22.5.86 Official Journal of the European Communities No C 122/7 
Amendment to the proposal for a Council Directive amending Directive 81/852/EEC on the 
approximation of the laws of the Member States relating to analytical, pharmacotoxicological 
and clinical standards and protocols in respect of the testing of veterinary medicinal products 
COM(86) 117 final 
(Submitted by the Commission to the Council pursuant to the second paragraph of Article 149 of 
the EEC Treaty on 14 March 1986) 
(86/C 112/10) 
On 25 September 1984, the Commission presented the 
above proposal to the Council. For the reasons outlined 
in the explanatory memorandum, the original proposal is 
hereby amended as follows: 
1. In Article 1, the following point 2 is inserted: 
'2. Part 1 of the Annex, "Analytical (physico-
chemical, biological or microbiological) tests of 
veterinary medicinal products", is amended as 
follows: 
(a) In Part 1 A the following section 4 is inserted: 
"4. An explanation should be provided with 
regard to the choice of composition, 
constituents and container, supported by 
data on development pharmaceutics. The 
overage, with justification thereof, should 
be stated." 
(b) In Part 1 B the following fifth indent is 
inserted: 
0) OJ No C 293, 5. 11. 1984, p. 6. "— experimental studies validating the manufacturing 
process, where a non-standard method of manu­
facture is used or where it is critical for the 
product." 
(c) In Part 1 C (2), subparagraph (b) is replaced 
by the following: 
"(b) the description of the substance, set 
down in a form similar to that used in a 
descriptive item in the European Phar­
macopoeia, shall be accompanied by any 
necessary explanatory evidence, 
especially concerning the molecular 
structure where appropriate; it must be 
accompanied by an appropriate 
description of the method of synthetic 
preparation. Where substances can only 
be described by their method of 
preparation, the description should be 
sufficiently detailed to characterize a 
substance which is constant both in its 
composition and in its effects;".' 
2. In Article 1, the existing point 2 becomes point 3. 
Amendment to the proposal for a Council recommendation concerning tests relating to the 
placing on the market of proprietary medicinal products 
COM(86) 117 final 
(Submitted by the Commission to the Council pursuant to the second paragraph of Article 149 of 
the EEC Treaty on 14 March 1986) 
(86/C 112/11) 
On 25 September 1984 the Commission presented the above proposal to the Council. For the 
reasons outlined in the explanatory memorandum, the original proposal is hereby amended as 
follows: 
The following Annex XIII 'Anti-anginal drugs' and Annex XrV 'Corticosteroids intended for 
use on the skin' are added. 
0) OJ No C 293, 5. 11. 1984, p. 8. 
No C 122/8 Official Journal of the European Communities 22.5.86 
ANNEX XIII 
ANTI-ANGINAL DRUGS 
1. GENERAL 
The present notes are designed to provide guidance on clinical investigations to determine the value 
of drugs in preventing attacks of angina pectoris, irrespective of the nature, mode of action, or 
route of administration of these drugs. 
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 anti-anginal drugs. 
The clinical profile of such a drug needs to be studied both in the acute (experimental) situation, i.e. 
with provocation of anginal attacks or ischaemic episodes, and under conditions of normal practice. 
In both situations, valid data are only likely to be obtained if sufficient account is taken of such 
factors as the pronounced placebo effect in angina pectoris, the substantial variation in the nature 
and severity of the symptoms, and the subjective character of 'chest pain'. At all phases of study, the 
possibility that sudden withdrawal of an effective drug may cause an aggravation of symptoms 
should be considered. In those instances where the mechanism of action appears to be novel, special 
effort should be made to investigate it. Full studies of kinetics are highly desirable. 
A distinction has to be drawn between angina of effort and spontaneous angina (angina at rest). 
The mechanisms of the two may be different and they require separate investigation. 
2. ANGINA OF EFFORT 
Angina of effort is characterized by transient episodes of chest pain precipitated by exercise or by 
other situations resulting in an increased myocardial oxygen demand. 
2.1. Definition and selection of patients 
Patients deemed suitable for any phase of these studies should have coronary insufficiency with or 
without anginal pain, and reproducible ischaemic changes on exercise testing. 
(a) For any phase of clinical trials (see 5: field studies), patients should be suffering from stable 
angina of effort: their condition should be approximately stable, e.g. over a period of at least 
one month (') there should have been no clear deterioration or improvement. The severity of 
their condition should be accurately known. Since angina of effort is linked to fixed coronary-
artery occlusive disease, selective coronary arteriography, which is often performed in this type 
of patients, is of great value in this respect. Patients with resting electrocardiogram (ECG) 
anomalies from whatever origin, which render interpretation of ST-T changes difficult, should 
be excluded from trials. Risk factors such as smoking, hypertension or hypercholesterolaemia, as 
well as the use of anti-anginal and other drugs, should be carefully recorded. Other aspects of 
life style which may be relevant, e.g. exercise habits, should be noted and changes recorded. 
The following classes of patients should be excluded from the study: (a) those who have had a 
myocardial infarction during the preceding months (at least three months); (b) those with a 
clinical picture of impending infarction; (c) those who suffer from angina at rest; (d) those 
whose angina is due in whole or part to diseases other than coronary artery disease; (e) those 
suffering from any condition which might invalidate the results of the study. 
(') Nomenclature and criteria for diagnosis of ischaemic heart disease. Circulation (1979), 59, pp. 607-9. 
22.5.86 Official Journal of the European Communities No C 122/9 
A single-blind placebo run-in period is necessary to: 
(i) establish or verify the stability of the patients' condition; 
(ii) assess the severity of the patients' condition; i.e. the degree of physical effort or the 
intensity of provocation test required to elicit a positive response and/or the number of 
anginal attacks per week: a certain minimum is necessary in order to include the patients in 
the trial; 
(iii) obtain information about the patients' capability to keep a diary of angina attacks and 
nitrate use; 
(iv) accustom patients to the experimental routine and minimize subsequent placebo reaction 
during the study; 
(v) eliminate carry-over effects from previous treatment. 
The run-in period should last several weeks (e.g. two to six weeks), the exact duration 
depending on the severity and frequency of the anginal attacks and the nature of previous 
treatment; the period must be clearly long enough to meet aims (i) to (v) above. 
(b) For the acute experimental phase (see 4) e.g. quantified exercise tests, a run-in period of a few 
days may be adequate to familiarize patients with the exercise test to assess their physical per­
formance but it must be shown that this period is long enough to ensure a sufficient wash-out 
of the previously administered anti-anginal drugs. 
2.2. Use of placebo 
Because of the marked placebo effect in the treatment of angina pectoris, certain studies with a new 
drug in this field must be performed against a placebo and will be referred to below. All subjects 
engaged in studies of anti-anginal drugs should have short-acting nitrate available for use should an 
anginal attack occur, such use being recorded. 
2.3. Comparative studies 
To distinguish placebo reactions from drug effects, the initial (acute) investigations should be 
planned as double-blind comparative trials, e.g. with a cross-over design. In these studies it is useful 
to compare the agent being studied with a placebo. Each of the initial clinical studies should involve 
comparison either with a placebo and/or with a drug of recognized value. In the study as a whole 
there should be some comparisons with anti-anginal drugs of recognized value: these comparisons 
are useful for the future clinical use of the product. 
2.4. Acute (experimental) phase 
Anginal pain or signs of an acute ischaemic state should be provoked under controlled conditions, 
i.e. reproducible quantified exercise tests are required, performed with close supervision and 
monitoring. The tests should be performed under well-defined conditions, e.g. as regards the time 
of day, the period which has elapsed following administration of the drug or placebo, and the 
timing with respect to meals. The manner of administration should be appropriate to the suggested 
use of drug. 
The main objective variables are the maximum work-load and/or the total work-load reached at the 
time of: 
(a) pain of characteristically anginal nature; 
(b) ST-T changes; 
(c) dyspnea; 
(d) maximal heart-rate; 
(e) disturbance of rhythm and conduction; 
(f) inappropriate blood pressure changes; 
(g) excessive fatigue. 
No C 122/10 Official Journal of the European Communities 22. 5. 86 
The observations on (a) and (b) are directly concerned with the myocardial ischaemic state and 
should be considered separately from the observations on (c) to (g) which whilst important cannot 
be regarded themselves as specific criteria for an anti-anginal effect. 
Heart-rate and systolic blood pressure should be recorded. Techniques are now becoming available 
for detecting ischaemia and studying myocardial oxygen consumption and may prove of value (e.g. 
thallium scan, isotopic angiography). 
The design of the experiments should include the study of dose/effect relationships, the duration of 
effects of a single dose and if possible the relationship between blood levels and effects. The 
demonstration of a haemodynamic effect does not automatically imply that the drug will be 
effective in the relief of anginal pain. If such a parallel is postulated, it should be adequately 
demonstrated during long-term use of the drug. 
2.5. Clinical studies 
(a) Short-term studies (e.g. lasting some weeks) should be well designed and controlled to provide 
data on the efficacy of the experimental drug as compared to another agent. At least some of 
these investigations should be performed double blind against placebo. These initial studies 
should provide sufficient data on the dosage, duration of action and possible adverse reactions 
to define the pattern of further investigations. 
(b) Medium-term studies (e.g. lasting up to six months) should be designed to study efficacy and 
safety of the drug under conditions as close as possible to those in which it would be used, as 
well as to detect any decrease or increase of effect of the drug in prolonged use. Some of these 
studies should be comparative. Criteria of efficacy may be the number of anginal attacks, the 
nitrate consumption and/or exercise tolerance. Data on nitrate consumption should be regarded 
with some reserve unless it has previously been constant over a long period, which is rarely the 
case. In some studies exercise tolerance should be systematically explored. The drop-out rate 
and the reasons for drop-out, i.e. side effects, myocardial infarction, death with the diagnosis 
whenever possible, should be recorded. The possibility that sudden withdrawal of the drug 
might cause an aggravation of symptoms should be considered. 
Data should also be available to evaluate results obtained in earlier studies (e.g. with regard to 
adverse reactions), special claims which the manufacturer wishes to make (e.g. as regards the 
mechanism of action) and possible interactions with other drugs commonly taken by this 
category of patients. 
(c) Long-term studies (see also Notes for Guidance on 'Drugs for long-term use') 
Certain clinical observations (e.g. on 100 patients) should have been made over a period of at 
least one year, to detect any changes over this period in the clinical effect and to define 
undesirable effects. Long-term studies need not be comparative. Reasons for drop-out should be 
documented. 
It is clear that the planning of any study in which angina or ECG changes are provoked must take 
into account the need to avoid undue risks for the patient; see e.g. American Heart Journal (1978), 
95, No 1, pp.102-14. 
3. SPONTANEOUS ANGINA (ANGINA AT REST) 
Spontaneous angina (angina at rest) is characterized by chest discomfort and/or ischaemic episodes 
occuring at rest and often somewhat atypical, in the absence of any apparent eliciting factor. It is 
usually due to coronary arterial spasm (vasospastic angina). Many patients exhibit a mixed form of 
angina where spasm is associated with fixed coronary artery stenosis; these patients should be 
studied separately. Spasm may be elicited by agents which increase coronary artery tone such as 
ergonovine maleate and to a lesser extent alpha-adrenergic-receptor agonists or cold; however, such 
tests are hazardous and will not normally be demanded. Nevertheless, if the investigator himself 
considers them necessary for diagnosis and/or treatment, evidence from such procedures may be 
acceptable provided they are carried out in a coronary care unit (CCU),< Using standard methods to 
limit the risks. Some of the diagnostic methods used for angina of effort may be of value in this 
field, such as thallium scan or isotopic angiography. v 
22. 5. 86 Official Journal of the European Communities No C 122/11 
The following specific points should be taken into account: 
(a) circadian fluctuations; 
(b) extreme spontaneous variability of the disorder; 
(c) frequent recurrence of transient ECG changes typical of myocardial ischaemia in the absence of 
chest pain; 
(d) difficulty of diagnosis and frequency of severe complications which require admission of che 
patient to CCU; 
(e) ethical considerations raised by the serious nature of the disease. 
Although new methods of evaluation will probably become available in the future, the following 
general principles of testing provide a guide compatible with current practice. 
3.1. Patient selection 
Patients will be suffering from episodes of uncomplicated angina at rest associated with electro­
cardiographic changes of ischaemia and angiographic evidence in favour of vasospastic angina. 
Patients most suitable for investigation with currently available techniques are those experiencing 
painful and/or painless ischaemic episodes recurring at least three times per day. 
3.2. Clinical studies 
All subjects should have short-acting nitrates available for use should an anginal attack occur, such 
use being recorded. 
(a) Very short-term studies (some days) should be performed under close supervision in specialized 
units. The efficacy is assessed on one or several of the following criteria: 
— occurrence of spontaneous or evoked ST-T changes detected by continuous ECG 
monitoring, 
— frequency of spontaneous or evoked anginal attacks, 
— consumption of short-acting nitrates. 
Double-blind crossover studies against placebo are highly desirable and feasible. Considerable 
concern has been expressed about the use of double-blind ramdomized controlled studies, 
mainly against placebo, in patients with vasospastic angina. Acute myocardial infarction and 
sudden death have been reported to occur in such patients. However, if intractable angina with 
ECG evidence of ischaemia occurs during those trials, the patient should be withdrawn from the 
trial and given the appropriate treatment. 
(b) Medium-term studies (several weeks to several months) 
New compounds should generally be tested against drugs of established value. The main 
objective criteria of evaluation are: 
— frequency" of ehest pain, 
— consumption of short-acting nitrates, 
— number of episodes of transient ST segment shift detected through ambulatory ECG. 
monitoring (e.g. monthly), 
— failure of treatment leading to instability of angina or impending myocardial infarction, 
— sudden deaths, 
and eventually,, periodic responses to provocation tests. ,.. .,.,., 
Side-effects should be carefully monitored-. Particular attention ..should be devoted to a possible 
rebound effect on withdrawal of the drug. 
No C 122/12 Official Journal of the European Communities 22.5.86 
(c) Long-term studies 
Patients suffering from vasospastic angina may be treated for months or years; therefore it is 
desirable, as in the case of angina of effort, to have long term studies performed over a period 
of at least one year. 
When a new substance is claimed to be effective in angina of effort and angina at rest, clinical 
observations (e.g. 100 patients: see B 5(c)) should be conducted with consistant and repre­
sentative groups of each type of angina. 
When angina at rest is only being studied, fewer than 100 patients can be accepted, considering 
the difficulty of such studies: nevertheless, the number of patients should be sufficient to follow 
clinical activity and define long-term adverse effects. 
ANNEX XIV 
CORTICOSTEROIDS INTENDED FOR USE ON THE SKIN 
1. INTRODUCTION 
The following guidelines on clinical testing hold good in principle for all topical corticosteroids 
which are intended to be used on the skin. The effects including local adverse reactions are, in 
principle, the same for all corticosteroids, due to common properties, i.e. anti-inflammatory and 
mitosis-reducing action and inhibition of collagen synthesis. Apparent differences between subs­
tances in fact reflect differences in strength, concentration and rates of absorption and elimination. 
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 specific problems presented by topical forms of corticosteroids. The document deals with: 
— general characteristics of topical corticosteroids (see 2), 
— specific points which should be investigated in man for each new product containing a corti­
costeroid as active ingredient (see 3). 
The document does not specifically apply to studies on fixed combinations; nevertheless for such 
products, the general principles drawn up in the Notes for Guidance on Fixed Combinations are 
fully applicable; in particular, the advantages of such combinations and the significant contributions 
of each of their active ingredients to the clinical activity should be demonstrated. 
2. GENERAL CHARACTERISTICS OF TOPICAL CORTICOSTEROIDS 
2.1 Penetration and local activity 
To be locally effective, corticosteroids must penetrate the skin. The extent of absorption and 
therefore the clinical activity, as well as most of the adverse reactions, have been demonstrated to 
depend, both on the substance itself and, for a given corticosteroid, on several factors: 
(a) the concentration of the drug: 
However, above a certain concentration in a given vehicle, a further increase in concentration 
does not result in a proportionately greater effect but does increase the occurrence of side 
effects; 
(b) the pharmaceutical formulation: 
The penetration of the active substance depends on the physico-chemical properties of the base. 
The presence of other components or excipients can modify the penetration through the stratum 
corneum and/or the effect (e.g. salicylic acid, urea, propylene glycol, antibiotics and antiseptics, 
tar); 
22.5.86 Official Journal of the European Communities No C 122/13 
(c) site of application: 
A thick stratum corneum is responsible for the weak penetration in areas such as soles and 
palms. Due to opposite conditions, a very rapid and important absorption may occur, for 
example, through mucosa, scrotal skin, eyelids, and to a somewhat lesser extent, the skin of the 
forehead and the hair zone of the head; 
(d) skin condition: 
Penetration is increased in damaged skin (e.g. abrasion or pathological situations like 
parakeratosis). Damaged stratum corneum, however, often recovers within a few days of 
treatment. 
(e) conditions of application: 
Occlusion promotes the penetration: it may be unintentionally produced by napkins in babies or 
may result from application in intertriginous areas or flexures. 
The influence of these different factors should be taken into account during the clinical trials. 
2.2. Levels of activity and indications 
The activity of a product is controlled by the extent of cutaneous penetration (see 2.1), the intrinsic 
activity of the compound and the rate of its elimination. Among the known corticosteroids, it is 
customary to distinguish, depending on the substance and the concentration, four levels of activity 
ranging from mild via moderately strong and strong to very strong. The data in Table I annexed are 
adapted from J. A. Miller and D. D. Munro (Drugs, 1980, 19, pp. 119-34). 
This is a rough guide, as no direct comparison has been made between all these preparations. The 
borderline between the classes, in particular between the intermediate classes 'moderately strong' 
and 'strong' is not easy to define. Some corticosteroids are available in different concentrations, 
which may qualify them for inclusion in a different category of clinical activity. In addition, the 
influence of the vehicle can result in a shift to an adjacent level of activity (see 2.1. (b)). In view of 
these variables it would in principle be desirable to have available an objective comparison of all 
existing proprietary products of this type using a method the validity of which is universally 
acknowledged. However, in view of the large number of proprietary products and methodological 
uncertainties this is not yet feasible. 
It is generally accepted that some indications of corticosensitive dermatosis are directly linked to the 
level of activity of the preparation as reported in Tables I and II annexed: this list is only for 
guidance and may be adapted to national practices. 
2.3 Adverse effects 
With the majority of corticosteroids, under normal conditions of use, it is not the possible systemic 
adverse effects due to percutaneous resorption which are the first concern, but the often irreversible 
local side effects on the skin, such as dermatrophia. 
2.3.1 Local adverse reactions 
The stronger the preparations, the greater the chance of development of adverse effects, such as: 
(a) skin atrophy which becomes often irreversible producing clinical thinning of the skin, tele­
angiectasia, purpura, striae; 
(b) rosacea-like and perioral dermatitis with or without skin atrophy; 
(c) rebound which may lead to steroid 'dependence'; 
(d) impairment of healing; 
(e) effects on the eye: increased risk of glaucoma, cataract, exacerbation of mycosis and of herpes 
simplex; 
(f) miscellaneous: depigmentation, hypertrichosis, etc. 
No C 122/14 Official Journal of the European Communities 22.5.86 
The chance of development of dermal toxicity also increases with duration of treatments and when 
application is performed under occlusion or on particular sites such as the face (see 2.1 (c)). 
Due to the ingredients of the base, or to a substance incorporated in the preparation, and rarely to 
the corticosteroid itself, contact allergy may also occur. Due to the suppression of immune defence, 
masking and/or worsening of infection may be observed in case of erroneous use of corticosteroid 
preparations in fungal, viral or bacterial cutaneous diseases. 
2.3.2 Systemic effects 
In adults, as a result of hypothalamo-pituitary-adrenal (HPA) axis suppression, a fall in plasma 
Cortisol levels can generally be observed within the first days of treatment. Those systemic effects 
occur rarely. They occur more readily in children (e.g. acute adrenal insufficiency at the 
discontinuation of the drug, hypercorticism, arrest of growth, intracranial hypertension) because of 
the high surface/weight ratio and unintentional occlusion by napkins. 
These systemic effects are due to the high penetration of a strong compound (or of its active 
metabolite(s)); this occurs because one or more of the factors promoting penetration (see 2.1) apply. 
The risk of systemic effects increases with applications over large areas, use of large amounts of 
material, and prolonged administration. 
Local and systemic adverse effects can be generally avoided with well-studied and well-defined 
products, when the strength of the preparation and the nature of the pharmaceutical form are 
adequately chosen with regard to the type of dermatosis, the site of application, the period of 
treatment and the patient's age and when products are applied according to appropriate conditions 
of use as validated by clinical trials. 
3. GUIDE FOR CLINICAL TESTING 
In view of the characteristics listed under paragraph 2, it is necessary that a new product of this type 
be examined in such a way that the place of the corticosteroid in question (used in the 
concentration and base specified in the application) in the spectrum of corticosteroid products can 
be determined and conditions of use be defined. 
3.1 Pharmacodynamic studies 
The place of a new product in the spectrum of corticosteroid preparations and the optimal 
concentrations for clinical use can to a large extent be predicted on the basis of the results of a 
number of pharmacological tests (anti-inflammatory effect, mitosis inhibition) in animals or in vitro. 
Corticosteroid-induced vasonconstriction in man may provide a preliminary rough but useful guide 
to topical anti-inflammatory activity. Vasoconstriction tests derived from McKenzie & Stoughton 
(Archives of Dermatology, 1962, 86, pp. 608-10), using the new drug incorporated in its base should 
therefore be compared with the effects of established corticosteroid preparations, not only with 
those of approximately equal activity, but also with stronger and weaker preparations. 
Other methods can also be used or are currently under development. It is not considered desirable 
to specify particular methods of investigation as obligatory; regulatory agencies will be prepared to 
consider new methods provided the clinical relevance of these methods is demonstrated. The level 
of activity estimated in the light of these tests will always have to be confirmed by clinical 
investigation (see 3.2.1). 
22.5.86 Official Journal of the European Communities No C 122/15 
3.2 Clinical investigation 
3.2.1 Efficacy 
The level of activity, as estimated in the tests listed under 3.1, will have to be confirmed clinically. 
(a) A product should be studied in randomized double-blind investigations; single-blind 
investigation should only be permitted if it is virtually impossible to perform double-blind tests. 
Parallel groups are probably superior in most instances, but there have been conflicting opinions 
expressed about whether parallel groups are preferable to intrasubject half-side studies (left-
right comparisons). If studies of the latter type are used, however, attention should be paid to 
possible interactions of the treatments due to systemic transfer from one side to the other, 
especially when the comparison is being made between products of different activities applied 
on large areas. A product should be studied in principle against its base but also against known 
products of different activity. Where the product can be regarded as a minor modification of an 
existing one, it will often be possible to rely on a comparison with this latter product used as a 
reference, at least through an adequate vasoconstriction test. 
For new corticosteroids the optimal concentration for clinical use will have to be confirmed by 
comparative investigation of various concentrations. This is important because of the possibility 
of increase in the occurrence of adverse effects above a certain concentration (see 2.1 (a)) 
without notable improvement of therapeutic efficacy. Reports should give a clear picture of the 
frequency of application, especially in the initial period of treatment. When frequencies differ 
from those usually recommended (i.e. once or at most twice daily), it is desirable that this 
should be justified by the applicant. Reports should also clearly state the sites of application, the 
areas which have been treated and the amounts of product used per week. 
If the preparation is intended to be used under occlusion, the influence of this on the effect in 
clinical studies should be examined. 
(b) Valid comparisons can only be made between treatments given for the same condition. A 
product should be tested in a series of conditions, each requiring different degrees of intensity 
of treatment. 
Dermatoses advisable for clinical trials are listed in the left row of Table III. They are presented 
in two groups: one requiring preparations of very strong and strong activity and the other 
where moderately strong and mild products can be used, with psoriasis and atopic dermatitis, 
respectively, being the most suitable conditions for testing. From the efficacy observed in the 
different clinical forms of these dermatoses, the indications can be defined and the place of the 
new product in the spectrum of corticosteroid preparations definitively established (see classes 
of Table II). Provided they require treatment with products from the same class, extrapolation 
of the results is possible for skin conditions listed in the right row of Table III. Clinical trials 
may also be performed in skin conditions listed in the right row, but they do not allow extra­
polation to other skin diseases. Indications other than those listed can also be suggested, 
provided that positive results have been obtained in specific clinical studies conducted with an 
adequate methology. 
As a general principle it is not satisfactory to assume that a substance active at a certain level of 
dose will be equally suitable at other levels for more severe or less severe disease. However, it is 
recognized that under conditions of normal practice, a failure of treatment with a given product 
might lead to the use of a stronger preparation for only a few days, followed by the use of a 
weaker product for maintenance treatments. This mode of use should be mentioned in data 
sheets. 
(c) Short term studies over one or two weeks may not be the only relevant investigation for the 
clinical comparison of two topical steroids. In practice, these are sometimes applied over long 
periods of time and differences in clinical efficacy and safety may only become apparent after 
treatment for several weeks or months. For this reason, depending on the novelty of the product 
and the indications claimed, certain studies of efficacy as well as of safety in long term use (e.g. 
over a period of three months) will sometimes be necessary. 
No C 122/16 Official Journal of the European Communities 22.5.86 
3.2.2 Safety 
Since the importance of adverse effects may not inevitably run parallel with clinical activity, the 
possibility of their occurrence should be studied during clinical investigation. 
Where a product is claimed to produce less-frequent or severe adverse effects than a well-
established drug of the same degree of activity, this should be justified by controlled studies. 
(a) Local adverse effects 
— Atrophogenic activity 
The degree of atrophy induced by the product will have to be determined, after application 
of the product. The mode of use including the sites of application should be specified. The 
changes due to thinning of the epidermis and alteration of the dermis can be detected by 
different methods, such as measurement of the thickness of the skin (radiographical 
techniques, ultrasonography), histology, measurement of collagen fibrils, stereomicroscocy. 
They cannot be detected until a topical treatment has been given under normal conditions of 
use for four weeks. Nevertheless, in experimental conditions where application is performed 
with occlusion, the exposure can be shorter. 
— In any study, tolerance will have to be determined (drying of skin, irritation, sensitization) 
both for the product as a whole and for the base. After conclusion of the trial, patch tests 
should be performed with the pharmaceutical formulation and the base. 
(b) Systemic actions 
Interesting and practicable is the direct assessment of the effect on the HPA axis. In this respect, 
plasma Cortisol determinations give more information than studies of Cortisol metabolites in 
urine. When performing plasma Cortisol determinations account must be taken of the diurnal 
rhythm exhibited by plasma Cortisol levels and of factors which influence these levels, such as 
stress, sex, seasonal influences, use of oral contraceptives etc. 
Since healing of damaged stratum corneum, which often occurs within eight days of treatment, 
produces a decrease in the systemic passage, it is necessary to make repeated determinations 
during the exposure period. It is also customary to determine plasma Cortisol levels under 
normal and extreme conditions of application, the latter predisposing to maximum absorption. 
Therefore, it is desirable to determine plasma Cortisol levels under such conditions as: 
— at the fifth and at the 20th day of treatment without occlusion and at the fifth day with 
occlusion on the normal and diseased skin, 
— several times, in a number of patients treated for long periods. 
The ability of the HPA axis to respond to a stimulation can also be usefully assessed by 
determination of plasma Cortisol after stimulation (i.e. adrenocorticotrophic hormone (ACTH)). 
Comparative data with one or several reference products used under the same conditions would 
in principle be necessary to assess fully the extent of systemic absorption. 
Because the passage into the circulation depends on various factors (see 2.3.2), the precise 
conditions (i.e. sites and percentage of body surface treated, weight of product used) and mode 
of use should be specified for each subject treated. In the case of products for which the manu­
facturer wishes to claim the treatment of chronic conditions in an area of high absorption, an 
investigation of absorption will have to be performed after application to this area. If the 
product is to be recommended for use in young children, systemic effects should also be 
recorded in this age group, but particular attention should be given to the ethical aspects of 
such an investigation. 
22. 5. 86 Official Journal of the European Communities No C 122/17 
TABLE I 
Levels of activity of known corticosteroids 
(adapted from J. A. Miller and D. D. Munro, Drugs, 1980, 19, pp. 119—134) 
Corticosteroid 
Beclometasone dipropionate 
Betamethasone benzoate 
Betamethasone dipropionate 
Betamethasone valerate 
Clobetasol propionate 
Clobetasone butyrate 
Desonide 
Desoxymethasone 
Dexamethasone 
Diflorasone diacetate 
Diflucortolone valerate 
Fluclorolone acetonide 
Fludroxycortide (flurandrenolone) 
Flumethasone pivalate 
Fluocinolone acetonide 
Fluocinonide 
Fluocortin butylester 
Fluocortolone 
Fluoprednidene acetate 
Halcinonide 
Hydrocortisone 
Hydrocortisone butyrate 
Methylprednisolone 
Triamcinolone acetonide Very strong 
0,5 % 
— 
— 
— 
0,05 % 
— 
— 
— 
— 
— 
0,3 % 
— 
— 
— 
0,2 % 
— 
— 
— 
— 
— 
— 
— 
— Strong 
0,025 % 
0,025 % 
0,05 % 
0,1 % 
— 
— 
0,05 % 
0,25 % 
— 
0,05 % 
0,1 % 
0,025 % 
0,05 % 
— 
0,025 % 
0,05 % 
— 
0,5 % 
0,1 % 
0,1 % 
— 
0,1 % 
— 
0,1 % Moderately 
strong 
— 
— 
•— 
— 
— 
0,05 % 
— 
— 
— 
— 
— 
— 
0,0125 to 
0,025 % 
0,02 % 
0,01 % 
_ 
0,75 % 
0,2 % 
_ 
— Mild 
— 
— 
— 
— 
— 
— 
— 
0,01 % 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
0,1 to 1 % 
— 
0,25 % 
TABLE II 
Indications for topical corticosteroids in relationship to their level of activity 
VERY STRONG ACTIVITY 
Localized and resistant plaques of: 
— psoriasis 
— lichenification 
— discoid lupus erythematosus 
— lichen hypertrophic 
Hypertrophic scars 
STRONG ACTIVITY 
Psoriasis 
Lichenifications 
Lichen planus 
Lichen sclerosus et atrophicus 
Granuloma annulare 
Discoid lupus erythematosus 
Pustulosis palmaris and plantaris 
Mycosis fungoides 
NoC 122/18 Official Journal of the European Communities 22. 5. 86 
MODERATELY STRONG ACTIVITY 
Atopic dermatitis 
Irritant and/or allergic contact dermatitis 
Nummular dermatitis 
Pompholyx (dyshidrosis) 
MILD ACTIVITY 
Seborrheic dermatitis 
Stasis dermatitis 
Ano-genital pruritus. 
TABLE III 
Skin conditions advisable for clinical investigation of topical corticosteroids 
Advisable Non-advisable 
VERY STRONG AND STRONG CORTICOSTEROIDS 
— Psoriasis 
— Lichen planus 
— Lichen sclerosus et atrophicus (genital) 
— Pustulosis palmaris and plantaris 
— Localized lichenifications — Granuloma annulare 
— Discoid lupus erythematosus 
— Mycosis fungoides 
MODERATELY STRONG AND MILD CORTICOSTEROIDS 
— Atopic dermatitis 
— Seborrheic dermatitis 
— Nummular dermatitis — Irritant and/or allergic contact dermatitis 
— Stasis dermatitis 
— Pompholyx (dyshidrosis) 
— Ano-genital pruritus