CELEX: 51976PC0189
Language: en
Date: 1976-05-10
Title: Proposal for a COUNCIL DIRECTIVE on the approximation of the laws of member states relating to veterinary medicinal products#Proposal for a COUNCIL DIRECTIVE on the approximation of the laws of member states relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing of veterinary medicinal products (submitted to the Council by the Commission)

ARCHIVES HISTORIQUES
DE LA COMMISSION
COLLECTION RELIEE DES
DOCUMENTS "COM"
COM (76) 189
Vol. 1976/0059
 ---pagebreak--- Disclaimer
Conformément au règlement (CEE, Euratom) n° 354/83 du Conseil du 1er février 1983
concernant l'ouverture au public des archives historiques de la Communauté économique
européenne et de la Communauté européenne de l'énergie atomique (JO L 43 du 15.2.1983,
p. 1), tel que modifié par le règlement (CE, Euratom) n° 1700/2003 du 22 septembre 2003
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règlement.
In accordance with Council Regulation (EEC, Euratom) No 354/83 of 1 February 1983
concerning the opening to the public of the historical archives of the European Economic
Community and the European Atomic Energy Community (OJ L 43, 15.2.1983, p. 1), as
amended by Regulation (EC, Euratom) No 1700/2003 of 22 September 2003 (OJ L 243,
27.9.2003, p. 1), this file is open to the public. Where necessary, classified documents in this
file have been declassified in conformity with Article 5 of the aforementioned regulation.
In Übereinstimmung mit der Verordnung (EWG, Euratom) Nr. 354/83 des Rates vom 1.
Februar 1983 über die Freigabe der historischen Archive der Europäischen
Wirtschaftsgemeinschaft und der Europäischen Atomgemeinschaft (ABI. L 43 vom 15.2.1983,
S. 1), geändert durch die Verordnung (EG, Euratom) Nr. 1700/2003 vom 22. September 2003
(ABI. L 243 vom 27.9.2003, S. 1), ist diese Datei der Öffentlichkeit zugänglich. Soweit
erforderlich, wurden die Verschlusssachen in dieser Datei in Übereinstimmung mit Artikel 5
der genannten Verordnung freigegeben.
 ---pagebreak--- COMMISSION OF TOB EÜSOPEAN COMMÜOTHES
                                            COM(76)189 final.
                                            Brussels , 10 May 1976.
                                  Proposai for a
                                COUNCIL DIRECTIVE
       on the approximation of the laws of member states relating to
                          veterinary medicinal products
                                  Proposai for a
                                COUNCIL  DIRECTIVE
       on the approximation of the laws of member states relating to
  analytical , pharmaco-■toxicological and clinical standards and protocols
          in respect of the testing of veterinary medicinal products
               ( submitted to the Council by the Commission)
  COM(76 ) I89 final .
 ---pagebreak---   PROPOSAL FOR A COUNCIL DIRECTIVE ON THE
APPROXIMATION OP THE LAWS OP MEMBER STATES
RELATING TO VETERINARY MEDICINAL  PRODUCTS
 ---pagebreak---                             EXPLANATORY JMIORA1IDUI1
                         1 . General considérations
Medicinal products for veterinary use , like those for human therapy , are
governed "by different legal provisions from one Member State to another.
The need for Community rules is obvious from the economic point of view .
Although the number of preparations is distinctly smaller than in human
medicine - the proportion may be assessed at 1 to 10 - the consumption of and ,
therefore , the trade in these preparations are considerable . Stock-raising
is becoming more and more industrialized. The concentration and intensification
of stock-raising which results from this and the selection of highly productive
breeds increase tho risks of diseases and their economic consequences . With
the achievement of tho common agricultural market , the objectives of production ,
profitability , freedom of movement and undistorted competition have become
vital in this field .
The need for rules is even more evident from the standpoint of public health,
With the growing consumption of animal products , it is essential that the
consumer of the treated animal should suffer no harm. At this time , when
problems of quality are again claiming attention , it is hardly necessary to
stress the benefit to health which rules in this field would confer.
This proposal for a directive is based on tho principle that the requirements
laid down for veterinary medicinal products should not be less stringent than
those specified for pharmaceutical products for human use . This is in the
interests of consumers of products of animal origin , who must suffer no harm ,
and also in the interests of effective therapy.
 ---pagebreak---                                            - 2 -
    That is why , wherever possible , the provisions concerning proprietary medicinal
    products for human use ( l) have been taken across to this field. Nevertheless ,
    in order to make allowance for problems peculiar to the veterinary field , it
    was necessary to add certain special provisions ,
3 . The scope of the directives relating to human use and that of this Directive
    do not coincide . The structures of the two markets are different * On the markets
    of certain countrios , veterinary medicinal products are commercialized in the
    form of ready-made medicinal products and not proprietary medicinal products ,
    in order to keep down the cost of packaging. For the same reasons international
    trade is carried on mainly in ready-made medicinal products .
    In order to include most of the products entering into international trade it
    is therefore necessary to widen the scope of the Directive , This is also
    necessary for reasons of competition, since the strict regulation of one
    category of products would cause production to swing towards other less super­
    vised categories , and this would ultimately bo harmful to public health.
    Another peculiarity of veterinary medicinal products is the danger of residues
    in animal products . It must be borne in mind that people may be harmed by
    ingesting products derived from animals to which medicinal products have been
    administered. This raises the questions of the persistence of the medicinal
    product , the route and duration of elimination , and the necessary waiting
    period between use of the medicinal product and consumption of the animal
    product . This problem of residues only arises in the case of products
    administered to animals which are likely to provide Man with food. Less
    stringent demands might therefore have been expected in the case of medicinal
    products administered to certain animal species , pets , for instance . It never­
    theless seemed hazardous to create two separate categories of medicinal
    products in view of the corrupt and fraudulent practices which might have
    ensued and the problems of supervision which would then have arisen. It
    appeared wiser to allow certain waivers within the framework of the standards
    and protocols applicable to tests on veterinary medicinal products ,
     ( l) Council Directive No 65/65 /EEC , OJ 22 of 0.2.1$65
          Council Directive No 75/3l8/EEC » OJ L 147 of 9.6,1975          ./•
          Council Directive No 75/319/EEC , OJ L 147 of 9,6,1975
 ---pagebreak--- The aim of this work on the approximation of laws is to introduco free move­
ment of veterinary modicinal products while providing every safeguard for
public health.
Having taken steps to safeguard public health at the product testing, manu­
facturing and marketing stage , the next problem which arose was that of the
free movement of these products .
The introduction , at this stage , of freedom of movement might seem feasible
since the position with regard to veterinary medicinal products is not
identical with that of modicinal products for human use . The public health
hazards may seem less serious , since the animal is used as an intermediary
and therefore acts as a screen between the medicinal product and Han.
Community rules adopted for agriculture have mado it possible to onsure
freedom of movement for agricultural products while securing the protection
of public health.
Those arguments were not devoid of weight but they clashed with other arguments
concerning the need to progross by stages in a field which is closely related
to health and is of prime importance for the economy of certain countries .
Instead of weighing up conflicting arguments which contribute nothing towards
health and postpone free movement indefinitely , it appeared preferable to put
forward more moderate proposals for introducing, in the case of veterinary
modicinal products , the system of movement already adopted with regard to
modicinal products for human use . This should enable the periods for tho
adoption and implementation of tho texts to bo shortened and hence make it
possible to introduco free movement for veterinary modicinal products more
rapidly than over-ambitious proposals would allow.
 ---pagebreak---                                      - 4 T
                   II . Commentary on certain articles
Article 1
It goes without saying that the word " animal" refers to the whole of the
animal kingdom and not merely to farm animals . New definitions to supplement
those in Council Directive 65/65/EEC are necessary as the scope of the present
Directive has been widened to make allowance for the special circumstances
which prevail in this sector. Between the domain of the medicinal product
defined by the Directive of 19^5 and that of additives in feeding-stuffs ,
defined by Council Directive No 70/524 of 23 November 1970 ( 0J No L 270 of
14 December 1970), there is a whole range of products that must be covered
bjr the regulations if manufacturers are to be prevented from evading the
requirements by marketing under uncontrolled forms .
The ready-made veterinary medicinal product differs from the proprietary
medicinal product by the absence of a special name (trivial name ). It has
only a chemical name or an international non-proprietary name . Furthermore ,
it is not necessarily offered for sale in a special pack but may be supplied
in bulk. It is specified that the ready-made product is marketed in a
pharmaceutical form which may be used without further processing and it is
therefore at this stage that authorization must be obtained for it .
The pre-mix for medicated feeds is defined fundamentally by its purpose : it is
intended for ulterior use in a medicated feed. This is how it is distinguished
from the ready-made product which, may be used without further processing and
is not intended for this ulterior use. On the other hand, a pre-mix is not
necessarily a mixture : it is a medicinal preparation at the stage preceding
mixing*
                                                                      /.
 ---pagebreak---                                       - 5 -
In contrast f the medicated feed is a mixture of one or more medicinal
preparations with one or more feeding-stuffs , made before marketing. It ;can
be used Without further processing and this distinguishes it from the pre-mix.
Its therapeutic purpose differentiates it from the compound feeding-stuff.
Article 2
1 . Apart from the economic goals to be reached, the chief concern was to ensure
    that substances harmful to Man are not administered to him via his food.
    A medicinal preparation is a product likely to be hazardous and must there­
    fore be uade subject to authorization irrespective of the way in which it
    will be employed subsequently. Aside from the economic considerations
    already mentioned , this is the reason which has led to the widening of the
    scope of this Directive as oompared with the proposed directive on proprietary
    medicinal substances for human use .
2. On the other hand, the provisions of this Directive do not adequately cover
    certain specific cases ( sera and vaccines , medicinal products based on
    radioactive isotopes ) and it is advisable not to apply them to these products
                                                 /
    at présent .
    Similarly , it was not considered advisable to make these provisions mandatory
    in the case of products which can have no effect on intra-Community trade ,
    namely , veterinary medicinal products not prepared in advance ; this refers
    to medicinal products which correspond to drugs prepared according to
    prescription in human medicine , i.e. medicinal products prepared by a
    veterinarian for one particular animal , following diagnosis .
    Finally , in order to make the present rules effective , it has been necessary
    to regulate one aspect of the manufacture of medicated feeding-stuffs
    /Article 2 (3 YJ pending rules applicable to medicated feeding-stuffs,
 ---pagebreak--- Article 3
Paragraph 1 of this Article is wholly comparable to the provisions governing
proprietary medicinal products for human use .
Paragraph 2 has "been made necessary by the special situation which could arise
in this sector ; for a "parallel" market , subject to no supervision whatsoever ,
might emerge if the rule simple stated that any medicinal product placed on
the market must be subject to prior authorization. It would be possible to get
round the rules . The first step would be to procure , as a raw material, such
and such a substance for which no prophylactic or curative properties are
claimed ; no authorization would be necessary since it would be a raw material
and not a medicinal substance . Thereafter , the purchaser would employ this
substance as medication for his own livestock ; no authorization would be
necessary since this medicinal product would not have been placed on the
market as such .
Such a possibility would be unacceptable from the point of view of both public
health and the economy.
It has therefore been necessary to go beyond the idea of marketing and to
}ay down an 'unqualified prohibition of administration to an animal of a
medicinal product , in any form whatsoever , which has not been authorized
pursuant to the provisions of this Directive .. This provision assumes its full
meaning if reference is made to the concept of a medicinal product as laid
down in Article l(2 ) of Council Directive No 65/65 of 26 January 1965*
It is very certain that suoh a provision gives rise to difficult problems of
supervision. At the same , time , however, public authorities must be able to
counter the corrupt practices which could stom from the purchase of substances
not subject to the Directive 's provisions and yet employed for a therapeutic
purpose . If such practices are discovered they must be penalized ; this justifies
such a provision even if it is difficult to implement it .
An exception must be made in order to allow tests to be carried out on medicinal
products for which authorization has not yet been granted.
 ---pagebreak--- Article 4
Paragraph 5
The therapeutic indications must be taken in a broad sense : the "therapeutic
effect " concept must be understood to be the effect promised by the manu-
facturer# Mutatis mutandis , the therapeutic indications cover the indications
quoted for medicinal products alleged to possess curative or prophylactic
properties and also those quoted for medicinal products intended for making
a medical diagnosis or restoring, correcting or modifying physiological
functions in animals .
Paragraph 6
The phrase "dosage for the various animal species for which the medicinal
product is intended must be interpreted with common sense : if a different
dose has to be administered to calves , cows , heifers etc ., the dosage must
of course be given for these sub-categories .
Paragraph 7
The person responsible for placing the product on the market must provide
all necessary information concerning the precautions to be taken during use
of the product in order to ensure the safety of the person administering it «
Article 10
It may be forbidden tjy law to use certain substances for particular purposes ;
an example is tho use of oestrogens to fatten cattle . But if these substances
exert a therapeutic effect , they must be allowed to qualify for authorization
as medicinal products. In order to reconcile these requirements , authorization
may be refused if the medicinal product is offered for sale , for a use
prohibited under other Community provisions (Paragraph 3 ). On the other hand,
this refusal would be rescinded if this possible use were no longer
advertised.
 ---pagebreak--- Article 11
1 . In order to allow the marketing of medicinal products which are useful but
     which also present definite hazards , the authorization may entail the
     obligation to print the necessary warnings on the label and the package
     insert . The reference to clinical and pharmacological trials is designed
     to confer an objective character on this provision. The second paragraph
     of Article 13 enables the authorities to take account of items of
     information which emerge after the medicinal product is marketed and to
     reconsider the need to make warnings obligatory.
2 . At present the question of tracer substances does not appear important
     enough to require a study at Community level of all tracer substances and
     of all medicinal products which must be tagged. Nevertheless it would be
     desirable for Hember States not to specify different tracer substances .
     If joint consultation proved unsatisfactory and if this problem were to
    hamper freedom of movement , approximation measures would then be necessary.
     In any event , the manufacturer should be informed about the obligation to
    employ a tracer substance before and not after he determines the formula
     of his medicinal product .
 Artie .a iv
This Ar\j.cle makes it incumbent on the person responsible for placing the
 product <\ -the market to modify his testing methods if an improvement in
 testing ma£ result therefrom.
 It also makea it incumbent on him to notify the competent authorities of any
new factors wh,ch appear after the grant of marketing authorization:
         - new factyrs over which the person responsible for marketing has no
 control , such as a^d^-effects , interactions , contra-indications , etc.
 ( second paragraph):
 ---pagebreak---                                      - 9 -
      - any new factors which result from its uses modifications in the
composition, dosage , indications etc. (third paragraph). Naturally, in' accordance
with the provisions of the Directive , he will have to give the reasons for
these proposed changes .
It did not appear to "be necessary to specify the obligations of the competent
authorities ; they follow from the provisions of the Directive . The investigation
measures which they will be led to take will depend on the new factors
communicated "by the person responsible and , in accordance with the national
regulations , they will be led either to grant fresh authorization or to agree
to the modification simply by a letter to the person responsible .
Article 16
In regard to the Committee for Veterinary Medicinal Products it is proposed to
apply provisions based on those specified for the Committee for Proprietary
Medicinal Products in Chapter HI of Directive 75/319/EEC * for the reasons
put forward in the General Considerations ,
Article 23
It is proposed to apply all the provisions concerning manufacture and import
from third countries , contained in Directive 75/319/EEC * to veterinary
medicinal products . Moreover, it should be noted that veterinary medicine
appears among the scientific discipline listed in Article 23 of Directive
75/319/EEC : an article which lays down the minimum qualifications required
of persons who assume responsibility for the manufacture and testing controls
of proprietary medicinal products for human use .
 ---pagebreak---                                       - 10 -
Article 33
Paragraph 8
The expiration date has been made mandatory in all cases in order to ensure the
correct use of medicinal products and to avoid wastage which may he caused by
the absence of this item of information . In order not to give the user an
unjustified feeling of security when the medicinal product , although not out­
dated ! may have decomposed owing to bad storage , conditions , the next paragraph
makes it obligatory to mention any particular storage precautions that are
necessary .
Article 35
In particular , this concerns capsules on which it would be difficult to print
even the name .
Article 39
The package insert must , without exception , be included in the package of the
veterinary medicinal product for the purpose of information and the correct use
of the product . For example , the farmer must be informed concerning the
significance of the waiting period. A certain number of items axe needed so
that the package insert may fulfil this object and those items must correspond
to the information and documents supplied pursuant to Article 4 and verified
by the competent authorities in accordance with Article 10 .
On the other hand , the package insert must not contain any advertising matter}
it must concern solely the medicinal product which it accompanies . In the
interests of economy , this does not preclude mentioning the various forms of
this medicinal product on one and the same package insert .
Similarly , the name of another medicinal product may be included on it if the
marketing authorization prescribes such a reference pursuant to the first
paragraph of Article 11 . This would apply , for instance , to the antidote .
 ---pagebreak--- Instructions for correct administration axe necessary when the medicinal
products are completely effective only in certain functional states of the
organism ( e.g. when fasting) or in certain stages of the disease ( e.g.
treatment of parasitoses ) or in combination with certain concomitant measures
( e.g. stimulation of circulation ).
 ---pagebreak---                                          12 -
THE COUNCIL OF THE EUROPEAN COMMUNITIES ,
Having regard to the Treaty establishing the European Economic Community ,
 and in particular Article 100 thereof f
Having regard to the proposal from the Commissioin t
Having regard to the Opinion of the European Parliament f
Having regard to the Opinion of the Economic and Social Committee ,
Whereas the primary purpose of any rules for the- production and
distribution of veterinary medicinal products must be. the eafcguarding of public
health ;
Whereas , however , this objective must be achieved by means wnich will not
hinder the development of industry aril trade in medicinal products within the
Community ;
Whereas , insofar as tho Momber States already have certain provisions laid down
by law , regulation or Administrative action governing veterinary medicinal
products , such provisions differ in oocontial principles : and whereas this
?esults> in the hindering p£ trade in -. nedijcinalj products within tho •
Community and thereby directly affeels tho establishment and functioning of
tho common market ;'
i
Whereas such hindrances must accordingly be removed; and whereas this entails
 approximation of the relevant provisions ; '
Whereas the provisions of this Directive which concern veterinary medicinal
products are not adequate , although appropriate , for veterinary medicinal
 products used to confer active immunity, to diagnose the state of immunity
 and to confer passive immunity and for medicinal products based on radioactive
 isotopes ; whereas it is therefore advisable not to prescribe their application
 to such products for the present ;
                                                                       /.
 ---pagebreak---                                      - 13-
Whereas medicated feedxng-fctuffs do not come within the nmbit of this Directive ,
but whereas it is necessary , go nuch. for public health ao oaononio reasons', to
prohibit the use of unauthorized medicinal products in the manufacture of
medicated feeding-stuffs ;
Whereas marketing authorization shall be refused where a medicinal product
lacks therapeutic effect' or where there is insufficient proof of such effect
promised by the manufacturers ;
Whereas it is advisable , in order gradually to achieve freedom of movement "for
veterinary medicinal products , to facilitate the granting of narkoting-fewftttdrisar-
tions in several Member States for one and the same medicinal product ;
Whereas , for this purpose , a Committee for Veterinary Medicinal Products should
be set up, oonpoood      ^ representatives of the Member States and of the • •  '
Commission , responsible for giving an opinion as to whether a particular
veterinary medicinal product complies with the requirements set out in this
Directivs ;
Whereas thisDirective is only one stage in the achievement of the aim of
freedom of movement at- veterinary medicinal products ; whereas , for this purpose ,
new measures will prove necessary, in the light of oxporicrfoe gained -- •
especially within the said Committee , for tho ronove.1 of the
remaining barriers to freedom of movement ;
Whereas , in order to facilitate the movement of veterinary medicinal products
and to prevent the checks carried out in one Member State from being repeated
in another, minimum recjuirements for manufacture and imports from third
countries and the grant of authorization relating thereto, should be applied !
to veterinary medicinal products , as specified in Cotuioil Directive
75/3 19/EEC on the approximation of provisions laid down by law, regulation or
administrative action relating to proprietary medioinal products *
HaS ADOPTED THIS DIRECTIVE :
( 1 ) OJ No L 147, 9.6.1975, P. 13
 ---pagebreak---                                             - 14 -
                                 Chapter I - Definitions and scope        of c,pplic-vtiou .
Article 1
1. The definitions laid down in Article 1 of Council Directive No 65/65
    da 4ho apjir6iiir..'.atlon ofu-provicsions XoiS fioou-bjr-lari   v..,, .. ";v
    regulation or administrative action relating to proprietary medicinal
    products ^ shall apply to tMs Directive,
2 . Furthermore , for the purposes of this Directive , tho following f.cfinitiona shall
    apply
    – votorinary inodicinal product ahall irofiuCi. any^.no^-ioinalcpx^uoli intended for
      animais ,
    - Ready-made veterinary medicinal product fltiflll noiui 'aliyrimtn^riary"^odiciiial
    product prepared in advance and marketed in a pharmaceutical form which
      may '"be used without further processing;
    - pre-mix for medicated feeding-stuffs shall rj^^rafayrirDtcriiKiiy'3iQ^icinal
      product prepared in advance with a view to the subsequent manufacture
      of medicated feeding-stuffs , "
                                                                                      I
    - medicated feeding-stuffs ' shall- :\canany iiixturc^of c.vcteriiiary"' r.adicinr.l
      product or products and          feed or feeds which is ready prepare- for
      uarkotfcig and iatondod to bo fod to aaii.ials tri-thout further procaooing,
      bcccu3o of its curat iva oreprpvoutive proportion or othcrc&roportico
      of the medicinal substance covered by Article 1 ( 2 ) of the said
      Council Directive *
3 . The additives incorporated in animal feeding-stuffs and the supplementary
    animal feeding-stuffs covered by Council Directive No 70/524 - ' .3
                                                         2)
         concerning additives in feeding-stuffs           ' shall , for the purposes of
    the present Directive , not be considered as medicinal products .
Article 2
1 . The provisions of this Directive snail apply to veterinary medicinal products
^ OJ No 22 of 9.2.1965 » P. 20
^ OJ No L 270 of 14.12.1970 \
 ---pagebreak---                                        - 15 -
    whether offered for sale in the form of proprietary medicinal products ,
    ready-made veterinary medicinal products or pre-mixes .
2 . The provisions of this Directive shall not apply to :
    ( a) medicated feeding-stuffs ,
    (b) veterinary medicinal products used with a view to producing active
          immunity , diagnosing the state of immunity and producing passive
          immunity ,
    ( c ) veterinary medicinal products based on radioactive isotopes ,
    (d) veterinary medicinal products not prepared in advance and intended
          for one particular animal .
3 . However , pending separate provisions for medicated feeding-stuffs , a
    pre-mix shall not be uood for thc:Tianufaoturo of nadioatod fooding-ctuffo
    if it has not received the authorization referred to in Article 3 .
              Chapter II – Application for marketing authorization
                        for veterinary medicinal products
Article 3
1. .*& veterinary medicinal product shall not bo narkctcd in a :*e: ibor Stat .; if
    authorization has not been previously issued by the competent authority
    of that Member State .
2.    ^ veterinary medicinal product ahall not be acTutnictcrod to aninnla if tlio
    authorization provided for in the preceding paragraph has not beenlissued ,
    except where tests of medicinal products referred to in Article 4 { 10)
                                          ■ /
    are concerned .
Article 4
    For the p'trpose of obtaining the marketing authorization provided for in
    Article 3 | the person responsible for placing the product on the market
    shall lodge an application with the competent authority of the Member State .
 ---pagebreak---                                      - 16 -
    The following particulars and documents shall be appended to this application :
1 . name or corporate name and domicile or pemanont . address of ~thc porson responsible
    placing the medicinal product on tho market and , where applicable , of the
    manufacturer-, also ;
2 . name of the medicinal product ( trivial name , common name , with or without
    a trade mark or name of tho manufacturer } scientific name or formula,
    with or without a trade mark or name of the mmufacturer) j
3 . qualitative and quantitative particulars of all tho components of the
    medicinal produc-' 6®grossed in the /usual terns , " but excluding empirical : chemical
    formulae , with mention of the international non-proprietary name re­
    commended by the World Health Organization , 'if      such name exists ;
4 . brief description of tho method of preparation ;
5 . therapeutic indications , contra-indications and side-effects ;
6 . dosage for the various species of animal for which tho - medicinal product is
    intended , its pharoaceutical fora , method and noans of administration and
    expected shelf life ;
7 . reasons for the precautionaiy and safety measures to bo taken when using
    the medicinal product , if applicable ;
8. indication of the necessary delay .between tho . administration of        . n *
    the medicinal product to animals under normal conditions of use and the
    production of food stuffs fron- such, animals ^ in ordor "to ensure that such food
    does not contain any residues which might jeopardize the health of the
    consumer ;
 ---pagebreak---  9 . Description of tho testing methods employed "by the manufacturer ( qualitative
     and quantitative analysis of the components and the finished product , special
     tests , e.g. sterility tests , tests for the presence of pyrogonic substanoes ,
     for tho presence of heavy metals , "biological and toxicity tests , tests on
     intermediate products );
10 . Résulta of :
     - physicochemical , biologica! or microbiological tests ;
     - toxicological and pharmacological tests :
     - clinical trials .
 The results of the toxicological and pharmacological tests shall relate more
 particularly to the metabolism of the active components in the animal and in parti­
 cular;, -to the mode and duration of their elimination , if such data are
 important for the purpose of chocking the 1 indicatod dolayi
 Notwithstanding the foregomg ,
        a) a list of published references relating to the toxicological and ?
            pharmacological tests thfc clinical trials ,and    the data concerning
            the delay shall bo substituted for tho relevant tost results
            in the case of :      .
            i ) a medicinal product with an established use , which has been
                adequately tested on animals so that its effects , including
                sido-cffects , are already known and are included in tho published
                references ;
          ii ) a new medicinal product , in which the active
                components   arc identical to thoseof a known medicinal product
                with an established use ;
         iii ) a new medioinal product containing only known components that
                have already been used together " "• in comparable proportions
                in adequately tested medicinal products with an established use ;
 ---pagebreak---                                         - 18 -
           b) in the case of a now medioinal product containing known components
               not hitherto used i together         for therapeutic purposes ,
               references to published data shall bo substituted fbr the tests
               of such components ;
11 . one or more specimens or mock-ups of the sales presentation of the
      medicinal product together with a package insert ;
12 . a document showing that the manufacturer is authorized in his own country
      to produce medicinal products ;
13 . any authorization tor place the -relevant nedicin&i? proclliet on the Haricot ,
      which nay, havu "been obtain^ 1- in another Ilonbefr St&to or in a third country.
Article 5
Member States shall make all necessary arrangements tx> ensure > that , thec'dominsstits
and particulars listed in points 8,9 and 10, of the ^ second paragraph of Article 4>are
    drafted by experts with the requisite technical or professional
qualifications before being submitted to the competent authorities .
These documents and particulars shall be signed by the experts .
Article 6
According to their particular qualifications , the rile of the experts shall be :
1 . to carry out such work as falls within their particular discipline
    ( analysis , pharmacology and similar experimental sciences , clinic&l
    trials ) and to describe objectively the quantitative and qualitative
    results obtained :
    r   ■
                                                                           •A
 ---pagebreak---                                         - 19 -
2 . to describe their findings xn accordance with Council Directive of •«•...
    on the approximation of the laws of Ilember States relating to analytical ,
    pharmaco-toxicological and clinical standards and protocols in respect of
    the testing of veterinary medicinal products , and in particular to state :
                                                                                      I
    a) in the case of analysts , whether the product oonfoins> with the               j
        stated composition, providing        any reasons for the testing methods      i
       which the manufacturer nay use ;
    b) in the case of phamacologistff        similarly qualified specialists ,
       - the toxicity -of the product and the pharmacological
          properties observed ,
       - whether , after administration of the medicinal product under normal
          conditions of use and observance of the prescribed      delay, food
       stuffa obtained from the treated animals contain- residues which might
          constitute a hoalth hazard to tho consuner|
    c)^in the case of clinicians , whether they have found effects in aninals treated
       with the product     ~      corresponding to the information furnished by
       the manufacturer pursuant to Article 4 , whether the product is well
       tolerated , what dosage they recommend and what are the contra-indications
       and side-effects , if any ;
3 . to give reasons for the use of the references to published data referred
     to in provisos a) and b) of iton 10 in tho second paragraph of Article 4»aooordi
     to the conditions laid down by Council Directive of              on the
     approximation of the laws of Member States relating to analytical ,
     pharmac o-t oxicologic al and clinical standards and protocols in respect
     of the testing of veterinary medicinal products .
 ---pagebreak--- The experts' detailed reports shall form pairfc of the dossier which the
applicant shall lodge with the competent authorities .
           Chapter III -                  for application for authorization
                   Authorization  -  Renewal of authorization
Article 7
Member States shall take all appropriate measures to ensure that the procedure
for granting - authorization to place a veterinary medicinal product on the
market is completed within 120 days fron the date of subnission" of~ the application#
In exceptional cases this time-limit shall bo extended for a further 90 days®
The applicant shall be notified of such extension before the expiry of the
initial time-limit .
Article 8
In order to examine the application submitted pursuant to Article 4 , the
competent authorities of the Member States    shall :
1,        check that the particulars submitted in support of the application
    comply with the said Article 4 and, on the basis of the reports drawn up
    by the experts pursuant to Article 6 , ascertain whether the conditions for
    the issue of the marketing authorization have been fulfilled}
 2.     submit the medicinal product for testing by a State laboratory or a
    laboratory designated for this purpose , in order to ensure that the testing
    methods of control employed by the manufacturer and described in the
    dossier, in accordance with itoa 9 of the sooond paragraph of Article 4f&re
    satisfactory ;
 3»      where appropriate , require     the applicant ' "fc0  supplement the
    dossier as regards     the items listed in Article 4. Where the competent
    authorities avail themselves of this courso of action, the tlno-liaite
    specified
 ---pagebreak---                                       - 21 -
      in Article 1 shall be deferred until tho supplementary -data required have
      been provided. Similarly , those time-limits shall be deferred for the
     period allowed to the applicant , where appropriate , to explain himself
      orally or in writing.
Article 9
Member States shall take all appropriate measures in ordor that :
1*   the competent authorities may ascertain that tho manufacturers and importers
     of veterinary medicinal products from third countries are able to carry
     out manufacture in compliance with the details supplied pursuant to itoa 4 of ;
     tho second paragraph of Article 4 and/or to carry out the tests in accordance
     with tho nethods described in tho dossier under iten 9 of the second paragraph
     of Article 4 j
2.   the competent authorities may authorize manufacturers and importers of
     veterinary medicinal products from third countries , in exceptional and
     justified cases , to have certain stages of manufacture and/or certain of
     the tests referred to in paragraph 1 carried out by third parties ; in
     such cases the investigations by tho competent authorities shall also
      uo carried out in those establishments .
Article 10
Tho authorization provided for in Article 3 shall be withheld if , after
examination of the documents and particulars listed in Article 4 * it appears :
1.   that tho medicinal product is harmful as regards tho conditions of use stated at
                                                                                        i
     the tino of application for authorization, or that there is no therapeutic effec
   insufficient proof thereof by tho applicant as regards the epeoios of kninal
     which is to be treated, or that the qualitative or quantitative composition
                                                   * - *  '
      of the medicinal product is not as declared t
                                                                                      i
                                                                        •A            I
 ---pagebreak---                                      - 22 -
2.  that the waiting period recommended by the applicant is not long enough
    to ensure that foodstuffs obtained from the treated animal do not contain
    residues which might jeopardize the health of the consumer, or is
    insufficiently substantiated }
3.  that the medicinal product is offered for sale for a use prohibited under
    other Community provisions .
Authorization shall also "be withheld if the dossier submitted to the competent
authorities does not comply with Articles 4 » 5 and. 6 .
Article 11
The grant of authorisation provided for in Article 3 shall            •
    require        i  the person responsible for placing the veterinary
medicinal product on the market     tb-1 indicate on the container and/or the
outside wrapping and tho package insert other particulars essential for safety
or health protection ,         including any special precautions relating to
use and any other warnings resulting freer the clihical - and^ phamacoiofeical-'.i
trials specified in Iteor 3£> of Article 4» oi-fron experience" gained, during the
use of the medicinal product once it has been marketed.
Authorization shall also require the inclusion" of a traocr                 *-
substance in tho médicinal product .
Article 12
The granting of authorizati6n shall not dininish the legal - lability of the
manufacturer and, where appropriate , of the person responsible for placing
the veterinary medicinal product on the market .
Article 13
The person responsible for marketing shall aeonpt the tost method provided
for in iten 9' of article      accordance with the advancement of technology
and the progress of science if such adaptations ensures more reliable
testing of tho medicinal product .
                                                         ■              •/.
 ---pagebreak--- The person responsible for placing the veterinary medicinal product on the
market shall forthwith       inform       the competent authorities Qf any new
information which entails amendment of the particulars and documents referred
to in Article 4 or additional examination and more especially any prohibition
or restriction prescribed by the competent authorities of the States in which
the medicinal product is marketed.
The person responsible for placing the veterinary medicinal product on the
market shall immediately inform the competent authorities of any alteration he
proposes to make in the particulars and documents referred to in Article ;4.
Article 14
 Authorization shall be valid for five years and shall be renewablV for five~
 year periods , on application by the holder within the three months preceding
the .\date of expiry, in accordance with the previsions of Article 13 •
             Chapter IV - Committee for Veterinary Medicinal Products
 Article 15
 ls In order to facilitate the adoption of a common position by the Member
     States withxegard to narke>ingjwthoriMtions r a Comittee for Veterinary
     Medicinal Products , hereinafter called the "Committee", is hereby set up;
     it shall bo composed of representatives of the Member States and of the
     Commission,
 2, The Committee shall, when so requested by a Member State , examine questions
     relating to the implementation of Articles 10 , 20 and 33 » in accordance
     with Articles l6-2l!
 3 . The Committee shallldraw up its own rules of procedure.
 Article 16
 1. The Member State whioh has issued a marketing authorization for a
     veterinary medicinal product shall tr€fa3&-i.t to the Committee a dossier con­
     taining a> copy of this authorization together with the particulars and
     d6c\rihonts specified in the second paragraph of Article 4 » if the person
     responsible for narkoting       requested their transmission to at least five
 ---pagebreak---                                          - 24 -
     othei^MenhÊin States - 1
2 . The Committee shall forthwith temsnit- the 1 doS&ier- to^ the^o&pfetent
    authorities of the specifi-etirMenbefr Stattesv-
3 . Such transnissi on. . shall "be deemed to "be ^equivalent" td-» thfc submission "bf an- " '■
     applicatiomfor.- narketin^ authorization to the . said authorities' within "the
    □eamng of Artiole 4 .
Article 17
1. If , within a period of 120 days after the date of tranfeni ssi on - referred ■:
    to in Article 16 ( 2 ), ho objection has "beeniftotlfied to' the Goianittee "by the
    competent authorities of the Member States specified , the Committee shall
    formally record the fact and forthwith inform the Member States concerned,
2. Where a Member State considers that it is unable to authorize the marketing
    of the veterinary medicinal product , it shall forward its £eai3b&eii objection ,
    founded in Articlerl? within the. Said " period of 120 days#
Article 18
1. In the cases reforred to in Article 17 ( 2 ), the Committee shall consider the
    matter and shall deliver its reasoned opinion within -60 days from the
    expiry of the time limit laid down in Article 17.
2. The opinion of the Committee shall deal with the compliance of the veterinary
    medicinal product with the conditions sot out in Article 10,
    The Committee shall forthwith inform the Member States concerned of its
    opinion or , in the event of       dissenaionj of the opinions of its members.
3 . The Member States concerned shall reach a decision on the application for
    marketing authorization not latenthan 30 days after the date on which the
    information provided for in Article 17 ( l) or paragraph 2 Hereof ' ' ' *
    is given. They shall forthwith inform the Committee of their decision.
 ---pagebreak--- Article 19
1* If several applications have been subaifted in - accordance foLth Article 4
          for marketing authorization for the aane       veterinary medicinal
    product , and one or more Member States has granted- suoh authorization while
    one or more of the other Member States have refused it , one of the Member
    States concerned may bring the matter before the Committee .
    The same shall apply where one or more Member States have suspended or
    witfcdraira  marketing authorization while one" or oftho other Honber States
    have not done so,
2 . The Committee shall consider the matter and shall delivor its reasoned; opinion
    within 12© days at the latest#
3 . The opinion of the Committee shall only deal with the grounds on which
    authorization was refused, suspended or withdrovnu
    The Committee shall forthwith inform the Member States concerned of its
    opinion or , in the event of  dissension . , of the opinions of its members.
4* The Member States concerned shall give notice fwithin 30 days f of the action
    they intend to take following the Committee 's opinion.
Article 20
The Committee shall set a tine -limit for irfrosh exanination ion the basis of
particulars relating to the conditions laid down in Articles 10 , 26 or 40
obtained in the meantime by Member States and in particular by those which
have authorized the veterinary medioinal product .
 ---pagebreak---                                        - 26 -
Article 21
The competent authorities of Member States shall^i ill- sp&sifife c&Ses- where - the
interests of the Community are involved , refer the matter to the Committee
before reaching a decision on an application for       marketing authorization ,
its suspension or               ... .
Article 22
1 . The Commission shall report to the Council annually on the operation of the
    procedure laid down in this Chapter and its effects on the development of
    intra-Community trade . It shall nato it& ^firart frepiErti irwo yearg ai*t err" " :
    the entry into force of this Directive .
2 . In the light of experience the Commission shall , not later than four years
    after the entry into force of this Directive , submit to the Council a
    proposal containing appropriate measures leading       to%      the abolition of
    any remaining barriers to the , free movement of veterinary medicinal products ,
    still in eSlstehce *                                          -        .             t
    Bie Council shall take a decision on the Commission proposal not later
    than one year after its subnission»
 ---pagebreak---                                         - 27 -
         Chapter V - Manufacture and imports from third countries
Article 23
1. Member States shall take all appropriate measures to ensure that the
    manufacture and • iaportg -> from third countries of veterinary medicinal
   products aro subject to the holding of an authorization.
2. The provisions concerning manufacture and imports from third countries
    referred to in Chapter IV of the second Directive 75/319/SEC shall apply#
           Chapter VI -  Supervision  and  sanctions
Article 24
The competent authority of the Member State concerned shall ensure by means
of inspection^ that the legal requirements relating tp veterinary medicinal1,
products are complied with.
Such inspections shall be carried out by officials representing the competent
authority who shall be °>empowero4 -to t
1. .     Inspect jianufacturing or commercial establishments and any laboratories
    entrusted by the holder of the authorization referred to in Article 23 ( l)
    with the task of carrying out checks pursuant to Article 9 ( 2);
2.       Tafco sampless
3 . • •>          any documents relating to the object of the inspection , subject
    to QiUPront /provisions       in the Member States at the time of notification
    of this Directive which place restrictions on these powers with regard to
    the description of the method of preparation.
                                                                          ♦A
 ---pagebreak---                                      - 28 -
                                Artide 25
Member States shall talce all appropriate measures to ensure that the person
responsible for marketing a veterinary medicinal product and, where appropriate ,
the holder of the authorization referred to in Article 23(1 ) furnish proof
of the tests .carried out on the finished product and/or on the components
and - intermediate products of the manufacturing process , in accordance with
the methods laid down for the purposes of ~ marketing authorization.
                                Artitle 26
The competent authorities of the Mmber^6tatfcsi&ha1Ll^suspendTXTr3rttfi&r8^ftax!kDting
authorization   when it is clear that :
1 , the medicinal product may be harmful under the conditions of use stated at
    the time of application for authorization or subsequently, or that the nedi- ■
    cirtal product lacks therapeutic effect or that its qualitative and
    quantitative composition i3 not as declared ;
2» the recommended - . delays "     is inadequate to ensure that foodstuffs
  obtained from the treated animal do not contain residues which might
    endanger the health of the consumer ;
3 . the medicinal product is offered for sale for a use which is prohibited
    by other Community provisions ;
4. the information given in the dossier pursuant to Articles 4 and 13 is
    incorrect ;
5. the tests referred to in Article 25 have not been oarried out ;
6 . the obligations referred to in the second paragraph of Article 11 have
    not been fulfilled .
The therapeutio effect is aiBBing when it is established that the medicinal
product cannot produce thereapeutic results in the speoifes of aninal for -which
the treatment is intended.
Authorization nay also be suspended or withdrawn whore t
                                                               •••/•••
 ---pagebreak---                                       - 29 -
   – the particulars supporting the application , as provided for in Article 4,
     have not been amended in accordance with the first and third paragraphs of
     Article 13 ;
   – any new information referred to in the second paragraph of Article 13
     has not been communicated to the competent authorities .
                                    Article 27
1 . Notwithstanding the provisions of Article 26 , /- Member States shall take
    all necessary measures to ensure that supply of the veterinary medicinal
    product is prohibited and that such medicinal product is withdrawn from
    the market where :
    a« it is clear that the medicinal product is harmful under the conditions
         of use stated at the time of the application for authorization or
         subsequently, pursuant to the third paragraph of Article 13 ;
    b« the medicinal product laoksi thorapoutic,6ffoct I CHV the species^af ; animal for
         which the treatment was intended ;
    c . the qualitative and quantitative composition of the medicinal product
         is not as declared ;
    d. the recommended ■ dclajr' : ■ is inadequate to ensure that foodstuffs
         obtained from the treated animal do not contain residues which might
         endanger the health of the consumer ;
    e . the tests referred to in Article 25 have not been carried out or where
        another requirement or obligation relating to the grant of the
         authorization referred to in Article 23(1 ) has not been complied
        with.
2. The competent authority may confine its order prohibiting supply and
       the      withdrawal from the market solely to manufacturing batches
        over     which there is a dispute .
 ---pagebreak---                                              30 -
                                      Article 2o
 1 . The competent authority of a Member State shall suspend or withdraw rfche
      authorization referred to in Article 23 for a category of preparations or
      for all preparations when one of the requirements laid down for the
      obtaining of this authorization is no longer met .
2 . The competent authority of a Member State may , in addition to the
      measures set out in Article 27 » either suspend manufacture or
     imports    ^ of veterinary medioinal products from third countries or
      suspend or withdraw; "the ^^^rizatiion "referred "to TLn-ttrfctole "23' Tot a
      category of preparations or for all preparations in the event of non-
      observance of the provisions regarding manufacture or impori©                 from
      third countries .
                                      Article 29
Member States shall take all appropriate measures to ensure that the competent
authorities concerned communicate to each other such information as is appropriate
to secure compliance        with the requirements for the authorization referred to
in Article 23 ( l ) or for marketing authorization.
                                                                                  \
                                      Article 30
All decisions taken pursuant to Articles 10 , 26 and 27 t all negative decisions
taken pursuant to Articles              andi ilSfe) nfi-Miier Directive* and" all; 'decisions to
withhold' aujfchxjrization to narflifaeturei ®r -to-^ import frocr third1 countries' t>r to
suspend or withdraw         .manufacturing authorization shall state in detail ., the
reasons on whioh they are based .        Such decisions shall be notified to the
party concerned who shall at the same time be informed of the remedies
available to him under current legislation and the tine–limit within whioh
such       re&edie® fcfljs-t.be sought#
Authorizations to place veterinary medicinal productson the market and
decisions to revoke such authorizations ! shall- bfc- published by each Kenber" State
in its official gazette .
 ---pagebreak---                                                                          I
                                       - 31 -
                                 ' Article 31
   -■ Decisions to grant authorization to market ,     withhold , suspend or withdraw
authorization, to prohibit supply, to withdraw a product from the market
or to suspend manufacture or imports ■        from third countries of veterinary
medicinal products shall- only^lse^ tales n on the grounds set out in this
Directive .
                                   Article 32
Each Member State shall take all     •   appropriate measures to ensure that
decisions authorizing marketing, refusing or withdrawing & marketing authorization,
cancelling a decision refusing or withdrawing aarketiag^ (author! 2atidn, prohibiting
i'i 3upply or withdrawing a product from the market , together with the reasons
on which such decisions are based , are brought to the attention of the
Committee forthwith .
                                                                 • ••/ • • •
 ---pagebreak---                                       - 32 -
                      Chapter VII - Labelling and package inserts
                                    in the packaging of veterinary
                                    medicinal prodtttt s
                                   Article 33
The following particulars shall appear in legible characters on containers
and outer packages of medicinal products :
1.   Name of the medicinal product , v;hich mcy be a trivial name or a common name
     with or without a trade mark or name of the manufacturer or a scientific
     name or formula with or without a trade mark or name of the manufacturer ,
2.   Next to the name of the medicinal product , its qualitative and quantitative
     composition expressed in active components per dose-unit or as a percentage ,
     aocording to the pharmaceutical form and , in addition    in the cases-rcfeirreEl
     to in the second paragraph- of Article 11 the tracer substances^
     The international non–proprietary name3 recommended by the World Health
     Organization shall be used wherever thqy exist .
3.   Reference number for production identification (manufacturer 's batch
     number ).
4.   Number of the authorization for placing tho veterinary medicinal produot on
     the market •
5.   Name or corporate name and permanent address or hoa&qwartors of the person
     responsible for , plaoing tho veterinary nodicinal product on the - market' and.,
     whorb applicable , of the manufacturer also .
6.   The species of animal for which the medicinal product is intGilded ) the nothod
     and means of administration.
7-   Ueiay. if anyi .
 ---pagebreak---                                                     - 33
8.            Date- of . expiry-%
9.           Special storage precautions , if any,
10 .          The particulars idd'dcxm in the first paragraph of Article 11 , if
            necessary ,
11#           The words "For veterinary use".
              Hie pharmaceutical form and the contents by weight ,   volume or
             number of dose-units need only "be shown on the outer package •
               –  •» ■        ,      -            /
•; •••«: ' •.          <   •                                . Hhe provisions of the
Annex, Part 1 , A to Counoil Directive of •••.••••••••• on the approximation of
the laws of Member States relating to analytical , pharmaco–toxicologioal and
clinical standards and protoools in respect of the testing of veterinary
medicinal products in so far as they concern, the active components of veterinary
medicinal products described qualitatively and quantitatively shall apply to the
particulars given in point 2»                   Article 34
As regards ampoules , the particulars listed in the first paragraph of
Article 33 shall be given on the outer package • On the actual containers ,
however, only the following particulars shall "be necessary*
                 – naine of the médicinal product ,
                 – quant ity of active substances ,
                 «- means    of administration
                 – reference number for production identification
                       (manufactuer * s batch number )
                 – date of expiry
                 – the words "For veterinary use".
 ---pagebreak---                                        - 34
                                     Article 35
  As regards snail single-dose containers , other than ampoules , on which it
  is impossible to give the particulars mentioned in Article 34 | the require­
  ments of Article 33 shall apply only to the outer paokage .
                                     Article 36
  As regards narcotics , in addition to the particulars mentioned in Article
  33 , "both the outer package and the container shall hear a special sign
  consisting of a double red line .
                                     Article 37
  Where there is no outer package , all the particulars which should feature
  on such • package pursuant to the preceding Artioles shall "be shown on the
  container .
                                     Article 3°
  The particulars mentioned in items 6,7,8,9, 10 and 11 of the first paragraph
  of Article 33 and in the 3rd and 6th indents of Article 34 shall appear
  on the outer package and on the container of medicinal products in the
  language                or languages of the country in vhioh they are being
  placed on the marlcet .
                                     Article 39
  Member States shall take all appropriate measures to ensure that the package
- insert which must be inoiuded in the package dZh, veterinary medicinal
  product relates solely to that medicinal product .
  The package insert shall contain only the following particulars , which
  shall conform with the information and documents provided pursuant to
  Article 4 and which have "been approved by the competent authorities :
 ---pagebreak---                                      - 35 -
                                                                                     i
a) Name or oorporate name and permanent address or hoadcjuartors of 'the person
     responsible for plaoing the wterinorynoedicinal product on the market and,wheit
     applicable , of the manufacturer also f
b) Name of the medioinal product and a statement of its active oanpononts
     expressed qualitatively and quantitatively.
     The international non–proprietary names reoommended by the World Health
     Organization shall be used wherever they exist .
c ) The main therapeutio indioationB* , oontra–indications and side-effect3
     in so far as thoro particulars arc nocossary for tho use of the medicinal
     products j
d) The spcoies of animal for phioh the medioinal product is intended, the dosage
   - suitable for this speoies, tho nothod and mentis of administration and advice
    on oorroot administration, if necessary ;
e ) If necessary, all details concerning the delay. {
f) Special storage precautions , if necessary ;
g) The particulars required by the first paragraph of Artiole 11 , if
     necessary.
                                  Article 40
Where the provisions of this Chapter are not observed and a formal notice
addressed to the person ooncerned has boon ineffective , the competent
authorities of the Member States may suspend or withdraw the authorization to
place the veterinary medioinal product on the market .
All deoisions taken by virtue of the preceding paragraph shall state in detail
the reasons on which they are based.     A decision shall be notified to the party
concerned, along \fith the remedies available to hin under current legislation ,
and the tine allowed for cooking such rcmedios *
 ---pagebreak---                                          - 36 -
                                     Article 41
The.- requirements of Ifcnbcr^taios^cacnKJorning' craidlt ions ©f supply to the pablio ,
  the marking of prices on medicinal products for veterinary use and
  industrial property rights shall not he affeoted hy the provisions of this
  Chapter .
                         Chapter VIII – Implementing provisions and transitional
                                                            nea sures
                                     Article 42
  Member States shall "bring into force the lafos , regulations and administrative
  provisions •• necessary       to comply with this Directive within eighteen
  months of its notification and shall forthwith inform the Commission thereof .
 Member States shall ensure that the main provisions of national lav/ which
  they adopt in the field governed by this Directive are communicated to
  the Commission .
                                     Article 43
  1 . As regards the authorizations referred to in Article 23 which are issued
       before the expiry of the tine–limit laid down in Article 42 , Member
       States shall grant an additional period of on© yoar to the - undertakings
       concerned to enable them to comply with the provisions of Chapter V.
  2 . The other provisions of this Directive shall be applied progressively,
       within fifteen years of the notification referred to in Artiole 42 , to
       veterinary medicinal products placed on the market by virtue of previous
       provisions .
 ---pagebreak--- 3. Member States shall notify the Commission, within three years following
  ^ the notification of this Directive, of the number of veterinary medicinal
    products covered by paragraph 2, and, in each subsequent year, of the
    number of such products for which the marketing authorization referred
    to in Artiole 3 has not yet been issued.
                               Article 44
This Directive is addressed to the Member States .
 ---pagebreak---               PROPOSAL FOR A COU1TCIL DIRECTIVE
     01T THE APPRO XII1AT I Oil OF THE LAWS OF JJEIBER STATES
     RELATING TO AITALYTICAL , PHABMACO-TOXICOLOGICAL AJTD
              CLUICAL.. STANDARDS' AED ^PROTOCOLS ■
?TT RESPECT OF THE TESTHTG OF VETERHTARY MEDICI1TAL PRODUCTS
 ---pagebreak---                            Explanatory memorandum
As with proprietary medicinal products for human beings , it is necessary ,
in the case of veterinary medicinal products , to make certain additions to
the principles laid down "by the basic Directive in order to allow veterinary
medicinal products freedom of movement s By defining the data to he supplied
concerning the characteristics of medicinal products , by setting out a
common plan for the presentation of these data and by laying down the broad
lines for testing medicinal products , this Directive will , at one and the
same time , assist manufacturers , competent national authorities and- the
Committee on veterinary medicinal products envisaged in the Council
Directive        • •••• of ...••••• on the approximation of the laws of
Member States relating to veterinary medicinal products .
This proposal was drawn up on the basis of the studies made in the field of
proprietary medicinal products for use in human beings . However , the
special problems raised by veterinary medicinal products have led to a cer­
tain number of original provisions being made .
In the first place , it is important to protect the health of people who
consume animal products . Advanced phamaco–t oxicological studies have been
planned in order to determine the possible presence of residues in food­
stuffs obtained from treated animals and the effects of such residues .
These tests crust make it possible to establish the necessary waiting period
from the time when the medicinal product is administered to the animal
until foodstuffs are obtained from the animal , in order to eliminate human
health hazards . It is also important , however , to oonsider the protection
of the treated animal , sinoe , after all , this is the prime object of veterinary
medicinal products ; but this gives rise to a difficult question , i.e. the
extent of the assurances which the competent authorities may require as to
the safety of the product for the intended species of animal . In the case
of medicinal products for human use the answer is obvious – every possible
assurance is required. Where veterinary medicinal products are concerned
the answer is not so easy.
 ---pagebreak---  From the scientific standpoint it is clear that all the toxicity tests
  ( single dose toxicity tests , repeated dose toxicity tests and tolerance
tests ) must "be carried out in every case . By means of the first type of
test it is possible to determine whether the product is highly or fairly
toxic and generally to describe the acute symptoms of intoxication . The
second type of test provides information concerning the mechanism of the
intoxication process and make it possible to identify the side-effects
which are masked in the acute toxicity tests . Similarly , the tolerance
tests in the intended species of animal enable the maximum tolerated dose
and the intolerance symptoms to be established.
Prom the economic standpoint one must nevertheless consider whether all these
tests to safeguard the health of the treated animal will excessively penalize
veterinary medicinal products as against medicinal products for human use .
In the case of veterinary medicinal products , the toxicity tests are
numerous : one range of tests is intended to protect the treated animal 's
health , another range is intended to protect the consumer of animal products
( residue tests ). One must therefore prevent the cost burden imposed on veter­
inary research from handicapping the sales prospects of such medicinal
S;
products too heavily and thus fostering illegal dealings in this market ,
which would run counter to the aims pursued.
A compromise solution is therefore proposed : it is desirable that all the
tests for toxicity bo carried -out ?     nevertheless juct  , jit*.  ol
considering in particular the directions for the use of the medicinal product *
the investigator may submit reasons for not carrying out the repeated dose
toxicity tests ; these reasons will of course be appraised by the competent
authorities who can always insist that these tests obe carried out .
 ---pagebreak--- THE C0U1TCIL OP THE EUROPEA1T COiSIUlTITIES ,
Having regard to the Treaty establishing the European Economic Community ,
and in particular Artiole 100 thereof,
Having regard to the proposal from the Commission ,
Whereas the approximation begun by Council Directive             of ........
on the approximation of the laws of the Ilember States relating to veterinary
medicinal products should be continued and the implementation of the principles
laid down in that Directive should be ensured ;
Whereas among existing disparities those relating to the control of veterinary
medicinal products are of fundamental importance and point 10 of the- second para­
graph of Article 4 of the said Directive requires that applications for
authorization to place a veterinary medicinal product on the market should
be accompanied by particulars and documents relating to the results of
tests and trials carried out on the product concerned ;
Whereas standards and protocols for the performance of tests and trials on
veterinary medicinal products are an effective means of control of these
products and hence of protecting public health and can facilitate the move­
ment of these products by laying down uniform rules applicable to tests
and trials and the compilation of dossiers ;
Whereas the adoption of the same standards and protocols by all the Member
States will enable the competent authorities to arrive at their decisions
on the basis of uniform tests and by reference to uniform criteria and will
therefore help to obviate differences in evaluations
 ---pagebreak---                                       - 4 -
Whereas the physico-chemical , "biological or microbiological tests provided
for in poiht.. 10 pf th® second pajrttgraph T>f^ftrticlo 4»~tho 'said: Directive
are closely related- to points 3 » 4» 6 and $ , of the 6aid
paragraph and it is therefore necessary to specify the data to "be provided
under these points j
Whereas the waiting period referred to in point 8 of the second paragraph of the
said Article 4 nust he cietemined in
accordance with the results of the tests and trials provided for in point 10
"thereof ;
Whereas the concepts of harmfulness and therapeutic efficacy referred to in
Article 10 of the said Directive, can only be
examined in relation to each other and have only a relative significance
depending on the progress of scientific knowledge and the use for which the
medicinal product is intended ; whereas the particulars and documents which
must accompany an application for authorization to place a veterinary medi­
cinal product on the market must demonstrate that potential hazards are
outweighed by the therapeutic efficacy of the product 5 whereas ^failing such
demonstration , the application must be rejected ?
Whereas it is the quality of the tests and trials which is pre-eminent } where­
as the tests and trials carried out pursuant to these provisions must there­
fore be taken into consideration irrespective of the nationality of the
experts who perform them and the country where they are carried out j
Whereas technical progress requires rapid                  of "the provisions of the
 Annex to this Directive | wh©3jeas to nake, it easier to adapt to the measures
required for this purpose ,              should be •-         a procedure to^nsur©
close cooperation between the Member States and the Commission within the
Standing Committee on Medicinal Products .
HA.S ADOPTED THIS DIRECTIVE :
                                                                                 /•
 ---pagebreak---                                     Article 1
       Member States shall take all appropriate measures to ensure that
the particulars and documents which must accompany applications for authoriz­
ation to place a veterinary medicinal product on the market pursuant to
points 3 , 4 , 6 , 8 , 9 and 10 of the SQcond pajnagraph of :Artiole 4 of the Council
Directive               of ......... on the approximation of the laws of
Member States relating to veterinary medicinal products are submitted
by the persons concerned in accordance with the Annex to this Directive .
       Where , under point 10(a) or (b) of the sacon^ paragraph of Article 4
of the said Directive ,: references to published dataware
submitted , the provisions of this Directive shall apply in like manner.
                                    Article 2
       The amendments necessary for adapting the requirements of the Annex
to this Directive to technical progress shall be adopted in accordance with
the procedure laid down in Article 3(5) an^ ( 6 ) (as amended) of the Council Direct:
of                relating to analytical , pharmaco-toxicological and clinical
standards and protocols in respect of the testing of proprietary medicinal
products .
       The Committee referred to in Article 3 (&si.anended) of tho said
Directive may examine any question relating to the application of this
Directive which is brought up by its Chairman , either on his own initiative
or at the request of the representative of a Member State .
                                    Article 3
       Member States shall put* into force           laws , regulations and adninistrati
provisions needed in order to copply yith this Dirootiv© within 18 months of its
notification and: shall forthwith infom the Commission thsreof ,
       Member States shall ensure that
the text of the main provisions of national law which they adopt in the
field covered by this Directive are ooonunioated to the Commission#
                                    Article 4
       This Directive is adressed to 'the Member States
                                                                          ./■
 ---pagebreak--- A 1T ---pagebreak---                                        Part 1
ANALYTICAL (PHYSIC 0-0HEMICAL , BIOLOGIC/. L OR MICROBIOLOGICAL) TESTS OF
                         VETERINARY MEDICINAL PRODUCTS
A. Qualitative and quantitative particulars of. the component s
        The particulars and documents which must accompany applications for
marketing authorization$pursuant to Artiole 4 » point 3t second paragraph , of
Council Directive ...       .......... of                     on the approximation
of the laws of Member States relating to veterinary medicinal products shall
be submitted in accordance with the following requirements :
1.      " Qualitative particulars " of all the components of the midiciaal
produot means the designation or description of t
        - the active substance ( s )
        – the component(s ) of the excipients , whatever their nature or the
           quantity used, including colouring agents , pa»MEr*aifci»w, stafoi-licere *
           thickeners , emulsifiers , anti-agglutinating agents , flavouring and
           aromatio substances ? * gas propellante , etc ....
        – components of the pharmaceutical form ( e.g. capsule , cachet ) intended
           to be ingested or otherwise administered to animals .
        These particulars shall be supplemented by any relevant data concerning
the oontainer and , where appropriate , the way of closing it .
2.      The "usual terminology", to be used in describing the components of
medicinal produots , means,without prejudioe to the application of the
other provisions of Artiole 4i point 3 » of the said Directive :
        – compulsorily , in respect of substances which appear in the European
           Pharmacopoeia or, failing this , in the national pharmacopoeia of one
           of the Member States , the principal designation used in the relevant
           monograph, with referenoe to the pharmacopoeia concerned;
 ---pagebreak---                                       - 8 -
        - in respect of other substances , the international non-proprietary
          name recommended "by YJHO , which nay be accompanied by another non-
          proprietary name , or , failing these , the exact scientific , designation ;
          substances not having an international non-proprietary name or an
          exact scientific designation shall be described by a statement of
          how and from what they were prepared , supplemented , where appropriate ,
          any other relevant details ;
       - in respect of colouring agents , designation by the "E" code assigned
          to them in a future Council Directive on the approximation of the
          rules of the Member States concerning the colouring agents authorized
          for use in proprietary medicinal products .
3.      In order to give "quantitative particulars of all the components of
the medicinal product " it is necessary , depending on the pharmaceutical form
concerned, to specify in regard to the active substance(s ) the weight or the
number of international units , either per dosage-unit or per unit of weight
or volume and in regard to the components of the excipient , the weight or
the volume of each of them , with due allowance for the details provided in
section B below.
       This information shall be supplemented :
       - in respect of parenteral preparations , by the weight of each active
          substance in the unit container , taking into acoount the usable volume
          of the product j
       - in respect of medicinal products to be administered in drops , by
          the weight of each active substance contained in the number of drops
          corresponding to an average dose 3
       - in respect of syrups , emulsions , granules and other pharmaceutical
          forms to be administered in measured quantities , by the weight of
          each active substanee per measured quantity.
       Active substances present in the form of compounds or derivatives shall
be described quantitatively by their total weight , and if necessary or relevant ,
by the weight of the active moiety or moieties of the molecule ( in the case
of chloramphenicol palmitate , for example , the weight of the ester and that
of the corresponding chloramphenicol shall be given ).
 ---pagebreak---                                        - 9 -
        The "biological units of activity of products which have not been
defined chemically , and on which there is insufficient "bibliographical in­
formation , shall be expressed in such a way as to provide unambiguous infor­
mation on the activity of the substance , e.g. by stating the physiological
effect on which the method of determining the dose is based.
B# Description of method of cysee^gti-on
        The "brief description of the method of preparation" accompanying the
application for marketing authorization pursuant to Article 4, second paragraph ,
point -4# "■of.. Council Directive .............. of           shall be drafted
in such a way as to give an adequate idea of the nature of the operations
employed.
        For this purpose it shall include at least t
- mention of the various stages of manufacture , so that an assessment can
  be made of whether the processes employed in producing the pharmaceutical
  form might have brought about an adverse change in the components }
- in the case of a continuous process , full details concerning precautions
  taken to ensure the homogeneity of the final product j
  the actual manufacturing formula , with the quantitative particulars of
  all the substances used, the quantities of excipients , however , being
  given in approximate terms in so far as the pharmaceutical form makes
  this necessary ; mention shall be made of any substances that may disappear
  in the course of manufacture ;
- a statement of the stages of manufacture at which sampling is carried out
  for in^> process control tests , where other data in the documents supporting
  the application show such tests to be necessary for quality control of the
  medicinal product .
 ---pagebreak---                                      - 10 -
C. Checkin.T of br.sic substances
        For the purposes of this paragraph , ''basic substances 1' shall mean all
the components of the medicinal product and , if necessary, of its container ,
as referred to in paragraph A , point 1 , above .
        The particulars and documents which must accompany the application
for marketing authorization pursuant to Article 4» second paragraph , points
9 and 10 , of Council Directive •••••••••• of •••..•••• shall include the
results of the tests relating to quality control of all the components used.
These particulars and documents shall be submitted in accordance with the
following provisions .
1 . Basic substances listed in pharmacopoeia^
        The monographs of the Hhiropean Pharmacopoeia shall be applicable to
all substances appearing in it .
        In respect of other substances , each Ilember State may require observance
of its own national pharmacopeia with regard to products manufactured in its
territory.
        Components fulfilling the requirements of the Buropean Pharmacopoeia
or the pharmacopoeia of one of the Ilember States shall be deemed to comply
sufficiently with Article 4i second paragraph , point 9 » of Council Directive
              of                  In this case , the description of the analytical
methods may be replaced by a detailed reference to the pharmacopoeia in
question.
        Reference to any of the pharmacopoeias of non Member countries may
be permitted in cases where the substance is described neither in the
European Pharmacopoeia nor in the national pharmacopoeia concerned ! in that
case the monograph shall be submitted, aocompanied where necessary by a
translation for which the applicant shall be responsible .
 ---pagebreak---         Colouring agents shall , in all cases , satisfy the requirements of
a future Council Directive on the approximation of the laxra of the Hember
States conoeming the colouring agents authorized for use in proprietary
medicinal products *
       For routine tests on each "batch of basic substance , only that part
of the pharmacopoeia relating to verification tests ( purity and strengths )
shall be mandatory ; the full range of identity tests need not necessarily
be performed whore those - that have been performed permit an unambiguous
characterization . In this case , the reference to the monograph of the pharma­
copoeia mentioned above shall inolude details relating to this aspect .
2. Basic substances not in a pharmacqpoei^
        Components which are not given in any pharmacopoeia shall be described
in the form of a monograph under the following headings :
( a)   The name of the substance , meeting the requirements of paragraph A ,
point 2 , shall be supplemented by any trade or scientific synonyms ;
(b )   The description of the substance , set down in a form similar to that
used in a descriptive item in the European Pharmacopoeia , shall be accompanied
by any necessary explanatory evidence , especially concerning the molecular
structure where appropriate ; it must , in such a case , be accompanied by a
brief indication of the method of synthetic preparation . I!here substances
can only be described by their method of preparation ,, the description will
have to be sufficiently detailed to characterize a substance which is
constant both in its composition and in its effects ;
(c)     Methods of identification may be divided into complete techniques as
used for the formulation of the medicinal product , and tests which ought to
be carried out as a routine matter .
 ---pagebreak---                                                                                    1
                                          - 12 -
     ( d)   Purity tests shall be described in relation to the stun total of
    predictable impurities , especially those which may have a harmful effect ,
    and, if necessary , thoss tdaibfc , having regard to the medicinal association
    to which the application refers , might adversely affect the stability of
    the medicinal product or distort analytical results ,
     (e)    The assay technicrue(s ) must be described in sufficiently precise
    detail so as to be reproducible in checking tests carried out at the request
    of the competent authority ^ ar$ special apparatus and equipment which may be
    used shall be described in adequate detail , possibly accompanied by a
    diagram. The formulae of the laboratory reagents shall be supplemented, if
    necessary, by the method of preparation.
            The standard deviation of the method, its reliability and the accept­
    ability limits of the results shall be specified and, if necessary, justified
    in the light of feasibility and the progress of scientific knowledge .
            With regard to complex substances of plant or animal origin , a
    distinction must be made between the case where multiple pharmacological
    effects render a chemical , physical or biological check of the principal
    components necessary, and the case of substances containing one or more
    groups of principles exerting similar action , in respect of which an overall
    method of determination may be aocepted.
    ( f)    ^v               w.t ions that may >e necessary during storage
    v>.io substance and, if necessary, its storage life shall be given.
««--tu Checks during manufacture
            The particulars and documents which must accompany an application f»r-
    marketing authorization, pursuant to Article 4, second paragraph, points 9
    and 10 , of Council Directive                   of              shall more
    especially include particulars relating to -the product checks that may be
    carried out at an intermediate stage of the manufacturing process , with a
    view to ensuring consistency of the technical characteristics and the
    production prooess .
 ---pagebreak---                                          - 13. -
           These -tests axe essential to verify the conformity of the medicinal
 product with the formula when, exceptionally, an applicln^ proposes an
 analytical technique for testing the finished product which does not include
 the assay of all the active substances (or of all the components of the
 excipient subject to the same requirements as the active substances ).
  • (
           The same applies where quality control of the finished?* product depends
 on in–process checks , particularly A# "the                      ^^ essentially
 defined by its method of préparation.
 E. Chacks on the finished product
           The particulars and documents which muert accompany the ^plication
 for marketing authorization pursuant to Article 4, second, paxa^p^ points
 9 and 10 , of Council Directive                  of                    include
 particulars relating to checks on the finished product . They sl^ te sub_
 mitted in accordance with the following requirements .             /
-^ f fifinera.!         eristics of the | various p^m^eu^cal^f03^
         . Certain checks on the general characteristics of a product which can
 be carried out in the course of the manufacturing process shali be included
  among the tests on the finished product .
           As a guideline , and subject to the requirements of tfc© European
  Pharmacopoeia or the national pharmacopoeias of Member States , the general
   characteristics which are to be verified for various pharmaceutical forms
  are given at point 5 below.
           These checks shall , wherever applicable , relate to the verification
  of average weights and maximum deviations , to mechanical , physical or
  microbiological testsj organoleptic characteristics such as clarity, colour
  and taste , and physical characteristics such as density, pH , refractive
  index, etc . For each of these characteristics , standards and limits must
 be specified by the applicant in each particular case .
 ---pagebreak---                                     - 14 -
 2. Identification and assay of active snbstance(s )
        The description of the techniques for analysing the finished product
shall set out , in such precise detail that they oan be reproduced readily,
the methods used for identification and assay of the active substance(s )
either in a representative average sample from the production batch or in a
number of dosage-units considered individually.
        In every case , the methods must correspond to the state of scientific
progress at the time and give details and explanations concerning the standard
deviations , the reliability of the analytical method and the maximum accept­
able deviations .
        In certain exceptional cases of particularly complex mixtures , where
the assay of active substances which are either very numerous or present in
very small amounts would necessitate an intricate investigation difficult
to carry out in respect of each manufacturing batch , the assay of one or
more active substances in the finished product may be omitted, on the express
condition that such assays are made at intermediate stages in the production
process ? this relaxation may not be extended to cover the characterization
of the substances concerned. This simplified technique shall then be supple­
mented by a method of quantitative evaluation , enabling the competend authori­
ty to have the conformity of the medicinal produot with its formula verified
after it has been placed on the market .
        An assay of biological activity shall be obligatory when physico­
chemical methods cannot provide adequate information on the quality of the o
product .
        Where the particulars given in paragraph B show that a significant
overage of an active substance was employed in the manufacture of the
medicinal product , the description of the methods for checking the finished
product shall, include , where appropriate , the chemical and even the toxico-
pharmacological investigation of the changes that this substance has under­
gone , and the characterization or determination of the degradation products ,
if any.
                                                                        ./■
 ---pagebreak---                                       - 15 -
3. Identification and assay of components of excipients '   ""
         An upper-limit test shall be mandatory in respect of excipient compo­
nents which are subject to rules relating to toxic substances or which are
used as preservatives ; furthermore , components liable to affect physiological
functions shall be subjected to an assay.
         The method proposed for identifying colouring agents must enable a
verification to be made that such agents appear in the list to be appended
to a future Council Directive on the approximation of the laws of the Member
States concerning the colouring agents authorized for use in proprietary
medicinal products .
         In so far as is necessary , the components of the excipient shall be
subjected at least to characterization tests.
4. Safety tests
         Apart from the toxico-pharmaco logical tests submitted with the appli­
cation for marketing authorization , particulars of safety tests (abnormal
toxicity ) or local tolerance in animals shall be included in the analytical
dossier wherever such tests must be undertaken as a matter of routine in
order to verify the quality of the medicinal product .
5. General characteristics of medicinal products to be verified systematically ,
   depending on the pharmaceutical form of each product
         The following requirements are given for guidance and without pre­
judice to any requirements of the 3uropean Pharmacopoeia or national
pharmacopoeias of Member States ; for example , microbiological testing of
preparations to be ingested orally shall be performed in accordance with
the requirements of the European Pharmacopoeia.
- Tablets and pills : colour , weight and acceptable variations in unit weight ;
  if necessary , disintegration time with the method used to determine this.
- Coated tablets ? colour , disintegration time with the method used to determine
  this ; weight of finished tablet ; weight of core and acceptable variations
  m unit weight .
 ---pagebreak---                                          - 16 -
– Hard ge latine capsules and soft gelatine capsules : colour , disintegration
  time with the method used to determiner this 5 appearance and weight of
  content , "with acceptable variations in unit weight . •
– Enterio-coatcd preparations (tablets , hard and soft gel atine capsules ,
  granules ) : in addition to the requirements of the particular pharmaceutical
  form , resistance time in an artificial gastric fluid , with the method used
  to determine this ; disintegration time in an artificial intestinal fluid ,
  with the method used to determine this .
– Preparations with special protective coating ( tablets , hard and soft
  gelatine capsules , granules ) ; in addition to the requirements peculiar
  to each pharmaceutical form, verification of the effectiveness of the
  coating for the desired purpose .
– Preparations ensuring gradual release of the active substance : in addition
  to the requirements peculiar to each pharmaceutical form , requirements
  relating to gradual release , with the method used to determine this .
– Cachets' , packets and sachets : nature and weight of contents and acceptable
  variations in unit weight .
– Parenteral preparations ? colour , volume of contents and acceptable variations
  in this volume ; pH, clarity of solutes , size limit of particulate matter
  in the case of suspensions 5 sterility tests , with description of test
  methods and , if necessary, a pyrogen test with description - of method.
– Ampoules with solid content : quantity of medicinal product per ampoule and
  permitted variations in weight ; sterility requirements and tests .
– Drinkable ampoules : colour , appearance , volume 6f content and acceptable
  variations .
– Ointment s , creams , et c . : colour and consistency ; weight and acceptable
  margin of variation ; nature of container ; in certain cases , microbiological
  tests .
– Suspensions : colour ; where settlement occurs , the ease of re-suspendability.
- Enulsions : colour ; type ; stability.
 ---pagebreak--- - Suppositories , "bougies and preparations for intra-uterine administration :
  oolour, weight and acceptable variations inyfanit weight ; melting temperature
  or disintegration time , and description of the method.
- Aerosols : description of container and valve with details /of output ;
  particle size-limit , where the product is intended to "be inhaled.
- Eye drops , ophthalmic ointments , eye lotions ? colour ; appearojioe 5 sterility
  tests , with description of the method used ; where appropriate , clarity and
  size-limit of particulate matter in the case of suspensions ; pH determination.
– Syrups , solutés , etc. : colour , appearance
– Pre-mix formulations for medicated feeds : in addition to the requirements
  peculiar to each pharmaceutical form , all useful information on the
  characteristics of the pre-mix formulation enabling a sufficiently homo­
  geneous medicated feed to "be prepared.
- Preparations for administration within the udder via the teat canal : colour ,
  consistency ; weight of content and, in the case of products presented in
  single slow-release dose formulations , usable weight with acceptable
  deviation ; sterility test ; pH determination.                .
 P. Stability tests
         The particulars and documents which must accompany the application for
 marketing authorization pursuant to Article 4» second paragraph , points 6
 and 9 , of Counoil Directive                   of •••.•••••••• shall be submitted
 in accordance with the following requirements .
         A description shall be given of the investigations by which the shelf
 life proposed by the applicant has been determined.
         Where a finished product is liable to give rise to toxic degradation
 products the applicant must report these and indicate characterization or
 assay methods .
 ---pagebreak---                                     - 18 -
       The conclusions shall contain the results of analyses , justifying
the proposed shelf life under normal , or , where appropriate , under special
storage conditions .
       A study of the interaction "between the medicinal product and the
container shall he submitted wherever the risk of such interaction is
regarded as possible , especially where parenteral preparations or aerosols
for internal use are concerned.
 ---pagebreak---                                     - 19
          •                        Part 2
TOXICOLOGICAL AITD PHARi'IACOLOGICAL TSSTS
        The particulars and documents which must accompany the application
for marketing authorization pursuant to Article 4, second paragraph ,
point 10 , of Council Directive .•••••••••• of ••••••••••••• shall toe submitted
in accordance with the requirements of Chapters I and II below.
                           Chapter I ; Performance of tests
A. Introduction
        The toxicological and pharmacological tests must show :
1 . the potential toxicity of the medicinal product and any dangerous or
  . undesirable toxic effects that may occur under the proposed conditions
    of use in animals j these effects should be evaluated in relation to the
    gravity of the pathologioal condition concerned }
2. its pharmacological properties , in both qualitative and quantitative
    relationship to the proposed use in animals ;
3 . to what extent and for how long after use of this medicinal product in
    animals there exist residues in food products obtained from the animals ,
    what are their possible harmful effects on ISan and what are their draw­
    backs for the industrial processing of food.
        All results must be reliable and of general applicability. Whenever
appropriate , mathematical and statistical procedures shall be used in working
out the experimental methods and in evaluating the results . Furthermore , it
is necessary for clinioians to be given information about the therapeutic
potential of the product and about the hazards connected with its use .
 ---pagebreak---                                    - 20 -
B. Toxicity study
1 . Single-dose tonicity
        Singlc-dose toxicity test means a qualitative and quantitative study
of the toxic reactions which may result from a single administration of the
active substances contained in the medicinal product , in the proportions in
which they are present in the actual medicinal product .
        Wherever practicable , the product in its actual pharmaceutical form
shall "be subjected to an acute toxicity test .
        The single-dose toxicity test must be carried out in at least two
mammalian species of known strain , and at least two different routes of
administration shall normally be used. The study with two mammalian species
can be replaced by study with one mammalian species and an ajaimal species
of another class for which the medicinal product is intended. One of the
forms of administration must be identical with or similar to that proposed
for use in the animal for which the medicinal product is intended and the
other must.be a route ensuring systemic absorption of the product . The study
must be carried out on equal numbers of male and female animals .
        This study will describe the symptoms observed , including local
reactions. Where .possible, the LD^ value with its confidence limits (95 f°)
will be noted. The period during which the test animals are observed shall
be fixed by the investigator and shall not be less than one week .
        In the case of active substances in association , the study must be
carried out in such a way as to check whether or not potentiation phenomena
or new toxic effects occur .
2 . Repeated-dose toxicity
        Repeated-dose toxicity tests are intended to reveal any physiological
and/or morbid anatomical changes induced by repeated administration of the
active substance or association of active substances under examination , and
to determine how such changes are related to dosage .
 ---pagebreak---        Generally , it is desirable to perform at least one test the duration
of which shall depend on the conditions of clinical use 5 its purpose shall
he to determine "by experiment the non–toxic dose range of the product
examined during the trial . The investigator must give reasons for the extent
and duration of the trials and the dosages chosen .
       If , however , having regard in particular to the directions for use
of the medicinal product , the responsible investigator sees fit not to
carry out this examination he must give adequate reasons for his decision .
       Repeated-dose toxicity tests must be carried out on two species of
mammals one of which must be a non-rodent . Wherever it is feasible , the
study with two mammalian speoies shall be replaced by a study with one
species and another animal species for which the medicinal product is in­
tended. The choice of the route(s ) of administration must depend on those
envisaged for therapeutio use and on the possibilities of systemic absorption .
The method and frequency of administration and the length of the trials
shall be clearly stated.
       The maximum dose should be chosen , so as to bring harmful effects
to light . The lower doses will then enable the animal 's tolerance of the
new product to be determined.
       The evaluation of the toxic effects shall be based on observation of
behaviour, growth , blood picture and physiological tests , especially those
relating to the exoretory organs , and also on autopsy reports and accompanying
histological data. The choice and range of each group of tests will depend
on the species of animal used and the state of scientific knowledge at the
time .
 ---pagebreak---                                      21 a
      In the case of new combinations of known substances that have been
investigated in accordance with the provisions of this Directive , the
long–term tests may, except where acute and subacute toxicity tests have
demonstrated potentiation or novel toxic effects , be suitably modified by
the investigator who shall submit his reasons for such modifications#
Substances that have been shown to be safe by wide usagg "; over at least
three years in clinical treatment of human beings , and by the result of
controlled trials shall be treated in the same way as known substances which
have already been investigated in accordance with these standards and
protocols ,
         •xoipient Heed for the first tine in the pbazmoettiQal field < shall be
treated like an active ingredient ,
3 . Tolerance in the intended species of aninal
      This study must be carried out with all animal species for which the
medicinal product is intended . Its purpose is to carry out in all the
animal species for which the medicinal product is intended local and
general tolerance assays to establish the maximum does tolerated and the
olinical symptoms of intolerance using the recommended route or routes , in so far as
 ---pagebreak---                                     - 22 -
it is possible to attain this aim by increasing the therapeutic dose . The
report on the trials must contain as many details as possible on the expected
pharmacological effects and the adverse side-effects $ the latter must be
assessed with due regard to the fact that the experimental animals may be
of very high value .
       The medicinal product shall be administered via the routes likely to
produce the appearance of the pharmacological effects sought .
       Where the trials must be carried out with animals of high unit price
the sequential method may be used .
       This method consists in calculating a non-lethal theoretical dose for
       the animal concerned on the basis of the pharmacologically effective
       doses determined during the experimental trials with the medicinal
       product , bearing in mind the maximum tolerated doses observed during
       the single-dose toxicity study , in accordance with point B.l . This
       dose shsll then1 ba ^dminieterdd to an animal which shall be watched
       very carefully in order to obtain as much information as possible
       regarding the effects of the medicinal product . If the animal presents
       no symptoms of intolerance the test shall be recommenced with another
       animal using a higher dose the strength of which shall be left to the
       investigator 's discretion . If the animal easily tolerates this new
       dose the test shall be continued with a yet higher dose . The dose
       which must not be exceeded will be found when symptoms of toxicity
       appear . If the animal dies , the test shall be recommenced with a
       lower dose and so on . In every case the aim is to determine a single
       dosage which enables a favourable pharmacological effect to be obtained
       without harming the animal .
       Any exoipient employed for the first time in the pharmaceutical field
       shall be treated as an active substance .
                                                                        /.
 ---pagebreak---                                     - 23 -
4 . Foetal t exi cit.y
        This study consists in examining the toxic and abortifacient effects
observed in the progeny when the medicinal product under investigation is
also intended to be administered to the female during pregnancy. The tests
 in question may "be carried out as part of the clinical trials .
 5 . Examination of reproductive function
        If the results of the clinical trials reveal anything suggesting
impairment of male or female reproductive function or harmful effects on
progeny , the reproductive function must "be investigated by appropriate
tests .
                       I
C. Study of pharmacological properties
1 . Pharmacodynamics
        Pharmacodynamics means the study of the variations caused by the
medicinal product in the functions of the organism , irrespective of whether
these functions are normal or experimentally modified.
        This study must follow two distinct lines of approach .
        First , the actions on which the recommended application in practice
is based shall be adequately described . The results shall be expressed in
quantitative terms ( dose-effect curves , time-effect curves etc .) and ,
wherever possible , to comparison with a product whose activity is well
known . Where a higher therapeutic coefficient is claimed for a product ,
the difference shall be demonstrated by reference to the confidence limits .
        Secondly , the investigator shall give a general pharmacological
assessment of the substance , referring in particular to the possibility
of side-effects . In general , the main functions of the physiological
systems should be investigated ; the more closely the doses liable to produce
 side effects approximate to those producing the therapeutio effects for which
the product is being proposed , the more thorough this investigation must be .
                                                                          ./•
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        The experimental techniques , unless they are standard procedures ,
must be described in such detail as to allow them to be reproduced, and
the investigator must establish their heuristic value . The experimental
results shall be set out clearly and for oertain types of tests their
statistical significance shall be quoted.
        Unless good reasons are given to the oontrary , any quantitative
modification of effects resulting from repeated administration of the doses
shall also be investigated.
        Medicinal associations may result either from pharmacological premisses
or from clinical indications . In the first case , the pharmacodynamic study
shall demonstrate those interactions which might make the association itself
recommendable in clinical use . In the second case , where scientific justi­
fication for the medicinal association is sought through clinical experiment­
ation , the investigation must determine whether the effects expected from
the association can be demonstrated in animals , and at least the importance
of any side-effects shall be investigated. If an association includes a
new active substance , the latter must previously have been studied in depth.
2 . Pharmacokinetics
        Pharmacokinetics means the study of the fate of medicinal products
within the organism , and covers the study of the absorption , distribution ,
biotransformation ( or metabolism) and elimination of the products .
        The study of these different phases may be carried out by means of
physical , chemical or biological methods and by observation of the actual
pharmacodynamic activity of the medicine .
        Data concerning distribution find elimination shall be necessary in
respect of chemotherapeutic products ( antibiotics , etc.) and products whose
use depends on their non-pharmacjrdynamio effects , and in all cases where
such data are indispensable to determine the dosage for animals .
                                                                        /•
 ---pagebreak---                                         - 25 -
          In the case of new associations of known substances which ha*, been
   invested in accordance with the provision, of this Directive, pharmaco.
  kinetic studies .hall not be retired if the toxicity tests and clinical
    rials justify their emission. The same applies to substances that have
  been shown to bo effective and safe by very wide usage over a period of at
  least three years in human or animal therapy and by controlled trials
 D. Study of residues
           For the implementation of this Directive "residues' shall mean all
   active ingredients or metabolites thereof which remain jln meats or other
   food produced from the animal to which the medicinal product in question
   has been administered in accordance with the recommended directions for use .
           The purpose of studying residues is to determine whether , and if so ,
   under what conditions and to what extent , residues persist in food produced
   from treated animals , and "Eo ascertain -the waiting periods to be adhered to
   in order to obviate any hazard to human health arid/or-sny- drawbacks for -the ,
   industrial processing of food.
           Assessment- of the hazard due to residues entails ascertaining the
   presence of residues, if anyt and the investigation of the effects of these^
   r^rddues in the treat~"3nt .of animals under normal conditi ™*«? of use . "
1.        in-V    : ->T r-TMu.cs ;
        The determination of residues shall be carried out with . due regard
for the results of the pharmacokinetic tests . At varying times after the
test animal.-'has received the final dose of the medicinal product the quantities
of residues present shall be determined by appropriate physical , chemical
or biological methods ; the technical procedures and the reliability and
sensitivity of the methods employed must be specified. The results must be
checked as far as possible , and at the least , by sampling., in. the . sick
animals for v:hich the medicinal product is recommended.
                                                                          ./■
 ---pagebreak---                                       - 26
 2 . Invest ip;ation of the effects of residues
 a) ^dHsioic ( several months ) toxicity of orally administered residues .
          The study of the chronic ( several months ) toxicity of orally ad­
ministered residues shall he performed differently according to whether it
 is a medicinal product that is eliminated without transformation or one
that is metabolized. In the first case the researcher can work directly
 on the medicinal product . In the second case he must work similarly on the
principal metabolites which are found chiefly in food. If the metabolites
 cannot be isolated or synthesized , recourse shall be hod to the study of
 "relayed toxicity" which consists of operating with tissues in which the
greatest quantity of residues has been traced or with products from trcatsd
animals .
        ; The trials must be carried out , using the oral route , in two mammalian
species one of which must be non-rodent . The usual duration of the trials
shall be 3-6 months . If one works directly on the medicinal product or a
                                                             i
metabolite , the doses must be fixed with due regard for the residues actually
present and must be selected in such a way that the highest dose causes
harmful effects to appear as far as possible , while the lower doses then
enable the limit of tolerance in animals to be found. If the study of
"relayed toxicity" is adopted , the upward gradation of the doses is limited
by the quantity of residues actually present .
                                                                        *
          The evaluation of the toxic effects shall bo b~Ee& on rbncrvr.tion of
behaviour , growth , blood picture and physiological tests , especially those
relating to the excretory organs , and also on autopsy reports and accompanying
histological data. The choice and range of each group of tests will depend
on the species of animal used and the state of scientific knowledge at tho
time .
b ) Other effects of orally administered residues
         5he effects of residues on reproductive functions must be tested in
rodents .
 ---pagebreak---                                          - 27 -
          Tests to reveal carcinogenic effects are indispensable :
 1 . in respect of subsrt^cea-faaving, a close chemical analogy with known
     carcinogenic or cocarcinogenic compounds 3
2 . in respect of substaEflXB orhich have given rise to suspicious changes during
     the repea.ted-dose toxicity study .
          Tests to reveal teratogenic effects are indispensable :
1 . in respect of ettfeetaaawwi . basringa close chemical analogy with known
     teratogenic products j
2 . in respect of substances which have given rise to eSiapici OUB -ciyingea DURING the studj
     of effects on the reproductive functions .
         The stud;'- of teratogenic effects shall be carried out with at least
two animal species : a breed of rabbit sensitive to known teratogenic substances ,
and rats or mice ( specifying the strain ). The details of the test (number of
animals , amounts administered and criteria for evaluation of results ) shall
depend on the state of scientific knowledge at the time when the application
is lodged , and the level of statistical significance that the results must
attain .
           Furthermore , the study of mutagenic effects and allergic phenomena
is also desirable .
         Tests on the origination of resistant pathogenic germs are necessary
in the case of residues of the medicinal products used to prevent or treat
contagious diseases in Llan or animals .              ''
c ) Disadvantages for the industrial processing of food
          In certain cases it may be necessary to carry out tests to determine
whether residues constitute disadvantages for technological procedures in the
industrial processing of food.
 ---pagebreak---                                     - 28 -
        The study of the effects of residues in accordance vxith points a )
to c ) shall not he required if it has been established that the medicinal
product has been rapidly and completely    eliminated or if it is only used
occasionally. In such cases the waiting period shall be determined in such
a way that measurable residues are not included in the food.
E. Medicinal
           ÎM. products for topical use
        Where i medicinal product is intended for topical use , systemic
absorption must be investigated in the intended species of animal . If it
is proved that Systemic absorption is negligible , the repeated-dose toxicity
tests ,the foetalVtoxicity tests and the studies of reproductive function
referred to at pau.nts B.2 , B.4 and B.5 may be omitted,
        Ifithe medicinal product is absorbed systemically in a significant
quantity from the standpoint of view of residues or from that of pharmaco-
dynamics ( concentration ) or if such systemic absorption has to be expected
in the case of accidental oral ingestion of the medicinal product by the
animal , the mediciital product must be investigated in accordance with the
requirements of goijits B to D.
        In all casesl tests of local tolerance after repeated administration
shall be carried ova and shall include histological examinations . Where a
medicinal product wkich is not systemically absorbed may enter a food product
obtained from the treated animal ( mammary implants , etc .), the assay of
residues in accordeftoe with point D shall be carried out each time .
        Chapter II : Presentation of particulars and documents
        As in any scientific work , the dossier of toxicological and pharma­
cological tests shall include the following :
                               /
a) an introduction defining the subject , accompanied by any useful biblio­
   graphical references, particularly where the medicine has been used on
   human beings .
 ---pagebreak---                                    - 29 -
t>) a detailed experimental protocol giving the reasons for any omission of
    certain tests listed above , a description of the methods , apparatus and
    materials used , details of the species , "breed or strain of animals ,
    where they were obtained , their number and the conditions under which
    they were housed and fed , stating , inter alia , whether they were specific
    pathogen- free ( SPP) or not \
c ) all the important results obtained, whether favourable or unfavourable .
    The original data should be described in sufficient detail to allow the
    results to be critically evaluated independently of their interpretation
    by the author# By way of explanation and illustration , the results may
    be accompanied by reproductions of kymograms , photomicrographs , etc . 5
d ) a statistical analysis of the results , where such is called for by the
    test programme , and variance within the data 5
e ) an objective discussion of the results obtained, leasing to conclusions
    on the torcicological and pharmacological properties of the substance ,
    on its safety margins in the intended animal and its possible side-effects ,
    on its fields of application , on its active dose levels and any possible
    incompatibilities 5
f ) information showing whether the components of the medicinal product are
    used as medicinal products in humcn therapy ; if this is so , a report
    should be made on all the effects observed ( including side-effects ) in
    Han and on their cause , where appropriate in the light of trial results
    or bibliographical documents } where components of the medicinal product
    are themselves not used as medicinal products in human therapy the
    reasons should be stated ?
g ) a detailed description and a thorough discussion of the results of the
    study on the presence of residues in food and an assessment of the hazards
    they constitute for Man. Account should be taken of all the factors which
    may be of importance , particularly with regard to customary diet and levels
    of contamination by foreign matter present in the environment . In the
    case of each recommended use , this description shall be followed by pro­
    posals concerning the waiting periods which , allowing for an adequate
                                                                              /.
 ---pagebreak---                                      - 30 -
    safety margin , must be so established as to ensure that no farther
    residue remains in food or , if this is impossible , to ensure that any
    danger to I lan is eliminated by applying internationally recognized
    assessment criteria ( dose devoid of effect in animals , acceptable daily
    dose , safety margin of..l : 100 or       1 : 100 according to available
    information , etc. );
h ) all information necessary to acquaint the clinician as fully as possible
    with the utility of the proposed product . The discussion shall be
    supplemented by suggestions as to possible treatment for acute toxic
    reactions in animals to which the product is to be administered and
    for side-effects ,
i ) a summary together with preoise bibliographical references .
                                                                          /.
 ---pagebreak---                                      Part 3
CLUÏICAL TRIALS
        The particulars and documents which must accompany applications for
marketing authorizations puraaant to Article 4 » point 10 , second paragraph ,
of Council Directive                   of                shall toe submitted in
accordance with the provisions of Chapters I and II below.
                              Chapifer I : Conduct of trials
        The purpose of clinical trials is to demonstrate or to ascertain the
therapeutic effect of the medicinal product , to specify its indications and
contrar-indi cat ions according to species , its directions for use , any side-
effects it may have and its harmlessness under normal conditions of use .
        Clinical trials must be preceded by adequate pharmacological and
toxicity tests carried out in accordance with the provisions of this
Directive and, where they are practicable , by tests carried out preferably
on the one or more animal species for which the medicinal product is intended.
The investigator must acquaint himself with the conclusions of these
preliminary trials .
        As far as possible , clinical trials must be carried out with control
animals ( controlled clinical trials )? if it is economically justifiable , the
therapeutic effect obtained should be compared both with a placebo and with
absence of treatment and/or with the effect of a medioinal product of known
therapeutic value that has alreacly been used. All the results obtained ,
whether positive or negative , must be reported.
        The methods used to make the diagnosis mast be specified. The results
must be set out by making use of quantitative criteria or criteria represented
by symbols ( crosses , etc.).
                                                                           /.
 ---pagebreak--- k ■                                          * 32 -
\
f
                                Chapter II : Particulars and documents
                Particulars concerning clinical trials must be sufficiently detailed
       to enable an objective judgement to be made .
       1 . Records of clinical observations
                All the particulars must be supplied by each of the investigators on
       individual record-sheets of clinical observations in the ease of collective
       treatment .
                The particulars supplied shall be classified as follows :
    .. a ) name , address , function and university qualifications of investigator;
       b ) place and date of treatment } name and address of owner of the animals ;
       c ) in the case of individual treatment and collective treatment , if the
           latter has tjeen given , full identification of the trial animals , names
           or registered numbers , species , breeds or strains , age , weight , sex
           ( in the case of females , specify whether pregnant or in milk and, in
           the case of birds , in lay, etc.)}
       d) method, of rearing and feeding, stating the nature and quantity of any
           additives contained in the feed }
       e ) case history ( as full as possible )} occurrence and course of any inter-
           current diseases }
       f) diagnosis and means used to make it ;
       g ) symptoms and severity of the disease , if possible giving criteria represen–
       1 ted by symbols ( crosses , etc.);
       h) dosage of the medicinal product , method, route and frequency of administra­
           tion and precautions , if any, taken during administration ( duration of
           injection , etc.)}
       i ) duration of treatment and period of subsequent observation }
 ---pagebreak---                                     - 33 -
j ) all details concerning medicinal products ( other than that "being assayed)
     which have been administered during the period of examination , either
     prior to or concurrently with the test product and , in the latter case ,
     details of the interactions observed ;
k) all results of the clinical trials ( including unfavourable or negative
     results ) with a full statement of the clinical observations and the
     results of the objective tests of activity ( laboratory analyses , physio­
     logical tests ), required to evaluate the application ; the techniques
     used must be specified , and the significance of any variations in the
     results explained ( for example , variance in method , variance between
   , individuals or the effects of the medication ); demonstration of the
     pharmacodynamic effect in animals shall not alone suffice to justify
     conclusions concerning any therapeutio effect ;
l ) all particulars of the observed side-effects , whether harmful or not ,
     and of any measures taken in consequence ; relation of cause and effect must
     be investigated with the same care normally accorded to identifying a
     therapeutic effect ;
m) effect on animals 1 performances ( egg–laying , milk production and reproduc­
     tive function );
n ) an opinion concerning each individual case or , where several series of
     collective treatment are concerned , an opinion on each collective case .
         Omission of one or more of items a ) to n ) must be explained.
         When , in respect of particular therapeutic indications , the applicant
can show that he is unable to provide comprehensive data on therapeutic
effect because :
a ) the indications for which the medicinal product in question is intended
     are encountered so rarely that the applicant cannot reasonably be
     expected to provide comprehensive evidence ;
b ) in the present state of scientific knowledge , comprehensive information
     cannot be provided ,
 ---pagebreak---                                     - 34
marketing authorization may be granted subject to the following conditions :
a ) the medicinal product in question shall "be supplied on veterinary prescrip­
    tion only and shall , in certain cases , "be administered only under strict
    veterinary supervision ;
b ) the package insert and any other information shall draw the attention of
    the veterinary practitioner to the fact that , in certain specified respects ,
    the particulars available concerning the medicinal product in question
    axe as yet inadequate .
         The person responsible for placing the veterinary medicinal product
on the market shall make all necessary arrangements to ensure that the
original documents , which formed the basis of the data supplied , are kept
for at least five years as from the date of transmission of the dossier to
the competent authority .
2 . Sùmmary and conclusions
         The clinical observations referred to in paragraph 1 above shall be
summarised in a synopsis of the trials and their results , indicating:
a) the number of animals treated either individually or collectively, with a
    breakdown according to species , breed or strain , age and sex ;
b ) the number of animals withdrawn prematurely from the trials and the reasons
    for such withdrawal ?
c ) in the case of control animals , whether they have :
    – received no treatment ;
    - received a placebos
    – received another medicinal product of known effect j
d) the frequency of observed side–effects ;
                                                                         /.
 ---pagebreak---                                       - 35 -
e ) details concerning test animals which may he at increased risk owing to
    their age , their mode of rearing or feeding, or the purpose for which
    they are intended , or animals whose physiological or pathological condition
    requires special consideration ;
f^ a statistical evaluation of the results , when this is entailed "by the
    programming of the trials and the variability of the factors involved.
        Finally , the investigator shall draw general conclusions from the
experimental evidence , expressing his opinion on the fcarsleeenese -cf the no&icinr.l
product , under normal conditions of use , its therapeutic effect and any use­
ful information relating to indications and contrar-indi cat ions , dosage and
average duration of treatment and, where appropriate , any interactions
observed with other medicinal products or feed additives as well as any
special precautions to be taken during treatment and the clinical symptoms
of overdosage .
                                 . .. 000OOO000 ...