CELEX: 51999PC0315
Language: en
Date: 1999-06-28
Title: Proposal for a European Parliament and Council Directive on the Community code relating to medicinal products for human use - (codified version)

COMMISSION OF THE EUROPEAN COMMUNITIES
                                           Brussels, 28.06.1999
                                           COM(1999)315 final
                                           99/0134 (COD)
                        Proposal for a
EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE
  on the Community code relating to medicinal products for human use
                         (codified version)
              (presented by the Commission)
 ---pagebreak---  ---pagebreak---                                                      EXPLANATORY MEMORANDUM
I. In the context of apeople's Europe, the Commission attaches great importance to simplifying and clarifying Community
   law so as to make it clearer and more accessible to the ordinary citizen, thus giving him new opportunities and the chance
   t~ make use of the specific rights it gives him.
   This aim cannot be achieved so long as numerous provisions that have been amended several times, often quite
   substantially, remain scattered, so that they must be sought partly in the original instrument and partly in later amending
   ones. Considerable research work, comparing many· different instruments, is thus needed to identify the current rules.
   For this reason a codification of rules that have frequently been amended is also essential if Community law is to be clear
   and transparent.
2. On 1 April 1987 the Commission therefore decided to instruct its stall· that all legislative measures should be codified
   after no more than ten amendments, stressing that this was a minimum requirement and that departments should
   endeavour to condify at even shorter intervals the texts for which they were responsible, to ensure that the Community
   rules were clear and readily understandable.
3. The Conclusions of the Presider:tcY of the Edinourgh European Council (December J992) confinned this, stressing the
   importance of legislative codification as it offers certainty as to the law applicable to a given matter at a given time.
   It must be undertaken in full compliance with the normal Community legislative procedure.
   Given that no changes of substance may be made to the instruments affected by legislative codification, Parliament, the
   Council and the Commission have agreed, by an interinstitutional agreement dated 20 December 1994, that an
   accelerated procedure may be used for the fast-track adoption of codification instruments.
4. The purpose of this proposal I for legislative codification of Council Dir~ctives 65/65/EEC of 26 January 1965 on the
   approximation of provisions laid down by law, regulation or administrative · action relating to medicinal products;
    75/318/EEC of 20 May 1975 on the approximation of the laws of Member States relating to analytical, pharmaco-
   toxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products; 75/319/EEC
   of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to
   proprietary medicinal products; 89/342/EEC of 3 May 1989 extending the scope of Directives 65/65/EEC and
    75/319/EEC and laying down additional provisions for immunological medicinal products consisting of vaccines, toxins
    or serums and allergens; 89/343/EEC of 3 May 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC and
    laying down additional provisions for radiophannaceuticals; 89/381/EEC of 14 June 1989 extending the scope of
    Directives 65/65/EEC and 75/319/EEC on the approximation of provisions laid down by law, regulation or
    administrative action relating to medicinal products and laying down special provisions for proprietary medicinal
    products derived from human blood or human plasma; 92/25/EEC of 31 March 1992 on the wholesale distribution of
    medicinal products for human use; 92/26/EEC of 31 March 1992 concerning the classification for the supply of
    medicinal products for human use; 92/27/EEC of 31 March 1992 on the labelling of medicinal products for human use
    and on package leaflets; 92/28/EEC of 31 March 1992 on the advertising of medicinal products for human use; and
    92/73/EEC of22 September 1992 widening the scope of Directives 65/65/EEC and 75/319/EEC on the approximation of
   provisions laid down by law, regulation or administrative action relating to medicinal products and laying down
   additional provisions on. homeopathic medicinal products, prepared ~y the Legal Service in conjunction with the
   Directorate-General Ill, is to undertake official codification of this type. The new directive will supersede the various
   directives incorporated in it2, their content is fully preserved, and they are brought together with only such formal
    amendments as are required by the codification exercise itself.
4a In order to point out the satisfactory application of the codification of the Directive mentioned above, in order to take
     into account the fact that since the last Directive cited in point 4, the European Agency for the Evaluation of Medicinal
     Products has been established by Council Regulation (EEC) 2309/9~ of22 July 1993.
     In the same manner, in order to point out that this codification proposal concerning medicinal products for human use
     was created in parallel with the codification proposal for Directives relating to veterinary medicinal products.
      Entered in the legislative programme for 1998.
2     See Annex 11, Part A of this Proposal.
                                                                  2
 ---pagebreak--- 5. This legislative codification proposal was drawn up on the basis of a preliminary consolidation, in all the official
   languages. The. instruments ~ending it, carried out by the Office for Official Publications of the European
   Communities, by means of the data-proeessing system referred to in the conclusions of the European Council meeting at
   Edinburgh. Although the articles have been given new numbers, the old numbering has been retained in the margin for
   ease of reference; the correlation between the old and new numbers is shown in a table set out in Annex Ill of the
   consolidated Directive.
                                                          3
 ---pagebreak---                                                                       Proposal for a
                           EUROPEAN PARLIAMENT AND COUNCIL DIRECTIVE .••/ .../EC
                               on the Community code relating to medicinal products for human use
THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE EUROPEAN
 UNION,
 Having regard to the Treaty establishing the European Community, and in
 particular Article 95 thereof,
Having regard to the proposal from the Commission;
Having regard to the opinion of the Economic and Social Committee 1
Acting in accordance with the procedure laid down in Article 251 of the Treaty2,
( 1) Whereas Council Directive 65/65/EEC of 26 January 1965 on the
     approximation of provisions laid down by law, regulation or administrative
     action relating to medicinal products3, .Council Directive 75/318/EEC of
     20 May 1975 on the approximation of the laws of Member States relating
     to analytical, pharmaco-toxicological and clinical standards and protocols
     in r~spect of the testing of proprietary medicinal products4,
     Council Directive 75/319/EEC of 20 May 1975 on the approximation of
     provisions laid down by law' regulation or administrative action relating
     to proprietary medicinal productsS, Council Directive 89/342/EEC of
     3 May 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC
     and laying down additional provisions for immunological medicinal
     products consisting of vaccines, toxins or serums and allergens6,
     Council Directive 89/343/EEC of 3 May 1989 extending the scope of
     Directives 65/65/EEC and
     OJC
2
3    OJ 22, 9.2.1965, p. 369/65. Directive as last amended by Directive 93/39/EEC (OJ L 214, 24.8.1993, p. 22).
4    OJ L 147, 9.6.1975, p. I. Directive as last amended by Directive 93/39/EEC.
5    OJ L, 147, 9.6.1975, p. 13. Directive as last amended by Directive 93/39/EEC.
6    OJ L 142, 25.5.1989, p. 14.
                                                                              4
 ---pagebreak---      75/319/EEC             and laying   down      additional    provisions      for
     radiophannaceuticals 1, Council Directive 89/381/EEC of 14 June 1989
     extending the scope of Directives 65/65/EEC and 75/319/EEC on the
     approximation of provisions laid down by law, regulation or administrative
     action relating to medicinal products and laying down special provisions for
     proprietary medicinal products derived from human blood or human plasma2,
     Council Directive 92125/EEC of 31                 March     1992 on the
     wholesale distribution of medicinal products for human usel,
     Council Directive 92/26/EEC of 31 March t 992 concerning the
     classification for the supply of medicinal products for human usc4 ,
   · Council Directive 92/27/EEC of 31 March 1992 on the labelling of
     medicinal products for human use and on package leafletsS,
     Council Directive 92128/EEC of 3 f· March 1992 on the advertising of
     medicinal products for human use6, Council Directive 92/73/EEC of
     22 September 1992 widening the scope of Directives 65/65/EEC and
     75/319/EEC on the approximation of provisions laid down by law, regulation
     or administrative action relating to medicinal products and laying down
     additional provisions on homeopathic medicinal products7 have been
     frequently and substantially amended; whereas, in the interests of clarity and
     rationality, the said Directives should therefore be codified by assembling
     them in a single text;
(2) Whereas the essential aim of any rules governing the production, distribution    1. 89/341/EEC
     and use of medicinal products must be to safeguard public health;
(3) Whereas, however, this objective must be attained by means which will not        2. 65/65/EEC
     hinder the development of the pharmaceutical industry or trade in medicinal
     products within the Community;
I   OJ L 142, 2S.S.J989, p. 16.
2   OJ L 181, 21.6.1989, p. 44.
3   OJ L Jl3, 30.4.1992, p. I.
4   01 L 113, 30.4.1992, p. S.
s   OJ L 113, 30.4.1992, p. &.
6   OJ L 113, 30.4.1992, p. 13.
7   OJ L 297, 13.10.1992, p. 8.
                                                         5
 ---pagebreak--- (4) Whereas trade in medicinal products within the Community is hindered by         3. 65/65/EEC
     disparities between certain r:-ational provisions, in particular between           (adapted)
     provisions relating to medicinal products (excluding substances or
     combinations of substances which are foods, animal feeding-stuffs or toilet
     preparations); and whereas such disparities directly affect the functioning of
     the internal market;
(5) Whereas such hindrances must accordingly be removed; whereas this entails       4. 65/65/EEC
     approximation of the relevant provisions;
(6) Whereas in order to reduce the disparities which remain, rules should be laid   2. 75/319/EEC
     down on the control of medicinal products and the duties incumbent upon the       (adapted)
     Member States' competent- authorities should be specified with a view to
     ensuring compliance with legal requirements;
(7) Whereas the concepts of harmfulness and therapeutic efficacy can only be        7. 75/318/EEC
     examined in relation to each other and have only a relative significance          (adapted)
     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 marketing authorization for a medicinal
     product demonstrate that potential risks are outweighed by the therapeutic
     efficacy of the product;
(8) Whereas standards and protocols for the performance of tests and trials on      3. 75/318/EEC
     medicinal products are an effective means of control of these products and        (ad~pted)
     hence of protecting public health and can facilitate the movement of these
     products by laying down uniform rules applicable to tests and trials, the
     compilation of dossiers and the examination of applications;
(9) Whereas experience has shown that it is advisable to stipulate more precisely   2. 87/21/EEC
     the cases in which the results of toxicological and. pharmacological tests or     (adapted)
     clinical trials do not have to be provided with a view to obtaining
     authorization for a medicinal product which is essentially similar to an
     authorized product, w~ile ensuring that innovative firms are not placed at a
     disadvantage;
                                                        6
 ---pagebreak--- ( 10) Whereas, however, there are reasons of public policy for not conducting                                        4.  87/21/EEC
      repetitive tests on humans or animals without over-riding cause;
(ll)Whereas the adoption of the same standards and protocols by all the Member                                       4.  75/318/EEC
      States will enable the competent authorities to arrive at their decisions on the
      basis of uniform tests and by reference to uniform criteria and will therefore
      help to avoid differences in evaluation;
(12)Whereas, with the exception of those medicinal products which are subject to                                     4. 93/39/EEC
      the centralized Community authorization procedure established by Council                                          (adapted)
      Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community
      procedures for the authorization and supervision of medicinal products for
      human and veterinary use and establishing a European Agency for the
      Evaluation of Medicinal Products 1 a marketing authorization for a medicinal
      product granted by a competent authority in one Member State ought to be
      recognized by the competent authorities of the other Member States unless
     there are serious grounds for supposing that the authorization of the
      medicinal product concerned may present a risk to public health; whereas,· in
      the event of a disagreement between Member States about the quality, the
     safety or the efficacy of a medicinal product, a scientific evaluation of the
      matter should be undertaken according to a Community standard, leading to a
     single decision on the area of disagreement binding on the Member States
     concerned; whereas this decision should be adopted by a rapid procedure
     ensuring close cooperation between the Commission and the Member States;
( 13) Whereas, for this purpose, a Committee for Proprietary Medicinal Products                                      4. 75/319/EEC
     should be set up attached to the European Agency for the Evaluation of                                             (adapted)
     Medicinal Products established in the abovementioned Regulation (EEC)
     No 2309/93;
(14)Whereas this Directive represents an important step towards achievement of                                       5. 75/319/EEC
     the objective of the .free movement of medicinal products; whereas further                                         (adapted)
     measures may· abolish any remaining barriers to the free movement of
     proprietary medicinal products will be necessary in the light of experience
     gained, particularly in the abovementioned Committee for Proprietary
     Medicinal Products;
(15) Whereas in order better to protect public health and avoid any unnecessary                                      5. 93/39/EEC
     duplication of effort during the examination of application for a marketing                                        (adapted)
     authorization for medicinal products, Member States should systematically
     prepare assessment reports in respect of each medicinal product which is
     authorized by them, and exchange the reports upon request; whereas,
     furthermore, a Member State should be able to suspend the examination of an
     application for authorization to place a medicinal product on the market
     which is currently under active consideration in another Member State with a
     view to recognizing the decision reached by the latter Member State;
    OJ L214, 24.8.1993, p. I; Regulation as amended by Commission Regulation (EC) No 649198 (OJ L 88, 24.3.1998, p. 7).
                                                                        7
 ---pagebreak---  (16)Whereas following the establishment of the internal market, specific controls                                         6.         93/39/EEC
       to guarantee the quality of medicinal products imported from third countries
       can be waived only if appropriate arrangements have been made by the
       Community to ensure that .the necessary controls are carried out in the
       exporting country;
 (17)Whereas it is necessary to adopt specific provisions for immunological                                                8.         75/319/EEC
       medicinal products, homeopathic medicinal products, radiopharmaceuticals,                                                      (adapted)
       and medicinal products based on human blood or human plasma;
 (18)Whereas any rules governing radiopharmaceuticals must take into account                                               7.         89/343/EEC
      the provisions of Council Directive 84/466/Euratom of 3 September 1984                                                          (adapted)
       laying down basic measures for the radiation protection of persons
       undergoing medical examination or treatment 1; whereas account should also
       be taken of Council Directive 80/836/Euratom of 15 July 1980 amending the
       Directives laying down the basic safety standards for the health protection of
      the general public and workers against the dangers of ionizing radiation2, the
       objective of which is to prevent the exposure of workers or patients to
      excessive or unnecessarily high levels of ionizing radiation, and in particular
      of Article Se thereof, which requires prior authorization for the addition of
       radioactive substances to medicinal products as well as for the importation of
       such medicinal products;
 ( 19) Whereas the Community entirely supports the efforts of the Council of                                               5.         89/381/EEC
      Europe to promote voluntary unpaid blood and plasma donation to attain
      self-sufficiency throughout the Community in the supply of bl~od products,
      and to ensure respect for ethical principles in trade in therapeutic substances
      of human origin;
(20)Whereas the rules designed to guarantee the quality, safety and efficacy of                                            6.         89/381/EEC
      medicinal products derived from human blood or human plasma must be
      applied in the same manner to both public and private establishments, and to
      blood and plasma imported from third countries;
(21) Whereas, having regard to the particular characteristics of these homeopathic                                        10.        92173/EEC
      medicinal products, such as the very low level of active principles they                                                       (adapted)
      contain and the difficulty of applying to them the conventional statistical
      methods relating to clinical trials, it is desirable to provide a special,
      simplified registration procedure for those. homeopathic medicinal products
      which are placed on the market without therapeutic indications in a
      pharmaceutical fonn and dosage which do not present a risk for the patient;
(22) Whereas the anthroposophic medicinal products described in an official                                               4.         92173/EEC
      pharmacopoeia and prepared by a homeopathic method are to be treated, as
      regards registration and marketing authorization, in the same way as
      homeopathic medicinal products;
I    OJ L 265, 5.10.1984, p. I; Directive repealed with effect from 13 May 2000 by Direc;tive 97/43/Euratom (OJ L 180, 9.7.1997, p. 22).
2    OJ L 246, 17.9.1980, p. 1: Directive as amended by Directive 84/467/Euratom (OJ L 265, 5. 10. 1984, p. 4); repealed with effect from 13 May 2000 by
     Directive 96/29/Euratom (OJ L 314, 4.12.1996, p. 20).
                                                                             8
 ---pagebreak--- (23)Whereas it is desirable in the first instance to provide users of these              8.  92173/EEC
     homeopathic medicinal products with a very clear indication of their
     homeopathic character and with sufficient guarantees of their quality and
     safety;
(24)Whereas the rules relating to the manufacture, control and inspection of            9.   92/73/EEC
     homeopathic medicinal products must be harmonized to permit the
     circulation throughout the Community of medicinal products which are safe
     ~nd of good quality;
(25) Whereas the usual rules governing the authorization to market medicinal                92173/EEC
     products should be applied to homeopathic medicinal products placed on the
     market with therapeutic indications or in a fonn which may present risks
     which must be balanced against the desired therapeutic effect; whereas, in
     particular, those Member States which have a homeopathic tradition should
     be able to apply particular rules for the evaluation of the results of tests and
     trials intended to establish the safety and efficacy of these medicinal products
     provided that they notify them to the Commission,
(26)Whereas in order to facilitate the movement of medicinal products and to            6.  75/319/EEC
     prevent the controls carried out in one Member State from being repeated in            (adapted) .
    -another, minimum requirements should be laid down for manufacture and
     imports coming from third countries and for the grant of the authorization
     relating thereto;
(27)Whereas it should be ensured that, in the Member States, the supervision and        7.  75/319/EEC
     control of the manufacture of medicinal products is carried out by a person            (adapted)
     who fulfils minimum conditions of qualification;                                 ·
(28) Whereas, ·before an authorization to market an immunological medicinal             5.  89/342/EEC
· prod.uct or derived from human blood or human plasma can be granted, the                  (adapted)
     manufacturer must demonstrate his ability to attain batch-to-batch                 +
    consistency; whereas before and authorization to market a medicinal product         7.  89/381/EEC
    derived from human blood or human plasma can be granted, the                            (adapted)
    manufacturer must also demonstrate the absence of specific viral
    contamination, to the extent that the state of technology permits;
                                                          9
 ---pagebreak--- (29)Whereas the conditions governing the supply of medicinal products to the            3. 92/26/EEC
     public should be harmonized;                                                          (adapted)
(30)Whereas in this connection persons moving around within the Community               4: 92/26/EEC
     have the right to carry a reasonable quantity of medicinal products lawfully          (adapted)
     obtained for their personal use; whereas it must also be possible for a person
     established in one Member State to receive from another Member State a
     reasonable quantity of medicinal products intended for his personal use;
{3l)Whereas, in addition, by virtue of Regulation (EC) No 2309/93, certain              5. 92/26/EEC
     medicinal products are the subject of a Community marketing authorization;            (adapted)
     whereas, in this context, the classification for the supply of medicinal
     products covered by a Community marketing authorization needs to be
     established; whereas it is therefore important to set the criteria on the basis of
     which Community decisions will be taken;
(32) Whereas it is therefore appropriate, as an initial step, to harmonize the basic    6. 92/26/EEC
     principles applicable to the classification for the supply of medicinal products
   . in the Community or in the Member State concerned, while taking as a
     starting point the principles already established on this subject by the Council
     of Europe as well as the work of harmonization completed within the
     framework of the United Nations, concerning narcotic and psychotropic
     substances;
(33)Whereas the provisions dealing with the classification of medicinal products        7. 92/26/EEC
     for the purpose of supply do not infringe the national social security                (adapted)
     arrangements for reimbursell)ent or payment for medicinal products on
     prescription;
(34)Whereas many operations involving the wholesale distribution of medicinal           2. 92/25/EEC
     products for human use may cover several Member States simultaneously;                (adapted)
(35)Whereas it is necessary to exercise control over the entire chain of                3. 92/25/EEC
     distribution of medicinal products, from their manufacture or import into the
     Community through to supply to the public, so as to guarantee that such
     products are stored, transported and handled in suitable conditions; whereas
     the requirements which must be adopted for this purpose will considerably
     facilitate the withdrawal of defective products from the market and allow
     more effective efforts against counterfeit products;
                                                           10
 ---pagebreak--- .(36) Whereas any person involved in the wholesale distribution of medicinal                               4.  92/25/EEC
      products should be in possession of a special authorization; whereas                                     (adapted)
      pharmacists and persons authorized to supply medicinal products to the
      public, and who confine themselves to this activity, should be exempt from
     obtaining this authorization; whereas it is however necessary, in order to
      control the complete chain of distribution of medicinal products, that
      pharmacists and persons authorized to supply medicinal products to the
      public keep records showing transactions in products received;
(3 7) Whereas authorization must be subject to certain essential conditions and it is                      5. 92/25/EEC
      the responsibility of the Member State concerned to ensure that such
     conditions are met; whereas each Member State must recognize'
     authorizations granted by other Member States;
(38)Whereas certain Member States impose on wholesalers who supply medicinal                               6. 92/25/EEC
     products to pharmacists and on persons authorized to supply medicinal
     products to the public certain public service obligations; whereas those
      Member States must be able to continue to impose those obligations on
     wholesalers established within their territory; whereas they must also be able
     to impose them on wholesalers in other Member States on condition that they
     do not impose any obligation more stringent than those which they impose on
     their own wholesalers and provided that such obligations may be regarded as
     warranted on grounds of public health protection and are proportionate .in
     relation to the objective of such protection;
(39) Whereas rules . should be laid down as to how the labelling and package                               2. 92/27/EEC
     leaflets are to be presented;                                                                         +  (adapted)
                                                                                                           3.
(40)Whereas the provisions governing the information supplied to users should                              5. 92/27/EEC
     provide a high degree of consumer protection, in order that medicinal
     products may be used correctly on the basis of full and comprehensible
     information;
(41) Whereas the marketing of medicinal products whose labelling and package                               6. 92/27/EEC
     leaflets comply with this Directive should not be prohibited or impeded on
     grounds connected with .the labelling or package leaflet;
(42)Whereas this Directive is without prejudice to the application of measures                             I. 92/28/EEC
     adopted pursuant to Council Directive 84/450/EEC of 10 September 1984                                    (adapted)
     relating to the approximation of the laws, regulations and administrative
     provisions ofthe Member States concerning misleading advertisingl;
    OJ L 250, 19.9.1984, p. 17. Directive as amended by Directive 97/55/EC (OJ L 290,23. 10. 1997, p. 18).
                                                                           11
 ---pagebreak--- (43)Whereas all Member States have adopted further specific measures                                         2. 92/28/EEC
     concerning the adve~ising of medicinal products; whereas there are                                         (adapted)
     disparities between these measures; whereas these disparities are likely to
     have an impact on the functioning of the internal market, since advertising
     disseminated in one Member State is likely to have effects in other
     Member States;
(44)Whereas Council Directive 89/552/EEC of 3 October 1989 on the                                            3. 92/28/EEC
     coordination of certain provisions laid down by law, regulation or
     administrative action in Member States concerning the pursuit of television
     broadcasting activities 1 prohibits the television advertising of medicinal
     products which are available only on medical prescription in the
     Member State within whose jurisdiction the television broadcaster is located;
     whereas this principle should be made of general application by extending it
   · to oth~r media;
(45) Whereas advertising to the general public, even of non-prescription                                     4. 92/28/EEC
     medicinal products, could affect public health, were it to be excessive and ill-
     considered; whereas advertising of medicinal products to the general public,
     where it is permitted, ought therefore to satisfy certain essential criteria
     which ought to be defined;
(46) Whereas, furthermore, distribution of samples free of charge to the general                             5. 92/28/EEC
     public for promotional ends must be prohibited;
(47) Whereas the advertising of medicinal products to persons qualified to                                  6.  92/28/EEC
     prescribe or supply them contributes to the information available to such
     persons; whereas, nevertheless, this advertising should be subject to strict
     conditions and- effective monitoring, referring in particular to the work
     carried out within the framework of the Council of Europe;
(48) Whereas advertising of medicinal products should be subject to effective,                              !1. 92/28/EEC
     adequate monitoring; whereas reference in this regard should b~ made to the
     monitoring mechanisms set up by Directive 84/450/EEC;
(49)Whereas medical sales representatives have an important role in the                                      7. 92/28/EEC
     promotion of medicinal products; whereas, therefore, certain obligations
     should be imposed upon them, in particular the obligation to supply the
     person visited with a summary of product characteristics;
(50)Whereas persons qualified to prescribe medicinal products must be able to                               8.  92/28/EEC
     carry out these functions objectively without being influenced by direct or
     indirect financial inducements;
(5I)Whereas it should be possible within certain restrictive conditions to provide                          9.  92/28/EEC
     samples of medicinal products free of charge to persons qualified to prescribe
    'or supply them so that they can familiarize themselves with new products and
     acquire experience in dealing with them;
     OJ L 298, 17.10.1989, p. 23; Directive as amended by Directive 97/36/EC (OJ L 202,30. 7. 1997, p. 60).
                                                                            12
 ---pagebreak--- (52)Whereas persons qualified to prescribe or supply medicinal products must      10. 92/28/EEC
     have access to a neutral, objective source of information about products
     available on the market; whereas it is nevertheless for the Member States to
    take all measures necessary to this end, in the light of their own particular
    situation;
(53)Whereas each undertaking which manufactures or imports medicinal              12. 92/28/EEC
    products should set up a mechanism to ensure that all information supplied
     about a medicinal product conforms with the approved conditions of use;
(54) Whereas it is desirable to regulate and improve the cooperation and exchange 7.  93/39/EEC
    of information between Member States relating to the supervision of               (adapted)
    medicinal products and in particular the monitoring of adverse reactions
    under practical conditions of use through the national pharmacovigilance
    systems;
(55)Whereas the Commission should be empowered to adopt any necessary             8.  75/318/EEC
    changes to Annex I in order to take into account scientific and technical     +   (;ldapted)
     progress;                                                                    6.  89/342/EEC
                                                                                  +   (adapted)
                                                                                  6.  89/343/EEC
                                                                                  +   (adapted)
                                                                                  8.  89/381/EEC
                                                                                      (adapted)
(56)Whereas this Directive is without prejudice to the obligations of the
    Member States concerning the deadlines for transposition set out in Annex 11,
    Part B.
HAVE ADOPTED THIS DIRECTIVE:
                                                        13
 ---pagebreak---                                                     TITLE I
                                                  DEFINITIONS
                                                     Article 1
For the purposes of this Directive, the following tenns shall bear the following     65/65/EEC
meanings:                                                                            Art. I (I) to (3)
                                                                                     (adapted)
1.  Proprietary medicinal product:
    Any ready-prepared medicinal product placed on the market under a special name
   and in a special pack.               ·
2.  Medicinal product:
   Any substance or combination of substances presented for treating or preventing
   disease in human beings.
   Any substance or combination of substances which may be administered to human
    beings with a view to making a medical diagnosis or to restoring, correcting or
    modifying physiological functions in human beings is likewise considered a
    medicinal product.
3. Substance:
   Any matter irrespective of origin which may be:
        human, e.g.
        human blood and human blood products;
        animal, e.g.
        micro-organisms, whole animals, parts of organs, anima_l secretions, toxins,
        extracts, blood products;
        vegetable, e.g.
        micro-organisms, plants, parts of plants, vegetable secretions, extracts;
        chemical, e.g.
        elements, naturally occurring chemical materials and chemical products
        obtained by chemical change or synthesis. ·
                                                       14
 ---pagebreak--- 4. Immunological medicinal product:                                                     89/342/EEC
                                                                                        Art. I (1)
   Any medicinal product consisting of vaccines, toxins, serums or allergen products:   (adapted)
   (a) vaccines, toxins and serums shall cover in particular:                           89/342/EEC
                                                                                        Art. 1 (2), 2nd indent
        (i)   agents used to produce active immunity, such as cholera vaccine, BCG,     +
              polio vaccines, smallpox vaccine;                                         75/319/EEC
                                                                                        Annex
        (ii) agents used to diagnose the state of immunity, including in particular
              tuberculin and tuberculin PPD, toxins for the Schick and Dick Tests,
              brucellin;
        (iii) agents used to produce passive immunity, such as diphtheria antitoxin,
              anti-smallpox globulin, antilymphocytic globulin.
    (b) "allergen product" shall mean any medicinal product which is intended to        89/342/EEC
        identify or induce a specific acquired alteration in the immunological response Art. 1 (2), 1st indent
        to an allergizing agent.                                                        (adapted)
5. Homeopathic medicinal product:                                                       92173/EEC
                                                                                        Art. 1
   Any medicinal product prepared from products, substances or-compositions called      (adapted)
   homeopathic stocks in accordance with a homeopathic manufacturing procedure
   described by the European Pharmacopoeia or, in absence thereof, by the
   pharmacopoeias currently used official~y in the Member States.
   A homeopathic medicinal product may also contain a number of principles.
6. Radiopharmaceutical:                                                                 89/343/EEC
                                                                                        Art. 1 (2)
   Any medicinal product which, when ready for use, contains one or more                (adapted)
   radionuclides (radioactive isotopes) included for a medicinal purpose.
7. Radionuclide generator:
   Any system incorporating a fixed parent radionuclide from which is produced a
   daughter radionuclide which is to be obtained by elution or by any other method and
   used in a radiopharmaceutical.
8. Radionuc/ide kit:
   Any preparation to be reconsitituted or combined with radionuclides in the final
   radiopharmaceutical, usually prior to its administration.
9. Radionuclide precursor:
   Any other radionuclide produced for the radio-labelling of another substance prior
   to administration.
                                                       15
 ---pagebreak---  I 0. Medicinal products derived from human blood or human plasma:                           89/381/EEC
                                                                                             Art. I (I)
      Medicinal products based on blood constitutents which are prepared industrially by     (adapted)
      public or prjvate establishments, such medicinal products including, in particular,
      albumin, coagulating factors and immunoglobulins of human origin.
'11. Adverse reaction: .                                                                     75/319/EEC
                                                                                            Art. 29b
      A reaction which is harmful and unintended and which occurs at doses normally         (as amended by
      used in man for the prophylaxis, diagnosis or treatment. of disease or the            93/39/EEC Art. 3 (3))
      modification of physiological function.
 12. Serious adverse reaction:
      An adverse reaction which is fatal, life-threatening, disabling, incapacitating, or
      which results in or prolongs hospitalization.
 13. Unexpected adverse reaction:
      An adverse reaction which is not mentioned in the summary of product
      characteristics.
 14. Serious unexpected adverse reaction:
      An adverse reaction which is both serious and unexpected.
 15. Wholesale distribution ofmedicinal products:                                           92/25/EEC
                                                                                            Art. 1 (2)
      All activities consisting of procuring, holding, supplying or exporting medicinal
      products, apart from supplying medicinal products to the public; such activities are
      carried out with manufacturers or their depositories, importers, . other wholesale
      distributors or with pharmacists and persons authorized to supply medicinal products·
      to the public in the Member State concerned.
16. Public service obligation:
      The obligation placed on wholesalers to guarantee permanently an adequate range of
      medicinal products to meet the requirements of a specific geographical area and to
      deliver the supplies requested within a very short time over the whole of the area in
      question.                                                                     ·
17. Medicinal Prescription:                                                                 92/26/EEC
                                                                                            Art. J. (2), 2nd sentence
      Any medicinal prescription issued by a professional person qualified to. make such a  (adapted)
      prescription.
                                                          16
 ---pagebreak---  18. Name ofthe medicinal product:                                                         92/27/EEC
                                                                                           Art. 1 (2)
     The name given to a medicinal product, which may be either an invented name or a
     common or scientific name, together with a trade mark or the name of the
     manufacturer; the invented name shall not be liable to confusion with the common
     name.
 19. Common name:
     The international name recommended by the World Health Organization, or, if one
     does not exist, the usual common name .
.20. Strength ofthe medicinal product:
     The content of the active substances expressed quantitatively per dosage unit, per   (adapted)
     unit of volume or weight according to the dosage form.
 21. Immediate packaging:
     The container or other form of packaging immediately in contact with the medicinal
     product.
 22. Outer packaging:
     The packaging into which is placed the immediate packaging.
 23. Labelling:
     Information on the immediate or outer packaging.
 24. Package leaflet:
     A leaflet containing information for the user which accompanies the medicinal
     product.
 25. Agency:                                                                              75/319/EEC
                                                                                          Art. 8 (1)
     The European Agency for the Evaluation of Medicinal Products established by          (as amended by
     Regulation (EEC) No 2309/93.                                                         93/39/EEC Art. 3 (1))
                                                                                          (adapted)
26. Risk to public health:                                                                75/319/EEC
                                                                                          Art. 10 (1)
     All risks with regard to the ·quality, safety and efficacy of the medicinal product. (as amended by
     .          .                                 .
                                                                                          93/39/EEC Art. 3 (1))
                                                                                          (adapted)
                                                            17
 ---pagebreak---                                                        TITLE 11
                                                        SCOPE
                                                        Article 2
    The. provisions of this Directive shall apply to medicinal products for human use          65/65/EEC
    intended to be placed on the market in Member States.                                      Art. 2 (I)
                                                                                               (as amended by
                                                                                               89/341/EEC Art. I (3))
                                                                                               (adapted)
                                                        Article 3
    This Directive shall not apply to:                                                         65/65/EEC
                                                                                               Art. 1 (4) and (5) and
    I.   Any medicinal product prepared in a pharmacy in accordance with a medical             Art. 2 (3), Ist'indent
         prescription for an individual patient (commonly known as the magistral formula);     (as amended by
                                                                                               89/34I/EEC Art. 1 (2)
    2.   Any medicinal product which is prepared in a pharmacy in accordance with the          and (3))
         prescriptions of a pharmacopoeia and is intended to be supplied directly to the       (adapted)
         patients s~rved by the pharmacy in question (commonly known as the official
         formula); .
    3.   Medicinal products intended for research and development trials;                      65/65/EEC
                                                                                               Art. 2 (3), 2nd and 3rd
    4.   Intermediate products      intended for· further processing      by an   authorized   indents
         manufacturer;                                                                         (as amended by
                                                                                               89/341/EEC Art. I (3))
                                                                                               (adapted)
                                                                                                           \\
    5. Any radionuclides in the form of sealed sources;                                        89/343/EEC
                                                                                               Art. I (I) '
                                                                                               (adapted)
    6.   Whole blood, plasma or blood cells of human origin.                                   89/381/EEC
                                                                                             1 Art. 1 (2)
                                                        Article 4
    I. Nothing in this Directive shall in any way derogate from the Community rules for the 89/343/EEC
    radiation protection of persons undergoing medical examination or treatment, or from Art. 1 (3)
    the Community rules laying down the basic safety standards for the health protection of
    the general public and ~orkers against the dangers of ionizing radiation.
                                                            18
(2)
 ---pagebreak--- 2. This Directive shall be without prejudice to Council.Decision 86/346/EEC 1•                  89/381/EEC
                                                                                              1 Art. I (3)
3. The provisions of this Directive shall not affect the powers of the Member States'           65/65/EEC
authorities either as regards the setting of prices for medicinal products or their inclusion   Art. 3, 2nd subparagraph
in the scope of national health insurance schemes, on the basis of health, economic and         (as amended by
social conditions.                                                                              93/39/EEC Art. I (I))
4. This Directive shall not affect the application of national legislation prohibiting or       65/65/EEC
restricting the sale, supply or use · of medicinal products as contraceptives or                Art. 6
abortifacients. The Member States shall communicate the national legislation concerned          (as amended by
to the Commission.                                                                              93/39/EEC Art. I (5))
                                                       Article 5
A Member State may, in accordance with legislation in force and to fulfil special needs,        65/65/EEC
exclude from the provisions of this Directive medicinal products supplied in response to        Art. 2 (4)
a. bona fide unsolicited order, formulated in accordance with the specifications of an          (as amended by
authorized health care professional and for use by his individual patients on his direct        89/341/EEC Art. I (3))
personal responsibility~                                                                       (adapted)
    OJ L 207, 30.7.1986, p. I.
                                                         19
 ---pagebreak---                                                   TITLE Ill
                                      PLACING ON THE MARKET
                                                 Chapter 1
                                         Marketi~g authorization
                                                   Article 6
No medicinal product product may be placed on the market of a Member State unless a .65/65/EEC
marketing authorization has been issued by the competent authorities of that Member Art. 3 (1)
States in accordance with this Directive or an authorization has been granted in (as amended by
accordance with Regulation (EEC) No 2309/93.                                           93/39/EEC Art. 1 ( 1))
                                                                                       (adapted)
                                                   Article 7
A marketing authorization shall not be required for a radiopharmaceutical prepared at  89/343/EEC
the time of use by a person or by an establishment authorized, according to national   Art. 2, 2nd sentence
legislation, to use such medicinal products in an approved health care establishment   (adapted)
exclusively from authorized radionuclide generators, radionuclide kits or radionuclide
precursors in accordance with the manufacturer's instructions.
                                                   Article 8
I. In order to obtain an authorization to place a medicinal product on the market      65/65/EEC
regardless of the procedure established by Regulation (EEC) No 2309/93, an application Art. 4 (1)
shall be made to the competent authority of the Member State concerned.                (adapted)
2. A marketing authorization may only be granted to an applicant ·established in the   65/65/EEC
Community ..                                                                           Art. 4 (2)
                                                                                       (as amended by
                                                                                       93/39/EEC Art. 1 (2))
                                                                                       (adapted)
                                                       20
 ---pagebreak--- 3. The application shall be accompanied by the. following particulars and documents,           65/65/EEC
submitted in accordance with Annex 1:                                                          Art. 4, 3rd paragraph,
                                                                                               points I to 5
(a) Name or corporate name and permanent address of the applicant and, where                   (as amended by
     applicable, of the manufacturer:                                                          89/341/EEC Art. 1 (1))
                                                                                               (adapted)
(b) Name of th~ medicinal product.
                                                                                               +
(c) Qualitative and quantitative particulars of all the constituents of the medicinal
     product in usual tenninology, but excluding empirical chemical formulae, with
     mention ofthe_intemational name 'recommended by the World Health Organization             75/318/EEC
     where such name exists.                                                                   Art. i , 1st paragraph
                                                                                               (adapted)
(d) Description of the manufacturing method.
(e) ·Therapeutic indications, contra-indications and adverse reactions.
(t) Posology, pharmaceutical form, method and route of administration and expected             65/65/EEC
     shelf life.                                                                               Art. 4, 3rd paragraph,
                                                                                               point 6
(g) If applicable, reasons for any precautionary and safety measures to be taken for the (as amended by
     storage of the medicinal product, its administration to patients and for the disposal of 93/39/EEC Art. 1 (3))
     waste products, together with an indication of any potential risks presented by the
     medicinal product for the environment.
(h) Description of the control methods employed by the manufacturer (qualitative and           65/65/EEC
     quantitative analysis of the constituents and Qf the finished product, special tests~     Art. 4, 3rd paragraph,
     e.g. sterility tests, tests for the presence of pyrogenic su.bstances, the presence of    point 7
     heavy metals, stability tests, biological and toxicity tests, controls carried out at an (as amended by
     intermediat~ stage of the manufacturing process).                                         75/319/EEC Art. 35)
                                                                                               (adapted)
(i) Results of: .                                                                             65/65/EEC
                                                                                               Art. 4, 3rd paragraph,
          physico-chemical, biological or microbiological tests,                               point 8.1
                                                                                              ·(as amended by
          toxicological and phartnacological tests,                                            87/21/EEC Art. 1 (1))
          clinical trials.
                                                          21
 ---pagebreak--- (j) A summary, in accordance with Article 11, of the product characteristics, one or      65/65/EEC
     more specimens or mock-ups of the sales presentation of the medicinal product,       Art. 4, 3rd paragraph,
     ~ogether with a package leaflet.                                                     point 9
                                                                                          (as amended by ·
                                                                                          83/570/EEC Art. 1 ( 1)
                                                                                          (c) and 89/341/EEC
                                                                                          Art. I (I))
                                                                                          (adapted)
(k) A document showing that the manufacturer is authorised in his own country to          65/65/EEC
     produce medicinal.products. ·                                                        Art. 4, 3rd paragraph,
                                                                                          point 10
                                                                                          (as amended by
                                                                                          89/341 /EEC Art. 1 ( 1))
(I)   Copies of any authorisation obtained in another Member State or in a third country  65/65/EEC
     to place the medicinal product on the market, together with a list of those Member   Art. 4, 3rd paragraph,
     States in which an application for authorisation submitted in accordance ·with this  point 11
     Directive is under e~amination. Copies of the summary of the product characteristics (as amended by
     proposed by the applicant in accordance with Article 11 or approved by the           93/39/EEC Art. 1 (3))
     competent authorities of the Member State in accordance with Article 21. C~pies of   (adapted)
     the package leaflet proposed. in accordance with Article 59 or approved by the
     competent authorities of the Member State in accor~ce with Article 61. Details of
     any decision tO refuse authorization, whether in the Community or in a third
     country, and the reasons for such a decision.                       ·           ·
     This information shall be updated on a regular basis.
                                                        Article 9
In addition to the requirements set out in Articles 8 and 10 (l ), an application for     89/343/EEC
authorization to market a radionuclide generator shall also contain the following         Art. 3
information and particulars:                                                              (adapted)
     a general description of the system together with a detailed description of the
    .components of the system which may affect the composition or quality of the
     daughter nucleid preparation,                                            ·
     qualitative and quantitative particulars of the eluate or the sublimate.
                                                          22
 ---pagebreak---                                                                        Article 10
 I. In derogation of Article 8 (3) (i), and without prejudice to the law relating to the            65/65/EEC
protection of industrial and commercial property:                                                   Art. 4, 3rd paragraph,
                                                                                                    point 8, 2nd
(a) The applicant shall not be required to provide the results of toxicological and                 subparagraph
     pharmacological tests or the results of clinical trials if he can demonstrate:                 (as amended by
                                                                                                    87/21/EEC Art. 1 (I) and
     (i) either that the medicinal product is essentially similar to a medicinal product            89/341/EEC Art. 1 (l))
           authorized in the country concerned by the application and that the marketing            (adapted).
           authorization holder has consented to the toxicological, pharmacological and
           clinical references contained in the file on the original medicinal product being
           used for the purpose of examining the application in question;
     (ii) or that the constituent or constituents of the medicinal product have a well
           established medicinal use, with recognized efficacy and an acceptable level of
           safety, with a detailed scientific bibliography;
     (iii) or that the proprietary medicinal product is essentially similar to a medicinal
           product which has been· authorized within the Community, in accordance with
           Community provisions in force, for not less than six years and is marketed in
           the Member St:tte for which the application is made; this period shall be
           extended to I 0 years in the case of high-technology medicinal ·products
           having been authorised according to the procedure laid down in Article 2 (5) of
           Council Directive 87/22/EEC 1 ; furthermore, a Member State may also extend
           this period to I0 years by a single Decision covering all the medicinal products
           marketed on its territory where it considers this necessary in the interest of
           public health. Member States are at liberty not to apply the. six-year period
           beyond the date of expiry of a patent protecting the original medicinal product.
           However, where the medicinal product is intended for a different therapeutic use
           from that of the other medicinal products marketed or is to be administered by
           different routes or in different doses, the results of appropriate toxicological and
           pharmacological tests and of approp~iate clinical trials must _be provided.
I OJ LIS, 17.1.1987, p. 38; Directive repealed by ~irective 93/41/EEC (OJ L 214, 24.8.~993, p. 40).
                                                                           23
 ---pagebreak--- (b) In the case of new medicinal products containing known constituents not hitherto         65/65/EEC
     used in combination for the~peutic purposes, the results of toxicological and           Art. 4, 3rd paragraph,
     pharmacological tests and of clinical trials relating, to that combination must be      point 8, 2nd
     provided, but it shall not .be· necessary to provide references relating ·to each       subparagraph
     individual constituent.                                          ·                      (as amended by
                                                                                             87121/EEC Art. 1 (I) and
                                                                                             89/341/EEC Art. I (I))
                                                                                             (adapted)
2. Annex I shall apply by analogy where, pursuant to point (ii) of paragraph I, (a),         75/318/EEC
bibliographic references to published data are submitted.                                    Art. 1, 2nd paragraph
                                                                                             (adapted)
                                                       Article 11
The summary of the product characteristics shall contain the following information:          65/65/EEC
                                                                                             Art. 4a, points I to 5.4,
·1. Name of the medicinal product.                                                           (as amended by
                                                                                             83/570/EEC Art. 1 (2)
2. Qualitative and quantitative composition in terms of the active substances and            and 89/341/EEC ·
     constituents of the excipient, knowledge of which is essential for, proper              Art. I (I))
     administration of the medicinal product; the usual common· name .or chemical            (adapted)
   . descripti.on shall be used.
3.   Pharmaceutical form.
4.   Pharmacological properties and, in so far,as this information is useful for therapeutic
     purposes, pharmacokinetic particulars.
 5. Clinical particulars:
                                                                                             89/342/EEC
     5.1.     ·therapeut~c indications,                                                      Art.3
     5.2.      contra-indications,                                                           (adapted)
     5.3.      adverse reactions (frequency and seriousness),
     5.4.      special precautions for· use and, in the case of immunological medicinal
               products, any special precautions to be taken by persons handling such
               products and administering them to patients, together with any precautions
               to be taken by the patient,                        ·                     ·
     5.5.      use during pregnancy and lactation,
     5.6.      interaction with other medicaments and other forms of interaction,            65/65/EEC
     5.7.      posology and method of administration for adults and, where necessary, for    Art. 4a, points 5.5 to 6.4
               children,                                                                     (as amended by
     5.8.      overdose (symptoms, emergency procedures, antidotes),                         83/570/EEC, Art. 1(2)
     5.9.      special warnings,                                                             and 89/341/EEC,
     ~.10.     effects on ability to drive and to use machines.                              Art. 1(1)
                                                                                             (adapted)
                                                           24
 ---pagebreak--- 6. Pharmaceutical particulars:                                                           65/65/EEC
                                                                                         Art. 4a (I) to (6),
   6.1. major incompatibi~ities,                                                         point6.4
   6.2. shelf life, when necessary after reconstitution of the medicinal product or when (as amended by
        the immediate packaging is opened for the first time,                            83/570/EEC Art. I (2)
   6.3. special precautions for storage,                                                 and 89/341/EEC
   6.4. nature and .contents of the immediate packaging,                                 Art. I (1))
                                                                                         (adapted)
   6.5 special precautions for disposal of unused medicinal products or waste materials 65/65/EEC
        derived from such medicinal products, if appropriate;                            Art. 4a (6), point 6.6
                                                                                         (as amended by
                                                                                         89/341/EEC Art. 1 (4))
                                                                                         (adapted)
7. Name or corporate name and permanent address of the marketing authorization           65/65/EEC
   holder;                                                                               Art. 4a (6), point 6.5
                                                                                         (as amended by
8. For radiopharmaceuticals, fuU details of internal radiation dosimetry;                83/570/EEC Art. 1 (2))
                                                                                         (adapted)
9. For radiopharinaceuticals, additional detailed instructions for extemporaneous        89/343/EEC
   preparation and quality control of such preparation and, where appropriate,           Art. 4
   maximum storage time during which any intermediate preparation such as an eluate      (adapted)
   or the ready-to-use pharmaceutical will conform with its specifications.
                                                        25
 ---pagebreak---                                                        Article 12
1. Member States shall take all appropriate measures to ensure that the documents and        75/319/EEC
particulars listed ifl Article 8 (3) (h) and (i), and Article 10 (1) are drawn up by experts Art. 1
with the necessary technical or professional qualifications before they are submitted to     (adapted)
the competent authorities. These documents and ·particulars shall be signed by the
experts.
2. The duties of the experts according to their respective qualifications shall be:          75/319/EEC
                                                                                             Art. 2
(a) to perfoim tasks falling within their respective disciplines (analysis, pharmacology     (adapted)
     and similar experimental sciences, clinical trials) and to describe objectively the
     results obtained (qualitatively and quantitatively);
                                                               .
(b) to describe their observations in accordance with Annex I, and to state, in particular:
          in the case of the analyst, whether the medicinal product is consistent with the
          declared composition, giving any substantiation of the control methods
          employed by the manufacturer;
        · in the· case of the pharmacologist or the specialist with similar experimental
          competence, the toxicity of the medicinal product and the pharmacological
          properties observed;            ·
          in the case of the clinician, whether he has been able to ascertain effects on
          persons treated with the medicinal product which correspond to the particulars
          given by the applicant in accordance with Articles 8 and ·I 0, whether the patient
          tolerates the medicinal product w.ell, the posology the clinician advises and any
          contra-indications and adverse reactions;
(c) where applicable, .to state the grounds for using the bibliography mentioned in
     point (a)(ii) of Article 10 (1).
3. Detailed reports by the experts shall form part of the particulars accompanying the
application which the applicant submits to the competent authorities.
                                                           26
 ---pagebreak---                                                       Chapter 2
                                       Specific provisions applicable to
                                       homeopathic medicinal products
                                                        Article 13
 1. Member States shall ensure that homeopathic medicinal products manufactured and        92173/EEC
 placed on the market within the Community are registered or authorized in accordance      Art. 6 (1) and (2)
 with Articles 14, 15 and 16. Each Member State shall take due account of registrations    (adapted)
 and authorizations previously granted by another Member State.
2. A Member State may refrain from establishing a special, simplified registration
 procedure for the homeopathic medicinal products referred to in Article 14. A Member
 State shall inform the Commission accord4tgly. The Member State concerned shall
allow the use in its territory of homeopathic" medicinal products registered by other
Member States in accordance with Articles 14 and 15.
                                                       Article 14
 1. Only homeopathic medicinal products which satisfy all of the following conditions      92173/EEC
m~y   be subject to a special, simplified registration proced':lre:                        Art. 7 (I) and (4)
                                                                                           (adapted)
     they are administered orally or externally,
:-   no specific therapeutic indication appears on the labelling of the medicinal product
     or in any information relating thereto,
     there is a sufficient degree of dilution to guarantee the safety of the medicinal
     product; in particular, the medicinal product may· not contain either more than one
     part per 10 000 of the mother tincture or more than l/100th of the smallest dose used
     in allopathy with regard to active substances whose presence in an allopathic
     medicinal product results in the obligation to submit a doctor's prescription.
At the time of registration, Member States shall determine the classification for the
dispensing of the medicinal product.
2. The criteria and rules of procedure provided for in Articles 4 (4), 17, 18, 22 to 26,
112, 116 and 127 shall apply by analogy to the special, simplified registration procedure
for· homeopathic medicinal products, with the exception of the proof of therapeutic
efficacy.
                                                           27
 ---pagebreak--- 3. The proof of therapeutic efficacy shall not be required for homeopathic medicinal       92/73/EEC
products registered in accordance with paragraph I of this Article, or, where appropriate, Art. 4, 2nd paragraph
admitted in accordance with Article 13 (2).                                                (adapted)
                                                     Article 15
An application for special, simplified registration may cover a series of medicinal        92173/EEC
products derived from the same homeopathic stock or stocks~ The following documents        Art. 8
shall be included with the application in order to demonstrate, in particular, the         (adapted)
pharmaceutical quality and the batch-to-batch homogeneity of the produc~ concerned:
    scientific name or othername given in a pharmacopoeia of the homeopathic stock or
    stocks, together with a statement of the various routes of administration,
    pharmaceutical forms and degree of dilution to be registered,
    dossier describing how the homeopathic stock or stocks is/are obtained and
    controlled, and justifying its/their homeopathic nature, on the basis of an adequate
    bibliography,
    manufacturing and control file for each pharmaceutical form and a description of the
    method of dilution and potentization,
    manufacturing authorization for the medicinal product concerned,
     copies of any registrations or authorizations obtained for the same medicinal product
     in other Member States,
     one or more specimens or mock-ups of the sales presentation of the medicinal
    products to be registered,
    data concerning the stability of the medicinal product.
                                                         28
 ---pagebreak---                                                        Article 16
I. Homeopathic medicinal products other than those referred ~o in Article 14 (I) shall be 92173/EEC
authoriied in accordance witl_t Articles 8, I 0 (I) and 11.                               Art. 9
                                                                                          (adapted)
2. ·A Member State may introduce or retain in its territory specific rules for the·
toxicological and phannacological tests and clinical trials of homeopathic medicinal
products other than those referred to in Article 14 (I) in accordance with the principles
and characteristics o(homeopathy as practised in that Member State.
In this case, the Member State concerned shall notify the Commission of the specific
rules in force.                                                        ·
                                                          29
 ---pagebreak---                                                      Chapter3
                                          Procedures relevant to the
                                           marketing authorization
                                                      Article 17
I. Member States shall take all appropriate measures to ensure that the procedure for      65/65/EEC
granting an authorization to place a medicinal product on the market is completed within   Art. 7
210 days of the submission of a valid application.                                         (as amended by
                                                                                           93/39/EEC Art. 1 (6))
2. Where a Member State notes that an applicatioQ for authorization is already under       (adapted)
active examination in another Member State in respect of that medicinal product, the
Member State concerned may decide to suspend the detailed examination of the
application in order to await the assessment report prepared by the other Member State
in accordance with Article 21 (4).
The ·Member State concerned shall inform the other Member State and the applicant of
its decision to suspend detailed examination of the application in question. As soon as it
has completed the examination of the application and reached a decision, the other
Member State shall forward a copy of its assessment report to the Member State
concerned.
                                                      Article 18
Where a Member State is informed in accordance with Article 8 (3) (I) that another         65/65/EEC
Member State· has authorized a medicinal pr~duct which is the subject of an application    Art. 7a
for authorization in the Member State concerned, that Member State shall forthwith         (as amended by
request the authorities of the Member State which has granted the authorization to         93/39/EEC Art. 1 (7))
forward to it the assessment report referred to in Article 21 (4).                         (adapted)
Within 90 days of the receipt of the assessment report, the ·Member State concerned shall
either recognize the decision of the first Member State and the summary of the product
characteristics as approv~d by it or, if it considers that there are grounds for supposing
that the authorization of the medicinal product concerned may present a risk to public
health, it shall apply the procedures set out in Articles 29 to 34.
                                                           30
 ---pagebreak---                                                       Article 19
In order to examine the application submitted in accordance with Articles 8 and I 0 (I),      75/319/EEC
the competent authority of the Member State:                                                  Art. 4 (a)
                                                                                              (adapted)
I.   must verify whether the particulars submitted in support of the application comply
     with the said Article~ 8 and 10 ( 1) and examine whether the conditions for issuing
     an authorization to place medicinal products on the market (marketing
     authorization) are complied with;
2.. may submit the medicinal product for testing by a State laboratory or by a laboratory     75/319/EEC
     designated for that purpose in order to ensure that the control methods employed by      Art. 4 (b)
     the manufacturer and described in the particulars accompanying the application in        (as amended by
     accordance with Article 8 (3) (h) are satisfactory;                                      89/341/EEC Art. 3 (1))
3.   may, where appropriate, require the applicant to supplement the particulars              75/319/EEC
     accompanying the application in respect of the items listed in the Articles 8 (3) and    Art. 4 (c)
     10 (1). Where the competent authority avails itself of this option, the time limits laid (adapted)
     down in Article 17 shall be suspended until such time as the supplementary
     information required has been provided. Likewise, these time limits shall be
     suspended for the time allowed the applicant, where appropriate, for giving oral or
     written explanation.
                                                          31
 ---pagebreak---                                                        Article 20
 Member States shall take all appropriate measures to ensure that:                             75/319/EEC
                                                                                               Art. 5
 (a) the competent authorities verify that manufacturers and importers of medicinal            (adapted)
      products coming from third countries are able to carry out manufacture in
      compliance. with the particulars supplied pursuant to Article 8 (3) (d), and/or to carry
      out controls according to the methods described in the particulars accompanying the
      application in accordance with Article 8 (3) (h);
 (b) the competent authorities may allow manufacturers and importers of medicinal
      products coming from third countries, in exceptional and justifiable cases, to have
      certain stages of manufacture and/or certain of the controls referred to in (a) carried
      out by third parties; in such cases, the verifications by the competent authorities
      shall also be made in the establishment designated.
                                                       Article 21
  I. When the marketing authorization is issued, the holder shall be infonned, by the          65/65/EEC
 competent authorities of the Member State concerned, of the summary of the product            Art. 4b
 characteristics as approved by it.                                                            (as amended by
                                                                                               93/39/EEC Art. 1 (4))
 2. The. competent authorities shall take all necessary measures to ensure that the            (adapted)
 i~formation given in the summary is in confonnity with that accepted when the
 marketing authorization is issued or subsequently.
 3. The competent authorities shall forward to the Agency a notification of the
 authorization, or a copy of this, together with the summary of the product characteristics.
·4. The competent authorities ·shall draw up an assessment report and comments on the
 ~ossier as regards the results of the analytical and phannacotoxicological tests and· the
 clinical trials of the medicinal product concerned. The assessment report shall be
 updated whenever new information becomes available which is of importance for the
 evaluation of the quality, safety or efficacy of the medicinal product concerned.
                                                          32
 ---pagebreak---                                                        Article 22
  In exceptional circumstances, and following consultation with the applicant, an           65/65/EEC
  authorization may be granted subject to certain specific obligations, including:          Art. 10 (2)
                                                                                            (as amended by
      the carrying out of further studies following the granting of authorization,          93/39/EEC Art. I (9))
      the notification of adverse reactions to the medicinal product.
  These exceptional decisions may be adopted only for objective and verifiable reasons
  and shall be based on one of the causes referred to in Part 4 (G) of Annex I.
                                                       Article 23
  After an authorization has been issued, the authorization holder must, in respect of the  65/65/EEC
  methods of manufacture and control provided for in Article 8 (3) (d) and (h), take        Art. 9a
  account of scientific and technical progress and introduce any changes that may be        (as amended by
  required to enable the medicinal product to be manufactured and checked by means of       93/39/EEC Art. I (8))
. generally accepted scientific methods.                                                    (adapted)
  These changes shall be subject to the approval of the competent authority of the Member
  State concerned.
                                                       Article 24
  Authorization shall be valid for five years and shall be renewable for five-year periods, 65/65/EEC
  on application by the holder at least three months before the expiry date and after       Art. I 0 (I)
  consideration by the competent authority of a dossier containing in particular details of (as amended by
  the data on pharmacovigilance and other information relevant to the monitoring of the     93/39/EEC Art. I (9))
  medicinal product.
                                                       Article 25
  Authorization shall not affect the civil and criminal liability of the manufacturer and,  65/65/EEC
  where applicable, of the marketing authorization holder.                                  Art. 9
                                                                                            (adapted)
                                                          33
 ---pagebreak---                                                           Article 26
    The marketing authorisation shall be refused if, after. verification of the particulars and 65/65/EEC
    documents listed in Articles 8 and 10 ( 1), it proves that:                                 Art. 5
                                                                                                (as amended by
    (a) the medicinal product is harmful in. the normal conditions of use, or                   89/341/EEC Art. 1 (I))
                                                                                                (adapted)
    (b) that its therapeutic efficacy is .lacking or is insufficiently substantiated by the
        applicant, or              ·
    (c) that its qualitative and quantitative composition is not as declared.
    Authorisation shall likewise be refused if the particulars and docume.nts submitted .in
    support of the application do not comply with Articles 8 and I0 ( 1).
                                                              34
(3}
 ---pagebreak---                                                     Chaptcr4
                                   Mutual recognition of authorizations
                                                     Article 27
 1. In order to facilitate the adoption of common decisions by Member States on the         75/319/EEC
 authorization of medicinal products on the basis of the scientific criteria of quality,    Art. 8
 safety and efficacy, and to achieve thereby the free movement of medicinal products        (as amended by
 within the Community, a Committee for Proprietary Medicinal Products, hereinafter          93/39/EEC Art. 3 (1))
 referred to as "the Committee", is hereby set up. The Committee shall be part of the      (adapted)
 Agency.
 2. In addition to the other responsibilities conferred upon it by Community law, the
Committee shall examine any question relating to the granting, variation, suspension or .
withdrawal of marketing authorization which is submitted to it in accordance with this
Directive.
3. The Committee shall draw up its own Rules of Prodecure.
                                                     Article 28
 1. Before submitting the application for recognition of a marketing authorization, the    75/319/EEC
holder of the authorization shall infonn the Member State which ·granted the               Art. 9 (3)
~uthorization on which the application is based (hereinafter "referential Member State"),  (as amended by
that an application is to be made in accordance with this Directive and shall notify it of 93/39/EEC Art. 3 (I))
any additions to the original dossier; that Member State may require the applicant to      (adapted)
provide it with all the particulars and documents necessary to enable it to check that the
dossiers filed are identical.
In addition the holder of the authorization shall request the referential Member State to
prepare an assessment report in respect of the medicinal product concerned, or, if
necessary, to update any existing assessment report. That Member State shall prepare the
assessment report, or update it, within 90 days of the receipt of the request.
At the same time as the application is submitted in accordance with paragraph 2, the
referential Member State shall forward the assessment report to the Member State or
Member States concerned by the application.
2. In order to obtain the recognition according to the procedures laid down in this        75/319/EEC
Chapter in one or more of the Member States of a marketing authorization issued by a       Art. 9 ( 1)
Member State, the holder of the authorization shall submit an application to the           (as amended by
competent authorities of the Member State or Member States conc~med, together with         93/39/EEC Art. 3 (1))
the information and particulars referred to in Articles 8, 10 (1) and 11. He shall testify (adapted)
that the dossier is identical to that accepted by the referential Member S~te, or shall
identify any additions or amendments it may contain. In the latter case, he shall certify
that the summary of the product characteristics proposed by him in accordance with
Article 11 is identical to that· accepted by the referential Member State in accordance
with Article 21. Moreover, he shall certify that all the dossiers filed as part of the
procedure are identical.
                                                         35
 ---pagebreak--- 3. The holder of the marketing authorization shall communicate ·the application to the        75/319/EEC
Agency, inform it ofthe Member States concerned and of the dates of submission of the         Art. 9 (2)
application and send it a copy of the authorization granted by the referential Member         (as amended by
State. He shall also send the Agency copies of any such authorization which may have          93/39/EEC Art. 3 (1))
been gr~ted by the other Member States in respect of the medicinal product concerned,         (adapted)
and shall indicate whether any application for authorization is currently under
consideration in any Member State.
4. Save in the exceptional case provided for in Article 29(1 ), each Member State shall       75/319/EEC
recognize the .marketing authorization granted by the referential Member State within 90      Art. 9 (4)
days of receipt of the application and the assessment report. It shall inform the referential (as amended by
Member State which granted ·the initial authorization, the other Member States                93/39/EEC Art. 3 (I))
'concerned by the application, the Agency, and th~ marketing authorization holder             (adapted)
                                                     Article 29
 I. Where a Member State considers that there are grounds for supposing that the              75/3I9/EEC
marketing authorization of the medicinal product concerned may present a risk to public       Art. I 0
health, it shall forthwith inform the applicant, the referential Member State which           (as amended by
granted the initial authorization, any other Member States concerned by the application       93/39/EEC Art. 3 (I))
and the Agency. The Member State shall s~te its reasons in detail and shall indicate          (adapted)
what action may be necessary to correct any defect in the application.
2. All the Member States concerned shall use their best endeavours to reach agreement
on the action to be taken iri respect of the application. They shall provide the applicant
with the opportunity to make his point of view known orally or in writing. However, if
the Member States have not reached agreement within the time limit referred to in
Article 28 (4) they shall forthwith refer the matter to the Agency with regard. to the
Committee's reference for the application of the procedure laid down in Article 32.
3. Within the time limit referred to in Article 28(4), the Member States concerned. shall
provide the Committee with a detailed statement of the matters on which they have been
unable to reach agreement and the reasons for their disagreement. The applicant shall be
provided with a copy of this information.
4. As soon as he is informed that the matter has been referred to the Committee, the
applicant shall forthwith forward to the Committee a copy of the information and
particulars referred.to in Article 28 (2).·
                                                         36
 ---pagebreak---                                                       ·Article 30
- If several applications submitted in accordance with Articles 8, 10 (1) and Article 11     75/319/EEC
  have been made for marketing 'authorization for a particular medicinal product, and       Art. 11
  Member States have adopted divergent decisions concerning the authorization of the        (as amended by_
  medicinal product or its suspension ()r withdrawal, a Member State, or the Commission,    93/39/EEC Art. 3 (1))
  or the marketing authorisation holder may refer the matter to the Committee for           (adapted)
  application of the procedure laid down in Article 32.
  The Member State concerned, the marketing authorization holder or the Commission
  shall clearly identify the question which is referred to the Committee for consideration
  and, where appropriate, shall inform the holder.
  The Member State and the marketing authorization holder shall forward to the
  Committee all available information relating to the matter in question.
                                                       Article 31
  The Member States or the Commission or the applicant or holder of the marketing           75/319/EEC
  authorization may, in specific cases where the interests of the Community are involved,   Art. 12
  refer the matter to the Committee for the application of the· procedure laid down in      (as amended by
  Article 32 before reaching a decision on~ request for a marketing authorization or on the 93/39/EEC Art. 3 (I))
  suspension or withdrawal of an authorization, or on any other variation to the terms of a (adapted)
  marketing authorization which appears necessary, in particular to take -account of ~he
. information collected in accordance with Title IX.
  The Member State concerned or the Commission shall clearly identify the question
  which is referred to the Committee for consideration and shall inform the marketing
  authorization holder.
  The Member States and the marketing authorization holder shall forward to the
  Committee all available information relating to the matter in question.
                                                          37
 ---pagebreak---                                                        Article 32
· ·1. When reference is made to the procedure described in this Article, the Committee      75/319/EEC
  shall consider the matter concerned and issue a reasoned opinion within 90 days of the    Art. 13
  date on which the matter was referred to it.                                              (as amended by
                                                                                            93/39/EEC_Art. 3 (I))
  However, in cases submitted to the Committee in accordance with Articles 30 and 31,       (adapted)    ·
  this period :"lay be extended by 90 days.
  In case of urgency, on a proposal from its Chairman, the Committee may agree to a
  shorter deadline.
  2. In order to consider the matter, the Committee may appoint one of its members to act
  as rapporteur. The Committee may also appoint individual experts to advise it on
  specific questions. When appointing experts, ihe Committee shall define their tasks and
  specify the time-limit for the completion of these ~ks.
  3. In the cases referred to in Articles 29 and 30, before issuing its opamon, the
  Committee shall provide the marketing authorization holder with an opportunity to
  present written or oral explanations.
  In the case referred to in Article 31, the marketing authorization holder may be asked to
  explain .himself o~lly or in writing.
  If it considers it appropriate, the Committee may invite any other person to provide
  information relating to the matter before it.
  The Committee may suspend the time limit referred to in paragraph 1 in order to allow
  the marketing authorization holder to prepare explanations.          ·
                                                          38
 ---pagebreak--- 4. The Agency shall forthwith inform the marketing authorization holder where the           75/319/EEC
opinion of the Committee is that:                                                           Art. 13
                                                                                            (as amended by
     the application does not satisfy the criteria for authorization, or                    93/39/EEC Art. 3 (1))
                                                                                            (adapted)
     the summary of the product characteristics proposed by the applicant in accordance
     with Article l1 should be amended, or
     the authorization should be granted subject to conditions, with regard to conditions
     considered essential for the safe and effective use of the medicinal product including
     pharmacovigilance, or
     a marketing authorization should be suspended, varied or withdrawn,
Within 15 days of the receipt of the opinion, the marketing authorization holder may
notify the Agency in writing of his intention to appeal. In that case, he shall forward the
detailed grounds for appeal to the Agency within 60 days of receipt of the opinion.
Within 60 days of receipt of the grounds for appeal, the Committee shall consider
whether its opinion should be revised, and the conclusions reached on the appeal shall be
annexed to the assessment report referred to in paragraph 5.
5. Within 30 days of its adoption, the Agency shall ·forward the final opinion of the
Committee to the Member States, the Commission and the marketing authorization
holder together with a report describing the assessment of the medicinal product and
stating the reasons for its conclusions.
In the event of an opinion in favour of granting or maintaining an authorization to place
the medicinal product concerned on the market, the following documents shall be
annexed to the opinion.
(a) a draft summary of the product characteristics, as referred to in Article 11;
(b) any conditions affectin~ the authorization within the meaning of paragraph 4.
                                                           39
 ---pagebreak---                                                       Article 33
Within 30 days of the receipt of the opinion, the Commission shall prepare a draft of the  75/319/EEC
decision to be taken in respect of the application, taking into account Community law.     Art. 14 (1)
                                                                                           (as amended by
In the event of a draft decision which envisages the granting of marketing authorization,  93/39/EEC Art. J (1))
the documents referred to in Article 34 (5) (a) and (b) shall be annexed.                  (adapted)
Where, exceptionally, the draft decision is not in accordance with the opinion of the
Agency, the Commission shall also annex a detailed explanation of the reasons for the
differences.
The draft decision shall be forwarded to the Member States and the applicant.
                                                      Article 34
 1. A final decision on the application shall be adopted in accordance with the procedure  75/319/EEC
laid down in Article 124.                                                                  Art. 14 (2)
                                                                                           (as amended by
                                                                                           93/39/EEC Art. 3 (1))
2. The rules of procedure of the Standing Committee established by Article 120 shall be    75/319/EEC
adjusted to take account of the tasks incumbent upon it in accordance with this Chapter.   Art. 14 (3)
                                                                                           (as amended by
These adjustments shall involve the following:                                             93/39/EEC Art. 3 (1))
                                                                                           (adapted)
      except in cases referred to in the third paragraph of Article 33, the opinion of the
      Standing Committee shall be obtained in writing,
      each Member State is allowed at least 28 days to forward written observations on the
      draft decision to the Commission,
      each Member State is able to require in writing that the draft decision be discussed
      by th.e Standing Committee, giving its· reasons in detail.
 Where, in the opinion of the Commission, the written observations of a Member State
raise important new questions of a scientific or technical nature which have not been
addressed in the opinion of the Agency, the Chairman shall suspend the procedure and
refer the application back to the Agency for further consideration.
 The provisions necessary for the implementation of this paragraph shall be adopted by
the Commission in accordance with the procedure laid down in Article 122.
3. A decision as referred to in paragraph 1 shall be addressed to the Member States        75/319/EEC
concerned by the matter and reported to the marketing authorization holder. The            Art. 14 (4)
 Member States shall either grant or withdraw marketing authorization, or vary the terms   (as amended by
of a marketing authorization as necessary to coritply with the decision within 30 days of  93/39/EEC Art. 3 (1))
 its notification. They shall inform the Commission and the Agency thereof.                (adapted)
                                                           40
 ---pagebreak---                                                        Article 35
  l. Any application by the marketing authorization holder to vary a marketing              75/319/EEC
  authorimtion which has been granted in accordance with the provisions of this Chapter     Art. 15
· shall be submitted to all the Member States which have previously authorized the          (as amended by
  medicinal product concerned.                                                              93/39/EEC Art. 3 (I))
                                                                                            (adapted)
  The Commission shall~ in consultation with the Agency, adopt ·appropriate arrangements
  for the examination of variations to the terms of a marketing authorization.
  These arrangements shall include a notification system or administration procedures
  concerning minor variations and define precisely the concept of"a minor variation".
  These arrangements shall be adopted by the Commission in the form of an implementing
  Regulation in accordance with the procedure laid down in Article 122.
  2. The procedure laid down in Articles 32, 33 and 34 shall . apply by analogy to
  variations made to marketing authorizations for products.
                                                       Article 36
  I. Where a Member State considers that the variation of a marketing authorization which 75/319/EEC
  has been granted in accordance with the provisions of this Chapter or its suspension or Art. 15a
  withdrawal is necessary for the protection of public health, the Member State concerned   (as amended by
  shall forthwith refer the matter to the Agency for the application of the products laid   93/39/EEC Art. 3 (I))
  down in Articles 32, 33 and 34.                                                           (adapted)
  2. Without prejudice to the provisions of Article 31, in exceptional cases, where urgent
  action ·is essential to protect public health, until a definitive decision is adopted · a
  Member State may suspend the marketing and the use of the medicinal product
  concerned on its territory. It shall inform the Commission and the other Member States
  no later tb~ the following working day of the reasons for its action.
                                                          41
 ---pagebreak---                                                    Article 37
Articles 35 and 36 shall apply by analogy to medicinal products authorized by Member 75/319/EEC
States following an opinion of the Committee given in accordance with Article 4 of Art. l5b
Directive 87/22/EEC before l Janu_ary 1995.                                              (as amended by
                                                                                         93/39/EEC Art. 3 (I))
                                                   Article 38
 l. The Agency shall publish an annual report· on the operation of the procedures laid   75/319/EEC
down in this Chapter and shall forward that report to the European Parliament and the    Art.l5c
Council for information.                                                                 (as amended by
                                                                                         93/39/EEC Art. 3 (I))
2. By I January 2001, the Commission shall publish a detailed review of the operation of
the procedures laid down in this Chapter and shall propose any amendments which may
be necessary to improve these procedures.
_The Council shall decide, under the conditions provided for in the Treaty, on the
Commission proposal within one year of its submission.
                                                   Article 39
The provisions referred to in Articles 27 to 34 shall not apply .to the homeopathic      75/319/EEC
med~cinal products referred to in Article 16 (2).                                        Art. 14 (5)
                                                                                         (as amended by
                                                                                         93/39/EEC Art. 3 (1))
                                                                                         (adapted)
                                            /
                                                      42
 ---pagebreak---                                                      TITLE IV
                                MANUFACTURE AND IMPORTATION
                                                      Article 40
 1. Member States shall take· all appropriate measures to ensure that the manufacture of       75/319/EEC
~he  medicinal products within their territory is subject to the holding of an authorization. Art. 16 (1)
 This manufacturing authorization shall be required nothwithstanding th~t the medicinal       (as amended by
 products manufactured are intended for export.                                                89/341/EEC Art. 3 (3))
                                                                                              (adapted)
2. The authorization referred to in paragraph 1 shall be required for both total and partial  75/319/EEC
 manufacture, and for the various processes of dividing up, packaging or presentation.        Art. 16 (2) and (3)
                                                                                              (adapted)
 However, such authorization shall not be required for preparation, dividing up, changes
 in packaging or presentation where these processes are carried out, solely for retail
supply, by phannaci~ts in dispensing pharmacies or by persons legally authorized in the
 Member States to carry out such processes.
3. Authorization referred to in paragraph 1 shall also be required for imports coming
from third countries into a Member State; this Title and Article 118 (I) shall have
corresponding application to such imports as they have to manufacture.
                                                      Article-41
In order to obtain the manufacturing authorization, the applicant shall meet at least the     75/319/EEC
following requirements:                                                                       Art. 17
                                                                                              (adapted)
(a) specify the medicinal products and pharmaceutical fonns which are to be
     manufactured or imported and also the place where they are to be manufactured
     and/or controlled;
(b) have at his disposal, for the manufacture or import of the above, suitable and
     sufficient premis~s, technical equipment and control facilities ·complying with the
     legal requirements which the Member State concerned lays down as regards both
     manufacture and control and the storage of medicinal products, in accordance with
     Article 20;                                                ·
(c) have at his disposal the services of at least one qualified person within the meaning
     of Article 48.
The appli~ant shall provide particulars in support of the above in his application.
                                                         43
 ---pagebreak---                                                        Article 42
1. The competent authority of the Member State shall issue the manufacturing · 75/319/EEC
authorization only after having made sure of the accuracy of the particulars supplied Art. 18
pursuant to Article 41, by means of an inquiry carried out by its a~ents.                      (adapted)
2. In order to ensure that the requirements referred to in Article 41 are complied with,
authorization may be made conditional on the carrying out of certain obligations
imposed either when authorization is granted or at a later date.
3. The authorization shall apply only to the premises specified in the application and to
the medicinal products and pharmace.-tical forms specified in that same application.
                                                       Article 43
The Member States shall take all appropriate measures to ensure that the time taken for        75/319/EEC
the procedure for granting the manufacturing authorization does not exceed 90 days             Art. 20 ( 1)
from the day on which the competent authority receives the application.
                                                       Article 44
If .the holder of the manufacturing authorization requests a change in any of the              75/319/EEC
particulars referred to in the first paragraph of Article 41, the time taken for the           Art. 20 (2)
procedure relating to this request shall not exceed 30 days . .In exceptional cases this       (adapted)
period of time may be extended to 90 days.
                                                       Article 45
The competent authority of the Member State may require from the applicant further             75/319/EEC
information concerning the particulars supplied pursuant to Article 41 and concerning          Art. 20 (3)
the qualified person referred to in Article 48; where the competent authority concerned        (adapted)
exercises this right, application of the time-limits referred to in Article 43 and 44 shall be
suspended until the additiomd data required have been supplied.
                                                           44
 ---pagebreak---                                                     Article 46
The holder of a manufacturing authorization shall at least be obliged:                    75/319/EEC
                                                                                          Art. 19 (a) to (e)
(a) to have at his disposal the services of staff who comply with the legal requirements  (adapted)
     existing in the Member State concerned both as regards manufacture and controls;
(b) to dispose of the authorized medicinal products only in . accordance with the
     legi~lation of the Member States concerned;
(c) to give prior notice to the competent authority of any changes he may wish to make
     to any of the particulars supplied pursuant to Article 41; the codtpetent authority
     shall, in any event, be immediately informed if the qualified person referred to in
    Article 48 is replaced unexpectedly;
(d) to allow the agents of the competent authority of the Member State concerned access
    to his premises at any time;
(e) to enable the qualified person referred to in Article 48 ~o carry out his duties, for
    example by placing at his disposal all the necessary facilities;
(f) to comply with the principles and guidelines of good manufacturing practice for       75/319/EEC
    medicinal products as laid down by Community law.                                     Art. 19 (f)
                                                                                          (as amended by
                                                                                          89/341/EEC Art. 3 (4))
                                                    Article 47
The principles and guidelines of good manufacturing practices fo~ medicinal products      75/319/EEC
referred to in Article 46 (f) shall be adopted in the form of a directive, in accordance  Art. 19a
with·the procedure laid down in Article 122.                                              (as amended by
                                                                                          89/341/EEC Art. 3 (5))
Detailed guidelines in line with those principles will be published by the Commission     (adapt~d)
and revised as necessary to take account of technical and scientific progress.
                                                       45
 ---pagebreak---                                                      Article 48
I. Member States shall take all approprjate measures to ensure that the holder of the        75/319/EEC
manufacturing authorization .has permanently and continuously at his disposal the            Art. 21
services of at least one· qualified person, in accordance with the conditions laid down in
Article 49, responsible in particular for carrying out the duties·specified in Article 51.
2. If he personally fulfils the conditions laid down in Article 49, the holder of th~
authorization may himself assume the responsibility referred to in paragraph I.
                                                     Article 49
1. Member· States shall ensure that the qualified person referred to in Article 48 fulfils   75/3 I 9/EEC
the minimum conditio~s of qualification set out in paragraphs 2 and 3.                       Art. 23
                                                                                             (adapted)
2. A qualified person shall be in possession of a diploma, certificate or other evidence of
formal qualificatioQs. awarded on completion of a university cou~se of study, or a course
recognized as equivalent by the Member State concerned, extending over a period of at
least four years of theoretical and practical study in one of the ·following scientific
disciplines: pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical
chemistry and technology, biology.
However, the minimum duration of the university course may be three and a half years·
where the course is followed by a period of theoretical and practical training of a
minimum duration of one year and including a training period of at least six months in a
pharmacy open to the public, corroborated by an examination at university level.
Where two university courses or two. courses recognized by the State as equivalent
co-exist in a.Member State and where one of these extends over four years and the other
over three years, the three-year course leading to a diploma, certificate or other evidence
of formal qualifications awarded on c~mpletion of a university course or its recognJzed
equivalent shall be considered to fulfil the condition of duration ref~rred to in the second
subparagraph in so far as the dipl.omas, certificates or other evidence of formal
qualifications awarded on completion of both courses are recognized as equivalent by
the State in question.                     ·
                                                          46
 ---pagebreak---    The course shall include theoretical and practical study bearing upon at least the         75/319/EEC
  following basic subjects:                                                                   Art. 23
                                                                                              (adapted)
       Applied physics
       General and inorganic chemistry
       Organic chemistry
       Analytical chemistry
       Pharmaceutical chemistry, including analysis of medicinal products
       General and applied biochemistry (medical)
       Physiology
       Microbiology
       Phannacology
       Pharmaceutical technology
       Toxicology
       Phannacognosy (study of the composition and effects of the natural active
       substances of plant and animal origin).
  Studies in these subjects should be so balanced as to enable the person concerned to
  fulfil the obligations specified in Article 51.
  In so far as certain diplomas, certificates or other evidence of fonnal qualifications
  mentioned in the first subparagraph do not fulfil the criteria laid down in this paragraph,
  the. competent authority of the Member State shall ensure that the person concerned
  provides evidence of adequate knowledge of the subjects involved.
  3. The qualified person shall have acquired practical experienc~ ~ver at least two years,
. in one or more undertakings which are authorized to manufacture medicinal products, in
  the activities of qualitative analysis of medicinal products, of quantitative analysis of
  activ.e substances and of the testing and checking necessary to ensure the quality of ·
  medicinal products.                                       ·
  The duration of practical experit?nce may be reduced by one year where a u~iversity
  course lasts for at least five years and by a year and a half where the course lasts for at
  least six years.
                                                          47
 ---pagebreak---                                                        Article 50
I. A person engaging in the activities of the person referred to in Article 48 from the        75/319/EEC
time of the application of Directive 75/3 I 9/EEC, in a Member State without complying         Art. 24
with the provisions of Article 49 shall be eligible to continue to engage in those activities  (adapted)
in the State concerned.                                                                      ·
2. The bolder of a diploma, certificate or other evid.ence of formal qualifications
awarded on completion of a university course - or a course recognized as equivalent by
the Member State concerned - in a scientific discipline allowing him to engage in the
activities of the person referred to in Article 48r in accordance with the laws of that 'State
may - if he began his course prior to 21 May 1975 - be considered as qualified to carry
out in that State the duties of the person referred to in Article 48 provided that he has
previously engaged in the following activities for at least two· years before 21 May 1985
following notification of this directive . in one or more undertakings authorized to
manufacture: production supervision and/or qualitative and quantitative analysis of
acti~e substances, and the necessary testing and checking under the direct authority of
the person referred to in Article 48 to ensure the quality of the medicinal products.
If the person concerned has acquired the practical experience referred to in the first
subparagraph before 21 May 1965, a further one year's practical experience .in
accordance with the conditions referred to in the first subparagraph willl?e required to be
completed immediately before he engages in such activities.
                                                           48
 ---pagebreak---                                                       · Article 51
 I. Member States shall take all appropriate measures to ensure that the qualified person       75/319/EEC
referred to in Article 48, without prejudice to his relationship with the holder of the         Art. 22 (1); 1st and 2nd
manufacturing authorization, is responsible, in the context of the procedures referred to       subparagraphs
in Article 52, for securing:                                                                    (adapted)
(a) in the case of medicinal products manufactured within the Member States
      concerned, that each batch of medicinal products has been manufactured and
      checked in compliance with the laws in force in that Member State and in
      accordance with the requirements of the marketing authorization;
(b) in the case of medicinal products coming from third c_ountries, that each production
      batch has undergone in the importing Member State a full qualitative analysis, a
      quantitative analysis of at least all the active constituents and all the other tests or
      checks necessary to ensure the quality of medicinal products in accordance with the
      requirements of the marketing authorization.
The batches of medicinal products which have undergone such controls in a Member
State shall be exempt from the controls if they are marketed in another Member State,
accompanied by the control reports signed by the qualified person.
2. In the case of medicinal products imported from a third country, where appropriate 75/319/EEC
arrangements have been made by the Community with the exporting country to ensure Art. 22 (1}, 3rd
that the manufacturer of the medicinal product applies standards of good manufacturing subparagraph
practice at least equivalent to those laid down by the Community, and to ensure that the (as amended by
controls referred to under point (b) of the first subparagraph of paragraph 1 have been 93/39/EEC Art. 3 (2))
carried out in the exporting country, the qualified person may be relieved of
responsibility for _carrying out those controls.                                            ·
3. In all cases and particularly where the medicinal products are released for sale, the       75/319/EEC
qualified person must certify in a register or equivalent document provided for that           Art. 22 (2)
purpose, that each production batch satisfies the provisions of this Article; the said         (adapted)
register or equivalent document must be kept up to date as operations are carried out and
must remain at the disposal of the agents of the competent authority for the _period
specified in the provisions of the Member State concerned and in any event for at least
five years.              ·
                                                       Article 52
Member States shall ensure that the duties of qualified persons referred to in Article 48      7.5/319/EEC
are fulfilled, either by means of appropriate administrative measures or by making such        Art. 25
persons subject to a professional code of conduct.
Member States may provide for the temporary suspension of such a person upon the
commencement of administrative or disciplinary procedures against him for failure to
fulfil his obligations.
                                                       Article 53
The provisions of this Title shall apply to homeopathic medicinal products.                    92173/EEC
                                                                                               Art. 3
                                                                                               (adapted)
                                                           49
 ---pagebreak---                                                            TITLE V
                                     LABELLING AND PACKAGE LEAFLET
                                                            Article 54
    The following particulars shall appear on the outer packaging of medicinal products or,    92127/EEC
    where there is no outer packaging, on the immediate packaging:                             Art. 2 (1), points (a) to
                                                                                               (n)
    (a) the name of the medicinal product followed by the common name where the product (adapted)
         contains only one active substance and if its ·name is a brand name; where a
         medicinal product is available in· several phiU'J1laceutical forms and/or several
         strengths, the phartnaceutical form and/or the strength (baby, child or adult as
         appropriate) must be included in the name of the medicinal product;
    (b) a statement of the active substances expressed qualitatively and quantitatively per
         dosage u:nit or according to the form of administration for a given volume or weight,
         using their common names;
    (c) the pharmaceutical form       ~d  the contents by weight, by volume or by number of
         doses of the product;
    (d) a list of those excipients known to have a recognized action or effect and included in
         the guidelines. published pursuapt to Article 65. However, if the product is
         injectable, or a topical or eye preparation, all excipients must be stated;
    (e) the method and, if necessary, the route of administration;
    (t) a special warning that the medicinal product must be stored out of reach of children;
    (g) a spe,ial warning, if this is necessary for the medicinal product;
    (h) the expiry date in clear terms (month/year);
    (i) special storage precautions, if any;
    (j) special precautions for disposal of unused medicinal products or waste materials
       · from medicinal prQducts, if appropriate;                             ·
    (k) the name and address of the holder of the authorization for placing the medicinal
         product on the market;
    (I) the number of the authorization for placing the medicinal product on the market;
    (m) the manufacturer's batch number;
    (n) in the case of self-medication, ·instructions on the use of the medicinal products.
(4)                                                            so
 ---pagebreak---                                                          Article SS
 I. The particulars laid down in Articles 54 and 62 shall appear on immediate packagings   92/27/EEC
 other than those referred to in paragraphs 2 and 3.                                       Art. 3
 2. The following particulars· at least shall appear on immediate packagings ·which take
 the form of blister packs and are placed in an outer packaging that complies with the
 requirements laid down in Articles 54 and 62.
       the name of the medicinal product as laid down in Article 54 (a),
      ·the name of the holder of the authorization for placing the product on the market,
       the expiry date,
       the batch number.
3. The following particulars at least shall appear on small immediate packaging units on
which the particulars laid down in Articles 54 and 62 cannot be displayed:
       the name of the medicinal product and, if necessary, the strength and the route of
       administration,
       the method of administration,
       the expiry date,
       the batch nu~ber,
       the contents by weight, by volume or by unit.
                                                         Article 56
The particulars referr~d to in Articles 54, 55 and 62 shall be easily legible, clearly 192/27/EEC
comprehensible and indelible.                                             ·               Art. 4 ( 1)
                                                         Article 57
Notwithstanding Article 60, Member States may require the use of certain forms of 92/27/EEC
labelling of the medicinal product making it possible to ascertain:                       Art. 5 (2)
                                                                                          (adapted)
      the price of the medicinal product,
      the reimbursement conditions of social security organizations,
      the legal status for supply to the patient, in accordance with Titl~ VI,
   · .identification and authenticity.
                                                            51
 ---pagebreak---                                                        Article 58
The inclusion in the packaging of all medicinal products of a package leaflet shall be    92/27/EEC
obligatory unless all the information required by Articles 59 and 62 is directly conveyed Art. 6
on the outer packaging or on the.immediate packaging                                      (adapted)
                                                       Article 59
1. The package leaflet shall be drawn up in accordance with the summary of the product    92127/EEC
characteri~tics; it shall include, in the following order:                                Art. 7 ( 1)
                                                                                          (adapted)
(a) for the identification of the medicinal product:
         the name of the medicinal product, followed by the common name if the
         product contains only one active substance and if its name is a brand name;
         where a medicinal product is available in several pharmaceutical forms and/or
         several strengths, the pharmaceutical form and/or the strength (for exaniple,
         baby, child, adult) must be included in the name of the medicinal product,
         a full statement of the active substance and excipients expressed qualitatively
         and a statement of the active substance expressed quantitatively, using their
         common names, in the case of each presentation of the medicinal product,
         the pharmaceutical form and the contents by weight, by volume or by number of
         doses of the product, in the case of each presentation of the product,
         the pharmaco-therapeutic group, or type of activity in terms easily
         comprehensible for the patient,
         the name and address of the holder of the authorization for placing the
         medicinal product on the market and of the manufacturer;
(b) the therapeutic indications;
                                                           52
 ---pagebreak--- {c)   a list of information which is necessary before taking the medicinal product:         92/27/EEC
                                                                                            Art. 7 (1)
     -     contra-indications,                                                              (adapted)
     -     appropriate precautions for use,
     -     forms of interaction with other medicinal products and other forms of
           interaction (for example, alcohol, tobacco, foodstuffs) which may affect the
           action of. the medicinal product,
     -    special warnings;
     this list must:
     -    take into account the particular condition of certain categories of users
          (e.g. children, pregnant or breastfeeding women, the elderly, persons with
          specific pathological conditions),
     -    mention, if appropriate, potential effects on the ability to drive vehicles or to
         ·operate machinery,
          detail those excipients, knowledge of which is important for the safe and
          effective use of the medicinal product and included in the guidelines published
          pursuant to Article 65;
(d) the necessary and usual instructions for proper use, in particular:
    -     the dosage,
    -     the method and, if necessary, route of administration,
    -     the frequency of administration, specifying if necessary, the appropriate time at
          which the medicinal product may or must be administered,
    and, as appropriate, depending on the nature of the product:
    - the duration of treatment, where it should be limited,
    - the action to be taken in the case of an overdose (e.g., symptoms, emergency
         procedures),
    - the course of action to take when one or ~ore doses have not been taken, ·
    - indication, if necessary, of the risk of withdrawal effects;
                                                        53
 ---pagebreak--- (e)  a description of the undesirable effects which can occur under normal use of th~ . 92/27/EEC
     medicinal product and, if necessary, the action to be taken in such a case; the Art. 7(1)
     patient should be expressly invited to communicate any undesirable effect which is (adapted)
     not mentioned in the leaflet to his doctor or to his pharmacist;
(f)  a reference to the expiry date indicated on the label, with:
     - a warning again~t using the product after this date,
     - where appropriate, special storage precautions,
     -   if necessary, a warning against certain visible signs of deterioration;
(g) the date on which the package leaflet was last revised.
2. Notwithstanding paragraph 1 (b), the authority competent may decide that certain         92127/EEC
therapeutic indications shall not be mentioned . in the package leaflet, whe~ the           Art. 7 (2)
dissemination of such information might have serious disadvantages for the patient.         (adapted)
                                                     Article 60
Member States may not prohibit or impede the placing on the market of medicinal             92127/EEC
products within their territory on grounds connected with labelling or the package leaflet  Art. 5 (I) and Art. 9
where these comply with the ~equirements of this Title.                                     (adapted)
                                                     Article 61
I. One or more specimens or mock-ups of the outer packaging and the immediate               92127/EEC
packaging of a medicinal product, together with the draft package leaflet, shall be         Art. I 0 (I) to (4)
submitted to the authorities competent for authorizing marketing when the marketing         (adapted)
authorization is requested.
2. The competent authority shall refuse the marketing authorization if the labelling or the
package leaflet do riot comply with the provisions of this Title or if they are. not in
accordance with the particulars listed in the summary of product characteristics.
3. All proposed changes to an aspect of the labelling or the package leaflet covered by
this Title and not connected with the summary of product characteristics shall · be
submitted to the authorities competent for authorizing marketing. If the competent
authorities have not opposed a · proposed change within 90 days following the
introduction of the request, the applicant may put the change into effect.
4. The fact that the competent authority do not refuse a marketing authorization pursuant
to paragraph 2 or a change to the labelling or the package leaflet pursuant to paragraph 3
does not alter the general legal liability of the manufacturer or as appropriate the
marketing authorization holder.
                                                          54
 ---pagebreak---                                                         Article 62
The outer packaging and the package leaflet may include symbols or pictograms                   92127/EEC
designed to clarify certain information mentioned in Articles 54 and 59 (1) and other           Art. 2 (2) and
information compatible with the summary of the product characteristics which is useful          Art. 7 (3)
for health education, to the exclusion of any element of a promotional nature.                  (adapted)
                                                        Article 63
 1. The particulars for labelling listed in Articles 54, 59 and 62 shall appear in the official 92/27/EEC
language or languages of the Member State where the product is placed on the market.            Art. 4 (2)
                                                                                                (adapted)
The first subparagraph shall not prevent these particulars from being indicated in several
languages, provided that the same particulars appear in all the languages used.
2. The package leaflet must be written in clear and understandabl~ terms for the us~rs          92/27/EEC
and be clearly legible in the official language or languages of the Member State where          Art. 8
the medicinal product is placed on the market.                                                  (adapted)
The fli'St subparagraph shall not prevent the package leaflet being printed in several
languages, provided that the same information is given in all the languages used.
3. The competent authorities may exempt labels and package leaflets for specific                92/27/EEC
medicinal products from the obligation that c~rtain particulars shall appear and that the       Art. 10 (5)
leaflet must be in the official language or languages of the Member State where the
product is placed on the market,· when the product is not intended to be delivered to the
patient for self-administration.
                                                       Article 64
Where the provisions of this Title are not complied with, and a notice served on the            92/27/EEC
person concerned has remained without effect, the competent authorities of the                  Art. 11 (1)
Member States may suspend the marketing authorization, until the labelling and the              (adapted)
package leaflet of the medicinal product in question have been made to comply with the
requirements of this Title.
                                                       Article 65
As necessary, the Commission shall publish guidelines concerning in particular:                 92/27/EEC
                                                                                                Art. 12
     the formulation of certain special warnings for certain categories of medicinal            (adapted)
     products,
     the particular information needs relating to self-medication,
     the legibility of particulars on the labelling and package leaflet,
     methods for the identification and authentication of medicinal products,
     the list of excipients which must feature on the labelling of medicinal products and
     the way these excipients must be indicated.
These guidelines shall be adopted in the form of a Directive, in accordance with the
procedure laid down in Article 122.
                                                           55
 ---pagebreak---                                                          Article·66
   .I. The outer packaging and the container of medicinal products containing radionuclides     89/343/EEC
   shall be labelled in accordance with the regulations for the safe transport of radioactive   Art. 5
   materials laid down by the International Atomic Energy Agency. Moreover, the labelling       (adapted)
   shall comply with the provisions set out in paragraphs 2 and 3.
 · 2. The label on the shielding shall include the particulars mentioned in Article 54. In
   addition, the labelling on the shielding shall explain in full, the codings used on the vial
   and shall indicate, where necessary, for a given time and date, the amount of
   radioactivity per dose or per vial and the number of capsules, or, for liquids, the number
   of millilitres in the container;
   3. The vial shall be labelled with the following infonnation:
         the name or code of the medicinal product, including the name or chemical symbol
         of the radionuclide,
         the batch identification and expiry date,
         the international symbol for radioactivity,
       · the name of the manufacturer,
         the amount of radioactivity as specified in paragraph 2.
                                                         Article 67
   The competent authority shall ensure that a detailed instruction leaflet is enclosed with    89/343/EEC
   the packaging of radiophannaceuticals, radionuclide generators, radionuclide kits or         Art. 6 ( 1)
   radionuclide precursors. The text of this leaflet shall be established in accordance with    (adapted)
· the provisions of Article 59. In addition, the leaflet shall include any precautions to be
   taken by the user and the patient during the preparation and administration of the
   medicinal product and special precautions for the disposal of the packaging and its
   unused contents.
                                                            56
 ---pagebreak---                                                        Article 68
The homeopathic medicinal products shall be identified by a reference on their labels, in 92173/EEC
clear and legible form, to their homeopathic nature.                                        Art. 2 (2}
                                                                                            (adapted) .
                                                      Article69
 1. In addition to the clear mention of the words "homeopathic medicinal.product", the 92173/EEC
labelling and, where appropriate, the package insert for the·medicinal products referred Art. 7 (2) and (3)
to in Article 14 (1) shall bear the following, and no other, information:                   (adapted)
      the seientific name of the stock or stocks followed by the degree of dilution, making
       use of the symbols of the pharmacopoeia used in accordance with Article l (5),
      name and address of the registration holder and, where appropriate, . of the
      manufacturer,
      method of administration and, if necessary, route,
      expiry date, in clear terms (month, year},
      pharmaceutical form,
      contents of the sales presentation,
      special storage precautions, if any,
      a special warning if necessary for the medicinal product,
      manufacturer's batch number,
      registration number,
      "homeopathic medicinal product without approved therapeutic indications",
      a warning advising the user to consult a doctor if the symptoms persist during ·the
      use of the medicinal product.
2·. Notwithstanding paragraph I, Member States may require the use of certain typeS' of
labelling in order to show:
      the pri~ of the medicinal product,
    . the conditions for refunds by social security bodies.
                                                          57
 ---pagebreak---                                                       TITLE VI
                            CLASSIFICATION OF MEDICINAL PRODUCTS
                                                       Article 70
 I. When a marketing authorization is granted, the competent authorities shall specify the     92/26/EEC
classification of the medicinal product into:                                                  Art. 2
     a medicinal product subject to medical prescription,
     a medicinal product not subject to medical prescription.
To this end, the criteria laid down in Article 71 (1) shall apply.
2. The competent authorities may fix sub-categories for medici~al products which are
available on. medical prescription only. In that case, they shall refer to the following
classification:
(a) medicinal products on renewable or non-renewable medical prescription;
(b) medicinal products subject to special medical prescription;
(c) medicinal products on restricted medical prescription, reserved for use in certain
     specialized areas.
                                                      Article 71
1. Medicinal products shall be subject to medical prescription where they:                    92/26/EEC
                                                                                              Art. 3
     are likely to present a danger either directly or indirectly, even when used correctly,  (adapted)
     if utilized without medical supervision, or
     are frequently and to a very wide extent used incorrectly, and as a result are likely to
     present a direct or indirect danger to human health, or
    contain substances or preparations thereof, the activity and/or adverse reactions of
    which require further investigation, or
    are normally prescribed by a doctor to be administered parenterally.
                                                          58
 ---pagebreak--- 2. Where Member States provide for the sub-category of medicinal products subject to            92/26/EEC
special medical prescription, they shall take account of the following factors:                 Art. 3
                                                                                                (adapted)
     the medicinal product ·contains, in a non-exempt quantity, a substance .classified as a
     narcotic or a psychotropic substance within the meaning of the international
     conventions in force, such as the United Nations Conventions of 1961 and 1971, or
     the medicinal product is likely, if incorrectly used, to present a substantial risk of
     medicinal abuse, to lead to addiction or be misused for illegal purposes, or
     the medicinal product contains a substance which, by reason of its novelty or
     properties, could be considered as belonging to the group envisaged in the second
     indent as a precautionary measure.
3. Where Member States provide for the sub-category of medicinal products subject to
restricted prescription, they shall take account of the following factors:
     the medicinal product, because of its phannaceutical characteristics or novelty or in
     the interests of public health, is reserved for treatments which can only be followed
     in a hospital environment,                               ·
     the medicinal product is used in the treatment of conditions which must be
     diagnosed in a hospital environment or in institutions with adequate diagnostic
     facilities, although administration and follow-up may be carried out elsewhere, or
     the medicinal product is intended f~r outpatients but its use may produce very
     serious adverse reactions requiring a prescription drawn up as required by a
     specialist and special supervision throughout the treatment.
4. A competent authority may waive application of paragraphs 1, 2 and 3 having regard
to:
(a) the maximum single dose, the maximum daily dose, the strength, the phannaceutical
     form, certain types of packaging; and/or
(b) other circumstances of use which it has specified.
5. If a competent authority does not designate medicinal products into sub-categories
referred to in Article 70 (2), it shall nevertheless take into account the criteria referred to
in paragraphs 2 and 3 of this Article in determining whether any medicinal product shall
be classified as··a prescription-only medicine.
                                                           59
 ---pagebreak---                                                       Article 72
M~dicinal produc~ not subject to prescription shall be those which do not meet the 192/26/EEC
criteria listed in Article 71.                                                                Art. 4
                                                      Article 73
The competent authorities shall draw up a list of the medicinal products subject, on their    92/26/EEC
territory, to medical prescription, specifying, if necessary, the category of classification. Art. 5 (1)
They shall update this list annually.
                                                      Article 74
On the occasion of the five-yearly renewal of the marketing authorization or when new         92/26/EEC
facts are brought to their notice, the competent authorities shall examine and, as            Art. 5 (2)
appropriate, amend the classification of a medicinal product, by applying the criteria
listed in Article 71.
                                                     Article 75
Each year, Member States shall communicate to the Commission and to the other 192/26/EEC ·
Member States, the changes that have been made to the list referred to in Article 73.         Art. 6 (2)
                                                        60
 ---pagebreak---                                                      TITLE VII
                                    WHOLESALE DISTRIBUTION OF
                                         MEDICINAL PRODUCTS
                                                       Article 76
.Without prejudice to Article 6, Member States shall take all appropriate action to ensure  92/25/EEC
that only medicinal products in respect of which a marketing authorization has been         Art. 2
granted in accordance with Community law are distributed on their territory.
                                                      Article 77
 I. Member States shall take all appropriate measures to ensure that the wholesale          92/25/EEC
distribution of medicinal products is subject to· the possession of an authorization ~o     Art. 3
engage in activity as a wholesaler in medicinal products, stating the place for which it is (adapted)
valid.                                                                                  .
2. Where persons entitled to supply medicinal products to the public may also, under
national. law, engage in wholesale business, such persons shall be subject to the
authorization provid~d for in paragraph 1.
3. Possession of a manufacturing authorization shall include authorization to distribute
by wholesale the medicinal products covered by that authorization. Possession of an
authorization to engage in activity as a wholesaler in medicinal products shall not giv.e
dispensation from the obligation to possess a manufacturing authorization and to comply
with the conditions set out in that respect, even where the manufacturing or import
business is secondary.
4. At the request of the Commission or any Member State, Member States shall supply
all appropriate information concerning the individual authorizations which they have
granted under paragraph 1.
5. Checks on the persons authorized to engage in the activity of wholesaler in medicinal
products and the inspection of their premises, shall be carried out under the
responsibility of the Member State which granted the authorization.
6. The Member State which granted the authorization referred to in paragraph 1 shall
suspend or revoke that authorization if the conditions of authorization cease to be met. It
shall forthwith inform the other Member States and the Commission thereof.
7. Should a Member State consider that, in respect of a person holding an authorization
granted by another Member State under the terms of paragraph 1, the conditions of
authorization are not, or are no longer met, it shall forthwith inf~rm the Commission and
the other Member State involved. The latter shall take the measures necessary and shall
inform the Commission and the first Member State of the decisions taken and the
reasons for those decisions.
                                                          61
 ---pagebreak---                                                         Article 78
 Member States shall ensure that the time taken for the procedure for examining the          92/25/EEC
 application for the distribution authorization does not exceed 90 days from the day on     Art. 4 ( 1)
 which the comj>etent authority of the Member State c:;oncerned receives the application.   (adapted)
 The competent authority may,! if need be, require the applicant to supply all necessary
 information concerning the conditions of authorization. Where the authority exercises
 this option, the period laid down in the first ·paragraph shall be suspended until the
 requisite additional data have been supplied;
                                                        Article 79
 In order to obtain the distribution authorization, applicants must fulfil the following    92/25/EEC
minimum requirements:                                                                       Art. 5
                                                                                            (adapted)
(a) they must have suitable and adequate premises, installations and equipment, so as to
      ensure proper conservation and distribution of the medicinal pro.ducts;
(b) they must have· staff, and in particular, a qualified person designated as responsible,
      meeting the conditions provided for .by the legislation of" the Member State
      concerned;
(c) they must undertake to fulfil the obligations incumbent on them under the terms of
      Article 80.
                                                       Article 80
Holders of the distribution authorization must fulfil the · following minimum               92/25/EEC
requireptents:                                                                              Art. 6
                                                                                            (adapted)
(a) they must make the premises, installations and equipment referred to in
     Article 79 (a) accessible at all times to the persons responsible for inspecting them;
(b) they must obtain their supplies of medicinal products only from persons who are
     themselves in possession of the distribution authorization or who are exempt from
     obta~.ing such authorization under the terms of Article 77 (3);
(c) they must supply medicinal products only to persons who are themselves in
     possession of the distribution authorization or who are authorized or entitled to
     .supply medicinal products to the public in the Member State concerned;
(d) they must have an emergency plan which ensures effective implementation of any
     recall from the market ordered by the competent authorities or carried out in
     cooperation with the manufacturer or marketing authorization holder for the
     medicinal product concerned;
                                                           62
 ---pagebreak--- (e) they must keep records either ·in the form of purchase/sales invoices, or on          92/25/EEC
     computer, or in any other form, giving for any transaction in medicinal products     Art. 6
     received or dispatched at least the following information:                           (adapted)
         date,
          name of the medicinal product,
         quantity received or supplied,
          name and address of the supplier or consignee, as appropriate;
(f) they must keep the records referred to under (e) available to the          competen~
     authorities, for inspection purposes, for a period of five years;
(g) they must comply with the principles and guidelines of good distribution practice for
     medicinal products as laid down in Article 84.
                                                      Article 81
With regard to the supply of medicinal products to pharmacists and persons authorized     92/25/EEC
or entitled to supply medicinal prodUcts to the public, Member States shall not impose    Art. 7
upon the holder of a distribution authorization which has been granted by ·another        (adapted)
Member State,· any obligation, in particular public service obligations, more stringent
than those they impose on persons whom they have themselves authorized to engage in
equivalent activities.
The said obligations should, moreover, be justified, in keeping with the Treaty, on
grounds of public health protection and be proportionate in relation to the objective of
such protection.
                                                      Article 82
For all supplies of medicinal products to a person authorized or entitled to supply       92/25/EEC
medicinal products to the public in the Member State concerned, the authorized            Art. 8
wholesaler must enclose a document that makes it possible to ascertain:
     the date,
     the name and pharmaceutical form of the medicinal product,
     the quantity supplied, ·
     the name and address of the supplier and consignor.
Member States shall take all appropriate measures to ensure that persons authorized or
entitled to supply medicinal products to the. public are able to provide information that
makes it possible to trace the distribution path of every medicinal product.
                                                          63
 ---pagebreak---                                                     Article 83
The provisions of this Title shall not prevent the application of more stringent       92/25/EEC
requirements laid down by Member States in respect of the wholesale distribution of:   Art. 9
                                                                                       (adapted)
    narcotic or psychotropic substances within their territory,
    medicinal products d~rived from blood,
     immunological medicinal products,
    radiopharmaceuticals.
                                                    Article 84
The Commission shall publish guidelines on good distribution practice. To this end, it 92/25/EEC
shall consult the Committee for Proprietary Medicinal Products and the Pharmaceutical  Art. 10
Committee established by Council Decision 75/320/EECl.                                 (adapted)
                                                    Article 85
Member States shall,· in special cases, authorize the direct distribution of medicinal 92/28/EEC
products to the public, by the industry for promotional purposes.                      Art. 3 (6), 2nd sentence
                                                                                       (adapted)
    OJ L 147, 9.6.1975, p. 23.
                                                        64
 ---pagebreak---                                                    TITLE VIII
                                                ADVERTISING
                                                    Article 86
I. For the purposes of this Title, "advertising of medicinal products" shall include any  92/28/EEC
form of door-to-door information, canvassing activity or inducement designed to           Art. 1 (3) and (4)
promote the prescription, supply, sale or consumption of medicinal products; it shall
include in particular:
    the advertising of medicinal products to the general public,
    advertising of medicinal products to persons qualified to prescribe or supply them,
    visits by medical sales representatives to persons qualified to prescribe medicinal
    products,
    the supply of samples,
    the provision of inducements to prescribe or supply medicinal products by the gift,
    offer or promise of any benefit or bonus, whether in money or in kind, except when
    their intrinsic value is minimal,
    sponsorship of promotional meetings attended by persons qualified to prescribe or
    supply medicinal products,
    sponsorship of scientific congresses attended by persons qualified to prescribe or
    supply medicinal products and in particular payment of their travelling and
    ~ccommodation expenses in connection therewith.
2. The following are not covered by this Title:
    the labelling and the accompanying package leaflets, which are subject to the
    provisions of Title V;
    correspondence, possibly accompanied by material of a non-promotional nature,
    needed to answer a specific question about a particular medicinal product;
    factual, informative announcements and reference material relating, for example, to
    pack changes, adverse-reaction warnings as part of general drug precautions, trade
    catalogues and price lists, provided they include no product claims;
    statements relating to human health or diseases, provided there is no reference, even
    indirect, to medicinal products.
                                                        65
 ---pagebreak---                                                          Article 87
    I. Member States shall prohibit any advertising of a medicinal product in respect of 92/28/EEC
    which· a marketing authorization has not been granted in accordance with Community Art. 2
    law.
    2. All parts of the advertising of a medicinal product must comply with the particulars
    listed in the summary of product characteristics.
    3. The advertising of a medicinal product:
         shall encourage the rational use of the medicinal product, by presenting it
         objectively and without exaggerating its properties,
         shall not be misleading.
                                                         Article 88
    I. Member States shall prohibit the advertising to the general public of medicinal       92/28/EEC
    products which:                                                                          Art. 3 (I) to (6), 1st
                                                                                             sentence
         are available on medical prescription only, in accordance with Title VI,            (adapted)
         contain psychotropic or narcotic substances, such as the United Nations Conventions
         of 1961 and 1971,                                                        ·
         may not be advertised to the general public in accordance with the second
         subparagraph of paragraph 2.
    2. Medicinal products may be advertised to the general public which, by virtue of their
    composition and purpose, are intended and designed for use without the invervention of
    a medical practitioner for diagnostic purposes or for the prescription or monitoring of
    treatment, with the advice of the phamiacist, if necessary.
    Member States shall prohibit the mentioning in advertising to the general public of
    therapeutic indications such as:
         tuberculosis,
         sexually transmitted diseases,
         other serious infectious diseases,
         cancer and other tumoral diseases,
         chronic insomnia,
         diabetes and other metabolic ilinesses.
(5)                                                          66
 ---pagebreak--- 3. Member States shall be able to ban, on their territory, advertising to the general public 92/28/EEC
of medicinal products the cost of which may be reimbursed.                                   Art. 3 ( 1) to (6)
                                                                                             1st sentence
4. The prohibition referred to in paragraph 1 shall not apply to vaccination campaigns       (adapted)
carried out by the industry and approved by the competent authorities of the -Member
States.
5. The prohibition referred to in paragraph 1 shall apply without prejudice to Article 14
of Directive 89/552/EEC.
6. Member States shall prohibit the direct distribution of medicinal products to the public
by the industry for promotional purposes.
                                                      Article 89
1. Without prejudice to Article 88, all advertising to the general public of a medicinal     92/28/EEC .
product shall:                                                                               Art. 4
                                                                                             (adapted)
(a) be set out in such a way that it is clear that the message is an advertisement and that
    the product is clearly identified as a medicinal product;
(b) include the following minim.um information:
         the name of the medicinal product, as well as the common name if the
          medicinal product contains only one active substance,
         the information necessary for correct use of the medicinal product,
         an express, legible invitation to read carefully the instructions on   ~he package
          leafle~ or on the outer packaging, as the case may be.
2. Member States may decide that the advertising of a medicinal product to the general
public may, notwithstanding paragraph 1, include only the. name of the medicinal
product if it is intended solely as a reminder.
                                                          67
 ---pagebreak---                                                       Article 90
The advertising of a medicinal product to the general public shall not contain any           92/28/EEC
material which:                                                                              Art. 5
                                                                                             (adapted)
(a) gives the impression that a medical consultation or surgical operation is
     unnecessary, in particular by offering a diagnosis or by suggesting treatment by
     mail;
(b) suggests that the effects of taking the medicine are guaranteed, are unaccompanied
     by adverse reactions or are better than, or equivalent to, those of another treatment
     or medicinal product;
(c) suggests that the health of the subject can be enhanced by taking ~he medicine;
(d) suggests that the health of the subject could be affected by not taking the medicine;
     this prohibition shall not apply to the vaccination campaigns referred to in
     Article 88 (4);
(e) is directed exclusively or principally at children;
(f) refers to a recommendation by scientists, health professionals or persons who are
     neither of the foregoing but who, because of their celebrity, could encourage the
     consumption of medicinal products;
(g) suggests that the medicinal product is a foodstuff, cosmetic or other consumer
     product;
(h) suggests that the safety or efficacy of the medicinal product is due to the fact that it
     is natural; ·
(i) could, by a description or detailed representation of a case history, lead to erroneous
     self-diagnosis;
G)   refers, in improper, alarming or misleading terms, to cli;iims of recovery;
(k) uses, in improper, alarming or misleading terms, pictorial representations of changes
     in the human body caused by disease or injury, or of the action of a medicinal
   · product on the human body or parts thereof;
(I) mentions that the medicinal product has been granted a marketing authorization.
                                                         68
 ---pagebreak---                                                       Article 91
 I. Any advertising of a medicinal product to persons qualified to prescribe or supply       92/28/EEC
such products shall include:                                                                 Art. 6
     essential infonnation compatible with the summary of product characteristics;
     the supply classification of the medicinal product.
 Member States may also require such advertising to include the selling price or
 indicative price of the various presentations and the conditions for reimbursement by
social security bodies.
2. Member States may decide that the advertising of a medicinal product to persons
qualified to prescribe or supply such products may, notwithstanding paragraph l, include
only the name of the medicinal product, if it is intended solely as a reminder.
                                                     Article 92
.1. Any documentation relating to a medicinal product which is transmitted as part of the    92/28/EEC
promotion of that product to persons qualified to prescribe or supply it shall include, as a Art. 7
minimum, the particulars listed in Article 91 (1) and shall state the date on which it was
drawn up or last revised.
2. All the infonnation contained in the documentation referred to in paragraph I shall be
accurate, up-to-date, verifiable and sufficiently complete to enable the recipient to fonn
his or her own opinion of the therapeutic value of the medicinal product concerned.
3. Quotations as well as tables and other illustrative matter taken from medical journals
or other scientific works for use in the doctunentation referred to in paragraph I shall be
faithfully reproduced and the precise sources indicated.
                                                         69
 ---pagebreak---                                                        Article 93
  1. Medical .sales representatives shall be given adequate training by the firm which          92128/EEC
  employs them and shall have sufficient scientific knowledge to be able to provide             Art. 8
  information which is precise and as complete as possible about the medicinal products
  which they promote.
  2. During each visit, medical sales representatives shall give the persons visited, or have
  available for them, summaries of the product characteristics of each medicinal product
  they present together, if the legislation of the Member State so permits, with details of
  the price and conditions for reimbursement referred to in Article 91 ( 1).
  3. Medical sales representatives shall transmit to the scientific service referred to in
  Article 98 ( 1} any information about the use of the medicinal products they advertise,
  with particular reference to any adverse reactions reported to them by the persons they
  visit.
                                                       Article 94
  1. Where medicinal products are being promoted to persons qualified to prescribe or 92/28/EEC
  supply them, no gifts, pecuniary advantages or benefits in kind may be supplied, offered Art. 9
  or promised to such persons unless they are inexpensive and relevant to the practice of (adapted)
  medicine or pharmacy.
  2. Hospitality at sales promotion shall always be reasonable in level and secondary to the
  main purpose of the meeting and must not be extended to other than health
  professionals.
  3. Persons qualified to prescribe or supply medicinal products shall not solicit or accept
  any inducement prohibited under paragraph 1 or contrary to paragraph 2.
  4. Existing measures or trade practices in Member States relating to prices, margins and
  discounts shall not be affected by paragraphs 1, 2 and 3.                       ·
                                                       Article 95
. The provisions of Article 94 (1) shall not prevent hospitality being offered,. directly or 92/28/EEC
  indirectly, at events for purely professional and scientific purposes; such hospitality shall Art. 10
  always be reasonable in level and remain subordinate to the main scientific objective of
  the meeting; it must not be extended to persons other than health professionals.
                                                            70
 ---pagebreak---                                                       Article 96
 I. Free samples shall be provided on an exceptional basis only to persons qualified to  92/28/EEC
prescribe them and on the following conditions:                                          Art. 11
                                                                                         (adapted)
(a) the number of samples for each medicinal product each year on prescription shall
     be limited;
(b) any supply of samples shall be in response to a written request, signed and dated,
     from the prescribing agent;
(c) those supplying samples shall maintain an adequate system of control and
     accountability;
(d) each sample shall be identical with the smallest presentation on the market;
(e) each sample shall be marked "free medical sample- not for sale" or shall show some
     other wording having the same meaning;
(f) each sample shall be accompanied by a copy of the summary of product
     characteristics;
(g) no samples of medicinal products containing psychotropic or narcotic substances
     within the meaning of international conventions, such as the United Nations
     Conventions of 1961 and 1971, may be supplied.
2. Member States may also place further restrictions on the distribution of samples of
certain medicinal products.
                                                     Article 97
1. Member States shall ensure that there are adequate and effective methods to monitor 92/28/EEC
the advertising of medicinal products. Such methods, which may be based on a system Art. 12 (1) and (2)
of prior vetting, shall in any event include legal provisions under which persons or.
organizations regarded under national law as having a legitimate interest in prohibiting
any advertisement inconsistent 'with this Title, may take legal action against such
advertisement, or bring such advertisement before an adm!nistrative authority competent
either to decide on complaints or to initiate appropriate legal proceedings.
                                                         71
 ---pagebreak---  2. Under the legal provisions referred to in paragraph I, Member States shall confer            92/28/EEC
 upon the courts or administrative authorities powers enabling them, in cases where they         Art. 12 (1) and (2)
 deem such measures to be necessary, taking into account all the interests involved, and         (adapted)
 in particular the pub~ic interest:
       to order the cessation of, or to institute appropriate legal proceedings for an order for
       the cessation of, misleading advertising,
       or
     · if misleading advertising has not yet been published but publication is imminent, to
       or~er the prohibition of, or to institute appropriate legal proceedings for an order for
       the prohibition of, such publication,
 even without proof of actual loss or damage or of intention or negligence on the part of
.the advertiser."
 3. Member States shall make provision for the measures referred to in the second
 subparagraph to be taken under an accelerated procedure, either with interim effect or
 with defmitive effect. ·
 It shall be for each Member State to decide which of the two options set out in the first
 subparagraph to select..
 4. Member . States may confer upon the courts or administrative authorities powers
 enabling them, with a view to eliminating the continuing effects of misleading
 advertising the cessation of which has been ordered by a final decision: ·
       to require publication of that decision in full or in part and in such form as they
       deem adequate~
       to require in addition the publication of a corrective statement.
 5. Paragraphs 1 to 4 shall not exclude the voluntary control of advertising of medicinal        92/28/EEC
 products by self-regulatory bodies and recourse to such bodies, if proceedings before           Art. 12 (4)
 such bodies are possible in addition to the judicial or administrative proceedings referred     (adapted)
 to in paragraph 1.
                                                              72
 ---pagebreak---                                                      Article 98
 1. The marketing authorization holder shall establish, within his undertaking, a scientific  92/28/EEC
 service in charge of information about the medicinal products which he places on the         Art. 13
 market.                                                                                      (adapted)
 2. The marketing authorization holder shall:
     keep available for, or communicate to, the authorities or bodies responsible for
     monitoring advertising of medicinal products, a sample of aJI advertisements
     emanating from his undertaking together with a statement indicating the persons to
     whom it is addressed, the method of dissemination and the ·date of first
     disse~ination,
     ensure that advertising of medicinal products by his undertaking conforms to the
     requirements of this Title,
     verify that medical sales representatives employed by his undertaking have been
     adequately trained and fulfill the obligations imposed upon them by Article 93 (2)
     ~d (3),
     supply the authorities or bodies responsible for monitoring advertising of medicinal
     products with the information and assistance they require to carry out their
     responsibilities,
     ensure that the decisions taken by the authorities or bodies responsible for
     monitoring'advertising of medicinal products are immediately and fully complied
     with.
                                                     Article 99
Member States shall take the appropriate measures to ensure that the provisions of this      92/28/EEC
Title are applied and shall determine in particular what penalties shall be imposed should   Art. 14
the provisions adopted in the execution of Title be infringed.                               (adapted)
                                                    Article 100
Advertising of the homeopathic medicinal products referred to in Article 13 (2) and 92173/EEC
Article 14 (I) shall be subject to the provisions of this Title with the exception of Art. 6 (3)
Article 87 (1).
However, only the information specified in Article 69 (I) may be used in the advertising
of such medicinal products.
Moreover, each Member State may prohibit in its territory any advertising of the
homeopathic medicinal products referred to in Article 13 (2) and Article 14 (1).
                                                        73
 ---pagebreak---                                                     TITLE IX
                                         PHARMACOVIGILANCE
                                                    Article 101
The Member States shall take all appropriate measures to encourage doctors and other      75/319/EEC
health care professionals to report suspected adverse reactions to the competent          Art. 29e
authorities.                                                                              (as amended by
                                                                                          93/39/EEC Art. 3 (3)) .
The Member States may impose specific requirements on medical practitioners, in           (adapted)
respect of the reporting of suspected serious or unexpected adverse reactions, in
particular where such reporting is a condition of the marketing authorization.
                                                    Article 102
In order to ensure the adoption of appropriate regulatory decisions concerning the        75/319/EEC
medicinal products authorized within the Community, having regard to information          Art. 29a
obtained al>out adverse reactions to medicinal products under normal conditions of use,   (as amended by
the Member States shall establish a pharmacovigilance system. This system shall be used   93/39/EEC Art. 3 (3))
to collect information useful in the .surveillance of medicinal products, with particular
reference to adverse reactions in human beings, and to , evaluate such information
scientifically.
_Such information shall be collated with data on consumption of medicinal products.
This system shall also collate information on frequently observed misuse and serious
abuse of medicinal products.
                                                        74
 ---pagebreak---                                                     Article 103
The marketing authorization holder shall have permanently and continuously at his             75/31.9/EEC
disposal an appropriately qualified person responsible for pharmacovigilance.                 Art. 29c
                                                                                              (as amended by
That qualified person shall be responsible for the following:                                 93/39/EEC Art. 3 (3))
                                                                                              (adapted)
(a) the establishment and maintenance of a system which ensures that information about
     all suspected adverse reactions which are reported to the personnel of the company,
     and to medical representatives, is collected and collated at a single point within the
     Community;
(b) the preparation for the competent authorities of the reports referred to in Article I 04,
     in such form as may be laid down by those authorities, in accordance with the
     relevant national or Community guidelines;
(c) ensuring that any request from the competent authorities for the prov1s1on .of
     additional information necessary for the evaluation of the benefits and risks afforded
     by a medicinal product is answered fully and promptly, including the provision of
     information about the volume of sales or prescriptions of the medicinal product
     concerned.
                                                    Article 104
I. The marketing authorization holder shall be required to record and to report all           75/319/EEC
suspected serious adverse reactions which are brought to his attention by a health care       Art. 29d
professional to the competent authorities immediately, and in any case within 15 days of      (as amended by
their receipt at the latest.                                                                  93/39/EEC Art. 3 (3))
                                                                                              (adapted)
2. The marketing authorization holder shall be required to maintain detailed records of
all other suspected adverse reactions which are reported to him by a health care
professional.
Unless other requirements have been laid down as a condition of the granting of
authorization, these records shall be submitted to the competent authorities immediately
upon request or at least every six months during the first two years following
authorization, and once a year for the following three years. Thereafter, th~ records shall
be submitted at five-yearly intervals together with the application for renewal of the
authorization, or immediately upon request. These records shall· be accompanied by a
scientific evaluation.
                                                        75
 ---pagebreak---                                                      Article 105
The Member States shall ensure that reports of suspected serious adverse reactions are      75/319/EEC
immediately brought to the attention of the Agency and the marketing authorization          Art. 29f
hold~r, and in any case within 15 days of their notification, at the latest.                (as amended by
                                                                                            93/39/EEC Art. 3 (3))
                                                                                            (adapted)
                                                     Article 106
In order to facilitate the exchange of information about pharmacovigilarice within the      75/319/EEC
Community, the Commission, in consultation with the Agency, Member States and               Art. 29g
interested parties, shall draw up guidance on the collection, verification and presentation (as amended by
of adverse reaction reports.                                                                93/39/EEC Art. 3 (3))
This guidance shall take account of international harmonization work carried out with
regard to terminology and classification in the field of pharmacovigilance.
                                                     Article 107
Where, as a result of the evaluation of adverse reaction reports, a Member State            75/319/EEC
considers that a marketing authorization should be varied, suspended or withdrawn, it       Art. 29h
shall forthwith inform the Agency and the marketing authorization holder.                   (as amended by
                                                                                            93/39/EEC Art. 3 (3))
In case of urg~ncy,. the competent authority concerned may suspend the marketing of a       (adapted)
medicinal product, provided the Agency is informed ·at the late~t on the following
working day.
                                                     Article 108
Any amendments which may be necessary to update provisions of Articles 10 1 to I 07 to      7 5/319/EEC
take account of scientific and technical progress shall be adopted in accordance with the   Art. 29i
procedure laid down in Article 122.                                                         (as amended by
                                                                                            93/39/EEC Art. 3 (3))
                                                                                            (adapted)
                                                          76
 ---pagebreak---                                                      TITLE X
           SPECIAL PROVISIONS ON MEDICINAL PRODUCTS DERIVED FROM
                                    HUMAN BLOOD AND PLASMA
                                                    Article 109
1. In respect of the use of human blood or human plasma as a starting material for the 89/381/EEC
manufacture of medicinal products, Member States shall take the necessary measures to Art. 3 (1), (2) and (3)
prevent the transmission of infectious diseases. In so far as this is covered by the (~dapted)
amendments referred to in Article 121, as well as the application of the monographs of
the European Pharmacopoeia regarding blood and . plasma, these measures shall
comprise those recommended by the Council of Europe and the . World Health
Organization, particularly with reference to the selection and testing _of blood and plasma
donors.
2. Member States shall take the necessary measures to ensure _that human blood and
human plasma donors and donation centres are always clearly identifiable.
3. All the safety guarantees referred to in paragraphs I and 2 must also be given by
importers of human blood or human plasma from third countries.
                                                   Article 110
Member States shall take the necessary measures to promote Community                        89/381/EEC
self-sufficiency in human blood or human plasma. For this purpose, they shall encourage     Art. 3 (4)
the voluntary unpaid donation of blood and plasma and shall take the necessary              (adapted)
measures to develop the production and use of products derived from human blood or
human plasma coming from voluntary unpaid donations. They shall notify the
Commission of such measures.
                                                         77
 ---pagebreak---                                                   TITLE XI
                                    SUPERVISION AND SANCTIONS
                                                  Article 111
 I. The competent authority of the Member State concerned shall ensure, by means of 75/319/EEC
.repeated inspections, that the legal requirements governing medicinal products are Art. 26, 1st paragraph
complied with.                                                                          (as amended by
                                                                                        89/341/EEC Art. 3 (6))
Such inspections shall be carried out by officials representing the competent authority 75/319/EEC
who shall be empowered to:                                                              Art. 26 (2)
                                                                                        (adapted)
(a) inspect manufacturing or commercial establishments and any laboratories entrusted
     by ·the holder of the manufacturing authorization with the task of carrying out
     checks pursuant to Article 20;
(b) take samples;
(c) examine any documents relating to the object of the inspection, subject to the
     provisions in force in the Member States on 21 May 1975 and which place
     restrictions on these powers with regard ·to the descriptions of the method of
     preparation.
2. Member States shall. take all appropriate steps to ensure that the manufacturing     89/342/EEC
processes used in the manufacture of immunological products are properly validated and  Art. 4 ( 1)
attain batch-to-batch consistency.
3. After every inspection as referred to in paragraph 1, the officials representing the 75/319/EEC
competent authority shall report on whether the manufacturer complies with the          Art. 26, 3rd paragraph
principles and guidelines of good manufacturing practice laid down in Article 4 7. The  (as amended by
content of such reports shall be communicated to the manufacturer who has to undergo    89/341/EEC Art. 3 (6))
the inspection.                                                                         (adapted)
                                                  Article 112
Member States shall take all appropriate measures to ensure that the person responsible 65/65/EEC
for marketing a medicinal product and, where appropriate, the holder of the             Art. 8
manufacturing authoriza~ion, furnish proof of the controls carried out on the medicinal +
product and/or the ingredi~nts and of the controls carried out at an intermediate       75/319/EEC
stage of the manufacturing process, in accordance with the methods laid down in         Art. 27
Article 8 (3) (h).                                                                      (adapted)
                                                      78
 ---pagebreak---                                                       Article 113
"For the purpose of implementing Article 112, Member States may require manufacturers       89/342/EEC
 of immunological products to submit to a competent authority copies of all the control     Art. 4 (2)
 reports signed by the qualified person in accordance with Article 51.                      +
                                                                                            89/381/EEC
                                                                                            Art. 4 (2)
                                                      Article 114
  I. Where it considers it necessary in the interests of public health, a Member State may  89/342/EEC
 require the holder of an authorization for marketing:                                      Art. 4 (3)
                                                                                            (adapted)
      live vaccines,
      immunological medicinal products used in the primary immunization of infants or of
      other groups at risk,
      immunological medicinal products used in public health immunization programmes,
      new immunological medicinal products or immunological medicinal products
      manufactured using new or altered kinds of technology or new for a particular
      manufacturer, during a transitional period normally specified in the marketing
      authorization,
 to submit samples from each batch of the bulk and/or the medicinal product for
 examination by a State laboratory or a laboratory designated for that purpose before
 release on to the market unless, in the case of a batch manufactured in another Member
 State, the competent authority of that Member State has previously examined the batch
 in question and declared it to be in conformity with the approved specifications. Member
 States shall ensure that any such examiniation is completed within 60 days of the receipt
 of the samples.
 2. Where, in the interests of public health, the laws of a Member State so provide, the    89/381/EEC
competent authorities may require the marketing authorization holder for medicinal          Art. 4 (3)
 products derived from human blood or human plasma to submit samples from each              (adapted)
 batch of the bulk and/or the medicinal product for testing by a State laboratory or a
 laboratory designated for that purpose before being released into free circulation, unless
the competent authorities of another Member State have previously examined the batch
 in question and declared it to be in conformity with the approved specifications.
 Member States shall ensure that any such examination is completed within 60 days of
the receipt of the samples.
                                                          79
 ---pagebreak---                                                      Article 115
  ·Member States shall take all necessary measures to ensure that the manufacturing and       89/381/EEC
. purifying processes used in the preparation of medicinal products derived from human        Art. 4 ( 1)
  blood or human plasma are properly validated, attain batch-to-batch consistency and
  guarantee, insofar as the state of technology permits, the absence of specific viral
  contamination. To this end manufacturers shall notify the competent authorities of the
  method used to reduce or eliminate pathogenic viruses liable to be transmitted by
  medicinal products derived from human blood or human plasma. The competent
  authority may submit samples of the bulk and/or the medicinal product for testing by a
   State laboratory or a laboratory designated for that purpose, either during the
  examination of the application pursuant to Article 19, or after a marketing authorization
   has been granted.
                                                     Article 116
  The competent authorities of the Member States shall suspend or revoke an authorization     65/65/EEC
  to place a medicinal product on the market where that product proves to be harmful in       Art. 11, 1st paragraph
  the normal conditions of use, or where its therapeutic efficacy is lacking, or where its    (as amended by
  qualitative and quantitative composition is not as declared. Therapeutic efficacy is        89/341/EEC Art. 1 (1 ))
   lacking when it is established that therapeutic results cannot be obtained with the
  medicinal product.
  An authorization shall also be suspended or revoked where the particulars supporting the 65/65/EEC
  application as provided for in Articles 8, 10 (1) and 11 are incorrect or have not been . Art. 11, 2nd paragraph
  amended in accordance with Article 23.                                                      (as amended by
                                                                                            · 83/570/EEC Art. 1 (6))
                                                         80
 ---pagebreak---                                                       Article 117
 I. Notwithstanding the measures provided for in Article 116, Member States shall take       75/319/EEC
 all appropriate measures to ensure that the supply of the medicinal product shall be        Art. 28
prohibited and the medicinal product withdrawn from the market if:                           (adapted)
 (a) the medicinal product proves to be harmful under normal conditions of use, or
(b) it is lacking in therapeutic efficacy, or
(c) its qualitative and .quantitative composition is not as declared, or
(d) the controls on the m~dicinal product and/or on the ingredients and the controls at an
      intermediate stage of the manufacturing. process have not been carried out or if some
     other requirement or obligation relating to the grant of the manufacturing
     authorization has not been fulfilled.
2. The competent authority may limit the prohibition to supply the product, or its
withdrawal from the market, to those batches which are the subject of dispute.
                                                     Article 118
1. The competent authority shall suspend or revoke the marketing authorization for a        75/319/EEC
category of preparations or all preparations where any one of the requirements laid down    Art. 29
in Article 41 is no longer met.                                                             (adapted)
2. In addition to the measures specified in Article 117, the competent authority may
suspend manufacture or imports of medicinal products coming from third countries, or
suspend or revoke the manufacturing authorization for a category of preparations or all
preparations where Articles 42, 46, 51 and 112 are not complied with.
                                                     Article 119
The provisions ofthis Title shall apply to homeopathic medicinal products.                  92173/EEC
                                                                                            Art. 4 (1)
                                                                                            (adapted)
                                                         81
 ---pagebreak---                                                       TITLE XII
                                             STANDING COMMITTEE
                                                       Article 120
    1. A Standing Committee on Medicinal Products for Human Use on the Adaptation to          75/318/EEC
    Technical Progress of the Directives on the Removal ofTechni~al Barriers to trade in the  Art. 2b
    Medicinal Products Sector, hereinafter called "the Standing Committee", is hereby set     (adapted)
    up; it shall consist of representatives of the Member States with a representative of the
    Commission as chainnan. .
    2. The Standing Co!'lmittee shall adopt its own rules of procedure.
                                                       Article 121
    Any changes which are necessary in order to adapt Annex I to take account of scientific   75/3I8/EEC
    and technical progress shall be adopted in accordance with the procedure laid down in     Art. 2a, I st paragraph
    Article 122.                                                                              (as amended by
                                                                                              87/19/EEC Art. I (I))
                                                                                              (adapted)
                                                           82
(6)
 ---pagebreak---                                                    Article 122
Where the procedure laid down in this Article is to be followed, the Commission shall be   75/319/EEC
assisted by the Standing Committee.                                                        Art. 37a
                                                                                           (as amended by
The representative of the Commission shall submit to the Standing Committee a draft of     93/39/EEC Art. 3 (4))
the measures to be taken. The Standing Committee shall deliver its opinion on the draft    (adapted)
within a time limit which the Chairman may lay down according to the urgency of the
matter. The opinion shall be delivered by the majority laid down in Article 205 (2) of the
Treaty in the case of decisions which the Council is required to adopt on a proposal from
the Commission. The votes of the representatives of the Member States within the
Standing Committee shall be weighted in the manner set out in that Article. The
Chairman shall not vote.
The Commission shall adopt the measures envisaged if they are in accordance with the
opinion of the Standing Committee.
If the measures envisaged are not in accordance with the opinion of the Standing
Committee, or if no opinion is delivered, the Commission shall, without delay, submit to
the Council a proposal relating to the measures to be taken. The Council shall act by a
qualified majority.
If on the expiry of a period of three months from the date of referral to the Council, the
Council has not acted, the proposed measures shall be adopted by the Commission.
                                                   Article 123
Where the procedure laid down in this Article is to be followed, the Commission shall be   75/319/EEC
assisted by the Standing Committee.                                                        Art. 37b
                                                                                           (as amended by
The representative of the Commission shall submit to the Standing Committee a draft of     93/39/EEC Art. 3 (4))
the measures to be taken. The Standing Committee shall deliver its opinion on the draft    (adapted)
within a time limit which the Chairman may lay down according to the urgency of the
matter. The opinion shall be delivered by the majority laid down in Article 205 (2) of the
Treaty in the case of decisions which the Council is required to adopt on a proposal from
the Commission. The votes of the representatives of the Member States within the
Standing Committee shall be weighted in the manner set out in that Article. The
Chairman shall not vote.
The Commission shall adopt the measures envisaged if they are in accordance with the
opinion of the Standing Committee.
If the. measures envisaged are not in accordance with the opinion of the Standing
Committee, or if no opinion is delivered, the Commission shall, without delay, submit to
the Council a proposal relating to the measures to be taken. The Council shall act by a
qualified majority.
If on the expiry of a period of three months from the date of referral to the Council, the
Council has not acted, the proposed measures shall be adopted by the Commission, save
where the Council has decided against the said measures by a simple majority. ·
                                                        83
 ---pagebreak---                                                    TITLE XIII
                                          GENERAL PROVISIONS
                                                   . Article 124
Member States shall take all appropriate measures to ensure that the competent             75/319/EEC
authorities concerned communicate to each other such information as is appropriate to      Art. 30, 1st paragraph
guarantee that the requirements for the manufacturing authorizations or marketing          (adapted)
authorizations are fulfilled.
Upon reasoned request, Member States shall forthwith communicate the reports referred      75/319/EEC
to in Article Ill (3) to the competent authorities of another Member State. If, after      Art. 30, 2nd paragraph
considering the reports, the Member State receiving the reports considers that it cannot   (as amended by
accept the conclusions reached by the competent authorities of the Member State in         89/341/EEC Art. 3 (8))
which the report was established, it shall inform the competent authorities concerned of
its reasons and may request further information. The Member States concerned shall use
their best endeavours to reach agreement. If necessary, in the case of serious differences
of opinion, the Commission shall be informed by one of the Member States concerned.
                                                     Article 125
1. Each Member State shall take all the appropriate measures to ensure that decisions      75/319/EEC
authorizing marketing, refusing or revoking a marketing authorization, cancelling a        Art. 33 (1)
decision refusing or revoking a marketing authorization, prohibiting supply, or            (adapted)
withdrawing a product from the market, together with the reasons on which such
decisions are based, are brought to the attention of the Agency forthwith.
2. The marketing authorization holder shall be obliged to notify the Member States         75/319/EEC
concerned forthwith of any action taken by him to suspend the marketing of a medicinal     Art. 33 (2) to (4)
product or to withdraw a medicinal product from the market, together with the reasons      (as amended by
for such action if the latter concerns the efficacy of the medicinal product or the        89/341/EEC Art. 3 (9))
protection of public health. Member States shall ensure that this information is brought   (adapted)
to the attention of the Agency.
3. Member States shall ensure that appropriate information about action taken pursuant
to paragraphs 1 and 2 which may affect the protection of public health in third countries
is forthwith brought to the attention of the World Health Organization, with a copy to the
Agency.
4. The Commission shall publish annually a list of the medicinal products which are
prohibited in the Community.
                                                          84
 ---pagebreak---                                                     Article 126
Member States shall communicate to each other all the information necessary to            92173/EEC
guarantee the quality and safety of homeopathic medicinal products manufactured and       Art. 5
marketed within the Community, and in particular the information referred to in
Articles 124 and 125.
                                                    Article 127
Every decision referred to in this Directive which is taken by the competent authority of 65/65/EEEC
a Member State shall state in detail the reasons on which it is based.                    Art. 12
                                                                                          (adapted)
Such decision shall be notified to the party concerned, together with information as to +
the redress available to him under the laws in force and of the time-limit allowed for 75/319/EEC
access to such redress.                                                                   Art. 31
                                                                                          (adapted)
Marketing authorizations, and decisions to revoke such authorizations, shall be +
published by each Member State in the appropriate official publication.                   92/25/EEC
                                                                                          Art. 4 (2)
                                                                                          (adapted)
                                                                                          +
                                                                                          92/27/EEC
                                                                                          Art. 11 (2)
                                                                                          (adapted)
                                                                                          +
                                                                                          92/28/EEC
                                                                                          Art. 12 (3)
                                                                                          (adapted)
                                                         85
 ---pagebreak---                                                     Article 128
An authorization to market a medicinal product shall not be refused, suspended or 165/65/EEC
revoked except on the grounds set out in this Directive.                                    Art. 21
No decision concerning suspension of manufacture or of importation of medicinal 75/319/EEC
products coming from third countries, prohibition of supply or withdrawal from the Art. 32
market of a medicinal product may be taken except on the ground set out in Articles 117 (adapted)
and 118.            ·
                                                    Article 129
I. At the request of the manufacturer, the exporter or the authorities of an importing      75/319/EEC
third country, Member States.shall certify that a manufacturer of medicinal products is in  Art. 28a
possession of the manufacturing authorization. When issuing such certificates               (as amended by
Member. States shall comply with the following conditions:                                  89/341/EEC Art. 3 (7))
                                                                                            (adapted)
(a) they shall have regard to the prevailing administrative arrangements of the World
     Health Organi7.ation;
(b) for medicinal products intended for export which are already authorized on their
     territory, they shall supply the summary of the product characteristics as approved in
     accordance with Article 21.
2. When the manufacturer is not in possession of a marketing authorization he shall
provide the authorities responsible for establishing the certificate referred to . in
paragraph I, with a declaration explaining why no marketing authorization is available.
                                                        86
 ---pagebreak---                                                    TITLE XIV
                                             FINAL PROVISIONS
                                                    Article.130
Directives 65/65/EEC, . 75/318/EEC, 75/319/EEC, 89/342/EEC, 89/343/EEC,
89/381/EEC, 92/25/EEC, 92126/EEC, 92/27/EEC, 92/28/EEC and 92/73/EEC, amended
by the Directives referred to in Annex 11, Part A, are repealed, without prejudice to the
obligations ~f the Member States concerning the time-limits for implementation set out
in Annex 11, Part B. ·
References to the repealed Directives shall be construed as 'references to this Directive
and shall be read in accordance with the correlation table in Annex Ill.
                                                    Article 131
This Directive shall enter into force on 1 January 2000.
                                                    Article 132
This Directive is addressed to the Member States.
Done at Brussels,
For the European Parliament                                     For the Council
The President                                                   The President
                                                         87
 ---pagebreak---                                          ANNEX I
                ANALYTICAL, PHARMACOTOXICOLOGICAL
           AND CLINICAL STANDARDS AND PROTOCOLS IN
                                RESPECT OF THE TESTING OF
                                  MEDICINAL PRODUCTS
INTRODUCTION                                                                               75/318/EEC
                                                                                           Annex
The particulars and documents accompanying an application for marketing authorization      (as amended by
pursuant to Articles 8 and 10 (1) shall be presented in four parts, in accordance with the 91/507/EEC Art. 1)
requirements set out in this Annex and taking account of the guidance published by the     (adapted)
Commission in The rules governing medicinal products in the European Community,
Volume 2: Notice to applicants for marketing authorizations/or medicinal products for
human use in the Member States ofthe European Community.
In assembling the dossier for application for marketing authorization, applicants shall
take into account the Community guidelines relating to the quality, safety and efficacy of
medicinal products published by the Commission in The rules governing medicinal
products in the European Community, Volume 3 and its supplements: Guidelines on the
quality, safety and efficacy ofmedicinal products for human use.
All infonnation which is relevant to .the evaluation of the medicinal product concerned
shall be included in the application, whether favourable or unfavourable to the product.
In particular, all relevant details shall be given of any incomplete or abandoned
phannacotoxicological or clinical test or trial relating to the medicinal product.
Moreover, in order to monitor the benefit/risk assessment after marketing authorization
has been granted, any change to the data in the dossier, any new infonnation not in the
original application and all pharmacovigilance reports, shall be submitted to the
competent authorities.
The general sections of this Annex give the requirements for all categories of medicinal
products; they are supplemented by sections containing additional special requirements
for radiopharmaceuticals and for biological medicinal products, such as immunological
medicinal products derived from human blood or pl~ma. The additional special
requirements for biological medicinal products are also applicable to medicinal products
obtained through processes mentioned in the first indent of Part A and the first indent of
Part B of the Annex to Regulation (EEC) No 2309/93 ..
Member States shall also ensure that all tests on animals are conducted in accordance
with Council Directive 86/609/EEC of 24 November 1986 on the approximation of laws,
regulation and· administrative provisions of the Member States regarding the. protection
of animals for experimental and other scientific purposes 1 •
    OJ L 358, 18.12.1986, p. I.
                                                        88
 ---pagebreak---  PART I                                                                                    75/318/EEC
                                                                                           Annex
SUMMARY OF THE DOSSIER                                                                     (as amended by
                                                                                           91/507/EEC Art. 1)
A. Administrative data                                                                     (adapted}
The medicinal product which is the subject of the application shall be identified by name
and name of the active substance(s), together with the phannaceutical fonn, the method
of administration, the strength and the fmal presentation, including packaging.
The name and address of the applicant shall be given, together with the name and
address of the manufacturers and the sites involved in the different stages of the
manufacture (including the manufacturer of the finished product and the manufacturer(s)
of the active substance(s)), and where relevant the name and address of the importer.
The applicant shall identify the number of volumes of documentation submitted in
support of the application and indicate what samples, if any, are also provided.
Annexed to the administrative data shall be copies of the manufacturing authorization as
defmed in Article 40, together with a list of countries in which authorization has been
granted, copies of all the summaries of product characteristics in accordance with Article
11 as approved by Member States and a list of countries in which an application has
been submitted.
B. Summary of product characteristics
The applicant shall propose a summary of the product characteristics, in accordance with
Article 11.
In addition the applicant shall provide samples or mock-ups of the packaging, labels and
package leaflets for the medicinal product concerned.
                                                        89
 ---pagebreak--- C. Expert reports                                                                           75/318/EEC
                                                                                            Annex
In accordance with Article 12 (2), expert reports must be provided on the chemical,         (as amended by
phannaceutical and biological documentation, the phannacotoxicological documentation        91/507/EEC Art. 1)
and the clinical documentation respectively.                                                (adapted)
The expert report shall consist of a critical evaluation of the quality of the medicinal
product and the investigations carried out on animals and human beings and bring out all
the data relevant for evaluation. It shall be worded so as to enable the reader to obtain a
good understanding of the properties, quality, the proposed specifications and control
methods, the safety, the efficacy, the advantages and disadvantages of the medicinal
product.
All important data shall be summarized in an appendix to the expert report, whenever
possible including report formatS in tabular or in graphic form. The expert report and the
summaries shall contain precise cross references to the information contained in the
main documentation.
Each expert report shall be prepared by a suitably qualified and experienced person. It
shall be signed and dated by the expert, and attached to the report shall be brief
information about the educational background, training and professional experience of
the expert. The professional relationship of the expert to the applicant shall be declared.
                                                         90
 ---pagebreak---  PART2                                                                                       75/318/EEC
                                                                                             Annex
CHEMICAL, PHARMACEUTICAL                      AND      BIOLOGICAL          TESTING       OF  (as amended by
MEDICINAL PRODUCTS                                                                           911507/EEC Art. 1)
                                                                                             (adapted)
All the test procedures shall correspond to the state of scientific progress at the time and
shall be validated procedures; results of the validation studies shall be provided.
All the test procedure(s) shall be described in sufficiently precise detail so as to be
reproducible in control tests, carried out at the request of the competent authority; any
special apparatus and equipment which may be used shall be described in adequate
detail, possibly accompanied by a diagram. The formulae of the laboratory reagents shall
be supplemented, if necessary, by the manufacturing method. In the case of test
procedures included in the European Pharmacopoeia or the pharmacopoeia of a
Member State, this description may be replaced by a detailed reference to the
pharmacopoeia in question.
A. Qualitative and quantitative particulars of the constituents
The particulars and documents which must accompany· applications for marketing
auth~rization, pursuant to point 3 of Article 8 (3) (c) shall be submitted in accordance
with the following requirements.
I. Qualitative partiCulars
1.1. "Qualitative particulars" of all the constituents of the medicinal product shall mean
the designation or description of:
     the active substance(s),
     the constituent(s) of the excipients, whatever their nature or the quantity used,
     including colouring matter, preservatives, adjuvants, stabilizers, thickeners,
     emulsifiers, flavouring and aromatic substances, etc.,
     the constituents, intended to be ingested or otherwise administered ,to the patient, of
     the outer covering· of the medicinal products - capsules, gelatine capsules, rectal
     capsules, etc.
These particulars shall be supplemented by any relevant data concerning the container
and, where appropriate, its manner of closure, together with details of devices with
which the medicinal product will be used or administered and which will be delivered
with the medicinal product.
                                                         91
 ---pagebreak---  1.2. In the context of a radiopharmaceutical kit, which is to be radio labelled after supply             75/318/EEC
 by the manufacturer, the active substance is considered to be that part of the fonnulation               Annex
 which is intended to carry or bind the radionuclide. Details of the source of the                        (as amended by
 radionuclide shall be stated. In addition, any compounds essential for the radiolabelling                91/507/EEC Art. 1)
 shall be stated.                                                                                         (adapted)
 In a· generator, both mother and ~.aughter radionuclides are to be considered as active
 substances.
 2. The ''usual tenninology", to be used in describing the constituents of medicinal
 products, shall mean, notwithstanding the application of the other provisions in Article 8
 (3) (c):
      in respect of substances which appear in the European Pharmacopoeia or, failing
      this, in the national pharmacopoeia of one of the Member States, the main title at the
      head of the monograph in question, with reference to the pharmacopoeia concerned,
      in respect of other .substances, the international non-proprietary name recommended
      by the World Health Organization, which may be accompanied by another non-
      proprietary name, or, failing these, the exact scientific designation; substances not
      having an international non-proprietary name or an exact scientific designation shall
      be described by a statement of how and from what they were prepared,
      supplemented, where appropriate, by any other relevant details,
      in respect of colouring matter, designation by the "E" code assigned to them in
      Council ·Directive 78/25/EEC of 12 December 1977 on the approximation of the
      rules of the Member States concerning the colouring matters authorized for use in
      medicinal products 1•
.3. Quantitative particulars
 3.1. In order to give "quantitative particulars" of the active substances of t~e medicinal
 products, it is necessary, depending on the pharmaceutical fonn concerned, to specify
 the mass, or the number of units of biological activity, either per dosage-unit or per unit
 of mass or volume, of each active substance.
 Units of biological activity shall be used for substances which cannot be defmed
 chemically. Where an International Unit of biological activity has been defined by the
 World Health Organization, this shall be used. Where no International Unit has been
 defmed, the units of biological activity shall be expressed in such a way as to provide
 unambiguous infonnation on the activity of the substances.
 Whenever possible, biological activity per units of mass shall be indicated.
      OJ L 11, 14.1.1978, p. 18. Directive as last amended by the Act of Accession of Spain and Portugal.
                                                                              92
 ---pagebreak--- This information shall be supplemented:                                                     75/318/EEC
                                                                                            Annex
      in respect of injectable preparations, by the mass or units of biological activity of (as amended by
      each active substance in the unit container, taking into account the usable volume of 91/507/EEC Art. 1)
      the product, after reconstitution, where appropriate,                                 (adapted)
      in respect of medicinal products to be administered by drops, by the mass or units of
      biological activity of each active substance contained in the number of drops
      corresponding to 1 ml or 1 g of the preparation,
      in respect of syrups, emulsions, granular preparations and other pharmaceutical
      forms to be administered in measured quantities, by the mass or units of biological
      activity of each active substance per measured quantity.                         ·
3.2. Active substances present in the form of compounds or derivatives shall be
designated quantitatively by their total mass, and if necessary or relevant, by the mass of
the active entity or entities of the molecule.
3.3 .. For medicinal products containing an active substance which is the subject of an
application for marketing authorization in any Member State for the first time, the
quantitative statement of an active substance which is a salt. or hydrate shall be·
systematically· expressed in terms of the mass of the active entity or entities in the
molecule. All subsequently authorized medicinal products in the Member States shall
have their quantitative composition stated in the same way for the same active substance.
3.4. For immunological medicinal products, the quantitative particulars shall be
expressed by units of biological activity, except for well defined immunoligical
medicinal products for which the concentration may be expressed by mass/unit of
volume.
3.5. The requirement to 'express the content of active substances in terms of the mass of
active entities, as in point 3.3. above, may not apply to radiopharmaceuticals. For
radionuclides, radioactivity shall be expressed in becquerels at a given date and, if
necessary, time with reference to time zone. The type of radiation shall be indicated.
4. Development pharmaceutics
4.1. An explanation should be provided with ·regard to the choice of composition,
constituents arid container and the intended function of the excipients in the finished
product. This explanation shall be supported by scientific data on development
pharmaceutics. The overage during manufacture, with justification thereof, should be
stated.
4.2. For radiopharmaceuticals, this should include a consideration                       of
chemical/radiochemical purity and its relationship to biodistribution.
                                                          93
 ---pagebreak---                                                                                               75/318/EEC
B. Description of manufacturing method                                                        Annex
                                                                                              (as amended by
 1. The description of the manufacturing method accompanying. the application for 911507/EEC Art 1)
marketing authorization pursuant to point 4 of Article 8 (3) (d), shall be drafted in such a (adapted)
way ·as to give an adequate synopsis of the nature of the operations employed.
For this purpose it shall include at least:
     mention of the various stages of manufacture, so that an assessment can be made of
     whether the processes employed in producing the pharmaceutical form might have
     produced an adverse change in the constituents,
     in the case of continuous ma~ufacture, full details concerning precautions taken to
     ensure the homogeneity of the finished product,
     the actual manufacturing formula, with the quantitative particulars of all the
     substances used, the quantities of excipients, however, being given in approximate
     terms in so far as the pharmaceutical form makes this necessary; mention shall b'e
     made of any substances that may disappear in the course of manufacture; any
     overage shall be indicated and justified,
:-   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 the quality control of the finished product,
     experimental studies validating the manufacturing process, where a non-standard
     method of manufacture is used or where it is critical for the product,
     for sterile medicinal products, details of the sterilization processes   ~d/or   aseptic
     procedures used.
2. For radiopharmaceutical kits, the description of the manufacturing method shall also
include details of the manufacture of the kit and details of its recommended final
processing to produce the radioactive medicinal product.
For radionuclides, the nuclear reactions involved shall be discussed.
C. Controls of starting materials
 1. For the purposes of this section, "starting materials" shall mean all the constituents of
the medicinal product and, if necessary, of its container, as referred to in Section A,
point I~ above.
                                                          94
 ---pagebreak---  In the case of:                                                                              75/318/EEC
                                                                                             ·Annex
      an active substance not described in the European Pharmacopoeia or in the (as amended by
      pharmacopoeia of a Member State, or                                                     91/507/EEC Art. 1)
                                                                                             (adapted)
      an active substance described in the European Pharmacopoeia or in the
      pharmacopoeia of a Member State when prepared by a method liable to leave
      impurities not mentioned in the pharmacopoeia} monograph and for which the
      monograph is inappropriate to adequately control its quality,
which is manufactured by a person different from the applicant, the latter may arrange
 for the detailed description of the manufacturing method, quality control during
 manufacture and process validation to be supplied directly to the competent authorities
 by the manufacturer of the active substance. In this case, the manufacturer shall however
 provide the applicant with all the data which may be necessary for the latter to take
responsibility for the medicinal product. The manufacturer shall confirm in writing to
the applicant that he shall ensure batch to batch consistency and not modify the
manufacturing process or specifications without informing the applicant. Documents and
 particulars supporting the application for such a change shall be supplied to the
competent authorities.
The particulars and documents accompanying the application for marketing
authorization pursuant to Article 8 (3) (h) and (i) and 10 (1), shall include the results of
the tests, including batch analyses particularly for active substances, relating to quality
control of all the constituents used. These shall be submitted in accordance with the
following provisions.
 1.1. Starting materials listed in pharmacopoeias
The monographs of the European Pharmacopoeia shall be applicable to all substances
appearing in it.
-In respect of other substances, each Member State may require observance of its own
national pharmacopoeia with regard to products manufactured in its territory.
Constituents fulfilling- the requirements of the European Pharmacopoeia or the
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently with
Article 8 (3) (h). In this case the description of the analytical methods may be replaced
by a detailed reference to the pharmacopoeia in question.
                                                         95
 ---pagebreak---  However, where a starting material in the European Pharmacopoeia or in the                 75/318/EEC
 pharmacopoeia of a Member State has been prepared by a method liable to leave              Annex
 impurities not controlled in the pharmacopoeia monograph, these impurities and their       (as amended by
maximum tolerance limits must be declared and a suitable test procedure must be             91/507/EEC Art. I)
described.                                                                                  (adapted)
Colouring matter shall, in all cases, satisfy the requirements of Directive 78/25/EEC.
The routine tests carried out on each batch of starting materials must be as stated in the
application for ·marketing authorization. If tests other than those mentioned in the
 pharmacopoeia are used, proof must be supplied that the starting materials meet the
quality requirements of that pharmacopoeia.
 In cases where a specification contained in a monograph of the European
Pharmacopoeia or in the national pharmacopoeia of a Member State might be
 insufficient to ensure the quality of the substance, the competent authorities may request
mor~ appropriate spe_cifications from the marketing authorization holder.
The competent authorities shall inform the authorities responsible for the pharmacopoeia
'in question. The marketing authorization holder shall provide the authorities of that
pharmacopoeia with the details of the alleged insufficiency and the additional
specifications applied.
In cases where a starting material is described neither in the European Pharmacopoeia
nor In the pharmacopoeia of a Member State, compliance with the monograph of a third
country pharmacopoeia can be accepted; in such cases, the applicant shall submit a copy
of the monograph accompanied where necessary by the validation of the test procedures
contained in the monograph and by a translation where appropriate.
 1.2. Starting materials not in a pharmacopoeia
Constituents which are not given in any pharmacopoeia shall be described in the form of
a monograph under the following headings: ·
(a) The name of the substance, meeting the requirements of Section A, point 2, shall be
      supplemented by any trade or scientific synonyms;
(b) the definition of the substance, set down in a form similar to that used in the
      European Pharmacopoeia, shall be accompanied by any necessary explanatory
      evidence, especially concerning the molecular structure where appropriate; it must
      be accompanied by an appropriate description of the method of synthesis. Where
      substances can only be described by their manufacturing method, the description
      should be sufficiently detailed to characterize a substance which is constant both in
      its composition and in its effects;
(c) methods of identification may be described in the form of complete techniques as
      used for production of the substance, and in the form of tests which ought to be
      carried out as a routine matter;
                                                          96
 ---pagebreak---  (d) purity tests shall be described in relation to the sum total of predictable impurities, 75/318/EEC
     especially those which may have a harmful effect, and, if necessary, those which, Annex
     having regard to the combination of substances to which the application refers, (as amended by
     might adversely affect the stability of the medicinal product or distort analytical 911507/EEC Art. I)
     results;                                                                                                    (adapted)
(e) with regard to complex substances of plant or animal/human origin, a distinction
     must be made between the ~ase where multiple pharmacological effects render
     chemical, physical or biological control of the principal constituents necessary, and
     the case of substances containing one or more groups of principles having similar
     activity, in respect of which an overall method of assay may be accepted;
(f) when materials of animal/human origin are used, measures to ensure freedom from
     potentially pathogenic agents shall be described;
(g) for radionuclides, the nature of the radionuclide, the identity of the isotope, likely
     impurities, the carrier, the use and the specific activity shall be given;
(h) any special precautions that may be necessary during storage of the starting material
     and, if necessary, the maximum period of storage before retesting shall be given.
1.3. Physico-chemical characteristics liable to effect bio-availabi/ity
The following items of information concerning active substances, whether or not listed
in the pharmacopoeias, shall be provided as part of the general description of tbe active .
substances if the bio-availability of the medicinal product depends on them:
     crystalline form and solubility coefficients,
     particle size, where appropriate after pulverization,
     state of solvation,
     oiVwater coefficient of partition 1 •
The first three indents are not applicable to substances used solely in solution.
2. For biological medicinal products, such as immunological medicinal products and
medicinal products derived from human blood or plasma, the requirements of this
paragraph shall apply.
    The competent authorities may also request the pK and pH values if they think this infonnation is essential.
                                                                           97
 ---pagebreak---       For the purposes of this paragraph, starting materials shall mean any substance used in     75/318/EEC
      the manufacture of the medicinal product; this includes the constituents of the medicinal   Annex
      product, and, if necessary, of its container, as referred to in paragraph A, point I above, (as amended by
      as well as source materials such as microorganisms, tissues of either plant or animal       91/507/EEC Art. I)
      origin, cells or fluids (including blood) of human or animal origin, and biotechnological   (adapted)
      cell constructs. The origin and history of starting materials shall be described and
      documented.
      The description of the starting material shall include the manufacturing strategy,
      purification/inactivation procedures with their validation and all in-process control
      procedures designed to ensure the quality, safety and batch to batch consistency of the
      finished product.
      2.1. When cell banks are used, the cell characteristics shall be shown to have remained
      unchanged at the passage level used for the production and beyond.
    · 2.2. Seed materials, cell banks, pools of serum or plasma and other materials of
      biological origin and, whenever possible, the source materials from which they are
     derived shall be tested for adventitious agents.
      If the presence of potentially pathogenic adventitious agents is inevitable, the
      correspondant material shall be used only when further proc~ssing ensures their
      elimination and/or inactivation, and this shall be validated.
      2.3. Whenever possible, vaccine production shall be based on a seed lot system and on
      established cell banks; for serums, defined pools of starting materials shall be used.
      For bacterial and viral vaccines, the characteristics of the infectious agent shall be
      demonstrated on the seed. In addition, for live vaccines, the stability of the attenuation
      characteristics shall be demonstrated on the seed;· if this proof is not sufficient, the
      attenuation characteristics shall also .be demonstrated at the production stage.
      2.4. For immunological medicinal products, the specifications and control methods for
      the source materials shall be described in as much detail as possible. The description
      shall include particulars concerning collection, pretreatment and storage.
     2.5. For medicinal products derived from human blood or plasma, the origin and the
     criteria and procedures for collection, transportation and storage of the source material
     shall be described and documented .
     .Defined pools of source material shall be used.
     3. For radiopharmaceuticals, starting materials include irradiation target materials.
                                                               98
(7)
 ---pagebreak--- D. Control tests carried out at intermediate stages of the manufacturing process             75/318/EEC
                                                                                             Annex
I. The particulars and documents accompanying an application for marketing                   (as amended by
authorization, pursuant to Article 8 (3) (h) and (i) and Article IO, paragraph I of this     911507/EEC Art. 1)
Directive, shall include particulars relating to the product control tests that may be       (adapted)
carried out at an intermediate stage of the manufacturing process, with a view to
ensuring the consistency of the technical characteristics and the production process.
These tests are essential for checking the conformity of the medicinal product with the
formula when, exceptionally, an applicant proposes an analytical method for testing the
finished product which does not include the assay of all the active substances (or of all
the excipient constituents subject to the same requirements as the active substances).
The same applies where the quality control of the finished product depends on in-
process control tests, particularly if the medicinal product is essentially defined by its
method or preparation.
2. For biological medicinal products, such as immunological medicinal products and
medicinal products derived from human blood or plasma, the procedures and the criteria
of acceptability published as recommendations of the WHO (Requirements for
Biological Substances) shall serve as guidelines for all controls of production stages
which are not specified in the European Pharmacopoeia, or falling this, in the national
pharmacopoeia of a Member State.
For inactivated or detoxified vaccines, effective inactivation or detoxification shall be
verified during each production run, unless this control is dependent upon a test for
which the availability of susceptible animals is limited. In this case, the test shall be
carried out until consistency of production and correlation with appropriate in process
controls have been established and thereafter compensated by appropriate in-process
controls.
3. For modified or adsorbed immunological medicinal products, the products shall be
qualitatively and quantitatively characterized at an intermediate stage, as late as possible
in the manufacturing process.
E. Control tests on the finished product
1. For the control of the fmished product, a batch of a medicinal product comprises all
the units of a pharmaceutical form which are made from the same initial quantity of
material and have undergone the same series of manufacturing and/or sterilization
operations or, in the case of a continuous production process, all the units manufactured
in a given period of time.
                                                         99
 ---pagebreak---  The application for marketing authorization shall list those tests which are carried out    75/318/EEC
 routinely on each batch of finished product. The frequency of the tests which are not       Annex
carried out routinely shall be stated. Release Jjmits shall be indicated.                    (as amended by
                                                                                             91/507/EEC Art. I)
The particulars and documents accompanying the application for marketing                     (adapted)
authorization pursuant to Article 8 (3) (b) and (i) and Article 10 (I) of this Directive,
shall include particulars relating to control tests on the finished product at release. They
shall be submitted in accordance with the following requirements.
The provisions of the monographs for pharmaceutical forms, immunosera, vaccines and
radiopharmaceutical preparations of the European Pharmacopoeia or failing that, of a
Member State, shall be applicable to all products defined therein. For all controls of
biological medicinal products such as immunological medicinal proqucts and medicinal
products derived from human blood or plasma which are not specified in the European
Pharmacopoeia or failing this, in the pharmacopoeia of a Member State, the procedures
and the criteria of acceptability published as recommendations in the WHO
(Requirements for Biological Substances) shall serve as guidelines.
If test procedures and limits other than those mentioned in the monographs of the
European Pharmacopoeia, or failing this, in the national pharmacopoeia of a Member
State, are used, proof shall be supplied .that the finished product would, if tested in
accordance with those monographs, meet the quality requirements of that
pharmacopoeia for ~e pharmaceutical form concerned.
 1.1. General characteristics ofthe finished product
Certain tests of the general characteristics of a product shall alway~ be included among
the tests on the finished product. These tests shall, wherever applicable, relate to the
control of average masses and maximum deviations, to mechanical, physical or
microbiological tests, organoleptic characteristics, physical characteristics such as
density, pH, refractive index, etc. For each of these characteristics, standards and
tolerance limits shall be specified by the applicant in each particular case.
The conditions of the tests, where appropriate, the equipment/apparatus employed and
the standards shall be described in precise details whenever they are not given in the
European Pharmacopoeia or the pharmacopoeia of the Member States; the same shall
apply in cases where the methods prescribed by such pharmacopoeias are not applicable.
Furthermore, solid pharmaceutical forms having to be administered orally shall be
subjected to in vitro studies on the liberation and dissolution rate of the active substance
or substances; these studies shall also be carried out where administration is by another
means if the competent authorities of the Member State conc~rned consider this
necessary.
                                                         100
 ---pagebreak---   1.2. JdenJijication and assay ofactive substan~e(s)                                          75/318/EEC
                                                                                               Annex
 Identification and assay of the active substance(s) shall be carried out either in an         (as amended by
 average representative sample from the production batch or in a number of dosage-units        91/507/EEC Art. I)
 analysed individually.                                                                        (adapted)
 Unless there is appropriate justification, the maximum acceptable deviation in the active
 substance content of the finished product shall not exceed ± ·5% at the ·time of
 manufacture.
 On the basis of the stability tests, the manufacturer must propose and justify maximum
 acceptable tolerance limits in the active substance content of the finished product up to
 the end of the proposed shelf-life.
 In certain exceptional. cases of particularly complex mixtures, where. assay of active
 substances which are very numerous or present in very low amounts would necessitate
 an intricate investigation difficult to carry out in respect of each production batch, the
 assay of one or more active 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 the characterization of the substances
 concerned. This simplified technique shall be supplemented by a method of quantitative
 evaluation, enabling the competent authority to have the conformity of the medicinal
 product with its specification verified after it has been placed on the market.
 An in vivo or in vitro biological assay shall be obligatory when physico-chemical
 methods cannot provide adequate information on the quality of the product. Such an
assay shall, whenever possible, include reference materials and statistical analysis
 allowing calculation of confidence limits. Where these tests cannot be carried out on the
 finished product, they may be performed at an intermediate stage, as late as possible in
 the manufacturing process.
 Where the particulars given in section B show that a significant overage of an active
 substance is employed in the manufacture of the medicinal product, the description of
 the control tests 01:1 the finished product shall include, where appropriate, the chemical
and, if necessary, the toxico-pharmacological ~nvestigation of the changes that this
substance has undergone, and possibly the characterization and/or assay of the
degradation products.
 1.3. Identification and assay ofexcipient constituents
In so far as is necessary, the excipient(s) shall be subject at least to identification tests.
The test procedure proposed for identifying colouring matters must enable a verification
to be made that such matters appear in the list annexed to Directive 78/25/EEC.
A~    upper and lower limit test shall be obligatory in respect of preserving agents and an
upper limit test for any other excipient constituent liable to affect adversely organic
functions; an upper and lower limit test shall be obligatory in respect of the excipient if it
-is liable to affect the bio-availability of an active substance, unless bio-availability is
guaranteed by other appropriate tests.
                                                           101
 ---pagebreak---    1.4. Safety tests                                                                           75/318/EEC
                                                                                               Annex
  Apart from the phannacotoxicological tests submitted with the application for marketing      (as amended by
  authorization, particulars of safety tests, such as sterility, bacterial endotoxin,          91/507/EEC Art. I}
  pyrogenicity and local tolerance in animals shall be included in the analytical particulars  (adapted)
  wherever such tests must be undertaken as a mauer of routine in order to verify the
  quality of the product
  2. For all controls of biological medicinal. products, such as immunological medicinal
  products and medicinal products derived from human blood or plasma, which are not
  specified in the European Pharmacopoeia, or failing this, in the national pharmacopoeia
  of a Member State, the procedures and the ~riteria of acceptability published as
  recommendations in the World Health Organization (Requirements for Biological
  Substances) shall serve as guidelines.
  3. For· radiopharmaceuticals, radionuclidic purity, radiochemical purity and specific
  activity shall be described. For content of radioactivity, the deviation from that stated on
  the label should not exceed ± 10%.
  For generators, details on the testing for mother and daughter radionuclides are required.
  For generator-eluates, tests for mother radionuclides and for other components of the
  generator system s\lall be provided.
  For kits, the specifications of the finished product shall include tests on performance of
  products after radiolabelling. Appropriate controls on radiochemical and radionuclidic
  purity of the radiolabelled compound shall be included. Any material essential for
  radiolabelling shall be identified and assayed.
  F. Stability tests
  I. The particulars and documents accompanying the application for marketing
  authorization pursuant to Article 8 (3} (g) and (h) shall be submitted in accordance with
  the following requirements.
  A description shall be given of the investigations by which the shelf life, the
  recommended storage conditions and the specifications at the end of the shelf-life
  proposed by the applicant have been determined.
· Where a finished product is liable to give rise to degradation products, the applicant
  mus~ declare these and indicate characterization methods and test procedures.
  The conclusions shall contain the results of analyses, justifying the proposed shelf life
  under the recommended storage conditions and the specifications of the finished product
· at the end of the shelf-life under these recommended storage conditions.
                                                          102
 ---pagebreak--- The maximum acceptable level of degradation products at the end of shelf-life shall be         75/318/EEC
'indicated.                                                                                    Annex
                                                                                               (as amended by
A study of the interaction between product and container shall be submitted wherever           91/507/EEC Art. I)
the risk of such interaction is regarded as possible, especially where injectable              (adapted)
prep~ations or aerosols for internal use are concerned.
2. Where for biological medicinal products, such as immunological medicinal products
and medicinal products derived from human blood or plasma, stability tests cannot be
carried out on the finished products, it is acceptable to carry out stability indicating tests
at an intermediate stage of production as late as possible in the manufacturing process. In
addition, there should be an evaluation of the stability of the finished product using other
secondary tests.
3. For radiophannaceuticals, information on stability shall be given for radionuclide
generators, radionuclide kits and . radio labelled products. The stability during use of
radiophannaceuticals in multi-dose vials shall be documented.
                                                        103
 ---pagebreak---    PART3                                                                                                      75/318/EEC
                                                                                                              Annex
   TOXICOLOGICAL AND PHARMACOLOGICAL TESTS                                                                    (as amended by
                                                                                                              91/507/EEC Art. 1)
   I. Introduction                                                                                            (adapted)
   1. The particulars and documents accompanying the application for marketing
  authorization pursuant to Articles 8 (3) (i) and 10 (1) shall be given in accordance with
  the requirements below.
   Member States shall ensure that the safety tests are carried out in conformity with the
  provisions relating to good laboratory practice laid down by Council Directives
  87/18/EECI and 88/320/EEC2.
  The toxicological and pharmacological tests must show:
· (a) the potential toxicity of the product and any dangerous or undesirable toxic effects
        that may occur under the proposed conditions of use in human beings; these should
        be evaluated in relation to the pathological condition concerned;
  (b) the pharmacological properties of the product, in both qualitative and quantitative
        relationship to th'e ptoposed use in human beings. All results must be reliable and of
        general applicability. Whenever appropriate, mathematical and statistical procedures
        shall be used in designing the experimental methods and in evaluating the results.
  Additionally, it is necessary for clinicians to be given information about the therapeutic
  potential of the product.
  2. Where a medicinal product is intended for topical use, reabsorption must be
  investigated, due account also being taken of the possible use of the product on broken
  skin and absorption· through other relevant surfaces. Only if it is proved that systemic
  absorption under these conditions is negligible may repeated dose systemic toxicity tests,
  foetal toxicity tests and studies of reproductive function be omitted.
  If, however, reabsorption is demonstrated during therapeutic experimentation, toxicity
  tests shall be carried out on animals, including where necessary, foetal toxicity tests.
  In all cases, tests of local tolerance after repeated application shall. be carried out with
  particular care and include histological examinations; the possibility of sensitization
  shall be investigated and any carcinogenic potential investigated in the cases referred to
  in Section 11 E of this Part.
 I     OJ LIS, 17.1.1987, p. 29.
 2     OJ L 145, 11.6.1988, p. 35; .Directive as amended by Direc:tive 90/18/EEC (OJ L 11, 13.l.l990, p. 37).
                                                                              104
 ---pagebreak---    3. For biological medicinal products such as immunological medicinal products and          75/318/EEC
   medicinal products derived from human blood or plasma, the requirements of this Part       Annex
   may have to be adapted for individual products; therefore the testing programme carried    (as amended by
. out shall be justified by the applicant.                                                    9 11507/EEC Art. I)
                                                                                              (adapted)
  In establishing the testing programme, the following shall be taken into consideration:
        all tests requiring repeated administration of the product shall be designed to take
        account of the possible induction of, and interference by, antibodies;
        examination of reproductive function, of embryo/foetal and perinatal toxicity, of
        mutagenic potential and of carcinogenic potential shall be considered. Where
        components other than the active substance(s) are incriminated, validation of their
        removal may replace the study.
  4. For radiopharmaceuticals, it is appreciated .that toxicity may be associated with a
  radiation dose. In diagnosis, this is a consequence· of the use of radiophannaceuticals; in
  therapy, it is the wanted property. The evaluation of safety and efficacy of
  radiopharmaceuticals shall, therefore, address requirements for medicinal products and
  radiation dosimetry aspects. Organ/tissue exposure to radiation shall be documented.
  Absorbed radiation dose estimates shall be cal~ulated according to a specified,
  'internationally recognized system by a particular route of administration.
  5. The toxicology and pharmacokinetics of an excipient used for the first time in the
  pharmaceutical field shall be investigated.
  6. Where there is a possibility of significant degradation during storage of the medicinal
  product, the toxicology of degradation products must be considered.
  11. Performance of tests
  A. Toxicity
   I. Single dose toxicity
  An acute test is a qualitative and quantitative study of the toxic reactions which may
  result from a single administration of the active substance or substances contained in the
  medicinal product, in the proportions and physico-chemical state in which they are
  present in the actual product.
  The acute toxicity test must be carried out in two or more mammalian species of known
  strain unless a single species can be justified. At least two different routes of
  administration shall normally be used, one being identical with or similar to that
  proposed for use in human beings and the other ensuring systemic exposure to the
  substance.
                                                           I05
 ---pagebreak--- This study will cover the signs observed, including local reactions. The period during          75/318/EEC ·
which the test animals are observed shall be fixed by the investigator as being adequate        Annex
tc;l reveal tissue or organ d8:ffiage or recovery, usually for a period of 14 days but not less (as amended by
than 7 days, but without exposing the animals to prolonged suffering. Animals dying             91/507/EEC Art. 1)
during the observation period should be subject to autopsy as also should all animals           (adapted)
surviving to the end of the observation period. Histopathological examinations should be
considered on any organ showing macroscopic changes at autopsy. The maximum
amount of information should be obtained from the animals used in the study.
The -single dose toxicity tests should be conducted in such a way that signs of acute
toxicity are revealed and the mode of death assessed as far as reasonably possible. In
suitable species, a quantitative evaluation of the approximate lethal dose and information
on the dose effect relationship should be obtained, but a high level of precision is not
requ~red.
These studies may give some indication of the likely effects of acute overdosage in man
and may be. useful for the design of toxicity studies requiring repeated dosing on the
suitable animal species.
In the case of active substances in combination, the study must be carried out in such a
way as to check whether or not there is enhancement of toxicity or if novel toxic effects
occur.
2. Repeated dose toxicity (sub-acute or chronic toxicity),
Repeated dose toxicity tests are intended to reveal any physiological and/or anatomo-
pathological changes induced by repeated administration of the active substance or
combination of active substances under examination, and to determine how· these
changes are related to dosage.
Generally, it is desirable that two tests be performed: one short-term, lasting two to four
weeks, the other long-term. The duration of the latter shall depend on the conditions of
clinical use. Its purpose shall be to determine by experiment the non-toxic dose range of
the product and normally it shall last three to six months.
In respect of medicinal products to be administered once only to humans, a single test
lasting two to four weeks shall be performed.
If however, having regard to the proposed duration of use in ·human beings, the
investigator sees fit to carry out experiments of greater or lesser duration than indicated
above, he must give adequate reasons for doing so.
Reasons should.also be given forthe dosages chosen.
                                                            106
 ---pagebreak---  Repeated dose toxicity tests shall be carried out on two species of mammals one of 75/318/EEC
 which must be a non-rodent. The choice of route(s) of administration employed shall Annex
 depend on the intended therapeutic use and the possibilities of systemic absorption. The (as amended by
 method and frequency of dosage shall be clearly stated.                                  91/507/EEC Art. I)
                                                                                          (adapted)
 The maximum dose should be chosen so as to bring harmful effects to light. The lower
 doses will then enable the animal's tolerance of the product to be determined.
 Wherever possible, and always in experiments on small rodents, the design of the
 experiment and the control procedures must be suited to the scale of the problem being
 tackled and enable fiducial limits to be determined.
The evaluation of the toxic effects shall be ba8ed on observation of behaviour, growth,
 haematological and biochemical tests, especially those relating to the excretory
mechanism, and also on autopsy reports and accompanying histological data. The choice
and range of each group of tests will depend on the speci~s of animal used and the· state
of scientific knowledge at the time.
·Jn the case of new combinations of known substances that have been investigated in
accordance with the provisions of this Directive, the chronic long-term tests may, except
where acute and sub-acute toxicity tests have demonstrated potentiation or novel. toxic
effects, be suitably modified by the investigator who shall submit ~is reasons for such
modification.
B. Examination ofreproductive function
If the results of other tests reveal anything suggesting harmful effects on progeny or
impairment of male or female rep~oductive function, this shall be investigated by
appropriate tests.
C. Embryo/foetal and perinatal toxicity
This investigation comprises a demonstration of the toxic and especially the teratogenic
effects observed in the issue of conception when the medicinal product under
investigation has been ad!Dinistered to the female during pregnancy.
Although up to the present these tests have had only a limited predictive value in regard
to the application of the results to human beings, they are thought to provide important
information where the results show effects such as resorptions and other anomalies.
Omission of these tests, eith~r because the medicinal product will not normally be used
by women capable of child-bearing or for other reasons, must be adequately justified.
                                                        107
 ---pagebreak---  Embryo/foetal toxicity studies shall normally be conducted on two mammalian species,       75/318/EEC
 one of which should be other than a rodent. Peri- and postnatal studies shall be           Annex
 conducted in at least one species. Where metabolism of a medicinal product in a            (as amended by
 particular species is known to be similar to that in man, it is desirable to include this  91/507/EEC Art. 1)
 species. Also, it is desirable that one of the species is the same as in the repeated dose (adapted)
~oxicity studies.
 The details of the test (number of animals, amounts administered, timing of
 administration and· criteria for evaluation of results) shall depend on the state of
 scientific knowledge at the time when the application is lodged, and the level of
 stati~tical significance that the results must attain.
 D. Mutagenic potential
The purpose of the study of mutagenic potential is to reveal the changes which a
substance may cause in the genetic material of individuals or cells and which have the
effect of making successors permanently· and hereditarily different from their
predec~ssors. This study is obligatory for any new substance.
The number and types of results and the criteria for their evaluation shall depend on the
state of scientific knowledge at the time w:hen the application is lodged.
E. Carcinogenic potential
Tests to reveal carcinogenic effects shall normally be required:
(a) in respect of substances having a close chemical analogy with known carcinogenic
      or cocarcinogenic compounds;
(b) in respect of substances which have given rise to suspicious changes during the
      long-term toxicological tests;
(c) in respect of substances which have given rise to suspicious results in the mutagenic-
    . potential tests or in other short-term carcinogenicity tests.
Such tests may also be required in respect of substances to be included in medicinal
products likely to be administered regularly over aprolonged period of a patient's life.
The state of scientific knowledge at the time when the application is lodged shall be
taken into account when determining the details of the tests.
                                                          108
 ---pagebreak---  F. Pharmacodynamics                                                                        75/318/EEC
                                                                                            Annex
 This heading covers the variations caused by the medicinal product in the functions of (as amended by
 the physiological systems, whether these functions are normal or experim.entally 911507/EEC Art. I) ·
 modified.                                                                                  (adapted)
 This study shall follow two distinct lines of approach.
Firstly, the actions on which the recommended application in therapeutic practice is
 based shall be adequately described. The results shall be expressed in quantitative terms
 using, (for example, dose-effect curves, time-effect curves etc.), and wherever possible,
compared with data relating to a substance whose activity is known. Where a higher
therapeutic potency is being claimed for a substance, the difference shall be
demonstrated and shown to be statistically significant.
.Secondly, the investigator shall provide a general pharmacological characterization of
the substance, with special reference to adverse reactions. In general, the main functions
of the physiological systems should be investigated. The depth of this investigation must
be increased as the doses liable to produce adverse reactions approach those producing
the main effect for which the substance is being proposed.
The experimental techniques, unless they are standard procedures, must be described in
such detail as to allow them to be reproduced, and the investigator must establish their
validity. The experimental results shall be set out clearly and, when relevant to the test,
their statistical significance quoted.
Unless good reasons are given to the contrary, any quantitative modification of
responses resulting from repeated administration of the substance shall be investigated.
Tests on combinations of active substances may be prompted either by pharmacological
premisses or by indications of therapeutic effect
In the first case, the pharmacodynamic study shall demonstrate those interactions which
might make the combination of value in therapeutic use.
In the second case, where scientific justification for the combination is sought through
therapeutic experimentation, the investigation shall determine whether the effects
expected from the combination can be demonstrated in animals, and the importance of
any collateral effects shall at least be investigated.
If a combination includes a novel active substance, the latter must previously have been
studied in depth.
                                                         109
 ---pagebreak---  G. Pharmacokinetics                                                                      75/318/EEC
                                                                                          Annex
 PharmacokineticS means the study of the fate of the active substance within the          (as amended by
 organism, and covers the study of the absorption, distribution, biotransformation and    91/507/EEC Art. 1)
 excretion of the substance.                                                              (adapted)
 The study of these different phases may be carried out both by means of physical,
 chemical or biological methods, and by observation of the actual pharmacodynamic
 activity of the substance itself.
 Information on distribution and elimination (i.e. biotransformation and excretion) shall
 be necessary in all cases where such data are indispensable to determine the dosage for
 humans, and in respect of chemotherapeutic substances (antibiotics, etc.) and substances
 whose use depends on their non-pharmacodynamic effects (e.g. numerous diagnostic
 agents, etc.).
 Pharmacokinetic investigation ofpharmacologically active substances is necessary.
In the case of new combinations of known substances which have been investigated in
accordance with the provisions of this Directive, .pharmacokinetic studies may not be
required, if the toxicity tests and therapeutic experimentation justify their omission.
H. Local tolerance
The purpose of local tolerance studies is to ascertain whether medicinal products (both
.active substances and excipients) are tolerated at sites in the body which may come into
contact with the medicinal product as a result of its administration in clinical use. The
testing strategy shall be such that any mechanical effects of administration or purely
physico-chemical actions of the product can be distinguished from toxicological or
pharmacodynamic ones.
                                                         110
 ---pagebreak---     PART 4                                                                                      75/318/EEC
                                                                                                Annex
   CLINICAL DOCUMENTATION                                                                       (as amended by
                                                                                                91/507/EEC Art. I)
   The particulars and documents accompanying applications for marketing authorizations         (adapted)
   pursuant to Articles 8 (3) (i) and 10 (1) of this Directive shall be submitted in accordance
   with the provisions below.
   A clinical trial is any systematic study of medicinal products in human subjects whether
   in patients or non-patient volunteers in order to discover or verify the effects of and/or
   identify any adverse reaction to investigational products, and/or study their absorption,
   distribution, metabolism and excretion in order to ascertain the efficacy and safety of the
   products.
   Evaluation of the application for marketing authorization shall be based on clinical trials
   including clinical pharmacological trials designed to determine the efficacy and safety of
   the product under normal conditions of use, having regard to the therapeutic indications
   for use in human beings. Therapeutic advantages must outweigh potential risks.
   A. General requirements
   The clinical particulars to be provided pursuant to Articles 8 (3) (i) and 10 (1) must
   enable a sufficiently well-founded and scientifically valid opinion to be formed as to
   whether the medicinal product satisfies the criteria governing the granting of a marketing
   authorization. Consequently,. an essential requirement is that the results of all clinical
. trials should be communicated, both favourable and unfavourable.
  Clinical trials must always be preceded by adequate pharmacological and toxicological
   tests, carried out on animals in accordance with the requirements of Part 3 of this Annex.
   The investigator must acquaint himself with the conclusions drawn. from the
  pharmacological and toxicological studies and hence the applicant must provide him at
   least with the investigator's brochure, consisting of all the relevant information known
   prior to the onset of a clinical trial including chemical, pharmaceutical and biological
  data, toxicological, pharmacokinetic and pharmacodynamic data in animals and the
  results of earlier clinical trials, with adequate data to justify the nature, scale and
  duration of the proposed trial; the complete pharmacological and toxicological reports
  'shall be provided on request. For materials of human or animal origin, all available.
  means shall be.employed to ensure safety from transmission of infectious agents prior to
  the commencement of the trial.
                                                            Ill
 ---pagebreak--- B. Conduct of trials                                                                         75/318/EEC
                                                                                             Annex
 l. Good clinical practice                                                                   (as·amcndcd by
                                                                                             91/507/EEC Art. 1)
1.1. All phases of clinic~) investigation, including bioavailability and bioequivalence      (adapted)
studies, shall be designed, implemented and reported in accordance with good clinical
practice.
1.2. All clinical trials shall be carried out in accordance with the ethical principles laid
down in the current revision of the· Declaration of Helsinki. In principle, the freely given
informed consent of each trial subject shall be obtained and documented.
The trial protocol (including statistical design), the technical application and
documentation shall be submitted by the sponsof and/or investigator for an opinion to
the relevant ethics committee. The trials shall not begin before the opinion of this
committee has been received in writing~
1.3. Pre-estab~ished, systematic written procedures for the organization, conduct, data
collection, documentation and verification of clinical trials shall be required.
1.4. In the case of radiopharmaceuticals, clinical trials shall be carried out under the
responsibility of a medical doctor authorized to use radionuclides for medical purposes.
2. Archiving
The marketing authorization holder shall make arrangements for . archiving of
documentation.
(a) The investigator shall arrange for the retention of the patient identification codes for
     at least 15 years after the completion or discontinuation of the trial.
(b) Patient files and other source data shall be kept for the maximum period of time
     permitted by the hospital, institution or private practice.
(c) The sponsor or other owner of the data shall retain all other documentation
     pertaining to the trial as long as the product is authorized. These procedures shall
     include:
          the protocol including the rationale, objectives and statistical design and
          methodology of the trial, with conditions under which it is performed and
          managed, and details of the investigational product, the reference medicinal
          product and/or the placebo used,
          standard operating procedures,
          all written opinions on the protocol and procedures,
                                                          112
 ---pagebreak---           the investigator's brochure,                                                       75/318/EEC
                                                                                             Annex
          case report forms on each trial subject,                                           (as amended by
                                                                                             91/507/EEC Art. I)
          final report,                                                                      (adapted)
          audit certificate(s), if available.
(d) The final report shall be retained by the sponsor or subsequent owner, for five years
     after the medicinal product is no longer authorized.
Any change of ownership of the data shall be documented.
All data and documents shall be made available if requested by relevant authorities.
C. Presentation of results
 I. The particulars of each clinical trial must contain sufficient detail to allow an
objective judgement to be made:
     the protocol, including the rationale, objectives and statistical design and
     methodology of the trial, with conditions under which it is performed and managed,
     and details of the investigational medicinal product used,
     audit certificate(s), if available,
     the list of investigator(s), and each investigator shall give his name, address,
     appointments, qualifications and clinical duties, state where the trial was carried out
     and assemble the information in respect of each patient individually, including case
     report forms on each trial subject,
     final report signed by the investigator and for multicentre trials, by all the
     investigators or the coordinating (principal) investigator.
2. The particulars of clinical trials referred to above shall be forwarded to the competent
authorities. However, in agreement with the competent authorities, the applicant may
omit part of this information. Complete documentation shall be provided forthwith upon
request.
3. The clinical observations shall be summarized for each trial indicating:
(a) the number and sex of patients treated;
(b) the selection· and age-distribution of the groups of patients being investigated and
    the comparative tests;
                                                          113
 ---pagebreak---      (c) the number of patients withdrawn prematurely from the trials and the reasons for           75/318/EEC
           such withdrawal;                                                                         Annex
                                                                                                    (as amended by
     (d). where controlled trials were carried out under the above conditions, whether the          91~507/EECArt. I)
          control group:                                                                            (adapted)
               received no treatment,
               received a placebo,
               received another medicinal product of known effect,
               received treatment other than therapy using medicinal products;
     (e)  th~ frequency of observed adverse reactions;
     (f) details concerning. patients who may be at increased risk, e.g. elderly people,
          children, women during pregnancy or menstruation, or whose physiological or
          pathological condition requires special consideration;
     (g) parameters or evaluation criteria of efficacy and the results in terms of these
    ·     parameters;
    (h) a statistical evaluation of the results when this is called for by the design of the trials
          and the variable factors involved.
    4. The investigator shall, in his conclusions on the experimental evidence, express an
    opinion on the safety of the product under normal conditions of use, its tolerance, its
    efficacy and any useful information relating to indications and contra-indications,
    dosage and average duration of treatment as well as any special precautions to be taken
    during treatment and the clinical symptoms of overdosage. In reporting the results of a
    multi-centre study, the principal investigator shall, in his conclusions, express an opinion
    on the safety and efficacy of the investigational medicinal product on behalf of all
    centres.
    5. In addition, the investigator shall always indicate· his observations on:
    (a)   ~Y signs of habituation, addiction or difficulty in weaning patients from the
          medicinal product;
    (b) any interactions that have been observed with other medicinal products administered
          concomitantly;                                             ·
    (c) the criteria determining exclusion of certain patients from the trials;
    (d)   ~y  deaths whi~h occurred during the trial or within the follow-up period.
    6. Particulars concerning a new combination of medicinal substances must be identical
    to those required for new medicinal products and must substantiate the safety and
    efficacy of the combination.
(8)                                                           114
 ---pagebreak---      7. Total or partial omission of data must be explained. Should unexpected results occur      75/318/EEC
     during the course of the trials, further preclinical toxicological and pharmacological tests Annex
     must be undertaken and reviewed.                                                             (as amended by
                                                                                                  91/507/EEC Art. 1)
     If the medicinal product is intended for long-tenn administration, particulars shall be      (adapted)
     given of any modification of the pharmacological action following repeated
     administration, as well as tbe establishment of long-tenn dosage.
     D. Clinical pharmacology
      I. Pharmacodynamics ·
     The pharmacodynamic action correlated to the efficacy shall be demonstrated including:
           ihe dose-response relationship and its time course,
           justification for the dosage and conditions of administration,
           the mode of action, if possible.
     The pharmacodynamic action not related to efficacy shall be described.
     The demonstration of pharmacodynamic effects in human beings shall not in itself be
     sufficient to justify conclusions regarding any particular potential therapeutic effect.
     2. Pharmacokinetics
     The following phannacokinetic characteristics shall be described:
           absorption (rate and extent),
           distribution,
           metabolism,
         . excretion.
     Clinically significant features including the implication of the kinetic data for the dosage
     regimen especially for patients at risk, and differences between man and animal species
     used in the preclinical studies, shall be described .
....
                                                               115
 ---pagebreak---  3./nteractions                                                                                 75/3I8/EEC
                                                                                                Annex
 If the medicinal product is ·normally to be administered concomitantly with other              (as amended by
 medicinal products, particulars shall be given of joint administration tests performed to      911507/EEC Art. I)·
demonstrate possible modification of the pharmacological action.                                (adapted)
 If pharmacodynamic/pharmacokinetic interactions exist between the substance and other
 medical products or substances like alcohoJ, caffeine, tobacco or nicotine, likely to be
 taken simultaneously, or if such interactions are likely, they should be described and
 discussed; particularly from the point of view of clinical relevance and the relationship
 to the statement concerning interactions in the summary of product characteristics
 presented in accordance w.ith Article 11 point 5.6.
 E. Bioavailability/bioequivalence
 The assessment of bioavailability must be undertaken in all cases where it is necessary,
 e.g. where the therapeutic dose is near the toxic dose or where the previous tests have
 revealed anomalies which may .be related to pharmacodynamic properties, such as
 _variable absorption.
 In addition, an assessment of bioavailability shall be undertaken where necessary to
 demonstrate bioequivalence for the medicinal products referred to in Article 10 (I) (a).
 F. C~inical efficacy and safety
 I. In g~neral, clinical trials shall· be done as "controlled clinical trials" and if possible,
 randomized; any other design shall be justified. The treat.ment of the control groups will
 vary from ca8e to case and also will depend on ethical considerations; thus it may, in
 some instances, be more pertinent to compare the efficacy of a new medicinal product
 with that of an established medic~nal product of proven therapeutic value rather than
 with the effect of a placebo.                                           ·
As far as possible, and particularly in trials where the effect of the product cannot be
 objectively measured, steps shall be taken to avoid bias, including methods of
 randomization and blinding.
2. The protocol of the trial must include a thorough description of the statistical methods
to be employed, the number and reasons for inclusion of patients (including calculations
 of the power of the trial), the level of significance to be used and a description of the
 statistical unit. Measures taken to avoid bias, particularly methods of randomization,
 shall be documented. Inclusion of a large number of subjects in a trial must not be
:regarded as an adequate substitute for a properly controlled trial.
                                                           116
 ---pagebreak---  3. Clinical statements concerning the efficacy or safety of a medicinal product under       75/318/EEC
normal conditions of use which are not scientifically substantiated cannot be accepted as    Annex
valid evidence.                                                                              (as· amended by
                                                                                             91 /507/EEC Art. 1)
4. The value of data on the efficacy and safety. of a medicinal product under normal         (adapted)     ·
conditions of use will be very greatly enhanced if such data come from several
competent investigators working independently.
5. For vaccines and serums, the immunological status and age of the trial population and
the local epidemiology are of critical importance and shall be monitored during ~e trial
and fully described.
For live attenuated vaccines, clinical trials shall be so designed as to reveal potential
transmission of the immunizing agent from vaccinated to non-vaccinated subjects. If
transmission is possible, the genotypic and phenotypic stability of the immunizing agent
shall be studied.
For vaccines and immunological medicinal products, follow-up studies shall include
appropriate immunological tests, and where applicable, antibody assays.
6. The pertinence of the different trials to the assessment of safety and the validity of
methods of evaluation shall be discussed in the expert report.
7. All adverse events including abnormal laboratory values shall be presented
indiviilually -and discussed, ~specially:
     in terms of overall adverse experience and
     as a function of the nature, seriousness and causality of effects.
8. A critical assessment of relative safety, taking into account adverse reactions, shall be
made in relation to:·
     the disease to be treated,
     other therapeutic approaches,
     particular characteristics in sub-groups of patients,
     preclinical data on toxicology and pharmacology.
9. Recommendations shall be made for the conditions of use, with the intention of
reducing the incidence of adverse reactions.
                                                          117
 ---pagebreak---  G. Documentation for applications in ex~eptional circumstances                             75/318/EEC
                                                                                            Annex
'When, in respect of particular therapeutic indications, the applicant can show that he is  {as amended by
 unable to provide comprehensive data on the efficacy and safety under normal               91/507/EEC Art. I)
 conditions of use, because:                                                                {adapted)
      the indications for which the product in question is intended are encountered so
      rarely that the applicant cannot reasonably be expected to provide comprehensive
      evidence, or
      in the present state of scientific knowledge, comprehensive information cannot be
      provided, or
      it would be contrary to generally accepted principles of medical ethics to collect
      such information,
marketing authorization may be granted on the following conditions:
 (a) the applicant completes on identified programme of studies within a time period
    . specified by the competent authority, the results of which shall form the basis of a
      reassessment of the benefit/risk profile,                        ·
 (b) the medicinal product in question may be supplied on medical prescription only and
      may in certain cases be administered only under strict medical supervision, possibly
      in a hospital and for a radiophannaceutical, by an authorized person,
 (c) the package leaflet and any medical information shall draw the attention of the
      medical practitioner to the fact that the particulars available concerning the
      medicinal product in question are as yet inadequate in certain specified respects.
 H. Post-marketing experience
 I. If the medicinal product is already authorized in other countries, information shall be
 given in respect of adverse drug reactions of the medicinal product concerned and
 medicinal products containing the same active substance{s), in relation to the usage rates
 if possible. Information from. worldw.ide studies relevant to the safety of the medicinal
 product shall be included.
                                                         118
 ---pagebreak--- For this purpose, an adverse drug reaction is a reaction which is noxious and unintended 75/318/EEC
and which occurs at doses normally used in.man for prophylaxis, diagnosis or therapy of Annex
disease or for the modification of physiological function.                                 (as amended by
                                                                                           91/507/EEC Art. 1)
2. In the case of vaccines already authorized in other countries, information on the (adapted)
monitoring of vacc~nated subjects to evaluate the prevalence of the disease in question as
compared to non vaccinated subjects shall be submitted, .when availa~le.
3. For immunological medicinal products, response in periods of increased antigen.
exposure shall be identified.
                                                       119
 ---pagebreak---                                                  ANNEXII
                                                   Part A
                     Repealed Directives, with their successive amendments
                                        (referred to by Article 130)
Council Directive 65/65/EEC (OJ 22, 9. 2. 1965, p. 369)
   Council Directive 66/454/EEC (OJ 144, 5. 8. 1966, p. 2658/66)
   Council Directive 75/319/EEC (OJ L 147, 9.6.1975, p. 13)
   Council Directive 83/570/EEC (OJ L 332,28. 11. 1983, p. 1)
   Council Directive 87121/EEC (OJ L 15, 17. I. 1987, p. 36)
   Council Directive 89/341/EEC (OJ L 142,25. 5. 1989, p. 11)
   Council Directive 92127/EEC (OJ L 113, 30.4.1992, p. 8)
   Council Directive 93/39/EEC (OJ L 214,24. 8. 1993, p. 22)
Council Directive 75/318/EEC (OJ L 147, 9. 6. 1975, p. 1)
   Council Directive 83/570/EEC
   Council Directive 87/19/EEC (OJ L 15, 17. 1. 1987, p. 31)
   Council Directive 89/341/EEC
   Commission Directive 91/507/EEC (OJ L 270, 26. 9. 1991, p: 32)
   Council Directive 93/39/EEC
Council Directive 75/319/EEC
   Council Directive 78/420/EEC (OJ L 123, 11. 5. 1978, p. 26)
   Council Directive 83/570/EEC
   Council Directive 89/341/EEC
   Council Directive 92127/EEC
   Council Directive 93/39/EEC
Council Directive 89/342/EEC (OJ L 142,25. 5. 1989, p. 14)
Council Directive 89/343/EEC (OJ L 142,25. 5. 1989, p. 16)
Council Directive 89/381/EEC (OJ L 181,28. 6. 1989, p. 44)
Council Directive 92/25/EEC (OJ L 113,30. 4. 1992, p. 1)
Council Directive 92/26/EEC (OJ L 113, 30. 4. 1992, p. 5
Council Directive 92127/EEC .
Council Directive 92/28/EEC (OJ L 113, 30. 4. 1992, p. 13)
Council Directive 92173/EEC (OJ L 297, 13. 10. 1992, p. 8)
                                                   . 120
 ---pagebreak---                                                                            PartB
                                        Deadlines for transposition into national law
                                                             (referred to by ~rticle 130)
                                      Directive                                                       Deadline for transposition
 Directive 65/65/EEC                                                                      31 December 1966
 Directive 66/454/EEC                                                                     ---
 Directive 75/318/EEC                                                                     21 November 1976
 Directive 75/319/EEC                                                                     21 November 1976
 Directive 78/420/EEC                                                                     --
 Directive 83/570/EEC                                                                     31 October 1985
 Directive 87/19/EEC                                                                       l July 1~87
 Directive 87/21/EEC                                                                      1 July 1987.
                                                                                          1 January 19921
Directive 89/341/EEC                                                                      1. January 1992
Directive 89/342/EEC                                                                      1 January 1992
Directive 89/343/EEC                                                                      1 January 1992
Directive 89/381/EEC                                                                      1 January 1992
Directive 91/507/EEC                                                                      1 January 19922
                                                                                          1 January 19953
Directive 92/25/EEC                                                                       1 January 1993
Directive 92/26/EEC                                                                       1 January 1993
Directive 92127/EEC                                                                       I January 1993
Directive 92/28/EEC                                                                       1 January 1993
Directive 92173/EEC                                                                       31 December 1995
Directive 93/39/EEC                                                                       I January 19954
                                                                                          I January 19985
     Deadline for transposition applicab~e to Greece, Spain and Portupl.
2   Except Section A. point 3.3 in Part U of the Aanex.
3   Deadline for transposition applicable to Section A. point 3.3 in Part U of the Annex.
4   Except with reprd to Article I (6).
s   Deadline for transposition applic:able to Article I (7).
 ---pagebreak---                                                                            ANNEX Ill
                                                                  CORRELATION TABLE
  ThisDir.      65/65/EEC     75/318/EEC   75/319/EEC  89/342/EEC  89/343/EEC    89/381/EEC 92/25/EEC   92/26/EEC  92127/EEC  92128/EEC 92/73/EEC
Art. 1 (1) to  Art. 1 (I) to
(3)            (3)
Art. 1 (4)                                Annex       Art. 1 (1)
                                                      and(2)
Art. 1 (S)                                                                                                                              Art. 1
Art. 1 (6) to                                                     Art. 1 (2)
(9)
Art. 1 (10)                                                                     Art. 1 (1)
Art. 1 (11) to                            Art. 29b
(14)                                                                                                                            .
Art. 1 (IS)                                                                                 Art. 1 (2)
and (16)
Art. 1 (17)                                                                                            Art. 1 (2),
                                                                                                       2nd
                                                                                                       sentence
Art. 1 (18) to                                                                                                     Art. 1 (2)
(24)
Art. 1 (25)                              .Art. 8 (1)
Art. 1 (26)                               Art. 10 (1)
Art.2          Art. 2 (1)
Art. 3 (1)     Art. 1 (4)
and (2)        and (S)
               Art 2 (3), 1st
               indent
Art. 3 (3)     Art.2 (3),
and (4)        2nd and 3rd
               indents
Art. 3 (5)                                                        Art. 1 (1)
Art. 3 (6)                                                                      Art. 1 (2)
                                                                              122
 ---pagebreak---       This Dir.             65/65/EEC         75/318/EEC   75/319/EEC   89/342/EEC  89/343/EEC   89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92173/EEC
Art. 4 (1)                                                                         Art. 1 (3)
Art. 4 (2)                                                                                      Art. 1 (3)
Art. 4 (3)            Art.3,2nd
                      sub paragraph
Art. 4 (4)            Art.6
Art. 5                Art. 2 (4)
Art.6                 Art. 3 (l)
Art. 7                                                                             Art. 2,                                                                     I
                                                                                                                                                               I
                                                                                   2nd sentence
Art. 8 (1) and (2)    Art. 4.(1) and (2)
Art. 8 (3) (a) to (e) Art. 4, 3rd paragraph, Art. 1 (l)
                      points 1 to 5
Art. 8 (3) (f) to (i) Art. 4, 3rd paragraph,
                      points 6 to 8.1
Art. 8 (3) G) to (I)  Art. 4, 3rd paragraph,
                      points 9 to 11
                                                                                   .
Art.9                                                                              Art.3
Art. 10 (l)           Art. 4, 3rd paragraph,
                      point 8.2
Art. 10.(2)                                  Art. 1,
                                             2nd paragraph
Art. 11 , points 1 to Art. 4a, points 1 to
5.3                   5.3                                             '
Art. 11, point 5.4    Art. 4a, point 5.4                              Art.3
Art. 11, points 5.5   Art. 4a, points 5.5
to6.4                 to6.4
Art. 11, point 6.5    Art. 4a, point 6.6
Art. 11, point 7      Art. 4a, point 6.5
Art. 11, points 8                                                                  Art. 4
to 9
Art. 12 (l)                                                Art. 1
Art. 12 (2) and (3)                                        Art.2
Art.13                                                                                                                                              Art. 6 (I)
                                                                               ---
                                                                                                                                                    and (2)
                                                                                         123
 ---pagebreak--- . This Dir.  65/65/EEC  75/318/EEC 75/319/EEC  89/342/EEC 89/343/EEC 89/381/EEC 92125/EEC 92126/EEC . 92/27/EEC 92/28/EEC   92173/EEC
Art. 14 (1)                                                                                                               Art. 7 (1) and
and (2)                                                                                                                   (4)
Art. 14 (3)                                                                                                               Art. 4,
                                                                                                                          2nd paragraph
Art. 15                                                                                                                   Art.8
Art. 16                                                                                                                   Art.9
Art. 17     Art. 7
Art. 18     Art. 7a
Art. 19                            Art.4
Art. 20                            Art.S
Art. 21     Art. 4b
Art.22      Art. 10 (2)
Art.23      Art. 9a                                                                                                                       :
Art.24      Art. 10 (I)
Art.25      Art.9
Art.26      Art. s
Art. 27 .                          Art. 8
Art. 28 (1)                        Art. 9 (3)
Art. 28 (2)                        Art. 9 (1)
Art. 28 (3)                        Art. 9 (2)
Art. 28 (4)                        Art. 9 (4)
Art. 29                            Art. 10                                                                                             '"
Art. 30                            Art.ll
Art. 31                            Art. 12
Art.32                             Art. 13
Art. 33
~
                                   Art. 14 (I)
                                                                      124
 ---pagebreak---   ThisDir.  .6S/6SIEEC 75/318/EEC  75/319/EEC    89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC  .92/28/EEC  92/73/EEC
Art.34                            Art. 14 (2) to
                                  (4)
Art. 35                           Art. IS ·
Art.36                            Art. 1Sa
Art.37                            Art. 1Sb
Art.38                            Art. 1Sc
Art. 39                           Art. 14 (S)
Art. 40                           Art. 16
Art. 41                           Art. 17
Art. 42                           Art. 18
Art.43                            Art. 20 (1)
Art. 44                           Art. 20 (2)
Art. 4S                           Art. 20 (3)
Art. 46                           Art. 19
Art.47                            Art. 19a
Art.48                            Art.21
Art. 49 .                         Art.23
Art. so                            Art.24
Art. 51 (1)                        Art. 22 (1)
and (2)
Art. S1 (3)                        Art. 22 (2)
Art. 52                            Art.2S
Art.S3                                                                                                                      Art~3
Art.S4                                                                                                Art. 2 (1)
Art. SS                                                                                               Art.3
                                                                        125
 ---pagebreak---    This Dir.   65/65/EEC -75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92125/EEC  92126/EEC ·   92127/EEC     92128/EEC .92/73/EEC
 Art. 56                                                                                                Art. 4 (1)
 Art. 51                                                                                                 Art. 5 (2)
 Art. 58                                                                                                 Art.6
 Art. 59                                                                                                 Art. 7 (1) and
                                                                                                         (2)
 Art. 60                                                                                                 Art. 5 (1) and
                                                                                                         Art.9
 Art. 61                                                                                                 Art. 10 (1) to
                                                                                                         (4)
 Art. 62                                                                                                 Art. 2 (2) and
                                                                                                        ·Art. 7 (3)
 Art. 63"(1)                                                                                             Art. 4 (2)
.Art. 63 (2)                                                                                             Art.8
 Art. 63 (3) .                                                                                           Art. 10 (5)
 Art. 64                                                                                                 Art. 11 (1)
 Art. 65                                                                                                 Art. 12
 Art. 66 .                                                 Art. 5
 Art. 67                                                   Art. 6 (1)
 Art.68                                                                                                                           Art:2 (2)
 Art. 69                                                                                                                          Art. 7 (2) i
                                                                                                                                  and (3)
 Art. 70                                                                                   Art.2
 Art. 71                                                                                   Art.3
 Art. 72                                                                                   Art.4
 Art. 73                                                                                   Art. S (I)
 Art. 74                                                                                   Art. 5 (2)
                                                                       126
 ---pagebreak---    This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC  92/25/EEC  92/26/EEC 92/27/EEC  92/28/EEC    92173/EEC
 Art. 75                                                                                 Art. 6 (2)
 Art. 76                                                                      Art.2
 Art. 77                                                                      Art.3
 Art. 78                                                                      Art. 4 (1)
 Art. 79                                                                      Art. 5
 Art.80                                                                       Art.6
 Art.81                                                                       Art. 7
 Art.82                                                                       Art.8
 Art.83                                                                       Art.9
 Art.84                                                                       Art. 10
 Art.85                                                                                                       Art. 3 (6),
                                                                                                              2nd sentence
 Art. 86                                                                                                      Art. 1 (3)
                                                                                                              and (4)
 Art.87                                                                                                       Art. 2
 Art.88                                                                                                       Art. 3 (1) to
                                                                                                              (6), 1st                I
                                                                                                              sentence                I
 Art.89                                                                                                       Art.4
 Art.90                                                                                                       Art.5
 Art.91                                                                                                       Art.6
 Art.92                                                                                                       Art. 7
 Art.93                                                                                                       Art.8
 Art.94                                                                                                       Art.9
 Art. 95                                                                                                      Art. 10
,Art. 9~                                                                                                      Art.ll
                                                                    127
 ---pagebreak---   This Dir.   65/65/EEC 75/318/EEC 75/319/EEC   .89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92127/EEC  92128/EEC   92/73/EEC
Art. 97 (1)                                                                                                     Art. 12 (1)
to (4)                                                                                                          and (2)
Art. 97 (5)                                                                          /
                                                                                                                Art. 12 (4)
Art.98                                                                                                          Art. 13
Art99                                                                                                           Art. 14
Art. 100                                                                                                                    Art. 6 (3)
Art. 101                           Art.29e
Art. 102                           Art.29a
Art. 103                           Art.29c
Art. 104                           Art. 29d                                                                                            I
Art. 105                           Art.29f                                                                                             '
Art. 106                           Art.29g
Art. 107                           Art.29h
Art. 108                           Art. 29i
Art. 109                                                               Art.3
Art.llO                                                                Art. 3 (4)
Art. 111 (I)                       Art. 26, 1st
                                   and 2nd
                                   paragraph
Art. 111 (2)                                    Art. 4 (I)
Art. 111 (3)                       Art. 26, 3rd
                                   paragraph
Art. 112     Art. 8                Art.27
Art.113                                         Art. 4 (2)             Art. 4 (2)
Art. 114 (1)                                    Art. 4 (3)
Art. 114 (2)                                                           Art. 4 (3)
Art. 115                                                               Art. 4 (1)
Art. 116     Art. 11
Art. 117                           Art.28
                                                                        128
 ---pagebreak---      This Dir.  65/65/EEC  75/318/EEC  75/319/EEC  89/342/EEC  89/343/EEC  89/381/EEC    92/25/EEC   92/26/EEC   92/27/EEC   92/28/EEC   92/73/EEC
Art.ll8                               Art.29
Art.ll9                                                                                                                                Art. 4 (1)
Art. 120                  Art.2b
Art. 121                  Art. 2a (1)
Art. 122                              Art. 37a
Art. 123                              Art.37b
Art. 124                              Art.30
Art. 125                              Art. 33
Art. 126                                                                                                                               Art.5
Art. 127       Art. 12                Art. 31                                         . Art. 4 (2)             Art. 11 (2) Art. 12 (3)
Art. 128,      Art. 21
I st paragraph
Art. 128,                             Art. 32
2nd paragraph
Art. 129                              Art.28a
Art. 130       -          -           -           -           -           -             -          -           -           -           -           I
Art. 131 .     -          -           -           -           -           -             -          -           -           -           -           I
Art. 132       -          -           -           -           -           -             -          -.          -           -           -
     This Dir. 65/65/EEC  75/318/EEC  75/319/EEC  8.9/342/EEC 89/343/EEC  89/381/EEC    92125/EEC  92126/EEC   92/27/EEC   92128/EEC   92n3/EEC
     Annex I                Annex
     Annexll       -           -           -           -          -           -             -           -           -           -           -
   -Annex Ill      -           -           -           -          -           -             -           -           -           -           -
                                                                            129 .
 ---pagebreak---  ---pagebreak---                                                                ISSN 0254-1475
                                                    COM(1999) 315 final
                                       DOCUMENTS
EN                                                           05 15 02 01
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