2001L0083 — EN — 01.07.2003 — 002.001 — 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
(OJ L 311, 28.11.2001, p. 67)
Amended by:
Official Journal
No page date
►M1Directive 2002/98/EC of the European Parliament and of the Council of
27 January 2003L 33 30 8.2.2003
►M2Commission directive 2003/63/EC of 25 June 2003 L 159 46 27.6.2003
▼B
DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT
ANDOFTHECOUNCIL
of6November2001
on the Community code relating to medicinal products for human
use
THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE
EUROPEAN UNION,
Having regard to the Treaty establishing the European Community, and
in particular Article 95 thereof,
Having regard to the proposal from the Commission;
Having regard to the opinion of the Economic and Social
Committee (1),
Acting in accordance with the procedure laid down in Article 251 of
the Treaty (2),
Whereas:
(1)Council Directive 65/65/EEC of 26 January 1965 on the approx-
imation of provisions laid down by law, regulation oradministrative action relating to medicinal products (
3), Council
Directive 75/318/EEC of 20 May 1975 on the approximation ofthe laws of Member States relating to analytical, pharmaco-toxi-
cological and clinical standards and protocols in respect of the
testing of proprietary medicinal products (
4), Council Directive
75/319/EEC of 20 May 1975 on the approximation of provisionslaid down by law, regulation or administrative action relating toproprietary medicinal products (
5), Council Directive 89/342/
EEC of 3 May 1989 extending the scope of Directives 65/65/
EEC and 75/319/EEC and laying down additional provisions for
immunological medicinal products consisting of vaccines, toxinsor serums and allergens (
6), Council Directive 89/343/EEC of 3
May 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC and laying down additional provisions for radiophar-
maceuticals (
7), Council Directive 89/381/EEC of 14 June 1989
extending the scope of Directives 65/65/EEC and 75/319/EECon the approximation of provisions laid down by law, 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
the advertising of medicinal products for human use (12), Council
Directive 92/73/EEC of 22 September 1992 widening the scope2001L0083 — EN — 01.07.2003 — 002.001 — 2
(1) OJ C 368, 20.12.1999, p. 3.
(2) Opinion of the European Parliament of 3 July 2001 (not yet published in the
Official Journal) and Council Decision of 27 September 2001.
(3) OJ 22, 9.2.1965, p. 369/65. Directive as last amended by Directive 93/39/
EEC (OJ L 214, 24.8.1993, p. 22).
(4) OJ L 147, 9.6.1975, p. 1. Directive as last amended by Commission Direc-
tive 1999/83/EC (OJ L 243, 15.9.1999, p. 9).
(5) OJ L 147, 9.6.1975, p. 13. Directive as last amended by Commission Direc-
tive 2000/38/EC (OJ L 139, 10.6.2000, p. 28).
(6) OJ L 142, 25.5.1989, p. 14.
(7) OJ L 142, 25.5.1989, p. 16.
(8) OJ L 181, 28.6.1989, p. 44.
(9) OJ L 113, 30.4.1992, p. 1.
(10) OJ L 113, 30.4.1992, p. 5.
(11) OJ L 113, 30.4.1992, p. 8.
(12) OJ L 113, 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 administrativeaction relating to medicinal products and laying down additional
provisions on homeopathic medicinal products (
1) have been
frequently and substantially amended. In the interests of clarityand rationality, the said Directives should therefore be codifiedby assembling them in a single text.
(2)The essential aim of any rules governing the production, distri-bution and use of medicinal products must be to safeguardpublic health.
(3)However, this objective must be attained by means which willnot hinder the development of the pharmaceutical industry ortrade in medicinal products within the Community.
(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,
animal feeding-stuffs or toilet preparations), and such disparitiesdirectly affect the functioning of the internal market.
(5)Such hindrances must accordingly be removed; whereas thisentails approximation of the relevant provisions.
(6)In order to reduce the disparities which remain, rules should be
laid down on the control of medicinal products and the duties
incumbent upon the Member States' competent authorities shouldbe 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
particulars and documents which must accompany an application
for marketing authorization for a medicinal product demonstratethat potential risks are outweighed by the therapeutic efficacy ofthe product.
(8)Standards and protocols for the performance of tests and trialson medicinal products are an effective means of control of theseproducts and hence of protecting public health and can facilitatethe movement of these products by laying down uniform rules
applicable to tests and trials, the compilation of dossiers and
the examination of applications.
(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 a view to obtaining authorization for a 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
repetitive tests on humans or animals without over-riding cause.
(11)The adoption of the same standards and protocols by all theMember States will enable the competent authorities to arrive attheir decisions on the basis of uniform tests and by reference to
uniform criteria and will therefore helpto 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 22July 1993 laying down Community procedures for the authoriza-tion and supervision of medicinal products for human andveterinary use and establishing a European Agency for the2001L0083 — EN — 01.07.2003 — 002.001 — 3
(1) OJ L 297, 13.10.1992, p. 8.
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Evaluation of Medicinal Products (1) a marketing authorization
for a medicinal product granted by a competent authority in oneMember State ought to be recognized by the competent authori-
ties of the other Member States unless there are serious grounds
for supposing that the authorization of the medicinal productconcerned may present a risk to public health. In the event of adisagreement between Member States about the quality, thesafety or the efficacy of a medicinal product, a scientific evalua-
tion of the matter should be undertaken according to a
Community standard, leading to a single decision on the area ofdisagreement binding on the Member States concerned. 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 upattached to the Europ ean Agency forthe Evaluation of Medicinal Products established in the above-mentioned Regulation (EEC) No 2309/93.
(14)This Directive represents an important step towards achievementof the objective of the free movement of medicinal products.Further measures may abolish any remaining barriers to the freemovement of proprietary medicinal products will be necessary in
the light of experience gained, particularly in the abovemen-
tioned Committee for Proprietary Medicinal Products.
(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 by them,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 reachedby the latter Member State.
(16)Following the establishment of the internal market, specific
controls to guarantee the quality of medicinal products imported
from third countries can be waived only if appropriate arrange-ments have been made by the Community to ensure that thenecessary controls are carried out in the exporting country.
(17)It is necessary to adopt specific provisions for immunologicalmedicinal products, homeopathic medicinal products, radiophar-maceuticals, and medicinal products based on human blood orhuman plasma.
(18)Any rules governing radiopharmaceuticals must take into
account the provisions of Council Directive 84/466/Euratom of
3 September 1984 laying down basic measures for the radiationprotection of persons undergoing medical examination or treat-ment (
2). Account should also be taken of Council Directive 80/
836/Euratom of 15 July 1980 amending the Directives laying
down the basic safety standards for the health protection of the
general public and workers against the dangers of ionizing radia-tion (
3), the objective of which is to prevent the exposure of
workers or patients to excessive or unnecessarily high levels ofionizing radiation, and in particular of Article 5c thereof, whichrequires prior authorization for the addition of radioactive2001L0083 — EN — 01.07.2003 — 002.001 — 4
(1) OJ L 214, 24.8.1993, p. 1. Regulation as amended by Commission Regula-
tion (EC) No 649/98 (OJ L 88, 24.3.1998, p. 7).
(2) OJ L 265, 5.10.1984, p. 1. Directive repealed with effect from 13 May 2000
by Directive 97/43/Euratom (OJ L 180, 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 from 13 May
2000 by Directive 96/29/Euratom (OJ L 314, 4.12.1996, p. 20).
▼B
substances to medicinal products as well as for the importation
of such medicinal products.
(19)The Community entirely supports the efforts of the Council ofEurope to promote voluntary unpaid blood and plasma donationto attain self-sufficiency throughout the Community in thesupply of blood products, and to ensure respect for ethical prin-
ciples in trade in therapeutic substances of human origin.
(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 fromthird countries.
(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 form and dosage which do not present a risk for thepatient.
(22)The anthroposophic medicinal products described in an officialpharmacopoeia and prepared by a homeopathic method are tobe treated, as regards registration and marketing authorization,in the same way as homeopathic medicinal products.
(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 oftheir quality and safety.
(24)The rules relating to the manufacture, control and inspection ofhomeopathic medicinal products must be harmonized to permitthe circulation throughout the Community of medicinal productswhich are safe and of good quality.
(25)The usual rules governing the authorization to market medicinalproducts 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 applyparticular rules for the evaluation of the results of tests and trialsintended to establish the safety and efficacy of these medicinal
products provided that they notify them to the Commission.
(26)In order to facilitate the movement of medicinal products and to
prevent the controls carried out in one Member State from beingrepeated in another, minimum requirements should be laid down
for manufacture and imports coming from third countries and for
the grant of the authorization relating thereto.
(27)It should be ensured that, in the Member States, the supervision
and control of the manufacture of medicinal products is carried
out by a person who fulfils minimum conditions of qualification.
(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
state of technology permits.
(29)The conditions governing the supply of medicinal products to thepublic should be harmonized.
(30)In this connection persons moving around within the Communityhave the right to carry a reasonable quantity of medicinalproducts lawfully obtained for their personal use. It must also2001L0083 — EN — 01.07.2003 — 002.001 — 5
▼B
be possible for a person established in one Member State to
receive from another Member State a reasonable quantity ofmedicinal products intended for his personal use.
(31)In addition, by virtue of Regulation (EC) No 2309/93, certainmedicinal products are the subject of a Community marketingauthorization. In this context, the classification for the supply ofmedicinal products covered by a Community marketing authori-zation needs to be established. It is therefore important to set thecriteria on the basis of which Community decisions will be
taken.
(32)It is therefore appropriate, as an initial step, to harmonize the
basic principles applicable to the classification for the supply ofmedicinal products in the Community or in the Member Stateconcerned, while taking as a starting point the principles alreadyestablished 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
medicinal products on prescription.
(34)Many operations involving the wholesale distribution of medic-
inal products for human use may cover several Member Statessimultaneously.
(35)It is necessary to exercise control over the entire chain of distri-bution of medicinal products, from their manufacture or importinto the Community through to supply to the public, so as to
guarantee that such products are stored, transported and handled
in suitable conditions. The requirements which must be adoptedfor this purpose will considerably facilitate the withdrawal ofdefective products from the market and allow more effectiveefforts against counterfeit products.
(36)Any person involved in the wholesale distribution of medicinal
products should be in possession of a special authorization. Phar-
macists and persons authorized to supply medicinal products tothe public, and who confine themselves to this activity, shouldbe exempt from obtaining this authorization. It is however neces-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 showingtransactions in products received.
(37)Authorization must be subject to certain essential conditions andit is the responsibility of the Member State concerned to ensurethat such conditions are met; whereas each Member State must
recognize authorizations granted by other Member States.
(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 toimpose those obligations on wholesalers established within their
territory. They must also be able to impose them on wholesalers
in other Member States on condition that they do not impose anyobligation more stringent than those which they impose on theirown wholesalers and provided that such obligations may beregarded as warranted on grounds of public health protectionand are proportionate in relation to the objective of such protec-
tion.
(39)Rules should be laid down as to how the labelling and package
leaflets are to be presented.
(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 offull and comprehensible information.2001L0083 — EN — 01.07.2003 — 002.001 — 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 labellingor package leaflet.
(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 Statesconcerning misleading advertising (
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
have effects in other Member States.
(44)Council Directive 89/552/EEC of 3 October 1989 on the coordi-
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 onmedical prescription in the Member State within whose jurisdic-tion the television broadcaster is located. This principle shouldbe made of general application by extending it to other media.
(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 tosatisfy certain essential criteria which ought to be defined.
(46)Furthermore, distribution of samples free of charge to thegeneral public for promotional ends must be prohibited.
(47)The advertising of medicinal products to persons qualified toprescribe or supply them contributes to the information availableto such persons. Nevertheless, this advertising should be subjectto strict conditions and effective monitoring, referring in parti-cular to the work carried out within the framework of the
Council of Europe.
(48)Advertising of medicinal products should be subject to effective,
adequate monitoring. Reference in this regard should be made tothe monitoring mechanisms set upby Directive 84/450/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 tosupply the person visited with a summary of product characteris-
tics.
(50)Persons qualified to prescribe medicinal products must be able to
carry out these functions objectively without being influenced by
direct or indirect financial inducements.
(51)It should be possible within certain restrictive conditions to
provide samples of medicinal products free of charge to personsqualified to prescribe or supply them so that they can familiarize
themselves with new products and acquire experience in dealing
with them.
(52)Persons qualified to prescribe or supply medicinal products musthave access to a neutral, objective source of information about
products available on the market. Whereas it is nevertheless for
the Member States to take all measures necessary to this end, inthe light of their own particular situation.2001L0083 — EN — 01.07.2003 — 002.001 — 7
(1) OJ L 250, 19.9.1984, p. 17. Directive as amended by Directive 97/55/EC
(OJ L 290, 23.10.1997, p. 18).
(2) OJ L 298, 17.10.1989, p. 23. Directive as amended by Directive 97/36/EC
(OJ L 202, 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 theapproved conditions of use.
(54)In order to ensure the continued safety of medicinal products inuse, it is necessary to ensure that pharmacovigilance systems in
the Community are continually adapted to take account of scien-
tific and technical progress.
(55)It is necessary to take account of changes arising as a result ofinternational harmonisation of definitions, terminology and tech-nological developments in the field of pharmacovigilance.
(56)The increasing use of electronic networks for communication ofinformation on adverse reactions to medicinal products marketedin the Community is intended to allow competent authorities toshare the information at the same time.
(57)It is the interest of the Community to ensure that the pharmacov-
igilance systems for centrally authorised medicinal products and
those authorised by other procedures are consistent.
(58)Holders of marketing authorisations should be proactivelyresponsible for on-going pharmacovigilance of the medicinalproducts they place on the market.
(59)The measures necessary for the implementation of this Directiveshould 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 andtechnical progress.
(61)This Directive should be without prejudice to the obligations of
the Member States concerning the time-limits for transposition
of the Directives set out in Annex II, Part B.
HAVE ADOPTED THIS DIRECTIVE:
TITLE I
DEFINITIONS
Article 1
For the purposes of this Directive, the following terms shall bear the
following meanings:
1.Proprietary medicinal product:
Any ready-prepared medicinal product placed on the market under
a special name and in a special pack.
2.Medicinal product:
Any substance or combination of substances presented for treating
or preventing disease in human beings.
Any substance or combination of substances which may be 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:
Any matter irrespective of origin which may be:— human, e.g.2001L0083 — EN — 01.07.2003 — 002.001 — 8
(1) OJ L 184, 17.7.1999, p. 23.
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human blood and human blood products;
— animal, e.g.
micro-organisms, whole animals, parts of organs, animal secre-
tions, toxins, extracts, blood products;
— vegetable, e.g.
micro-organisms, plants, parts of plants, vegetable secretions,
extracts;
— chemical, e.g.
elements, naturally occurring chemical materials and chemical
products obtained by chemical change or synthesis.
4.Immunological medicinal product:
Any medicinal product consisting of vaccines, toxins, serums or
allergen products:
(a) vaccines, toxins and serums shall cover in particular:
(i) agents used to produce active immunity, such as cholera
vaccine, BCG, polio vaccines, smallpox vaccine;
(ii) agents used to diagnose the state of immunity, including in
particular tuberculin and tuberculin PPD, toxins for theSchick and Dick Tests, brucellin;
(iii) agents used to produce passive immunity, such as
diphtheria antitoxin, anti-smallpox globulin, antilympho-cytic globulin;
(b) ‘allergen product’ shall mean any medicinal product which is
intended to identify or induce a specific acquired alteration inthe immunological response to an allergizing agent.
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 pharmacopoeiascurrently used officially in the Member States.
A homeopathic medicinal product may also contain a number of
principles.
6.Radiopharmaceutical:
Any medicinal product which, when ready for use, contains one or
more radionuclides (radioactive isotopes) included for a medicinal
purpose.
7.Radionuclide generator:
Any system incorporating a fixed parent radionuclide from which
is produced a daughter radionuclide which is to be obtained byelution or by any other method and used in a radiopharmaceutical.
8.Radionuclide kit:
Any preparation to be reconsitituted or combined with radionu-
clides in the final radiopharmaceutical, usually prior to itsadministration.
9.Radionuclide precursor:
Any other radionuclide produced for the radio-labelling of another
substance prior to administration.
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
factors and immunoglobulins of human origin.
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 — 01.07.2003 — 002.001 — 9
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prophylaxis, diagnosis or therapy of disease or for the restoration,
correction or modification of physiological function.
12.Serious adverse reaction:
An adverse reaction which results in death, is life-threatening,
requires inpatient hospitalisation or prolongation of existing hospi-talisation, results in persistent or significant disability or incapacity,or is a congenital anomaly/birth defect.
13.Unexpected adverse reaction:
An adverse reaction, the nature, severity or outcome of which is
not consistent with the summary of product characteristics.
14.Periodic safety update reports:
The periodical reports containing the records referred to in Article
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 aim of identifying or quantifying a safetyhazard relating to an authorised medicinal product.
16.Abuse of medicinal products:
Persistent or sporadic, intentional excessive use of medicinal
products which is accompanied by harmful physical or psycholo-
gical effets.
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 or with pharmacists and persons authorized or entitledto supply medicinal products to the public in the Member Stateconcerned.
18.Public service obligation:
The obligation placed on wholesalers to guarantee permanently an
adequate range of medicinal products to meet the requirements of a
specific geographical area and to deliver the supplies requestedwithin a very short time over the whole of the area in question.
19.Medicinal Prescription:
Any medicinal prescription issued by a professional person quali-
fied to do so.
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 nameshall not be liable to confusion with the common name.
21.Common name:
The international non-proprietary name recommended by the
World Health Organization, or, if one does not exist, the usualcommon name.
22.Strength of the medicinal product:
The content of the active substances expressed quantitatively per
dosage unit, per unit of volume or weight according to the dosage
form.
23.Immediate packaging:
The container or other form of packaging immediately in contact
with the medicinal product.
24.Outer packaging:
The packaging into which is placed the immediate packaging.2001L0083 — EN — 01.07.2003 — 002.001 — 10
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25.Labelling:
Information on the immediate or outer packaging.
26.Package leaflet:
A leaflet containing information for the user which accompanies
the medicinal product.
27.Agency:
The European Agency for the Evaluation of Medicinal Products
established by Regulation (EEC) No 2309/93.
28.Riskto public health:
All risks with regard to the quality, safety and efficacy of the
medicinal product.
TITLE II
SCOPE
Article 2
The provisions of this Directive shall apply to industrially produced
medicinal products for human use intended to be placed on the marketin Member States.
Article 3
This Directive shall not apply to:
1. Any medicinal product prepared in a pharmacy in accordance with a
medical prescription for an individual patient (commonly known as
the magistral formula).
2. Any medicinal product which is prepared in a pharmacy in accor-
dance with the prescriptions of a pharmacopoeia and is intended tobe supplied directly to the patients served by the pharmacy in ques-tion (commonly known as the official formula).
3. Medicinal products intended for research and development trials.4. Intermediate products intended for further processing by an author-
ized manufacturer.
5. Any radionuclides in the form of sealed sources.6. Whole blood, plasma or blood cells of human origin.
Article 4
1. Nothing in this Directive shall in any way derogate from the
Community rules for the radiation protection of persons undergoingmedical examination or treatment, or from the Community rules layingdown the basic safety standards for the health protection of the general
public and workers against the dangers of ionizing radiation.
2. This Directive shall be without prejudice to Council Decision 86/
346/EEC of 25 June 1986 accepting on behalf of the Community the
European Agreement on the Exchange of Therapeutic Substances of
Human Origin (
1).
3. The provisions of this Directive shall not affect the powers of the
Member States' authorities either as regards the setting of prices for
medicinal products or their inclusion in the scope of national healthinsurance schemes, on the basis of health, economic and social condi-tions.
4. This Directive shall not affect the application of national legisla-
tion prohibiting or restricting the sale, supply or use of medicinalproducts as contraceptives or abortifacients. The Member States shallcommunicate the national legislation concerned to the Commission.2001L0083 — EN — 01.07.2003 — 002.001 — 11
(1) OJ L 207, 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 from the provisions of this Directive
medicinal products supplied in response to a bona fide unsolicited
order, formulated in accordance with the specifications of an authorizedhealth care professional and for use by his individual patients on hisdirect personal responsibility.
TITLE III
PLACINGONTHEMARKET
CHAPTER 1
Marketingauthorization
Article 6
1. No medicinal product may be placed on the market of a Member
State unless a marketing authorization has been issued by the compe-tent authorities of that Member State in accordance with this Directiveor an authorization has been granted in accordance with Regulation
(EEC) No 2309/93.
2. The authorisation referred to in paragraph 1 shall also be required
for radionuclide generators, radionuclide kits, radionuclide precursorradiopharmaceuticals and industrially prepared radiopharmaceuticals.
Article 7
A marketing authorization shall not be required for a radiopharmaceu-
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 radionuclideprecursors in accordance with the manufacturer's instructions.
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 competentauthority of the Member State concerned.
2. A marketing authorization may only be granted to an applicant
established in the Community.
3. The application shall be accompanied by the following particulars
and documents, submitted in accordance with Annex I:
(a) Name or corporate name and permanent address of the applicant
and, where applicable, of the manufacturer.
(b) Name of the medicinal product.
(c) Qualitative and quantitative particulars of all the constituents of the
medicinal product in usual terminology, but excluding empiricalchemical formulae, with mention of the international non-proprie-
tary name recommended by the World Health Organization where
such name exists.
(d) Description of the manufacturing method.
(e) Therapeutic indications, contra-indications and adverse reactions.
(f) Posology, pharmaceutical form, method and route of administration
and expected shelf life.
(g) If applicable, reasons for any precautionary and safety measures to
be taken for the storage of the medicinal product, its administrationto patients and for the disposal of waste products, together with anindication of any potential risks presented by the medicinal productfor the environment.2001L0083 — EN — 01.07.2003 — 002.001 — 12
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(h) Description of the control methods employed by the manufacturer
(qualitative and quantitative analysis of the constituents and of thefinished 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 atan intermediate stage of the manufacturing process).
(i) Results of:
— physico-chemical, biological or microbiological tests,
— toxicological and pharmacological tests,— clinical trials.
(j) A summary, in accordance with Article 11, of the product charac-
teristics, one or more specimens or mock-ups of the outerpackaging and the immediate packaging of the medicinal product,together with a package leaflet.
(k) A document showing that the manufacturer is authorised in his own
country to produce medicinal products.
(l) Copies of any authorisation obtained in another Member State or in
a third country to place the medicinal product on the market,together with a list of those Member States in which an applicationfor authorisation submitted in accordance with this Directive is
under examination. Copies of the summary of the product charac-
teristics proposed by the applicant in accordance with Article 11 orapproved by the competent authorities of the Member State inaccordance with Article 21. Copies of the package leaflet proposedin accordance with Article 59 or approved by the competent autho-
rities of the Member State in accordance with Article 61. Details of
any decision to refuse authorization, whether in the Community orin a third country, and the reasons for such a decision.
This information shall be updated on a regular basis.
Article 9
In addition to the requirements set out in Articles 8 and 10(1), an appli-
cation for authorization to market a radionuclide generator shall alsocontain the following information and particulars:
— a general description of the system together with a detailed descrip-
tion of the components of the system which may affect thecomposition or quality of the daughter nucleid preparation,
— qualitative and quantitative particulars of the eluate or the subli-
mate.
Article 10
1. In derogation of Article 8(3)(i), and without prejudice to the law
relating to the protection of industrial and commercial property:
(a) The applicant shall not be required to provide the results of toxico-
logical and pharmacological tests or the results of clinical trials ifhe can demonstrate:
(i) either that the medicinal product is essentially similar to a
medicinal product authorized in the Member State concernedby the application and that the holder of the marketing author-
ization for the original medicinal product has consented to the
toxicological, pharmacological and/or clinical referencescontained in the file on the original medicinal product beingused for the purpose of examining the application in question;
(ii) or that the constituent or constituents of the medicinal product
have a well established medicinal use, with recognized effi-
cacy and an acceptable level of safety, by means of a
detailed scientific bibliography;
(iii) or that the medicinal product is essentially similar to a medic-
inal product which has been authorized within the Community,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 — 01.07.2003 — 002.001 — 13
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to 10 years in the case of high-technology medicinal 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
years by a single Decision covering all the medicinal productsmarketed 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
patent protecting the original medicinal product.
However, where the medicinal product is intended for a
different therapeutic use from that of the other medicinal
products marketed or is to be administered by different routes
or in different doses, the results of appropriate toxicologicaland pharmacological tests and/or of appropriate clinical trialsmust be provided.
(b) In the case of new medicinal products containing known constitu-
ents not hitherto used in combination for therapeutic 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
The summary of the product characteristics shall contain the following
information:
1. Name of the medicinal product.
2. Qualitative and quantitative composition in terms of the active
substances and constituents of the excipient, knowledge of whichis essential for proper administration of the medicinal product.The usual common name or chemical description shall be used.
3. Pharmaceutical form.
4. Pharmacological properties and, in so far as this information is
useful for therapeutic purposes, pharmacokinetic particulars.
5. Clinical particulars:
5.1. therapeutic indications,5.2. contra-indications,5.3. adverse reactions (frequency and seriousness),5.4. special precautions for use and, in the case of immunological
medicinal products, any special precautions to be taken by
persons handling such products and administering them to
patients, together with any precautions to be taken by the patient,
5.5. use during pregnancy and lactation,5.6. interaction with other medicaments and other forms of interac-
tion,
5.7. posology and method of administration for adults and, where
necessary, for children,
5.8. overdose (symptoms, emergency procedures, antidotes),5.9. special warnings,5.10. effects on ability to drive and to use machines.
6. Pharmaceutical particulars:2001L0083 — EN — 01.07.2003 — 002.001 — 14
(1) OJ L 15, 17.1.1987, p. 38. Directive repealed by Directive 93/41/EEC (OJ L
214, 24.8.1993, p. 40).
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6.1. major incompatibilities,
6.2. shelf life, when necessary after reconstitution of the medicinal
product or when the immediate packaging is opened for the firsttime,
6.3. special precautions for storage,
6.4. nature and contents of the immediate packaging,
6.5. special precautions for disposal of unused medicinal products or
waste materials derived from such medicinal products, if appro-priate.
7. Name or corporate name and permanent address of the marketing
authorization holder.
8. For radiopharmaceuticals, full details of internal radiation dosi-
metry.
9. For radiopharmaceuticals, additional detailed instructions for
extemporaneous preparation and quality control of such prepara-tion and, where appropriate, maximum storage time during which
any intermediate preparation such as an eluate or the ready-to-use
pharmaceutical will conform with its specifications.
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 upby exp erts with the necessary tech-nical or professional qualifications before they are submitted to thecompetent authorities. These documents and particulars shall be signed
by the experts.
2. The duties of the experts according to their respective qualifica-
tions shall be:
(a) to perform tasks falling within their respective disciplines (analysis,
pharmacology and similar experimental sciences, clinical trials) andto describe objectively the results obtained (qualitatively and quan-titatively);
(b) to describe their observations in accordance with Annex I, and to
state, in particular:
— in the case of the analyst, whether the medicinal product is
consistent with the declared composition, giving any substantia-
tion of the control methods employed by the manufacturer;
— in the case of the pharmacologist or the specialist with similar
experimental competence, the toxicity of the medicinal product
and the pharmacological properties observed;
— in the case of the clinician, whether he has been able to ascer-
tain effects on persons treated with the medicinal product whichcorrespond 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
any contra-indications and adverse reactions;
(c) where applicable, to state the grounds for using the bibliography
mentioned in point (a)(ii) of Article 10(1).
3. Detailed reports by the experts shall form part of the particulars
accompanying the application which the applicant submits to the
competent authorities.
CHAPTER 2
Specificprovisionsapplicabletohomeopathicmedicinalproducts
Article 13
1. Member States shall ensure that homeopathic medicinal products
manufactured and placed on the market within the Community areregistered or authorized in accordance with Articles 14, 15 and 16,except where the products are covered by a registration or authorization2001L0083 — EN — 01.07.2003 — 002.001 — 15
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which was granted under national law on or before 31 December 1993
(and whether or not that registration or authorization has been renewedafter that date). Each Member State shall take due account of registra-
tions and authorizations previously granted by another Member State.
2. A Member State may refrain from establishing a special, simpli-
fied registration procedure for the homeopathic medicinal products
referred to in Article 14. A Member State shall inform the Commission
accordingly. The Member State concerned shall allow the use in itsterritory of homeopathic medicinal products registered by otherMember States in accordance with Articles 14 and 15.
Article 14
1. Only homeopathic medicinal products which satisfy all of the
following conditions may be subject to a special, simplified registration
procedure:
— they are administered orally or externally,
— no specific therapeutic indication appears on the labelling of the
medicinal product or in any information relating thereto,
— there is a sufficient degree of dilution to guarantee the safety of the
medicinal product; in particular, the medicinal product may notcontain either more than one part per 10000 of the mother tinctureor more than 1/100th of the smallest dose used in allopathy withregard to active substances whose presence in an allopathic medic-inal product results in the obligation to submit a doctor's
prescription.
At the time of registration, Member States shall determine the classifi-
cation for the dispensing of the medicinal product.
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
therapeutic efficacy.
3. The proof of therapeutic efficacy shall not be required for homeo-
pathic medicinal products registered in accordance with paragraph 1 of
this Article, or, where appropriate, admitted in accordance with Article13(2).
Article 15
An application for special, simplified registration may cover a series of
medicinal products derived from the same homeopathic stock or stocks.The following documents shall be included with the application inorder to demonstrate, in particular, the pharmaceutical quality and the
batch-to-batch homogeneity of the products concerned:
— 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 degreeof dilution to be registered,
— dossier describing how the homeopathic stock or stocks is/are
obtained and controlled, and justifying its/their homeopathic nature,on the basis of an adequate bibliography,
— manufacturing and control file for each pharmaceutical form and a
description of the method of dilution and potentization,
— manufacturing authorization for the medicinal product concerned,— copies of any registrations or authorizations obtained for the same
medicinal product in other Member States,
— one or more specimens or mock-ups of the outer packaging and the
immediate packaging of the medicinal products to be registered,
— data concerning the stability of the medicinal product.2001L0083 — EN — 01.07.2003 — 002.001 — 16
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Article 16
1. Homeopathic medicinal products other than those referred to in
Article 14(1) shall be authorized and labelled in accordance with Arti-cles 8, 10 and 11.
2. A Member State may introduce or retain in its territory specific
rules for the toxicological and pharmacological tests and clinical trialsof homeopathic medicinal products other than those referred to inArticle 14(1) in accordance with the principles and characteristics ofhomeopathy as practised in that Member State.
In this case, the Member State concerned shall notify the Commission
of the specific rules in force.
3. Title IX shall apply to homeopathic medicinal products, with the
exception of those referred to in Article 14(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
product on the market is completed within 210 days of the submissionof a valid application.
2. Where a Member State notes that an application for authorization
is already under active examination in another Member State in respectof that medicinal product, the Member State concerned may decide tosuspend the detailed examination of the application in order to awaitthe assessment report prepared by the other Member State in accor-
dance with Article 21(4).
The Member State concerned shall inform the other Member State and
the applicant of its decision to suspend detailed examination of the
application in question. As soon as it has completed the examination
of the application and reached a decision, the other Member State shallforward a copy of its assessment report to the Member State concerned.
Article 18
Where a Member State is informed in accordance with Article 8(3)(l)
that another Member State has authorized a medicinal product which isthe subject of an application for authorization in the Member Stateconcerned, that Member State shall forthwith request the authorities of
the Member State which has granted the authorization to forward to it
the assessment report referred to in Article 21(4).
Within 90 days of the receipt of the assessment report, the Member
State concerned shall either recognize the decision of the first Member
State and the summary of the product characteristics as approved by itor, if it considers that there are grounds for supposing that the author-ization of the medicinal product concerned may present a risk to publichealth, it shall apply the procedures set out in Articles 29 to 34.
Article 19
In order to examine the application submitted in accordance with Arti-
cles 8 and 10(1), the competent authority of the Member State:
1. must verify whether the particulars submitted in support of the
application comply with the said Articles 8 and 10(1) and examine
whether the conditions for issuing an authorization to place medic-
inal products on the market (marketing authorization) are compliedwith.
2. may submit the medicinal product, its starting materials and, if need
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 — 01.07.2003 — 002.001 — 17
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the manufacturer and described in the particulars accompanying the
application in accordance with Article 8(3)(h) are satisfactory.
3. may, where appropriate, require the applicant to supplement the
particulars accompanying the application in respect of the itemslisted in the Articles 8(3) and 10(1). Where the competent authority
avails itself of this option, the time limits laid down in Article 17
shall be suspended until such time as the supplementary informationrequired has been provided. Likewise, these time limits shall besuspended for the time allowed the applicant, where appropriate,for giving oral or written explanation.
Article 20
Member States shall take all appropriate measures to ensure that:
(a) the competent authorities verify that manufacturers and importers
of medicinal products coming from third countries are able to carryout manufacture in compliance with the particulars supplied
pursuant to Article 8(3)(d), and/or to carry out controls according
to the methods described in the particulars accompanying the appli-cation in accordance with Article 8(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/orcertain of the controls referred to in (a) carried out by third parties;in such cases, the verifications by the competent authorities shallalso be made in the establishment designated.
Article 21
1. When the marketing authorization is issued, the holder shall be
informed, by the competent authorities of the Member State concerned,of the summary of the product characteristics as approved by it.
2. The competent authorities shall take all necessary measures to
ensure that the information given in the summary is in conformitywith that accepted when the marketing authorization is issued or subse-quently.
3. The competent authorities shall forward to the Agency a copy of
the authorization together with the summary of the product characteris-
tics.
4. The competent authorities shall draw up an assessment report and
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:
— the carrying out of further studies following the granting of author-
ization,
— the notification of adverse reactions to the medicinal product.
These exceptional decisions may be adopted only for objective and
verifiable reasons and shall be based on one of the causes referred toin►
M2Part II, point 6 ◄of Annex I.
Article 23
After an authorization has been issued, the authorization holder must,
in respect of the methods of manufacture and control provided for inArticle 8(3)(d) and (h), take account of scientific and technical progressand introduce any changes that may be required to enable the medic-2001L0083 — EN — 01.07.2003 — 002.001 — 18
▼B
inal product to be manufactured and checked by means of generally
accepted scientific methods.
These changes shall be subject to the approval of the competent
authority of the Member State concerned.
Article 24
Authorization shall be valid for five years and shall be renewable for
five-year periods, 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 and other information relevant to the monitoring of
the medicinal product.
Article 25
Authorization shall not affect the civil and criminal liability of the
manufacturer and, where applicable, of the marketing authorizationholder.
Article 26
The marketing authorisation shall be refused if, after verification of the
particulars and documents listed in Articles 8 and 10(1), it proves that:
(a) the medicinal product is harmful in the normal conditions of use, or
(b) that its therapeutic efficacy is lacking or is insufficiently substan-
tiated by the applicant, or
(c) that its qualitative and quantitative composition is not as declared.
Authorisation shall likewise be refused if the particulars and documents
submitted in support of the application do not comply with Articles 8
and 10(1).
CHAPTER 4
Mutualrecognitionofauthorizations
Article 27
1. In order to facilitate the adoption of common decisions by
Member States on the authorization of medicinal products on the basis
of the scientific criteria of quality, safety and efficacy, and to achieve
thereby the free movement of medicinal products within the Commu-nity, a Committee for Proprietary Medicinal Products, hereinafterreferred to as ‘the Committee’, is hereby set up. The Committee shallbe part of the Agency.
2. In addition to the other responsibilities conferred upon it by
Community law, the Committee shall examine any question relating
to the granting, variation, suspension or withdrawal of marketingauthorization which is submitted to it in accordance with this Directive.
3. The Committee shall draw upits own Rules of Prodecure.
Article 28
1. Before submitting the application for recognition of a marketing
authorization, the holder of the authorization shall inform the Member
State which granted the authorization on which the application is based
(hereinafter ‘reference Member State’), that an application is to bemade in accordance with this Directive and shall notify it of any addi-tions to the original dossier; that Member State may require theapplicant to provide it with all the particulars and documents necessary
to enable it to check that the dossiers filed are identical.
In addition the holder of the authorization shall request the reference
Member State to prepare an assessment report in respect of the medic-inal product concerned, or, if necessary, to update any existingassessment report. That Member State shall prepare the assessmentreport, or update it, within 90 days of the receipt of the request.2001L0083 — EN — 01.07.2003 — 002.001 — 19
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At the same time as the application is submitted in accordance with
paragraph 2, the reference Member State shall forward the assessmentreport to the Member State or Member States concerned by the appli-
cation.
2. In order to obtain the recognition according to the procedures laid
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 and particulars referred to in Articles 8, 10(1) and 11. 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 ofthe product characteristics proposed by him in accordance with Article11 is identical to that accepted by the reference Member State in accor-dance with Article 21. Moreover, he shall certify that all the dossiers
filed as part of the procedure are identical.
3. The holder of the marketing authorization shall communicate the
application to the Agency, inform it of the Member 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 mayhave been granted by the other Member States in respect of the medic-inal product concerned, and shall indicate whether any application for
authorization is currently under consideration in any Member State.
4. Save in the exceptional case provided for in Article 29(1), each
Member State shall recognize the marketing authorization granted by
the reference Member State within 90 days of receipt of the applicationand the assessment report. It shall inform the reference Member Statewhich granted the initial authorization, the other Member Statesconcerned by the application, the Agency, and the marketing authoriza-tion holder.
Article 29
1. Where a Member State considers that there are grounds for
supposing that the marketing authorization of the medicinal productconcerned may present a risk to public health, it shall forthwith informthe 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 defectin the application.
2. All the Member States concerned shall use their best endeavours
to reach agreement on the action to be taken in respect of the applica-tion. They shall provide the applicant with the opportunity to make hispoint of view known orally or in writing. However, if the MemberStates have not reached agreement within the time limit referred to in
Article 28(4) they shall forthwith refer the matter to the Agency with
regard to the Committee's reference for the application of the procedurelaid down in Article 32.
3. Within the time limit referred to in Article 28(4), the Member
States concerned shall provide the Committee with a detailed statementof the matters on which they have been unable to reach agreement andthe reasons for their disagreement. The applicant shall be provided witha copy of this information.
4. As soon as he is informed that the matter has been referred to the
Committee, the applicant shall forthwith forward to the Committee a
copy of the information and particulars referred to in Article 28(2).
Article 30
If several applications submitted in accordance with Articles 8, 10(1)
and Article 11 have been made for marketing authorization for a parti-cular medicinal product, and Member States have adopted divergentdecisions concerning the authorization of the medicinal product or its2001L0083 — EN — 01.07.2003 — 002.001 — 20
▼B
suspension or withdrawal, a Member State, or the Commission, or the
marketing authorization holder may refer the matter to the Committeefor application of the procedure laid down in Article 32.
The Member State concerned, the marketing authorization holder or the
Commission shall clearly identify the question which is referred to theCommittee for consideration and, where appropriate, shall inform the
holder.
The Member State and the marketing authorization holder shall
forward to the Committee all available information relating to the
matter in question.
Article 31
The Member States or the Commission or the applicant or holder of the
marketing 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
the suspension or withdrawal of an authorization, or on any other varia-
tion to the terms of a marketing authorization which appears necessary,in particular to take account of the information collected in accordancewith Title IX.
The Member State concerned or the Commission shall clearly identify
the question which is referred to the Committee for consideration andshall inform the marketing authorization holder.
The Member States and the marketing authorization holder shall
forward to the Committee all available information relating to thematter in question.
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
was referred to it.
However, in cases submitted to the Committee in accordance with Arti-
cles 30 and 31, this period may be extended by 90 days.
In case of urgency, on a proposal from its Chairman, the Committee
may agree to a shorter deadline.
2. In order to consider the matter, the Committee may appoint one
of its members to act as rapporteur. The Committee may also appointindividual experts to advise it on specific questions. When appointingexperts, the Committee shall define their tasks and specify the time-
limit for the completion of these tasks.
3. In the cases referred to in Articles 29 and 30, before issuing its
opinion, the Committee shall provide the marketing authorization
holder with an opportunity to present written or oral explanations.
In the case referred to in Article 31, the marketing authorization holder
may be asked to explain himself orally or in writing.
If it considers it appropriate, the Committee may invite any other
person to provide information relating to the matter before it.
The Committee may suspend the time limit referred to in paragraph 1
in order to allow the marketing authorization holder to prepare explana-tions.
4. The Agency shall forthwith inform the marketing authorization
holder where the opinion of the Committee is that:
— the application does not satisfy the criteria for authorization, or
— the summary of the product characteristics proposed by the appli-
cant in accordance with Article 11 should be amended, or2001L0083 — EN — 01.07.2003 — 002.001 — 21
▼B
— the authorization should be granted subject to conditions, with
regard to conditions considered essential for the safe and effectiveuse of the medicinal product including pharmacovigilance, or
— a marketing authorization should be suspended, varied or with-
drawn.
Within 15 days of the receipt of the opinion, the marketing authoriza-
tion holder may notify the Agency in writing of his intention to appeal.In that case, he shall forward the detailed grounds for appeal to theAgency within 60 days of receipt of the opinion. Within 60 days ofreceipt of the grounds for appeal, the Committee shall consider whether
its opinion should be revised, and the conclusions reached on the
appeal shall be annexed to the assessment report referred to in para-graph 5.
5. Within 30 days of its adoption, the Agency shall forward the final
opinion of the Committee to the Member States, the Commission and
the marketing authorization holder together with a report describing the
assessment of the medicinal product and stating the reasons for itsconclusions.
In the event of an opinion in favour of granting or maintaining an
authorization to place the medicinal product concerned on the market,the following documents shall be annexed to the opinion.
(a) a draft summary of the product characteristics, as referred to in
Article 11;
(b) any conditions affecting the authorization within the meaning of
paragraph 4.
Article 33
Within 30 days of the receipt of the opinion, the Commission shall
prepare a draft of the decision to be taken in respect of the application,taking into account Community law.
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) shall be annexed.
Where, exceptionally, the draft decision is not in accordance with the
opinion of the Agency, the Commission shall also annex a detailedexplanation of the reasons for the differences.
The draft decision shall be forwarded to the Member States and the
applicant.
Article 34
1. A final decision on the application shall be adopted in accordance
with the procedure referred to in Article 121(2).
2. The rules of procedure of the Standing Committee established by
Article 121(1) shall be adjusted to take account of the tasks incumbentupon it in accordance with this Chapter.
These adjustments shall involve the following:
— except in cases referred to in the third paragraph of Article 33, the
opinion of the Standing Committee shall be obtained in writing,
— each Member State is allowed at least 28 days to forward written
observations on the draft decision to the Commission,
— each Member State is able to require in writing that the draft deci-
sion be discussed by the Standing Committee, giving its reasons in
detail.
Where, in the opinion of the Commission, the written observations of a
Member State raise important new questions of a scientific or technicalnature which have not been addressed in the opinion of the Agency, theChairman shall suspend the procedure and refer the application back tothe Agency for further consideration.2001L0083 — EN — 01.07.2003 — 002.001 — 22
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The provisions necessary for the implementation of this paragraph shall
be adopted by the Commission in accordance with the procedurereferred to in Article 121(2).
3. A decision as referred to in paragraph 1 shall be addressed to the
Member States concerned by the matter and reported to the marketingauthorization holder. The Member States shall either grant or withdrawmarketing authorization, or vary the terms of a marketing authorization
as necessary to comply with the decision within 30 days of its notifica-
tion. They shall inform the Commission and the Agency thereof.
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-
priate arrangements for the examination of variations to the terms of a
marketing authorization.
These arrangements shall include a notification system or administra-
tion procedures concerning minor variations and define precisely the
concept of ‘a minor variation’.
These arrangements shall be adopted by the Commission in the form of
an implementing Regulation in accordance with the procedure referredto in Article 121(2).
2. In case of arbitration submitted to the Commission, the procedure
laid down in Articles 32, 33 and 34 shall apply by analogy to variationsmade to marketing authorizations.
Article 36
1. Where a Member State considers that the variation of a marketing
authorization which has been granted in accordance with the provisionsof this Chapter or its suspension or withdrawal is necessary for theprotection of public health, the Member State concerned shall forthwithrefer the matter to the Agency for the application of the procedures laid
down in Articles 32, 33 and 34.
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
marketing and the use of the medicinal product concerned on its terri-
tory. It shall inform the Commission and the other Member States nolater than the following working day of the reasons for its action.
Article 37
Articles 35 and 36 shall apply by analogy to medicinal products author-
ized by Member States following an opinion of the Committee given in
accordance with Article 4 of Directive 87/22/EEC before 1 January1995.
Article 38
1. The Agency shall publish an annual report on the operation of the
procedures laid down in this Chapter and shall forward that report tothe European Parliament and the Council for information.
2. By 1 January 2001, the Commission shall publish a detailed
review of the operation of the procedures laid down in this Chapter
and shall propose any amendments which may be necessary to improvethese procedures.
The Council shall decide, under the conditions provided for in the
Treaty, on the Commission proposal within one year of its submission.2001L0083 — EN — 01.07.2003 — 002.001 — 23
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Article 39
The provisions referred to in Articles 27 to 34 shall not apply to the
homeopathic medicinal products referred to in Article 16(2).
TITLE IV
MANUFACTUREANDIMPORTATION
Article 40
1. Member States shall take all appropriate measures to ensure that
the manufacture of the medicinal products within their territory issubject to the holding of an authorization. This manufacturing authori-zation shall be required nothwithstanding that the medicinal products
manufactured are intended for export.
2. The authorization referred to in paragraph 1 shall be required for
both total and partial manufacture, and for the various processes of
dividing up, packaging or presentation.
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 indispensing pharmacies or by persons legally authorized in the MemberStates to carry out such processes.
3. Authorization referred to in paragraph 1 shall also be required for
imports coming from third countries into a Member State; this Titleand Article 118 shall have corresponding application to such imports
as they have to manufacture.
Article 41
In order to obtain the manufacturing authorization, the applicant shall
meet at least the following requirements:
(a) specify the medicinal products and pharmaceutical forms which are
to be manufactured or imported and also the place where they are
to be manufactured and/or controlled;
(b) have at his disposal, for the manufacture or import of the above,
suitable and sufficient premises, technical equipment and controlfacilities complying with the legal requirements which the MemberState concerned lays down as regards both manufacture and control
and the storage of medicinal products, in accordance with Article
20;
(c) have at his disposal the services of at least one qualified person
within the meaning of Article 48.
The 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-racy of the particulars supplied pursuant to Article 41, by means of aninquiry carried out by its agents.
2. In order to ensure that the requirements referred to in Article 41
are complied with, authorization may be made conditional on thecarrying out of certain obligations imposed either when authorization
is granted or at a later date.
3. The authorization shall apply only to the premises specified in the
application and to the medicinal products and pharmaceutical forms
specified in that same application.
Article 43
The Member States shall take all appropriate measures to ensure that
the time taken for the procedure for granting the manufacturing author-2001L0083 — EN — 01.07.2003 — 002.001 — 24
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ization does not exceed 90 days from the day on which the competent
authority receives the application.
Article 44
If the holder of the manufacturing authorization requests a change in
any of the particulars referred to in points (a) and (b) of the first para-graph of Article 41, the time taken for the procedure relating to thisrequest shall not exceed 30 days. In exceptional cases this period of
time may be extended to 90 days.
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
The holder of a manufacturing authorization shall at least be obliged:
(a) to have at his disposal the services of staff who comply with the
legal requirements existing in the Member State concerned both asregards manufacture and controls;
(b) to dispose of the authorized medicinal products only in accordance
with the legislation of the Member States concerned;
(c) to give prior notice to the competent authority of any changes he
may wish to make to any of the particulars supplied pursuant toArticle 41; the competent authority shall, in any event, be immedi-ately informed if the qualified person referred to in Article 48 is
replaced unexpectedly;
(d) to allow the agents of the competent authority of the Member State
concerned access to his premises at any time;
(e) to enable the qualified person referred to in Article 48 to carry out
his duties, for example by placing at his disposal all the necessary
facilities;
(f) to comply with the principles and guidelines of good manufac-
turing practice for medicinal products as laid down by Community
law.
Article 47
The principles and guidelines of good manufacturing practices for
medicinal products referred to in Article 46(f) shall be adopted in theform of a directive, in accordance with the procedure referred to in
Article 121(2).
Detailed guidelines in line with those principles will be published by
the Commission and revised necessary to take account of technicaland scientific progress.
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,
responsible in particular for carrying out the duties specified in Article
51.
2. If he personally fulfils the conditions laid down in Article 49, the
holder of the authorization may himself assume the responsibilityreferred to in paragraph 1.2001L0083 — EN — 01.07.2003 — 002.001 — 25
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Article 49
1. Member States shall ensure that the qualified person referred to in
Article 48 fulfils the minimum conditions of qualification set out inparagraphs 2 and 3.
2. A qualified person shall be in possession of a diploma, certificate
or other evidence of formal qualifications awarded on completion of a
university course of study, or a course recognized as equivalent by theMember State concerned, extending over a period of at least four yearsof theoretical and practical study in one of the following scientificdisciplines: pharmacy, medicine, veterinary medicine, chemistry, phar-maceutical chemistry and technology, biology.
However, the minimum duration of the university course may be three
and a half years where the course is followed by a period of theoretical
and practical training of a minimum duration of one year and includinga training period of at least six months in a pharmacy open to thepublic, corroborated by an examination at university level.
Where two university courses or two courses recognized by the State as
equivalent co-exist in a Member State and where one of these extendsover four years and the other over three years, the three-year course
leading to a diploma, certificate or other evidence of formal qualifica-
tions awarded on completion of a university course or its recognizedequivalent shall be considered to fulfil the condition of durationreferred to in the second subparagraph in so far as the diplomas, certi-ficates or other evidence of formal qualifications awarded on
completion of both courses are recognized as equivalent by the State
in question.
The course shall include theoretical and practical study bearing upon at
least the following basic subjects:
— Applied physics
— General and inorganic chemistry— Organic chemistry
— Analytical chemistry
— Pharmaceutical chemistry, including analysis of medicinal products— General and applied biochemistry (medical)— Physiology
— Microbiology
— Pharmacology— Pharmaceutical technology— Toxicology
— Pharmacognosy (study of the composition and effects of the natural
active substances of plant and animal origin).
Studies in these subjects should be so balanced as to enable the person
concerned to fulfil the obligations specified in Article 51.
In so far as certain diplomas, certificates or other evidence of formal
qualifications mentioned in the first subparagraph do not fulfil thecriteria laid down in this paragraph, the competent authority of theMember State shall ensure that the person concerned provides evidenceof adequate knowledge of the subjects involved.
3. The qualified person shall have acquired practical experience over
at least two years, in one or more undertakings which are authorized to
manufacture medicinal products, in the activities of qualitative analysis
of medicinal products, of quantitative analysis of active substances andof the testing and checking necessary to ensure the quality of medicinalproducts.
The duration of practical experience may be reduced by one year
where a university course lasts for at least five years and by a yearand a half where the course lasts for at least six years.2001L0083 — EN — 01.07.2003 — 002.001 — 26
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Article 50
1. A person engaging in the activities of the person referred to in
Article 48 from the time of the application of Directive 75/319/EEC,
in a Member State without complying with the provisions of Article
49 shall be eligible to continue to engage in those activities in the Stateconcerned.
2. The holder of a diploma, certificate or other evidence of formal
qualifications awarded on completion of a university course — or a
course recognized as equivalent by the Member State concerned — in
a scientific discipline allowing him to engage in the activities of 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
May 1985 following notification of this directive in one or more under-takings authorized to manufacture: production supervision and/orqualitative and quantitative analysis of active substances, and thenecessary testing and checking under the direct authority of the person
referred to in Article 48 to ensure the quality of the medicinal products.
If the person concerned has acquired the practical experience referred
to in the first subparagraph before 21 May 1965, a further one year'spractical experience in accordance with the conditions referred to inthe first subparagraph will be required to be completed immediatelybefore he engages in such activities.
Article 51
1. Member States shall take all appropriate measures to ensure that
the qualified person referred to in Article 48, without prejudice to hisrelationshipwith the holder of the manufacturing authorization, isresponsible, in the context of the procedures referred to in Article 52,for securing:
(a) in the case of medicinal products manufactured within the Member
States concerned, that each batch of medicinal products has beenmanufactured and checked in compliance with the laws in force inthat Member State and in accordance with the requirements of themarketing authorization;
(b) in the case of medicinal products coming from third countries, 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
with the requirements of the marketing authorization.
The batches of medicinal products which have undergone such controls
in a Member State shall be exempt from the controls if they aremarketed in another Member State, accompanied by the control reportssigned by the qualified person.
2. In the case of medicinal products imported from a third country,
where appropriate arrangements have been made by the Communitywith the exporting country to ensure that the manufacturer of themedicinal product applies standards of good manufacturing 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 outthose controls.
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
batch satisfies the provisions of this Article; the said register or equiva-lent document must be kept up to date as operations are carried out andmust remain at the disposal of the agents of the competent authority forthe period specified in the provisions of the Member State concernedand in any event for at least five years.2001L0083 — EN — 01.07.2003 — 002.001 — 27
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Article 52
Member States shall ensure that the duties of qualified persons referred
to in Article 48 are fulfilled, either by means of appropriate administra-tive measures or by making such persons subject to a professional codeof conduct.
Member States may provide for the temporary suspension of such a
person upon the commencement of administrative or disciplinaryprocedures against him for failure to fulfil his obligations.
Article 53
The provisions of this Title shall also apply to homeopathic medicinal
products.
TITLE V
LABELLINGANDPACKAGELEAFLET
Article 54
The following particulars shall appear on the outer packaging of medic-
inal products or, where there is no outer packaging, on the immediatepackaging:
(a) the name of the medicinal product followed by the common name
where the product contains only one active substance and if itsname is an invented name; where a medicinal product is availablein several pharmaceutical forms and/or several strengths, the phar-
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
quantitatively per dosage unit or according to the form of adminis-tration for a given volume or weight, using their common names;
(c) the pharmaceutical form and the contents by weight, by volume or
by number of doses of the product;
(d) a list of those excipients known to have a recognized action or
effect and included in the guidelines published pursuant to Article
65. However, if the product is injectable, or a topical or eyepreparation, all excipients must be stated;
(e) the method and, if necessary, the route of administration;
(f) a special warning that the medicinal product must be stored out of
reach of children;
(g) a special warning, if this is necessary for the medicinal product;(h) the expiry date in clear terms (month/year);
(i) special storage precautions, if any;(j) special precautions for disposal of unused medicinal products or
waste materials from medicinal products, if appropriate;
(k) the name and address of the holder of the authorization for placing
the medicinal product on the market;
(l) the number of the authorization for placing the medicinal product
on the market;
(m) the manufacturer's batch number;
(n) in the case of self-medication, instructions on the use of the
medicinal products.
Article 55
1. The particulars laid down in Articles 54 and 62 shall appear on
immediate packagings other than those referred to in paragraphs 2 and
3.
2. The following particulars at least shall appear on immediate
packagings which take the form of blister packs and are placed in an2001L0083 — EN — 01.07.2003 — 002.001 — 28
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outer packaging that complies with the requirements laid down in Arti-
cles 54 and 62.
— the name of the medicinal product as laid down in Article 54(a),
— the name of the holder of the authorization for placing the product
on the market,
— the expiry date,
— the batch number.
3. The following particulars at least shall appear on small immediate
packaging units on which the particulars laid down in Articles 54 and62 cannot be displayed:
— the name of the medicinal product and, if necessary, the strength
and the route of administration,
— the method of administration,
— the expiry date,
— the batch number,— the contents by weight, by volume or by unit.
Article 56
The particulars referred to in Articles 54, 55 and 62 shall be easily
legible, clearly comprehensible and indelible.
Article 57
Notwithstanding Article 60, Member States may require the use of
certain forms of labelling of the medicinal product making it possible
to ascertain:
— the price of the medicinal product,
— the reimbursement conditions of social security organizations,— the legal status for supply to the patient, in accordance with Title
VI,
— identification and authenticity.
Article 58
The inclusion in the packaging of all medicinal products of a package
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
immediate packaging.
Article 59
1. The package leaflet shall be drawn up in accordance with the
summary of the product characteristics; it shall include, in the
following order:
(a) for the identification of the medicinal product:
— the name of the medicinal product, followed by the common
name if the product contains only one active substance and 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 ofthe medicinal product,
— a full statement of the active substances and excipients
expressed qualitatively and a statement of the active substancesexpressed quantitatively, using their common names, in the caseof each presentation of the medicinal product,
— the pharmaceutical form and the contents by weight, by volume
or by number of doses of the product, in the case of each
presentation of the product,
— the pharmaco-therapeutic group, or type of activity in terms
easily comprehensible for the patient,2001L0083 — EN — 01.07.2003 — 002.001 — 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) the therapeutic indications;
(c) list of information which is necessary before taking the medicinal
product:
— contra-indications,
— appropriate precautions for use,— forms of interaction with other medicinal products and other
forms of interaction
(e.g. alcohol, tobacco, foodstuffs) which may affect the action
of the medicinal product,
— special warnings;
this list must:
— take into account the particular condition of certain categories
of users (e.g. children, pregnant or breastfeeding women, the
elderly, persons with specific pathological conditions),
— mention, if appropriate, potential effects on the ability to drive
vehicles or to operate machinery,
— detail those excipients, knowledge of which is important for the
safe and effective use of the medicinal product and included inthe guidelines published pursuant to Article 65;
(d) the necessary and usual instructions for proper use, in particular:
— the dosage,
— the method and, if necessary, route of administration,— the frequency of administration, specifying if necessary, the
appropriate time at which the medicinal product may or must
be administered,
and, as appropriate, depending on the nature of the product:
— the duration of treatment, where it should be limited,
— the action to be taken in the case of an overdose (e.g., symp-
toms, emergency procedures),
— the course of action to take when one or more doses have not
been taken,
— indication, if necessary, of the risk of withdrawal effects;
(e) a description of the undesirable effects which can occur under
normal use of the medicinal product and, if necessary, the action
to be taken in such a case; the patient should be expressly invited
to communicate any undesirable effect which is not mentioned inthe leaflet to his doctor or to his pharmacist;
(f) a reference to the expiry date indicated on the label, with:
— a warning against using the product after this date,
— where appropriate, special storage precautions,— if necessary, a warning against certain visible signs of deteriora-
tion;
(g) the date on which the package leaflet was last revised.
2. Notwithstanding paragraph 1(b), the authority competent may
decide that certain therapeutic indications shall not be mentioned inthe package leaflet, where the dissemination of such information might
have serious disadvantages for the patient.
Article 60
Member States may not prohibit or impede the placing on the market
of medicinal products within their territory on grounds connected withlabelling or the package leaflet where these comply with the require-ments of this Title.2001L0083 — EN — 01.07.2003 — 002.001 — 30
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Article 61
1. One or more specimens or mock-ups of the 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
if the labelling or the package leaflet do not comply with the provisions
of this Title or if they are not in accordance with the particulars listedin the summary of product characteristics.
3. All proposed changes to an aspect of the labelling or the package
leaflet covered by this Title and not connected with the summary 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
of the request, the applicant may put the change into effect.
4. The fact that the competent authority do not refuse a marketing
authorization pursuant to paragraph 2 or a change to the labelling or
the package leaflet pursuant to paragraph 3 does not alter the generallegal liability of the manufacturer or as appropriate the marketingauthorization holder.
Article 62
The outer packaging and the package leaflet may include symbols or
pictograms designed to clarify certain information mentioned in Arti-
cles 54 and 59(1) and other information compatible with the summaryof the product characteristics which is useful for health education, tothe exclusion of any element of a promotional nature.
Article 63
1. The particulars for labelling listed in Articles 54, 59 and 62 shall
appear in the official language or languages of the Member State wherethe product is placed on the market.
The first subparagraph shall not prevent these particulars from being
indicated in several languages, provided that the same particularsappear in all the languages used.
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 is placedon the market.
The first subparagraph shall not prevent the package leaflet being
printed in several languages, provided that the same information isgiven in all the languages used.
3. The competent authorities may exempt labels and package leaflets
for specific medicinal products from the obligation that certain particu-
lars shall appear and that the leaflet must be in the official language or
languages of the Member State where the product is placed on themarket, when the product is not intended to be delivered to the patientfor self-administration.
Article 64
Where the provisions of this Title are not complied with, and a notice
served on the person concerned has remained without effect, thecompetent authorities of the Member States may suspend the marketingauthorization, until the labelling and the package leaflet of the medic-inal product in question have been made to comply with therequirements of this Title.2001L0083 — EN — 01.07.2003 — 002.001 — 31
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Article 65
As necessary, the Commission shall publish guidelines concerning in
particular:
— the formulation of certain special warnings for certain categories of
medicinal products,
— the particular information needs relating to self-medication,— the legibility of particulars on the labelling and package leaflet,
— methods for the identification and authentication of medicinal
products,
— the list of excipients which must feature on the labelling of medic-
inal products and the way these excipients must be indicated.
These guidelines shall be adopted in the form of a Directive, in accor-
dance with the procedure referred to in Article 121(2).
Article 66
1. The outer carton and the container of medicinal products
containing radionuclides shall be labelled in accordance with the regu-lations for the safe transport of radioactive materials laid down by theInternational Atomic Energy Agency. Moreover, the labelling shallcomply with the provisions set out in paragraphs 2 and 3.
2. The label on the shielding shall include the particulars mentioned
in Article 54. In addition, the labelling on the shielding shall explain infull, the codings used on the vial and shall indicate, where necessary,
for a given time and date, the amount of radioactivity per dose or per
vial and the number of capsules, or, for liquids, the number of millili-tres in the container.
3. The vial shall be labelled with the following information:
— the name or code of the medicinal product, including the name or
chemical symbol of the radionuclide,
— the batch identification and expiry date,
— the international symbol for radioactivity,
— the name of the manufacturer,
— the amount of radioactivity as specified in paragraph 2.
Article 67
The competent authority shall ensure that a detailed instruction leaflet
is enclosed with 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
taken by the user and the patient during the preparation and administra-tion of the medicinal product and special precautions for the disposalof the packaging and its unused contents.
Article 68
Without prejudice to the provisions of Article 69, homeopathic medic-
inal products shall be labelled in accordance with the provisions of thistitle and shall be identified by a reference on their labels, in clear andlegible form, to their homeopathic nature.
Article 69
1. In addition to the clear mention of the words ‘homeopathic
medicinal product’, the labelling and, where appropriate, the packageinsert for the medicinal products referred to in Article 14(1) shall bearthe following, and no other, information:
— the scientific name of the stock or stocks followed by the degree of
dilution, making use of the symbols of the pharmacopoeia used in
accordance with Article 1(5),
— name and address of the registration holder and, where appropriate,
of the manufacturer,2001L0083 — EN — 01.07.2003 — 002.001 — 32
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— method of administration and, if necessary, route,
— expiry date, in clear terms (month, year),— pharmaceutical form,— contents of the sales presentation,
— special storage precautions, if any,
— a special warning if necessary for the medicinal product,— manufacturer's batch number,— registration number,— ‘homeopathic medicinal product without approved therapeutic indi-
cations’,
— a warning advising the user to consult a doctor if the symptoms
persist during the use of the medicinal product.
2. Notwithstanding paragraph 1, Member States may require the use
of certain types of labelling in order to show:
— the price of the medicinal product,
— the conditions for refunds by social security bodies.
TITLE VI
CLASSIFICATIONOFMEDICINALPRODUCTS
Article 70
1. When a marketing authorization is granted, the competent autho-
rities shall specify the classification of the medicinal product into:
— a medicinal product subject to medical prescription,
— a medicinal product not subject to medical prescription.
To this end, the criteria laid down in Article 71(1) shall apply.2. The competent authorities may fix sub-categories for medicinal
products which are available on medical prescription only. In that
case, they shall refer to the following classification:
(a) medicinal products on renewable or non-renewable medical
prescription;
(b) medicinal products subject to special medical prescription;
(c) medicinal products on restricted medical prescription, reserved for
use in certain specialized areas.
Article 71
1. Medicinal products shall be subject to medical prescription where
they:
— are likely to present a danger either directly or indirectly, even
when used correctly, if utilized without medical supervision, or
— are frequently and to a very wide extent used incorrectly, and as a
result are likely to present a direct or indirect danger to humanhealth, or
— contain substances or preparations thereof, the activity and/or
adverse reactions of which require further investigation, or
— are normally prescribed by a doctor to be administered parenterally.
2. Where Member States provide for the sub-category of medicinal
products subject to special medical prescription, they shall take accountof the following factors:
— the medicinal product contains, in a non-exempt quantity, a
substance classified as a narcotic or a psychotropic substance withinthe meaning of the international conventions in force, such as theUnited Nations Conventions of 1961 and 1971, or
— the medicinal product is likely, if incorrectly used, to present a
substantial risk of medicinal abuse, to lead to addiction or bemisused for illegal purposes, or2001L0083 — EN — 01.07.2003 — 002.001 — 33
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— the medicinal product contains a substance which, by reason of its
novelty or properties, could be considered as belonging to the groupenvisaged in the second indent as a precautionary measure.
3. Where Member States provide for the sub-category of medicinal
products subject to restricted prescription, they shall take account of
the following factors:
— the medicinal product, because of its pharmaceutical characteristics
or novelty or in the interests of public health, is reserved for treat-ments which can only be followed in a hospital environment,
— the medicinal product is used in the treatment of conditions which
must be diagnosed in a hospital environment or in institutions with
adequate diagnostic facilities, although administration and follow-
upmay be carried out elsewhere, 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
throughout the treatment.
4. A competent authority may waive application of paragraphs 1, 2
and 3 having regard to:
(a) the maximum single dose, the maximum daily dose, the strength,
the pharmaceutical form, certain types of packaging; and/or
(b) other circumstances of use which it has specified.
5. If a competent authority does not designate medicinal products
into sub-categories referred to in Article 70(2), it shall nevertheless
take into account the criteria referred to in paragraphs 2 and 3 of this
Article in determining whether any medicinal product shall be classi-fied as a prescription-only medicine.
Article 72
Medicinal products not subject to prescription shall be those which do
not meet the criteria listed in Article 71.
Article 73
The competent authorities shall draw up a list of the medicinal
products subject, on their territory, to medical prescription, specifying,
if necessary, the category of classification. They shall update this list
annually.
Article 74
On the occasion of the five-yearly renewal of the marketing authoriza-
tion or when new facts are brought to their notice, the competentauthorities shall examine and, as appropriate, amend the classification
of a medicinal product, by applying the criteria listed in Article 71.
Article 75
Each year, Member States shall communicate to the Commission and
to the other Member States, the changes that have been made to thelist referred to in Article 73.
TITLE VII
WHOLESALEDISTRIBUTIONOFMEDICINALPRODUCTS
Article 76
Without prejudice to Article 6, Member States shall take all appropriate
action to ensure that only medicinal products in respect of which amarketing authorization has been granted in accordance with Commu-nity law are distributed on their territory.2001L0083 — EN — 01.07.2003 — 002.001 — 34
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Article 77
1. Member States shall take all appropriate measures to ensure that
the wholesale distribution of medicinal products is subject to thepossession of an authorization to engage in activity as a wholesaler inmedicinal products, stating the place for which it is valid.
2. Where persons authorized or entitled to supply medicinal
products to the public may also, under national law, engage in whole-
sale business, such persons shall be subject to the authorization
provided for in paragraph 1.
3. Possession of a manufacturing authorization shall include author-
ization to distribute by wholesale the medicinal products covered bythat authorization. Possession of an authorization to engage in activityas a wholesaler in medicinal products shall not give dispensation fromthe obligation to possess a manufacturing authorization and to complywith the conditions set out in that respect, even where the manufac-
turing or import business is secondary.
4. At the request of the Commission or any Member State, Member
States shall supply all appropriate information concerning the indivi-
dual authorizations which they have granted under paragraph 1.
5. Checks on the persons authorized to engage in the activity of
wholesaler in medicinal products and the inspection of their premises,shall be carried out under the responsibility of the Member State whichgranted the authorization.
6. The Member State which granted the authorization referred to in
paragraph 1 shall suspend or revoke that authorization if the conditionsof authorization cease to be met. It shall forthwith inform the otherMember States and the Commission thereof.
7. Should a Member State consider that, in respect of a person
holding an authorization granted by another Member State under the
terms of paragraph 1, the conditions of authorization are not, or are
no longer met, it shall forthwith inform the Commission and the otherMember State involved. The latter shall take the measures necessaryand shall inform the Commission and the first Member State of thedecisions taken and the reasons for those decisions.
Article 78
Member States shall ensure that the time taken for the procedure for
examining the application for the distribution authorization does notexceed 90 days from the day on which the competent authority of theMember State concerned receives the application.
The competent authority may, if need be, require the applicant to
supply all necessary information concerning the conditions of authori-zation. Where the authority exercises this option, the period laid down
in the first paragraph shall be suspended until the requisite additional
data have been supplied.
Article 79
In order to obtain the distribution authorization, applicants must fulfil
the following minimum requirements:
(a) they must have suitable and adequate premises, installations and
equipment, so as to ensure proper conservation and distribution of
the medicinal products;
(b) they must have staff, and in particular, a qualified person desig-
nated as responsible, meeting the conditions provided for by thelegislation of the Member State concerned;
(c) they must undertake to fulfil the obligations incumbent on them
under the terms of Article 80.2001L0083 — EN — 01.07.2003 — 002.001 — 35
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Article 80
Holders of the distribution authorization must fulfil the following
minimum requirements:
(a) they must make the premises, installations and equipment referred
to in Article 79(a) accessible at all times to the persons responsiblefor inspecting them;
(b) they must obtain their supplies of medicinal products only from
persons who are themselves in possession of the distribution
authorization or who are exempt from obtaining such authorizationunder the terms of Article 77(3);
(c) they must supply medicinal products only to persons who are them-
selves in possession of the distribution authorization or who areauthorized or entitled to supply medicinal products to the publicin the Member State concerned;
(d) they must have an emergency plan which ensures effective imple-
mentation of any recall from the market ordered by the competentauthorities or carried out in cooperation with the manufacturer ormarketing authorization holder for the medicinal productconcerned;
(e) they must keeprecords either in the form of p urchase/sales
invoices, or on computer, or in any other form, giving for anytransaction in medicinal products received or dispatched at leastthe following information:
— date,
— name of the medicinal product,— quantity received or supplied,— name and address of the supplier or consignee, as appropriate;
(f) they must keepthe records referred to under (e) available to the
competent authorities, for inspection purposes, for a period of fiveyears;
(g) they must comply with the principles and guidelines of good distri-
bution practice for medicinal products as laid down in Article 84.
Article 81
With regard to the supply of medicinal products to pharmacists and
persons authorized or entitled to supply medicinal products to the
public, Member States shall not impose upon the holder of a distribu-
tion authorization which has been granted by another Member State,any obligation, in particular public service obligations, more stringentthan those they impose on persons whom they have themselves author-ized to engage in equivalent activities.
The said obligations should, moreover, be justified, in keeping with the
Treaty, on grounds of public health protection and be proportionate in
relation to the objective of such protection.
Article 82
For all supplies of medicinal products to a person authorized or entitled
to supply medicinal products to the public in the Member Stateconcerned, the authorized wholesaler must enclose a document thatmakes it possible to ascertain:
— the date,
— the name and pharmaceutical form of the medicinal product,— the quantity supplied,— the name and address of the supplier and consignor.
Member States shall take all appropriate measures to ensure that
persons authorized or entitled to supply medicinal products to thepublic are able to provide information that makes it possible to tracethe distribution path of every medicinal product.2001L0083 — EN — 01.07.2003 — 002.001 — 36
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Article 83
The provisions of this Title shall not prevent the application of more
stringent requirements laid down by Member States in respect of thewholesale distribution of:
— narcotic or psychotropic substances within their territory,
— medicinal products derived from blood,— immunological medicinal products,— radiopharmaceuticals.
Article 84
The Commission shall publish guidelines on good distribution practice.
To this end, it shall consult the Committee for Proprietary MedicinalProducts and the Pharmaceutical Committee established by CouncilDecision 75/320/EEC (
1).
Article 85
The provisions of this Title shall apply to homeopathic medicinal
products, with the exception of those referred to in Article 14(1).
TITLE VIII
ADVERTISING
Article 86
1. For the purposes of this Title, ‘advertising of medicinal products’
shall include any form of door-to-door information, canvassing activity
or inducement designed to promote the prescription, supply, sale or
consumption of medicinal products; it shall include in particular:
— the advertising of medicinal products to the general public,
— advertising of medicinal products to persons qualified to prescribe
or supply them,
— visits by medical sales representatives to persons qualified to
prescribe medicinal products,
— the supply of samples,
— the provision of inducements to prescribe or supply medicinal
products by the gift, offer or promise of any benefit or bonus,whether in money or in kind, except when their intrinsic value isminimal,
— sponsorship of promotional meetings attended by persons qualified
to prescribe or supply medicinal products,
— sponsorship of scientific congresses attended by persons qualified to
prescribe or supply medicinal products and in particular payment oftheir travelling and accommodation expenses in connection there-with.
2. The following are not covered by this Title:
— the labelling and the accompanying package leaflets, which are
subject to the provisions of Title V,
— correspondence, possibly accompanied by material of a non-promo-
tional nature, needed to answer a specific question about aparticular medicinal product,
— factual, informative announcements and reference material relating,
for example, to pack changes, adverse-reaction warnings as part ofgeneral drug precautions, trade catalogues and price lists, providedthey include no product claims,
— statements relating to human health or diseases, provided there is
no reference, even indirect, to medicinal products.2001L0083 — EN — 01.07.2003 — 002.001 — 37
(1) OJ L 187, 9.6.1975, p. 23.
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Article 87
1. Member States shall prohibit any advertising of a medicinal
product in respect of which a marketing authorization has not beengranted in accordance with Community law.
2. All parts of the advertising of a medicinal product must comply
with the particulars listed in the summary of product characteristics.
3. The advertising of a medicinal product:
— shall encourage the rational use of the medicinal product, by
presenting it objectively and without exaggerating its properties,
— shall not be misleading.
Article 88
1. Member States shall prohibit the advertising to the general public
of medicinal products which:
— are available on medical prescription only, in accordance with Title
VI,
— contain psychotropic or narcotic substances, such as the United
Nations Conventions of 1961 and 1971,
— may not be advertised to the general public in accordance with the
second subparagraph of paragraph 2.
2. Medicinal products may be advertised to the general public
which, by virtue of their composition and purpose, are intended anddesigned for use without the intervention of a medical practitioner for
diagnostic purposes or for the prescription or monitoring of treatment,
with the advice of the pharmacist, if necessary.
Member States shall prohibit the mentioning in advertising to the
general public of therapeutic indications such as:
— tuberculosis,
— sexually transmitted diseases,
— other serious infectious diseases,
— cancer and other tumoral diseases,
— chronic insomnia,— diabetes and other metabolic illnesses.
3. Member States shall be able to ban, on their territory, 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
the competent authorities of the Member States.
5. The prohibition referred to in paragraph 1 shall apply without
prejudice to Article 14 of Directive 89/552/EEC.
6. Member States shall prohibit the direct distribution of medicinal
products to the public by the industry for promotional purposes; theymay, however, authorize such distribution in special cases for otherpurposes.
Article 89
1. Without prejudice to Article 88, all advertising to the general
public of a medicinal product shall:
(a) be set out in such a way that it is clear that the message is an
advertisement and that the product is clearly identified as a medic-
inal product;
(b) include the following minimum information:
— the name of the medicinal product, as well as the common
name if the medicinal product contains only one activesubstance,2001L0083 — EN — 01.07.2003 — 002.001 — 38
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— 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
may be.
2. Member States may decide that the advertising of a medicinal
product to the general public may, notwithstanding paragraph 1,include only the name of the medicinal product if it is intended solelyas a reminder.
Article 90
The advertising of a medicinal product to the general public shall not
contain any material which:
(a) gives the impression that a medical consultation or surgical opera-
tion is unnecessary, in particular by offering a diagnosis or bysuggesting treatment by mail;
(b) suggests that the effects of taking the medicine are guaranteed, are
unaccompanied by adverse reactions or are better than, or equiva-lent to, those of another treatment or medicinal product;
(c) suggests that the health of the subject can be enhanced by taking
the medicine;
(d) suggests that the health of the subject could be affected by not
taking the medicine; this prohibition shall not apply to the vaccina-tion campaigns referred to in Article 88(4);
(e) is directed exclusively or principally at children;
(f) refers to a recommendation by scientists, health professionals or
persons who are neither of the foregoing but who, because of their
celebrity, could encourage the consumption of medicinal products;
(g) suggests that the medicinal product is a foodstuff, cosmetic or other
consumer product;
(h) suggests that the safety or efficacy of the medicinal product is due
to the fact that it is natural;
(i) could, by a description or detailed representation of a case history,
lead to erroneous self-diagnosis;
(j) refers, in improper, alarming or misleading terms, to claims of
recovery;
(k) uses, in improper, alarming or misleading terms, pictorial represen-
tations of changes in the human body caused by disease or injury,or of the action of a medicinal product on the human body or partsthereof;
(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
prescribe or supply such products shall include:
— essential information compatible with the summary of product char-
acteristics;
— the supply classification of the medicinal product.
Member States may also require such advertising to include the selling
price or indicative price of the various presentations and the conditions
for reimbursement by social security bodies.
2. Member States may decide that the advertising of a medicinal
product to persons qualified to prescribe or supply such products may,notwithstanding paragraph 1, include only the name of the medicinalproduct, if it is intended solely as a reminder.2001L0083 — EN — 01.07.2003 — 002.001 — 39
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Article 92
1. Any documentation relating to a medicinal product which is
transmitted as part of the promotion of that product to persons qualifiedto prescribe or supply it shall include, as a minimum, the particularslisted in Article 91(1) and shall state the date on which it was drawnupor last revised.
2. All the information contained in the documentation referred to in
paragraph 1 shall be accurate, up-to-date, verifiable and sufficientlycomplete to enable the recipient to form his or her own opinion of thetherapeutic value of the medicinal product concerned.
3. Quotations as well as tables and other illustrative matter taken
from medical journals or other scientific works for use in the documen-tation referred to in paragraph 1 shall be faithfully reproduced and the
precise sources indicated.
Article 93
1. Medical sales representatives shall be given adequate training by
the firm which employs them and shall have sufficient scientificknowledge to be able to provide information which is precise and ascomplete as possible about the medicinal products which they promote.
2. During each visit, medical sales representatives shall give the
persons visited, or have available for them, summaries of the productcharacteristics of each medicinal product they present together, if thelegislation of the Member State so permits, with details of the priceand conditions for reimbursement referred to in Article 91(1).
3. Medical sales representatives shall transmit to the scientific
service referred to in Article 98(1) any information about the use ofthe medicinal products they advertise, with particular reference to anyadverse reactions reported to them by the persons they visit.
Article 94
1. Where medicinal products are being promoted to persons quali-
fied to prescribe or supply them, no gifts, pecuniary advantages or
benefits in kind may be supplied, offered or promised to such personsunless they are inexpensive and relevant to the practice of medicine orpharmacy.
2. Hospitality at sales promotion shall always be reasonable in level
and secondary to the main purpose of the meeting and must not beextended to other than health professionals.
3. Persons qualified to prescribe or supply medicinal products shall
not solicit or accept any inducement prohibited under paragraph 1 orcontrary to paragraph 2.
4. Existing measures or trade practices in Member States relating to
prices, margins and discounts shall not be affected by paragraphs 1, 2
and 3.
Article 95
The provisions of Article 94(1) shall not prevent hospitality being
offered, directly or indirectly, at events for purely professional andscientific purposes; such hospitality shall always be reasonable in leveland remain subordinate to the main scientific objective of the meeting;it must not be extended to persons other than health professionals.
Article 96
1. Free samples shall be provided on an exceptional basis only to
persons qualified to prescribe them and on the following conditions:
(a) the number of samples for each medicinal product each year on
prescription shall be limited;
(b) any supply of samples shall be in response to a written request,
signed and dated, from the prescribing agent;2001L0083 — EN — 01.07.2003 — 002.001 — 40
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(c) those supplying samples shall maintain an adequate system of
control and accountability;
(d) each sample shall be identical with the smallest presentation on the
market;
(e) each sample shall be marked ‘free medical sample — not for sale’
or shall show some other wording having the same meaning;
(f) each sample shall be accompanied by a copy of the summary of
product characteristics;
(g) no samples of medicinal products containing psychotropic or
narcotic substances within the meaning of international conven-
tions, such as the United Nations Conventions of 1961 and 1971,may be supplied.
2. Member States may also place further restrictions on the distribu-
tion of samples of certain medicinal products.
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 oncomplaints or to initiate appropriate legal proceedings.
2. Under the legal provisions referred to in paragraph 1, Member
States shall confer upon the courts or administrative authorities powersenabling them, in cases where they deem such measures to be neces-sary, taking into account all the interests involved, and in particularthe public interest:
— to order the cessation of, or to institute appropriate legal proceed-
ings for an order for the cessation of, misleading advertising, or
— if misleading advertising has not yet been published but publication
is imminent, to order the prohibition of, or to institute appropriatelegal proceedings for an order for the prohibition of, such publica-tion,
even without proof of actual loss or damage or of intention or negli-
gence on the part of the advertiser.
3. Member States shall make provision for the measures referred to
in the second subparagraph to be taken under an accelerated procedure,
either with interim effect or with definitive effect.
It shall be for each Member State to decide which of the two options
set out in the first subparagraph to select.
4. Member States may confer upon the courts or administrative
authorities powers enabling them, with a view to eliminating the conti-nuing effects of misleading advertising the cessation of which has been
ordered by a final decision:
— to require publication of that decision in full or in part and in such
form as they deem adequate,
— to require in addition the publication of a corrective statement.
5. Paragraphs 1 to 4 shall not exclude the voluntary control of
advertising of medicinal products by self-regulatory bodies and
recourse to such bodies, if proceedings before such bodies are possiblein addition to the judicial or administrative proceedings referred to inparagraph 1.
Article 98
1. The marketing authorization holder shall establish, within his
undertaking, a scientific service in charge of information about themedicinal products which he places on the market.2001L0083 — EN — 01.07.2003 — 002.001 — 41
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2. The marketing authorization holder shall:
— keepavailable 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
conforms to the requirements of this Title,
— verify that medical sales representatives employed by his under-
taking have been adequately trained and fulfill the obligations
imposed upon them by Article 93(2) and (3),
— supply the authorities or bodies responsible for monitoring adver-
tising of medicinal products with the information and assistancethey require to carry out their responsibilities,
— ensure that the decisions taken by the authorities or bodies respon-
sible for monitoring advertising of medicinal products are
immediately and fully complied with.
Article 99
Member States shall take the appropriate measures to ensure that the
provisions of this Title are applied and shall determine in particular
what penalties shall be imposed should the provisions adopted in the
execution of Title be infringed.
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
this Title with the exception of Article 87(1).
However, only the information specified in Article 69(1) may be used
in the advertising of such medicinal products.
Moreover, each Member State may prohibit in its territory any adver-
tising of the homeopathic medicinal products referred to in Article13(2) and Article 14(1).
TITLE IX
PHARMACOVIGILANCE
Article 101
The Member States shall take all appropriate measures to encourage
doctors and other health care professionals to report suspected adversereactions to the competent authorities.
The Member States may impose specific requirements on doctors and
other health care professionals, in respect of the reporting of suspectedserious or unexpected adverse reactions, in particular where suchreporting is a condition of the marketing authorization.
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 tomedicinal products under normal conditions of use, the Member States
shall establish a pharmacovigilance system. This system shall be used
to collect information useful in the surveillance of medicinal products,with particular reference to adverse reactions in human beings, and toevaluate such information scientifically.
Such information shall be collated with data on consumption of medic-
inal products.
This system shall also take into account any available information on
misuse and abuse of medicinal products which may have an impacton the evaluation of their benefits and risks.2001L0083 — EN — 01.07.2003 — 002.001 — 42
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Article 103
The marketing authorization holder shall have permanently and
continuously at his disposal an appropriately qualified person respon-
sible for pharmacovigilance.
That qualified person shall be responsible for the following:
(a) the establishment and maintenance of a system which ensures that
information about all suspected adverse reactions which arereported to the personnel of the company, and to medical represen-
tatives, is collected and collated in order to be accessible at least at
one point within the Community;
(b) the preparation for the competent authorities of the reports referred
to in Article 104, in such form as may be laid down by those
authorities, in accordance with the guidance referred to in Article
106(1);
(c) ensuring that any request from the competent authorities for the
provision of additional information necessary for the evaluation of
the benefits and risks afforded by a medicinal product is answered
fully and promptly, including the provision of information aboutthe volume of sales or prescriptions of the medicinal productconcerned;
(d) the provision to the competent authorities, of any other information
relevant to the evaluation of the benefits and risks afforded by amedicinal product, including appropriate information on post-authorization safety studies.
Article 104
1. The marketing authorization holder shall be required to maintain
detailed records of all suspected adverse reactions occurring either in
the Community or in a third country.
2. The marketing authorization holder shall be required to record
and to report all suspected serious adverse reactions which are broughtto his attention by a health care professional immediately to the compe-tent authority of the Member State in whose territory the incident
occurred, and in no case later than 15 calendar days following the
receipt of the information.
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
Article 106(1) of which he can reasonably be expected to have knowl-
edge immediately to the competent authority of the Member State inwhose territory the incident occurred, and in no case later than 15calendar days following the receipt of the information.
4. The marketing authorization holder shall ensure that all suspected
serious and unexpected adverse reactions occurring in the territory of a
third country and brought to his attention by a health care professional
are reported immediately in accordance with the guidance referred to inArticle 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
following the receipt of the information.
5. In the case of medicinal products which have been considered
within the scope of Directive 87/22/EEC, or which have benefitedfrom the procedures of mutual recognition foreseen in Articles 17 and18 of this Directive, Article 28(4) of this Directive, and medicinalproducts for which there has been a referral to the procedures foreseen
by Articles 32, 33 and 34 of this Directive, the marketing authorisation
holder shall additionally ensure that all suspected serious adverse reac-tions occurring in the Community are reported in the format and atintervals to be agreed with the reference Member State, or a competentauthority acting as the reference Member State, in such a way so as tobe accessible to the reference Member State.2001L0083 — EN — 01.07.2003 — 002.001 — 43
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6. Unless other requirements have been laid down as a condition of
the granting of authorisation, or subsequently as indicated in theguidance referred to in Article 106(1), records of all adverse reactions
shall be submitted to the competent authorities in the form of a peri-
odic safety update report, either immediately upon request orperiodically as follows: six monthly for the first two years after author-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 of the benefit and risks afforded by themedicinal products.
7. Following the granting of a marketing authorisation, the
marketing authorisation holder may request the amendment of the
periods referred to in this article according to the procedure laid down
by Commission Regulation (EC) No 541/95 (
1).
Article 105
1. The Agency, in collaboration with the Member States and the
Commission shall set upa data-p rocessing network to facilitate theexchange of pharmacovigilance information regarding medicinalproducts marketed in the Community intended to allow all competentauthorities to share the information at the same time.
2. Making use of the network foreseen in paragraph 1, Member
States shall ensure that reports of suspected serious adverse reactions
that have taken place on their territory are immediately made availableto the Agency and the other Member States, and in any case within 15calendar days of their notification, at the latest.
3. The Member States shall ensure that reports of suspected serious
adverse reactions that have taken place on their territory are immedi-
ately made available to the marketing authorisation holder, and in any
case within 15 calendar days of their notification, at the latest.
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
exchange of pharmacovigilance information in accordance with interna-
tionally agreed formats and shall publish a reference to aninternationally agreed medical terminology.
This guidance shall be published in Volume 9 of The rules governing
medicinal products in the European Community and shall take accountof international harmonisation work carried out in the field of pharma-covigilance.
2. For the interpretation of the definitions referred to in Article 1
points 11 to 16 and the principles outlined in this Title, the marketingauthorisation holder and the competent authorities shall refer to theguidance referred to in paragraph 1.
Article 107
1. Where, as a result of the evaluation of pharmacovigilance data, a
Member State considers that a marketing authorisation should besuspended, withdrawn or varied in accordance with the guidance
referred to in Article 106(1), it shall forthwith inform the Agency, the
other Member States and the marketing authorisation holder.
2. In case of urgency, the Member State concerned may suspend the
marketing authorisation of a medicinal product, provided the Agency,2001L0083 — EN — 01.07.2003 — 002.001 — 44
(1) OJ L 55, 11.3.1995, p. 7. Regulation amended by Regulation (EC) No 1146/
98 (OJ L 159, 3.6.1998, p. 31).
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the Commission and the other Member States are informed at the latest
on the following working day.
Article 108
Any amendments which may be necessary to update provisions of Arti-
cles 101 to 107 to take account of scientific and technical progress
shall be adopted in accordance with the procedure referred to in Article
121(2).
TITLE X
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, storage and distribution of human bloodand blood components and amending Directive 2001/83/EC (
1) shall
apply.
Article 110
Member States shall take the necessary measures to promote 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 humanplasma coming from voluntary unpaid donations. They shall notify the
Commission of such measures.
TITLE XI
SUPERVISIONANDSANCTIONS
Article 111
1. The competent authority of the Member State concerned shall
ensure, by means of repeated inspections, that the legal requirementsgoverning medicinal products are complied with.
Such inspections shall be carried out by officials representing the
competent authority who shall be empowered to:
(a) inspect manufacturing or commercial establishments and any
laboratories entrusted by the holder of the manufacturing authoriza-
tion with the task of carrying out checks pursuant to Article 20;
(b) take samples;
(c) examine any documents relating to the object of the inspection,
subject to the provisions in force in the Member States on 21 May1975 and which place restrictions on these powers with regard tothe descriptions of the method of preparation.
2. Member States shall take all appropriate steps to ensure that the
manufacturing processes used in the manufacture of immunologicalproducts are properly validated and attain batch-to-batch consistency.
3. After every inspection as referred to in paragraph 1, the officials
representing the competent authority shall report on whether the manu-facturer complies with the principles and guidelines of goodmanufacturing practice laid down in Article 47. The content of suchreports shall be communicated to the manufacturer who has to undergothe inspection.2001L0083 — EN — 01.07.2003 — 002.001 — 45
(1) OJ L 33, 8.2.2003, p. 30.▼M1
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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,furnish proof of the controls carried out on the medicinal product and/or the ingredients and of the controls carried out at an intermediatestage of the manufacturing process, in accordance with the methods
laid down in Article 8(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
qualified person in accordance with Article 51.
Article 114
1. Where it considers it necessary in the interests of public health, a
Member State may require the holder of an authorization for
marketing:
— live vaccines,
— immunological medicinal products used in the primary immuniza-
tion of infants or of other groups at risk,
— immunological medicinal products used in public health immuniza-
tion programmes,
— new immunological medicinal products or immunological medicinal
products manufactured using new or altered kinds of technology or
new for a particular manufacturer, during a transitional periodnormally specified in the marketing authorization,
to submit samples from each batch of the bulk and/or the medicinal
product for examination by a State laboratory or a laboratory desig-
nated for that purpose before release on to the market unless, in the
case of a batch manufactured in another Member State, the competentauthority of that Member State has previously examined the batch inquestion and declared it to be in conformity with the approved specifi-cations. Member States shall ensure that any such examination is
completed within 60 days of the receipt of the samples.
2. Where, in the interests of public health, the laws of a Member
State so provide, the competent authorities may require the marketingauthorization holder for medicinal products derived from human bloodor human plasma to submit samples from each batch of the bulk and/or
the medicinal product for testing by a State laboratory or a laboratory
designated for that purpose before being released into free circulation,unless the competent authorities of another Member State 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
receipt of the samples.
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,insofar as the state of technology permits, the absence of specific viralcontamination. 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 submitsamples of the bulk and/or the medicinal product for testing by a Statelaboratory or a laboratory designated for that purpose, either during theexamination of the application pursuant to Article 19, or after amarketing authorization has been granted.2001L0083 — EN — 01.07.2003 — 002.001 — 46
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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, or where its therapeutic efficacy is lacking, or where its qualitativeand quantitative composition is not as declared. Therapeutic efficacy islacking when it is established that therapeutic results cannot beobtained with the medicinal product.
An authorization shall also be suspended or revoked where the particu-
lars supporting the application as provided for in Articles 8, 10(1) and
11 are incorrect or have not been amended in accordance with Article23, or where the controls referred to in Article 112 have not beencarried out.
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
product withdrawn from the market if:
(a) the medicinal product proves to be harmful under normal condi-
tions of use, or
(b) it is lacking in therapeutic efficacy, or
(c) its qualitative and quantitative composition is not as declared, or
(d) the controls on the medicinal product and/or on the ingredients and
the controls at an intermediate stage of the manufacturing process
have not been carried out or if some other requirement or obliga-
tion relating to the grant of the manufacturing authorization hasnot been fulfilled.
2. The competent authority may limit the prohibition to supply the
product, or its withdrawal from the market, to those batches which arethe subject of dispute.
Article 118
1. The competent authority shall suspend or revoke the marketing
authorization for a category of preparations or all preparations where
any one of the requirements laid down in Article 41 is no longer met.
2. In addition to the measures specified in Article 117, the compe-
tent authority may suspend manufacture or imports of medicinalproducts coming from third countries, or suspend or revoke the manu-facturing authorization for a category of preparations or all preparations
where Articles 42, 46, 51 and 112 are not complied with.
Article 119
The provisions of this Title shall apply to homeopathic medicinal
products, subject to the provisions of Article 14(3).
TITLE XII
STANDINGCOMMITTEE
Article 120
Any changes which are necessary in order to adapt Annex I to take
account of scientific and technical progress shall be adopted in accor-
dance with the procedure referred to in Article 121(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 Products Sector, (hereinafter referred to as the‘Standing Committee’).2001L0083 — EN — 01.07.2003 — 002.001 — 47
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2. Where reference is made to this paragraph, Articles 5 and 7 of
Decision 1999/468/EC shall apply, having regard to Article 8 thereof.
The period provided for in Article 5(6) of Decision 1999/468/EC shall
be set at three months.
3. The Standing Committee shall adopt its rules of procedure.
TITLE XIII
GENERALPROVISIONS
Article 122
Member States shall take all appropriate measures to ensure that the
competent authorities concerned communicate to each other such infor-mation as is appropriate to guarantee that the requirements for themanufacturing authorizations or marketing authorizations are fulfilled.
Upon reasoned request, Member States shall forthwith communicate
the reports referred to in Article 111(3) to the competent authorities of
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 inwhich the report was established, it shall inform the competent autho-rities concerned of its reasons and may request further information. 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
from the market, together with the reasons on which such decisions
are based, are brought to the attention of the Agency forthwith.
2. The marketing authorization holder shall be obliged to notify the
Member States concerned forthwith of any action taken by him tosuspend the marketing of a medicinal product or to withdraw a medic-inal product from the market, together with the reasons for such actionif the latter concerns the efficacy of the medicinal product or the
protection of public health. Member States shall ensure that this infor-
mation is brought to the attention of the Agency.
3. Member States shall ensure that appropriate information about
action taken pursuant to paragraphs 1 and 2 which may affect 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
products which are prohibited in the Community.
Article 124
Member States shall communicate to each other all the information
necessary to guarantee the quality and safety of homeopathic medicinal
products manufactured and marketed within the Community, and inparticular the information referred to in Articles 122 and 123.
Article 125
Every decision referred to in this Directive which is taken by the
competent authority of a Member State shall state in detail the reasonson which it is based.
Such decision shall be notified to the party concerned, together with
information as to the redress available to him under the laws in forceand of the time-limit allowed for access to such redress.2001L0083 — EN — 01.07.2003 — 002.001 — 48
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Marketing authorizations, and decisions to 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,
suspended or revoked except on the grounds set out in this Directive.
No decision concerning suspension of manufacture or of importation of
medicinal products coming from third countries, prohibition of supplyor withdrawal from the market of a medicinal product may be takenexcept on the grounds set out in Articles 117 and 118.
Article 127
1. At the request of the manufacturer, the exporter or the authorities
of an importing third country, Member States shall certify that a manu-facturer of medicinal products is in possession of the manufacturing
authorization. When issuing such certificates Member States shall
comply with the following conditions:
(a) they shall have regard to the prevailing administrative arrange-
ments of the World Health Organization;
(b) for medicinal products intended for export which are already
authorized on their territory, they shall supply the summary of the
product characteristics as approved in accordance with Article 21.
2. When the manufacturer is not in possession of a marketing
authorization he shall provide the authorities responsible for estab-lishing the certificate referred to in paragraph 1, with a declarationexplaining why no marketing authorization is available.
TITLE XIV
FINALPROVISIONS
Article 128
Directives 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 and92/73/EEC, amended by the Directives referred to in Annex II, Part A,are repealed, without prejudice to the obligations of the Member Statesconcerning the time-limits for implementation set out in Annex II, PartB.
References to the repealed Directives shall be construed as references
to this Directive and shall be read in accordance with the correlation
table in Annex III.
Article 129
This Directive shall enter into force on the twentieth day following that
of its publication in the Official Journal of the European Communities .
Article 130
This Directive is addressed to the Member States.2001L0083 — EN — 01.07.2003 — 002.001 — 49
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ANNEX I
ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLINICAL STANDARDS AND
PROTOCOLSINRESPECTOFTHETESTINGOFMEDICINALPRODUCTS
TABLE OF CONTENTS
Introduction and general principles ... ..................................................
Part I: Standardised marketing authorisation dossier requirements ............................
1. Module 1: Administrative information .. ......................................
1.1. Table of contents .. .......................................................
1.2. Application form .. .......................................................
1.3. Summary of product characteristics, labelling and package leaflet . ................
1.3.1. Summary of product characteristics ..........................................
1.3.2. Labelling and package leaflet ... ............................................
1.3.3. Mock-ups and specimens .. .................................................
1.3.4. Summaries of product characteristics already approved in the Member States ... .....
1.4. Information about the experts ... ............................................
1.5. Specific requirements for different types of applications ... ......................
1.6. Environmental risk assessment .. ............................................
2. Module 2: Summaries .....................................................
2.1. Overall table of contents .. .................................................
2.2. Introduction .. ............................................................
2.3. Quality overall summary .. .................................................
2.4. Non-clinical overview .....................................................
2.5. Clinical overview .. .......................................................
2.6. Non-clinical summary .....................................................
2.7. Clinical Summary .. .......................................................
3. Module 3: Chemical, pharmaceutical and biological information for medicinal products
containing chemical and/or biological active substances ..........................
3.1. Format and presentation ... .................................................
3.2. Content: basic principles and requirements ... .................................
3.2.1. Active substance(s) . .......................................................
3.2.1.1. General information and information related to the starting and raw materials .. .....
3.2.1.2. Manufacturing process of the active substance(s) ...............................
3.2.1.3. Characterisation of the active substance(s) .....................................
3.2.1.4. Control of active substance(s) ... ............................................
3.2.1.5. Reference standards or materials . ............................................
3.2.1.6. Container and closure system of the active substance . ...........................
3.2.1.7. Stability of the active substance(s) ...........................................
3.2.2. Finished medicinal product .................................................
3.2.2.1. Description and composition of the finished medicinal product ....................
3.2.2.2. Pharmaceutical development ................................................
3.2.2.3. Manufacturing process of the finished medicinal product ... ......................
3.2.2.4. Control of excipients ......................................................
3.2.2.5. Control of the finished medicinal product .....................................
3.2.2.6. Reference standards or materials . ............................................
3.2.2.7. Container and closure of the finished medicinal product ... ......................
3.2.2.8. Stability of the finished medicinal product .....................................
4. Module 4: Non-clinical reports .. ............................................
4.1. Format and Presentation .. .................................................2001L0083 — EN — 01.07.2003 — 002.001 — 50
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4.2. Content: basic principles and requirements ... .................................
4.2.1. Pharmacology ............................................................
4.2.2. Pharmaco-kinetics .. .......................................................
4.2.3. Toxicology .. ............................................................
5. Module 5: Clinical study reports . ............................................
5.1. Format and Presentation .. .................................................
5.2. Content: basic principles and requirements ... .................................
5.2.1. Reports of bio-pharmaceutics studies ... ......................................
5.2.2. Reports of studies pertinent to pharmaco-kinetics using human bio-materials ... .....
5.2.3. Reports of human pharmaco-kinetic studies ... .................................
5.2.4. Reports of human pharmaco-dynamic studies . .................................
5.2.5. Reports of efficacy and safety studies .. ......................................
5.2.5.1. Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication .....
5.2.5.2. Study reports of uncontrolled clinical studies reports of analyses of data from more than
one study and other clinical study reports .....................................
5.2.6. Reports of post-marketing experience ... ......................................
5.2.7. Case reports forms and individual patient listings ...............................
Part II: Specific marketing authorisation dossiers and requirements ..........................
1. Well-established medicinal use .. ............................................
2. Essentially similar medicinal products .. ......................................
3. Additional data required in specific situations . .................................
4. Similar biological medicinal products ... ......................................
5. Fixed combination medicinal products .. ......................................
6. Documentation for applications in exceptional circumstances .....................
7. Mixed marketing authorisation applications ... .................................
Part III: Particular medicinal products ..................................................
1. Biological medicinal products ... ............................................
1.1. Plasma-derived medicinal product ............................................
1.2. Vaccines ................................................................
2. Radio-pharmaceuticals and precursors .. ......................................
2.1. Radio-pharmaceuticals .....................................................
2.2. Radio-pharmaceutical precursors for radio-labelling purposes .....................
3. Homeopathic medicinal products ............................................
4. Herbal medicinal products . .................................................
5. Orphan Medicinal Products .................................................
Part IV: Advanced therapy medicinal products ...........................................
1. Gene therapy medicinal products (human and xenogeneic) . ......................
1.1. Diversity of gene therapy medicinal products . .................................
1.2. Specific requirements regarding Module 3 .....................................
2. Somatic cell therapy medicinal products (human and xenogeneic) . ................
3. Specific requirements for gene therapy and somatic cell therapy (human and xeno-
geneic) medicinal products regarding Modules 4 and 5 ..........................
3.1. Module 4 ................................................................
3.2. Module 5 ................................................................
3.2.1. Human pharmacology and efficacy studies ... .................................2001L0083 — EN — 01.07.2003 — 002.001 — 51
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3.2.2. Safety ..................................................................
4. Specific Statement on Xeno-transplantation Medicinal Products ... ................2001L0083 — EN — 01.07.2003 — 002.001 — 52
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Introductionandgeneral principles
(1) The particulars and documents accompanying an application for
marketing authorisation pursuant to Articles 8 and 10 (1) shall be
presented in accordance with the requirements set out in this Annex
and shall follow the guidance published by the Commission in The
rules governing medicinal products in the European Community,
Volume 2 B, Notice to applicants, Medicinal products for human use,
Presentation and content of the dossier, Common Technical Document
(CTD).
(2) The particulars and documents shall be presented as five modules:
Module 1 provides European Community specific administrative data;
Module 2 provides quality, non-clinical and clinical summaries,
Module 3 provides chemical, pharmaceutical and biological informa-
tion, Module 4 provides non-clinical reports and Module 5 provides
clinical study reports. This presentation implements a common format
for all ICH(1) regions (European Community, United States of
America, Japan). These five Modules shall be presented in strict accor-
dance with the format, content and numbering system delineated in
details in Volume 2 B of the Notice to Applicants referred to above.
(3) The European Community-CTD-presentation is applicable for all types
of marketing authorisation applications irrespective of the procedure to
be applied (i.e. centralised, mutual recognition or national) and of
whether they are based on a full or abridged application. It is also
applicable for all types of products including new chemical entities
(NCE), radio-pharmaceuticals, plasma derivatives, vaccines, herbal
medicinal products, etc.
(4) In assembling the dossier for application for marketing authorisation,
applicants shall also take into account the scientific guidelines relating
to the quality, safety and efficacy of medicinal products for human use
as adopted by the Committee for Proprietary Medicinal Products
(CPMP) and published by the European Medicine Evaluation Agency
(EMEA) and the other pharmaceutical Community guidelines published
by the Commission in the different volumes of The rules governing
medicinal products in the European Community.
(5) With respect to the quality part (chemical, pharmaceutical and biolo-
gical) of the dossier, all monographs including general monographs
and general chapters of the European Pharmacopoeia are applicable.
(6) The manufacturing process shall comply with the requirements of
Commission Directive 91/356/EEC laying down the principles and
guidelines of Good Manufacturing Practice (GMP) for medicinal
products for human use(2) and with the principles and guidelines on
GMP, published by the Commission in The rules governing medicinal
products in the European Community, Volume 4.
(7) All information, which is relevant to the evaluation of the medicinal
product concerned, shall be included in the application, whether favour-able or unfavourable to the product. In particular, all relevant details
shall be given of any incomplete or abandoned pharmaco-toxicological
or clinical test or trial relating to the medicinal product and/or
completed trials concerning therapeutic indications not covered by the
application.
(8) All clinical trials, conducted within the European Community, must
comply with the requirements of Directive 2001/20/EC of the European
Parliament and of the Council on the approximation of the laws, regula-
tions and administrative provisions of the Member States relating to the
implementation of good clinical practice in the conduct of clinical trials
on medicinal products for human use(
3). To be taken into account
during the assessment of an application, clinical trials, conducted
outside the European Community, which relate to medicinal products
intended to be used in the European Community, shall be designed,
implemented and reported on what good clinical practice and ethical
principles are concerned, on the basis of principles, which are equiva-
lent to the provisions of Directive 2001/20/EC. They shall be carried
out in accordance with the ethical principles that are reflected, for
example, in the Declaration of Helsinki.2001L0083 — EN — 01.07.2003 — 002.001 — 53
(1) International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use.
(2) OJ L 193, 17.7.1991, p. 30.
(3) OJ L 121, 1.5.2001, p. 34.
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(9) Non-clinical (pharmaco-toxicological) studies shall be carried out in
conformity with the provisions related to Good Laboratory Practice
laid down in Council Directives 87/18/EEC on the harmonisation of
regulations and administrative provisions relating to the application of
the principles of good laboratory practice and the verification of their
application for tests in chemical substances (1) and 88/320/EEC on the
inspection and verification of good laboratory practice (GLP)(2).
(10) Member States shall also ensure that all tests on animals are conducted
in accordance with Council Directive 86/609/EEC of 24 November
1986 on the approximation of laws, regulation and administrative provi-
sions of the Member States regarding the protection of animals for
experimental and other scientific purposes.
(11) In order to monitor the benefit/risk assessment, any new information
not in the original application and all pharmaco-vigilance information
shall be submitted to the competent authority. After marketing authori-
sation has been granted, any change to the data in the dossier shall be
submitted to the competent authorities in accordance with the require-
ments of Commission Regulations (EC) No 1084/2003 (3) and (EC) No
1085/2003(4) of the Commission or, if relevant, in accordance with
national provisions, as well as the requirements in Volume 9 of
Commission publication The rules governing medicinal products in the
European Community.
This Annex is divided in four different parts:
— Part I describes the application format, the summary of product
characteristics, the labelling, the leaflet and presentation require-
ments for standard applications (Modules 1 to 5).
— Part II provides derogation for ‘Specific applications’, i.e. well-
established medicinal use, essentially similar products, fixed combi-
nations, similar biological products, exceptional circumstances and
mixed applications (part bibliographic and part own studies).
— Part III deals with ‘Particular application requirements’ for biolo-
gical medicinal products (Plasma Master File; Vaccine Antigen
Master File), radio-pharmaceuticals, homeopathic medicinal
products, herbal medicinal products and orphan medicinal products.
— Part IV deals with ‘Advanced therapy medicinal products’ and
concerns specific requirements for gene therapy medicinal products
(using human autologous or allogeneic system, or xenogeneic
system) and cell therapy medicinal products both of human or
animal origin and xenogeneic transplantation medicinal products.
PART I
STANDARDISED MARKETING AUTHORISATION DOSSIER
REQUIREMENTS
1. MODULE 1: ADMINISTRATIVE INFORMATION
1.1.Tableofcontents
A comprehensive table of contents of Modules 1 to 5 of the dossier
submitted for marketing authorisation application shall be presented.
1.2.Applicationform
The medicinal product, which is the subject of the application, shall be
identified by name and name of the active substance(s), together with
the pharmaceutical form, the route of administration, the strength and
the final presentation, including packaging.
The name and address of the applicant shall be given, together with the
name and address of the manufacturers and the sites involved in the
different stages of the manufacture (including the manufacturer of the
finished product and the manufacturer(s) of the active substance(s)),
and where relevant the name and address of the importer.
The applicant shall identify the type of application and indicate what
samples, if any, are also provided.2001L0083 — EN — 01.07.2003 — 002.001 — 54
(1) OJ L 15, 17.1.1987, p. 29.
(2) OJ L 145, 11.6.1988, p. 35.
(3) See p. 1 of this Official Journal.
(4) See p. 24 of this Official Journal.
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Annexed to the administrative data shall be copies of the manufacturing
authorisation as defined in Article 40, together with a list of countries
in which authorisation 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.
As outlined in the application form, the applicants shall provide, inter
alia, details of the medicinal product subject of the application, the
legal basis of the application, the proposed marketing authorisation
holder and manufacture(s), information on orphan medicinal product
status, scientific advice and paediatric development program.
1.3.Summaryofproductcharacteristics, labellingandpackageleaflet
1.3.1. Summary of product characteristics
The applicant shall propose a summary of the product characteristics, in
accordance with Article 11.
1.3.2. Labelling and package leaflet
A proposed labelling text for immediate and outer packaging as well as
for the package leaflet shall be provided. These shall be in accordance
with all mandatory items listed in Title V on the labelling of medicinal
products for human use (Article 63) and on package leaflet (Article 59).
1.3.3. Mock-ups and specimens
The applicant shall provide specimen and/or mock-ups of the
immediate and outer packaging, labels and package leaflets for themedicinal product concerned.
1.3.4. Summaries of product characteristics already approved in the Member
States
Annexed to the administrative data of the application form shall be
copies of all the summaries of product characteristics in accordance
with Articles 11 and 21 as approved by Member States, where applic-
able and a list of countries in which an application has been submitted.
1.4.Informationabouttheexperts
In accordance with Article 12 (2) experts must provide detailed reports
of their observations on the documents and particulars which constitute
the marketing authorisation dossier and in particular on Modules 3, 4
and 5 (chemical, pharmaceutical and biological documentation, non-
clinical documentation and clinical documentation, respectively). The
experts are required to address the critical points related to the quality
of the medicinal product and of the investigations carried out on
animals and human beings and bring out all the data relevant for
evaluation.
These requirements shall be met by providing a quality overall
summary, a non-clinical overview (data from studies carried out in
animals) and a clinical overview that shall be located in Module 2 of
the marketing authorisation application dossier. A declaration signed
by the experts together with brief information on their educational
background, training and occupational experience shall be presented in
Module 1. The experts shall have suitable technical or professional
qualifications. The professional relationship of the expert to the appli-
cant shall be declared.
1.5.Specificrequirementsfordifferenttypesofapplications
Specific requirements for different types of applications are addressed
in Part II of the present Annex.2001L0083 — EN — 01.07.2003 — 002.001 — 55
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1.6.Environmentalriskassessment
Where applicable, applications for marketing authorisations shall
include a risk assessment overview evaluating possible risks to the
environment due to the use and/or disposal of the medicinal product
and make proposals for appropriate labelling provisions. Environmental
risk connected with the release of medicinal products containing or
consisting of GMOs (Genetically Modified Organisms) within the
meaning of Article 2 of Directive 2001/18/EC of the European Parlia-
ment and of the Council of 12 March 2001 on the deliberate release
into the environment of modified organisms and repealing Council
Directive 90/220/EEC (1) shall be addressed.
Information pertaining to the environmental risk shall appear as an
appendix to Module 1.
The information shall be presented in accordance with the provisions of
Directive 2001/18/EC, taking into account any guidance documents
published by the Commission in connection with the implementation
of the said Directive.
The information shall consist of:
— an introduction;
— a copy of any written consent or consents to the deliberate release
into the environment of the GMO(s) for research and development
purposes according to Part B of Directive 2001/18/EC;
— the information requested in Annexes II to IV of the Directive 2001/
18/EC, including detection and identification methods as well as
unique code of the GMO, plus any additional information on the
GMO or the product of relevance to evaluating the environmental
risk;
— an environment risk assessment (ERA) report prepared on basis of
the information specified in Annexes III and IV of Directive 2001/
18/EC and in accordance with Annex II of Directive 2001/18/EC;
— taking into account the above information and the ERA, a conclu-
sion which proposes an appropriate risk management strategy
which includes, as relevant to the GMO and product in question, a
post-market monitoring plan and the identification of any special
particulars which need to appear in the Summary of Product Char-
acteristics, labelling and package leaflet;
— appropriate measures in order to inform the public.
A dated signature of the author, information on the author's educational,
training and occupational experience, and a statement of the author's
relationship with the applicant, shall be included.
2. MODULE 2: SUMMARIES
This Module aims to summarise the chemical, pharmaceutical and
biological data, the non-clinical data and the clinical data presented in
Modules 3, 4 and 5 of the dossier for marketing authorisation, and to
provide the reports/overviews described in Article 12 of this Directive.
Critical points shall be addressed and analysed. Factual summaries
including tabular formats shall be provided. Those reports shall provide
cross-references to tabular formats or to the information contained in
the main documentation presented in Module 3 (chemical, pharmaceu-
tical and biological documentation), Module 4 (non-clinical
documentation) and Module 5 (clinical documentation).
Information contained in Module 2 shall be presented in accordance
with the format, content and numbering system delineated in the
Volume 2 of the Notice to Applicants. The overviews and summaries
shall comply with the basic principles and requirements as laid down
herewith:
2.1.Overall tableofcontents
Module 2 shall contain a table of contents for the scientific documenta-
tion submitted in Modules 2 to 5.2001L0083 — EN — 01.07.2003 — 002.001 — 56
(1) OJ L 106, 17.4.2001, p. 1.
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2.2.Introduction
Information on the pharmacological class, mode of action and proposed
clinical use of the medicinal product for which a marketing authorisa-
tion is requested shall be supplied.
2.3.Qualityoverall summary
A review of the information related to the chemical, pharmaceutical and
biological data shall be provided in a quality overall summary.
Key critical parameters and issues related to quality aspects shall be
emphasised as well as justification in cases where the relevant guide-
lines are not followed. This document shall follow the scope and
outline of the corresponding detailed data presented in Module 3.
2.4.Non-clinicaloverview
An integrated and critical assessment of the non-clinical evaluation of
the medicinal product in animals/in vitro shall be required. Discussion
and justification of the testing strategy and of deviation from the rele-
vant guidelines shall be included.
Except for biological medicinal products, an assessment of the impuri-
ties and degradation products shall be included along with their
potential pharmacological and toxicological effects. The implications
of any differences in the chirality, chemical form, and impurity profile
between the compound used in the non-clinical studies and the product
to be marketed shall be discussed.
For biological medicinal products, comparability of material used in
non-clinical studies, clinical studies, and the medicinal product for
marketing shall be assessed.
Any novel excipient shall be the subject of a specific safety assessment.
The characteristics of the medicinal product, as demonstrated by the
non-clinical studies shall be defined and the implications of the findings
for the safety of the medicinal product for the intended clinical use in
human shall be discussed.
2.5.Clinicaloverview
The clinical overview is intended to provide a critical analysis of the
clinical data included in the clinical summary and Module 5. The
approach to the clinical development of the medicinal product,
including critical study design, decisions related to and performance of
the studies shall be provided.
A brief overview of the clinical findings, including important limita-
tions as well as an evaluation of benefits and risks based on the
conclusions of the clinical studies shall be provided. An interpretation
of the way the efficacy and safety findings support the proposed dose
and target indications and an evaluation of how the summary of product
characteristics and other approaches will optimise the benefits and
manage the risks is required.
Efficacy or safety issues encountered in development and unresolved
issues shall be explained.
2.6.Non-clinicalsummary
The results of pharmacology, pharmaco-kinetics and toxicology studies
carried out in animals/in vitro shall be provided as factual written and
tabulated summaries which shall be presented in the following order:
— Introduction
— Pharmacology Written Summary— Pharmacology Tabulated Summary— Pharmaco-kinetics Written Summary
— Pharmaco-kinetics Tabulated Summary
— Toxicology Written Summary— Toxicology Tabulated Summary.
2.7.ClinicalSummary
A detailed, factual summary of the clinical information on the medic-
inal product included in Module 5 shall be provided. This shall
include the results of all bio-pharmaceutics studies, of clinical pharma-2001L0083 — EN — 01.07.2003 — 002.001 — 57
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cology studies, and of clinical efficacy and safety studies. A synopsis of
the individual studies is required.
Summarised clinical information shall be presented in the following
order:
— Summary of Bio-pharmaceutics and Associated Analytical Methods
— Summary of Clinical Pharmacology Studies
— Summary of Clinical Efficacy— Summary of Clinical Safety
— Synopses of Individual Studies
3. MODULE 3: CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL
INFORMATION FOR MEDICINAL PRODUCTS CONTAINING
CHEMICAL AND/OR BIOLOGICAL ACTIVE SUBSTANCES
3.1.Formatandpresentation
The general outline of Module 3 is as follows:
— Table of contents
— Body of data
—Active substance
General Information
— Nomenclature
— Structure
— General Properties
Manufacture— Manufacturer(s)
— Description of Manufacturing Process and Process Controls
— Control of Materials
— Controls of Critical Steps and Intermediates
— Process Validation and/or Evaluation
— Manufacturing Process Development
Characterisation— Elucidation of Structure and other Characteristics
— Impurities
Control of Active Substance— Specification
— Analytical Procedures
— Validation of Analytical Procedures
— Batch Analyses
— Justification of Specification
Reference Standards or MaterialsContainer Closure SystemStability— Stability Summary and Conclusions
— Post-approval Stability Protocol and Stability Commitment
— Stability Data
—Finished Medicinal Product
Description and Composition of the Medicinal
Product
Pharmaceutical Development
— Components of the Medicinal Product
— Active Substance
— Excipients
— Medicinal Product
— Formulation Development
— Overages
— Physicochemical and Biological Properties
— Manufacturing Process Development— Container Closure System
— Microbiological Attributes
— Compatibility2001L0083 — EN — 01.07.2003 — 002.001 — 58
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Manufacture
— Manufacturer(s)
— Batch Formula
— Description of Manufacturing Process and Process Controls
— Controls of Critical Steps and Intermediates
— Process Validation and/or Evaluation
Control of Excipients— Specifications
— Analytical Procedures
— Validation of Analytical Procedures
— Justification of Specifications— Excipients of Human or Animal Origin
— Novel Excipients
Control of Finished Medicinal Product— Specification(s)
— Analytical Procedures— Validation of Analytical Procedures
— Batch Analyses
— Characterisation of Impurities
— Justification of Specification(s)
Reference Standards or Materials
Container Closure SystemStability— Stability Summary and Conclusion
— Post-approval Stability Protocol and Stability Commitment
— Stability Data
—Appendices
— Facilities and Equipment (Biological Medicinal Products
only)
— Adventitious Agents Safety Evaluation
— Excipients
—European Community Additional Information
— Process Validation Scheme for the Medicinal Product
— Medical Device— Certificate(s) of Suitability
— Medicinal products containing or using in the manufacturing
process materials of animal and/or human origin (TSE
procedure)
— Literature References
3.2.Content:basicprinciplesandrequirements
(1) The chemical, pharmaceutical and biological data that shall be
provided shall include for the active substance(s) and for the
finished medicinal product all of relevant information on: the
development, the manufacturing process, the characterisation and
properties, the quality control operations and requirements, the
stability as well as a description of the composition and presenta-
tion of the finished medicinal product.
(2) Two main sets of information shall be provided, dealing with the
active substance(s) and with the finished medicinal product,
respectively.
(3) This Module shall in addition supply detailed information on the
starting and raw materials used during the manufacturing opera-
tions of the active substance(s) and on the excipients incorporated
in the formulation of the finished medicinal product.
(4) All the procedures and methods used for manufacturing and
controlling the active substance and the finished medicinal product
shall be described in sufficient details to enable them to berepeated in control tests, carried out at the request of the compe-
tent authority. All test procedures shall correspond to the state of
scientific progress at the time and shall be validated. Results of
the validation studies shall be provided. In the case of test proce-
dures included in the European Pharmacopoeia, this description2001L0083 — EN — 01.07.2003 — 002.001 — 59
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shall be replaced by the appropriate detailed reference to the
monograph(s) and general chapter(s).
(5) The monographs of the European Pharmacopoeia shall be applic-
able to all substances, preparations and pharmaceutical forms
appearing in it. In respect of other substances, each Member State
may require observance of its own national pharmacopoeia.
However, where a 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 pharmaco-
poeia monograph, these impurities and their maximum tolerance
limits must be declared and a suitable test procedure must be
described. In cases where a specification contained in a mono-
graph of the European Pharmacopoeia or in the national
pharmacopoeia of a Member State might be insufficient to ensure
the quality of the substance, the competent authorities may request
more appropriate specifications from the marketing authorisation
holder. The competent authorities shall inform the authorities
responsible for the pharmacopoeia in question. The marketing
authorisation holder shall provide the authorities of that pharmaco-
poeia with the details of the alleged insufficiency and the
additional specifications applied.
In the case of analytical procedures included in the European
Pharmacopoeia, this description shall be replaced in each relevant
section by the appropriate detailed reference to the monograph(s)
and general chapter(s).
(6) In case where starting and raw materials, active substance(s) or
excipient(s) are described neither in the European Pharmacopoeia
nor in the pharmacopoeia of a Member State, compliance with the
monograph of a third country pharmacopoeia can be accepted. In
such cases, the applicant shall submit a copy of the monograph
accompanied by the validation of the analytical procedures
contained in the monograph and by a translation where appro-
priate.
(7) Where the active substance and/or a raw and starting material or
excipient(s) are the subject of a monograph of the European Phar-
macopoeia, the applicant can apply for a certificate of suitability
that, where granted by the European Directorate for the Quality
of Medicines, shall be presented in the relevant section of this
Module. Those certificates of suitability of the monograph of the
European Pharmacopoeia are deemed to replace the relevant data
of the corresponding sections described in this Module. The manu-
facturer shall give the assurance in writing to the applicant that the
manufacturing process has not been modified since the granting of
the certificate of suitability by the European Directorate for the
Quality of Medicines.
(8) For a well-defined active substance, the active substance manufac-
turer or the applicant may arrange for the
(i) detailed description of the manufacturing process,
(ii) quality control during manufacture, and(iii) process validation
to be supplied in a separate document directly to the competent
authorities by the manufacturer of the active substance as an
Active Substance Master File.
In this case, the manufacturer shall, however, provide the appli-
cant with all of the data, which may be necessary for the latter to
take responsibility for the medicinal product. The manufacturer
shall confirm in writing to the applicant that he shall ensure batch
to batch consistency and not modify the manufacturing process or
specifications without informing the applicant. Documents and
particulars supporting the application for such a change shall be
supplied to the competent authorities; these documents and parti-
culars will be also supplied to the applicant when they concern
the open part of the active substance master file.
(9) Specific measures concerning the prevention of the transmission
of animal spongiform encephalopathies (materials from ruminant
origin): at each step of the manufacturing process, the applicant
must demonstrate the compliance of the materials used with the
Note for Guidance on Minimising the Risk of Transmitting
Animal Spongiform Encephalopathy Agents via Medicinal
Products and its updates, published by the Commission in the
Official Journal of the European Union. Demonstration of compli-2001L0083 — EN — 01.07.2003 — 002.001 — 60
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ance with the said Note for Guidance can be done by submitting
either, preferably a certificate of suitability to the relevant mono-
graph of the European Pharmacopoeia that has been granted by
the European Directorate for the Quality of Medicines or by the
supply of scientific data to substantiate this compliance.
(10) For adventitious agents, information assessing the risk with respect
to potential contamination with adventitious agents, whether they
are non-viral or viral, as laid down in relevant guidelines as well
as in relevant general monograph and general chapter of the
European Pharmacopoeia, shall be provided.
(11) Any special apparatus and equipment, which may be used at any
stage of the manufacturing process and control operations of the
medicinal product, shall be described in adequate details.
(12) Where applicable and if needed, a CE marking which is required
by Community legislation on medical devices shall be provided.
Special attention shall be paid to the following selected elements.
3.2.1. Active substance(s)
3.2.1.1. General information and information related to the starting
and raw materials
a) Information on the nomenclature of the active substance shall be
provided, including recommended International Non-proprietary
Name (INN), European Pharmacopoeia name if relevant, chemical
name(s).
The structural formula, including relative and absolute stereo-chem-
istry, the molecular formula, and the relative molecular mass shall
be provided. For biotechnological medicinal products if appropriate,
the schematic amino acid sequence and relative molecular mass
shall be provided.
A list shall be provided of physicochemical and other relevant prop-
erties of the active substance, including biological activity for
biological medicinal products.
b) For the purposes of this Annex, starting materials shall mean all the
materials from which the active substance is manufactured or
extracted.
For biological medicinal products, starting materials shall mean any
substance of biological origin such as micro-organisms, organs and
tissues of either plant or animal origin, cells or fluids (including
blood or plasma) of human or animal origin, and biotechnological
cell constructs (cell substrates, whether they are recombinant or
not, including primary cells).
A biological medicinal product is a product, the active substance of
which is a biological substance. A biological substance is a
substance that is produced by or extracted from a biological source
and that needs for its characterisation and the determination of its
quality a combination of physico-chemical-biological testing,
together with the production process and its control. The following
shall be considered as biological medicinal products: immunological
medicinal products and medicinal products derived from human
blood and human plasma as defined, respectively in paragraphs (4)
and (10) of Article 1; medicinal products falling within the scope of
Part A of the Annex to Regulation (EEC) No 2309/93; advanced
therapy medicinal products as defined in Part IV of this Annex.
Any other substances used for manufacturing or extracting the active
substance(s) but from which this active substance is not directly
derived, such as reagents, culture media, foetal calf serum, additives,
and buffers involved in chromatography, etc. are known as raw
materials.
3.2.1.2. Manufacturing process of the active substance(s)
a) The description of the active substance manufacturing process repre-
sents the applicant's commitment for the manufacture of the active
substance. To adequately describe the manufacturing process and
process controls, appropriate information as laid down in guidelines
published by the Agency shall be provided.
b) All materials needed in order to manufacture the active substance(s)
shall be listed, identifying where each material is used in the
process. Information on the quality and control of these materials
shall be provided. Information demonstrating that materials meet
standards appropriate for their intended use shall be provided.2001L0083 — EN — 01.07.2003 — 002.001 — 61
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Raw materials shall be listed and their quality and controls shall also
be documented.
The name, address, and responsibility of each manufacturer,
including contractors, and each proposed production site or facility
involved in manufacturing and testing shall be provided.
c) For biological medicinal products, the following additional require-
ments shall apply.
The origin and history of starting materials shall be described and
documented.
Regarding the specific measures for the prevention of the Transmis-
sion of animal Spongiform Encephalopathies, the applicant must
demonstrate that the active substance complies with the Note for
Guidance on Minimising the Risk of Transmitting Animal Spongi-
form Encephalopathy Agents via Medicinal Products and its
updates, published by the Commission in the Official Journal of the
European Union.
When cell banks are used, the cell characteristics shall be shown to
have remained unchanged at the passage level used for the produc-
tion and beyond.
Seed materials, cell banks, pools of serum or plasma and other mate-
rials of biological origin and, whenever possible, the materials from
which they are derived shall be tested for adventitious agents.
If the presence of potentially pathogenic adventitious agents is inevi-
table, the corresponding material shall be used only when further
processing ensures their elimination and/or inactivation, and this
shall be validated.
Whenever possible, vaccine production shall be based on a seed lot
system and on established cell banks. For bacterial and viral
vaccines, the characteristics of the infectious agent shall be demon-
strated on the seed. In addition, for live vaccines, the stability of the
attenuation characteristics shall be demonstrated on the seed; if thisproof is not sufficient, the attenuation characteristics shall also be
demonstrated at the production stage.
For medicinal products derived from human blood or plasma, the
origin and the criteria and procedures for collection, transportation
and storage of the starting material shall be described and docu-
mented in accordance with provisions laid down in Part III of this
Annex.
The manufacturing facilities and equipment shall be described.
d) Tests and acceptance criteria carried out at every critical step, infor-
mation on the quality and control of intermediates and process
validation and/or evaluation studies shall be provided as appropriate.
e) If the presence of potentially pathogenic adventitious agents is inevi-
table, the correspondent material shall be used only when further
processing ensures their elimination and/or inactivation and this
shall be validated in the section dealing with viral safety evaluation.
f) A description and discussion of the significant changes made to the
manufacturing process during development and/or manufacturing
site of the active substance shall be provided.
3.2.1.3. Characterisation of the active substance(s)
Data highlighting the structure and other characteristics of the active
substance(s) shall be provided.
Confirmation of the structure of the active substance(s) based on any
physico-chemical and/or immuno-chemical and/or biological methods,
as well as information on impurities shall be provided.
3.2.1.4. Control of active substance(s)
Detailed information on the specifications used for routine control of
active substance(s), justification for the choice of these specifications,
methods of analysis and their validation shall be provided.
The results of control carried out on individual batches manufactured
during development shall be presented.
3.2.1.5. Reference standards or materials
Reference preparations and standards shall be identified and described
in detail. Where relevant, chemical and biological reference material
of the European Pharmacopoeia shall be used.2001L0083 — EN — 01.07.2003 — 002.001 — 62
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3.2.1.6. Container and closure system of the active substance
A description of the container and the closure system(s) and their speci-
fications shall be provided.
3.2.1.7. Stability of the active substance (s)
a) The types of studies conducted, protocols used, and the results of the
studies shall be summarised
b) Detailed results of the stability studies, including information on the
analytical procedures used to generate the data and validation of
these procedures shall be presented in an appropriate format
c) The post authorisation stability protocol and stability commitment
shall be provided
3.2.2. Finished medicinal product
3.2.2.1. Description and composition of the finished medicinal
product
A description of the finished medicinal product and its composition
shall be provided. The information shall include the description of the
pharmaceutical form and composition with all the constituents of the
finished medicinal product, their amount on a per-unit basis, the func-
tion of the constituents of:
— the active substance(s),
— the constituent(s) of the excipients, whatever their nature or the
quantity used, including colouring matter, preservatives, adjuvants,
stabilisers, thickeners, emulsifiers, flavouring and aromatic
substances, etc.,
— the constituents, intended to be ingested or otherwise administered
to the patient, of the outer covering of the medicinal products(hard capsules, soft capsules, rectal capsules, coated tablets, films-
coated tablets, etc.),
— these particulars shall be supplemented by any relevant data
concerning the type of container and, where appropriate, its manner
of closure, together with details of devices with which the medicinal
product will be used or administered and which will be delivered
with the medicinal product.
The ‘usual terminology’, to be used in describing the constituents of
medicinal products, shall mean, notwithstanding the application of the
other provisions in Article 8 (3) (c):
— in respect of substances which appear in the European Pharmaco-
poeia or, failing this, in the national pharmacopoeia of one of the
Member States, the main title at the head of the monograph in ques-
tion, with reference to the pharmacopoeia concerned,
— in respect of other substances, the international non-proprietary
name (INN) recommended by the World Health Organisation, or,
failing this, the exact scientific designation; substances not having
an international non-proprietary name or an exact scientific designa-
tion shall be described by a statement of how and from what they
were prepared, supplemented, where appropriate, by any other rele-
vant details,
— in respect of colouring matter, designation by the ‘E’ code assigned
to them in Council Directive 78/25/EEC of 12 December 1977 on
the approximation of the rules of the Member States concerning
the colouring matters authorised for use in medicinal products (
1)
and/or European Parliament and Council Directive 94/36/EC of
30 June 1994 on colours for use in foodstuffs(2).
In order to give the ‘quantitative composition’ of the active substance(s)
of the finished medicinal products, it is necessary, depending on the
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 active substance.
Active substances present in the form of compounds or derivatives shall
be designated quantitatively by their total mass, and if necessary or
relevant, by the mass of active entity or entities of the molecule.
For medicinal products containing an active substance, which is the
subject of an application for marketing authorisation in any Member2001L0083 — EN — 01.07.2003 — 002.001 — 63
(1) OJ L 11, 14.1.1978, p. 18.
(2) OJ L 237, 10.9.1994, p. 13.
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State for the first time, the quantitative statement of an active
substance, which is a salt or hydrate shall be systematically expressed
in terms of the mass of the active entity or entities in the molecule.
All subsequently authorised medicinal products in the Member States
shall have their quantitative composition stated in the same way for
the same active substance.
Units of biological activity shall be used for substances, which cannot
be defined molecularly. Where an International Unit of biological
activity has been defined by the World Health Organisation, this shall
be used. Where no International Unit has been defined, the units of
biological activity shall be expressed in such a way as to provide unam-
biguous information on the activity of the substances by using where
applicable the European Pharmacopoeia Units.
3.2.2.2. Pharmaceutical development
This chapter shall be devoted to information on the development studies
conducted to establish that the dosage form, the formulation, manufac-
turing process, container closure system, microbiological attributes and
usage instructions are appropriate for the intended use specified in the
marketing authorisation application dossier.
The studies described in this chapter are distinct from routine control
tests conducted according to specifications. Critical parameters of the
formulation and process attributes that can influence batch reproduci-
bility, medicinal product performance and medicinal product quality
shall be identified and described. Additional supportive data, where
appropriate, shall be referenced to the relevant chapters of Module 4
(Non Clinical Study Reports) and Module 5 (Clinical Study Reports)
of the marketing authorisation application dossier.
a) The compatibility of the active substance with excipients as well as
key physicochemical characteristics of the active substance that can
influence the performance of the finished product or the compat-
ibility of different active substances with each other in the case of
combination products, shall be documented.
b) The choice of excipients, in particular relative to their respective
functions and concentration shall be documented.
c) A description of the development of the finished product shall be
provided, taking into consideration the proposed route of administra-
tion and usage.
d) Any overages in the formulation(s) shall be warranted.
e) As far as the physiochemical and biological properties are
concerned, any parameter relevant to the performance of finished
product shall be addressed and documented.
f) The selection and optimisation of the manufacturing process as well
as differences between the manufacturing process(es) used to
produce pivotal clinical batches and the process used for manufac-
turing the proposed finished medicinal product shall be provided.
g) The suitability of the container and closure system used for the
storage, shipping and use of the finished product shall be docu-
mented. A possible interaction between medicinal product and
container may need to be considered.
h) The microbiological attributes of the dosage form in relation with
non-sterile and sterile products shall be in accordance with and
documented as prescribed in the European Pharmacopoeia.
i) In order to provide appropriate and supportive information for the
labelling the compatibility of the finished product with reconstitution
diluent(s) or dosage devices shall be documented.
3.2.2.3. Manufacturing process of the finished medicinal pr oduct
a) The description of the manufacturing method accompanying the
application for Marketing Authorisation pursuant to Article 8 (3) (d),
shall be drafted in such a way as to give an adequate synopsis of the
nature of the operations employed.
For this purpose it shall include at least:
— mention of the various stages of manufacture including process
controls and corresponding acceptance criteria, so that an assess-
ment can be made of whether the processes employed in
producing the pharmaceutical form might have produced an
adverse change in the constituents,2001L0083 — EN — 01.07.2003 — 002.001 — 64
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— in the case of continuous manufacture, full details concerning
precautions taken to ensure the homogeneity of the finished
product,
— experimental studies validating the manufacturing process, where
a non-standard method of manufacture is used or where it is
critical for the product,
— for sterile medicinal products, details of the sterilisation
processes and/or aseptic procedures used,
— a detailed batch formula.
The name, address, and responsibility of each manufacturer,
including contractors, and each proposed production site or facility
involved in manufacturing and testing shall be provided.
b) Particulars relating to the product control tests that may be carried
out at an intermediate stage of the manufacturing process, with a
view to ensuring the consistency of the production process shall be
included.
These tests are essential for checking the conformity of the medic-
inal product with the formula when, exceptionally, an applicant
proposes an analytical method for testing the finished product which
does not include the assay of all the active substances (or of all the
excipient constituents subject to the same requirements as the active
substances).
The same applies where the quality control of the finished product
depends on in-process control tests, particularly if the medicinal
product is essentially defined by its method of preparation.
c) Description, documentation, and results of the validation studies for
critical steps or critical assays used in the manufacturing process
shall be provided.
3.2.2.4. Control of excipients
a) All the materials needed in order to manufacture the excipient(s)
shall be listed identifying where each material is used in the process.
Information on the quality and control of these materials shall be
provided. Information demonstrating that materials meet standards
appropriate for their intended use shall be provided.
Colouring matter shall, in all cases, satisfy the requirements of
Directives 78/25/EEC and/or 94/36/EC. In addition, colouring matter
shall meet purity criteria as laid down in Directive 95/45/EC, as
amended.
b) For each excipient, the specifications and their justifications shall be
detailed. The analytical procedures shall be described and duly vali-
dated.
c) Specific attention shall be paid to excipients of human or animal
origin.
Regarding the specific measures for the prevention of the Transmis-
sion of animal Spongiform Encephalopathies, the applicant must
demonstrate also for excipients that the medicinal product is manu-
factured in accordance with the Note for Guidance on Minimising
the Risk of Transmitting Animal Spongiform Encephalopathy
Agents via Medicinal Products and its updates, published by the
Commission in the Official Journal of the European Union.
Demonstration of compliance with the aforementioned Note for
Guidance can be done by submitting either preferably a certificate
of suitability to the relevant monograph on Transmissible Spongi-
form Encephalopathies of the European Pharmacopoeia, or by the
supply of scientific data to substantiate this compliance.
d) Novel excipients:
For excipient(s) used for the first time in a medicinal product or by
a new route of administration, full details of manufacture, character-
isation, and controls, with cross references to supporting safety data,
both non-clinical and clinical, shall be provided according to the
active substance format previously described.
A document containing the detailed chemical, pharmaceutical and
biological information shall be presented. This information shall be
formatted in the same order as the chapter devoted to Active
Substance(s) of Module 3.
Information on novel excipient(s) may be presented as a stand-alone
document following the format described in the former paragraphs.
Where the applicant differs from the novel excipient manufacturer2001L0083 — EN — 01.07.2003 — 002.001 — 65
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the said stand-alone document shall be made available to the appli-
cant for submission to the competent authority.
Additional information on toxicity studies with the novel excipient
shall be provided in Module 4 of the dossier.
Clinical studies shall be provided in Module 5.
3.2.2.5. Control of the finished medicinal pr oduct
For the control of the finished medicinal product, a batch of a medicinal
product is an entity which comprises all the units of a pharmaceutical
form which are made from the same initial quantity of material and
have undergone the same series of manufacturing and/or sterilisation
operations or, in the case of a continuous production process, all the
units manufactured in a given period of time.
Unless there is appropriate justification, the maximum acceptable devia-
tion in the active substance content of the finished product shall not
exceed ± 5 % at the time of manufacture.
Detailed information on the specifications, (release and shelf life) justi-
fication for their choice, methods of analysis and their validation shall
be provided.
3.2.2.6. Reference standards or materials
Reference preparations and standards used for testing of the finished
medicinal product shall be identified and described in detail, if not
previously provided in the section related to the active substance.
3.2.2.7. Container and closure of the finished medicinal product
A description of the container and the closure system(s) including the
identity of each immediate packaging material and their specifications
shall be provided. The specifications shall include description and iden-
tification. Non-pharmacopoeial methods (with validation) shall be
included where appropriate.
For non-functional outer packaging materials only a brief description
shall be provided. For functional outer packaging materials additional
information shall be provided.
3.2.2.8. Stability of the finished medicinal pr oduct
a) The types of studies conducted, protocols used, and the results of the
studies shall be summarised;
b) Detailed results of the stability studies, including information on the
analytical procedures used to generate the data and validation of
these procedures shall be presented in an appropriate format; in
case of vaccines, information on cumulative stability shall be
provided where appropriate;
c) The post authorisation stability protocol and stability commitment
shall be provided.
4. MODULE 4: NON-CLINICAL REPORTS
4.1.FormatandPresentation
The general outline of Module 4 is as follows:
— Table of contents
— Study reports
—Pharmacology
— Primary Pharmaco-dynamics
— Secondary Pharmaco-dynamics
— Safety Pharmacology
— Pharmaco-dynamic Interactions
—Pharmaco-kinetics
— Analytical Methods and Validation Reports
— Absorption
— Distribution
— Metabolism— Excretion
— Pharmaco-kinetic Interactions (non-clinical)
— Other Pharmaco-kinetic Studies2001L0083 — EN — 01.07.2003 — 002.001 — 66
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—Toxicology
— Single-Dose Toxicity
— Repeat-Dose Toxicity
— Genotoxicity
— In vitro
— In vivo (including supportive toxico-kinetics evaluations)
— Carcinogenicity
— Long-term studies
— Short- or medium-term studies
— Other studies
— Reproductive and Developmental Toxicity
— Fertility and early embryonic development
— Embryo-fetal development
— Prenatal and postnatal development
— Studies in which the offspring (juvenile animals) are
dosed and/or further evaluated
— Local Tolerance
—Other Toxicity Studies
— Antigenicity
— Immuno-toxicity
— Mechanistic studies
— Dependence
— Metabolites
— Impurities
— Other
— Literature references
4.2.Content:basicprinciplesandrequirements
Special attention shall be paid to the following selected elements.
(1) The pharmacological and toxicological tests must show:
a) the potential toxicity of the product and any dangerous or unde-
sirable toxic effects that may occur under the proposed
conditions of use in human beings; these should be evaluated
in relation to the pathological condition concerned;
b) the pharmacological properties of the product, in both qualita-
tive and quantitative relationship to the proposed use in human
beings. All results must be reliable and of general applicability.
Whenever appropriate, mathematical and statistical procedures
shall be used in designing the experimental methods and in eval-
uating the results.
Additionally, it is necessary for clinicians to be given informa-
tion about the therapeutic and toxicological potential of the
product.
(2) For biological medicinal products such as immunological medicinal
products and medicinal products derived from human blood or
plasma, the requirements of this Module may have to be adapted
for individual products; therefore the testing program carried out
shall be justified by the applicant.
In establishing the testing program, 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 interfer-
ence by, antibodies;
examination of reproductive function, of embryo/foetal and peri-
natal toxicity, of mutagenic potential and of carcinogenic potential
shall be considered. Where constituents other than the active
substance(s) are incriminated, validation of their removal may
replace the study.
(3) The toxicology and pharmaco-kinetics of an excipient used for the
first time in the pharmaceutical field shall be investigated.
(4) Where there is a possibility of significant degradation during
storage of the medicinal product, the toxicology of degradation
products must be considered.2001L0083 — EN — 01.07.2003 — 002.001 — 67
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4.2.1. Pharmacology
Pharmacology study shall follow two distinct lines of approach.
— Firstly, the actions relating to the proposed therapeutic use shall be
adequately investigated and described. Where possible, recognised
and validated assays, both in vivo and in vitro, shall be used. Novel
experimental techniques must be described in such detail as to allow
them to be reproduced. The results shall be expressed in quantitative
terms using, for example, dose-effect curves, time-effect curves, etc.
Wherever possible, comparisons shall be made with data relating to
a substance or substances with a similar therapeutic action.
— Secondly, the applicant shall investigate the potential undesirable
pharmaco-dynamic effects of the substance on physiological func-
tions. These investigations shall be performed at exposures in the
anticipated therapeutic range and above. The experimental techni-
ques, unless they are standard procedures, must be described in
such detail as to allow them to be reproduced, and the investigator
must establish their validity. Any suspected modification of
responses resulting from repeated administration of the substance
shall be investigated.
For the pharmaco-dynamic medicinal product interaction, tests on
combinations of active substances may be prompted either by pharma-
cological premises or by indications of therapeutic effect. In the first
case, the pharmaco-dynamic study shall demonstrate those interactions,
which might make the combination of value in therapeutic use. In the
second case, where scientific justification for the combination is sought
through therapeutic experimentation, the investigation shall determine
whether the effects expected from the combination can be demonstrated
in animals, and the importance of any collateral effects shall at least be
investigated.
4.2.2. Pharmaco-kinetics
Pharmaco-kinetics means the study of the fate of the active substance,
and its metabolites, within the organism, and covers the study of the
absorption, distribution, metabolism (bio-transformation) and excretion
of these substances.
The study of these different phases may be carried mainly by means of
physical, chemical or possibly by biological methods, and by observa-
tion of the actual pharmaco-dynamic activity of the substance itself.
Information on distribution and elimination shall be necessary in all
cases where such data are indispensable to determine the dosage for
humans, and in respect of chemo-therapeutic substances (antibiotics,
etc.) and substances whose use depends on their non-pharmaco-dynamic
effects (e.g. numerous diagnostic agents, etc.).
In vitro studies also can be carried out with the advantage of using
human material for comparison with animal material (i.e. protein
binding, metabolism, drug-drug interaction).
Pharmaco-kinetic investigation of all pharmacologically active
substances is necessary. In the case of new combinations of known
substances, which have been investigated in accordance with the provi-
sions of this Directive, pharmaco-kinetic studies may not be required, if
the toxicity tests and therapeutic experimentation justify their omission.
The pharmaco-kinetic program shall be design to allow comparison and
extrapolation between animal and human.
4.2.3. Toxicology
a) Single-dose toxicity
A single-dose toxicity test shall mean a qualitative and quantitative
study of the toxic reactions, which may result from a single admin-
istration of the active substance or substances contained in the
medicinal product, in the proportions and physico-chemical state in
which they are present in the actual product.
The single-dose toxicity test must be carried out in accordance with
the relevant guidelines published by the Agency.
b) Repeat-dose toxicity
Repeated dose toxicity tests are intended to reveal any physiological
and/or anatomo-pathological changes induced by repeated adminis-
tration of the active substance or combination of active substances
under examination, and to determine how these changes are related
to dosage.2001L0083 — EN — 01.07.2003 — 002.001 — 68
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Generally, it is desirable that two tests be performed: one short term,
lasting two to four weeks, the other long-term. The duration of the
latter shall depend on the conditions of clinical use. Its purpose is to
describe potential adverse effects to which attention should be paid
in clinical studies. The duration is defined in the relevant guidelines
published by the Agency.
c) Geno-toxicity
The purposes of the study of mutagenic and clastogenic potential is
to reveal the changes which a substance may cause in the genetic
material of individuals or cells. Mutagenic substances may present
a hazard to health since exposure to a mutagen carries the risk of
inducing germ-line mutation, with the possibility of inherited disor-
ders, and the risk of somatic mutations including those leading to
cancer. These studies are obligatory for any new substance.
d) Carcino-genicity
Tests to reveal carcinogenic effects shall normally be required:
1. These studies shall be performed for any medicinal product
whose expected clinical use is for a prolonged period of a
patient's life, either continuously or repeatedly in an intermittent
manner.
2. These studies are recommended for some medicinal products if
there is concern about their carcinogenic potential, e.g. from
product of the same class or similar structure, or from evidence
in repeated dose toxicity studies.
3. Studies with unequivocally geno-toxic compounds are not
needed, as they are presumed to be trans-species carcinogens,
implying a hazard to humans. If such a medicinal product is
intended to be administered chronically to humans a chronic
study may be necessary to detect early tumorigenic effects.
e) Reproductive and developmental toxicity
Investigation of possible impairment of male or female reproductive
function as well as harmful effects on progeny shall be performed
by appropriate tests.
These tests comprise studies of effect on adult male or female repro-
ductive function, studies of the toxic and teratogenic effects at all
stages of development from conception to sexual maturity as well
as latent effects, when the medicinal product under investigation
has been administered to the female during pregnancy.
Omission of these tests must be adequately justified.Depending on the indicated use of the medicinal product, additional
studies addressing development when administering the medicinal
product of the offspring may be warranted.
Embryo/foetal toxicity studies shall normally be conducted on two
mammalian species, one of which shall be other than a rodent.
Peri- and postnatal studies shall be conducted in at least one species.
If the metabolism of a medicinal product in particular species is
known to be similar to that in man, it is desirable to include this
species. It is also desirable that one of the species is the same as in
the repeated dose toxicity studies.
The state of scientific knowledge at the time when the application is
lodged shall be taken into account when determining the study
design.
f) Local tolerance
The purpose of local tolerance studies is to ascertain whether medic-
inal products (both active substances and excipients) are tolerated at
sites in the body, which may come into contact with the medicinal
product as a result of its administration in clinical use. The testing
strategy shall be such that any mechanical effects of administration
or purely physico-chemical actions of the product can be distin-
guished from toxicological or pharmaco-dynamic ones.
Local tolerance testing shall be conducted with the preparation being
developed for human use, using the vehicle and/or excipients in
treating the control group(s). Positive controls/reference substances
shall be included where necessary.
The design of local tolerance tests (choice of species, duration,
frequency and route of administration, doses) will depend upon the
problem to be investigated and the proposed conditions of adminis-
tration in clinical use. Reversibility of local lesions shall be
performed where relevant.2001L0083 — EN — 01.07.2003 — 002.001 — 69
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Studies in animals can be substituted by validated in vitro tests
provided that the test results are of comparable quality and useful-
ness for the purpose of safety evaluation.
For chemicals applied to the skin (e.g. dermal, rectal, vaginal) the
sensitising potential shall be evaluated in at least one of the test
systems currently available (the guinea pig assay or the local lymph
node assay).
5. MODULE 5: CLINICAL STUDY REPORTS
5.1.FormatandPresentation
The general outline of Module 5 is as follows:
— Table of contents for clinical study reports
— Tabular listing of all clinical studies— Clinical study reports
—Reports of Bio-pharmaceutical Studies
— Bio-availability Study Reports
— Comparative Bio-availability and Bio-equivalence Study
Reports
— In vitro — In vivo Correlation Study Report
— Reports of Bio-analytical and Analytical Methods
—Reports of Studies Pertinent to Pharmaco-kinetics Using Human
Bio-materials
— Plasma Protein Binding Study Reports
— Reports of Hepatic Metabolism and Interaction Studies
— Reports of Studies Using Other Human Bio-materials
—Reports of Human Pharmaco-kinetic Studies
— Healthy subjects Pharmaco-kinetics and Initial Tolerability
Study Reports
— Patient Pharmaco-kinetics and Initial Tolerability Study
Reports
— Intrinsic Factor Pharmaco-kinetics Study Reports— Extrinsic Factor Pharmaco-kinetics Study Reports
— Population Pharmaco-kinetics Study Reports
—Reports of Human Pharmaco-dynamic Studies
— Healthy Subject Pharmaco-dynamic and Pharmaco-kinetics/
Pharmaco-dynamic Study Reports
— Patient Pharmaco-dynamic and Pharmaco-kinetics/Phar-
maco-dynamic Studies Study Reports
—Reports of Efficacy and Safety Studies
— Study Reports of Controlled Clinical Studies Pertinent to the
Claimed Indication
— Study Reports of Uncontrolled Clinical Studies
— Reports of Analyses of Data from More than One Study
including any formal integrated analyses, meta-analyses and
bridging analyses
— Other Study Reports
—Reports of Post-marketing Experience
— Literature references
5.2.Content:basicprinciplesandrequirements
Special attention shall be paid to the following selected elements.
a) The clinical particulars to be provided pursuant to Articles 8 (3) (i)
and 10 (1) must enable a sufficiently well-founded and scientifically
valid opinion to be formed as to whether the medicinal product
satisfies the criteria governing the granting of a marketing authorisa-
tion. Consequently, an essential requirement is that the results of all
clinical trials should be communicated, both favourable and unfa-
vourable.
b) Clinical trials must always be preceded by adequate pharmacological
and toxicological tests, carried out on animals in accordance with
the requirements of Module 4 of this Annex. The investigator must
acquaint himself with the conclusions drawn from the pharmacolo-
gical and toxicological studies and hence the applicant must
provide him at least with the investigator's brochure, consisting of
all the relevant information known prior to the onset of a clinical2001L0083 — EN — 01.07.2003 — 002.001 — 70
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trial including chemical, pharmaceutical and biological data, toxico-
logical, pharmaco-kinetic and pharmaco-dynamic data in animals
and the results of earlier clinical trials, with adequate data to justify
the nature, scale and duration of the proposed trial; the complete
pharmacological and toxicological reports shall be provided on
request. For materials of human or animal origin, all available
means shall be employed to ensure safety from transmission of
infectious agents prior to the commencement of the trial.
c) Marketing authorisation holders must arrange for essential clinical
trial documents (including case report forms) other than subject's
medical files, to be kept by the owners of the data:
— for at least 15 years after completion or discontinuation of the
trial,
— or for at least two years after the granting of the last marketing
authorisation in the European Community and when there are no
pending or contemplated marketing applications in the European
Community,
— or for at least two years after formal discontinuation of clinical
development of the investigational product.
Subject's medical files should be retained in accordance with applic-
able legislation and in accordance with the maximum period of time
permitted by the hospital, institution or private practice.
The documents can be retained for a longer period, however, if
required by the applicable regulatory requirements or by agreement
with the sponsor. It is the responsibility of the sponsor to inform the
hospital, institution or practice as to when these documents no
longer need to be retained.
The sponsor or other owner of the data shall retain all other docu-
mentation pertaining to the trial as long as the product is
authorised. This documentation shall include: the protocol including
the rationale, objectives and statistical design and methodology of
the trial, with conditions under which it is performed and managed,
and details of the investigational product, the reference medicinal
product and/or the placebo used; standard operating procedures; all
written opinions on the protocol and procedures; the investigator's
brochure; case report forms on each trial subject; final report; audit
certificate(s), if available. The final report shall be retained by the
sponsor or subsequent owner, for five years after the medicinal
product is no longer authorised.
In addition for trials conducted within the European Community, the
marketing authorisation holder shall make any additional arrange-
ments for archiving of documentation in accordance with the
provisions of Directive 2001/20/EC and implementing detailed
guidelines.
Any change of ownershipof the data shall be documented.
All data and documents shall be made available if requested by rele-
vant authorities.
d) The particulars of each clinical trial must contain sufficient detail to
allow an objective judgement to be made:
— the protocol, including the rationale, objectives and statistical
design and methodology of the trial, with conditions under
which it is performed and managed, and details of the investiga-
tional medicinal product used
— audit certificate(s), if available— the list of investigator(s), and each investigator shall give his
name, address, appointments, qualifications and clinical duties,
state where the trial was carried out and assemble the informa-
tion in respect of each patient individually, including case
report forms on each trial subject
— final report signed by the investigator and for multi-centre trials,
by all the investigators or the co-ordinating (principal) investi-
gator.
e) The particulars of clinical trials referred to above shall be forwarded
to the competent authorities. However, in agreement with the
competent authorities, the applicant may omit part of this informa-
tion. Complete documentation shall be provided forthwith upon
request.
The investigator shall, in his conclusions on the experimental
evidence, express an opinion on the safety of the product under
normal conditions of use, its tolerance, its efficacy and any useful
information relating to indications and contra-indications, dosage2001L0083 — EN — 01.07.2003 — 002.001 — 71
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and average duration of treatment as well as any special precautions
to be taken during treatment and the clinical symptoms of over
dosage. In reporting the results of a multi-centre study, the principal
investigator shall, in his conclusions, express an opinion on the
safety and efficacy of the investigational medicinal product on
behalf of all centres.
f) The clinical observations shall be summarised for each trial indi-
cating:
1) the number and sex of subjects treated;
2) the selection and age-distribution of the groups of patients being
investigated and the comparative tests;
3) the number of patients withdrawn prematurely from the trials and
the reasons for such withdrawal;
4) where controlled trials were carried out under the above condi-
tions, whether the control group:
— received no treatment
— received a placebo— received another medicinal product of known effect— received treatment other than therapy using medicinal
products
5) the frequency of observed adverse reactions;6) details concerning patients who may be at increased risk, e.g.
elderly people, children, women during pregnancy or menstrua-
tion, or whose physiological or pathological condition requires
special consideration;
7) parameters or evaluation criteria of efficacy and the results in
terms of these parameters;
8) a statistical evaluation of the results when this is called for by the
design of the trials and the variable factors involved.
g) In addition, the investigator shall always indicate his observations
on:
1) any signs of habituation, addiction or difficulty in weaning
patients from the medicinal product;
2) any interactions that have been observed with other medicinal
products administered concomitantly;
3) the criteria determining exclusion of certain patients from the
trials;
4) any deaths which occurred during the trial or within the follow-
upp eriod.
h) Particulars concerning a new combination of medicinal substances
must be identical to those required for new medicinal products and
must substantiate the safety and efficacy of the combination.
i) Total or partial omission of data must be explained. Should unex-
pected results occur during the course of the trials, further pre
clinical toxicological and pharmacological tests must be undertaken
and reviewed.
j) If the medicinal product is intended for long-term administration,
particulars shall be given of any modification of the pharmacolo-
gical action following repeated administration, as well as the
establishment of long-term dosage.
5.2.1. Reports of bio-pharmaceutics studies
Bio-availability study reports, comparative bio-availability, bio-equiva-
lence study reports, reports on in vitro and in vivo correlation study,
and bio-analytical and analytical methods shall be provided.
In addition, an assessment of bio-availability shall be undertaken where
necessary to demonstrate bio-equivalence for the medicinal products
referred to in Article 10 (1) (a).
5.2.2. Reports of studies pertinent to pharmaco-kinetics using human bio-
materials
For the purposes of this Annex, human bio-materials shall mean any
proteins, cells, tissues and related materials derived from human sources
that are used in vitro or ex vivo to assess pharmaco-kinetics properties
of drug substances.2001L0083 — EN — 01.07.2003 — 002.001 — 72
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In this respect, reports of plasma protein binding study, hepatic metabo-
lism and active substance interaction studies and studies using other
human bio-materials shall be provided.
5.2.3. Reports of human pharmaco-kinetic studies
a) The following pharmaco-kinetic characteristics shall be described:
— absorption (rate and extent),
— distribution,— metabolism,
— excretion.
Clinically significant features including the implication of the
kinetic data for the dosage regimen especially for patients at risk,
and differences between man and animal species used in the pre
clinical studies, shall be described.
In addition to standard multiple-sample pharmaco-kinetics studies,
population pharmaco-kinetics analyses based on sparse sampling
during clinical studies can also address questions about the contribu-
tions of intrinsic and extrinsic factors to the variability in the dose-
pharmaco-kinetics response relationship. Reports of pharmaco-
kinetic and initial tolerability studies in healthy subjects and inpatients, reports of pharmaco-kinetic studies to assess effects of
intrinsic and extrinsic factors, and reports of population pharmaco-
kinetic studies shall be provided.
b) If the medicinal product is normally to be administered concomi-
tantly with other medicinal products, particulars shall be given of
joint administration tests performed to demonstrate possible modifi-
cation of the pharmacological action.
Pharmaco-kinetic interactions between the active substance and
other medicinal products or substances shall be investigated.
5.2.4. Reports of human pharmaco-dynamic studies
a) The pharmaco-dynamic action correlated to the efficacy shall be
demonstrated including:
— the dose-response relationship and its time course,
— justification for the dosage and conditions of administration,
— the mode of action, if possible.
The pharmaco-dynamic action not related to efficacy shall be
described.
The demonstration of pharmaco-dynamic effects in human beings
shall not in itself be sufficient to justify conclusions regarding any
particular potential therapeutic effect.
b) If the medicinal product is normally to be administered concomi-
tantly with other medicinal products, particulars shall be given of
joint administration tests performed to demonstrate possible modifi-
cation of the pharmacological action.
Pharmaco-dynamic interactions between the active substance and
other medicinal products or substances shall be investigated.
5.2.5. Reports of efficacy and safety studies
5.2.5.1. Study Reports of Controlled Clinical Studies Pertinent to
the Claimed Indication
In general, clinical trials shall be done as ‘controlled clinical trials’ if
possible, randomised and as appropriate versus placebo and versus an
established medicinal product of proven therapeutic value; any other
design shall be justified. The treatment of the control groups will vary
from case to case and also will depend on ethical considerations and
therapeutic area; thus it may, in some instances, be more pertinent to
compare the efficacy of a new medicinal product with that of an estab-
lished medicinal product of proven therapeutic value rather than with
the effect of a placebo.
(1) As far as possible, and particularly in trials where the effect of the
product cannot be objectively measured, steps shall be taken to
avoid bias, including methods of randomisation and blinding.
(2) The protocol of the trial must include a thorough description of the
statistical methods to be employed, the number and reasons for
inclusion of patients (including calculations of the power of the
trial), the level of significance to be used and a description of the
statistical unit. Measures taken to avoid bias, particularly methods
of randomisation, shall be documented. Inclusion of a large number2001L0083 — EN — 01.07.2003 — 002.001 — 73
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of subjects in a trial must not be regarded as an adequate substitute
for a properly controlled trial.
The safety data shall be reviewed taking into account guidelines
published by the Commission, with particular attention to events
resulting in changes of dose or need for concomitant medication,
serious adverse events, events resulting in withdrawal, and deaths. Any
patients or patient groups at increased risk shall be identified and parti-
cular attention paid to potentially vulnerable patients who may be
present in small numbers, e.g., children, pregnant women, frail elderly,
people with marked abnormalities of metabolism or excretion etc. The
implication of the safety evaluation for the possible uses of the medic-
inal product shall be described.
5.2.5.2. Study reports of uncontrolled clinical studies reports of
analyses of data from more than one study and other clin-
ical study reports
These reports shall be provided.
5.2.6. Reports of post-marketing experience
If the medicinal product is already authorised in third countries, infor-
mation shall be given in respect of adverse reactions of the medicinal
product concerned and medicinal products containing the same active
substance(s), in relation to the usage rates if possible.
5.2.7. Case reports forms and individual patient listings
When submitted in accordance with the relevant Guideline published by
the Agency, case report forms and individual patient data listings shall
be provided and presented in the same order as the clinical study
reports and indexed by study.
PART II
SPECIFIC MARKETING AUTHORISATION DOSSIERS AND
REQUIREMENTS
Some medicinal products present specific features which are such that all the
requirements of the marketing authorisation application dossier as laid down in
Part I of this Annex need to be adapted. To take account of these particular
situations, an appropriate and adapted presentation of the dossier shall be
followed by applicants.
1. WELL-ESTABLISHED MEDICINAL USE
For medicinal products the active substance(s) of which has/have a
‘well-established medicinal use’ as referred to Article 10(1)(a)(ii), with
recognised efficacy and an acceptable level of safety, the following
specific rules shall apply.
The applicant shall submit Modules 1, 2 and 3 as described in part I of
this Annex.
For Modules 4 and 5, a detailed scientific bibliography shall address
non-clinical and clinical characteristics.
The following specific rules shall apply in order to demonstrate the
well-established medicinal use:
a) Factors which have to be taken into account in order to establish a
well-established medicinal use of constituents of medicinal products
are:
— the time over which a substance has been used,
— quantitative aspects of the use of the substance,
— the degree of scientific interest in the use of the substance
(reflected in the published scientific literature) and
— the coherence of scientific assessments.
Therefore different periods of time may be necessary for estab-
lishing well-established use of different substances. In any case,
however, the period of time required for establishing a well estab-
lished medicinal use of a constituent of a medicinal product must
not be less than one decade from the first systematic and docu-
mented use of that substance as a medicinal product in the
Community.
b) The documentation submitted by the applicant should cover all
aspects of the safety and/or efficacy assessment and must include
or refer to a review of the relevant literature, taking into account
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concerning experience in the form of epidemiological studies and in
particular of comparative epidemiological studies. All documenta-
tion, both favourable and unfavourable, must be communicated.
With respect to the provisions on ‘well-established medicinal use’
it is in particular necessary to clarify that ‘bibliographic reference’
to other sources of evidence (post marketing studies, epidemiolo-
gical studies, etc.) and not just data related to tests and trials may
serve as a valid proof of safety and efficacy of a product if an appli-
cation explains and justifies the use of these sources of information
satisfactorily.
c) Particular attention must be paid to any missing information and
justification must be given why demonstration of an acceptable level
of safety and/or efficacy can be supported although some studies are
lacking.
d) The non-clinical and/or clinical overviews must explain the rele-
vance of any data submitted which concern a product different
from the product intended for marketing. A judgement must be
made whether the product studied can be considered as similar to
the product, for which application for a marketing authorisation has
been made in spite of the existing differences.
e) Post-marketing experience with other products containing the same
constituents is of particular importance and applicants should put a
special emphasis on this issue.
2. ESSENTIALLY SIMILAR MEDICINAL PRODUCTS
a) Applications based upon Article 10(1) (a) (i) (essentially similar
products) shall contain the data described in Modules 1, 2 and 3 of
Part I of this Annex provided the applicant has been granted the
consent of the holder of the original marketing authorisation to cross
refer to the content of his Modules 4 and 5.
b) Applications based upon Article 10(1) (a) (iii) (essentially similar
products i.e. generics) shall contain the data described in Modules 1,
2 and 3 of Part I of this Annex together with data showing bio-avail-
ability and bio-equivalence with the original medicinal product
provided the latter is not a biological medicinal product (see Part II,
4 Similar biological medicinal products).
For these products the non-clinical/clinical overviews/summaries shall
particularly focus on the following elements:
— the grounds for claiming essential similarity;
— a summary of impurities present in batches of the active
substance(s) as well as those of the finished medicinal product
(and where relevant decomposition products arising during storage)
as proposed for use in the product to be marketed together with an
evaluation of these impurities;
— an evaluation of the bio-equivalence studies or a justification why
studies were not performed with respect to the guideline on ‘Inves-
tigation of Bio-availability and Bio-equivalence’;
— an update of published literature relevant to the substance and the
present application. It may be acceptable for articles in ‘peer
review’ journals to be annotated for this purpose;
— every claim in the summary of product characteristics not known
from or inferred from the properties of the medicinal product and/
or its therapeutic group should be discussed in the non clinical/clin-
ical overviews/summaries and substantiated by published literature
and/or additional studies.
— if applicable, additional data in order to demonstrate evidence on
the equivalence of safety and efficacy properties of different salts,
esters or derivatives of an authorised active substance should be
provided by the applicant when he claims essential similarity.
3. ADDITIONAL DATA REQUIRED IN SPECIFIC SITUATIONS
Where the active substance of an essentially similar medicinal product
contains the same therapeutic moiety as the original authorised product
associated with a different salt/ester complex/derivative evidence that
there is no change in the pharmaco-kinetics of the moiety, pharmaco-
dynamics and/or in toxicity which could change the safety/efficacy
profile shall be demonstrated. Should this not be the case, this associa-
tion shall be considered as a new active substance.
Where a medicinal product is intended for a different therapeutic use or
presented in a different pharmaceutical form or to be administered by
different routes or in different doses or with a different posology, the2001L0083 — EN — 01.07.2003 — 002.001 — 75
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results of appropriate toxicological and pharmacological tests and/or of
clinical trials shall be provided.
4. SIMILAR BIOLOGICAL MEDICINAL PRODUCTS
The provisions of Article 10(1)(a) (iii) may not be sufficient in the case
of biological medicinal products. If the information required in the case
of essentially similar products (generics) does not permit the demonstra-
tion of the similar nature of two biological medicinal products,
additional data, in particular, the toxicological and clinical profile shall
be provided.
When a biological medicinal product as defined in Part I, paragraph 3.2
of this Annex, which refers to an original medicinal product having
been granted a marketing authorisation in the Community, is submitted
for a marketing authorisation by an independent applicant after the
expiry of data protection period, the following approach shall be
applied.
— Information to be supplied shall not be limited to Modules 1, 2 and 3
(pharmaceutical, chemical and biological data), supplemented with
bio-equivalence and bio-availability data. The type and amount of
additional data (i.e. toxicological and other non-clinical and appro-
priate clinical data) shall be determined on a case by case basis in
accordance with relevant scientific guidelines.
— Due to the diversity of biological medicinal products, the need for
identified studies foreseen in Modules 4 and 5, shall be required
by the competent authority, taking into account the specific charac-
teristic of each individual medicinal product.
The general principles to be applied are addressed in a guideline taking
into account the characteristics of the concerned biological medicinal
product published by the Agency. In case the originally authorised
medicinal product has more than one indication, the efficacy and safety
of the medicinal product claimed to be similar has to be justified or, if
necessary, demonstrated separately for each of the claimed indications.
5. FIXED COMBINATION MEDICINAL PRODUCTS
Applications based upon Article 10 (1) (b) shall relate to new medicinal
products made of at least two active substances not previously
authorised as a fixed combination medicinal product.
For those applications a full dossier (Modules 1 to 5) shall be provided
for the fixed combination medicinal product. Where applicable, infor-
mation regarding the manufacturing sites and the adventitious agents,
safety evaluation shall be provided.
6. DOCUMENTATION FOR APPLICATIONS IN EXCEPTIONAL
CIRCUMSTANCES
When, as provided for in Article 22, the applicant can show that he is
unable to provide comprehensive data on the efficacy and safety under
normal conditions of use, because:
— the indications for which the product in question is intended are
encountered so rarely that the applicant cannot reasonably be
expected to provide comprehensive evidence, or
— in the present state of scientific knowledge, comprehensive informa-
tion cannot be provided, or
— it would be contrary to generally accepted principles of medical
ethics to collect such information,
marketing authorisation may be granted subject to certain specific obli-
gations.
These obligations may include the following:
— the applicant shall complete an identified programme of studies
within a time period specified by the competent authority, the
results of which shall form the basis of a reassessment of the
benefit/risk profile,
— the medicinal product in question may be supplied on medical
prescription only and may in certain cases be administered only
under strict medical supervision, possibly in a hospital and in the
case of a radio-pharmaceutical, by an authorised person,
— the package leaflet and any medical information shall draw the
attention of the medical practitioner to the fact that the particulars
available concerning the medicinal product in question are as yet
inadequate in certain specified respects.2001L0083 — EN — 01.07.2003 — 002.001 — 76
▼M2
7. MIXED MARKETING AUTHORISATION APPLICATIONS
Mixed marketing-authorisation applications shall mean marketing-
authorisation application dossiers where Module 4 and/or 5 consists of
a combination of reports of limited non-clinical and/or clinical studies
carried out by the applicant and of bibliographical references. All other
Module(s) are in accordance with the structure described in Part I of
this Annex. The competent authority shall accept the proposed format
presented by the applicant on a case by case basis.
PART III
PARTICULARMEDICINALPRODUCTS
This Part lays down specific requirements related to the nature of identified
medicinal products.
1. BIOLOGICAL MEDICINAL PRODUCTS
1.1.Plasma-derivedmedicinalproduct
For medicinal products derived from human blood or plasma and by
derogation from the provisions of Module 3, the dossier requirements
mentioned in ‘Information related to the starting and raw materials’,
for starting materials made of human blood/plasma may be replaced
by a Plasma Master File certified in accordance with this Part.
a) Principles
For the purposes of this Annex:
— Plasma Master File shall mean a stand-alone documentation, which
is separate from the dossier for marketing authorisation which
provides all relevant detailed information on the characteristics of
the entire human plasma used as a starting material and/or a raw
material for the manufacture of sub/intermediate fractions, constitu-
ents of the excipient and active substance(s), which are part of
medicinal products or medical devices referred to in Directive
2000/70/EC of the European Parliament and of the Council of
16 November 2000 amending Council Directive 93/42/EC as
regards medical devices incorporating stable derivatives of humanblood or human plasma (
1).
— Every centre or establishment for fractionation/processing of human
plasma shall prepare and keep updated the set of detailed relevant
information referred to in the Plasma Master File.
— The Plasma Master File shall be submitted to the Agency or to the
competent authority by the applicant for a marketing authorisation
or the holder of the marketing authorisation. Where the applicant
for a marketing authorisation or the marketing authorisation holder
differs from the holder of the Plasma Master File, the Plasma
Master File shall be made available to the applicant or marketing
authorisation holder for submission to the competent authority. In
any case, the applicant or marketing authorisation holder shall take
responsibility for the medicinal product.
— The competent authority that is evaluating the marketing authorisa-
tion shall await for the Agency to issue the certificate before
deciding on the application.
— Any marketing authorisation dossier containing a human plasma-
derived constituent shall refer to the Plasma Master File corre-
sponding to the plasma used as a starting/raw material.
b) Content
In accordance with the provisions of Article 109, as amended by Direc-
tive 2002/98/EC, which refers to the requirements for donors and the
testing of donations, the Plasma Master File shall include information
on the plasma used as starting/raw material, in particular:
(1) Plasma origin
(i) information on centres or establishments in which blood/
plasma collection is carried out, including inspection and
approval, and epidemiological data on blood transmissible
infections.2001L0083 — EN — 01.07.2003 — 002.001 — 77
(1) OJ L 313, 13.12.2000, p. 22.
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(ii) information on centres or establishments in which testing of
donations and plasma pools is carried out, including inspection
and approval status.
(iii) selection/exclusion criteria for blood/plasma donors.(iv) system in place which enables the path taken by each donation
to be traced from the blood/plasma collection establishment
through to finished products and vice versa.
(2) Plasma quality and safety
(i) compliance with European Pharmacopoeia Monographs.
(ii) testing of blood/plasma donations and pools for infectious
agents, including information on test methods and, in the case
of plasma pools, validation data on the tests used.
(iii) technical characteristics of bags for blood and plasma collec-
tion, including information on anticoagulants solutions used.
(iv) conditions of storage and transport of plasma.(v) procedures for any inventory hold and/or quarantine period.(vi) characterisation of the plasma pool.
(3) System in place between the plasma-derived medicinal product
manufacturer and/or plasma fractionator/processor on the one
hand, and blood/plasma collection and testing centres or establish-
ments on the other hand, which defines the conditions of their
interaction and their agreed specifications.
In addition, the Plasma Master File shall provide a list of the
medicinal products for which the Plasma Master File is valid,
whether the medicinal products have been granted a marketing
authorisation or are in the process of being granted such an author-
isation, including medicinal products referred to in Article 2 of
Directive 2001/20/EC of the European Parliament and of the
Council relating to the implementation of good clinical practice in
the conduct of clinical trials on medicinal products for human use.
c) Evaluation and Certification— For medicinal products not yet authorised, the marketing authorisa-
tion applicant shall submit a full dossier to a competent authority,
which shall be accompanied by a separate Plasma Master File
where one does not already exist.
— The Plasma Master File is subject to a scientific and technical
evaluation carried out by the Agency. A positive evaluation shall
result in a certificate of compliance with Community legislation
for the Plasma Master File, which shall be accompanied by the
evaluation report. The certificate issued shall apply throughout the
Community.
— The Plasma Master File shall be updated and re-certified on an
annual basis.
— Changes subsequently introduced to the terms of a Plasma Master
File must follow evaluation procedure laid down by Commission
Regulation (EC) No 542/95(
1) concerning the examination of varia-
tions to the terms of a marketing authorisation falling within the
scope of Council regulation (EEC) No 2309/93 of 22 July 1993
laying down Community procedures for the authorisation and super-
vision of medicinal products for human and veterinary use and
establishing a European Agency for the Evaluation of Medicinal
Products(2). Conditions for the assessment of these changes are
laid down by Regulation (EC) No 1085/2003.
— As a second stepto the p rovisions in the first, second, third and
fourth indents, the competent authority that will grant or has granted
the marketing authorisation shall take into account the certification,
re-certification or variation of the Plasma Master File on the
concerned medicinal product(s).
— By derogation from the provisions of the second indent of the
present point (evaluation and certification), where a Plasma Master
File corresponds only to blood/plasma-derived medicinal products
the marketing authorisation of which is restricted to a single
Member State, the scientific and technical evaluation of the said
Plasma Master File shall be carried out by the national competent
authority of that Member State.2001L0083 — EN — 01.07.2003 — 002.001 — 78
(1) OJ L 55, 11.3.1995, p. 15.
(2) OJ L 214, 24.8.1993, p. 1.
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1.2.Vaccines
For vaccines for human use and by derogation from the provisions of
Module 3 on ‘Active substance(s)’, the following requirements when
based on the use of a Vaccine Antigen Master File system shall apply.
The marketing authorisation application dossier of a vaccine other than
human influenza vaccine, shall be required to include a Vaccine
Antigen Master File for every vaccine antigen that is an active
substance of this vaccine.
a) PrinciplesFor the purposes of this Annex:
— Vaccine Antigen Master File shall mean a stand-alone part of the
marketing authorisation application dossier for a vaccine, which
contains all relevant information of biological, pharmaceutical and
chemical nature concerning each of the active substances, which
are part of this medicinal product. The stand-alone part may be
common to one or more monovalent and/or combined vaccines
presented by the same applicant or marketing authorisation holder.
— A vaccine may contain one or several distinct vaccine antigens.
There are as many active substance(s) as vaccine antigen(s) present
in a vaccine.
— A combined vaccine contains at least two distinct vaccine antigens
aimed at preventing a single or several infectious diseases.
— A monovalent vaccine is a vaccine, which contains one vaccine
antigen aimed at preventing a single infectious disease.
b) Content
The Vaccine Antigen Master File shall contain the following informa-
tion extracted from the relevant part (Active substance) of Module 3 on
‘Quality Data’ as delineated in Part I of this Annex:
Active Substance1. General Information, including compliance with the relevant mono-
graph(s) of the European Pharmacopoeia.
2. Information on the manufacture of the active substance: this heading
must cover the manufacturing process, information on the starting
and raw materials, specific measures on TSEs and adventitious
agents safety evaluation and facilities and equipment.
3. Characterisation of the active substance4. Quality control of the active substance5. Reference standard and materials6. Container and closure system of the active substance7. Stability of the active substance.
c) Evaluation and Certification— For novel vaccines, which contain a novel vaccine antigen, the
applicant shall submit to a competent authority a full marketing-
authorisation application dossier including all the Vaccine Antigen
Master Files corresponding to each single vaccine antigen that is
part of the novel vaccine where no master file already exists for
the single vaccine antigen. A scientific and technical evaluation of
each Vaccine Antigen Master File shall be carried out by the
Agency. A positive evaluation shall result in a certificate of compli-
ance to the European legislation for each Vaccine Antigen Master
File, which shall be accompanied by the evaluation report. The
certificate shall apply throughout the Community.
— The provisions of the first indent shall also apply to every vaccine,
which consists of a novel combination of vaccine antigens, irrespec-
tive of whether or not one or more of these vaccine antigens are
part of vaccines already authorised in the Community.
— Changes to the content of a Vaccine Antigen Master File for a
vaccine authorised in the Community shall be subject to a scientific
and technical evaluation carried out by the Agency in accordance
with the procedure laid down in Commission Regulation (EC)
No 1085/2003. In the case of a positive evaluation the Agency shall
issue a certificate of compliance with Community legislation for the
Vaccine Antigen Master File. The certificate issued shall apply
throughout the Community.
— By derogation from the provisions of the first, second and third
indents of the present point (evaluation and certification), where a2001L0083 — EN — 01.07.2003 — 002.001 — 79
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Vaccine Antigen Master File corresponds only to a vaccine which is
the subject of a marketing authorisation which has not been/will not
be granted according to a Community procedure, and, provided the
authorised vaccine includes vaccine antigens which have not been
evaluated through a Community procedure, the scientific and tech-
nical evaluation of the said Vaccine Antigen Master File and its
subsequent changes, shall be carried out by the national competent
authority that has granted the marketing authorisation.
— As a second stepto the p rovisions in the first, second, third and
fourth indents, the competent authority that will grant or has granted
the marketing authorisation shall take into account the certification,
re-certification or variation of the Vaccine Antigen Master File on
the concerned medicinal product(s).
2. RADIO-PHARMACEUTICALS AND PRECURSORS
2.1.Radio-pharmaceuticals
For the purposes of this chapter, applications based upon Articles 6 (2)
and 9 shall provide a full dossier in which the following specific details
shall be included:
Module 3
a) In the context of a radio-pharmaceutical kit, which is to be radio-
labelled after supply by the manufacturer, the active substance is
considered to be that part of the formulation which is intended tocarry or bind the radio-nuclide. The description of the manufacturing
method of radio-pharmaceutical kits shall include details of the
manufacture of the kit and details of its recommended final proces-
sing to produce the radioactive medicinal product. The necessary
specifications of the radio-nuclide shall be described in accordance,
where relevant, with the general monograph or specific monographs
of the European Pharmacopoeia . In addition, any compounds essen-
tial for the radio-labelling shall be described. The structure of the
radio-labelled compound shall also be described.
For radio-nuclides, the nuclear reactions involved shall be discussed.In a generator, both mother and daughter radio-nuclides shall be
considered as active substances.
b) Details of the nature of the radio-nuclide, the identity of the isotope,
likely impurities, the carrier, the use and the specific activity shall
be provided.
c) Starting materials include irradiation target materials.
d) Considerations on chemical/radiochemical purity and its relationship
to bio-distribution shall be provided.
e) Radio-nuclide purity, radiochemical purity and specific activity shall
be described.
f) For generators, details on the testing for mother and daughter radio-
nuclides are required. For generator-eluates, tests for mother radio-
nuclides and for other constituents of the generator system shall be
provided.
g) The requirement to express the content of active substances in terms
of the mass of active entities shall onlyapply to radio-pharmaceutical
kits. For radio-nuclides, radioactivity shall be expressed inBecquerels at a given date and, if necessary, time with reference to
time zone. The type of radiation shall be indicated.
h) For kits, the specifications of the finished product shall include tests
on performance of products after radio-labelling. Appropriate
controls on radiochemical and radio-nuclidic purity of the radio-
labelled compound shall be included. Any material essential for
radio-labelling shall be identified and assayed.
i) Information on stability shall be given for radio-nuclide generators,
radio-nuclide kits and radio-labelled products. The stability during
use of radio-pharmaceuticals in multi-dose vials shall be docu-
mented.
Module 4
It is appreciated that toxicity may be associated with a radiation dose.
In diagnosis, this is a consequence of the use of radio-pharmaceuticals;
in therapy, it is the property desired. The evaluation of safety and effi-
cacy of radio-pharmaceuticals shall, therefore, address requirements for
medicinal products and radiation dosimetry aspects. Organ/tissue expo-
sure to radiation shall be documented. Absorbed radiation dose2001L0083 — EN — 01.07.2003 — 002.001 — 80
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estimates shall be calculated according to a specified, internationally
recognised system by a particular route of administration.
Module 5The results of clinical trials shall be provided where applicable other-
wise justified in the clinical overviews.
2.2.Radio-pharmaceuticalprecursorsforradio-labelling purposes
In the specific case of a radio-pharmaceutical precursor intended solely
for radio-labelling purposes, the primary objective shall be to presentinformation which would address the possible consequences of poor
radio-labeling efficiency or in vivo dissociation of the radio-labeled
conjugate, i.e. questions related to the effects produced in the patient
by free radio-nuclide. In addition, it is also necessary to present relevant
information relating to occupational hazards, i.e. radiation exposure to
hospital staff and to the environment.
In particular, the following information where applicable shall be
provided:
Module 3The provisions of Module 3 shall apply to the registration of radio-
pharmaceutical precursors as define above (indents a) to i)), where
applicable.
Module 4Concerning single dose and repeat dose toxicity, the results of studies
carried out in conformity with the provisions related to good laboratory
practice laid down in Council Directives 87/18/EEC and 88/320/EEC
shall be provided, unless otherwise justified.
Mutagenicity studies on the radio-nuclide are not considered to be
useful in this particular case.
Information relating to the chemical toxicity and disposition of the rele-
vant ‘cold’ nuclide shall be presented.
Module 5Clinical information generated from clinical studies using on the
precursor itself is not considered to be relevant in the specific case of
a radio-pharmaceutical precursor intended solely for radio-labelling
purposes.
However, information demonstrating the clinical utility of the radio-
pharmaceutical precursor when attached to relevant carrier molecules
shall be presented.
3. HOMEOPATHIC MEDICINAL PRODUCTS
This section sets out specific provisions on the application of Modules 3
and 4 to homeopathic medicinal products as defined in Article 1(5).
Module 3The provisions of Module 3 shall apply to the documents submitted in
accordance with Article 15 in the simplified registration of homeopathic
medicinal products referred to in Article 14(1) as well as to the docu-
ments for authorisation of other homeopathic medicinal products
referred to in Article 16(1) with the following modifications.
a) Terminology
The Latin name of the homeopathic stock described in the marketing
authorisation application dossier must be in accordance with the
Latin title of the European Pharmacopoeia or, in absence thereof,
by an official pharmacopoeia of a Member State. Where relevant
the traditional name(s) used in each Member State shall be provided.
b) Control of starting materials
The particulars and documents on the starting materials, i.e. all of
the materials used including raw materials and intermediates upto
the final dilution to be incorporated into the finished medicinal
product, accompanying the application shall be supplemented by
additional data on the homeopathic stock.
The general quality requirements shall apply to all of the starting
and raw materials as well as intermediate steps of the manufacturing
process up to the final dilution to be incorporated into the finished
medicinal product. If possible, an assay is required if toxic compo-2001L0083 — EN — 01.07.2003 — 002.001 — 81
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nents are present and if the quality cannot be controlled on final
dilution to be incorporated because of the high dilution degree.
Every stepof the manufacturing p rocess from the starting materials
upto the final dilution to be incorp orated into the finished medicinal
product must be fully described.
In case dilutions are involved, these dilution steps should be done in
accordance with the homeopathicmanufacturing methods laid down
in the relevant monograph of the European Pharmacopoeia or, in
absence thereof, by an official pharmacopoeia of a Member State.
c) Control tests on the finished medicinal product
The general quality requirements shall apply to the homeopathic
finished medicinal products, any exception needs to be duly justified
by the applicant.
Identification and assay of all the toxicologically relevant constitu-
ents shall be carried out. If it can be justified that an identification
and/or an assay on all the toxicologically relevant constituents is not
possible e.g. due to their dilution in the finished medicinal product
the quality shall be demonstrated by complete validation of the
manufacturing and dilution process.
d) Stability tests
The stability of the finished medicinal product must be demon-
strated. Stability data from the homeopathic stocks are generally
transferable to dilutions/triturations obtained thereof. If no identifica-
tion or assay of the active substance is possible due to the degree of
dilution, stability data of the pharmaceutical form may be consid-
ered.
Module 4
The provisions of Module 4 shall apply to the simplified registration of
homeopathic medicinal products referred to in Article 14(1) with the
following specifications.
Any missing information must be justified, e.g., justification must be
given why demonstration of an acceptable level of safety can be
supported although some studies are lacking.
4. HERBAL MEDICINAL PRODUCTS
Applications for herbal medicinal products shall provide a full dossier
in which the following specific details shall be included.
Module 3
The provisions of Module 3, including compliance with monograph(s)
of the European Pharmacopoeia, shall apply to the authorisation of
herbal medicinal products. The state of scientific knowledge at the
time when the application is lodged shall be taken into account.
The following aspects specific to herbal medicinal products shall be
considered:
(1) Herbal substances and herbal preparations
For the purposes of this Annex the terms ‘herbal substances and
preparations’ shall be considered equivalent to the terms ‘herbal drugs
and herbal drug preparations’, as defined in the European Pharmaco-
poeia.
With respect to the nomencRlature of the herbal substance, the bino-
mial scientific name of plant (genus, species, variety and author), and
chemotype (where applicable), the parts of the plants, the definition of
the herbal substance, the other names (synonyms mentioned in other
Pharmacopoeias) and the laboratory code shall be provided.
With respect to the nomenclature of the herbal preparation, the bino-
mial scientific name of plant (genus, species, variety and author), and
chemotype (where applicable), the parts of the plants, the definition of
the herbal preparation, the ratio of the herbal substance to the herbal
preparation, the extraction solvent(s), the other names (synonyms
mentioned in other Pharmacopoeias) and the laboratory code shall be
provided.
To document the section of the structure for herbal substance(s) and
herbal preparation(s) where applicable, the physical form, the descrip-
tion of the constituents with known therapeutic activity or markers
(molecular formula, relative molecular mass, structural formula,
including relative and absolute stereo-chemistry, the molecular formula,2001L0083 — EN — 01.07.2003 — 002.001 — 82
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and the relative molecular mass) as well as other constituent(s) shall be
provided.
To document the section on the manufacturer of the herbal substance,
the name, address, and responsibility of each supplier, including
contractors, and each proposed site or facility involved in production/
collection and testing of the herbal substance shall be provided, where
appropriate.
To document the section on the manufacturer of the herbal preparation,
the name, address, and responsibility of each manufacturer, including
contractors, and each proposed manufacturing site or facility involved
in manufacturing and testing of the herbal preparation shall be
provided, where appropriate.
With respect to the description of manufacturing process and process
controls for the herbal substance, information shall be provided to
adequately describe the plant production and plant collection, including
the geographical source of the medicinal plant and cultivation,
harvesting, drying and storage conditions.
With respect to the description of manufacturing process and process
controls for the herbal preparation, information shall be provided to
adequately describe the manufacturing process of the herbal prepara-
tion, including description of the processing, solvents and reagents,
purification stages and standardisation.
With respect to the manufacturing process development, a brief
summary describing the development of the herbal substance(s) and
herbal preparation(s) where applicable shall be provided, taking into
consideration the proposed route of administration and usage. Results
comparing the phyto-chemical composition of the herbal substance(s)
and herbal preparation(s) where applicable used in supporting biblio-
graphic data and the herbal substance(s) and herbal preparation(s),
where applicable, contained as active substance(s) in the herbal medic-
inal product applied for shall be discussed, where appropriate.
With respect to the elucidation of the structure and other characteristics
of the herbal substance, information on the botanical, macroscopical,
microscopical, phyto-chemical characterisation, and biological activity
if necessary, shall be provided.
With respect to the elucidation of the structure and other characteristics
of the herbal preparation, information on the phyto- and physicochem-
ical characterisation, and biological activity if necessary, shall be
provided.
The specifications for the herbal substance(s) and herbal preparation(s)
where applicable shall be provided.
The analytical procedures used for testing the herbal substance(s) and
herbal preparation(s) where applicable shall be provided.
With respect to the validation of analytical procedures, analytical vali-
dation information, including experimental data for the analytical
procedures used for testing the herbal substance(s) and herbal prepara-
tion(s) where applicable shall be provided.
With respect to batch analyses, description of batches and results of
batch analyses for the herbal substance(s) and herbal preparation(s)
where applicable shall be provided, including those for pharmacopoeial
substances.
Justification for the specifications of the herbal substance(s) and herbal
preparation(s) where applicable shall be provided.
Information on the reference standards or reference materials used for
testing of the herbal substance(s) and herbal preparation(s) where
applicable shall be provided.
Where the herbal substance or the herbal preparation is the subject of a
monograph, the applicant can apply for a certificate of suitability thatwas granted by the European Directorate for the Quality of Medicines.
(2) Herbal Medicinal ProductsWith respect to the formulation development, a brief summary
describing the development of the herbal medicinal product should be
provided, taking into consideration the proposed route of administration
and usage. Results comparing the phyto-chemical composition of the
products used in supporting bibliographic data and the herbal medicinal
product applied for shall be discussed, where appropriate.2001L0083 — EN — 01.07.2003 — 002.001 — 83
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5. ORPHAN MEDICINAL PRODUCTS
— In the case of an orphan medicinal product in the meaning of Regu-
lation (EC) No 141/2000, general provisions of Part II-6
(exceptional circumstances) can be applied. The applicant shall
then justify in the non-clinical and clinical summaries the reasons
for which it is not possible to provide the complete information
and shall provide a justification of the benefit/risk balance for the
orphan medicinal product concerned.
— When an applicant for an marketing authorisation for an orphan
medicinal product invokes the provisions of Article 10 (1)(a)(ii)
and Part II-1 of this Annex (well-established medicinal use), the
systematic and documented use of the concerned substance can refer
— as way of derogation — to the use of that substance in accor-
dance with the provisions of Article 5 of this Directive.
PART IV
ADVANCEDTHERAPYMEDICINALPRODUCTS
Advanced therapy medicinal products are based on manufacturing processes
focussed on various gene transfer-produced bio-molecules, and/or biologically
advanced therapeutic modified cells as active substances or part of active
substances.
For those medicinal products the presentation of the Marketing Authorisation
application dossier shall fulfil the format requirements as described in Part I of
this Annex.
Modules 1 to 5 shall apply. For Genetically Modified Organisms deliberate
release in the environment, attention shall be paid to the persistence of the
Genetically Modified Organisms in the recipient and to the possible replication
and/or modification of the Genetically Modified Organisms when released in the
environment. The information concerning the environmental risk should appear
in the Annex to Module 1.
1. GENE THERAPY MEDICINAL PRODUCTS (HUMAN AND XENO-
GENEIC)
For the purposes of this Annex, gene therapy medicinal product shall
mean a product obtained through a set of manufacturing processes
aimed at the transfer, to be performed either in vivo or ex vivo, of a
prophylactic, diagnostic or therapeutic gene (i.e. a piece of nucleic
acid), to human/animal cells and its subsequent expression in vivo.
The gene transfer involves an expression system contained in a delivery
system known as a vector, which can be of viral, as well as non-viral
origin. The vector can also be included in a human or animal cell.
1.1.Diversityofgenetherapymedicinalproducts
a) Gene therapy medicinal products based on allogeneic or xenogeneic
cells
The vector is ready-prepared and stored before its transfer into the
host cells.
The cells have been obtained previously and may be processed as a
cell bank (bank collection or bank established from procurement of
primary cells) with a limited viability.
The cells genetically modified by the vector represent an active
substance.
Additional steps may be carried out in order to obtain the finished
product. By essence, such a medicinal product is intended to be
administered to a certain number of patients.
b) Gene therapy medicinal products using autologous human cells
The active substance is a batch of ready-prepared vector stored
before its transfer into the autologous cells.
Additional steps may be carried out in order to obtain the finished
medicinal product.
Those products are prepared from cells obtained from an individual
patient. The cells are then genetically modified using a ready-
prepared vector containing the appropriate gene that has been
prepared in advance and that constitutes the active substance. The
preparation is re-injected into the patient and is by definition2001L0083 — EN — 01.07.2003 — 002.001 — 84
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intended to a single patient. The whole manufacturing process from
the collection of the cells from the patient up to the re-injection to
the patient shall be considered as one intervention.
c) Administration of ready-prepared vectors with inserted (prophy-
lactic, diagnostic or therapeutic) genetic material
The active substance is a batch of ready-prepared vector.Additional steps may be carried out in order to obtain the finished
medicinal product. This type of medicinal product is intended to be
administered to several patients.
Transfer of genetic material may be carried out by direct injection of
the ready-prepared vector to the recipients.
1.2.SpecificrequirementsregardingModule3
Gene therapy medicinal products include:
— naked nucleic acid
— complex nucleic acid or non viral vectors
— viral vectors
— genetically modified cells
As for other medicinal products, one can identify the three main
elements of the manufacturing process, i.e.:
— starting materials: materials from which the active substance is
manufactured such as, gene of interest, expression plasmids, cell
banks and virus stocks or non viral vector;
— active substance: recombinant vector, virus, naked or complex plas-
mids, virus producing cells, in vitro genetically modified cells;
— finished medicinal product: active substance formulated in its final
immediate container for the intended medical use. Depending on the
type of gene therapy medicinal product, the route of administration
and conditions of use may necessitate an ex vivo treatment of the
cells of the patient (see 1.1.b).
A special attention shall be paid to the following items:
a) Information shall be provided on the relevant characteristics of the
gene therapy medicinal product including its expression in the target
cell population. Information concerning the source, construction,
characterisation and verification of the encoding gene sequence
including its integrity and stability shall be provided. Apart from
therapeutic gene, the complete sequence of other genes, regulatory
elements and the vector backbone shall be provided.
b) Information concerning the characterisation of the vector used to
transfer and deliver the gene shall be provided. This must include
its physico-chemical characterisation and/or biological/immunolo-
gical characterisation.
For medicinal products that utilise a micro-organism such as bacteria
or viruses to facilitate gene transfer (biological gene transfer), data
on the pathogenesis of the parental strain and on its tropism for
specific tissues and cell types as well as the cell cycle-dependence
of the interaction shall be provided.
For medicinal products that utilise non-biological means to facilitate
gene transfer, the physico-chemical properties of the constituents
individually and in combination shall be provided.
c) The principles for cell banking or seed lot establishment and charac-
terisation shall apply to gene transfer medicinal products as
appropriate.
d) The source of the cells hosting the recombinant vector shall be
provided.
The characteristics of the human source such as age, sex, results of
microbiological and viral testing, exclusion criteria and country of
origin shall be documented.
For cells of animal origin, detailed information related to the
following items shall be provided:
— Sourcing of the animals
— Animal husbandry and care
— Transgenic animals (methods of creation, characterisation of
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— Measures to prevent and monitor infections in the source/donor
animals
— Testing for infectious agents
— Facilities
— Control of starting and raw materials.
Description of cell collection methodology including location, type
of tissue, operating process, transportation, storage and traceability
as well as controls carried out during the collection process shall
be documented.
e) The evaluation of the viral safety as well as the traceability of the
products from the donor to the finished medicinal product, are an
essential part of the documentation to be supplied. E.g., the presence
of replication competent virus in stocks of non-replication competent
viral vectors must be excluded.
2. SOMATIC CELL THERAPY MEDICINAL PRODUCTS (HUMAN
AND XENOGENEIC)
For the purposes of this Annex, somatic cell therapy medicinal products
shall mean the use in humans of autologous (emanating from the patient
himself), allogeneic (coming from another human being) or xenogeneic
(coming from animals) somatic living cells, the biological characteris-
tics of which have been substantially altered as a result of their
manipulation to obtain a therapeutic, diagnostic or preventive effect
through metabolic, pharmacological and immunological means. This
manipulation includes the expansion or activation of autologous cell
populations ex vivo (e.g., adoptive immuno-therapy), the use of allo-
geneic and xenogeneic cells associated with medical devices used ex
vivo or in vivo (e.g., micro-capsules, intrinsic matrix scaffolds, bio-
degradable or not).
Specific requirements for cell therapy medicinal products regarding
Module 3
Somatic cell therapy medicinal products include:
— Cells manipulated to modify their immunological, metabolic or
other functional properties in qualitative or quantitative aspects;
— Cells sorted, selected and manipulated and subsequently undergoing
a manufacturing process in order to obtain the finished medicinal
product;
— Cells manipulated and combined with non-cellular components (e.g.
biological or inert matrixes or medical devices) and exerting the
principle intended action in the finished product;
— Autologous cell derivatives expressed in vitro under specific culture
conditions;
— Cells genetically modified or otherwise manipulated to express
previously unexpressed homologous or non-homologous functional
properties.
The whole manufacturing process from the collection of the cells from
the patient (autologous situation) up to the re-injection to the patient
shall be considered as one single intervention.
As for other medicinal products, the three elements of the manufac-
turing process are identified:
— starting materials: materials from which the active substance is
manufactured, i.e., organs, tissues, body fluids or cells;
— active substance: manipulated cells, cell lysates, proliferating cells
and cells used in conjunction with inert matrixes and medical
devices;
— finished medicinal products: active substance formulated in its final
immediate container for the intended medical use.
a) General information on active substance(s)
The active substances of cell therapy medicinal products consist of
cells which as a consequence of in vitro processing display prophy-
lactic, diagnostic or therapeutic properties different from the original
physiological and biological one.
This section shall describe the type of cells and culture concerned.
Tissues, organs or biological fluids from which cells are derived as
well as the autologous, allogeneic, or xenogeneic nature of the dona-
tion and its geographical origin shall be documented. Collection of
the cells, sampling and storage prior further processing shall be
detailed. For allogeneic cells, special attention shall be paid to the
very first stepof the p rocess, which covers selection of donors. The2001L0083 — EN — 01.07.2003 — 002.001 — 86
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type of manipulation carried out and the physiological function of
the cells that are used as active substance shall be provided.
b) Information related to the starting materials of active substance(s)
1. Human somatic cells
Human somatic cell therapy medicinal products are made of a
defined number (pool) of viable cells, which are derived from a
manufacturing process starting either at the level of organs or tissues
retrieved from a human being, or, at the level of a well defined cell
bank system where the pool of cells relies on continuous cell lines.
For the purposes of this chapter, active substance shall mean the
seed pool of human cells and finished medicinal product shall
mean seed pool of human cells formulated for the intended medical
use.
Starting materials and each stepof the manufacturing p rocess shall
be fully documented including viral safety aspects.
(1) Organs, tissues, body fluids and cells of human origin
The characteristics of the human source such as age, sex, microbio-
logical status, exclusion criteria and country of origin shall be
documented.
Description of sampling including site, type, operating process,
pooling, transportation, storage and traceability as well as controls
carried out on sampling shall be documented.
(2) Cell banking systems
Relevant requirements depicted in part I shall apply for the prepara-
tion and quality control of cell banking systems. This may
essentially be the case for allogeneic or xenogeneic cells.
(3) Ancillary materials or ancillary medical devices
Information shall be provided on the use of any raw materials (e.g.,
cytokines, growth factors, culture media) or of possible ancillary
products and medical devices e.g., cell sorting devices, biocompa-
tible polymers, matrix, fibres, beads in terms of bio-compatibility,
functionality as well as the risk of infectious agents.
2. Animal somatic cells (xenogeneic)
Detailed information related to the following items shall be
provided:
— Sourcing of the animals
— Animal husbandry and care— Genetically modified animals (methods of creation, characterisa-
tion of transgenic cells, nature of the inserted or excised (knock
out) gene)
— Measures to prevent and monitor infections in the source/donor
animals
— Testing for infectious agents including vertically transmitted
micro-organisms (also endogenous retro viruses)
— Facilities— Cell banking systems— Control of starting and raw materials.
a) Information on the manufacturing process of the active
substance(s) and the finished product
The different steps of the manufacturing process such as organ/tissue
dissociation, selection of the cell population of interest, in vitro cell
culture, cell transformation either by physico-chemical agents or
gene transfer shall be documented.
b) Characterisation of active substance(s)
All of the relevant information on the characterisation of the cell
population of interest in terms of identity (species of origin, banding
cytogenetics, morphological analysis), purity (adventitious microbial
agents and cellular contaminants), potency (defined biological2001L0083 — EN — 01.07.2003 — 002.001 — 87
▼M2
activity), and suitability (karyology and tumorigenicity tests) for the
intended medicinal use shall be provided.
c) Pharmaceutical development of finished medicinal product
Apart from the specific method of administration used (intravenous
infusion, site-injection, transplantation surgery), information shall
also be provided on the use of possible ancillary medical devices
(bio-compatible polymers, matrix, fibres, beads) in terms of bio-
compatibility and durability.
d) Traceability
A detailed flow chart shall be provided insuring the traceability of
the products from the donor to the finished medicinal product.
3. SPECIFIC REQUIREMENTS FOR GENE THERAPY AND
SOMATIC CELL THERAPY (HUMAN AND XENOGENEIC)
MEDICINAL PRODUCTS REGARDING MODULES 4 AND 5
3.1.Module4
For gene and somatic cell therapy medicinal products, it is recognised
that conventional requirements as laid down in Module 4 for non-clin-
ical testing of medicinal products may not always be appropriate due to
unique and diverse structural and biological properties of the products
in question, including high degree of species specificity, subject speci-
ficity, immunological barriers and differences in pleiotropic responses.
The rationale underpinning the non-clinical development and the
criteria used to choose relevant species and models shall be properly
captioned in Module 2.
It may be necessary to identify or developnew animal models in order
to assist in the extrapolation of specific findings on functional endpoints
and toxicity to in vivo activity of the products in human beings. The
scientific justification for the use of these animal models of disease to
support safety and proof of concept for efficacy shall be provided.
3.2.Module5
The efficacy of advanced therapy medicinal products must be demon-
strated as described in Module 5. For some products and for some
therapeutic indications, however, it may not be possible to perform
conventional clinical trials. Any deviation from the existing guidelines
shall be justified in Module 2.
The clinical development of advanced therapy medicinal products will
have some special features owing to the complex and labile nature of
the active substances. It requires additional considerations because of
issues related to viability, proliferation, migration and differentiation
of cells (somatic cell therapy), because of the special clinical circum-
stances where the products are used or because of the special mode of
action through gene expression (somatic gene therapy).
Special risks associated with such products arising from potential
contamination with infectious agents must be addressed in the applica-
tion for marketing authorisation for advanced therapy medicinal
products. Special emphasis should be put on both the early stages of
development in one hand, including the choice of donors in the case
of cell therapy medicinal products, and on the therapeutic intervention
as a whole, including the proper handling and administration of the
product on the other hand.
Furthermore, Module 5 of the application should contain, as relevant,
data on the measures to surveying and control of the functions and
development of living cells in the recipient, to prevent transmission of
infectious agents to the recipient and to minimise any potential risks to
public health.
3.2.1. Human pharmacology and efficacy studies
Human pharmacology studies should provide information on the
expected mode of action, expected efficacy based on justified end-
points, bio-distribution, adequate dose, schedule, and methods of
administration or modality of use desirable for efficacy studies.
Conventional pharmaco-kinetic studies may not be relevant for some
advanced therapy products. Sometimes studies in healthy volunteers
are not feasible and the establishment of dose and kinetics will be diffi-2001L0083 — EN — 01.07.2003 — 002.001 — 88
▼M2
cult to determine in clinical trials. It is necessary, however, to study the
distribution and in vivo behaviour of the product including cell prolif-
eration and long-term function as well as the extent, distribution of the
gene product and duration of the desired gene expression. Appropriate
tests shall be used and, if necessary, developed for the tracing of the
cell product or cell expressing the desired gene in the human body and
for the monitoring of the function of the cells that were administered or
transfected.
The assessment of the efficacy and safety of an advanced therapy
medicinal product must include the careful description and evaluation
of the therapeutic procedure as a whole, including special ways of
administration, (such as transfection of cells ex vivo, in vitro manipula-
tion, or use of interventional techniques), and testing of the possible
associated regimens (including immuno-suppressive, antiviral, cytotoxic
treatment).
The whole procedure must be tested in clinical trials and described in
the product information.
3.2.2. Safety
Safety issues arising from immune response to the medicinal products
or to the expressed proteins, immune rejection, immuno-suppression,
and breakdown of immuno-isolation devices shall be considered.
Certain advanced gene therapy and somatic cell therapy medicinal
products (e.g. xenogeneic cell therapy and certain gene transfer
products) may contain replication-competent particles and/or infectious
agents. The patient may have to be monitored for the development of
possible infections and/or their pathological sequelae during pre- and/
or post-authorisation phases; this surveillance may have to be extended
to close contacts of the patient including health-care workers.
The risk of contamination with potentially transmissible agents cannot
be totally eliminated in the use of certain somatic cell therapy medic-
inal products and certain gene transfer medicinal products. The risk
can be minimised, however, by appropriate measures as described in
Module 3.
The measures included in the production process must be comple-
mented with accompanied testing methods, quality control processes
and by appropriate surveillance methods that must be described in
Module 5.
The use of certain advanced somatic cell therapy medicinal products
may have to be limited, temporarily or permanently, to establishments
that have documented expertise and facilities for assuring a specific
follow up of the safety of the patients. A similar approach may be rele-
vant for certain gene therapy medicinal products that are associated
with a potential risk of replication-competent infectious agents.
The long term monitoring aspects for the development of late complica-
tions shall also be considered and addressed in the submission, where
relevant.
Where appropriate, the applicant has to submit a detailed risk manage-
ment plan covering clinical and laboratory data of the patient, emerging
epidemiological data, and, if relevant, data from archives of tissue
samples from the donor and the recipient. Such a system is needed to
ensure the traceability of the medicinal product and the rapid response
to suspicious patterns of adverse events.
4. SPECIFIC STATEMENT ON XENO-TRANSPLANTATION MEDIC-
INAL PRODUCTS
For the purposes of this Annex, xeno-transplantation shall mean any
procedure that involves the transplantation, implantation, or infusion
into a human recipient of either live tissues or organs retrieved from
animals, or, human body fluids, cells, tissues or organs that have under-
gone ex vivo contact with live non-human animal cells, tissues or
organs.
Specific emphasis shall be paid to the starting materials.
In this respect, detailed information related to the following items shall
be provided according to specific guidelines:
— Sourcing of the animals
— Animal husbandry and care2001L0083 — EN — 01.07.2003 — 002.001 — 89
▼M2
— Genetically modified animals (methods of creation, characterisation
of transgenic cells, nature of the inserted or excised (knock out)
gene)
— Measures to prevent and monitor infections in the source/donor
animals
— Testing for infectious agents— Facilities— Control of starting and raw materials— Traceability.2001L0083 — EN — 01.07.2003 — 002.001 — 90
▼B
ANNEX II
PART A
Repealed Directives, with their successive amendments (referred to by
Article 128)
Council Directive 65/65/EEC (OJ 22, 9. 2. 1965, p. 369/65)
Council Directive 66/454/EEC (OJ 144, 5. 8. 1966, p. 2658/66)
Council Directive 75/319/EEC (OJ L 147, 9. 6. 1975, p. 13)
Council Directive 83/570/EEC (OJ L 332, 28. 11. 1983, p. 1)
Council Directive 87/21/EEC (OJ L 15, 17. 1. 1987, p. 36)Council Directive 89/341/EEC (OJ L 142, 25. 5. 1989, p. 11)
Council Directive 92/27/EEC (OJ L 113, 30. 4. 1992, p. 8)
Council Directive 93/39/EEC (OJ L 214, 24. 8. 1993, p. 22)
Council Directive 75/318/EEC (OJ L 147, 9. 6. 1975, p. 1)
Council Directive 83/570/EEC
Council Directive 87/19/EEC (OJ L 15, 17. 1. 1987, p. 31)
Council Directive 89/341/EEC
Commission Directive 91/507/EEC (OJ L 270, 26. 9. 1991, p. 32)Council Directive 93/39/EECCommission Directive 1999/82/EC (OJ L 243, 15. 9. 1999, p. 7)
Commission Directive 1999/83/EC (OJ L 243, 15. 9. 1999, p. 9)
Council Directive 75/319/EEC
Council Directive 78/420/EEC (OJ L 123, 11. 5. 1978, p. 26)
Council Directive 83/570/EECCouncil Directive 89/341/EEC
Council Directive 92/27/EEC
Council Directive 93/39/EECCommission Directive 2000/38/EC (OJ L 139, 10. 6. 2000, p. 28)
Council Directive 89/342/EEC (OJ L 142, 25. 5. 1989, p. 14)
Council Directive 89/343/EEC (OJ L 142, 25. 5. 1989, p. 16)Council Directive 89/381/EEC (OJ L 181, 28. 6. 1989, p. 44)
Council Directive 92/25/EEC (OJ L 113, 30. 4. 1992, p. 1)
Council Directive 92/26/EEC (OJ L 113, 30. 4. 1992, p. 5)
Council Directive 92/27/EEC
Council Directive 92/28/EEC (OJ L 113, 30. 4. 1992, p. 13)
Council Directive 92/73/EEC (OJ L 297, 13. 10. 1992, p. 8)2001L0083 — EN — 01.07.2003 — 002.001 — 91
▼B
PART B
Time-limitsfortranspositionintonationallaw(referred tobyArticle 128)
Directive Deadline for transposition
Directive 65/65/EEC 31 December 1966
Directive 66/454/EEC —
Directive 75/318/EEC 21 November 1976
Directive 75/319/EEC 21 November 1976
Directive 78/420/EEC —Directive 83/570/EEC 31 October 1985
Directive 87/19/EEC 1 July 1987
Directive 87/21/EEC 1 July 1987
1 January 1992 (
1)
Directive 89/341/EEC 1 January 1992
Directive 89/342/EEC 1 January 1992
Directive 89/343/EEC 1 January 1992
Directive 89/381/EEC 1 January 1992
Directive 91/507/EEC 1 January 1992 (2)
1 January 1995 (3)
Directive 92/25/EEC 1 January 1993
Directive 92/26/EEC 1 January 1993
Directive 92/27/EEC 1 January 1993
Directive 92/28/EEC 1 January 1993
Directive 92/73/EEC 31 December 1993
Directive 93/39/EEC 1 January 1995 (4)
1 January 1998 (5)
Directive 1999/82/EC 1 January 2000
Directive 1999/83/EC 1 March 2000
Directive 2000/38/EC 5 December 2001
(1) Deadline for transposition applicable to Greece, Spain and Portugal.
(2) Except Section A, point 3.3 in Part II of the Annex.
(3) Deadline for transposition applicable to Section A, point 3.3 in Part II of the Annex.
(4) Except with regard to Article 1(6).
(5) Deadline for transposition applicable to Article 1(7).2001L0083 — EN — 01.07.2003 — 002.001 — 92
ANNEX III
CORRELATIONTABLE
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 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)
Art 2(3), 1st
indent▼B2001L0083 — EN — 01.07.2003 — 002.001 — 93
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Art. 3(3) and
(4)Art.2(3), 2nd
and 3rd
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., points 1
to 5Art. 1, 1st
paragraph
Art. 8(3)(f) to
(i)Art. 4, 3rd
para., points 6
to 8.1
Art. 8(3)(j) to
(l)Art. 4, 3rd
para., points 9
to 11▼B2001L0083 — EN — 01.07.2003 — 002.001 — 94
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Art. 9 Art. 3
Art. 10(1) Art. 4, 3rd
paragraph,
point 8.2
Art. 10(2) Art. 1, 2nd
paragraph
Art. 11, points
1 to 5.3Art. 4a, points
1 to 5.3
Art. 11, point
5.4Art. 4a, point
5.4Art. 3
Art. 11, points
5.5 to 6.4Art. 4a, points
5.5 to 6.4
Art. 11, point
6.5Art. 4a, point
6.6
Art. 11, point 7 Art. 4a, point
6.5
Art. 11, points
8t o9Art. 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 — 01.07.2003 — 002.001 — 95
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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 — 01.07.2003 — 002.001 — 96
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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
Art. 50 Art. 24▼B2001L0083 — EN — 01.07.2003 — 002.001 — 97
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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 — 01.07.2003 — 002.001 — 98
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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
Art. 83 Art. 9▼B2001L0083 — EN — 01.07.2003 — 002.001 — 99
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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 — 01.07.2003 — 002.001 — 100
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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
and 2nd para-
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 — 01.07.2003 — 002.001 — 101
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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 — — —————————
Annex I Annex▼B2001L0083 — EN — 01.07.2003 — 002.001 — 102
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Annex II — — —————————
Annex III — — —————————▼B2001L0083 — EN — 01.07.2003 — 002.001 — 103