
and expensive studies which cannot all be performed before licensing. 
Therefore, the only studies which should be reasonably submitted before marketing 
are those which seem to be necessary in regard to the properties, indications, con-
tra-indications, routes of elimination, scheme of administration of the drug and 
which are required to define the necessary dosage changes which cannot be calcu­
lated from the pharmacokinetic parameters available from volunteers under stan­
dardized conditions and in patients without functional disturbances of the systems 
of absorption, distribution or elimination. 
In so far as the indications render this relevant, kinetics should be studied in 
patients of extremes of age (infants, children and the elderly). For drugs intended 
to be orally administered, it is important to study the effects of food on absorption. 
Other factors like body weight, time of the day, environmental factors, genetic dif­
ferences, alcohol, smoking habits, concomitant medication, sex, may markedly 
interfere, and if there is particular reason to believe that these may interfere, and if 
there is particular reason to believe that these may markedly influence the results 
and the interpretation of later clinical studies, kinetic studies should be extended 
accordingly. 
3. METHODOLOGY 
The quality of pharmacokinetic analysis can be no better than the quality of the experi­
mental data that serve as input for such analyses. The following principles should there­
fore be kept in mind: 
(a) Sampling 
The number of blood samples should be large enough and the timing appropriate 
to allow an adequate determination of the absorption and/or distribution and eli­
mination phases. Plasma concentrations in the post-absorptive phase should, 
whenever possible, be determined over at least two or three half-lives to avoid con­
fusion between distribution, and elimination half-lives. If there is any evidence for 
a very long terminal half-life, plasma concentrations should be followed for a much 
longer time. If urinary data are obtained, the urine should be collected until there is 
no further detectable excretion of parent drug or metabolites within the limits of the 
method used. 
(b) Stability 
The stability of the substance during sampling and storage requires careful atten­
tion. 
(c) Analytical procedures 
Specificity, precision (sensitivity and reproducibility) and accuracy (e.g. as regards 
recovery) of the methods should be mentioned. Both for reasons of safety and for 
technical reasons, cold analytical methods are often to be preferred to tracer 
radioactive techniques. If radioactive isotopes are used the tracer dose should 
always be combined with a quantity of non-labelled drug within the therapeutic 
5. 11. 84 Official Journal of the European Communities No C 293/43 
dose range. However, in most cases it will be necessary to develop suitable cold 
analytical methods to separate and assay quantitatively the metabolites and/or the 
parent compound. 
(d) Interpretation of data 
The mathematical methods used (graphical representation, computer analysis, 
pharmacokinetic formulas) should be stated, including the confidence limits. 
(e) Presentation and evaluation of the results 
In summarizing data obtained from more than one subject, it is usually preferable 
to analyze individual data and at a later stage to average the pharmacokinetic con­
stants so obtained. 
Proper statistical analysis of the data obtained should be made and the inter- and 
intra-individual variations estimated, in at least some of the studies where the num­
ber of subjects is large enough. 
Proposal for a Council Directive amending Directive 65/65/EEC on the approximation 
of provisions laid down by law, regulation or administrative action relating to proprietary 
medicinal products 
COM(84) 437final 
(Submitted by the Commission to the Council on 3 October 1984) 
(84/C 293/05) 
THE COUNCIL OF THE EUROPEAN 
COMMUNITIES, 
Having regard to the Treaty establishing the Euro­
pean Economic Community, and in particular 
Article 100 thereof, 
Having regard to the proposal from the Commis­
sion, 
Having regard to the opinion of the European Par­
liament, 
Having regard to the opinion of the Economic and 
Social Committee, 
Whereas point 8 of the second paragraph of 
Article 4 of Council Directive 65/65/EEC ('), as last 
amended by Directive 83/570/EEC (2) provides that 
various types of proof of the safety and efficacy of a 
proprietary medicinal product may be put forward 
in an application for marketing authorization 
depending upon the objective situation of the medi­
cinal product in question; 
Whereas experience has shown that it is advisable to 
stipulate more precisely the cases in which the results of pharmacological and toxicological tests or 
clinical trials do not have to be provided with a view 
to obtaining authorization for a medicinal product 
which is essentially similar to an authorized prod­
uct, while ensuring that innovative firms are not 
placed at a disadvantage; 
Whereas additional details were provided in respect 
of the application of the abovementioned provision 
by Council Directive 75/318/EEC of 20 May 1975 
on the approximation of the laws of the Member 
States relating to analytical, pharmaco-toxicological 
and clinical standards and protocols in respect of 
the testing of proprietary medicinal products (3), as 
amended by Directive 83/570/EEC; 
Whereas, however, considerations of public policy 
are against the repetition of tests on animals or trials 
in man without pressing reasons; 
Whereas it is also advisable to make the packaging 
of certain medicinal products, particularly sought 
after by drug addicts, more commonplace by sup­
pressing the obligation to mark the outer packaging 
(') OJ No 22, 9. 2. 1965, p. 369/65. 
O OJ No L 332, 28. 11. 1983, p. 1. O OJ No L 147, 9. 6. 1975, p. 1.