2001L0083—EN—08.02.2003—001.001—1
This document is meant purely as a documentation tool and the institutions do not assume any liability for its contents
►B DIRECTIVE2001/83/ECOFTHEEUROPEANPARLIAMENTANDOFTHECOUNCIL
of6November2001
ontheCommunitycoderelatingtomedicinalproductsforhumanuse
(OJL311,28.11.2001,p.67)
Amendedby:
OfficialJournal
No page date
►M1Directive2002/98/ECoftheEuropeanParliamentandoftheCouncilof
27January2003L33 30 8.2.2003
▼B
DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT
ANDOFTHECOUNCIL
of6November2001
on the Community code relating to medicinal products for human
use
THEEUROPEANPARLIAMENTANDTHECOUNCILOFTHE
EUROPEANUNION,
HavingregardtotheTreatyestablishingtheEuropeanCommunity,and
inparticularArticle95thereof,
HavingregardtotheproposalfromtheCommission;
Having regard to the opinion of the Economic and Social
Committee(1),
Acting in accordance with the procedure laid down in Article 251 of
theTreaty(2),
Whereas:
(1)CouncilDirective65/65/EECof26January1965ontheapprox-
imation of provisions laid down by law, regulation oradministrative action relating to medicinal products(
3), Council
Directive 75/318/EEC of20May1975ontheapproximation ofthelawsofMemberStatesrelatingtoanalytical,pharmaco-toxi-
cological and clinical standards and protocols in respect of the
testing of proprietary medicinal products(
4), Council Directive
75/319/EECof20May1975ontheapproximationofprovisionslaiddownbylaw,regulationoradministrative actionrelatingtoproprietary medicinal products(
5), Council Directive 89/342/
EEC of 3 May 1989 extending the scope of Directives 65/65/
EECand75/319/EECandlayingdownadditionalprovisionsfor
immunologicalmedicinalproductsconsistingofvaccines,toxinsor serums and allergens(
6), Council Directive 89/343/EEC of 3
May1989extendingthescopeofDirectives65/65/EECand75/319/EEC and laying down additional provisions for radiophar-
maceuticals(
7), Council Directive 89/381/EEC of 14 June 1989
extending the scope of Directives 65/65/EEC and 75/319/EEContheapproximationofprovisionslaiddownbylaw,regulationor administrative action relating to medicinal products andlaying down special provisions for proprietary medicinalproducts derived from human blood or human plasma(
8),
Council Directive 92/25/EEC of 31 March 1992 on the whole-
sale distribution of medicinal products for human use(9),
Council Directive 92/26/EEC of 31 March 1992 concerning theclassification for the supply of medicinal products for humanuse(
10), Council Directive 92/27/EEC of 31 March 1992 on the
labelling of medicinal products for human use and on package
leaflets(11), Council Directive 92/28/EEC of 31 March 1992 on
theadvertisingofmedicinalproductsforhumanuse(12),Council
Directive 92/73/EEC of22September 1992widening the scope2001L0083—EN—08.02.2003—001.001—2
(1) OJC368,20.12.1999,p.3.
(2) OpinionoftheEuropeanParliamentof3July2001(notyetpublishedinthe
OfficialJournal)andCouncilDecisionof27September2001.
(3) OJ 22, 9.2.1965, p. 369/65. Directive as last amended by Directive 93/39/
EEC(OJL214,24.8.1993,p.22).
(4) OJL147,9.6.1975,p.1.DirectiveaslastamendedbyCommissionDirec-
tive1999/83/EC(OJL243,15.9.1999,p.9).
(5) OJL147,9.6.1975,p.13.DirectiveaslastamendedbyCommissionDirec-
tive2000/38/EC(OJL139,10.6.2000,p.28).
(6) OJL142,25.5.1989,p.14.
(7) OJL142,25.5.1989,p.16.
(8) OJL181,28.6.1989,p.44.
(9) OJL113,30.4.1992,p.1.
(10) OJL113,30.4.1992,p.5.
(11) OJL113,30.4.1992,p.8.
(12) OJL113,30.4.1992,p.13.
▼B
of Directives 65/65/EEC and 75/319/EEC on the approximation
of provisions laid down by law, regulation or administrativeactionrelatingtomedicinalproductsandlayingdownadditional
provisions on homeopathic medicinal products(
1) have been
frequently and substantially amended. In the interests of clarityand rationality, the said Directives should therefore be codifiedbyassemblingtheminasingletext.
(2)The essential aimof any rules governing the production, distri-bution and use of medicinal products must be to safeguardpublichealth.
(3)However, this objective must be attained by means which willnot hinder the development of the pharmaceutical industry ortradeinmedicinalproductswithintheCommunity.
(4)Trade in medicinal products within the Community is hinderedby disparities between certain national provisions, in particularbetween provisions relating to medicinal products (excluding
substances or combinations of substances which are foods,
animalfeeding-stuffsortoiletpreparations),andsuchdisparitiesdirectlyaffectthefunctioningoftheinternalmarket.
(5)Such hindrances must accordingly be removed; whereas thisentailsapproximationoftherelevantprovisions.
(6)Inorder toreduce the disparities which remain, rules shouldbe
laid down on the control of medicinal products and the duties
incumbentupontheMemberStates'competentauthoritiesshouldbe specified with a view to ensuring compliance with legalrequirements.
(7)The concepts of harmfulness and therapeutic efficacy can onlybe examined in relation to each other and have only a relativesignificance depending on the progress of scientific knowledgeand the use for which the medicinal product is intended. The
particularsanddocumentswhichmustaccompanyanapplication
formarketingauthorization foramedicinal productdemonstratethatpotentialrisksareoutweighedbythetherapeuticefficacyoftheproduct.
(8)Standards and protocols for the performance of tests and trialsonmedicinalproductsareaneffectivemeansofcontroloftheseproductsandhenceofprotectingpublichealthandcanfacilitatethe movement of these products by laying down uniform rules
applicable to tests and trials, the compilation of dossiers and
theexaminationofapplications.
(9)Experience has shown that it is advisable to stipulate more
precisely the cases in which the results of toxicological and
pharmacological tests or clinical trials do not have to beprovided with aview to obtaining authorization fora medicinalproduct which is essentially similar to an authorized product,while ensuring that innovative firms are not placed at a disad-
vantage.
(10)However, there are reasons of public policy for not conducting
repetitivetestsonhumansoranimalswithoutover-ridingcause.
(11)The adoption of the same standards and protocols by all theMemberStateswillenablethecompetentauthoritiestoarriveattheirdecisionsonthebasisofuniformtestsandbyreference to
uniformcriteria and will therefore help to avoid differences in
evaluation.
(12)With the exception of those medicinal products which aresubject to the centralized Community authorization procedureestablished by Council Regulation (EEC) No 2309/93 of 22July1993layingdownCommunityproceduresfortheauthoriza-tion and supervision of medicinal products for human andveterinary use and establishing a European Agency for the2001L0083—EN—08.02.2003—001.001—3
(1) OJL297,13.10.1992,p.8.
▼B
Evaluation of Medicinal Products(1) a marketing authorization
foramedicinalproductgrantedbyacompetentauthorityinoneMemberStateoughttoberecognizedbythecompetentauthori-
tiesoftheotherMemberStatesunlessthereareseriousgrounds
for supposing that the authorization of the medicinal productconcernedmaypresentarisktopublichealth.Intheeventofadisagreement between Member States about the quality, thesafetyortheefficacyofamedicinalproduct,ascientificevalua-
tion of the matter should be undertaken according to a
Communitystandard,leadingtoasingledecisionontheareaofdisagreementbindingontheMemberStatesconcerned.Whereasthis decision should be adopted by a rapid procedure ensuringclose cooperation between the Commission and the MemberStates.
(13)For this purpose, a Committee for Proprietary MedicinalProducts should be set up attached to the European Agency forthe Evaluation of Medicinal Products established in the above-mentionedRegulation(EEC)No2309/93.
(14)ThisDirectiverepresentsanimportantsteptowardsachievementof the objective of the free movement of medicinal products.Furthermeasuresmayabolishanyremainingbarrierstothefreemovementofproprietarymedicinalproductswillbenecessaryin
the light of experience gained, particularly in the abovemen-
tionedCommitteeforProprietaryMedicinalProducts.
(15)In order better to protect public health and avoid any unneces-sary duplication of effort during the examination of application
for a marketing authorization for medicinal products, Member
States should systematically prepare assessment reports inrespect of each medicinal product which is authorized bythem,and exchange the reports upon request. Furthermore, a MemberState should be able to suspend the examination of an applica-tion 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 reachedbythelatterMemberState.
(16)Following the establishment of the internal market, specific
controlstoguaranteethequalityofmedicinalproductsimported
fromthird countries can be waived only if appropriate arrange-ments have been made by the Community to ensure that thenecessarycontrolsarecarriedoutintheexportingcountry.
(17)It is necessary to adopt specific provisions for immunologicalmedicinal products, homeopathic medicinal products, radiophar-maceuticals, and medicinal products based on human blood orhumanplasma.
(18)Any rules governing radiopharmaceuticals must take into
account the provisions of Council Directive 84/466/Euratomof
3September 1984laying downbasicmeasuresfortheradiationprotection of persons undergoing medical examination or treat-ment(
2).AccountshouldalsobetakenofCouncil Directive 80/
836/Euratomof 15 July 1980 am ending the Directives laying
down the basic safety standards for the health protection of the
generalpublicandworkersagainstthedangersofionizingradia-tion(
3), the objective of which is to prevent the exposure of
workers or patients to excessive or unnecessarily high levels ofionizingradiation, andinparticular ofArticle5cthereof,whichrequires prior authorization for the addition of radioactive2001L0083—EN—08.02.2003—001.001—4
(1) OJL214,24.8.1993,p.1.RegulationasamendedbyCommissionRegula-
tion(EC)No649/98(OJL88,24.3.1998,p.7).
(2) OJL265,5.10.1984,p.1.Directiverepealedwitheffectfrom13May2000
byDirective97/43/Euratom(OJL180,9.7.1997,p.22).
(3) 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 from13 May
2000byDirective96/29/Euratom(OJL314,4.12.1996,p.20).
▼B
substances to medicinal products as well as for the importation
ofsuchmedicinalproducts.
(19)The Community entirely supports the efforts of the Council ofEuropetopromote voluntaryunpaidbloodandplasmadonationto attain self-sufficiency throughout the Community in thesupplyofbloodproducts,andtoensurerespectforethicalprin-
ciplesintradeintherapeuticsubstancesofhumanorigin.
(20)The rules designed to guarantee the quality, safety and efficacy
of 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 fromthirdcountries.
(21)Having regard to the particular characteristics of these homeo-pathic medicinal products, such as the very low level of activeprinciples they contain and the difficulty of applying to themthe conventional statistical methods relating to clinical trials, itis desirable to provide a special, simplified registration proce-dure for those homeopathic medicinal products which are
placed on the market without therapeutic indications in a phar-
maceutical formanddosagewhichdonotpresentariskforthepatient.
(22)The anthroposophic medicinal products described in an officialpharmacopoeia and prepared by a homeopathic method are tobe treated, as regards registration and marketing authorization,inthesamewayashomeopathicmedicinalproducts.
(23)It is desirable in the first instance to provide users of thesehomeopathic medicinal products with a very clear indication oftheir homeopathic character and with sufficient guarantees oftheirqualityandsafety.
(24)The rules relating to the manufacture, control and inspection ofhomeopathic medicinal products must be harmonized to permitthecirculationthroughouttheCommunityofmedicinalproductswhicharesafeandofgoodquality.
(25)Theusualrulesgoverningtheauthorization tomarketmedicinalproducts should be applied to homeopathic medicinal productsplaced on the market with therapeutic indications or in a form
which may present risks which must be balanced against the
desired therapeutic effect. In particular, those Member Stateswhich have a homeopathic tradition should be able to applyparticularrulesfortheevaluationoftheresultsoftestsandtrialsintended to establish the safety and efficacy of these medicinal
productsprovidedthattheynotifythemtotheCommission.
(26)Inordertofacilitatethemovementofmedicinalproductsandto
preventthecontrolscarriedoutinoneMemberStatefrombeingrepeatedinanother,minimumrequirementsshouldbelaiddown
formanufactureandimportscomingfromthirdcountriesandfor
thegrantoftheauthorizationrelatingthereto.
(27)Itshouldbeensuredthat,intheMemberStates,thesupervision
and control of the manufacture of medicinal products is carried
outbyapersonwhofulfilsminimumconditionsofqualification.
(28)Before an authorization to market an immunological medicinal
product or derived from human blood or human plasma can be
granted, the manufacturer must demonstrate his ability to attainbatch-to-batch consistency. Before an authorization to market amedicinal product derived from human blood or human plasmacan be granted, the manufacturer must also demonstrate the
absence of specific viral contamination, to the extent that the
stateoftechnologypermits.
(29)Theconditionsgoverningthesupplyofmedicinalproductstothepublicshouldbeharmonized.
(30)InthisconnectionpersonsmovingaroundwithintheCommunityhave the right to carry a reasonable quantity of medicinalproducts lawfully obtained for their personal use. It must also2001L0083—EN—08.02.2003—001.001—5
▼B
be possible for a person established in one Member State to
receive fromanother Mem ber State a reasonable quantity ofmedicinalproductsintendedforhispersonaluse.
(31)In addition, by virtue of Regulation (EC) No 2309/93, certainmedicinal products are the subject of a Community marketingauthorization.Inthiscontext,theclassificationforthesupplyofmedicinal productscoveredbyaCommunitymarketingauthori-zationneedstobeestablished.Itisthereforeimportanttosetthecriteria on the basis of which Community decisions will be
taken.
(32)It is therefore appropriate, as an initial step, to harmonize the
basicprinciplesapplicable totheclassification forthesupplyofmedicinal products in the Community or in the Member Stateconcerned,whiletakingasastartingpointtheprinciplesalreadyestablished 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 psychotropicsubstances.
(33)The provisions dealing with the classification of medicinalproducts for the purpose of supply do not infringe the nationalsocial security arrangements for reimbursement or payment for
medicinalproductsonprescription.
(34)Many operations involving the wholesale distribution of medic-
inal products for human use may cover several Member Statessimultaneously.
(35)Itisnecessarytoexercisecontrolovertheentirechainofdistri-bution of medicinal products, from their manufacture or importinto the Community through to supply to the public, so as to
guaranteethatsuchproductsarestored,transportedandhandled
insuitable conditions.Therequirements whichmustbeadoptedfor this purpose will considerably facilitate the withdrawal ofdefective products from the market and allow more effectiveeffortsagainstcounterfeitproducts.
(36)Any person involved in the wholesale distribution of medicinal
productsshouldbeinpossessionofaspecialauthorization.Phar-
macists and persons authorized to supply medicinal products tothe public, and who confine themselves to this activity, shouldbeexemptfromobtainingthisauthorization.Itishoweverneces-sary, 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 showingtransactionsinproductsreceived.
(37)Authorizationmustbesubjecttocertainessentialconditionsanditistheresponsibility oftheMemberStateconcerned toensurethat such conditions are met; whereas each Member State must
recognizeauthorizationsgrantedbyotherMemberStates.
(38)Certain Member States impose on wholesalers who supply
medicinal products to pharmacists and on persons authorized tosupply medicinal products to the public certain public serviceobligations. Those Member States must be able to continue toimposethoseobligationsonwholesalersestablishedwithintheir
territory.Theymustalsobeabletoimposethemonwholesalers
inotherMemberStatesonconditionthattheydonotimposeanyobligationmorestringentthanthosewhichtheyimposeontheirown wholesalers and provided that such obligations may beregarded as warranted on grounds of public health protectionandareproportionateinrelationtotheobjectiveofsuchprotec-
tion.
(39)Rulesshouldbelaid downastohowthe labelling andpackage
leafletsaretobepresented.
(40)The provisions governing the information supplied to usersshould provide a high degree of consumer protection, in orderthat medicinal products may be used correctly on the basis offullandcomprehensibleinformation.2001L0083—EN—08.02.2003—001.001—6
▼B
(41)The marketing of medicinal products whose labelling and
package leaflets comply with this Directive should not be
prohibited or impeded on grounds connected with the labellingorpackageleaflet.
(42)This Directive is without prejudice to the application of
measures adopted pursuant to Council Directive 84/450/EEC of
10 September 1984 relating to the approximation of the laws,regulations and administrative provisions of the Member Statesconcerningmisleadingadvertising(
1).
(43)All Member States have adopted further specific measuresconcerning the advertising of medicinal products. There aredisparities between these measures. These disparities are likelyto have an impact on the functioning of the internal market,since advertising disseminated in one Member State is likely to
haveeffectsinotherMemberStates.
(44)CouncilDirective89/552/EECof3October1989onthecoordi-
nation of certain provisions laid down by law, regulation oradministrative action in Member States concerning the pursuit
of television broadcasting activities(
2) prohibits the television
advertising of medicinal products which are available only onmedicalprescriptionintheMemberStatewithinwhosejurisdic-tion the television broadcaster is located. This principle shouldbemadeofgeneralapplicationbyextendingittoothermedia.
(45)Advertising to the general public, even of non-prescriptionmedicinal products, could affect public health, were it to beexcessive and ill-considered. Advertising of medicinal productsto the general public, where it is permitted, ought therefore tosatisfycertainessentialcriteriawhichoughttobedefined.
(46)Furthermore, distribution of samples free of charge to thegeneralpublicforpromotionalendsmustbeprohibited.
(47)The advertising of medicinal products to persons qualified toprescribeorsupplythemcontributestotheinformationavailabletosuchpersons.Nevertheless,thisadvertisingshouldbesubjectto strict conditions and effective monitoring, referring in parti-cular to the work carried out within the framework of the
CouncilofEurope.
(48)Advertisingofmedicinalproductsshouldbesubjecttoeffective,
adequatemonitoring.ReferenceinthisregardshouldbemadetothemonitoringmechanismssetupbyDirective84/450/EEC.
(49)Medical sales representatives have an important role in thepromotion of medicinal products. Therefore, certain obligationsshould be imposed upon them, in particular the obligation tosupplythepersonvisitedwithasummaryofproductcharacteris-
tics.
(50)Personsqualifiedtoprescribemedicinalproductsmustbeableto
carryoutthesefunctionsobjectivelywithoutbeinginfluencedby
directorindirectfinancialinducements.
(51)It should be possible within certain restrictive conditions to
providesamplesofmedicinalproductsfreeofchargetopersonsqualifiedtoprescribeorsupplythemsothattheycanfamiliarize
themselveswithnewproductsandacquireexperienceindealing
withthem.
(52)Personsqualifiedtoprescribeorsupplymedicinalproductsmusthave access to a neutral, objective source of information about
productsavailable onthe market. Whereas it isneverthelessfor
theMemberStatestotakeallmeasuresnecessarytothisend,inthelightoftheirownparticularsituation.2001L0083—EN—08.02.2003—001.001—7
(1) OJ L 250, 19.9.1984, p. 17. Directive as amended by Directive 97/55/EC
(OJL290,23.10.1997,p.18).
(2) OJ L 298, 17.10.1989, p. 23. Directive as amended by Directive 97/36/EC
(OJL202,30.7.1997,p.60).
▼B
(53)Each undertaking which manufactures or imports medicinal
products should set up a mechanism to ensure that all informa-
tion supplied about a medicinal product conforms with theapprovedconditionsofuse.
(54)Inordertoensurethecontinuedsafetyofmedicinal productsinuse,it isnecessary toensure that pharmacovigilance systemsin
theCommunityarecontinuallyadaptedtotakeaccountofscien-
tificandtechnicalprogress.
(55)It is necessary to take account of changes arising as a result ofinternationalharmonisationofdefinitions,terminologyandtech-nologicaldevelopmentsinthefieldofpharmacovigilance.
(56)Theincreasinguseofelectronicnetworksforcommunication ofinformationonadversereactionstomedicinalproductsmarketedin the Community is intended to allow competent authorities tosharetheinformationatthesametime.
(57)ItistheinterestoftheCommunitytoensurethatthepharmacov-
igilance systemsforcentrallyauthorisedmedicinal productsand
thoseauthorisedbyotherproceduresareconsistent.
(58)Holders of marketing authorisations should be proactivelyresponsible for on-going pharmacovigilance of the medicinalproductstheyplaceonthemarket.
(59)ThemeasuresnecessaryfortheimplementationofthisDirectiveshould be adopted in accordance with Council Decision 1999/468/EC of 28 June 1999 laying down the procedures for theexercise of implementing powers conferred on the Commis-sion(
1).
(60)The Commission should be empowered to adopt any necessarychanges to Annex I in order to take into account scientific andtechnicalprogress.
(61)ThisDirective shouldbewithoutprejudice tothe obligations of
the Member States concerning the time-limits for transposition
oftheDirectivessetoutinAnnexII,PartB.
HAVEADOPTEDTHISDIRECTIVE:
TITLEI
DEFINITIONS
Article 1
For the purposes of this Directive, the following terms shall bear the
followingmeanings:
1.Proprietary medicinal product:
Anyready-preparedmedicinalproductplacedonthemarketunder
aspecialnameandinaspecialpack.
2.Medicinal product:
Anysubstanceorcombination ofsubstancespresentedfortreating
orpreventingdiseaseinhumanbeings.
Any substance or combination of substances which may be admi-
nistered to human beings with a view to making a medicaldiagnosis or to restoring, correcting or modifying physiologicalfunctions in human beings is likewise considered a medicinalproduct.
3.Substance:
Anymatterirrespectiveoforiginwhichmaybe:— human,e.g.2001L0083—EN—08.02.2003—001.001—8
(1) OJL184,17.7.1999,p.23.
▼B
humanbloodandhumanbloodproducts;
— animal,e.g.
micro-organisms,wholeanimals,partsoforgans,animalsecre-
tions,toxins,extracts,bloodproducts;
— vegetable,e.g.
micro-organisms, plants, parts of plants, vegetable secretions,
extracts;
— chemical,e.g.
elements, naturally occurring chemical materials and chemical
productsobtainedbychemicalchangeorsynthesis.
4.Immunological medicinal product:
Any medicinal product consisting of vaccines, toxins, serums or
allergenproducts:
(a) vaccines,toxinsandserumsshallcoverinparticular:
(i) agents used to produce active immunity, such as cholera
vaccine,BCG,poliovaccines,smallpoxvaccine;
(ii) agentsusedtodiagnosethestateofimmunity,includingin
particular tuberculin and tuberculin PPD, toxins for theSchickandDickTests,brucellin;
(iii) agents used to produce passive immunity, such as
diphtheria antitoxin, anti-smallpox globulin, antilympho-cyticglobulin;
(b) ‘allergen product’ shall mean any medicinal product which is
intended to identify or induce a specific acquired alteration intheimmunologicalresponsetoanallergizingagent.
5.Homeopathic medicinal product:
Any medicinal product prepared from products, substances or
compositions called homeopathic stocks in accordance with a
homeopathic manufacturing procedure described by the EuropeanPharmacopoeia or, in absence thereof, by the pharmacopoeiascurrentlyusedofficiallyintheMemberStates.
A homeopathic medicinal product may also contain a number of
principles.
6.Radiopharmaceutical:
Anymedicinalproductwhich,whenreadyforuse,containsoneor
more radionuclides (radioactive isotopes) included fora medicinal
purpose.
7.Radionuclide generator:
Any systemincorporating a fixed parent radionuclide fromwhich
is produced a daughter radionuclide which is to be obtained byelutionorbyanyothermethodandusedinaradiopharmaceutical.
8.Radionuclide kit:
Any preparation to be reconsitituted or combined with radionu-
clides in the final radiopharmaceutical, usually prior to itsadministration.
9.Radionuclide precursor:
Anyotherradionuclide producedfortheradio-labelling ofanother
substancepriortoadministration.
10.Medicinal products derived from human blood or human plasma:
Medicinal products based on blood constitutents which are
prepared industrially by public or private establishments, such
medicinal products including, in particular, albumin, coagulating
factorsandimmunoglobulinsofhumanorigin.
11.Adverse reaction:
A response to a medicinal product which is noxious and unin-
tended and which occurs at doses normally used in man for the2001L0083—EN—08.02.2003—001.001—9
▼B
prophylaxis, diagnosis or therapy of disease or for the restoration,
correctionormodificationofphysiologicalfunction.
12.Serious adverse reaction:
An adverse reaction which results in death, is life-threatening,
requiresinpatienthospitalisationorprolongationofexistinghospi-talisation,resultsinpersistentorsignificantdisabilityorincapacity,orisacongenitalanomaly/birthdefect.
13.Unexpected adverse reaction:
An adverse reaction, the nature, severity or outcome of which is
notconsistentwiththesummaryofproductcharacteristics.
14.Periodic safety update reports:
Theperiodical reportscontaining therecordsreferredtoinArticle
104.
15.Post-authorisation safety study:
A pharmacoepidemiological study or a clinical trial carried out in
accordance with the terms of the marketing authorisation,
conducted with the aimof identifying or quantifying a safetyhazardrelatingtoanauthorisedmedicinalproduct.
16.Abuse of medicinal products:
Persistent or sporadic, intentional excessive use of medicinal
products which is accompanied by harmful physical or psycholo-
gicaleffets.
17.Wholesale distribution of medicinal products:
All activities consisting of procuring, holding, supplying or
exporting medicinal products, apart from supplying medicinalproducts to the public. Such activities are carried out with manu-
facturers or their depositories, importers, other wholesale
distributors orwith pharmacists andpersonsauthorized orentitledto supply medicinal products to the public in the Member Stateconcerned.
18.Public service obligation:
Theobligationplaced onwholesalerstoguarantee permanently an
adequaterangeofmedicinalproductstomeettherequirementsofa
specific geographical area and to deliver the supplies requestedwithinaveryshorttimeoverthewholeoftheareainquestion.
19.Medicinal Prescription:
Any medicinal prescription issued by a professional person quali-
fiedtodoso.
20.Name of the medicinal product:
The name given to a medicinal product, which may be either an
invented name or a common or scientific name, together with atrade mark or the name of the manufacturer; the invented nameshallnotbeliabletoconfusionwiththecommonname.
21.Common name:
The international non-proprietary name recommended by the
World Health Organization, or, if one does not exist, the usualcommonname.
22.Strength of the medicinal product:
The content of the active substances expressed quantitatively per
dosageunit,perunitofvolumeorweightaccordingtothedosage
form.
23.Immediate packaging:
The container or other form of packaging immediately in contact
withthemedicinalproduct.
24.Outer packaging:
Thepackagingintowhichisplacedtheimmediatepackaging.2001L0083—EN—08.02.2003—001.001—10
▼B
25.Labelling:
Informationontheimmediateorouterpackaging.
26.Package leaflet:
A leaflet containing information for the user which accompanies
themedicinalproduct.
27.Agency:
The European Agency for the Evaluation of Medicinal Products
establishedbyRegulation(EEC)No2309/93.
28.Risk to public health:
All risks with regard to the quality, safety and efficacy of the
medicinalproduct.
TITLEII
SCOPE
Article 2
The provisions of this Directive shall apply to industrially produced
medicinalproductsforhumanuseintendedtobeplacedonthemarketinMemberStates.
Article 3
ThisDirectiveshallnotapplyto:
1. Anymedicinalproductpreparedinapharmacyinaccordancewitha
medical prescription foranindividual patient (commonly knownas
themagistralformula).
2. Any medicinal product which is prepared in a pharmacy in accor-
dance withthe prescriptions ofapharmacopoeia andisintended tobesupplieddirectlytothepatientsservedbythepharmacyinques-tion(commonlyknownastheofficialformula).
3. Medicinalproductsintendedforresearchanddevelopmenttrials.4. Intermediate products intended for further processing byan author-
izedmanufacturer.
5. Anyradionuclidesintheformofsealedsources.6. Wholeblood,plasmaorbloodcellsofhumanorigin.
Article 4
1. Nothing in this Directive shall in any way derogate fromthe
Community rules for the radiation protection of persons undergoingmedicalexaminationortreatment,orfromtheCommunityruleslayingdownthebasicsafetystandardsforthehealthprotectionofthegeneral
publicandworkersagainstthedangersofionizingradiation.
2. ThisDirectiveshallbewithoutprejudicetoCouncilDecision86/
346/EEC of 25 June 1986 accepting on behalf of the Community the
European Agreement on the Exchange of Therapeutic Substances of
HumanOrigin(
1).
3. TheprovisionsofthisDirectiveshallnotaffectthepowersofthe
Member States' authorities either as regards the setting of prices for
medicinal products or their inclusion in the scope of national healthinsurance schemes, onthebasisofhealth, economic andsocial condi-tions.
4. ThisDirective shallnotaffecttheapplication ofnationallegisla-
tion prohibiting or restricting the sale, supply or use of medicinalproducts as contraceptives or abortifacients. The Member States shallcommunicatethenationallegislationconcernedtotheCommission.2001L0083—EN—08.02.2003—001.001—11
(1) OJL207,30.7.1986,p.1.
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Article 5
A Member State may, in accordance with legislation in force and to
fulfil special needs, exclude fromthe provisions of this Directive
medicinal products supplied in response to a bona fide unsolicited
order,formulatedinaccordancewiththespecificationsofanauthorizedhealth care professional and for use by his individual patients on hisdirectpersonalresponsibility.
TITLEIII
PLACINGONTHEMARKET
CHAPTER 1
Marketingauthorization
Article 6
1. NomedicinalproductmaybeplacedonthemarketofaMember
State unless a marketing authorization has been issued by the compe-tentauthoritiesofthatMemberStateinaccordancewiththisDirectiveor an authorization has been granted in accordance with Regulation
(EEC)No2309/93.
2. Theauthorisationreferredtoinparagraph1shallalsoberequired
for radionuclide generators, radionuclide kits, radionuclide precursorradiopharmaceuticals andindustriallypreparedradiopharmaceuticals.
Article 7
Amarketingauthorization shallnotberequiredforaradiopharmaceu-
tical prepared at the time of use by a person or by an establishmentauthorized, according to national legislation, to use such medicinal
products in an approved health care establishment exclusively from
authorized radionuclide generators, radionuclide kits or radionuclideprecursorsinaccordancewiththemanufacturer'sinstructions.
Article 8
1. In order to obtain an authorization to place a medicinal product
on the market regardless of the procedure established by Regulation(EEC) No 2309/93, an application shall be made to the competentauthorityoftheMemberStateconcerned.
2. A marketing authorization may only be granted to an applicant
establishedintheCommunity.
3. Theapplicationshallbeaccompaniedbythefollowingparticulars
anddocuments,submittedinaccordancewithAnnexI:
(a) Name or corporate name and permanent address of the applicant
and,whereapplicable,ofthemanufacturer.
(b) Nameofthemedicinalproduct.
(c) Qualitativeandquantitativeparticularsofalltheconstituentsofthe
medicinal product in usual terminology, but excluding empiricalchemical formulae, with mention of the international non-proprie-
tary name recommended bythe World Health Organization where
suchnameexists.
(d) Descriptionofthemanufacturingmethod.
(e) Therapeuticindications,contra-indicationsandadversereactions.
(f) Posology,pharmaceuticalform,methodandrouteofadministration
andexpectedshelflife.
(g) Ifapplicable,reasonsforanyprecautionaryandsafetymeasuresto
betakenforthestorageofthemedicinalproduct,itsadministrationtopatientsandforthedisposalofwasteproducts,togetherwithanindicationofanypotentialriskspresentedbythemedicinalproductfortheenvironment.2001L0083—EN—08.02.2003—001.001—12
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(h) Description of the control methods employed by the manufacturer
(qualitative andquantitative analysisoftheconstituentsandofthefinished product, special tests, e.g. sterility tests, tests for the
presence of pyrogenic substances, the presence of heavy metals,
stability tests, biological and toxicity tests, controls carried out atanintermediatestageofthemanufacturingprocess).
(i) Resultsof:
— physico-chemical,biologicalormicrobiologicaltests,
— toxicologicalandpharmacologicaltests,— clinicaltrials.
(j) Asummary,inaccordance withArticle 11,oftheproduct charac-
teristics, one or more specimens or mock-ups of the outerpackaging and the immediate packaging of the medicinal product,togetherwithapackageleaflet.
(k) Adocumentshowingthatthemanufacturerisauthorisedinhisown
countrytoproducemedicinalproducts.
(l) CopiesofanyauthorisationobtainedinanotherMemberStateorin
a third country to place the medicinal product on the market,togetherwithalistofthoseMemberStatesinwhichanapplicationfor authorisation submitted in accordance with this Directive is
under examination. Copies of the summary of the product charac-
teristicsproposedbytheapplicantinaccordancewithArticle11orapproved by the competent authorities of the Member State inaccordancewithArticle21.CopiesofthepackageleafletproposedinaccordancewithArticle59orapprovedbythecompetentautho-
ritiesoftheMemberStateinaccordancewithArticle61.Detailsof
anydecisiontorefuseauthorization, whetherintheCommunityorinathirdcountry,andthereasonsforsuchadecision.
Thisinformationshallbeupdatedonaregularbasis.
Article 9
InadditiontotherequirementssetoutinArticles8and10(1),anappli-
cation for authorization to market a radionuclide generator shall alsocontainthefollowinginformationandparticulars:
— ageneraldescriptionofthesystemtogetherwithadetaileddescrip-
tion of the components of the system which may affect thecompositionorqualityofthedaughternucleidpreparation,
— qualitative and quantitative particulars of the eluate or the subli-
mate.
Article 10
1. Inderogation ofArticle 8(3)(i),andwithoutprejudice tothelaw
relatingtotheprotectionofindustrialandcommercialproperty:
(a) Theapplicantshallnotberequiredtoprovidetheresultsoftoxico-
logical and pharmacological tests or the results of clinical trials ifhecandemonstrate:
(i) either that the medicinal product is essentially similar to a
medicinal product authorized in the Member State concernedbytheapplicationandthattheholderofthemarketingauthor-
izationfortheoriginalmedicinalproducthasconsentedtothe
toxicological, pharmacological and/or clinical referencescontained in the file on the original medicinal product beingusedforthepurposeofexaminingtheapplicationinquestion;
(ii) orthattheconstituentorconstituentsofthemedicinalproduct
have a well established medicinal use, with recognized effi-
cacy and an acceptable level of safety, by means of a
detailedscientificbibliography;
(iii) orthatthemedicinalproductisessentiallysimilartoamedic-
inalproductwhichhasbeenauthorizedwithintheCommunity,in accordance with Community provisions in force, for notless than six years and is marketed in the Member State forwhich the application is made. This period shall be extended2001L0083—EN—08.02.2003—001.001—13
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to10yearsinthecaseofhigh-technologymedicinal products
having been authorised according to the procedure laid downin Article 2(5) of Council Directive 87/22/EEC(
1). Further-
more, a Member State may also extend this period to 10
yearsbyasingleDecisioncoveringallthemedicinalproductsmarketed on its territory where it considers this necessary inthe interest of public health. Member States are at liberty notto apply the six-year period beyond the date of expiry of a
patentprotectingtheoriginalmedicinalproduct.
However, where the medicinal product is intended for a
different therapeutic use fromthat of the other m edicinal
productsmarketedoristobeadministeredbydifferentroutes
or in different doses, the results of appropriate toxicologicaland pharmacological tests and/or of appropriate clinical trialsmustbeprovided.
(b) In the case of new medicinal products containing known constitu-
entsnothitherto usedincombination fortherapeutic purposes,the
results of toxicological and pharmacological tests and of clinicaltrials relating to that combination must be provided, but it shallnot be necessary to provide references relating to each individualconstituent.
2. Annex I shall apply by analogy where, pursuant to point (ii) of
paragraph 1, (a), bibliographic references to published data are
submitted.
Article 11
Thesummaryoftheproductcharacteristicsshallcontainthefollowing
information:
1. Nameofthemedicinalproduct.
2. Qualitative and quantitative composition in terms of the active
substancesandconstituentsoftheexcipient,knowledgeofwhichis essential for proper administration of the medicinal product.Theusualcommonnameorchemicaldescriptionshallbeused.
3. Pharmaceuticalform.
4. Pharmacological properties and, in so far as this information is
usefulfortherapeuticpurposes,pharmacokineticparticulars.
5. Clinicalparticulars:
5.1. therapeuticindications,5.2. contra-indications,5.3. adversereactions(frequencyandseriousness),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,togetherwithanyprecautionstobetakenbythepatient,
5.5. useduringpregnancyandlactation,5.6. interaction with other medicaments and other forms of interac-
tion,
5.7. posology and method of administration for adults and, where
necessary,forchildren,
5.8. overdose(symptoms,emergencyprocedures,antidotes),5.9. specialwarnings,5.10. effectsonabilitytodriveandtousemachines.
6. Pharmaceuticalparticulars:2001L0083—EN—08.02.2003—001.001—14
(1) OJL15,17.1.1987,p.38.DirectiverepealedbyDirective93/41/EEC(OJL
214,24.8.1993,p.40).
▼B
6.1. majorincompatibilities,
6.2. shelf life, when necessary after reconstitution of the medicinal
productorwhentheimmediate packagingisopenedforthefirsttime,
6.3. specialprecautionsforstorage,
6.4. natureandcontentsoftheimmediatepackaging,
6.5. special precautions fordisposal of unusedmedicinal products or
waste materials derived from such medicinal products, if appro-priate.
7. Nameorcorporatenameandpermanentaddressofthemarketing
authorizationholder.
8. For radiopharmaceuticals, full details of internal radiation dosi-
metry.
9. For radiopharmaceuticals, additional detailed instructions for
extemporaneous preparation andquality control ofsuchprepara-tionand,whereappropriate,maximumstoragetimeduringwhich
anyintermediatepreparationsuchasaneluateortheready-to-use
pharmaceutical willconformwithitsspecifications.
Article 12
1. Member States shall take all appropriate measures to ensure that
the documents and particulars listed in Article 8(3)(h) and (i), andArticle 10(1)(a)(ii) are drawn up by experts with the necessary tech-nical or professional qualifications before they are submitted to thecompetentauthorities.Thesedocumentsandparticularsshallbesigned
bytheexperts.
2. The duties of the experts according to their respective qualifica-
tionsshallbe:
(a) toperformtasksfallingwithintheirrespectivedisciplines(analysis,
pharmacologyandsimilarexperimentalsciences,clinicaltrials)andtodescribeobjectivelytheresultsobtained(qualitativelyandquan-titatively);
(b) to describe their observations in accordance with Annex I, and to
state,inparticular:
— in the case of the analyst, whether the medicinal product is
consistentwiththedeclaredcomposition,givinganysubstantia-
tionofthecontrolmethodsemployedbythemanufacturer;
— in the case of the pharmacologist or the specialist with similar
experimental competence, thetoxicityofthemedicinal product
andthepharmacologicalpropertiesobserved;
— inthecaseoftheclinician, whetherhehasbeenabletoascer-
taineffectsonpersonstreatedwiththemedicinalproductwhichcorrespond to the particulars given by the applicant in accor-dance with Articles 8 and 10, whether the patient tolerates the
medicinal product well, the posology the clinician advises and
anycontra-indicationsandadversereactions;
(c) where applicable, to state the grounds for using the bibliography
mentionedinpoint(a)(ii)ofArticle10(1).
3. Detailed reports by the experts shall formpart of the particulars
accompanying the application which the applicant submits to the
competentauthorities.
CHAPTER 2
Specificprovisionsapplicabletohomeopathicmedicinalproducts
Article 13
1. MemberStatesshall ensurethat homeopathic medicinal products
manufactured and placed on the market within the Community areregistered or authorized in accordance with Articles 14, 15 and 16,exceptwheretheproductsarecoveredbyaregistrationorauthorization2001L0083—EN—08.02.2003—001.001—15
▼B
whichwasgrantedundernationallawonorbefore31December1993
(andwhetherornotthatregistrationorauthorizationhasbeenrenewedafterthatdate).EachMemberStateshalltakedueaccountofregistra-
tionsandauthorizationspreviouslygrantedbyanotherMemberState.
2. AMember State may refrain from establishing a special, simpli-
fied registration procedure for the homeopathic medicinal products
referredtoinArticle14.AMemberStateshallinformtheCommission
accordingly. The Member State concerned shall allow the use in itsterritory of homeopathic medicinal products registered by otherMemberStatesinaccordancewithArticles14and15.
Article 14
1. Only homeopathic medicinal products which satisfy all of the
followingconditionsmaybesubjecttoaspecial,simplifiedregistration
procedure:
— theyareadministeredorallyorexternally,
— no specific therapeutic indication appears on the labelling of the
medicinalproductorinanyinformationrelatingthereto,
— thereisasufficientdegreeofdilutiontoguaranteethesafetyofthe
medicinal product; in particular, the medicinal product may notcontaineithermorethanonepartper10000ofthemothertinctureor more than 1/100th of the smallest dose used in allopathy withregardtoactivesubstanceswhosepresenceinanallopathicmedic-inal product results in the obligation to submit a doctor's
prescription.
Atthetimeofregistration,MemberStatesshalldeterminetheclassifi-
cationforthedispensingofthemedicinalproduct.
2. The criteria and rules of procedure provided for in Article 4(4),
Article 17(1) and Articles 22 to 26, 112, 116 and 125 shall apply byanalogy to the special, simplified registration procedure for homeo-
pathic medicinal products, with the exception of the proof of
therapeuticefficacy.
3. Theproofoftherapeuticefficacyshallnotberequiredforhomeo-
pathicmedicinalproductsregisteredinaccordancewithparagraph1of
thisArticle,or,whereappropriate,admittedinaccordancewithArticle13(2).
Article 15
Anapplicationforspecial,simplifiedregistrationmaycoveraseriesof
medicinalproductsderivedfromthesamehomeopathicstockorstocks.The following documents shall be included with the application inorder to demonstrate, in particular, the pharmaceutical quality and the
batch-to-batchhomogeneityoftheproductsconcerned:
— scientific name or other name given in a pharmacopoeia of the
homeopathic stock or stocks, together with a statement of thevarious routes of administration, pharmaceutical forms and degreeofdilutiontoberegistered,
— dossier describing how the homeopathic stock or stocks is/are
obtainedandcontrolled,andjustifyingits/theirhomeopathicnature,onthebasisofanadequatebibliography,
— manufacturing andcontrolfileforeach pharmaceuticalformanda
descriptionofthemethodofdilutionandpotentization,
— manufacturingauthorizationforthemedicinalproductconcerned,— copies of any registrations or authorizations obtained for the same
medicinalproductinotherMemberStates,
— oneormorespecimensormock-upsoftheouterpackagingandthe
immediatepackagingofthemedicinalproductstoberegistered,
— dataconcerningthestabilityofthemedicinalproduct.2001L0083—EN—08.02.2003—001.001—16
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Article 16
1. Homeopathic medicinal products other than those referred to in
Article14(1)shallbeauthorizedandlabelledinaccordancewithArti-cles8,10and11.
2. A Member State may introduce or retain in its territory specific
rulesforthetoxicological andpharmacological testsandclinical trialsof homeopathic medicinal products other than those referred to inArticle 14(1) in accordance with the principles and characteristics ofhomeopathyaspractisedinthatMemberState.
Inthiscase,theMemberStateconcernedshallnotifytheCommission
ofthespecificrulesinforce.
3. Title IXshallapplytohomeopathicmedicinal products,withthe
exceptionofthosereferredtoinArticle14(1).
CHAPTER 3
Procedures relevant tothemarketingauthorization
Article 17
1. Member States shall take all appropriate measures to ensure that
the procedure for granting an authorization to place a medicinal
productonthemarketiscompletedwithin210daysofthesubmissionofavalidapplication.
2. WhereaMemberStatenotesthatanapplicationforauthorization
isalreadyunderactiveexaminationinanotherMemberStateinrespectofthat medicinal product,the MemberState concerned maydecide tosuspend the detailed examination of the application in order to awaitthe assessment report prepared by the other Member State in accor-
dancewithArticle21(4).
TheMemberStateconcernedshallinformtheotherMemberStateand
the applicant of its decision to suspend detailed examination of the
application in question. As soon as it has completed the examination
oftheapplicationandreachedadecision,theotherMemberStateshallforwardacopyofitsassessmentreporttotheMemberStateconcerned.
Article 18
Where a Member State is informed in accordance with Article 8(3)(l)
thatanotherMemberStatehasauthorizedamedicinalproductwhichisthe subject of an application for authorization in the Member Stateconcerned,thatMemberStateshallforthwithrequesttheauthoritiesof
theMemberStatewhichhasgrantedtheauthorization toforwardtoit
theassessmentreportreferredtoinArticle21(4).
Within 90 days of the receipt of the assessment report, the Member
StateconcernedshalleitherrecognizethedecisionofthefirstMember
Stateandthesummaryoftheproductcharacteristics asapprovedbyitor,ifitconsidersthattherearegroundsforsupposingthattheauthor-izationofthemedicinalproductconcernedmaypresentarisktopublichealth,itshallapplytheproceduressetoutinArticles29to34.
Article 19
InordertoexaminetheapplicationsubmittedinaccordancewithArti-
cles8and10(1),thecompetentauthorityoftheMemberState:
1. must verify whether the particulars submitted in support of the
application comply with the said Articles 8and 10(1) andexamine
whether the conditions for issuing an authorization to place medic-
inal products on the market (marketing authorization) are compliedwith.
2. maysubmitthemedicinalproduct,itsstartingmaterialsand,ifneed
be, its intermediate products or other constituent materials, fortesting by a State laboratory or by a laboratory designated for thatpurpose in order to ensure that the control methods employed by2001L0083—EN—08.02.2003—001.001—17
▼B
themanufacturer anddescribedintheparticularsaccompanying the
applicationinaccordancewithArticle8(3)(h)aresatisfactory.
3. may, where appropriate, require the applicant to supplement the
particulars accompanying the application in respect of the itemslistedintheArticles8(3)and10(1).Wherethecompetentauthority
avails itself of this option, the time limits laid down in Article 17
shallbesuspendeduntilsuchtimeasthesupplementaryinformationrequired has been provided. Likewise, these time limits shall besuspended for the time allowed the applicant, where appropriate,forgivingoralorwrittenexplanation.
Article 20
MemberStatesshalltakeallappropriatemeasurestoensurethat:
(a) the competent authorities verify that manufacturers and importers
ofmedicinalproductscomingfromthirdcountriesareabletocarryout manufacture in compliance with the particulars supplied
pursuant to Article 8(3)(d), and/or to carry out controls according
tothemethodsdescribedintheparticularsaccompanyingtheappli-cationinaccordancewithArticle8(3)(h);
(b) the competent authorities may allow manufacturers and importers
of medicinal products coming from third countries, in exceptionaland justifiable cases, to have certain stages of manufacture and/orcertainofthecontrolsreferredtoin(a)carriedoutbythirdparties;in such cases, the verifications by the competent authorities shallalsobemadeintheestablishmentdesignated.
Article 21
1. When the marketing authorization is issued, the holder shall be
informed,bythecompetentauthoritiesoftheMemberStateconcerned,ofthesummaryoftheproductcharacteristicsasapprovedbyit.
2. The competent authorities shall take all necessary measures to
ensure that the information given in the summary is in conformitywiththatacceptedwhenthemarketingauthorizationisissuedorsubse-quently.
3. Thecompetent authoritiesshallforwardtotheAgencyacopyof
theauthorizationtogetherwiththesummaryoftheproductcharacteris-
tics.
4. Thecompetentauthoritiesshalldrawupanassessmentreportand
comments on the dossier as regards the results of the analytical andpharmacotoxicological 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 theevaluation of the quality, safety or efficacy of the medicinal productconcerned.
Article 22
In exceptional circumstances, and following consultation with the
applicant, an authorization may be granted subject to certain specificobligations,including:
— thecarryingoutoffurtherstudiesfollowingthegrantingofauthor-
ization,
— thenotificationofadversereactionstothemedicinalproduct.
These exceptional decisions may be adopted only for objective and
verifiable reasons and shall be based on one of the causes referred toinPart4(G)ofAnnexI.
Article 23
After an authorization has been issued, the authorization holder must,
in respect of the methods of manufacture and control provided for inArticle8(3)(d)and(h),takeaccountofscientificandtechnicalprogressand introduce any changes that may be required to enable the medic-2001L0083—EN—08.02.2003—001.001—18
▼B
inal product to be manufactured and checked by means of generally
acceptedscientificmethods.
These changes shall be subject to the approval of the competent
authorityoftheMemberStateconcerned.
Article 24
Authorization shall be valid for five years and shall be renewable for
five-year periods, on application by the holder at least three monthsbefore the expiry date and after consideration by the competentauthority of a dossier containing in particular details of the data on
pharmacovigilance andotherinformationrelevanttothemonitoringof
themedicinalproduct.
Article 25
Authorization shall not affect the civil and criminal liability of the
manufacturer and, where applicable, of the marketing authorizationholder.
Article 26
Themarketingauthorisationshallberefusedif,afterverificationofthe
particularsanddocumentslistedinArticles8and10(1),itprovesthat:
(a) themedicinalproductisharmfulinthenormalconditionsofuse,or
(b) that its therapeutic efficacy is lacking or is insufficiently substan-
tiatedbytheapplicant,or
(c) thatitsqualitativeandquantitativecompositionisnotasdeclared.
Authorisationshalllikewiseberefusediftheparticularsanddocuments
submitted in support of the application donot comply with Articles 8
and10(1).
CHAPTER 4
Mutualrecognitionofauthorizations
Article 27
1. In order to facilitate the adoption of common decisions by
MemberStatesontheauthorizationofmedicinalproductsonthebasis
ofthe scientific criteria ofquality, safety andefficacy, andtoachieve
thereby the free movement of medicinal products within the Commu-nity, a Committee for Proprietary Medicinal Products, hereinafterreferred to as‘the Committee’, ishereby set up.TheCommittee shallbepartoftheAgency.
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 marketingauthorizationwhichissubmittedtoitinaccordancewiththisDirective.
3. TheCommitteeshalldrawupitsownRulesofProdecure.
Article 28
1. Before submitting the application for recognition of a marketing
authorization, theholderoftheauthorization shallinformtheMember
Statewhichgrantedtheauthorizationonwhichtheapplicationisbased
(hereinafter ‘reference Member State’), that an application is to bemadeinaccordancewiththisDirectiveandshallnotifyitofanyaddi-tions to the original dossier; that Member State may require theapplicanttoprovideitwithalltheparticularsanddocumentsnecessary
toenableittocheckthatthedossiersfiledareidentical.
In addition the holder of the authorization shall request the reference
MemberStatetoprepareanassessmentreportinrespectofthemedic-inal product concerned, or, if necessary, to update any existingassessment report. That Member State shall prepare the assessmentreport,orupdateit,within90daysofthereceiptoftherequest.2001L0083—EN—08.02.2003—001.001—19
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At the same time as the application is submitted in accordance with
paragraph 2,the reference Member State shall forwardthe assessmentreport tothe MemberState orMemberStatesconcerned bytheappli-
cation.
2. Inordertoobtaintherecognitionaccordingtotheprocedureslaid
down in this Chapter in one or more of the Member States of a
marketing authorization issued by a Member State, the holder of theauthorization shall submit an application to the competent authoritiesof the Member State or Member States concerned, together with theinformation andparticulars referred toinArticles 8,10(1)and11.He
shall testify that the dossier is identical to that accepted by the refer-
ence Member State, or shall identify any additions or amendments itmay contain. In the latter case, he shall certify that the summary oftheproductcharacteristicsproposedbyhiminaccordancewithArticle11isidenticaltothatacceptedbythereferenceMemberStateinaccor-dance with Article 21. Moreover, he shall certify that all the dossiers
filedaspartoftheprocedureareidentical.
3. Theholderofthemarketing authorization shallcommunicate the
application to the Agency, informit of the Mem ber States concerned
and of the dates of submission of the application and send it a copyof the authorization granted by the reference Member State. He shallalso send the Agency copies of any such authorization which mayhavebeengrantedbytheotherMemberStatesinrespectofthemedic-inal product concerned, and shall indicate whether any application for
authorizationiscurrentlyunderconsiderationinanyMemberState.
4. Save in the exceptional case provided for in Article 29(1), each
Member State shall recognize the marketing authorization granted by
thereferenceMemberStatewithin90daysofreceiptoftheapplicationand the assessment report. It shall inform the reference Member Statewhich granted the initial authorization, the other Member Statesconcernedbytheapplication,theAgency,andthemarketingauthoriza-tionholder.
Article 29
1. Where a Member State considers that there are grounds for
supposing that the marketing authorization of the medicinal productconcernedmaypresentarisktopublichealth,itshallforthwithinformthe applicant, the reference Member State which granted the initialauthorization, any other Member States concerned by the application
and the Agency. The Member State shall state its reasons in detail
and shall indicate what action may be necessary to correct any defectintheapplication.
2. AlltheMemberStatesconcerned shallusetheirbestendeavours
toreachagreementontheactiontobetakeninrespectoftheapplica-tion.Theyshallprovidetheapplicantwiththeopportunitytomakehispoint of view known orally or in writing. However, if the MemberStates havenotreached agreement withinthe time limit referred toin
Article 28(4) they shall forthwith refer the matter to the Agency with
regardtotheCommittee'sreferencefortheapplicationoftheprocedurelaiddowninArticle32.
3. Within the time limit referred to in Article 28(4), the Member
StatesconcernedshallprovidetheCommitteewithadetailedstatementofthemattersonwhichtheyhavebeenunabletoreachagreementandthereasonsfortheirdisagreement.Theapplicantshallbeprovidedwithacopyofthisinformation.
4. Assoonasheisinformedthatthematterhasbeenreferredtothe
Committee, the applicant shall forthwith forward to the Committee a
copyoftheinformationandparticularsreferredtoinArticle28(2).
Article 30
If several applications submitted in accordance with Articles 8, 10(1)
andArticle11havebeenmadeformarketingauthorizationforaparti-cular medicinal product, and Member States have adopted divergentdecisions concerning the authorization of the medicinal product or its2001L0083—EN—08.02.2003—001.001—20
▼B
suspensionorwithdrawal, aMemberState, orthe Commission,orthe
marketing authorization holder may refer the matter to the CommitteeforapplicationoftheprocedurelaiddowninArticle32.
TheMemberStateconcerned,themarketingauthorizationholderorthe
CommissionshallclearlyidentifythequestionwhichisreferredtotheCommittee 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
matterinquestion.
Article 31
TheMemberStatesortheCommissionortheapplicantorholderofthe
marketing authorization may, in specific cases where the interests ofthe Community are involved, refer the matter to the Committee forthe application of the procedure laid down in Article 32 beforereaching a decision on a request for a marketing authorization or on
thesuspensionorwithdrawalofanauthorization,oronanyothervaria-
tiontothetermsofamarketingauthorizationwhichappearsnecessary,inparticulartotakeaccountoftheinformationcollectedinaccordancewithTitleIX.
TheMemberStateconcernedortheCommissionshallclearly identify
the question which is referred to the Committee for consideration andshallinformthemarketingauthorizationholder.
The Member States and the marketing authorization holder shall
forward to the Committee all available information relating to thematterinquestion.
Article 32
1. When reference is made to the procedure described in this
Article, the Committee shall consider the matter concerned and issuea reasoned opinion within 90 days of the date on which the matter
wasreferredtoit.
However,incasessubmittedtotheCommitteeinaccordancewithArti-
cles30and31,thisperiodmaybeextendedby90days.
In case of urgency, on a proposal from its Chairman, the Committee
mayagreetoashorterdeadline.
2. In order to consider the matter, the Committee may appoint one
of its members to act as rapporteur. The Committee may also appointindividual experts to advise it on specific questions. When appointingexperts, the Committee shall define their tasks and specify the time-
limitforthecompletionofthesetasks.
3. In the cases referred to in Articles 29 and 30, before issuing its
opinion, the Committee shall provide the marketing authorization
holderwithanopportunitytopresentwrittenororalexplanations.
InthecasereferredtoinArticle31,themarketingauthorizationholder
maybeaskedtoexplainhimselforallyorinwriting.
If it considers it appropriate, the Committee may invite any other
persontoprovideinformationrelatingtothematterbeforeit.
TheCommittee maysuspendthetime limit referred toinparagraph 1
inordertoallowthemarketingauthorizationholdertoprepareexplana-tions.
4. The Agency shall forthwith informthe m arketing authorization
holderwheretheopinionoftheCommitteeisthat:
— theapplicationdoesnotsatisfythecriteriaforauthorization,or
— the summary of the product characteristics proposed by the appli-
cantinaccordancewithArticle11shouldbeamended,or2001L0083—EN—08.02.2003—001.001—21
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— the authorization should be granted subject to conditions, with
regard to conditions considered essential for the safe and effectiveuseofthemedicinalproductincludingpharmacovigilance, or
— a marketing authorization should be suspended, varied or with-
drawn.
Within 15daysofthereceipt oftheopinion,themarketing authoriza-
tionholdermaynotifytheAgencyinwritingofhisintentiontoappeal.In that case, he shall forward the detailed grounds for appeal to theAgency within 60 days of receipt of the opinion. Within 60 days ofreceiptofthegroundsforappeal,theCommitteeshallconsiderwhether
its opinion should be revised, and the conclusions reached on the
appeal shall be annexed to the assessment report referred to in para-graph5.
5. Within30daysofitsadoption,theAgencyshallforwardthefinal
opinion of the Committee to the Member States, the Commission and
themarketingauthorizationholdertogetherwithareportdescribingthe
assessment of the medicinal product and stating the reasons for itsconclusions.
In the event of an opinion in favour of granting or maintaining an
authorization toplace the medicinal product concerned onthe market,thefollowingdocumentsshallbeannexedtotheopinion.
(a) a draft summary of the product characteristics, as referred to in
Article11;
(b) any conditions affecting the authorization within the meaning of
paragraph4.
Article 33
Within 30 days of the receipt of the opinion, the Commission shall
prepareadraftofthedecisiontobetakeninrespectoftheapplication,takingintoaccountCommunitylaw.
In the event of a draft decision which envisages the granting of
marketing authorization, the documents referred to in Article 32(5)(a)
and(b)shallbeannexed.
Where, exceptionally, the draft decision is not in accordance with the
opinion of the Agency, the Commission shall also annex a detailedexplanationofthereasonsforthedifferences.
The draft decision shall be forwarded to the Member States and the
applicant.
Article 34
1. Afinaldecisionontheapplicationshallbeadoptedinaccordance
withtheprocedurereferredtoinArticle121(2).
2. TherulesofprocedureoftheStandingCommitteeestablishedby
Article121(1)shallbeadjustedtotakeaccountofthetasksincumbentuponitinaccordancewiththisChapter.
Theseadjustmentsshallinvolvethefollowing:
— exceptincasesreferredtointhethirdparagraphofArticle33,the
opinionoftheStandingCommitteeshallbeobtainedinwriting,
— each Member State is allowed at least 28 days to forward written
observationsonthedraftdecisiontotheCommission,
— eachMemberStateisabletorequireinwritingthatthedraftdeci-
sionbediscussedbytheStandingCommittee,givingitsreasonsin
detail.
Where,intheopinionoftheCommission,thewrittenobservationsofa
MemberStateraiseimportantnewquestionsofascientificortechnicalnaturewhichhavenotbeenaddressedintheopinionoftheAgency,theChairmanshallsuspendtheprocedureandrefertheapplicationbacktotheAgencyforfurtherconsideration.2001L0083—EN—08.02.2003—001.001—22
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Theprovisionsnecessaryfortheimplementationofthisparagraphshall
be adopted by the Commission in accordance with the procedurereferredtoinArticle121(2).
3. Adecisionasreferredtoinparagraph1shallbeaddressedtothe
MemberStatesconcerned bythematter andreportedtothemarketingauthorizationholder.TheMemberStatesshalleithergrantorwithdrawmarketingauthorization,orvarythetermsofamarketingauthorization
asnecessarytocomplywiththedecisionwithin30daysofitsnotifica-
tion.TheyshallinformtheCommissionandtheAgencythereof.
Article 35
1. Any application by the marketing authorization holder to vary a
marketing authorization which has been granted in accordance with
the provisions of this Chapter shall be submitted to all the MemberStates which have previously authorized the medicinal productconcerned.
The Commission shall, in consultation with the Agency, adopt appro-
priatearrangementsfortheexaminationofvariationstothetermsofa
marketingauthorization.
These arrangements shall include a notification system or administra-
tion procedures concerning minor variations and define precisely the
conceptof‘aminorvariation’.
ThesearrangementsshallbeadoptedbytheCommissionintheformof
animplementingRegulationinaccordancewiththeprocedurereferredtoinArticle121(2).
2. IncaseofarbitrationsubmittedtotheCommission,theprocedure
laiddowninArticles32,33and34shallapplybyanalogytovariationsmadetomarketingauthorizations.
Article 36
1. WhereaMemberStateconsidersthatthevariationofamarketing
authorizationwhichhasbeengrantedinaccordancewiththeprovisionsof this Chapter or its suspension or withdrawal is necessary for theprotectionofpublichealth,theMemberStateconcernedshallforthwithreferthemattertotheAgencyfortheapplicationoftheprocedureslaid
downinArticles32,33and34.
2. Without prejudice to the provisions of Article 31, in exceptional
cases, where urgent action is essential to protect public health, until adefinitive decision is adopted a Member State may suspend the
marketingandtheuseofthemedicinal productconcernedonitsterri-
tory. It shall inform the Commission and the other Member States nolaterthanthefollowingworkingdayofthereasonsforitsaction.
Article 37
Articles35and36shallapplybyanalogytomedicinalproductsauthor-
izedbyMemberStatesfollowinganopinionoftheCommitteegivenin
accordance with Article 4 of Directive 87/22/EEC before 1 January1995.
Article 38
1. TheAgencyshallpublishanannualreportontheoperationofthe
procedures laid down in this Chapter and shall forward that report totheEuropeanParliamentandtheCouncilforinformation.
2. By 1 January 2001, the Commission shall publish a detailed
review of the operation of the procedures laid down in this Chapter
andshallproposeanyamendmentswhichmaybenecessarytoimprovetheseprocedures.
The Council shall decide, under the conditions provided for in the
Treaty,ontheCommissionproposalwithinoneyearofitssubmission.2001L0083—EN—08.02.2003—001.001—23
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Article 39
The provisions referred to in Articles 27 to 34 shall not apply to the
homeopathicmedicinalproductsreferredtoinArticle16(2).
TITLEIV
MANUFACTUREANDIMPORTATION
Article 40
1. Member States shall take all appropriate measures to ensure that
the manufacture of the medicinal products within their territory issubjecttotheholdingofanauthorization.Thismanufacturingauthori-zation shall be required nothwithstanding that the medicinal products
manufacturedareintendedforexport.
2. Theauthorizationreferredtoinparagraph1shallberequiredfor
both total and partial manufacture, and for the various processes of
dividingup,packagingorpresentation.
However, such authorization shall not be required for preparation,
dividing up, changes in packaging or presentation where theseprocesses are carried out, solely for retail supply, by pharmacists indispensingpharmaciesorbypersonslegallyauthorizedintheMemberStatestocarryoutsuchprocesses.
3. Authorizationreferredtoinparagraph1shallalsoberequiredfor
imports coming from third countries into a Member State; this Titleand Article 118 shall have corresponding application to such imports
astheyhavetomanufacture.
Article 41
In order to obtain the manufacturing authorization, the applicant shall
meetatleastthefollowingrequirements:
(a) specifythemedicinalproductsandpharmaceuticalformswhichare
tobemanufacturedorimported andalsothe place wheretheyare
tobemanufacturedand/orcontrolled;
(b) have at his disposal, for the manufacture or import of the above,
suitable and sufficient premises, technical equipment and controlfacilitiescomplyingwiththelegalrequirementswhichtheMemberStateconcernedlaysdownasregardsbothmanufactureandcontrol
and the storage of medicinal products, in accordance with Article
20;
(c) have at his disposal the services of at least one qualified person
withinthemeaningofArticle48.
The applicant shall provide particulars in support of the above in his
application.
Article 42
1. The competent authority of the Member State shall issue the
manufacturing authorization only after having made sure of the accu-racyoftheparticularssuppliedpursuanttoArticle41,bymeansofaninquirycarriedoutbyitsagents.
2. Inorder toensure that the requirements referred toinArticle 41
are complied with, authorization may be made conditional on thecarrying out of certain obligations imposed either when authorization
isgrantedoratalaterdate.
3. Theauthorizationshallapplyonlytothepremisesspecifiedinthe
application and to the medicinal products and pharmaceutical forms
specifiedinthatsameapplication.
Article 43
The Member States shall take all appropriate measures to ensure that
thetimetakenfortheprocedureforgrantingthemanufacturingauthor-2001L0083—EN—08.02.2003—001.001—24
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izationdoesnotexceed90daysfromthedayonwhichthecompetent
authorityreceivestheapplication.
Article 44
If the holder of the manufacturing authorization requests a change in
anyoftheparticularsreferredtoinpoints(a)and(b)ofthefirstpara-graph of Article 41, the time taken for the procedure relating to thisrequest shall not exceed 30 days. In exceptional cases this period of
timemaybeextendedto90days.
Article 45
The competent authority of the Member State may require from the
applicant further information concerning the particulars suppliedpursuant to Article 41 and concerning the qualified person referred to
in Article 48; where the competent authority concerned exercises this
right, application of the time-limits referred to in Article 43 and 44shall be suspended until the additional data required have beensupplied.
Article 46
Theholderofamanufacturingauthorizationshallatleastbeobliged:
(a) to have at his disposal the services of staff who comply with the
legalrequirementsexistingintheMemberStateconcernedbothasregardsmanufactureandcontrols;
(b) todisposeoftheauthorizedmedicinalproductsonlyinaccordance
withthelegislationoftheMemberStatesconcerned;
(c) to give prior notice to the competent authority of any changes he
may wish to make to any of the particulars supplied pursuant toArticle41;thecompetentauthorityshall,inanyevent,beimmedi-ately informed if the qualified person referred to in Article 48 is
replacedunexpectedly;
(d) toallowtheagentsofthecompetentauthorityoftheMemberState
concernedaccesstohispremisesatanytime;
(e) toenablethequalifiedpersonreferredtoinArticle48tocarryout
hisduties,forexamplebyplacingathisdisposalallthenecessary
facilities;
(f) to comply with the principles and guidelines of good manufac-
turingpracticeformedicinalproductsaslaiddownbyCommunity
law.
Article 47
The principles and guidelines of good manufacturing practices for
medicinal products referred to in Article 46(f) shall be adopted in theformof a directive, in accordance with the procedure referred to in
Article121(2).
Detailed guidelines in line with those principles will be published by
the Commission and revised necessary to take account of technicalandscientificprogress.
Article 48
1. Member States shall take all appropriate measures to ensure that
the holder of the manufacturing authorization has permanently andcontinuously at his disposal the services of at least one qualifiedperson, in accordance with the conditions laid down in Article 49,
responsibleinparticularforcarryingoutthedutiesspecifiedinArticle
51.
2. IfhepersonallyfulfilstheconditionslaiddowninArticle49,the
holder of the authorization may himself assume the responsibilityreferredtoinparagraph1.2001L0083—EN—08.02.2003—001.001—25
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Article 49
1. MemberStatesshallensurethatthequalifiedpersonreferredtoin
Article 48 fulfils the minimum conditions of qualification set out inparagraphs2and3.
2. Aqualifiedpersonshallbeinpossessionofadiploma,certificate
orotherevidenceofformalqualifications awardedoncompletion ofa
universitycourseofstudy,oracourserecognizedasequivalentbytheMemberStateconcerned,extendingoveraperiodofatleastfouryearsof theoretical and practical study in one of the following scientificdisciplines: pharmacy, medicine, veterinary medicine, chemistry,phar-maceuticalchemistryandtechnology,biology.
However,theminimumdurationoftheuniversitycoursemaybethree
andahalfyearswherethecourseisfollowedbyaperiodoftheoretical
andpracticaltrainingofaminimumdurationofoneyearandincludinga training period of at least six months in a pharmacy open to thepublic,corroboratedbyanexaminationatuniversitylevel.
WheretwouniversitycoursesortwocoursesrecognizedbytheStateas
equivalent co-existinaMemberStateandwhereoneoftheseextendsover four years and the other over three years, the three-year course
leadingtoadiploma, certificate orotherevidence offormalqualifica-
tions awarded on completion of a university course or its recognizedequivalent shall be considered to fulfil the condition of durationreferredtointhesecondsubparagraphinsofarasthediplomas,certi-ficates or other evidence of formal qualifications awarded on
completion of both courses are recognized as equivalent by the State
inquestion.
Thecourseshallincludetheoreticalandpracticalstudybearinguponat
leastthefollowingbasicsubjects:
— Appliedphysics
— Generalandinorganicchemistry— Organicchemistry
— Analyticalchemistry
— Pharmaceuticalchemistry,includinganalysisofmedicinalproducts— Generalandappliedbiochemistry(medical)— Physiology
— Microbiology
— Pharmacology— Pharmaceuticaltechnology— Toxicology
— Pharmacognosy(studyofthecompositionandeffectsofthenatural
activesubstancesofplantandanimalorigin).
Studiesinthesesubjectsshouldbesobalancedastoenabletheperson
concernedtofulfiltheobligationsspecifiedinArticle51.
In so far as certain diplomas, certificates or other evidence of formal
qualifications mentioned in the first subparagraph do not fulfil thecriteria laid down in this paragraph, the competent authority of theMemberStateshallensurethatthepersonconcernedprovidesevidenceofadequateknowledgeofthesubjectsinvolved.
3. Thequalifiedpersonshallhaveacquiredpracticalexperienceover
atleasttwoyears,inoneormoreundertakingswhichareauthorizedto
manufacturemedicinalproducts,intheactivitiesofqualitativeanalysis
ofmedicinalproducts,ofquantitativeanalysisofactivesubstancesandofthetestingandcheckingnecessarytoensurethequalityofmedicinalproducts.
The duration of practical experience may be reduced by one year
where a university course lasts for at least five years and by a yearandahalfwherethecourselastsforatleastsixyears.2001L0083—EN—08.02.2003—001.001—26
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Article 50
1. A person engaging in the activities of the person referred to in
Article 48 fromthe tim e of the application of Directive 75/319/EEC,
in a Member State without complying with the provisions of Article
49shallbeeligibletocontinuetoengageinthoseactivitiesintheStateconcerned.
2. The holder of a diploma, certificate or other evidence of formal
qualifications awarded on completion of a university course — or a
courserecognized asequivalent bytheMemberStateconcerned —in
a scientific discipline allowing himto engage in the activities of theperson referred to in Article 48 in accordance with the laws of thatState may — if he began his course prior to 21 May 1975 — beconsidered as qualified to carry out in that State the duties of theperson referred to in Article 48 provided that he has previously
engaged in the following activities for at least two years before 21
May1985followingnotificationofthisdirectiveinoneormoreunder-takings authorized to manufacture: production supervision and/orqualitative and quantitative analysis of active substances, and thenecessarytestingandcheckingunderthedirectauthorityoftheperson
referredtoinArticle48toensurethequalityofthemedicinalproducts.
If the person concerned has acquired the practical experience referred
to in the first subparagraph before 21 May 1965, a further one year'spractical experience in accordance with the conditions referred to inthe first subparagraph will be required to be completed immediatelybeforeheengagesinsuchactivities.
Article 51
1. Member States shall take all appropriate measures to ensure that
the qualified person referred to in Article 48, without prejudice to hisrelationship with the holder of the manufacturing authorization, isresponsible, in the context of the procedures referred to in Article 52,forsecuring:
(a) inthecaseofmedicinalproductsmanufacturedwithintheMember
States concerned, that each batch of medicinal products has beenmanufacturedandcheckedincompliancewiththelawsinforceinthatMemberStateandinaccordance withtherequirements ofthemarketingauthorization;
(b) inthecaseofmedicinalproductscomingfromthirdcountries,that
each production batch has undergone in the importing MemberState a full qualitative analysis, a quantitative analysis of at leastall the active constituents and all the other tests or checks neces-
sary to ensure the quality of medicinal products in accordance
withtherequirementsofthemarketingauthorization.
Thebatchesofmedicinalproductswhichhaveundergonesuchcontrols
in a Member State shall be exempt from the controls if they aremarketedinanotherMemberState,accompaniedbythecontrolreportssignedbythequalifiedperson.
2. Inthecaseofmedicinal productsimported from athirdcountry,
where appropriate arrangements have been made by the Communitywith the exporting country to ensure that the manufacturer of themedicinal product applies standardsofgoodmanufacturing practice atleast equivalent to those laid down by the Community, and to ensurethat the controls referred to under point (b) of the first subparagraph
of paragraph 1 have been carried out in the exporting country, the
qualified person may be relieved of responsibility for carrying outthosecontrols.
3. In all cases and particularly where the medicinal products are
released for sale, the qualified person must certify in a register or
equivalent document provided for that purpose, that each production
batchsatisfiestheprovisionsofthisArticle;thesaidregisterorequiva-lentdocumentmustbekeptuptodateasoperationsarecarriedoutandmustremainatthedisposaloftheagentsofthecompetentauthorityforthe period specified in the provisions of the Member State concernedandinanyeventforatleastfiveyears.2001L0083—EN—08.02.2003—001.001—27
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Article 52
MemberStatesshallensurethatthedutiesofqualifiedpersonsreferred
toinArticle48arefulfilled,eitherbymeansofappropriateadministra-tivemeasuresorbymakingsuchpersonssubjecttoaprofessionalcodeofconduct.
Member States may provide for the temporary suspension of such a
person upon the commencement of administrative or disciplinaryproceduresagainsthimforfailuretofulfilhisobligations.
Article 53
TheprovisionsofthisTitle shallalsoapplytohomeopathic medicinal
products.
TITLEV
LABELLINGANDPACKAGELEAFLET
Article 54
Thefollowingparticularsshallappearontheouterpackagingofmedic-
inal products or,where there is noouter packaging, onthe immediatepackaging:
(a) thenameofthemedicinalproductfollowedbythecommonname
where the product contains only one active substance and if itsnameisaninventedname;whereamedicinalproductisavailableinseveralpharmaceuticalformsand/orseveralstrengths,thephar-
maceutical form and/or the strength (baby, child or adult as
appropriate) must be included in the name of the medicinalproduct;
(b) a statement of the active substances expressed qualitatively and
quantitativelyperdosageunitoraccordingtotheformofadminis-trationforagivenvolumeorweight,usingtheircommonnames;
(c) thepharmaceuticalformandthecontentsbyweight,byvolumeor
bynumberofdosesoftheproduct;
(d) a list of those excipients known to have a recognized action or
effectandincludedintheguidelinespublishedpursuanttoArticle
65. However, if the product is injectable, or a topical or eyepreparation,allexcipientsmustbestated;
(e) themethodand,ifnecessary,therouteofadministration;
(f) aspecialwarningthatthemedicinalproductmustbestoredoutof
reachofchildren;
(g) aspecialwarning,ifthisisnecessaryforthemedicinalproduct;(h) theexpirydateinclearterms(month/year);
(i) specialstorageprecautions,ifany;(j) special precautions for disposal of unused medicinal products or
wastematerialsfrommedicinalproducts,ifappropriate;
(k) thenameandaddressoftheholderoftheauthorizationforplacing
themedicinalproductonthemarket;
(l) thenumberoftheauthorization forplacing themedicinal product
onthemarket;
(m) themanufacturer'sbatchnumber;
(n) in the case of self-medication, instructions on the use of the
medicinalproducts.
Article 55
1. The particulars laid down in Articles 54 and 62 shall appear on
immediatepackagingsotherthanthosereferredtoinparagraphs2and
3.
2. The following particulars at least shall appear on immediate
packagings which take the formof blister packs and are placed in an2001L0083—EN—08.02.2003—001.001—28
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outerpackagingthatcomplieswiththerequirementslaiddowninArti-
cles54and62.
— thenameofthemedicinalproductaslaiddowninArticle54(a),
— thenameoftheholderoftheauthorization forplacingtheproduct
onthemarket,
— theexpirydate,
— thebatchnumber.
3. Thefollowingparticularsatleastshallappearonsmallimmediate
packaging unitsonwhichtheparticulars laid downinArticles 54and62cannotbedisplayed:
— the name of the medicinal product and, if necessary, the strength
andtherouteofadministration,
— themethodofadministration,
— theexpirydate,
— thebatchnumber,— thecontentsbyweight,byvolumeorbyunit.
Article 56
The particulars referred to in Articles 54, 55 and 62 shall be easily
legible,clearlycomprehensibleandindelible.
Article 57
Notwithstanding Article 60, Member States may require the use of
certain forms of labelling of the medicinal product making it possible
toascertain:
— thepriceofthemedicinalproduct,
— thereimbursementconditionsofsocialsecurityorganizations,— the legal status for supply to the patient, in accordance with Title
VI,
— identificationandauthenticity.
Article 58
Theinclusioninthepackaging ofallmedicinal productsofapackage
leaflet shall be obligatory unless all the information required by Arti-
cles 59 and 62 is directly conveyed on the outer packaging or on the
immediatepackaging.
Article 59
1. The package leaflet shall be drawn up in accordance with the
summary of the product characteristics; it shall include, in the
followingorder:
(a) fortheidentificationofthemedicinalproduct:
— the name of the medicinal product, followed by the common
name if the product contains only one active substance and ifits name is an invented name; where a medicinal product is
available in several pharmaceutical forms and/or several
strengths, the pharmaceutical form and/or the strength (forexample, baby, child, adult) must be included in the name ofthemedicinalproduct,
— a full statement of the active substances and excipients
expressedqualitativelyandastatementoftheactivesubstancesexpressedquantitatively,usingtheircommonnames,inthecaseofeachpresentationofthemedicinalproduct,
— thepharmaceuticalformandthecontentsbyweight,byvolume
or by number of doses of the product, in the case of each
presentationoftheproduct,
— the pharmaco-therapeutic group, or type of activity in terms
easilycomprehensibleforthepatient,2001L0083—EN—08.02.2003—001.001—29
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— the name and address of the holder of the authorization for
placing the medicinal product on the market and of the manu-facturer;
(b) thetherapeuticindications;
(c) list of information which is necessary before taking the medicinal
product:
— contra-indications,
— appropriateprecautionsforuse,— forms of interaction with other medicinal products and other
formsofinteraction
(e.g. alcohol, tobacco, foodstuffs) which may affect the action
ofthemedicinalproduct,
— specialwarnings;
thislistmust:
— take into account the particular condition of certain categories
of users (e.g. children, pregnant or breastfeeding women, the
elderly,personswithspecificpathologicalconditions),
— mention, ifappropriate, potential effects onthe ability todrive
vehiclesortooperatemachinery,
— detailthoseexcipients,knowledgeofwhichisimportantforthe
safeandeffectiveuseofthemedicinalproductandincludedintheguidelinespublishedpursuanttoArticle65;
(d) thenecessaryandusualinstructionsforproperuse,inparticular:
— thedosage,
— themethodand,ifnecessary,routeofadministration,— the frequency of administration, specifying if necessary, the
appropriate time at which the medicinal product may or must
beadministered,
and,asappropriate,dependingonthenatureoftheproduct:
— thedurationoftreatment,whereitshouldbelimited,
— the action to be taken in the case of an overdose (e.g., symp-
toms,emergencyprocedures),
— the course of action to take when one or more doses have not
beentaken,
— indication,ifnecessary,oftheriskofwithdrawaleffects;
(e) a description of the undesirable effects which can occur under
normal use of the medicinal product and, if necessary, the action
tobetaken insuchacase; the patient shouldbeexpresslyinvited
to communicate any undesirable effect which is not mentioned intheleaflettohisdoctorortohispharmacist;
(f) areferencetotheexpirydateindicatedonthelabel,with:
— awarningagainstusingtheproductafterthisdate,
— whereappropriate,specialstorageprecautions,— ifnecessary,awarningagainstcertainvisiblesignsofdeteriora-
tion;
(g) thedateonwhichthepackageleafletwaslastrevised.
2. Notwithstanding paragraph 1(b), the authority competent may
decide that certain therapeutic indications shall not be mentioned inthepackageleaflet,wherethedisseminationofsuchinformationmight
haveseriousdisadvantagesforthepatient.
Article 60
Member States may not prohibit or impede the placing on the market
ofmedicinal productswithintheirterritoryongroundsconnectedwithlabelling or the package leaflet where these comply with the require-mentsofthisTitle.2001L0083—EN—08.02.2003—001.001—30
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Article 61
1. One ormore specimens ormock-ups ofthe outer packaging and
the immediate packaging of a medicinal product, together with thedraft package leaflet, shall be submitted to the authorities competentfor authorizing marketing when the marketing authorization is
requested.
2. The competent authority shall refuse the marketing authorization
ifthelabellingorthepackageleafletdonotcomplywiththeprovisions
ofthisTitleoriftheyarenotinaccordance withtheparticularslistedinthesummaryofproductcharacteristics.
3. Allproposedchangestoanaspectofthelabellingorthepackage
leaflet covered by this Title and not connected with the summary ofproduct characteristics shall be submitted to the authorities competentfor authorizing marketing. If the competent authorities have notopposed a proposed change within 90 days following the introduction
oftherequest,theapplicantmayputthechangeintoeffect.
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 generallegal liability of the manufacturer or as appropriate the marketingauthorizationholder.
Article 62
The outer packaging and the package leaflet may include symbols or
pictograms designed to clarify certain information mentioned in Arti-
cles54and59(1)andotherinformation compatible withthesummaryof the product characteristics which is useful for health education, totheexclusionofanyelementofapromotionalnature.
Article 63
1. TheparticularsforlabellinglistedinArticles54,59and62shall
appearintheofficiallanguageorlanguagesoftheMemberStatewheretheproductisplacedonthemarket.
The first subparagraph shall not prevent these particulars frombeing
indicated in several languages, provided that the same particularsappearinallthelanguagesused.
2. The package leaflet must be written in clear and understandable
terms for the users and be clearly legible in the official language orlanguages of the Member State where the medicinal product isplacedonthemarket.
The first subparagraph shall not prevent the package leaflet being
printed in several languages, provided that the same information isgiveninallthelanguagesused.
3. Thecompetentauthoritiesmayexemptlabelsandpackageleaflets
forspecificmedicinalproductsfromtheobligationthatcertainparticu-
larsshallappearandthattheleafletmustbeintheofficiallanguageor
languages of the Member State where the product is placed on themarket,whentheproductisnotintendedtobedeliveredtothepatientforself-administration.
Article 64
WheretheprovisionsofthisTitlearenotcomplied with,andanotice
served on the person concerned has remained without effect, thecompetentauthoritiesoftheMemberStatesmaysuspendthemarketingauthorization, until the labelling andthe package leaflet ofthe medic-inal product in question have been made to comply with therequirementsofthisTitle.2001L0083—EN—08.02.2003—001.001—31
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Article 65
As necessary, the Commission shall publish guidelines concerning in
particular:
— theformulationofcertainspecialwarningsforcertaincategoriesof
medicinalproducts,
— theparticularinformationneedsrelatingtoself-medication,— thelegibilityofparticularsonthelabellingandpackageleaflet,
— methods for the identification and authentication of medicinal
products,
— thelistofexcipientswhichmustfeatureonthelabellingofmedic-
inalproductsandthewaytheseexcipientsmustbeindicated.
TheseguidelinesshallbeadoptedintheformofaDirective,inaccor-
dancewiththeprocedurereferredtoinArticle121(2).
Article 66
1. The outer carton and the container of medicinal products
containingradionuclidesshallbelabelledinaccordancewiththeregu-lationsforthesafetransportofradioactive materials laiddownbytheInternational Atomic Energy Agency. Moreover, the labelling shallcomplywiththeprovisionssetoutinparagraphs2and3.
2. Thelabelontheshieldingshallincludetheparticularsmentioned
inArticle54.Inaddition,thelabellingontheshieldingshallexplaininfull, the codings used on the vial and shall indicate, where necessary,
foragiven time anddate, theamount ofradioactivity perdoseorper
vialandthenumberofcapsules,or,forliquids,thenumberofmillili-tresinthecontainer.
3. Thevialshallbelabelledwiththefollowinginformation:
— the name or code of the medicinal product, including the name or
chemicalsymboloftheradionuclide,
— thebatchidentificationandexpirydate,
— theinternationalsymbolforradioactivity,
— thenameofthemanufacturer,
— theamountofradioactivityasspecifiedinparagraph2.
Article 67
The competent authority shall ensure that a detailed instruction leaflet
is enclosed with the packaging of radiopharmaceuticals, radionuclidegenerators, radionuclide kits or radionuclide precursors. The text ofthis leaflet shall be established in accordance with the provisions of
Article 59. In addition, the leaflet shall include any precautions to be
takenbytheuserandthepatientduringthepreparationandadministra-tion of the medicinal product and special precautions for the disposalofthepackaginganditsunusedcontents.
Article 68
WithoutprejudicetotheprovisionsofArticle69,homeopathicmedic-
inalproductsshallbelabelledinaccordancewiththeprovisionsofthistitleandshallbeidentified byareferenceontheirlabels,inclearandlegibleform,totheirhomeopathicnature.
Article 69
1. In addition to the clear mention of the words ‘homeopathic
medicinal product’, the labelling and, where appropriate, the packageinsertforthemedicinalproductsreferredtoinArticle14(1)shallbearthefollowing,andnoother,information:
— thescientificnameofthestockorstocksfollowedbythedegreeof
dilution, making use of the symbols of the pharmacopoeia used in
accordancewithArticle1(5),
— nameandaddressoftheregistrationholderand,whereappropriate,
ofthemanufacturer,2001L0083—EN—08.02.2003—001.001—32
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— methodofadministrationand,ifnecessary,route,
— expirydate,inclearterms(month,year),— pharmaceuticalform,— contentsofthesalespresentation,
— specialstorageprecautions,ifany,
— aspecialwarningifnecessaryforthemedicinalproduct,— manufacturer'sbatchnumber,— registrationnumber,— ‘homeopathicmedicinalproductwithoutapprovedtherapeutic indi-
cations’,
— a warning advising the user to consult a doctor if the symptoms
persistduringtheuseofthemedicinalproduct.
2. Notwithstandingparagraph1,MemberStatesmayrequiretheuse
ofcertaintypesoflabellinginordertoshow:
— thepriceofthemedicinalproduct,
— theconditionsforrefundsbysocialsecuritybodies.
TITLEVI
CLASSIFICATIONOFMEDICINALPRODUCTS
Article 70
1. Whenamarketingauthorizationisgranted,thecompetent autho-
ritiesshallspecifytheclassificationofthemedicinalproductinto:
— amedicinalproductsubjecttomedicalprescription,
— amedicinalproductnotsubjecttomedicalprescription.
Tothisend,thecriterialaiddowninArticle71(1)shallapply.2. The competent authorities may fix sub-categories for medicinal
products which are available on medical prescription only. In that
case,theyshallrefertothefollowingclassification:
(a) medicinal products on renewable or non-renewable medical
prescription;
(b) medicinalproductssubjecttospecialmedicalprescription;
(c) medicinal products on restricted medical prescription, reserved for
useincertainspecializedareas.
Article 71
1. Medicinalproductsshallbesubjecttomedicalprescriptionwhere
they:
— are likely to present a danger either directly or indirectly, even
whenusedcorrectly,ifutilizedwithoutmedicalsupervision,or
— arefrequently andtoaverywideextentusedincorrectly, andasa
result are likely to present a direct or indirect danger to humanhealth,or
— contain substances or preparations thereof, the activity and/or
adversereactionsofwhichrequirefurtherinvestigation,or
— arenormallyprescribedbyadoctortobeadministeredparenterally.
2. Where Member States provide for the sub-category of medicinal
productssubjecttospecialmedicalprescription,theyshalltakeaccountofthefollowingfactors:
— the medicinal product contains, in a non-exempt quantity, a
substanceclassifiedasanarcoticorapsychotropicsubstancewithinthe meaning of the international conventions in force, such as theUnitedNationsConventionsof1961and1971,or
— the medicinal product is likely, if incorrectly used, to present a
substantial risk of medicinal abuse, to lead to addiction or bemisusedforillegalpurposes,or2001L0083—EN—08.02.2003—001.001—33
▼B
— the medicinal product contains a substance which,byreasonof its
noveltyorproperties,couldbeconsideredasbelongingtothegroupenvisagedinthesecondindentasaprecautionarymeasure.
3. Where Member States provide for the sub-category of medicinal
products subject to restricted prescription, they shall take account of
thefollowingfactors:
— themedicinalproduct,becauseofitspharmaceutical characteristics
ornoveltyorintheinterestsofpublichealth,isreservedfortreat-mentswhichcanonlybefollowedinahospitalenvironment,
— the medicinal product isusedin the treatment ofconditions which
mustbediagnosedinahospitalenvironmentorininstitutionswith
adequate diagnostic facilities, although administration and follow-
upmaybecarriedoutelsewhere,or
— the medicinal product is intended for outpatients but its use may
produce very serious adverse reactions requiring a prescription
drawn up as required by a specialist and special supervision
throughoutthetreatment.
4. Acompetent authority may waive application of paragraphs 1,2
and3havingregardto:
(a) the maximum single dose, the maximum daily dose, the strength,
thepharmaceutical form,certaintypesofpackaging;and/or
(b) othercircumstancesofusewhichithasspecified.
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 toin paragraphs 2and 3ofthis
Article in determining whether any medicinal product shall be classi-fiedasaprescription-onlymedicine.
Article 72
Medicinalproductsnotsubjecttoprescriptionshallbethosewhichdo
notmeetthecriterialistedinArticle71.
Article 73
The competent authorities shall draw up a list of the medicinal
productssubject,ontheirterritory,tomedical prescription, specifying,
if necessary, the category of classification. They shall update this list
annually.
Article 74
Ontheoccasionofthefive-yearlyrenewalofthemarketingauthoriza-
tion or when new facts are brought to their notice, the competentauthorities shall examine and, as appropriate, amend the classification
ofamedicinalproduct,byapplyingthecriterialistedinArticle71.
Article 75
Each year, Member States shall communicate to the Commission and
to the other Member States, the changes that have been made to thelistreferredtoinArticle73.
TITLEVII
WHOLESALEDISTRIBUTIONOFMEDICINALPRODUCTS
Article 76
WithoutprejudicetoArticle6,MemberStatesshalltakeallappropriate
action to ensure that only medicinal products in respect of which amarketing authorization hasbeen granted inaccordance withCommu-nitylawaredistributedontheirterritory.2001L0083—EN—08.02.2003—001.001—34
▼B
Article 77
1. Member States shall take all appropriate measures to ensure that
the wholesale distribution of medicinal products is subject to thepossessionofanauthorization toengageinactivity asawholesaler inmedicinalproducts,statingtheplaceforwhichitisvalid.
2. Where persons authorized or entitled to supply medicinal
productstothepublic mayalso,undernational law,engageinwhole-
sale business, such persons shall be subject to the authorization
providedforinparagraph1.
3. Possessionofamanufacturing authorization shallincludeauthor-
ization to distribute by wholesale the medicinal products covered bythat authorization.Possessionofanauthorization toengage inactivityasawholesalerinmedicinal productsshallnotgivedispensationfromtheobligation topossessamanufacturing authorization andtocomplywith the conditions set out in that respect, even where the manufac-
turingorimportbusinessissecondary.
4. AttherequestoftheCommissionoranyMemberState,Member
States shall supply all appropriate information concerning the indivi-
dualauthorizationswhichtheyhavegrantedunderparagraph1.
5. Checks on the persons authorized to engage in the activity of
wholesaler in medicinal products and the inspection of their premises,shallbecarriedoutundertheresponsibilityoftheMemberStatewhichgrantedtheauthorization.
6. TheMemberStatewhichgrantedtheauthorization referredtoin
paragraph1shallsuspendorrevokethatauthorizationiftheconditionsof authorization cease to be met. It shall forthwith inform the otherMemberStatesandtheCommissionthereof.
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
nolongermet,itshallforthwithinformtheCommissionandtheotherMember State involved. The latter shall take the measures necessaryand shall inform the Commission and the first Member State of thedecisionstakenandthereasonsforthosedecisions.
Article 78
Member States shall ensure that the time taken for the procedure for
examining the application for the distribution authorization does notexceed 90daysfromthedayonwhichthecompetent authority oftheMemberStateconcernedreceivestheapplication.
The competent authority may, if need be, require the applicant to
supply all necessary information concerning the conditions of authori-zation.Wheretheauthorityexercisesthisoption,theperiodlaiddown
in the first paragraph shall be suspended until the requisite additional
datahavebeensupplied.
Article 79
In order to obtain the distribution authorization, applicants must fulfil
thefollowingminimumrequirements:
(a) they must have suitable and adequate premises, installations and
equipment, soasto ensure proper conservation and distribution of
themedicinalproducts;
(b) they must have staff, and in particular, a qualified person desig-
nated as responsible, meeting the conditions provided for by thelegislationoftheMemberStateconcerned;
(c) they must undertake to fulfil the obligations incumbent on them
underthetermsofArticle80.2001L0083—EN—08.02.2003—001.001—35
▼B
Article 80
Holders of the distribution authorization must fulfil the following
minimumrequirements:
(a) they must make the premises, installations and equipment referred
toinArticle79(a)accessibleatalltimestothepersonsresponsibleforinspectingthem;
(b) they must obtain their supplies of medicinal products only from
persons who are themselves in possession of the distribution
authorizationorwhoareexemptfromobtainingsuchauthorizationunderthetermsofArticle77(3);
(c) theymustsupplymedicinalproductsonlytopersonswhoarethem-
selves in possession of the distribution authorization or who areauthorized or entitled to supply medicinal products to the publicintheMemberStateconcerned;
(d) they musthave an emergency plan whichensureseffective imple-
mentation ofanyrecall fromthemarket orderedbythecompetentauthorities or carried out in cooperation with the manufacturer ormarketing authorization holder for the medicinal productconcerned;
(e) they must keep records either in the form of purchase/sales
invoices, or on computer, or in any other form, giving for anytransaction in medicinal products received or dispatched at leastthefollowinginformation:
— date,
— nameofthemedicinalproduct,— quantityreceivedorsupplied,— nameandaddressofthesupplierorconsignee,asappropriate;
(f) they must keep the records referred to under (e) available to the
competent authorities, forinspectionpurposes,foraperiodoffiveyears;
(g) theymustcomplywiththeprinciplesandguidelinesofgooddistri-
butionpracticeformedicinalproductsaslaiddowninArticle84.
Article 81
With regard to the supply of medicinal products to pharmacists and
persons authorized or entitled to supply medicinal products to the
public, Member Statesshall notimpose uponthe holder ofa distribu-
tion authorization which has been granted by another Member State,any obligation, in particular public service obligations, more stringentthanthosetheyimposeonpersonswhomtheyhavethemselvesauthor-izedtoengageinequivalentactivities.
Thesaidobligationsshould,moreover,bejustified,inkeepingwiththe
Treaty, ongroundsofpublic health protection andbeproportionate in
relationtotheobjectiveofsuchprotection.
Article 82
Forallsuppliesofmedicinalproductstoapersonauthorizedorentitled
to supply medicinal products to the public in the Member Stateconcerned, the authorized wholesaler must enclose a document thatmakesitpossibletoascertain:
— thedate,
— thenameandpharmaceutical formofthemedicinalproduct,— thequantitysupplied,— thenameandaddressofthesupplierandconsignor.
Member States shall take all appropriate measures to ensure that
persons authorized or entitled to supply medicinal products to thepublic are able to provide information that makes it possible to tracethedistributionpathofeverymedicinalproduct.2001L0083—EN—08.02.2003—001.001—36
▼B
Article 83
The provisions of this Title shall not prevent the application of more
stringent requirements laid down by Member States in respect of thewholesaledistributionof:
— narcoticorpsychotropicsubstanceswithintheirterritory,
— medicinalproductsderivedfromblood,— immunologicalmedicinalproducts,— radiopharmaceuticals.
Article 84
TheCommissionshallpublishguidelinesongooddistributionpractice.
To this end, it shall consult the Committee for Proprietary MedicinalProducts and the Pharmaceutical Committee established by CouncilDecision75/320/EEC(
1).
Article 85
The provisions of this Title shall apply to homeopathic medicinal
products,withtheexceptionofthosereferredtoinArticle14(1).
TITLEVIII
ADVERTISING
Article 86
1. ForthepurposesofthisTitle,‘advertisingofmedicinalproducts’
shallincludeanyformofdoor-to-doorinformation,canvassingactivity
or inducement designed to promote the prescription, supply, sale or
consumptionofmedicinalproducts;itshallincludeinparticular:
— theadvertisingofmedicinalproductstothegeneralpublic,
— advertising of medicinal products to persons qualified to prescribe
orsupplythem,
— visits by medical sales representatives to persons qualified to
prescribemedicinalproducts,
— thesupplyofsamples,
— 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 isminimal,
— sponsorshipof promotional meetings attended bypersonsqualified
toprescribeorsupplymedicinalproducts,
— sponsorshipofscientificcongressesattendedbypersonsqualifiedto
prescribeorsupplymedicinalproductsandinparticularpaymentoftheir travelling and accommodation expenses in connection there-with.
2. ThefollowingarenotcoveredbythisTitle:
— the labelling and the accompanying package leaflets, which are
subjecttotheprovisionsofTitleV,
— correspondence,possiblyaccompaniedbymaterialofanon-promo-
tional nature, needed to answer a specific question about aparticularmedicinalproduct,
— factual,informativeannouncementsandreferencematerialrelating,
forexample, topackchanges,adverse-reaction warningsaspartofgeneral drugprecautions, trade catalogues and price lists, providedtheyincludenoproductclaims,
— statements relating to human health or diseases, provided there is
noreference,evenindirect,tomedicinalproducts.2001L0083—EN—08.02.2003—001.001—37
(1) OJL187,9.6.1975,p.23.
▼B
Article 87
1. Member States shall prohibit any advertising of a medicinal
product in respect of which a marketing authorization has not beengrantedinaccordancewithCommunitylaw.
2. All parts of the advertising of a medicinal product must comply
withtheparticularslistedinthesummaryofproductcharacteristics.
3. Theadvertisingofamedicinalproduct:
— shall encourage the rational use of the medicinal product, by
presentingitobjectivelyandwithoutexaggeratingitsproperties,
— shallnotbemisleading.
Article 88
1. MemberStatesshallprohibittheadvertisingtothegeneralpublic
ofmedicinalproductswhich:
— areavailableonmedicalprescriptiononly,inaccordancewithTitle
VI,
— contain psychotropic or narcotic substances, such as the United
NationsConventionsof1961and1971,
— maynotbeadvertisedtothegeneralpublicinaccordance withthe
secondsubparagraphofparagraph2.
2. Medicinal products may be advertised to the general public
which, by virtue of their composition and purpose, are intended anddesigned forusewithout the intervention ofa medical practitioner for
diagnostic purposesorforthe prescription ormonitoring oftreatment,
withtheadviceofthepharmacist,ifnecessary.
Member States shall prohibit the mentioning in advertising to the
generalpublicoftherapeuticindicationssuchas:
— tuberculosis,
— sexuallytransmitteddiseases,
— otherseriousinfectiousdiseases,
— cancerandothertumoraldiseases,
— chronicinsomnia,— diabetesandothermetabolicillnesses.
3. MemberStatesshallbeabletoban,ontheirterritory,advertising
to the general public of medicinal products the cost of which may be
reimbursed.
4. The prohibition referred to in paragraph 1 shall not apply to
vaccination campaigns carried out by the industry and approved by
thecompetentauthoritiesoftheMemberStates.
5. The prohibition referred to in paragraph 1 shall apply without
prejudicetoArticle14ofDirective89/552/EEC.
6. Member States shall prohibit the direct distribution of medicinal
products to the public by the industry for promotional purposes; theymay, however, authorize such distribution in special cases for otherpurposes.
Article 89
1. Without prejudice to Article 88, all advertising to the general
publicofamedicinalproductshall:
(a) be set out in such a way that it is clear that the message is an
advertisementandthattheproductisclearlyidentifiedasamedic-
inalproduct;
(b) includethefollowingminimuminformation:
— the name of the medicinal product, as well as the common
name if the medicinal product contains only one activesubstance,2001L0083—EN—08.02.2003—001.001—38
▼B
— the information necessary for correct use of the medicinal
product,
— an express, legible invitation to read carefully the instructions
on the package leaflet or on the outer packaging, as the case
maybe.
2. Member States may decide that the advertising of a medicinal
product to the general public may, notwithstanding paragraph 1,includeonlythenameofthemedicinal productifitisintendedsolelyasareminder.
Article 90
The advertising of a medicinal product to the general public shall not
containanymaterialwhich:
(a) givestheimpressionthatamedical consultationorsurgicalopera-
tion is unnecessary, in particular by offering a diagnosis or bysuggestingtreatmentbymail;
(b) suggeststhattheeffectsoftakingthemedicineareguaranteed,are
unaccompanied by adverse reactions or are better than, or equiva-lentto,thoseofanothertreatmentormedicinalproduct;
(c) suggests that the health of the subject can be enhanced by taking
themedicine;
(d) suggests that the health of the subject could be affected by not
takingthemedicine;thisprohibitionshallnotapplytothevaccina-tioncampaignsreferredtoinArticle88(4);
(e) isdirectedexclusivelyorprincipallyatchildren;
(f) refers to a recommendation by scientists, health professionals or
personswhoareneitheroftheforegoingbutwho,becauseoftheir
celebrity,couldencouragetheconsumptionofmedicinalproducts;
(g) suggeststhatthemedicinalproductisafoodstuff,cosmeticorother
consumerproduct;
(h) suggeststhatthesafetyorefficacyofthemedicinalproductisdue
tothefactthatitisnatural;
(i) could,byadescriptionordetailedrepresentationofacasehistory,
leadtoerroneousself-diagnosis;
(j) refers, in improper, alarming or misleading terms, to claims of
recovery;
(k) uses,inimproper,alarmingormisleadingterms,pictorialrepresen-
tationsofchanges inthehumanbodycausedbydiseaseorinjury,oroftheactionofamedicinalproductonthehumanbodyorpartsthereof;
(l) mentions that the medicinal product has been granted a marketing
authorization.
Article 91
1. Any advertising of a medicinal product to persons qualified to
prescribeorsupplysuchproductsshallinclude:
— essentialinformationcompatiblewiththesummaryofproductchar-
acteristics;
— thesupplyclassificationofthemedicinalproduct.
MemberStatesmayalsorequiresuchadvertisingtoincludetheselling
priceorindicativepriceofthevariouspresentationsandtheconditions
forreimbursementbysocialsecuritybodies.
2. Member States may decide that the advertising of a medicinal
producttopersonsqualifiedtoprescribeorsupplysuchproductsmay,notwithstanding paragraph 1, include only the name of the medicinalproduct,ifitisintendedsolelyasareminder.2001L0083—EN—08.02.2003—001.001—39
▼B
Article 92
1. Any documentation relating to a medicinal product which is
transmittedaspartofthepromotionofthatproducttopersonsqualifiedto prescribe or supply it shall include, as a minimum, the particularslisted in Article 91(1) and shall state the date on which it was drawnuporlastrevised.
2. Alltheinformationcontainedinthedocumentationreferredtoin
paragraph 1 shall be accurate, up-to-date, verifiable and sufficientlycompletetoenabletherecipienttoformhisorherownopinionofthetherapeuticvalueofthemedicinalproductconcerned.
3. Quotations as well as tables and other illustrative matter taken
frommedicaljournalsorotherscientificworksforuseinthedocumen-tationreferredtoinparagraph1shallbefaithfullyreproducedandthe
precisesourcesindicated.
Article 93
1. Medical salesrepresentatives shallbegiven adequate training by
the firmwhich em ploys themand shall have sufficient scientificknowledge to be able to provide information which is precise and ascompleteaspossibleaboutthemedicinalproductswhichtheypromote.
2. During each visit, medical sales representatives shall give the
persons visited, or have available for them, summaries of the productcharacteristics of each medicinal product they present together, if thelegislation of the Member State so permits, with details of the priceandconditionsforreimbursementreferredtoinArticle91(1).
3. Medical sales representatives shall transmit to the scientific
service referred to in Article 98(1) any information about the use ofthe medicinal products they advertise, with particular reference to anyadversereactionsreportedtothembythepersonstheyvisit.
Article 94
1. Where medicinal products are being promoted to persons quali-
fied to prescribe or supply them, no gifts, pecuniary advantages or
benefits inkindmaybesupplied,offeredorpromisedtosuchpersonsunlesstheyareinexpensiveandrelevanttothepracticeofmedicineorpharmacy.
2. Hospitalityatsalespromotionshallalwaysbereasonableinlevel
and secondary to the main purpose of the meeting and must not beextendedtootherthanhealthprofessionals.
3. Personsqualified to prescribe or supply medicinal products shall
not solicit or accept any inducement prohibited under paragraph 1 orcontrarytoparagraph2.
4. ExistingmeasuresortradepracticesinMemberStatesrelatingto
prices, marginsanddiscountsshall notbeaffected byparagraphs 1,2
and3.
Article 95
The provisions of Article 94(1) shall not prevent hospitality being
offered, directly or indirectly, at events for purely professional andscientificpurposes;suchhospitalityshallalwaysbereasonableinlevelandremainsubordinatetothemainscientificobjectiveofthemeeting;itmustnotbeextendedtopersonsotherthanhealthprofessionals.
Article 96
1. Free samples shall be provided on an exceptional basis only to
personsqualifiedtoprescribethemandonthefollowingconditions:
(a) the number of samples for each medicinal product each year on
prescriptionshallbelimited;
(b) any supply of samples shall be in response to a written request,
signedanddated,fromtheprescribingagent;2001L0083—EN—08.02.2003—001.001—40
▼B
(c) those supplying samples shall maintain an adequate system of
controlandaccountability;
(d) eachsampleshallbeidenticalwiththesmallestpresentationonthe
market;
(e) eachsampleshallbemarked‘freemedicalsample—notforsale’
orshallshowsomeotherwordinghavingthesamemeaning;
(f) each sample shall be accompanied by a copy of the summary of
productcharacteristics;
(g) no samples of medicinal products containing psychotropic or
narcotic substances within the meaning of international conven-
tions, such as the United Nations Conventions of 1961 and 1971,maybesupplied.
2. MemberStatesmayalsoplacefurtherrestrictionsonthedistribu-
tionofsamplesofcertainmedicinalproducts.
Article 97
1. Member States shall ensure that there are adequate and effective
methods to monitor the advertising of medicinal products. Suchmethods, which may be based on a system of prior vetting, shall inany event include legal provisions under which persons or organiza-tions 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 advertisementbefore an administrative authority competent either to decide oncomplaintsortoinitiateappropriatelegalproceedings.
2. Under the legal provisions referred to in paragraph 1, Member
Statesshallconferuponthecourtsoradministrativeauthoritiespowersenabling them, in cases where they deem such measures to be neces-sary, taking into account all the interests involved, and in particularthepublicinterest:
— to order the cessation of, or to institute appropriate legal proceed-
ingsforanorderforthecessationof,misleadingadvertising,or
— ifmisleadingadvertisinghasnotyetbeenpublishedbutpublication
is imminent, to order the prohibition of, or to institute appropriatelegal proceedings foranorderfortheprohibition of,suchpublica-tion,
even without proof of actual loss or damage or of intention or negli-
genceonthepartoftheadvertiser.
3. MemberStatesshallmakeprovisionforthemeasuresreferredto
inthesecondsubparagraphtobetakenunderanacceleratedprocedure,
eitherwithinterimeffectorwithdefinitiveeffect.
It shall be for each Member State to decide which of the two options
setoutinthefirstsubparagraphtoselect.
4. Member States may confer upon the courts or administrative
authoritiespowersenablingthem,withaviewtoeliminatingtheconti-nuingeffectsofmisleadingadvertisingthecessationofwhichhasbeen
orderedbyafinaldecision:
— torequirepublicationofthatdecisioninfullorinpartandinsuch
formastheydeemadequate,
— torequireinadditionthepublicationofacorrectivestatement.
5. Paragraphs 1 to 4 shall not exclude the voluntary control of
advertising of medicinal products by self-regulatory bodies and
recoursetosuchbodies,ifproceedingsbeforesuchbodiesarepossiblein addition to the judicial or administrative proceedings referred to inparagraph1.
Article 98
1. The marketing authorization holder shall establish, within his
undertaking, a scientific service in charge of information about themedicinalproductswhichheplacesonthemarket.2001L0083—EN—08.02.2003—001.001—41
▼B
2. Themarketingauthorizationholdershall:
— keep available for, or communicate to, the authorities or bodies
responsible for monitoring advertising of medicinal products, asample of all advertisements emanating from his undertakingtogether with a statement indicating the persons to whom it is
addressed, the method of dissemination and the date of first disse-
mination,
— ensure that advertising of medicinal products by his undertaking
conformstotherequirementsofthisTitle,
— verify that medical sales representatives employed by his under-
taking have been adequately trained and fulfill the obligations
imposeduponthembyArticle93(2)and(3),
— supply the authorities or bodies responsible for monitoring adver-
tising of medicinal products with the information and assistancetheyrequiretocarryouttheirresponsibilities,
— ensurethatthedecisionstakenbytheauthoritiesorbodiesrespon-
sible for monitoring advertising of medicinal products are
immediatelyandfullycompliedwith.
Article 99
Member States shall take the appropriate measures to ensure that the
provisions of this Title are applied and shall determine in particular
what penalties shall be imposed should the provisions adopted in the
executionofTitlebeinfringed.
Article 100
Advertising of the homeopathic medicinal products referred to in
Article 13(2) and Article 14(1) shall be subject to the provisions of
thisTitlewiththeexceptionofArticle87(1).
However,onlytheinformation specified inArticle 69(1)maybeused
intheadvertisingofsuchmedicinalproducts.
Moreover, each Member State may prohibit in its territory any adver-
tising of the homeopathic medicinal products referred to in Article13(2)andArticle14(1).
TITLEIX
PHARMACOVIGILANCE
Article 101
The Member States shall take all appropriate measures to encourage
doctorsandotherhealthcareprofessionalstoreportsuspectedadversereactionstothecompetentauthorities.
The Member States may impose specific requirements on doctors and
otherhealthcareprofessionals,inrespectofthereportingofsuspectedserious or unexpected adverse reactions, in particular where suchreportingisaconditionofthemarketingauthorization.
Article 102
In order to ensure the adoption of appropriate regulatory decisions
concerning the medicinal products authorized within the Community,having regard to information obtained about adverse reactions tomedicinalproductsundernormalconditionsofuse,theMemberStates
shall establish a pharmacovigilance system. This system shall be used
tocollectinformationusefulinthesurveillance ofmedicinal products,with particular reference to adverse reactions in human beings, and toevaluatesuchinformationscientifically.
Suchinformationshallbecollatedwithdataonconsumptionofmedic-
inalproducts.
This systemshall also take into account any available inform ation on
misuse and abuse of medicinal products which may have an impactontheevaluationoftheirbenefitsandrisks.2001L0083—EN—08.02.2003—001.001—42
▼B
Article 103
The marketing authorization holder shall have permanently and
continuously at his disposal an appropriately qualified person respon-
sibleforpharmacovigilance.
Thatqualifiedpersonshallberesponsibleforthefollowing:
(a) theestablishment andmaintenance ofa systemwhichensuresthat
information about all suspected adverse reactions which arereportedtothepersonnelofthecompany,andtomedicalrepresen-
tatives,iscollectedandcollatedinordertobeaccessibleatleastat
onepointwithintheCommunity;
(b) thepreparationforthecompetentauthoritiesofthereportsreferred
to in Article 104, in such formas m ay be laid down by those
authorities, in accordance with the guidance referred to in Article
106(1);
(c) ensuring that any request fromthe com petent authorities for the
provisionofadditional information necessary fortheevaluation of
thebenefitsandrisksaffordedbyamedicinal productisanswered
fully and promptly, including the provision of information aboutthe volume of sales or prescriptions of the medicinal productconcerned;
(d) theprovisiontothecompetentauthorities,ofanyotherinformation
relevant to the evaluation of the benefits and risks afforded by amedicinal product, including appropriate information on post-authorizationsafetystudies.
Article 104
1. The marketing authorization holder shall be required to maintain
detailed records of all suspected adverse reactions occurring either in
theCommunityorinathirdcountry.
2. The marketing authorization holder shall be required to record
andtoreportallsuspectedseriousadversereactionswhicharebroughttohisattentionbyahealthcareprofessionalimmediatelytothecompe-tent authority of the Member State in whose territory the incident
occurred, and in no case later than 15 calendar days following the
receiptoftheinformation.
3. The marketing authorization holder shall be required to record
and report all other suspected serious adverse reactions which meetthe reporting criteria in accordance with the guidance referred to in
Article106(1)ofwhichhecanreasonablybeexpectedtohaveknowl-
edge immediately to the competent authority of the Member State inwhose territory the incident occurred, and in no case later than 15calendardaysfollowingthereceiptoftheinformation.
4. Themarketingauthorizationholdershallensurethatallsuspected
seriousandunexpectedadversereactionsoccurringintheterritoryofa
thirdcountryandbroughttohisattentionbyahealthcareprofessional
arereportedimmediatelyinaccordancewiththeguidancereferredtoinArticle 106(1), so that they are available to the Agency and to thecompetent authorities of the Member States where the medicinalproduct is authorised, and in no case later than 15 calendar days
followingthereceiptoftheinformation.
5. In the case of medicinal products which have been considered
within the scope of Directive 87/22/EEC, or which have benefitedfromtheproceduresofmutual recognition foreseeninArticles17and18 of this Directive, Article 28(4) of this Directive, and medicinalproductsforwhichtherehasbeenareferraltotheproceduresforeseen
byArticles32,33and34ofthisDirective,themarketingauthorisation
holdershalladditionallyensurethatallsuspectedseriousadversereac-tions occurring in the Community are reported in the format and atintervalstobeagreedwiththereferenceMemberState,oracompetentauthorityactingasthereferenceMemberState,insuchawaysoastobeaccessibletothereferenceMemberState.2001L0083—EN—08.02.2003—001.001—43
▼B
6. Unlessotherrequirementshavebeenlaiddownasaconditionof
the granting of authorisation, or subsequently as indicated in theguidance referred toinArticle 106(1),recordsofalladversereactions
shall be submitted to the competent authorities in the form of a peri-
odic safety update report, either immediately upon request orperiodicallyasfollows:sixmonthlyforthefirsttwoyearsafterauthor-isation, annually for the subsequent two years, and at the time of thefirst renewal. Thereafter the periodic safety update reports shall be
submitted at five-yearly intervals together with the application for
renewal of the authorisation. The periodic safety update reports shallinclude a scientific evaluation ofthe benefit andrisksafforded bythemedicinalproducts.
7. Following the granting of a marketing authorisation, the
marketing authorisation holder may request the amendment of the
periodsreferredtointhisarticleaccordingtotheprocedurelaiddown
byCommissionRegulation(EC)No541/95(
1).
Article 105
1. The Agency, in collaboration with the Member States and the
Commission shall set up a data-processing network to facilitate theexchange of pharmacovigilance information regarding medicinalproducts marketed in the Community intended to allow all competentauthoritiestosharetheinformationatthesametime.
2. Making use of the network foreseen in paragraph 1, Member
States shall ensure that reports of suspected serious adverse reactions
thathavetakenplaceontheirterritoryareimmediatelymadeavailabletotheAgencyandtheotherMemberStates,andinanycasewithin15calendardaysoftheirnotification,atthelatest.
3. TheMemberStatesshallensurethatreportsofsuspectedserious
adverse reactions that have taken place on their territory are immedi-
ately madeavailable tothemarketing authorisation holder,andinany
casewithin15calendardaysoftheirnotification,atthelatest.
Article 106
1. In order to facilitate the exchange of information about pharma-
covigilance within the Community, the Commission, in consultationwith the Agency, Member States and interested parties, shall draw upguidance on the collection, verification and presentation of adversereaction reports, including technical requirements for electronic
exchangeofpharmacovigilanceinformationinaccordancewithinterna-
tionally agreed formats and shall publish a reference to aninternationallyagreedmedicalterminology.
This guidance shall be published inVolume 9of The rules governing
medicinalproductsintheEuropeanCommunityandshalltakeaccountofinternationalharmonisationworkcarriedoutinthefieldofpharma-covigilance.
2. For the interpretation of the definitions referred to in Article 1
points11to16andtheprinciples outlinedinthisTitle, themarketingauthorisation holder and the competent authorities shall refer to theguidancereferredtoinparagraph1.
Article 107
1. Where,asaresultoftheevaluationofpharmacovigilance data,a
Member State considers that a marketing authorisation should besuspended, withdrawn or varied in accordance with the guidance
referred toinArticle 106(1),itshallforthwithinformtheAgency,the
otherMemberStatesandthemarketingauthorisationholder.
2. Incaseofurgency,theMemberStateconcernedmaysuspendthe
marketing authorisation of a medicinal product, provided the Agency,2001L0083—EN—08.02.2003—001.001—44
(1) OJL55,11.3.1995,p.7.RegulationamendedbyRegulation(EC)No1146/
98(OJL159,3.6.1998,p.31).
▼B
theCommissionandtheotherMemberStatesareinformedatthelatest
onthefollowingworkingday.
Article 108
AnyamendmentswhichmaybenecessarytoupdateprovisionsofArti-
cles 101 to 107 to take account of scientific and technical progress
shallbeadoptedinaccordancewiththeprocedurereferredtoinArticle
121(2).
TITLEX
SPECIALPROVISIONSONMEDICINALPRODUCTSDERIVEDFROM
HUMANBLOODANDPLASMA
Article 109
For the collection and testing of human blood and human plasma,
Directive 2002/98/EC of the European Parliament and of the Council
of 27 January 2003 setting standards of quality and safety for the
collection,testing,processing,storageanddistributionofhumanbloodand blood components and amending Directive 2001/83/EC(
1) shall
apply.
Article 110
MemberStatesshall take thenecessary measures topromote Commu-
nity self-sufficiency in human blood or human plasma. For thispurpose, they shall encourage the voluntary unpaid donation of bloodand plasma and shall take the necessary measures to develop theproduction and use of products derived from human blood or humanplasmacomingfromvoluntaryunpaiddonations.Theyshallnotifythe
Commissionofsuchmeasures.
TITLEXI
SUPERVISIONANDSANCTIONS
Article 111
1. The competent authority of the Member State concerned shall
ensure, by means of repeated inspections, that the legal requirementsgoverningmedicinalproductsarecompliedwith.
Such inspections shall be carried out by officials representing the
competentauthoritywhoshallbeempoweredto:
(a) inspect manufacturing or commercial establishments and any
laboratoriesentrustedbytheholderofthemanufacturingauthoriza-
tionwiththetaskofcarryingoutcheckspursuanttoArticle20;
(b) takesamples;
(c) examine any documents relating to the object of the inspection,
subjecttotheprovisionsinforceintheMemberStateson21May1975 and which place restrictions on these powers with regard tothedescriptionsofthemethodofpreparation.
2. Member States shall take all appropriate steps to ensure that the
manufacturing processes used in the manufacture of immunologicalproductsareproperlyvalidatedandattainbatch-to-batchconsistency.
3. Aftereveryinspectionasreferredtoinparagraph 1,theofficials
representingthecompetentauthorityshallreportonwhetherthemanu-facturer complies with the principles and guidelines of goodmanufacturing practice laid down in Article 47. The content of suchreportsshallbecommunicatedtothemanufacturerwhohastoundergotheinspection.2001L0083—EN—08.02.2003—001.001—45
(1) OJL33,8.2.2003,p.30.▼M1
▼B
▼B
Article 112
Member States shall take all appropriate measures to ensure that the
holder of the marketing authorization for a medicinal product and,where appropriate, the holder of the manufacturing authorization,furnishproofofthecontrolscarriedoutonthemedicinalproductand/or the ingredients and of the controls carried out at an intermediatestage of the manufacturing process, in accordance with the methods
laiddowninArticle8(3)(h).
Article 113
For the purpose of implementing Article 112, Member States may
require manufacturers of immunological products to submit to a
competent authority copies of all the control reports signed by the
qualifiedpersoninaccordancewithArticle51.
Article 114
1. Whereitconsidersitnecessaryintheinterestsofpublichealth,a
Member State may require the holder of an authorization for
marketing:
— livevaccines,
— immunological medicinal products used in the primary immuniza-
tionofinfantsorofothergroupsatrisk,
— immunologicalmedicinalproductsusedinpublichealthimmuniza-
tionprogrammes,
— newimmunologicalmedicinalproductsorimmunologicalmedicinal
productsmanufacturedusingneworalteredkindsoftechnologyor
new for a particular manufacturer, during a transitional periodnormallyspecifiedinthemarketingauthorization,
to submit samples from each batch of the bulk and/or the medicinal
product for examination by a State laboratory or a laboratory desig-
nated for that purpose before release on to the market unless, in the
caseofabatchmanufactured inanotherMemberState, thecompetentauthority of that Member State has previously examined the batch inquestionanddeclaredittobeinconformitywiththeapprovedspecifi-cations. Member States shall ensure that any such examination is
completedwithin60daysofthereceiptofthesamples.
2. Where, in the interests of public health, the laws of a Member
State so provide, the competent authorities may require the marketingauthorization holderformedicinalproductsderivedfromhumanbloodorhumanplasmatosubmitsamplesfromeachbatchofthebulkand/or
the medicinal product fortesting bya State laboratory ora laboratory
designated forthat purposebefore being released intofree circulation,unless the competent authorities of another Member State havepreviously examined the batch in question and declared it to be inconformity with the approved specifications. Member States shall
ensure that any such examination is completed within 60 days of the
receiptofthesamples.
Article 115
Member States shall take all necessary measures to ensure that the
manufacturing and purifying processes used in the preparation of
medicinal products derived from human blood or human plasma are
properly validated, attain batch-to-batch consistency and guarantee,insofarasthestateoftechnologypermits,theabsenceofspecificviralcontamination. To this end manufacturers shall notify the competentauthorities 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 submitsamplesofthebulkand/orthemedicinalproductfortestingbyaStatelaboratoryoralaboratorydesignatedforthatpurpose,eitherduringtheexamination of the application pursuant to Article 19, or after amarketingauthorizationhasbeengranted.2001L0083—EN—08.02.2003—001.001—46
▼B
Article 116
The competent authorities of the Member States shall suspend or
revoke an authorization to place a medicinal product on the market
where that product proves to be harmful in the normal conditions of
use,orwhereitstherapeuticefficacyislacking,orwhereitsqualitativeandquantitativecompositionisnotasdeclared.Therapeuticefficacyislacking when it is established that therapeutic results cannot beobtainedwiththemedicinalproduct.
Anauthorizationshallalsobesuspendedorrevokedwheretheparticu-
larssupportingtheapplication asprovidedforinArticles8,10(1)and
11areincorrect orhavenotbeenamended inaccordance withArticle23, or where the controls referred to in Article 112 have not beencarriedout.
Article 117
1. Notwithstanding the measures provided for in Article 116,
Member States shall take all appropriate measures to ensure that thesupply of the medicinal product shall be prohibited and the medicinal
productwithdrawnfromthemarketif:
(a) the medicinal product proves to be harmful under normal condi-
tionsofuse,or
(b) itislackingintherapeuticefficacy,or
(c) itsqualitativeandquantitativecompositionisnotasdeclared,or
(d) thecontrolsonthemedicinalproductand/orontheingredientsand
the controls at an intermediate stage of the manufacturing process
have not been carried out or if some other requirement or obliga-
tion relating to the grant of the manufacturing authorization hasnotbeenfulfilled.
2. The competent authority may limit the prohibition to supply the
product,oritswithdrawalfromthemarket,tothosebatcheswhicharethesubjectofdispute.
Article 118
1. The competent authority shall suspend or revoke the marketing
authorization for a category of preparations or all preparations where
anyoneoftherequirementslaiddowninArticle41isnolongermet.
2. In addition to the measures specified in Article 117, the compe-
tent authority may suspend manufacture or imports of medicinalproductscomingfromthirdcountries,orsuspendorrevokethemanu-facturingauthorizationforacategoryofpreparationsorallpreparations
whereArticles42,46,51and112arenotcompliedwith.
Article 119
The provisions of this Title shall apply to homeopathic medicinal
products,subjecttotheprovisionsofArticle14(3).
TITLEXII
STANDINGCOMMITTEE
Article 120
Any changes which are necessary in order to adapt Annex I to take
account of scientific and technical progressshall be adopted in accor-
dancewiththeprocedurereferredtoinArticle121(2).
Article 121
1. The Commission shall be assisted by a Standing Committee on
Medicinal Products for Human Use on the Adaptation to TechnicalProgress of the Directives on the Removal of Technical Barriers toTrade in the Medicinal ProductsSector, (hereinafter referred to as the‘StandingCommittee’).2001L0083—EN—08.02.2003—001.001—47
▼B
2. Where reference is made to this paragraph, Articles 5 and 7 of
Decision1999/468/ECshallapply,havingregardtoArticle8thereof.
TheperiodprovidedforinArticle5(6)ofDecision1999/468/ECshall
besetatthreemonths.
3. TheStandingCommitteeshalladoptitsrulesofprocedure.
TITLEXIII
GENERALPROVISIONS
Article 122
Member States shall take all appropriate measures to ensure that the
competentauthoritiesconcernedcommunicatetoeachothersuchinfor-mation as is appropriate to guarantee that the requirements for themanufacturingauthorizationsormarketingauthorizationsarefulfilled.
Upon reasoned request, Member States shall forthwith communicate
thereportsreferredtoinArticle111(3)tothecompetentauthoritiesof
another Member State. If, after considering the reports, the Member
State receiving the reports considers that it cannot accept the conclu-sions reached by the competent authorities of the Member State inwhichthe report wasestablished, it shall informthe com petent autho-ritiesconcernedofitsreasonsandmayrequestfurtherinformation.TheMember 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 Statesconcerned.
Article 123
1. Each Member State shall take all the appropriate measures to
ensure that decisions authorizing marketing, refusing or revoking amarketing authorization, cancelling a decision refusing or revoking amarketing authorization, prohibiting supply, or withdrawing a product
fromthe m arket, together with the reasons on which such decisions
arebased,arebroughttotheattentionoftheAgencyforthwith.
2. Themarketingauthorization holdershallbeobligedtonotifythe
Member States concerned forthwith of any action taken by him tosuspendthemarketingofamedicinalproductortowithdrawamedic-inalproductfromthemarket,togetherwiththereasonsforsuchactionif the latter concerns the efficacy of the medicinal product or the
protectionofpublichealth.MemberStatesshallensurethatthisinfor-
mationisbroughttotheattentionoftheAgency.
3. Member States shall ensure that appropriate information about
action taken pursuant to paragraphs 1 and 2 which may affect theprotection of public health in third countries is forthwith brought tothe attention of the World Health Organization, with a copy to theAgency.
4. The Commission shall publish annually a list of the medicinal
productswhichareprohibitedintheCommunity.
Article 124
Member States shall communicate to each other all the information
necessarytoguaranteethequalityandsafetyofhomeopathicmedicinal
products manufactured and marketed within the Community, and inparticulartheinformationreferredtoinArticles122and123.
Article 125
Every decision referred to in this Directive which is taken by the
competentauthorityofaMemberStateshallstateindetailthereasonsonwhichitisbased.
Such decision shall be notified to the party concerned, together with
information as to the redress available to him under the laws in forceandofthetime-limitallowedforaccesstosuchredress.2001L0083—EN—08.02.2003—001.001—48
▼B
Marketing authorizations, and decisionsto revoke such authorizations,
shall be published by each Member State in the appropriate officialpublication.
Article 126
An authorization to market a medicinal product shall not be refused,
suspendedorrevokedexceptonthegroundssetoutinthisDirective.
Nodecisionconcerningsuspensionofmanufactureorofimportationof
medicinal products coming from third countries, prohibition of supplyor withdrawal from the market of a medicinal product may be takenexceptonthegroundssetoutinArticles117and118.
Article 127
1. Attherequestofthemanufacturer,theexporterortheauthorities
ofanimportingthirdcountry,MemberStatesshallcertifythatamanu-facturer of medicinal products is in possession of the manufacturing
authorization. When issuing such certificates Member States shall
complywiththefollowingconditions:
(a) they shall have regard to the prevailing administrative arrange-
mentsoftheWorldHealthOrganization;
(b) for medicinal products intended for export which are already
authorized ontheirterritory, theyshallsupplythesummaryofthe
productcharacteristicsasapprovedinaccordancewithArticle21.
2. When the manufacturer is not in possession of a marketing
authorization he shall provide the authorities responsible for estab-lishing the certificate referred to in paragraph 1, with a declarationexplainingwhynomarketingauthorizationisavailable.
TITLEXIV
FINALPROVISIONS
Article 128
Directives65/65/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/EECand92/73/EEC,amendedbytheDirectivesreferredtoinAnnexII,PartA,arerepealed,withoutprejudicetotheobligationsoftheMemberStatesconcerningthetime-limitsforimplementationsetoutinAnnexII,PartB.
References to the repealed Directives shall be construed as references
to this Directive and shall be read in accordance with the correlation
tableinAnnexIII.
Article 129
ThisDirectiveshallenterintoforceonthetwentiethdayfollowingthat
ofitspublicationinthe Official Journal of the European Communities .
Article 130
ThisDirectiveisaddressedtotheMemberStates.2001L0083—EN—08.02.2003—001.001—49
▼B
ANNEX I
ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLINICAL
STANDARDS AND PROTOCOLS IN RESPECT OF THE TESTING OF
MEDICINALPRODUCTS
INTRODUCTION
The particulars and documents accompanying an application for marketing
authorization pursuant to Articles 8 and 10(1) shall be presented in four parts,
in accordance with the requirements set out in this Annex and taking account
oftheguidancepublishedbytheCommissionin The rules governing medicinal
products in the European Community ,Volume II: Notice to applicants for
marketing authorizations for medicinal products for human use in the Member
States of the European Community .
Inassemblingthedossierforapplicationformarketingauthorization,applicants
shalltakeintoaccounttheCommunityguidelinesrelatingtothequality,safety
and efficacy of medicinal products published by the Commission in The rules
governing medicinal products in the European Community , Volume III and its
supplements: Guidelines on the quality, safety and efficacy of medicinal
products for human use .
All information which is relevant to the evaluation of the medicinal product
concernedshallbeincludedintheapplication,whetherfavourableorunfavour-
able to the product. In particular, all relevant details shall be given of any
incomplete orabandoned pharmacotoxicological orclinical test ortrial relating
tothemedicinal product.Moreover,inordertomonitorthebenefit/riskassess-
mentafter marketing authorization hasbeengranted,anychangetothedatain
thedossier,anynewinformationnotintheoriginalapplicationandallpharma-
covigilancereports,shallbesubmittedtothecompetentauthorities.
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,suchasimmunologicalmedicinalproductsderivedfromhumanblood
orplasma.Theadditionalspecialrequirementsforbiologicalmedicinalproducts
arealsoapplicabletomedicinalproductsobtainedthroughprocessesmentioned
in Part Aand the first indent of Part B of the Annex to Regulation (EEC) No
2309/93.
MemberStatesshallalsoensurethatalltestsonanimalsareconductedinaccor-
dance with Council Directive 86/609/EEC of 24 November 1986 on the
approximation oflaws,regulationandadministrative provisionsoftheMember
States regarding the protection of animals for experimental and other scientific
purposes(1).
PARTI
SUMMARYOFTHEDOSSIER
A.Administrativedata
Themedicinalproductwhichisthesubjectoftheapplicationshallbeiden-
tified by name and name of the active substance(s), together with the
pharmaceutical form, the method of administration, the strength and the
finalpresentation,includingpackaging.
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
whererelevantthenameandaddressoftheimporter.
The applicant shall identify the number of volumes of documentation
submitted in support of the application and indicate what samples, if any,
arealsoprovided.
Annexed to the administrative data shall be copies of the manufacturing
authorization as defined 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.2001L0083—EN—08.02.2003—001.001—50
(1) OJL358,18.12.1986,p.1.
▼B
B.Summaryofproductcharacteristics
The applicant shall propose a summary of the product characteristics, in
accordancewithArticle11.
In addition the applicant shall provide samples or mock-ups ofthe packa-
ging,labelsandpackageleafletsforthemedicinalproductconcerned.
C.Expertreports
In accordance with Article 12(2), expert reports must be provided on the
chemical, pharmaceutical andbiologicaldocumentation,thepharmacotoxi-
cologicaldocumentationandtheclinicaldocumentationrespectively.
Theexpertreportshallconsistofacriticalevaluationofthequalityofthe
medicinalproductandtheinvestigationscarriedoutonanimalsandhuman
beingsandbringoutallthedatarelevantforevaluation.Itshallbeworded
soastoenablethereadertoobtainagoodunderstandingoftheproperties,
quality, the proposed specifications and control methods, the safety, the
efficacy,theadvantagesanddisadvantagesofthemedicinalproduct.
Allimportantdatashallbesummarizedinanappendixtotheexpertreport,
whenever possible including report formats in tabular or in graphic form.
Theexpertreportandthesummariesshallcontainprecisecrossreferences
totheinformationcontainedinthemaindocumentation.
Each expert report shall be prepared by a suitably qualified and experi-
enced 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 rela-
tionshipoftheexperttotheapplicantshallbedeclared.
PART2
CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL TESTING OF
MEDICINALPRODUCTS
Allthetestproceduresshallcorrespondtothestateofscientificprogressatthe
timeandshallbevalidatedprocedures;resultsofthevalidationstudiesshallbe
provided.
Allthetestprocedure(s)shallbedescribedinsufficientlyprecisedetailsoasto
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
describedinadequatedetail,possiblyaccompaniedbyadiagram.Theformulae
ofthelaboratoryreagentsshallbesupplemented,ifnecessary,bythemanufac-
turing method. In the case of test procedures included in the European
Pharmacopoeia orthe pharmacopoeia of aMemberState, this description may
bereplacedbyadetailedreferencetothepharmacopoeiainquestion.
A.Qualitativeandquantitativeparticularsoftheconstituents
The particulars and documents which must accompany applications for
marketingauthorization,pursuanttopoint3ofArticle8(3)(c)shallbesubmitted
inaccordancewiththefollowingrequirements.
1.Qualitative particulars
1.1. ‘Qualitative particulars’ of all the constituents of the medicinal product
shallmeanthedesignationordescriptionof:
— theactivesubstance(s),
— theconstituent(s)oftheexcipients,whatevertheirnatureorthequantity
used, including colouring matter, preservatives, adjuvants, stabilizers,
thickeners,emulsifiers,flavouringandaromaticsubstances,etc.,
— the constituents, intended to be ingested or otherwise administered to
thepatient,oftheoutercoveringofthemedicinalproducts—capsules,
gelatinecapsules,rectalcapsules,etc.
These particulars shall be supplemented by any relevant data concerning
the container and, where appropriate, its manner of closure, together with
details ofdeviceswithwhichthemedicinal productwillbeusedoradmi-
nisteredandwhichwillbedeliveredwiththemedicinalproduct.
1.2. In the context of a radiopharmaceutical kit, which is to be radiolabelled
after supply by the manufacturer, the active substance is considered to be
thatpartoftheformulationwhichisintendedtocarryorbindtheradionu-
clide.Detailsofthesourceoftheradionuclideshallbestated.Inaddition,
anycompoundsessentialfortheradiolabellingshallbestated.2001L0083—EN—08.02.2003—001.001—51
▼B
Inagenerator,bothmotheranddaughterradionuclidesaretobeconsidered
asactivesubstances.
2. The‘usualterminology’,tobeusedindescribingtheconstituentsofmedic-
inal products, shall mean, notwithstanding the application of the other
provisionsinArticle8(3)(c):
— inrespectofsubstanceswhichappearinthe 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
referencetothepharmacopoeiaconcerned,
— in respect of other substances, the international non-proprietary name
recommendedbytheWorldHealthOrganization,whichmaybeaccom-
panied 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, supple-
mented,whereappropriate,byanyotherrelevantdetails,
— inrespectofcolouringmatter, designationbythe‘E’codeassignedto
themin Council Directive 78/25/EEC of 12 Decem ber 1977 on the
approximation of the rules of the Member States concerning the
colouringmattersauthorizedforuseinmedicinalproducts(1).
3.Quantitative particulars
3.1. In order to give ‘quantitative particulars’ of the active substances of the
medicinal products,it isnecessary, depending onthe pharmaceutical form
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
activesubstance.
Units of biological activity shall be used for substances which cannot be
defined chemically. Where an International Unit of biological activity has
beendefinedbytheWorldHealthOrganization, thisshallbeused.Where
noInternationalUnithasbeendefined,theunitsofbiologicalactivityshall
beexpressedinsuchawayastoprovideunambiguousinformationonthe
activityofthesubstances.
Wheneverpossible,biologicalactivityperunitsofmassshallbeindicated.
Thisinformationshallbesupplemented:
— inrespectofinjectable preparations,bythemassorunitsofbiological
activity of each active substance in the unit container, taking into
account the usable volume of the product, after reconstitution, where
appropriate,
— in respect of medicinal products to be administered by drops, by the
mass or units of biological activity of each active substance contained
inthenumberofdropscorrespondingto1mlor1gofthepreparation,
— inrespectofsyrups,emulsions,granularpreparationsandotherpharma-
ceutical forms to be administered in measured quantities, by the mass
or units of biological activity of each active substance per measured
quantity.
3.2. Activesubstancespresentintheformofcompoundsorderivativesshallbe
designated quantitatively by their total mass, and if necessary or relevant,
bythemassoftheactiveentityorentitiesofthemolecule.
3.3. Formedicinalproductscontaininganactivesubstancewhichisthesubject
ofanapplication formarketing authorization inanyMemberStateforthe
firsttime,thequantitative statement ofanactive substancewhichisasalt
or hydrate shall be systematically expressed in terms of the mass of the
activeentityorentitiesinthemolecule.Allsubsequentlyauthorizedmedic-
inal products in the Member States shall have their quantitative
compositionstatedinthesamewayforthesameactivesubstance.
3.4. For allergen products, the quantitative particulars shall be expressed by
units of biological activity, except for well defined allergen products for
whichtheconcentrationmaybeexpressedbymass/unitofvolume.
3.5. Therequirementtoexpressthecontentofactivesubstancesintermsofthe
massofactiveentities,asinpoint3.3.above,maynotapplytoradiophar-
maceuticals. For radionuclides, radioactivity shall be expressed in
becquerels at a given date and, if necessary, time with reference to time
zone.Thetypeofradiationshallbeindicated.2001L0083—EN—08.02.2003—001.001—52
(1) OJL11,14.1.1978,p.18.Directiveaslastamendedbythe1985ActofAccession.
▼B
4.Development pharmaceutics
4.1. An explanation should be provided with regard to the choice of composi-
tion,constituentsandcontainerandtheintendedfunctionoftheexcipients
in the finished product. This explanation shall be supported by scientific
data on development pharmaceutics. The overage during manufacture,
withjustificationthereof,shouldbestated.
4.2. Forradiopharmaceuticals, this should include a consideration of chemical/
radiochemicalpurityanditsrelationshiptobiodistribution.
B.Descriptionofmanufacturingmethod
1. Thedescriptionofthemanufacturingmethodaccompanyingtheapplication
for marketing authorization pursuant to Article 8(3)(d),shall be drafted in
suchawayastogiveanadequatesynopsisofthenatureoftheoperations
employed.
Forthispurposeitshallincludeatleast:
— mentionofthevariousstagesofmanufacture,sothatanassessmentcan
be made of whether the processesemployed in producing the pharma-ceutical formm ight have produced an adverse change in the
constituents,
— in the case of continuous manufacture, full details concerning precau-
tionstakentoensurethehomogeneityofthefinishedproduct,
— theactualmanufacturingformula,withthequantitativeparticularsofall
the substancesused, the quantities ofexcipients, however,being given
in approximate terms in so far as the pharmaceutical form makes this
necessary;mentionshallbemadeofanysubstancesthatmaydisappear
inthecourseofmanufacture; anyoverageshallbeindicatedandjusti-
fied,
— 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
qualitycontrolofthefinishedproduct,
— experimentalstudiesvalidatingthemanufacturingprocess,whereanon-
standard method of manufacture is used or where it is critical for the
product,
— forsterilemedicinalproducts,detailsofthesterilizationprocessesand/
orasepticproceduresused.
2. Forradiopharmaceutical kits,the description ofthe 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.
Forradionuclides,thenuclearreactionsinvolvedshallbediscussed.
C.Controlsofstartingmaterials
1. For the purposes of this section, ‘starting materials’ shall mean all the
constituentsofthemedicinal productand,ifnecessary,ofitscontainer, as
referredtoinSectionA,point1,above.
Inthecaseof:
— anactivesubstancenotdescribedinthe European Pharmacopoeia orin
thepharmacopoeiaofaMemberState,or
— anactivesubstancedescribedinthe European Pharmacopoeia orinthe
pharmacopoeiaofaMemberStatewhenpreparedbyamethodliableto
leave impurities not mentioned in the pharmacopoeial 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
providetheapplicantwithallthedatawhichmaybenecessaryforthe
lattertotakeresponsibilityforthemedicinalproduct.Themanufacturer
shall confirmin writing to the applicant that he shall ensure batch to
batchconsistencyandnotmodifythemanufacturingprocessorspecifi-
cations without informing the applicant. Documents and particulars
supporting the application for such a change shall be supplied to the
competentauthorities.
Theparticularsanddocumentsaccompanyingtheapplicationformarketing
authorizationpursuanttoArticle8(3)(h)and(i)and10(1),shallincludethe2001L0083—EN—08.02.2003—001.001—53
▼B
results of the tests, including batch analyses particularly for active
substances, relating to quality control of all the constituents used. These
shallbesubmittedinaccordancewiththefollowingprovisions.
1.1. Starting materials listed in pharmacopoeias
Themonographsofthe European Pharmacopoeia shallbeapplicabletoall
substancesappearinginit.
Inrespectofothersubstances,eachMemberStatemayrequireobservance
ofitsownnationalpharmacopoeiawithregardtoproductsmanufacturedin
itsterritory.
Constituentsfulfillingtherequirementsofthe European Pharmacopoeia or
thepharmacopoeiaofoneoftheMemberStatesshallbedeemedtocomply
sufficiently with Article 8(3)(h). In this case the description of the analy-
tical methods may be replaced by a detailed reference to the
pharmacopoeiainquestion.
However, where a starting material in the European Pharmacopoeia or in
the pharmacopoeia of a Member State has been prepared by a method
liable to leave impurities not controlled in the pharmacopoeia monograph,
theseimpuritiesandtheirmaximumtolerancelimitsmustbedeclaredanda
suitabletestproceduremustbedescribed.
Colouring matter shall, in all cases, satisfy the requirements of Directive
78/25/EEC.
Theroutinetestscarriedoutoneachbatchofstartingmaterialsmustbeas
stated in the application for marketing authorization. If tests other than
those mentioned in the pharmacopoeia are used, proof must be supplied
thatthestartingmaterialsmeet thequalityrequirements ofthatpharmaco-
poeia.
In cases where a specification contained in a monograph of the European
Pharmacopoeia orinthenationalpharmacopoeiaofaMemberStatemight
beinsufficienttoensurethequalityofthesubstance,thecompetentautho-
rities may request more appropriate specifications from the marketing
authorizationholder.
The competent authorities shall inform the authorities responsible for the
pharmacopoeia in question. The marketing authorization holder shall
providetheauthoritiesofthatpharmacopoeiawiththedetailsofthealleged
insufficiencyandtheadditionalspecificationsapplied.
In cases where a starting material is described neither in the European
Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance
withthemonographofathirdcountrypharmacopoeia canbeaccepted; in
such cases, the applicant shall submit a copy of the monograph accompa-
niedwherenecessarybythevalidation ofthetestprocedurescontained in
themonographandbyatranslationwhereappropriate.
1.2. Starting materials not in a pharmacopoeia
Constituentswhicharenotgiveninanypharmacopoeia shallbedescribed
intheformofamonographunderthefollowingheadings:
(a) the name of the substance, meeting the requirements of Section A,
point2,shallbesupplementedbyanytradeorscientificsynonyms;
(b) thedefinitionofthesubstance,setdowninaformsimilartothatused
in the European Pharmacopoeia, shall be accompanied by any neces-
sary explanatory evidence, especially concerning the molecular
structurewhereappropriate;itmustbeaccompaniedbyanappropriate
description of the method of synthesis. Where substances can only be
described by their manufacturing method, the description should be
sufficiently detailed tocharacterize asubstancewhichisconstantboth
initscompositionandinitseffects;
(c) methods of identification may be described in the form of complete
techniquesasusedforproductionofthesubstance,andintheformof
testswhichoughttobecarriedoutasaroutinematter;
(d) puritytestsshallbedescribedinrelationtothesumtotalofpredictable
impurities, especially those which may have a harmful effect, and, if
necessary,thosewhich,havingregardtothecombinationofsubstances
to which the application refers, might adversely affect the stability of
themedicinalproductordistortanalyticalresults;
(e) with regard to complex substances of plant or animal/human origin, a
distinctionmustbemadebetweenthecasewheremultiplepharmacolo-
gical effects render chemical, physical or biological control of the
principal constituents necessary, andthe case ofsubstances containing2001L0083—EN—08.02.2003—001.001—54
▼B
one ormore groupsofprinciples having similar activity, inrespect of
whichanoverallmethodofassaymaybeaccepted;
(f) when materials of animal/human origin are used, measures to ensure
freedomfrompotentiallypathogenicagentsshallbedescribed;
(g) for radionuclides, the nature of the radionuclide, the identity of the
isotope, likely impurities, the carrier, the use and the specific activity
shallbegiven;
(h) any special precautions that may be necessary during storage of the
starting material and, if necessary, the maximum period of storage
beforeretestingshallbegiven.
1.3. Physico-chemical characteristics liable to effect bio-avail-
ability
The following items of information concerning active substances, whether
ornotlistedinthepharmacopoeias,shallbeprovidedaspartofthegeneral
descriptionoftheactive substancesifthebio-availability ofthemedicinal
productdependsonthem:
— crystallineformandsolubilitycoefficients,
— particlesize,whereappropriateafterpulverization,
— stateofsolvation,
— oil/watercoefficientofpartition(1).
Thefirstthreeindentsarenotapplicabletosubstancesusedsolelyinsolu-
tion.
2. For biological medicinal products, such as immunological medicinal
productsandmedicinalproductsderivedfromhumanbloodorplasma,the
requirementsofthisparagraphshallapply.
For the purposes of this paragraph, starting materials shall mean any
substance used in the manufacture of the medicinal product; this includes
theconstituentsofthemedicinalproduct,and,ifnecessary,ofitscontainer,
as referred to in paragraph A, point 1 above, as well as source materials
such as microorganisms, tissues of either plant or animal origin, cells or
fluids (including blood) of human or animal origin, and biotechnological
cell constructs. The origin and history of starting materials shall be
describedanddocumented.
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
batchtobatchconsistencyofthefinishedproduct.
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. Seedmaterials,cellbanks,poolsofserumorplasmaandothermaterialsof
biological origin and, whenever possible, the source materials from which
theyarederivedshallbetestedforadventitiousagents.
If the presence of potentially pathogenic adventitious agents is inevitable,
the correspondant material shall be used only when further processing
ensurestheireliminationand/orinactivation,andthisshallbevalidated.
2.3. Wheneverpossible,vaccineproductionshallbebasedonaseedlotsystem
and on established cell banks; for serums, defined pools of starting mate-
rialsshallbeused.
For bacterial and viral vaccines, the characteristics of the infectious agent
shallbedemonstratedontheseed.Inaddition,forlivevaccines,thestabi-
lity ofthe attenuation characteristics shall be demonstrated onthe seed; if
this proof is not sufficient, the attenuation characteristics shall also be
demonstratedattheproductionstage.
2.4. Forallergenproducts,thespecificationsandcontrolmethodsforthesource
materials shallbedescribedinasmuchdetail aspossible.Thedescription
shallincludeparticularsconcerningcollection,pretreatmentandstorage.
2.5. For medicinal products derived from human blood or plasma, the origin
andthecriteriaandproceduresforcollection,transportationandstorageof
thesourcematerialshallbedescribedanddocumented.
Definedpoolsofsourcematerialshallbeused.2001L0083—EN—08.02.2003—001.001—55
(1) The competent authorities may also request the pK and pH values if they think this
informationisessential.
▼B
3. Forradiopharmaceuticals,startingmaterialsincludeirradiationtargetmate-
rials.
D.Specific measures concerning the prevention of the transmission of
animalspongiformencephalopathies
Theapplicantmustdemonstratethatthemedicinalproductismanufactured
in accordance with the Note for Guidance on Minimising the Risk of
Transmitting Animal Spongiform Encephalopathy Agents via Medicinal
Productsanditsupdates,publishedbytheCommissioninVolume3ofits
publication The rules governing medicinal products in the European
Community.
E.Control tests carried out at intermediate stages of the manufacturing
process
1. Theparticularsanddocumentsaccompanyinganapplicationformarketing
authorization, pursuanttoArticle8(3)(h)and(i)andArticle10,paragraph
1ofthisDirective, shallinclude particulars relating totheproductcontrol
teststhatmaybecarriedoutatanintermediatestageofthemanufacturing
process,withaviewtoensuringtheconsistencyofthetechnicalcharacter-
isticsandtheproductionprocess.
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
subjecttothesamerequirementsastheactivesubstances).
Thesameapplieswherethequalitycontrolofthefinishedproductdepends
on in-process control tests, particularly if the medicinal product is essen-
tiallydefinedbyitsmethodorpreparation.
2. For biological medicinal products, such as immunological medicinal
productsandmedicinalproductsderivedfromhumanbloodorplasma,the
procedures and the criteria of acceptability published as recommendations
oftheWHO( Requirements for Biological Substances )shallserveasguide-
lines for all controls of production stages which are not specified in the
European Pharmacopoeia , or falling this, in the national pharmacopoeia
ofaMemberState.
For inactivated or detoxified vaccines, effective inactivation or detoxifica-
tion 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
establishedandthereaftercompensatedbyappropriatein-processcontrols.
3. For modified or adsorbed allergen products, the products shall be qualita-
tively and quantitatively characterized at an intermediate stage, as late as
possibleinthemanufacturingprocess.
F.Controltestsonthefinishedproduct
1. For the control of the finished product, a batch of a medicinal product
comprisesalltheunitsofapharmaceutical formwhicharemadefromthe
same initial quantity of material and have undergone the same series of
manufacturingand/orsterilizationoperationsor,inthecaseofacontinuous
productionprocess,alltheunitsmanufacturedinagivenperiodoftime.
Theapplication formarketing authorization shalllistthosetestswhichare
carried out routinely on each batch of finished product. The frequency of
thetestswhicharenotcarriedoutroutinely shallbestated.Releaselimits
shallbeindicated.
Theparticularsanddocumentsaccompanyingtheapplicationformarketing
authorization pursuant to Article 8(3)(h) and (i) and Article 10(1) of this
Directive, shall include particulars relating to control tests on the finished
product at release. They shall be submitted in accordance with the
followingrequirements.
The provisions of the monographs for pharmaceutical forms, immunosera,
vaccinesandradiopharmaceutical preparationsofthe European Pharmaco-
poeiaorfailingthat,ofaMemberState,shallbeapplicabletoallproducts
defined therein. For all controls of biological medicinal products such as
immunological medicinal products and medicinal products derived from
humanbloodor plasma whichare notspecified in the European Pharma-
copoeiaor failing this, in the pharmacopoeia of a Member State, the
procedures and the criteria of acceptability published as recommendations2001L0083—EN—08.02.2003—001.001—56
▼B
intheWHO( Requirements for Biological Substances )shallserveasguide-
lines.
Iftestproceduresandlimitsotherthanthosementionedinthemonographs
oftheEuropean Pharmacopoeia ,orfailingthis,inthenationalpharmaco-
poeiaofaMemberState,areused,proofshallbesuppliedthatthefinished
product would, if tested in accordance with those monographs, meet the
quality requirements of that pharmacopoeia for the pharmaceutical form
concerned.
1.1. General characteristics of the finished product
Certain tests of the general characteristics of a product shall always be
included among the tests on the finished product. These tests shall, wher-
ever 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.Foreachofthesecharacteristics, standardsandtolerance limits
shallbespecifiedbytheapplicantineachparticularcase.
The conditions of the tests, where appropriate, the equipment/apparatus
employed andthestandardsshallbedescribedinprecisedetailswhenever
they are not given in the European Pharmacopoeia or the pharmacopoeia
of the Member States; the same shall apply in cases where the methods
prescribedbysuchpharmacopoeiasarenotapplicable.
Furthermore, solid pharmaceutical forms having to be administered orally
shall be subjected to in vitrostudies on the liberation and dissolution rate
oftheactivesubstanceorsubstances;thesestudiesshallalsobecarriedout
where administration is by another means if the competent authorities of
theMemberStateconcernedconsiderthisnecessary.
1.2. Identification and assay of active substance(s)
Identificationandassayoftheactivesubstance(s)shallbecarriedouteither
in an average representative sample from the production batch or in a
numberofdosage-unitsanalysedindividually.
Unlessthereisappropriatejustification,themaximumacceptabledeviation
in the active substance content of the finished product shall not exceed
±5%atthetimeofmanufacture.
On the basis of the stability tests, the manufacturer must propose and
justifymaximumacceptabletolerancelimitsintheactivesubstancecontent
ofthefinishedproductuptotheendoftheproposedshelf-life.
Incertain exceptional casesofparticularly complexmixtures, whereassay
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
substancesinthefinishedproductmaybeomitted,ontheexpresscondition
thatsuchassaysaremadeatintermediatestagesintheproductionprocess.
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
havetheconformityofthemedicinalproductwithitsspecificationverified
afterithasbeenplacedonthemarket.
Anin vivoorin vitrobiological 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 thesetestscannot becarried outonthefinishedproduct, theymay
be performed at an intermediate stage, aslate as possible in the manufac-
turingprocess.
WheretheparticularsgiveninsectionBshowthatasignificantoverageof
an active substance is employed in the manufacture of the medicinal
product, the description of the control tests on the finished product shall
include,whereappropriate,thechemicaland,ifnecessary,thetoxico-phar-
macologicalinvestigationofthechangesthatthissubstancehasundergone,
andpossiblythecharacterizationand/orassayofthedegradationproducts.
1.3. Identification and assay of excipient constituents
Insofarasisnecessary,theexcipient(s)shallbesubjectatleasttoidenti-
ficationtests.
Thetest procedure proposedforidentifying colouringmatters mustenable
a verification to be made that such matters appear in the list annexed to
Directive78/25/EEC.2001L0083—EN—08.02.2003—001.001—57
▼B
An upper and lower limit test shall be obligatory in respect of preserving
agents and an upperlimit 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-avail-
ability of an active substance, unless bio-availability is guaranteed by
otherappropriatetests.
1.4. Safety tests1. Apart from the pharmacotoxicological tests submitted withthe application
for marketing authorization, particulars of safety tests, such as sterility,
bacterial endotoxin, pyrogenicity and local tolerance in animals shall be
included in the analytical particulars wherever such tests must be under-
takenasamatterofroutineinordertoverifythequalityoftheproduct.
2. For all controls of biological medicinal products, such as immunological
medicinal products and medicinal products derived from human blood or
plasma,whicharenotspecifiedinthe European Pharmacopoeia ,orfailing
this,inthenationalpharmacopoeiaofaMemberState,theproceduresand
the criteria of acceptability published as recommendations in the World
Health Organization ( Requirements for Biological Substances ) shall serve
asguidelines.
3. For radiopharmaceuticals, radionuclidic purity, radiochemical purity and
specificactivity shallbedescribed.Forcontentofradioactivity, thedevia-
tionfromthatstatedonthelabelshouldnotexceed±10%.
Forgenerators,detailsonthetestingformotheranddaughterradionuclides
are required. For generator-eluates, tests for mother radionuclides and for
othercomponentsofthegeneratorsystemshallbeprovided.
For kits, the specifications of the finished product shall include tests on
performanceofproductsafterradiolabelling.Appropriatecontrolsonradio-
chemical and radionuclidic purity of the radiolabelled compound shall be
included. Any material essential for radiolabelling shall be identified and
assayed.
G.Stabilitytests
1. Theparticularsanddocumentsaccompanyingtheapplicationformarketing
authorization pursuant to Article 8(3)(g) and (h) shall be submitted in
accordancewiththefollowingrequirements.
A description shall be given of the investigations by which the shelf life,
the recommended storage conditions and the specifications at the end of
theshelf-lifeproposedbytheapplicanthavebeendetermined.
Whereafinishedproductisliabletogiverisetodegradationproducts,the
applicantmustdeclaretheseandindicatecharacterizationmethodsandtest
procedures.
The conclusions shall contain the results of analyses, justifying the
proposed shelf life under the recommended storage conditions and the
specificationsofthefinishedproductattheendoftheshelf-lifeunderthese
recommendedstorageconditions.
Themaximumacceptablelevelofdegradationproductsattheendofshelf-
lifeshallbeindicated.
Astudyoftheinteractionbetweenproductandcontainershallbesubmitted
wherever the risk of such interaction is regarded as possible, especially
whereinjectablepreparationsoraerosolsforinternaluseareconcerned.
2. Whereforbiologicalmedicinalproducts,suchasimmunologicalmedicinal
products and medicinal products derived from human blood or plasma,
stabilitytestscannotbecarriedoutonthefinishedproducts,itisacceptable
tocarryoutstabilityindicatingtestsatanintermediatestageofproduction
as late as possible in the manufacturing process. In addition, there should
be an evaluation of the stability of the finished product using other
secondarytests.
3. Forradiopharmaceuticals, informationonstabilityshallbegivenforradio-
nuclide generators, radionuclide kits and radiolabelled products. The
stability during use of radiopharmaceuticals in multi-dose vials shall bedocumented.
PART3
TOXICOLOGICALANDPHARMACOLOGICALTESTS2001L0083—EN—08.02.2003—001.001—58
▼B
I.Introduction
1. Theparticularsanddocumentsaccompanyingtheapplicationformarketing
authorizationpursuanttoArticles8(3)(i)and10(1)shallbegiveninaccor-
dancewiththerequirementsbelow.
Member States shall ensure that the safety tests are carried out in confor-
mitywiththeprovisionsrelatingtogoodlaboratory practice laiddownby
CouncilDirectives87/18/EEC(1)and88/320/EEC(2).
Thetoxicologicalandpharmacologicaltestsmustshow:
(a) the potential toxicity of the product and any dangerous or undesirable
toxic effects that may occur under the proposed conditions of use in
humanbeings;theseshouldbeevaluatedinrelationtothepathological
conditionconcerned;
(b) the pharmacological properties of the product, in both qualitative and
quantitative relationship to the proposed use in human beings. All
results must be reliable and of general applicability. Whenever appro-
priate, mathematical and statistical procedures shall be used in
designingtheexperimentalmethodsandinevaluatingtheresults.
Additionally,itisnecessaryforclinicianstobegiveninformationaboutthe
therapeuticpotentialoftheproduct.
2. Whereamedicinalproductisintendedfortopicaluse,systemicabsorption
must be investigated, due account also being taken of the possible use of
theproductonbrokenskinandabsorptionthroughotherrelevantsurfaces.
Onlyifitisprovedthatsystemicabsorptionundertheseconditionsisnegli-
gible may repeated dose systemic toxicity tests, foetal toxicity tests and
studiesofreproductivefunctionbeomitted.
If,however,systemicabsorptionisdemonstratedduringtherapeuticexperi-
mentation, toxicity tests shall be carried out on animals, including where
necessary,foetaltoxicitytests.
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
potentialinvestigatedinthecasesreferredtoinSectionIIEofthisPart.
3. For biological medicinal products such as immunological medicinal
productsandmedicinalproductsderivedfromhumanbloodorplasma,the
requirements of this Part may have to be adapted for individual products;
thereforethetestingprogrammecarriedoutshallbejustifiedbytheappli-
cant.
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,validationoftheirremovalmayreplacethestudy.
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
radiopharmaceuticals; intherapy,itisthewantedproperty.Theevaluation
of safety and efficacy of radiopharmaceuticals shall, therefore, address
requirements for medicinal products and radiation dosimetry aspects.
Organ/tissueexposuretoradiationshallbedocumented.Absorbedradiation
dose estimates shall be calculated according to a specified, internationally
recognizedsystembyaparticularrouteofadministration.
5. Thetoxicologyandpharmacokineticsofanexcipientusedforthefirsttime
inthepharmaceuticalfieldshallbeinvestigated.
6. Wherethereisapossibilityofsignificantdegradationduringstorageofthe
medicinal product,thetoxicologyofdegradation productsmustbeconsid-
ered.2001L0083—EN—08.02.2003—001.001—59
(1) OJL15,17.1.1987,p.29.
(2) OJ L 145, 11.6.1988, p. 35. Directive as amended by Directive 90/18/EEC (OJL 11,
13.1.1990,p.37).
▼B
II.PERFORMANCE OF TESTS
A.Toxicity
1.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-chemicalstateinwhichtheyarepresentintheactualproduct.
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 withorsimilartothatproposedforuseinhumanbeingsandthe
otherensuringsystemicexposuretothesubstance.
This study will cover the signs observed, including local reactions. The
period during which the test animals are observed shall be fixed by the
investigator as being adequate to reveal tissue or organ damage or
recovery, usually for a period of 14 days but not less than 7 days, but
withoutexposingtheanimalstoprolongedsuffering.Animalsdyingduring
the observation period should be subject to autopsy as also should all
animals 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
obtainedfromtheanimalsusedinthestudy.
Thesingledosetoxicitytestsshouldbeconductedinsuchawaythatsigns
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
shouldbeobtained,butahighlevelofprecisionisnotrequired.
Thesestudiesmaygivesomeindicationofthelikelyeffectsofacuteover-
dosage in man and may be useful for the design of toxicity studies
requiringrepeateddosingonthesuitableanimalspecies.
Inthecaseofactive substancesincombination, thestudymustbecarried
outinsuchawayastocheckwhetherornotthereisenhancementoftoxi-
cityorifnoveltoxiceffectsoccur.
2.Repeated dose toxicity (sub-acute or chronic toxicity)
Repeateddosetoxicitytestsareintendedtorevealanyphysiologicaland/or
anatomo-pathological changes induced by repeated administration of the
active substance or combination of active substances under examination,
andtodeterminehowthesechangesarerelatedtodosage.
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
shalldependontheconditionsofclinicaluse.Itspurposeshallbetodeter-
minebyexperiment thenon-toxicdoserangeoftheproductandnormally
itshalllastthreetosixmonths.
Inrespectofmedicinalproductstobeadministeredonceonlytohumans,a
singletestlastingtwotofourweeksshallbeperformed.
Ifhowever,havingregardtotheproposeddurationofuseinhumanbeings,
the investigator seesfit tocarryout experiments ofgreater orlesserdura-
tionthanindicatedabove,hemustgiveadequatereasonsfordoingso.
Reasonsshouldalsobegivenforthedosageschosen.Repeated dose toxicity tests shall be carried out on two species of
mammals one of which must be a non-rodent. The choice of route(s) of
administration employed shall depend on the intended therapeutic useand
the possibilities of systemic absorption. The method and frequency of
dosageshallbeclearlystated.
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
producttobedetermined.
Whereverpossible,andalwaysinexperimentsonsmallrodents,thedesign
oftheexperimentandthecontrolproceduresmustbesuitedtothescaleof
theproblembeingtackledandenablefiduciallimitstobedetermined.
The evaluation of the toxic effects shall be basedon observation of beha-
viour, 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 of2001L0083—EN—08.02.2003—001.001—60
▼B
tests will depend on the species of animal used and the state of scientific
knowledgeatthetime.
Inthecaseofnewcombinationsofknownsubstancesthathavebeeninves-
tigated in accordance with the provisions of this Directive, the chronic
long-termtests m ay, except where acute and sub-acute toxicity tests have
demonstrated potentiation or novel toxic effects, be suitably modified by
theinvestigatorwhoshallsubmithisreasonsforsuchmodification.
B.Examinationofreproductivefunction
If the results of other tests reveal anything suggesting harmful effects on
progeny or impairment of male or female reproductive function, this shall
beinvestigatedbyappropriatetests.
C.Embryo/foetal andperinataltoxicity
Thisinvestigationcomprisesademonstrationofthetoxicandespeciallythe
teratogenic effectsobservedintheissueofconceptionwhenthemedicinal
product under investigation has been administered to the female during
pregnancy.
Although up to the present these tests have had only a limited predictive
value in regard tothe application ofthe resultstohuman beings,they are
thought to provide important information where the results show effects
suchasresorptionsandotheranomalies.
Omission of these tests, either because the medicinal product will not
normallybeusedbywomencapable ofchild-bearing orforotherreasons,
mustbeadequatelyjustified.
Embryo/foetal toxicity studies shall normally be conducted on two
mammalian species,oneofwhichshouldbeotherthanarodent.Peri-and
postnatalstudiesshallbeconductedinatleastonespecies.Wheremetabo-
lismofamedicinalproductinaparticularspeciesisknowntobesimilarto
thatinman,itisdesirabletoincludethisspecies.Also,itisdesirablethat
oneofthespeciesisthesameasintherepeateddosetoxicitystudies.
Thedetailsofthetest(numberofanimals,amountsadministered,timingof
administration and criteria for evaluation of results) shall depend on the
state of scientific knowledge at the time when the application is lodged,
andthelevelofstatisticalsignificancethattheresultsmustattain.
D.Mutagenicpotential
The purpose of the study of mutagenic potential is to reveal the changes
whichasubstancemaycauseinthegeneticmaterialofindividualsorcellsandwhichhavetheeffectofmakingsuccessorspermanentlyandheredita-
rilydifferentfromtheirpredecessors.Thisstudyisobligatoryforanynew
substance.
The number and types of results and the criteria for their evaluation shall
depend on the state of scientific knowledge at the time when the applica-
tionislodged.
E.Carcinogenicpotential
Teststorevealcarcinogeniceffectsshallnormallyberequired:
(a) in respect of substances having a close chemical analogy with known
carcinogenicorcocarcinogeniccompounds;
(b) in respect of substances which have given rise to suspicious changes
duringthelong-termtoxicologicaltests;
(c) inrespect ofsubstances whichhave given riseto suspiciousresults in
the mutagenic-potential tests or in other short-term carcinogenicity
tests.
Suchtestsmayalsoberequiredinrespect ofsubstancestobeincluded in
medicinal products likely to be administered regularly over a prolonged
periodofapatient'slife.
Thestateofscientificknowledgeatthetimewhentheapplicationislodged
shallbetakenintoaccountwhendeterminingthedetailsofthetests.
F.Pharmacodynamics
Thisheading coversthe variations caused by the medicinal product inthe
functionsofthephysiologicalsystems,whetherthesefunctionsarenormal
orexperimentallymodified.
Thisstudyshallfollowtwodistinctlinesofapproach.2001L0083—EN—08.02.2003—001.001—61
▼B
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, (e.g. dose-effect curves, time-effect
curves etc.), and wherever possible, compared with data relating to a
substance whoseactivity is known.Where a higher therapeutic potency is
being claimed for a substance, the difference shall be demonstrated and
showntobestatisticallysignificant.
Secondly,theinvestigator shallprovideageneral pharmacological charac-
terization of the substance, with special reference to adverse reactions. In
general,themainfunctionsofthephysiologicalsystemsshouldbeinvesti-
gated.Thedepthofthisinvestigationmustbeincreasedasthedosesliable
toproduceadverse reactionsapproach thoseproducingthemaineffect for
whichthesubstanceisbeingproposed.
Theexperimental techniques,unlesstheyarestandardprocedures,mustbe
describedinsuchdetailastoallowthemtobereproduced,andtheinves-
tigator 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 modifica-
tion of responses resulting fromrepeated adm inistration of the substance
shallbeinvestigated.
Tests on combinations of active substances may be prompted either by
pharmacologicalpremissesorbyindicationsoftherapeuticeffect.
Inthefirstcase,thepharmacodynamicstudyshalldemonstratethoseinter-
actionswhichmightmakethecombinationofvalueintherapeuticuse.
In the second case, where scientific justification for the combination is
sought through therapeutic experimentation, the investigation shall deter-
mine whether the effects expected from the combination can be
demonstratedinanimals,andtheimportanceofanycollateral effectsshall
atleastbeinvestigated.
If a combination includes a novel active substance, the latter must
previouslyhavebeenstudiedindepth.
G.Pharmacokinetics
Pharmacokineticsmeansthestudyofthefateoftheactivesubstancewithin
theorganism,andcoversthestudyoftheabsorption,distribution,biotrans-
formationandexcretionofthesubstance.
The study of these different phases may be carried out both by means of
physical,chemical orbiologicalmethods,andbyobservationoftheactual
pharmacodynamicactivityofthesubstanceitself.
Information on distribution and elimination (i.e. biotransformation and
excretion)shallbenecessaryinallcaseswheresuchdataareindispensable
to determine the dosage for humans, and in respect of chemotherapeutic
substances (antibiotics, etc.) and substances whose use depends on their
non-pharmacodynamiceffects(e.g.numerousdiagnosticagents,etc.).
Pharmacokinetic investigation of pharmacologically active substances is
necessary.
In the case of new combinations of known substances which have been
investigatedinaccordancewiththeprovisionsofthisDirective,pharmaco-
kinetic studies may not be required, if the toxicity tests and therapeutic
experimentationjustifytheiromission.
H.Localtolerance
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 actionsoftheproductcanbedistinguishedfromtoxicological or
pharmacodynamicones.
I.Well-establishedmedicinaluse
Forthe purpose of demonstrating, pursuant to Article 10(1)(a)(ii), that the
component(s) of a medicinal product have a well established use, with an
acceptablelevelofsafety,thefollowingspecificrulesshallapply:
(a) Factors which have to be taken into account in order to establish a
‘well established medicinal use’ of components of medicinal products
arethetimeoverwhichasubstancehasbeenused,quantitativeaspects2001L0083—EN—08.02.2003—001.001—62
▼B
ofthe useof the substance,the degree of scientific interest in the use
ofthesubstance(reflectedinthepublishedscientificliterature)andthe
coherenceofscientificassessments.Thereforedifferentperiodsoftime
may be necessary for establishing ‘well established use’ of different
substances.Inanycase,however,theperiodoftimerequiredforestab-
lishing a ‘well established medicinal use’ of a component of a
medicinal product must not be less than one decade from the first
systematic and documented use of that substance as a medicinal
productintheCommunity.
(b) Thedocumentationsubmittedbytheapplicantshouldcoverallaspects
of the safety assessment and must include or refer to a review of the
relevant literature, taking into account pre- and postmarketing studies
and published scientific literature concerning experience in the form
ofepidemiologicalstudiesandinparticularofcomparativeepidemiolo-
gical studies. All documentation, both favourable and unfavourable,
shouldbecommunicated.
(c) Particularattentionmustbepaidtoanymissinginformation andjusti-
fication must be given why demonstration of an acceptable level of
safetycanbesupportedalthoughsomestudiesarelacking.
(d) The Expert report must explain the relevance of any data submitted
which concern a product different fromthe product intended for
marketing.Ajudgmentmustbemadewhethertheproductstudiedcan
be considered as similar to the product which will be granted a
marketingauthorisationinspiteoftheexistingdifferences.
(e) Post-marketing experience with other products containing the same
components is of particular importance and applicants should put a
specialemphasisonthisissue.
PART4
CLINICALDOCUMENTATION
Theparticularsanddocumentsaccompanyingapplicationsformarketingauthor-
izations pursuant to Articles 8(3)(i) and 10(1) of this Directive shall be
submittedinaccordancewiththeprovisionsbelow.
Aclinicaltrialisanysystematicstudyofmedicinalproductsinhumansubjects
whether in patients or non-patient volunteers in order to discover or verify the
effectsofand/oridentifyanyadversereactiontoinvestigationalproducts,and/or
studytheirabsorption,distribution,metabolismandexcretioninordertoascer-
taintheefficacyandsafetyoftheproducts.
Evaluationoftheapplicationformarketingauthorizationshallbebasedonclin-
ical trials including clinical pharmacological trials designed to determine the
efficacyandsafetyoftheproductundernormalconditionsofuse,havingregard
to the therapeutic indications for use in human beings. Therapeutic advantages
mustoutweighpotentialrisks.
A.General requirements
TheclinicalparticularstobeprovidedpursuanttoArticles8(3)(i)and10(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,bothfavourableandunfavourable.
Clinical trials must always be preceded by adequate pharmacological and
toxicological tests, carried out on animals in accordance with the require-
ments of Part 3 of this Annex. The investigator must acquaint himself
with the conclusions drawn fromthe pharm acological and toxicological
studiesandhencetheapplicantmustprovidehimatleastwiththeinvesti-
gator's brochure, consisting of all the relevant information known prior to
the onset of a clinical trial including chemical, pharmaceutical and biolo-
gical data, toxicological, pharmacokinetic and pharmacodynamic data in
animals and the results of earlier clinical trials, with adequate data tojustify 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
thecommencementofthetrial.2001L0083—EN—08.02.2003—001.001—63
▼B
B.Conductoftrials
1.Good clinical practice
1.1. Allphasesofclinicalinvestigation,includingbioavailabilityandbioequiva-
lence studies, shall be designed, implemented and reported in accordance
withgoodclinicalpractice.
1.2. Allclinicaltrialsshallbecarriedoutinaccordancewiththeethicalprinci-
ples laid down in the current revision of the Declaration of Helsinki. In
principle, the freely given informed consent of each trial subject shall be
obtainedanddocumented.
The trial protocol (including statistical design), the technical application
and documentation shall be submitted by the sponsor and/or investigator
for an opinion to the relevant ethics committee. The trials shall not begin
beforetheopinionofthiscommitteehasbeenreceivedinwriting.
1.3. Pre-established, systematic written procedures for the organization,
conduct, data collection, documentation and verification of clinical trials
shallberequired.
1.4. Inthecaseofradiopharmaceuticals,clinicaltrialsshallbecarriedoutunder
the responsibility of a medical doctor authorized to use radionuclides for
medicalpurposes.
2.Archiving
The marketing authorization holder shall make arrangements forarchiving
ofdocumentation.
(a) Theinvestigatorshallarrangefortheretentionofthepatientidentifica-
tioncodesforatleast15yearsafterthecompletionordiscontinuation
ofthetrial.
(b) Patient files and other source data shall be kept for the maximum
periodoftimepermittedbythehospital,institutionorprivatepractice.
(c) Thesponsororotherownerofthedatashallretainallotherdocumen-
tationpertainingtothetrialaslongastheproductisauthorized.These
proceduresshallinclude:
— theprotocolincludingtherationale,objectivesandstatisticaldesign
and methodology of the trial, with conditions under which it is
performedandmanaged,anddetailsoftheinvestigational product,
thereferencemedicinalproductand/ortheplaceboused,
— standardoperatingprocedures,
— allwrittenopinionsontheprotocolandprocedures,
— theinvestigator'sbrochure,— casereportformsoneachtrialsubject,— finalreport,— auditcertificate(s),ifavailable.
(d) Thefinalreportshallberetainedbythesponsororsubsequentowner,
forfiveyearsafterthemedicinalproductisnolongerauthorized.
Anychangeofownershipofthedatashallbedocumented.
All data and documents shall be made available if requested by rele-
vantauthorities.
C.Presentationofresults
1. Theparticularsofeachclinicaltrialmustcontainsufficientdetailtoallow
anobjectivejudgementtobemade:
— 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
productused,
— auditcertificate(s),ifavailable,
— 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 signedbytheinvestigator andformulticentre trials, byall
theinvestigatorsorthecoordinating(principal)investigator.
2. Theparticularsofclinicaltrialsreferredtoaboveshallbeforwardedtothe
competent authorities. However,in agreement withthe competent authori-
ties, the applicant may omit part of this information. Complete
documentationshallbeprovidedforthwithuponrequest.2001L0083—EN—08.02.2003—001.001—64
▼B
3. Theclinicalobservationsshallbesummarizedforeachtrialindicating:
(a) thenumberandsexofpatientstreated;
(b) theselectionandage-distributionofthegroupsofpatientsbeinginves-
tigatedandthecomparativetests;
(c) the number of patients withdrawn prematurely from the trials and the
reasonsforsuchwithdrawal;
(d) where controlled trials were carried out under the above conditions,
whetherthecontrolgroup:
— receivednotreatment,
— receivedaplacebo,
— receivedanothermedicinalproductofknowneffect,
— receivedtreatmentotherthantherapyusingmedicinalproducts;
(e) thefrequencyofobservedadversereactions;
(f) details concerning patients who may be at increased risk, e.g. elderly
people, children, women during pregnancy or menstruation, or whose
physiologicalorpathologicalconditionrequiresspecialconsideration;
(g) parametersorevaluationcriteriaofefficacyandtheresultsintermsof
theseparameters;
(h) a statistical evaluation of the results when this is called for by the
designofthetrialsandthevariablefactorsinvolved.
4. The investigator shall, in his conclusions on the experimental evidence,
express an opinion on the safety of the product under normal conditions
ofuse,itstolerance,itsefficacyandanyusefulinformationrelatingtoindi-
cationsandcontra-indications,dosageandaveragedurationoftreatmentas
wellasanyspecialprecautionstobetakenduringtreatmentandtheclinical
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
ofallcentres.
5. Inaddition,theinvestigatorshallalwaysindicatehisobservationson:
(a) any signs of habituation, addiction or difficulty in weaning patients
fromthemedicinalproduct;
(b) anyinteractionsthathavebeenobservedwithothermedicinalproducts
administeredconcomitantly;
(c) thecriteriadeterminingexclusionofcertainpatientsfromthetrials;
(d) any deaths which occurred during the trial or within the follow-up
period.
6. Particularsconcerninganewcombinationofmedicinalsubstancesmustbe
identical to those required for new medicinal products and must
substantiatethesafetyandefficacyofthecombination.
7. Total or partial omission of data must be explained. Should unexpected
resultsoccurduringthecourseofthetrials,furtherpreclinicaltoxicological
andpharmacologicaltestsmustbeundertakenandreviewed.
If the medicinal product is intended for long-term administration, particu-
lars shall be given of any modification of the pharmacological action
following repeated administration, as well as the establishment of long-
termdosage.
D.Clinical pharmacology
1.Pharmacodynamics
The pharmacodynamic action correlated to the efficacy shall be demon-
stratedincluding:
— thedose-responserelationshipanditstimecourse,
— justificationforthedosageandconditionsofadministration,— themodeofaction,ifpossible.
Thepharmacodynamicactionnotrelatedtoefficacyshallbedescribed.
The demonstration ofpharmacodynamic effects in human beingsshall not
initselfbesufficienttojustifyconclusionsregardinganyparticularpoten-
tialtherapeuticeffect.2001L0083—EN—08.02.2003—001.001—65
▼B
2.Pharmacokinetics
Thefollowingpharmacokineticcharacteristicsshallbedescribed:
— absorption(rateandextent),
— 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.
3.Interactions
Ifthemedicinalproductisnormallytobeadministeredconcomitantlywith
other medicinal products,particulars shall be given of joint administration
tests performed to demonstrate possible modification of the pharmacolo-
gicalaction.
If pharmacodynamic/pharmacokinetic interactions exist between the
substance and other medical products or substances like alcohol, caffeine,
tobacco or nicotine, likely to be taken simultaneously, or if such interac-
tions are likely, they should be described and discussed; particularly from
thepointofviewofclinicalrelevanceandtherelationshiptothestatement
concerninginteractionsinthesummaryofproductcharacteristicspresented
inaccordancewithArticle11point5.6.
E.Bioavailability/bioequivalence
Theassessmentofbioavailability mustbeundertakeninallcaseswhereit
isnecessary,e.g.wherethetherapeuticdoseisnearthetoxicdoseorwhere
the previous tests have revealed anomalies which may be related to phar-
macodynamicproperties,suchasvariableabsorption.
In addition, an assessment of bioavailability shall be undertaken where
necessary to demonstrate bioequivalence for the medicinal products
referredtoinArticle10(1)(a).
F.Clinical efficacyandsafety
1. Ingeneral, clinical trials shallbedone as‘controlled clinical trials’ and if
possible,randomized; anyotherdesignshallbejustified.Thetreatment of
the control groups will vary fromcase to case and also will depend on
ethicalconsiderations;thusitmay,insomeinstances,bemorepertinentto
compare the efficacy of a new medicinal product with that of an estab-
lished medicinal product of proven therapeutic value rather than with the
effectofaplacebo.
Asfaraspossible,andparticularlyintrialswheretheeffectoftheproduct
cannot be objectively measured, steps shall be taken to avoid bias,
includingmethodsofrandomizationandblinding.
2. Theprotocol ofthetrial mustinclude athoroughdescriptionofthestatis-
tical 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 docu-
mented. Inclusion of a large number of subjects in a trial must not be
regardedasanadequatesubstituteforaproperlycontrolledtrial.
3. Clinicalstatementsconcerningtheefficacyorsafetyofamedicinalproduct
under normal conditions of use which are not scientifically substantiated
cannotbeacceptedasvalidevidence.
4. Thevalueofdataontheefficacy andsafetyofamedicinal productunder
normal conditions of usewill be very greatly enhanced ifsuchdata come
fromseveralcompetentinvestigatorsworkingindependently.
5. For vaccines and serums, the immunological status and age of the trial
population and thelocal epidemiology are ofcritical importance andshall
bemonitoredduringthetrialandfullydescribed.
Forliveattenuatedvaccines,clinicaltrialsshallbesodesignedastoreveal
potential transmission of the immunizing agent from vaccinated to non-
vaccinated subjects. If transmission is possible, the genotypic and pheno-
typicstabilityoftheimmunizingagentshallbestudied.
For vaccines and allergen products, follow-up studies shall include appro-
priateimmunologicaltests,andwhereapplicable,antibodyassays.2001L0083—EN—08.02.2003—001.001—66
▼B
6. The pertinence of the different trials to the assessment of safety and the
validityofmethodsofevaluationshallbediscussedintheexpertreport.
7. Alladverseeventsincludingabnormallaboratoryvaluesshallbepresented
individuallyanddiscussed,especially:
— intermsofoveralladverseexperience,and
— asafunctionofthenature,seriousnessandcausalityofeffects.
8. A critical assessment of relative safety, taking into account adverse reac-
tions,shallbemadeinrelationto:
— thediseasetobetreated,
— othertherapeuticapproaches,
— particularcharacteristicsinsub-groupsofpatients,
— preclinicaldataontoxicologyandpharmacology.
9. Recommendations shall bemade fortheconditionsofuse,withtheinten-
tionofreducingtheincidenceofadversereactions.
G.Documentationforapplicationsinexceptionalcircumstances
When, in respect of particular therapeutic indications, the applicant can
showthat heisunable toprovidecomprehensive data onthe efficacy and
safetyundernormalconditionsofuse,because:
— the indications for which the product in question is intended are
encountered sorarelythattheapplicant cannotreasonablybeexpected
toprovidecomprehensiveevidence,or
— inthepresentstateofscientificknowledge,comprehensiveinformation
cannotbeprovided,or
— itwouldbecontrary togenerally accepted principles ofmedical ethics
tocollectsuchinformation,
marketingauthorizationmaybegrantedonthefollowingconditions:
(a) the applicant completes on identified programme of studies within a
time period specified by the competent authority, the results of which
shallformthebasisofareassessmentofthebenefit/riskprofile,
(b) themedicinalproductinquestionmaybesuppliedonmedicalprescrip-
tion only and may in certain cases be administered only under strict
medical supervision, possibly in a hospital and for a radiopharmaceu-
tical,byanauthorizedperson,
(c) the package leaflet and any medical information shall draw the atten-
tion of the medical practitioner to the fact that the particulars
availableconcerningthemedicinalproductinquestionareasyetinade-quateincertainspecifiedrespects.
H.Post-marketingexperience
1. If the medicinal product is already authorized in other countries, informa-
tion 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
worldwide studies relevant to the safety of the medicinal product shall be
included.
For this purpose, an adverse drug reaction is a reaction which is noxious
and unintended and which occurs at doses normally used in man for
prophylaxis, diagnosis or therapy of disease or for the modification of
physiologicalfunction.
2. In the case of vaccines already authorized in other countries, information
onthemonitoringofvaccinated subjectstoevaluate theprevalence ofthe
disease in question as compared to nonvaccinated subjects shall be
submitted,whenavailable.
3. For allergen products, response in periods of increased antigen exposure
shallbeidentified.
I.Well-establishedmedicinaluse
Forthe purpose of demonstrating, pursuant to Article 10(1)(a)(ii), that the
component(s) of a medicinal product have a well established use, with
recognisedefficacy,thefollowingspecificrulesshallapply:
(a) Factors which have to be taken into account in order to establish a
‘well established medicinal use’ of components of medicinal products
arethetimeoverwhichasubstancehasbeenused,quantitativeaspects
ofthe useof the substance,the degree of scientific interest in the use2001L0083—EN—08.02.2003—001.001—67
▼B
ofthesubstance(reflectedinthepublishedscientificliterature)andthe
coherenceofscientificassessments.Thereforedifferentperiodsoftime
may be necessary for establishing ‘well established use’ of different
substances.Inanycase,however,theperiodoftimerequiredforestab-
lishing a ‘well established medicinal use’ of a component of a
medicinal product must not be less than one decade from the first
systematic and documented use of that substance as a medicinal
productintheCommunity.
(b) Thedocumentationsubmittedbytheapplicantshouldcoverallaspects
oftheefficacyassessmentandmustincludeorrefertoareviewofthe
relevant literature, taking into account pre- and postmarketing studies
and published scientific literature concerning experience in the form
ofepidemiologicalstudiesandinparticularofcomparativeepidemiolo-
gical studies. All documentation, both favourable and unfavourable,
shouldbecommunicated.
(c) Particularattentionmustbepaidtoanymissinginformation andjusti-
ficationmustbegivenwhydemonstrationofefficacycanbesupported
althoughsomestudiesarelacking.
(d) The Expert report must explain the relevance of any data submitted
which concern a product different fromthe product intended for
marketing.Ajudgmentmustbemadewhethertheproductstudiedcan
be considered as similar to the product which will be granted a
marketingauthorisationinspiteoftheexistingdifferences.
(e) Post-marketing experience with other products containing the same
components is of particular importance and applicants should put a
specialemphasisonthisissue.2001L0083—EN—08.02.2003—001.001—68
▼B
ANNEX II
PARTA
Repealed Directives, with their successive amendments (referred to by
Article 128)
CouncilDirective65/65/EEC(OJ22,9.2.1965,p.369/65)
CouncilDirective66/454/EEC(OJ144,5.8.1966,p.2658/66)
CouncilDirective75/319/EEC(OJL147,9.6.1975,p.13)
CouncilDirective83/570/EEC(OJL332,28.11.1983,p.1)
CouncilDirective87/21/EEC(OJL15,17.1.1987,p.36)CouncilDirective89/341/EEC(OJL142,25.5.1989,p.11)
CouncilDirective92/27/EEC(OJL113,30.4.1992,p.8)
CouncilDirective93/39/EEC(OJL214,24.8.1993,p.22)
CouncilDirective75/318/EEC(OJL147,9.6.1975,p.1)
CouncilDirective83/570/EEC
CouncilDirective87/19/EEC(OJL15,17.1.1987,p.31)
CouncilDirective89/341/EEC
CommissionDirective91/507/EEC(OJL270,26.9.1991,p.32)CouncilDirective93/39/EECCommissionDirective1999/82/EC(OJL243,15.9.1999,p.7)
CommissionDirective1999/83/EC(OJL243,15.9.1999,p.9)
CouncilDirective75/319/EEC
CouncilDirective78/420/EEC(OJL123,11.5.1978,p.26)
CouncilDirective83/570/EECCouncilDirective89/341/EEC
CouncilDirective92/27/EEC
CouncilDirective93/39/EECCommissionDirective2000/38/EC(OJL139,10.6.2000,p.28)
CouncilDirective89/342/EEC(OJL142,25.5.1989,p.14)
CouncilDirective89/343/EEC(OJL142,25.5.1989,p.16)CouncilDirective89/381/EEC(OJL181,28.6.1989,p.44)
CouncilDirective92/25/EEC(OJL113,30.4.1992,p.1)
CouncilDirective92/26/EEC(OJL113,30.4.1992,p.5)
CouncilDirective92/27/EEC
CouncilDirective92/28/EEC(OJL113,30.4.1992,p.13)
CouncilDirective92/73/EEC(OJL297,13.10.1992,p.8)2001L0083—EN—08.02.2003—001.001—69
▼B
PARTB
Time-limitsfortranspositionintonationallaw(referred tobyArticle 128)
Directive Deadlinefortransposition
Directive65/65/EEC 31December1966
Directive66/454/EEC —
Directive75/318/EEC 21November1976
Directive75/319/EEC 21November1976
Directive78/420/EEC —Directive83/570/EEC 31October1985
Directive87/19/EEC 1July1987
Directive87/21/EEC 1July1987
1January1992(
1)
Directive89/341/EEC 1January1992
Directive89/342/EEC 1January1992
Directive89/343/EEC 1January1992
Directive89/381/EEC 1January1992
Directive91/507/EEC 1January1992(2)
1January1995(3)
Directive92/25/EEC 1January1993
Directive92/26/EEC 1January1993
Directive92/27/EEC 1January1993
Directive92/28/EEC 1January1993
Directive92/73/EEC 31December1993
Directive93/39/EEC 1January1995(4)
1January1998(5)
Directive1999/82/EC 1January2000
Directive1999/83/EC 1March2000
Directive2000/38/EC 5December2001
(1) DeadlinefortranspositionapplicabletoGreece,SpainandPortugal.
(2) ExceptSectionA,point3.3inPartIIoftheAnnex.
(3) DeadlinefortranspositionapplicabletoSectionA,point3.3inPartIIoftheAnnex.
(4) ExceptwithregardtoArticle1(6).
(5) DeadlinefortranspositionapplicabletoArticle1(7).2001L0083—EN—08.02.2003—001.001—70
ANNEX III
CORRELATIONTABLE
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 92/27/EEC 92/28/EEC 92/73/EEC
Art.1(1)to(3) Art.1(1)to
(3)
Art.1(4) Annex Art.1(1)and
(2)
Art.1(5) Art.1
Art.1(6)to(9) Art.1(2)Art.1(10) Art.1(1)
Art.1(11)to
(16)Art.29b,1st
paragraph
Art.1(17)and
(18)Art.1(2)
Art.1(19) Art.1(2),2nd
sentence
Art.1(20)to
(26)Art.1(2)
Art.1(27) Art.8(1)
Art.1(28) Art.10(1)Art.2 Art.2(1)Art.3(1)and
(2)Art.1(4)and
(5)
Art2(3),1st
indent▼B2001L0083—EN—08.02.2003—001.001—71
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 92/27/EEC 92/28/EEC 92/73/EEC
Art.3(3)and
(4)Art.2(3),2nd
and3rd
indents
Art.3(5) Art.1(1)Art.3(6) Art.1(2)
Art.4(1) Art.1(3)
Art.4(2) Art.1(3)
Art.4(3) Art.3,2nd
subparagraph
Art.4(4) Art.6Art.5 Art.2(4)Art.6(1) Art.3(1)
Art.6(2) Art.2,1st
sentence
Art.7 Art.2,2nd
sentence
Art.8(1)and
(2)Art.4(1)and
(2)
Art.8(3)(a)to
(e)Art.4,3rd
para.,points1
to5Art.1,1st
paragraph
Art.8(3)(f)to
(i)Art.4,3rd
para.,points6
to8.1
Art.8(3)(j)to
(l)Art.4,3rd
para.,points9
to11▼B2001L0083—EN—08.02.2003—001.001—72
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 92/27/EEC 92/28/EEC 92/73/EEC
Art.9 Art.3
Art.10(1) Art.4,3rd
paragraph,
point8.2
Art.10(2) Art.1,2nd
paragraph
Art.11,points
1to5.3Art.4a,points
1to5.3
Art.11,point
5.4Art.4a,point
5.4Art.3
Art.11,points
5.5to6.4Art.4a,points
5.5to6.4
Art.11,point
6.5Art.4a,point
6.6
Art.11,point7 Art.4a,point
6.5
Art.11,points
8to9Art.4
Art.12(1) Art.1
Art.12(2)and
(3)Art.2
Art.13 Art.6(1)and
(2)
Art.14(1)and
(2)Art.7(1)and
(4)
Art.14(3) Art.4,2nd
paragraph▼B2001L0083—EN—08.02.2003—001.001—73
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 92/27/EEC 92/28/EEC 92/73/EEC
Art.15 Art.8
Art.16 Art.9
Art.17 Art.7
Art.18 Art.7a
Art.19 Art.4Art.20 Art.5Art.21 Art.4b
Art.22 Art.10(2)
Art.23 Art.9aArt.24 Art.10(1)Art.25 Art.9
Art.26 Art.5
Art.27 Art.8Art.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.10Art.30 Art.11Art.31 Art.12▼B2001L0083—EN—08.02.2003—001.001—74
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 92/27/EEC 92/28/EEC 92/73/EEC
Art.32 Art.13
Art.33 Art.14(1)
Art.34 Art.14(2)to
(4)
Art.35 Art.15
Art.36 Art.15a
Art.37 Art.15b
Art.38 Art.15c
Art.39 Art.14(5)
Art.40 Art.16
Art.41 Art.17
Art.42 Art.18
Art.43 Art.20(1)
Art.44 Art.20(2)
Art.45 Art.20(3)
Art.46 Art.19
Art.47 Art.19a
Art.48 Art.21
Art.49 Art.23
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Art.51(1)and
(2)Art.22(1)
Art.51(3) Art.22(2)
Art.52 Art.25
Art.53 Art.3
Art.54 Art.2(1)
Art.55 Art.3
Art.56 Art.4(1)
Art.57 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)▼B2001L0083—EN—08.02.2003—001.001—76
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Art.65 Art.12
Art.66 Art.5
Art.67 Art.6(1)
Art.68 Art.2(2)
Art.69 Art.7(2)and
(3)
Art.70 Art.2
Art.71 Art.3
Art.72 Art.4
Art.73 Art.5(1)
Art.74 Art.5(2)
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
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Art.84 Art.10
Art.85 Art.9
Art.86 Art.1(3)and
(4)
Art.87 Art.2
Art.88 Art.3(1)to
(6)
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.96 Art.11
Art.97(1)to
(4)Art.12(1)and
(2)
Art.97(5) Art.12(4)
Art.98 Art.13
Art.99 Art.14
Art.100 Art.6(3)▼B2001L0083—EN—08.02.2003—001.001—78
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Art.101 Art.29e
Art.102 Art.29aArt.103 Art.29c
Art.104 Art.29d
Art.105 Art.29fArt.106(1) Art.29gArt.106(2) Art.29b,2nd
paragraph
Art.107 Art.29hArt.108 Art.29i
Art.109 Art.3(1)to
(3)
Art.110 Art.3(4)
Art.111(1) Art.26,1st
and2ndpara-
graph
Art.111(2) Art.4(1)Art.111(3) Art.26,3rd
paragraph
Art.112 Art.8 Art.27Art.113 Art.4(2) Art.4(2)Art.114(1) Art.4(3)Art.114(2) Art.4(3)▼B2001L0083—EN—08.02.2003—001.001—79
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Art.115 Art.4(1)
Art.116 Art.11
Art.117 Art.28Art.118 Art.29
Art.119 Art.4(1)
Art.120 Art.2a,1st
paragraph
Art.121 Art.2b Art.37a
Art.122 Art.30Art.123 Art.33Art.124 Art.5
Art.125 Art.12 Art.31 Art.4(2) Art.11(2) Art.12(3)
Art.126,1st
paragraphArt.21
Art.126,2nd
paragraphArt.32
Art.127 Art.28a
Art.128 — — —————————
Art.129 — — —————————
Art.130 — — —————————
AnnexI Annex▼B2001L0083—EN—08.02.2003—001.001—80
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AnnexII — — —————————
AnnexIII — — —————————▼B2001L0083—EN—08.02.2003—001.001—81