CELEX: 51986PC0117(04)
Language: en
Date: 1986-03-05
Title: AMENDMENT TO THE PROPOSAL FOR A COUNCIL RECOMMENDATION CONCERNING TESTS RELATING TO THE PLACING ON THE MARKET OF PROPRIETARY MEDICINAL PRODUCTS

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                   "— experimental studies validating the manufacturing
above proposal to the Council. For the reasons outlined                   process, where a non-standard method of manu-
in the explanatory memorandum, the original proposal is                   facture is used or where it is critical for the
hereby amended as follows:                                                product."
1. In Article 1, the following point 2 is inserted:                         (c) In Part 1 C (2), subparagraph (b) is replaced
                                                                                by the following:
    '2. Part 1 of the Annex, "Analytical (physico-                              "(b) the description of the substance, set
        chemical, biological or microbiological) tests of                             down in a form similar to that used in a
        veterinary medicinal products", is amended as                                 descriptive item in the European Phar-
        follows:                                                                      macopoeia, shall be accompanied by any
        (a) In Part 1 A the following section 4 is inserted:                          necessary       explanatory        evidence,
                                                                                      especially concerning the molecular
             "4. An explanation should be provided with                               structure where appropriate; it must be
                  regard to the choice of composition,                                accompanied       by     an    appropriate
                  constituents and container, supported by                            description of the method of synthetic
                  data on development pharmaceutics. The                              preparation. Where substances can only
                  overage, with justification thereof, should                         be described by their method of
                  be stated."                                                         preparation, the description should be
        (b) In Part 1 B the following fifth indent is                                 sufficiently detailed to characterize a
             inserted:                                                                substance which is constant both in its
                                                                                      composition and in its effects;".'
0) OJ No C 293, 5. 11. 1984, p. 6.                                   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.
 ---pagebreak--- N o C 122/8                                 Official J o u r n a l of the E u r o p e a n C o m m u n i t i e s             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.
 ---pagebreak--- 22.5.86                               Official J o u r n a l of the E u r o p e a n C o m m u n i t i e s             N o 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
             T o 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.
 ---pagebreak--- N o C 122/10                             Official J o u r n a l of the E u r o p e a n C o m m u n i t i e s              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
 ---pagebreak--- 22. 5. 86                              Official J o u r n a l of the E u r o p e a n C o m m u n i t i e s             N o 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.
 ---pagebreak--- N o C 122/12                            Official J o u r n a l of the E u r o p e a n C o m m u n i t i e s               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 I N T E N D E D FOR USE O N T H E 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);
 ---pagebreak--- 22.5.86                              Official J o u r n a l of the E u r o p e a n C o m m u n i t i e s                 N o 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.
 ---pagebreak--- N o C 122/14                              Official J o u r n a l of the E u r o p e a n C o m m u n i t i e s                 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).
 ---pagebreak--- 22.5.86                               Official J o u r n a l of the E u r o p e a n C o m m u n i t i e s                N o 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.
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            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.
 ---pagebreak--- 22. 5. 86                               Official J o u r n a l of the E u r o p e a n C o m m u n i t i e s                       N o 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)
                                                                                                            Moderately
                              Corticosteroid                         Very strong          Strong                           Mild
                                                                                                              strong
          Beclometasone dipropionate                                  0,5     %         0,025   %               —
          Betamethasone benzoate                                         —              0,025   %               —           —
          Betamethasone dipropionate                                     —              0,05    %               • —         —
          Betamethasone valerate                                         —              0,1     %               —           —
          Clobetasol propionate                                       0,05 %                —                   —           —
          Clobetasone butyrate                                           —                  —               0,05    %       —
          Desonide                                                       —              0,05    %               —           —
          Desoxymethasone                                                —              0,25    %               —           —
          Dexamethasone                                                  —                  —                   —        0,01 %
          Diflorasone diacetate                                          —              0,05    %               —           —
          Diflucortolone valerate                                     0,3     %         0,1     %               —           —
          Fluclorolone acetonide                                         —              0,025   %               —           —
          Fludroxycortide (flurandrenolone)                              —              0,05    %           0,0125 to       —
                                                                                                            0,025 %
          Flumethasone pivalate                                          —                  —               0,02 %          —
          Fluocinolone acetonide                                      0,2     %         0,025 %             0,01 %          —
          Fluocinonide                                                   —              0,05 %                  _          —
          Fluocortin butylester                                          —                  —               0,75    %      —
          Fluocortolone                                                  —              0,5     %           0,2     %       —
          Fluoprednidene acetate                                         —              0,1     %                           —
          Halcinonide                                                    —              0,1     %               _           —
          Hydrocortisone                                                 —                  —                          0,1 to 1 %
          Hydrocortisone butyrate                                        —              0,1     %                           —
          Methylprednisolone                                             —                  —                            0,25 %
          Triamcinolone acetonide                                                       0,1     %               —
                                                                  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
 ---pagebreak--- N o C 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                                                — Granuloma annulare
           —  Lichen planus                                            — Discoid lupus erythematosus
           —  Lichen sclerosus et atrophicus (genital)                 — Mycosis fungoides
           —  Pustulosis palmaris and plantaris
           —  Localized lichenifications
                                MODERATELY STRONG AND MILD CORTICOSTEROIDS
           — Atopic dermatitis                                         —   Irritant and/or allergic contact dermatitis
           — Seborrheic dermatitis                                     —   Stasis dermatitis
           — Nummular dermatitis                                       —   Pompholyx (dyshidrosis)
                                                                       —   Ano-genital pruritus