Legislative Decree 04/24/2006 n.219
Legislative Decree 24 April 2006, n. 219
"Implementation of directive 2001/83/EC (and subsequent amending directives) relating to a Community code relating to medicinal products for human use, as well as of directive 2003/94/EC"
published in the Official Gazette no. 142 of 21 June 2006 – Ordinary Supplement no. 153
THE PRESIDENT OF THE REPUBLIC
Having regard to articles 76 and 87 of the Constitution;
Given the law of 18 April 2005, n. 62, containing provisions for the fulfillment of obligations deriving from Italy's membership of the European Communities. Community law 2004, and in particular article 1 and annex A;
Having regard to Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001, bearing the Community code relating to medicinal products for human use;
Having regard to directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004, which amends, as regards traditional herbal medicinal products, directive 2001/83/EC, bearing the Community code relating to medicinal products for human use;
Having regard to directive 2004/27/EC of the European Parliament and of the Council, of 31 March 2004, which amends directive 2001/83/EC, bearing the Community code relating to medicinal products for human use;
Having regard to Directive 2003/94/EC of the Commission of 8 October 2003, which establishes the principles and guidelines of good manufacturing practice relating to medicinal products for human use and medicinal products for human use in the experimental stage;
Given the legislative decree 29 May 1991, n. 178, and subsequent amendments, incorporating the directives of the European Economic Community in the matter of proprietary medicines;
Given the legislative decree 30 December 1992, n. 538, and subsequent amendments, implementing directive 92/25/EEC, concerning the wholesale distribution of medicines for human use;
Given the legislative decree 30 December 1992, n. 539, and subsequent amendments, implementing directive 92/26/EEC, concerning the classification in the supply of medicines for human use;
Given the legislative decree 30 December 1992, n. 540, and subsequent amendments, implementing directive 92/27/EEC, concerning the labeling and package leaflet of medicines for human use;
Given the legislative decree 30 December 1992, n. 541, and subsequent amendments, implementing directive 92/28/EEC, concerning the advertising of medicines for human use;
Given the legislative decree 17 March 1995, n. 185, and subsequent amendments, implementing directive 92/73/EEC, concerning homeopathic medicines;
Given the legislative decree February 18, 1997, n. 44, and subsequent amendments, implementing directive 93/39/EEC, which modifies directives 65/65/EEC, 75/318/EEC and 75/319/EEC, relating to medicinal products;
Given the legislative decree 24 June 2003, n. 211, and subsequent amendments, implementing directive 2001/20/EC relating to the application of good clinical practice in the execution of clinical trials of medicinal products for clinical use;
Given the preliminary resolution of the Council of Ministers, adopted in the meeting of 2 December 2005;
Acquired the opinion of the Permanent Conference for relations between the State, the regions and the autonomous provinces of Trento and Bolzano, in the session of 9 February 2006;
Having acquired the opinions expressed by the competent Commissions of the Chamber of Deputies;
Considering that the competent Commissions of the Senate of the Republic have not expressed their opinion within the time limit set by article 1, paragraph 3, of the law of 18 April 2005, n. 62;
Given the resolution of the Council of Ministers, adopted in the meeting of 6 April 2006;
On the proposal of the Minister for Community Policies and the Minister of Health, in consultation with the Ministers of Foreign Affairs, Justice and the Economy and Finance;
And mana
the following legislative decree
TITLE I
DEFINITIONS
Article 1.
Definitions
1. For the purposes of this decree, the following definitions apply:
a) medicinal product or medicinal product, hereinafter referred to as "medicine":
1) any substance or combination of substances presented as having curative or prophylactic properties of human disease;
2) any substance or combination of substances which can be used on humans or administered to humans for the purpose of restoring, correcting or modifying physiological functions, by exerting a pharmacological, immunological or metabolic action, or to establish a medical diagnosis;
b) substance: any material, regardless of its origin; this origin can be:
1) human, such as: human blood and its derivatives;
2) animal, such as: microorganisms, whole animals, parts of organs, animal secretions, toxins, substances obtained by extraction, blood products;
3) vegetable, such as: microorganisms, plants, parts of plants, vegetable secretions, substances obtained by extraction;
4) chemistry, such as: elements, natural chemical materials and chemical products of transformation and synthesis;
c) immunological medicinal product any medicinal product consisting of vaccines, toxins, serums or allergens. Vaccines, toxins or serums include in particular: agents used for the purpose of inducing active immunity or passive immunity and agents used for the purpose of diagnosing the state of immunity. Allergens are medicines that have the purpose of identifying or inducing a specific acquired modification of the immune response towards an allergenic agent;
d) homeopathic medicinal product any medicinal product obtained from substances known as starting materials for homeopathic preparations or homeopathic strains, according to a homeopathic production process described by the European Pharmacopoeia or, in the absence of such description, by the pharmacopoeias officially used in the Member States of the European Community ; a homeopathic medicine can contain multiple substances;
e) radiopharmac any medicinal product which, when ready for use, includes one or more radionuclides (radioactive isotopes) incorporated for medical purposes;
f) radionuclide generator: any system which includes a determined parent radionuclide from which a daughter radionuclide is produced which is then removed by elution or any other method and used in a radiopharmaceutical;
g) kit: any preparation to be reconstituted or combined with radionuclides in the final radiopharmaceutical, usually before administration;
h) radionuclide precursor: any other radionuclide produced for use as a tracer of another substance prior to administration;
i) medicinal products derived from human blood or plasma: medicinal products based on blood components industrially prepared in public or private establishments; such medicinal products include in particular albumin, coagulation factors and immunoglobulins of human origin;
l) adverse reaction: the harmful and unintentional reaction to a medicinal product used at doses normally administered to man for prophylactic, diagnostic or therapeutic purposes or to restore, correct or modify its physiological functions;
m) serious adverse reaction: the adverse reaction that causes the death of an individual, or endangers his life, requires or prolongs hospitalization, causes persistent or significant disability or incapacity or involves a congenital anomaly or a defect in the birth;
n) unexpected adverse reaction: the adverse reaction whose nature, severity or outcome are not foreseen in the summary of product characteristics;
o) periodic safety update reports: periodic reports containing the information specified in Article 130;
p) post-authorisation study on the safety of medicinal products: the pharmacoepidemiological study or clinical trial carried out in accordance with the conditions established in the marketing authorization with the aim of identifying or quantifying a safety risk, related to a medicinal product for which an authorization has already been issued;
q) abuse of medicines: deliberately excessive, prolonged or sporadic use of medicines related to harmful effects on the physical or mental level;
r) wholesale distribution of medicines: any activity consisting in procuring, holding, supplying or exporting medicines, except for the supply of medicines to the public; these activities are carried out with producers or their custodians, with importers, with other wholesale distributors and with respect to pharmacists or other subjects authorized to supply medicines to the public;
s) public service obligation the obligation for wholesalers to guarantee a permanent assortment of medicines sufficient to meet the needs of a geographically specific territory and to provide for the delivery of the requested supplies in a very short time throughout the territory in question;
t) representative of the marketing authorization holder means the person designated by the marketing authorization holder to represent him in the Member State concerned as local representative;
u) medical prescription: any medical prescription issued by a professional authorized to prescribe medicinal products;
v) name of the medicinal product: the name which can be a fancy name that cannot be confused with the common name or a common or scientific name accompanied by a trademark or the name of the marketing authorization holder;
z) common name: the international common name recommended by the World Health Organization (WHO), usually in the official Italian version or, if this is not yet available, in the English version; only, in the absence of this, the common customary denomination is used;
aa) dosage of the medicinal product: the active substance content expressed, according to the pharmaceutical form, in quantity per dosage unit, per unit of volume or weight;
bb) primary packaging the container or any other form of packaging which is in direct contact with the medicinal product;
cc) outer packaging or secondary packaging the packaging in which the primary packaging is placed;
dd) labelling: the information given on the external packaging or on the primary packaging;
ee) illustrative leaflet the leaflet containing information intended for the user and which accompanies the medicinal product;
ff) EMEA (European Medicines Agency): the European Medicines Agency established by Regulation (EC) no. 726/2004 of the European Parliament and of the Council, of 31 March 2004, which establishes Community procedures for the authorization and supervision of medicinal products for human and veterinary use, and which establishes the European Medicines Agency, hereinafter referred to as "Regulation (EC) no. 726/2004";
gg) risks associated with the use of the medicinal product:
1) any risk related to the quality, safety or efficacy of the medicinal product for the health of the patient or public health;
2) any risk of undesirable effects on the environment;
hh) risk/benefit ratio an evaluation of the positive therapeutic effects of the medicinal product with respect to the risks defined in letter gg), number 1);
ii) traditional medicinal product of herbal origin or traditional phytotherapeutic: medicinal product which meets the requirements of article 21, paragraph 1;
ll) medicinal product of herbal origin or phytotherapic any medicinal product which contains exclusively as active substances one or more herbal substances or one or more herbal preparations, or one or more herbal substances in association with one or more herbal preparations;
mm) vegetable substances: all plants, parts of plants, algae, fungi and lichens, whole, in pieces or cut, in an untreated form, usually dried, but sometimes also fresh. Certain exudates not subjected to a specific treatment are also considered herbal substances. The vegetable substances are precisely defined on the basis of the part of the plant used and the botanical denomination according to the binomial denomination (genus, species, variety and author);
nn) herbal preparations: preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, pressing, fractionation, purification, concentration or fermentation. This definition also includes ground or pulverized vegetable substances, tinctures, extracts, essential oils, juices obtained by squeezing and processed exudates;
oo) medicinal gas: any medicinal product consisting of one or more gaseous active substances mixed or not with gaseous excipients;
pp) AIFA: Italian drug agency established by article 48, paragraph 2, of the decree-law of 30 September 2003, n. 269, converted, with amendments, by law 24 November 2003, n. 326;
qq) AIC: marketing authorisation.
TITLE II
FIELD OF APPLICATION
Article 2.
Field of application; prevalence of the discipline of medicinal products over other disciplines
1. This decree applies to medicinal products for human use, prepared industrially or in whose production an industrial process is involved, intended to be placed on the market in the national territory, without prejudice to the provisions of paragraph 3.
2. In case of doubt, if a product, taking into account all of its characteristics, can simultaneously fall under the definition of "medicine" and the definition of a product governed by other Community legislation, the provisions of this decree shall apply .
3. Medicinal products intended exclusively for export and intermediate products are subject only to the provisions of Title IV of this decree.
4. The provisions on the production of medicinal products contained in title IV, those of title VII and those of title XI extend, as far as applicable, to pharmacologically active raw materials.
Article 3.
Cases excluded from the discipline
1. The provisions of this decree do not apply
a) medicines prepared in pharmacies on the basis of a medical prescription intended for a particular patient, called «master formulas», which remain governed by article 5 of the decree-law of 17 February 1998, n. 23, converted, with modifications, by law 8 April 1998, n. 94;
b) medicinal products prepared in pharmacies on the basis of the indications of the European Pharmacopoeia or of the national pharmacopoeias in force in the Member States of the European Union, called "officinal formulas", and intended to be supplied directly to the patients served by this pharmacy;
c) medicinal products intended for research and development trials, without prejudice to the provisions of article 53, paragraphs 13 and 14, and those of chapter II of title IV of this decree and without prejudice to the provisions of the legislative decree of 24 June 2003, no. 211, relating to the application of good clinical practice in the execution of clinical trials of medicines for human use;
d) intermediate products intended for further processing by an authorized producer, without prejudice to the provisions of article 2, paragraph 3;
e) radionuclides used in pre-packaged form;
f) whole blood, plasma, blood cells of human origin, except for plasma whose production involves an industrial process.
Article 4.
Safeguarding radiological protection standards; matters excluded from the scope
1. None of the provisions of this decree can be interpreted as derogating from the regulations relating to the radiological protection of persons undergoing medical examinations or treatments or from the Community regulations which establish the basic rules relating to the health protection of the population and workers against the dangers deriving from radiation ionizing.
2. The regulation of the prices of medicinal products and that of their inclusion in the classes of medicinal products supplied at the expense of the National Health Service are outside the scope of this decree.
Article 5.
Cases of non-application of title III
1. The provisions of title III do not apply to industrially prepared medicinal products at the request, written and unsolicited, of the doctor, deemed suitable for this by the regulations in force, who undertakes to use the aforementioned medicinal products on a particular patient of his own or structure in which it operates, under its direct and personal responsibility; to this hypothesis, for the purposes of the prescription, the provisions foreseen for magistral preparations by article 5 of the decree-law of 17 February 1998, n. 23, converted, with modifications, by law 8 April 1998, n. 94.
2. In the event of suspected or confirmed dispersion of potentially harmful pathogens, toxins, chemical agents or nuclear radiation, the Minister of Health may authorize the temporary distribution of a medicinal product for which marketing is not authorized, in order to promptly deal with the emergency.
3. In the case governed by paragraph 2, the marketing authorization holders, producers and health professionals are not subject to civil or administrative liability for the consequences deriving from the use of a medicinal product outside the indications authorized or from the use of an unauthorized medicinal product, when such use is recommended or prescribed by the Minister of Health.
4. The liability for damages from defective products remains unaffected, as provided for by the legislative decree of 6 September 2005, n. 206.
TITLE III
MARKETING
Chapter I
MARKETING AUTHORIZATION
Article 6.
Extension and effects of the authorisation
1. No medicinal product can be placed on the market in the national territory without having obtained an authorization from AIFA or a Community authorization pursuant to regulation (EC) n. 726/2004.
2. When a marketing authorization has been issued for a medicinal product pursuant to paragraph 1, any further dosage, pharmaceutical form, route of administration and presentation, as well as variations and extensions are equally subject to authorization pursuant to the same paragraph 1; the subsequent MAs are considered, together with the initial one, as forming part of the same overall authorisation, in particular for the purposes of the application of article 10, paragraph 1.
3. The marketing authorization holder is responsible for marketing the medicinal product. The designation of a representative does not relieve the marketing authorization holder of his legal responsibility.
4. The authorization referred to in paragraph 1 is also required for radionuclide generators, kits and radiopharmaceuticals precursors of radionuclides, as well as for industrially prepared radiopharmaceuticals.
Article 7.
Radiopharmaceuticals prepared at the time of use
1. AIC is not required for radiopharmaceuticals prepared at the moment of use, according to the manufacturer's instructions, by persons or establishments authorized to use such medicinal products, in one of the authorized treatment centers and provided that the radiopharmaceutical is prepared at starting from generators, kits or precursor radiopharmaceuticals for which the MA has been issued.
Article 8.
Application for authorization
1. To obtain an AIC, the applicant submits an application to AIFA, with the exception of the cases governed by regulation (EC) no. 726/2004.
2. An AIC can only be issued to applicants established in the Community territory.
3. The application contains the information and documentation listed below which are presented in accordance with Annex 1 to this decree, hereinafter referred to as the «technical annex on the marketing authorization application»:
a) name or company name and domicile or registered office of the applicant and of the producer, if different from the first; in the case of co-production, in addition to the locations of the plants, Italian or foreign, the production and control phases pertaining to each of them must be specified;
b) name of the medicinal product;
c) qualitative and quantitative composition of the medicinal product referred to all the components reported using the common name;
d) assessment of the risks that the medicinal product may pose for the environment. This impact must be studied and specific measures to limit it must be envisaged on a case-by-case basis;
e) description of the manufacturing method;
f) therapeutic indications, contraindications and adverse reactions;
g) dosage, pharmaceutical form, method and route of administration and presumed duration of stability;
h) reasons for the precautionary and safety measures to be taken for the conservation of the medicinal product, for its administration to patients and for the elimination of residues, together with an indication of the potential risks which the medicinal product presents for the environment;
i) description of the control methods used by the producer;
l) results:
1) pharmaceutical tests (chemical-physical, biological or microbiological);
2) preclinical tests (toxicological and pharmacological);
3) clinical trials;
m) detailed description of the pharmacovigilance system and, if applicable, the risk management system to be implemented by the applicant;
n) a declaration certifying that all clinical trials carried out outside the European Union comply with the ethical requirements contained in the legislative decree of 24 June 2003, n. 211;
o) a summary of the characteristics of the product drawn up in accordance with Article 14, a model of the outer packaging, with the indications referred to in Article 73, and of the immediate packaging of the medicinal product, with the indications referred to in Article 74, as well as the leaflet compliant with article 77;
p) a suitable document showing that the manufacturer has obtained authorization to produce medicinal products in his own country;
q) copy of each MA relating to the medicinal product in question, obtained in another member state of the European Community or in a third country together with the list of member states of the European Community, where a corresponding application is being examined, and a copy of the summary of product characteristics and the package leaflet, already approved by the Member State or only proposed by the applicant, as well as a copy of the detailed documentation containing the reasons for any refusals of authorisation, both in the European Community and in a third country ;
r) copy of the designation of the medicinal product as an orphan medicinal product pursuant to Regulation (EC) No. 141/2000 of the European Parliament and of the Council, of 16 December 1999, concerning orphan medicinal products, together with a copy of the relative opinion of the EMEA;
s) certification that the applicant has a qualified responsible for pharmacovigilance and the means necessary to report any adverse reactions, which are suspected to have occurred in the European Community or in a third country.
4. The information referred to in letter q) of paragraph 3 is updated whenever changes occur in the documentation or in the legal and factual situations referred to in the same letter.
5. The documents and information relating to the results of the pharmaceutical and preclinical tests and clinical trials, referred to in paragraph 3, letter l), are accompanied by detailed summaries pursuant to article 15.
6. The provisions of this article and those of the technical annex on the marketing authorization application can be modified and supplemented by decree of the Minister of Health, in compliance with the directives and recommendations of the European Community.
Article 9.
Additional information and documents accompanying the MA application for radionuclide generators
1. The application for MA of a radionuclide generator is also accompanied by the following information and documents:
a) a general description of the system with a detailed description of the components of the same which may influence the composition or the quality of the preparation of the radionuclide derivative;
b) the qualitative and quantitative characteristics of the eluate or sublimate.
Article 10.
Simplified MA applications for generic medicines
1. By way of derogation from article 8, paragraph 3, letter l), and without prejudice to the discipline of the protection of industrial and commercial property, the applicant is not required to provide the results of the preclinical tests and clinical trials if he can demonstrate that the medicinal product is a generic medicinal product of a reference medicinal product which has been authorized or has been authorized pursuant to Article 6 for at least eight years in Italy or in the European Community.
2. A generic medicinal product authorized pursuant to this article may not be placed on the market until ten years have passed from the initial authorization of the reference medicinal product. A clear reference to this prohibition is contained in the AIC provision.
3. If the reference medicinal product has not been authorized in Italy but in another Member State of the European Community, the applicant shall indicate in the application the name of the Member State in which the reference medicinal product is or has been authorised. AIFA requests the competent authority of the other Member State to send, within one month, the confirmation that the reference medicinal product is authorized or has been authorised, together with the complete composition of the reference medicinal product and, if necessary, another other pertinent documentation, with reference, in particular, to the date of the marketing authorization issued in the foreign country.
4. The ten-year period referred to in paragraph 2 is extended to a maximum of eleven years if during the first eight years of this decade the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, from the evaluation prior to authorisation, were deemed such as to bring a significant clinical benefit compared to existing therapies.
5. For the purposes of this article, the following definitions apply:
(a) reference medicinal product a medicinal product authorized in accordance with Article 6 in compliance with the requirements of Article 8;
b) generic medicinal product a medicinal product which has the same qualitative and quantitative composition of active substances and the same pharmaceutical form as the reference medicinal product as well as bioequivalence with the reference medicinal product demonstrated by appropriate bioavailability studies. The various salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance are considered to be the same active substance if, on the basis of the supplementary information provided by the applicant, they do not exhibit significant differences, nor any safety-related properties nor those relating to efficacy. For the purposes of this letter, the various oral immediate release pharmaceutical forms are considered to be the same pharmaceutical form. The applicant may not submit bioavailability studies if he can prove that the generic medicinal product meets the relevant criteria set out in the appropriate guidelines. The generic medicine is defined as equivalent pursuant to article 1-bis of the decree-law of 27 May 2005, n. 87, converted, with amendments, by law 26 July 2005, n. 149.
6. If the medicinal product does not fall within the definition of generic medicinal product referred to in paragraph 5, letter b), or if it is not possible to demonstrate bioequivalence with bioavailability studies, or in the event of changes to the active substance(s), the therapeutic indications strength, pharmaceutical form or route of administration compared to those of the reference medicinal product, the applicant should provide the results of the appropriate pre-clinical trials or clinical trials.
7. When a biological medicinal product similar to a reference biological medicinal product does not meet the conditions of the definition of a generic medicinal product due, in particular, to differences in raw materials or to differences in the production processes of the biological medicinal product and the reference biological medicinal product , the applicant is required to provide the results of appropriate preclinical tests or clinical trials related to these conditions. The additional data to be provided meets the relevant criteria set out in the technical annex on the marketing authorization application and related guidelines. It is not necessary to provide the results of other tests and trials contained in the reference medicinal product dossier. If the results presented are not deemed sufficient to guarantee the equivalence of the biogeneric or biosimilar with the reference biological medicinal product, an application shall be submitted in compliance with all the requirements set out in Article 8.
8. In addition to the provisions of paragraphs 1 to 4, if an application for a new indication is submitted for a substance with a well-known medical use, a non-cumulative period of exclusivity of one year is granted for the related data, provided that significant preclinical or clinical studies have been conducted for the new indication. The exclusivity period is reported in the AIC provision.
9. The execution of the studies and experiments necessary for the application of paragraphs 1, 2, 3, 4, 5, 6, and 7, do not prejudice the protection of industrial and commercial property.
10. The periods of protection referred to in paragraphs 1 to 4 do not apply to reference medicinal products for which an application for marketing authorization was presented before the date of entry into force of this decree. The provisions already provided for by article 8, paragraphs 5 and 6, of the legislative decree of 29 May 1991, n. 178, and subsequent modifications.
Article 11.
AIC bibliographic questions
1. By way of derogation from article 8, paragraph 3, letter l), and without prejudice to the law on the protection of industrial and commercial property, the applicant is not required to provide the results of preclinical tests or clinical trials, if he can demonstrate that the active substances of the medicinal product have been in well-established medical use in the European Community for at least ten years and have recognized efficacy and an acceptable level of safety, according to the conditions set out in the technical annex to the marketing authorization application. In this case the results of the preclinical and clinical studies are replaced by data obtained from the appropriate scientific literature.
Article 12.
Fixed associations
1. In the case of medicinal products containing active substances present in the composition of authorized medicinal products but not yet used in combination for therapeutic purposes, the results of the new preclinical tests and new clinical trials relating to the combination are presented pursuant to article 8, paragraph 3, letter l); the applicant is not required to provide the scientific documentation relating to each single active substance.
Article 13.
Consent to the use of the dossier by third parties
1. After the marketing authorization has been granted, the marketing authorization holder may allow use of the pharmaceutical, preclinical and clinical documentation contained in the dossier of his medicinal product for the subsequent submission of an application relating to other medicinal products having an identical composition qualitative and quantitative in active substances and the same pharmaceutical form.
Article 14.
Summary of product characteristics
1. The summary of product characteristics contains the information listed in attachment 2 to this decree in the order and numbering indicated.
2. For the authorizations referred to in Article 10, those parts of the summary of product characteristics of the reference medicinal product which refer to indications or dosages still covered by patent at the time the generic medicinal product was placed on the market are not included.
3. The content of the summary of product characteristics can be modified by decree of the Minister of Health, in accordance with Community provisions.
Article 15.
Experts who process the documentation
1. The applicant, the detailed summaries referred to in article 8, paragraph 5, before being presented to AIFA, must be drawn up and signed by experts in possession of the necessary technical or professional qualifications, related to the subject matter, specified in a short CV.
2. Persons in possession of the technical and professional qualifications referred to in paragraph 1 justify any recourse to the scientific literature referred to in article 11, in accordance with the provisions of the technical annex on the application for marketing authorization.
3. The detailed summaries are part of the dossier that the applicant submits to AIFA.
Chapter II
SPECIAL RULES APPLICABLE TO HOMEOPATHIC MEDICINES
Article 16.
Simplified registration procedure
1. A homeopathic medicinal product is subject, for the purposes of placing it on the market, to a simplified registration procedure, only if the medicinal product:
a) it is intended to be administered orally or externally;
b) does not bear specific therapeutic indications on the label or in the information of any kind referring to the product;
c) has a degree of dilution such as to guarantee its safety; in any case, the medicinal product cannot contain more than one part per ten thousand of mother tincture, nor more than 1/100 of the smallest dose possibly used in allopathy for active substances whose presence in an allopathic medicinal product implies the obligation to submit a prescription.
2. Any new parameters concerning the safety of the homeopathic medicinal product shall be adopted by decree of the Minister of Health to replace or supplement those envisaged by letter c) of paragraph 1, in accordance with the provisions of the European Community.
3. At the time of registration, AIFA establishes the supply regime of the medicinal product.
4. The provisions of articles 8, paragraph 3, 29, paragraph 1, from 33 to 40, 52, paragraph 8, letters a), b) and c), and 141 apply, by analogy, to the simplified procedure for the registration of medicinal products homeopathic, with the exception of trials of therapeutic efficacy.
Article 17.
Content of the simplified registration application
1. The simplified registration application may concern a series of medicinal products obtained from the same starting materials for homeopathic preparations or homeopathic strains.
2. In any case, the simplified registration application, to be submitted in accordance with a specific model established by AIFA within three months of the date of entry into force of this decree and published in the Official Gazette of the Italian Republic, must contain and be accompanied by the following data and documents intended, in particular, to demonstrate the pharmaceutical quality and the homogeneity of the production batches:
a) scientific name of the starting material or materials for homeopathic preparations or homeopathic strains or other name appearing in a pharmacopoeia, with indication of the different routes of administration, pharmaceutical forms and degrees of dilution to be recorded;
b) proper denomination of the homeopathic tradition;
c) dossier describing the methods by which each starting material for homeopathic preparations or homeopathic strains is obtained and controlled and demonstrates its homeopathic use through an adequate bibliography;
d) documentation concerning the production and control methods for each pharmaceutical form and a description of the dilution and dynamisation methods;
e) authorization for the production of medicinal products covered by the application;
f) copy of any registration or authorization obtained for the same medicinal product in other Member States of the European Community;
g) a model of the outer packaging and the immediate packaging of the medicinal products to be registered;
h) data concerning the stability of the medicinal product.
Article 18.
Homeopathic medicines to which the simplified registration procedure does not apply
1. Homeopathic medicinal products other than those referred to in article 16, paragraph 1, must be authorized and labeled in accordance with articles 8, 10, 11, 12, 13 and 14. As regards the documentation presented in support of the application, applies the provisions of article 8, paragraph 4. For these products, specific rules relating to preclinical tests and clinical trials may be provided for by decree of the Minister of Health, on a proposal from AIFA, in line with the principles and characteristics of homeopathic medicine practiced in Italy.
2. Title IX of this decree applies to homeopathic medicinal products, with the exception of those to which article 16, paragraph 1 refers.
Article 19.
Community communications
1. AIFA communicates to the other Member States of the European Community all the information necessary to guarantee the quality and safety of the homeopathic medicinal products produced and marketed in the European Community.
Article 20.
Transitional provision on homeopathic medicines; extension of the discipline to anthroposophic medicines
1. For homeopathic medicinal products present on the Italian market on 6 June 1995, the provisions of the legislation in force on the date of entry into force of this decree remain unchanged; the authorization or simplified registration of these products is issued according to the provisions of this decree.
2. In any case, the provisions set out in title IX apply to the products referred to in paragraph 1.
3. Anthroposophic medicines described in an official pharmacopoeia and prepared according to a homeopathic method are comparable, for the purposes of this decree, to homeopathic medicines.
Chapter III
SPECIAL PROVISIONS RELATING TO TRADITIONAL PLANT-DERIVED MEDICINES
Article 21.
Registration based on traditional employment
1. A simplified registration procedure, hereinafter referred to as: "traditional use-based registration", applies, for the purpose of placing on the market, medicinal products of herbal origin that meet all of the following criteria:
a) have indications appropriate exclusively for medicinal products of traditional herbal origin which, due to their composition and their therapeutic objective, are designed and manufactured to be used without medical intervention for diagnosis or for prescription or for surveillance in the course of the treatment;
b) its administration is envisaged exclusively at a specific dosage and schedule;
c) they are preparations for oral, external or inhalation use;
d) have been subject to traditional use for a period compliant with the provisions of article 23, paragraph 1, letter c);
e) have sufficient traditional employment data; in particular, they have been shown not to be harmful under the indicated conditions of use, and their pharmacological effects or effectiveness are plausible based on experience and long-standing use.
2. Notwithstanding the provisions of article 1, paragraph 1, letter ll), the presence in the medicinal product of herbal origin of vitamins or minerals, for the safety of which there is well-documented evidence, does not prevent the product from being eligible for registration in the pursuant to paragraph 1, provided that the action of the vitamins or minerals is secondary to that of the active plant substances as regards the specific indications requested.
3. The provisions of this chapter do not apply, however, in cases where the competent authorities consider that a medicinal product of traditional herbal origin satisfies the criteria for authorization under Article 6 or for registration under the article 16.
Article 22.
Establishment of the applicant and holder of the registration and competent authority for the registration
1. The applicant and holder of the registration are established in the European Community.
2. The application aimed at obtaining a registration based on traditional employment must be submitted to AIFA.
Article 23.
Application content
1. The application is accompanied by the elements specified below:
a) the information and documents:
1) pursuant to article 8, paragraph 3, letters from a) to i), o) and p);
2) the results of the pharmaceutical trials referred to in article 8, paragraph 3, letter l), number 1);
3) the summary of product characteristics set out in Annex 2 without the data set out in section 5;
4) in the case of combinations of herbal substances or preparations such as those described in article 1, letter ll), or in article 21, paragraph 2, the information referred to in article 21, paragraph 1, letter e), refer to the association of herbal substances or preparations as such; if the individual active substances are not sufficiently known, the data must also refer to each active substance;
b) any authorization or registration obtained by the applicant in another Member State of the European Community or in a third country for placing the medicinal product on the market and detailed information concerning any decisions to refuse an authorization or registration in the European Community or in a Third country, with an indication of the reasons underlying each refusal;
c) the bibliographic documentation or expert certificates proving that the medicinal product in question or a corresponding product has had a traditional use for a period of at least thirty years prior to the date of submission of the application, of which at least fifteen years in the European Community; where necessary, AIFA may ask the Committee for Medicinal Products of Herbal Origin established by Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004, hereinafter Directive 2004/24/EC, to express an opinion on the adequacy evidence of long-standing use of the medicinal product in question or the corresponding product. In this case, AIFA presents the documentation deemed relevant in support of the request;
d) a bibliographic review of the safety data together with the expert's report. AIFA may request further data to evaluate the safety of the medicinal product in question.
2. The technical attachment to the marketing authorization application also applies, by analogy, to the information and documents referred to in letter a) of paragraph 1.
3. For the purposes of paragraph 1, letter c), a product which contains the same active substances regardless of the excipients used, has the same or similar indications, has an equivalent dosage and dosage and is administered for the same route of administration or by a similar route to that of the medicinal product covered by the request.
4. The requirement of medicinal use for a period of thirty years, referred to in paragraph 1, letter c), is considered satisfied even if the product was marketed in the absence of a specific authorisation. It is equally satisfied if during this period the number or quantity of the active substances of the medicinal product has been reduced.
5. If the product has been used in the European Community for less than fifteen years, but is eligible for simplified registration for any other aspect, AIFA consults the Committee for Herbal Medicinal Products set up by Directive 2004/24/EC regarding the product in question, by submitting the relevant documentation in support of the registration request. In adopting the final decision, AIFA takes into account the evaluations of the Committee and the Community monograph on the vegetable substance that it may draft, pertinent to the product object of the application.
Article 24.
Application of the mutual recognition procedure and the decentralized procedure to traditional herbal medicinal products.
1. Without prejudice to the provisions of article 16-h, paragraph 1, of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use, and subsequent amendments, hereinafter Directive 2001/83/EC, chapter V of this title applies, by analogy, to registrations granted pursuant to article 21, provided that:
a) a Community monograph on herbs has been drawn up, pursuant to article 16-h, paragraph 3, of Directive 2001/83/EC; or;
b) the medicinal product of herbal origin consists of herbal substances, herbal preparations or their combinations appearing in the list referred to in Article 26.
2. For the other medicinal products of herbal origin referred to in article 21, AIFA, in assessing an application for registration based on traditional use, takes into due consideration the registrations issued by another Member State of the European Community pursuant to chapter 2-bis of title III of directive 2001/83/EC.
Article 25.
Registration Denial
1. Registration of the product based on traditional use is denied if the application does not comply with articles 21, 22 or 23 or if at least one of the following conditions exists:
a) the qualitative and/or quantitative composition does not correspond to the one declared;
(b) the indications do not comply with the conditions set out in Article 21;
c) the product could be harmful under normal conditions of use;
d) data on traditional use are insufficient, in particular if the pharmacological effects or efficacy are not plausible on the basis of experience and long-standing use;
e) the pharmaceutical quality is not sufficiently demonstrated.
2. AIFA communicates to the applicant, to the European Commission and to any competent authority that requests it, decisions to refuse registration based on traditional employment and the related reasons.
Article 26.
Questions relating to substances or preparations included in the specific Community list
1. If the application for registration of the product based on traditional use refers to a vegetable substance, a vegetable preparation or an association thereof appearing in the list provided for by article 16-septies of directive 2001/83/EC, it is not necessary provide the information referred to in article 23, paragraph 1, letters b), c) and d), and consequently the provision of article 25, paragraph 1, letters c) and d), does not apply.
2. If a herbal substance, a herbal preparation or an association thereof are canceled from the list referred to in paragraph 1, the registrations of medicinal products of herbal origin containing this substance or an association issued pursuant to the same paragraph are revoked, except in the case where to which the information and documents referred to in article 23, paragraph 1 are presented within three months.
Article 27.
Other provisions applicable to traditional herbal medicines
1. Article 3, paragraph 1, letters a) and b), article 6, paragraph 1, article 15, the article 29, paragraph 1, articles 30, 34, 38, 39, articles from 50 to 56, from 87 to 98, from 129 to 134, from 140 to 148, article 152, paragraph 2, and article 155, as well as the good manufacturing standards relating to medicines for human use established by the European Community.
2. In addition to the provisions of articles 73 to 82, the labeling and package leaflet of medicinal products of traditional herbal origin also bear a wording which specifies that:
a) the product is a medicinal product of herbal origin for traditional use to be used for specific indications based exclusively on long-standing use; And;
b) the user must consult a doctor or a qualified health professional if symptoms persist during use of the medicinal product in question or if adverse reactions not listed in the package leaflet arise.
3. The labeling and the package leaflet also indicate the type of traditional use referred to.
4. In addition to the provisions of articles 113 to 127, any form of advertising of a medicinal product registered pursuant to this chapter bears the following wording: medicinal product of traditional plant origin (or traditional herbal medicine) to be used for specific indications based exclusively on long-term employment.
5. In order to allow the full application of this decree by 20 May 2011, the Ministry of Health, by 20 May 2010, also on the basis of the guidelines adopted on the matter by the European Commission and the Court of Justice, dictates specific indications to clarify the demarcation line between the regulation of traditional medicinal products of plant origin referred to in this chapter and that of foods or other types of products subject to Community legislation.
Article 28.
Italian participation in the committee for medicinal products of herbal origin
1. The Italian member and the Italian alternate member of the Committee for Medicinal Products of Herbal Origin established by Directive 2004/24/EC are appointed by decree of the Minister of Health, in compliance with Community regulations.
Chapter IV
PROCEDURE FOR THE ISSUANCE OF THE AUTHORIZATION OF THE INVESTIGATION
Article 29.
Duration of the proceedings; effects induced by applications presented in other Member States
1. Without prejudice to the provisions of paragraph 2, AIFA adopts its own decisions on the AIC application, within two hundred and ten days of receiving a valid application.
2. If the application for the release of an authorization is presented not only in Italy but also in another member State of the European Community, articles 41 to 49 shall apply.
3. AIFA, if during the investigation it finds that another application for marketing authorization for the same medicinal product is under examination in another member state of the European Community, does not proceed with the evaluation of the application and informs the applicant that Articles 41 to 49 apply.
4. AIFA, when during the investigation it is informed, pursuant to article 8, paragraph 3, letter q), that another member State of the European Community has authorized the medicinal product which is the subject of the application for marketing authorisation, it rejects the application if it has not been submitted in accordance with articles 41 to 49.
Article 30.
Investigation of the application
1. For the purposes of the investigation of the application presented pursuant to articles 8, 10, 11, 12 and 13, AIFA:
a) verifies the compliance of the file submitted in accordance with articles 8, 10, 11, 12 and 13 and ascertains the existence of the conditions for the release of the MA;
b) may submit the medicinal product, its raw materials and, possibly, the intermediate products or other components to the control of the Higher Institute of Health, as the official medicinal control laboratory, to ascertain that the control methods used by the manufacturer and described in the documentation, in accordance with Article 8, paragraph 3, letter i), are satisfactory; AIFA may also order, with regard to the medicinal product object of the authorization request, inspections aimed at ascertaining the veracity of the experimental data, the compliance with the good manufacturing standards of the production process, the ethics of the clinical trials carried out and the compliance of the trials to current standards;
c) may, if necessary, require the applicant to complete the documentation accompanying the application with reference to the elements referred to in article 8, paragraph 3, and in articles 10, 11, 12 and 13. When AIFA makes use of of this faculty, the terms referred to in paragraph 1 of article 29 are suspended until the requested additional data have been provided. Likewise, these terms are suspended for any time allowed to the applicant to provide the requested clarifications.
2. AIFA ascertains that the producers and importers of medicines from third countries are able to carry out the production in compliance with the indications provided pursuant to article 8, paragraph 3, letter e), and to carry out the according to the methods described in the documentation, in compliance with article 8, paragraph 3, letter i). When there is a justified reason, it can allow manufacturers and importers of medicinal products from third countries to have certain stages of production and the above controls carried out by third parties; in this case, the AIFA checks are also carried out in the establishment indicated by the manufacturer or importer.
Article 31.
Information on the AIC
1. AIFA, when it issues the AIC, notifies the holder of the relative determination including the summary of the product characteristics, the package leaflet and the labelling.
2. AIFA annually adopts a program for checking the conformity of the information contained in the summary of product characteristics or package leaflets of medicinal products with those approved at the time of the release of the marketing authorization or with a subsequent provision by AIFA.
3. AIFA takes care of the prompt publication in the Official Gazette of the Italian Republic, by extract, of the AIC provision and makes public the summary of the product characteristics and its subsequent modifications.
Article 32.
Evaluation report
1. AIFA, availing itself of the technical-scientific advisory commission established pursuant to article 19 of the decree of the Minister of Health of 20 September 2004, n. 245, draws up an evaluation report and formulates any observations on the documentation submitted with the application regarding the results of the pharmaceutical, preclinical tests and clinical trials. The evaluation report is updated whenever new information relevant to the evaluation of the quality, safety or efficacy of the medicinal product in question becomes available.
2. AIFA shall promptly make the evaluation report, together with its reasoned decisions, accessible to the public via the website, after deleting all commercial information of a confidential nature. The justification of the decisions is provided separately for each indication requested.
Article 33.
Authorization subject to conditions
1. In exceptional circumstances and after consulting the applicant, the authorization can be granted on condition that the applicant fulfills certain obligations, in particular relating to the safety of the medicinal product, to notify AIFA of any adverse event connected to the use of the medicinal product and particular measures to be adopted.
2. This authorization can only be issued for objective and verifiable reasons and must be based on one of the reasons set out in the technical annex to the marketing authorization application.
3. Maintenance of the authorization is subject to the annual assessment of compliance with these conditions. The list of conditions is made accessible, without delay, with the publication on the AIFA website. The deadlines set for the obligations and the date of their implementation are made public in the same way.
Article 34.
Obligations of the MA holder
1. After the marketing authorization is granted, the holder takes into account the scientific and technical progress in the production and control methods referred to in article 8, paragraph 3, letters e) and i), and introduces the necessary variations so that the medicinal product is manufactured and tested according to generally accepted scientific methods.
2. The variations referred to in paragraph 1 must be approved by AIFA.
3. The authorization holder immediately informs AIFA of any new data which may imply changes to the information or documents referred to in articles 8, paragraph 3, and 10, 11, 12, 13 and 14 or in article 32, paragraph 5 of Directive 2001/83/EC, or in the technical annex on the marketing authorization application. In particular, the AIFA is immediately notified of the prohibitions or restrictions imposed by the competent authorities of any country in which the medicinal product is marketed and any other new data which may influence the evaluation of the benefits and risks of the same.
4. For the purposes of continuous assessment of the risk/benefit ratio, AIFA may ask the MA holder at any time to submit data demonstrating that the risk/benefit ratio remains favourable.
5. After the release of the authorisation, the holder informs AIFA of the date of effective marketing of the medicinal product in the national territory, taking into account the various authorized presentations.
6. The holder also notifies AIFA of the temporary or definitive cessation of the marketing of the medicinal product in the national territory. This communication is made no less than two months before the interruption of the marketing of the product, except in the case of interruption due to unforeseeable and exceptional circumstances. The term does not apply to suspensions of marketing related to product safety reasons.
7. When taking an initiative aimed at withdrawing the product from the market or suspending its marketing, for reasons relating to the efficacy of the medicinal product or the protection of public health, the person responsible for placing the medicinal product on the market immediately notifies AIFA and to the competent health authorities of the other countries of the European Community concerned; AIFA notifies the EMEA of the initiative notified by the person responsible for placing the medicinal product on the market.
8. The marketing authorization holder provides, at the request of AIFA, in particular in the context of pharmacovigilance, all the data relating to the sales volumes of the medicinal product and any data in its possession relating to the volume of prescriptions.
Article 35.
Permission Changes
1. The provisions of Regulation (EC) no. 1084/2003 of the Commission, of 3 June 2003, concerning the examination of the modifications of the terms of a marketing authorization for medicinal products for human use or for veterinary use issued by a competent authority of a member state, and subsequent modifications, hereinafter regulation (EC) no. 1084/2003, even if the authorizations do not fall within the specific hypotheses contemplated by article 1 of the aforementioned regulation.
Article 36.
Urgent restraining measures for safety reasons
1. If the holder of an AIC, issued by AIFA pursuant to this decree, takes urgent restrictive measures in the event of a risk to public health, he must immediately inform AIFA. If AIFA does not raise objections within twenty-four hours of receiving the information, the urgent restrictive measures are considered approved.
2. The urgent restrictive measure must be applied within a period of time agreed with AIFA.
3. The request for variation concerning the urgent restrictive measure must be presented immediately, and in any case within fifteen days from the date of entry into force of the restrictive measure, to AIFA, for the consequent determinations.
4. If AIFA imposes urgent restrictive measures on the holder for safety reasons, the holder is obliged to submit an application for a variation which takes into account the restrictive measures imposed by AIFA.
5. The urgent restrictive measure must be applied within a period of time agreed with AIFA.
6. The request for variation concerning the urgent restrictive measure, including the documentation supporting the modification, must be presented immediately and, in any case, within fifteen days from the date of entry into force of the imposition of the urgent restrictive measure, to AIFA for the resulting decisions.
7. The provisions of paragraphs 4, 5 and 6 are without prejudice to the provisions of article 47, paragraphs 2 and 3.
Article 37.
Inventory disposal or deadline for the withdrawal of the packages following the authorization of changes
1. In cases of modifications authorized pursuant to article 35, AIFA, when public health or market transparency reasons do not prevent this, having assessed the possible request of the company concerned, grants the disposal of the drug stocks subject to modification or a deadline for the withdrawal from the market of the packages for which the modification has taken place.
Article 38.
Duration, renewal, forfeiture and renunciation of the authorisation
1. Without prejudice to the provisions of paragraphs 4 and 5, the AIC is valid for five years.
2. The AIC, even if issued before the date of entry into force of this decree, can be renewed after five years on the basis of a new assessment of the risk/benefit ratio carried out by AIFA. To this end, the marketing authorization holder provides AIFA, at least six months before the expiry date of the validity of the authorization pursuant to paragraph 1, an updated version of the medicinal product authorization dossier relating to all aspects relating to quality , safety and efficacy, including all changes made after the issuance of the marketing authorization. Any changes to the dossier that are necessary to update it for renewal purposes are presented separately to the competent AIFA office; they are listed in the renewal application.
3. After renewal, the MA has unlimited validity, unless AIFA decides, for justified reasons connected with pharmacovigilance, to proceed with a further five-year renewal pursuant to paragraph 2.
4. Medicinal products which at the time of entry into force of this decree have already obtained one or more renewals of the MA, submit a further application pursuant to paragraph 2. After this renewal, unless otherwise provided by AIFA, the The AIC has unlimited validity.
5. Any marketing authorization for a medicinal product lapses if it is not followed by effective marketing on the national territory within the three years following issue. If a medicinal product is not placed on the market in the national territory within sixty days from the effective date of the authorization issued by AIFA, the person responsible for placing it on the market is required to notify AIFA of the delay in marketing and, subsequently, of the effective start of the same. The data relating to the lapsed MAs are published in the Official Gazette of the Italian Republic by AIFA.
6. Paragraph 5 also applies to medicines authorized before the date of entry into force of this decree; for them, the three-year period starts from the aforesaid date.
7. The authorization also expires if an authorized and marketed medicinal product is no longer effectively marketed for three consecutive years on the national territory.
8. AIFA, in exceptional cases and for public health reasons, can exempt, with a reasoned provision, the medicinal product from the forfeiture provided for by paragraphs 5, 6 and 7.
9. When the holder renounces the authorization granted to him, AIFA, in ordering the revocation of the authorisation, may grant, when public health reasons do not prevent this, a deadline for the withdrawal from the market of the medicinal product subject to revocation.
Article 39.
Effects of the authorisation
1. The release of the authorization does not exclude the liability, even penal, of the producer and the marketing authorization holder.
Article 40.
Denial of Authorization
1. Marketing authorization is denied when, from the verification of the documents and information referred to in articles 8, 9, 10, 11, 12 and 13, it appears that:
a) the risk/benefit ratio is not considered favourable;
b) the therapeutic efficacy of the medicinal product is not sufficiently documented by the applicant;
c) the medicinal product does not have the declared qualitative and quantitative composition.
2. Authorization is also denied if the documentation or information presented in support of the application does not comply with articles 8, 9, 10, 11, 12 and 13.
3. The applicant or marketing authorization holder is responsible for the accuracy of the documents and data he has provided.
4. The denial of the authorization, in any case justified, is notified within the terms referred to in paragraph 1 of article 29. The interested party may present an opposition to the denial measure to AIFA, which decides within ninety days.
Head V
MUTUAL RECOGNITION PROCEDURE AND DECENTRALIZED PROCEDURE
Article 41.
Submission of the application in the mutual recognition procedure and in the decentralized procedure
1. When, pursuant to Article 28 of Directive 2001/83/EC, the applicant submits an application based on an identical file also in other Member States of the European Community, the application file includes the information and documents referred to in Articles 8, 10, 11, 12, 13 and 14 of this decree, as well as the list of Member States to which the application has been presented.
Article 42.
Hypothesis in which Italy acts as reference Member State
1. If the applicant, who submits an application in several Member States of the European Community pursuant to article 28 of Directive 2001/83/EC, requests that the Italian State act as the reference Member State, AIFA shall comply with the procedures referred to in paragraphs 2, 3, 4, 5 and 6.
2. If at the time of submitting the application in other Member States, the medicinal product has already obtained marketing authorization in Italy, AIFA, at the request of the applicant, prepares, within ninety days from the date of receipt of a valid application, a report evaluation report or, if necessary, update the already existing evaluation report. AIFA sends the approved assessment report, summary of product characteristics, labeling and package leaflet to the Member States concerned and to the applicant.
3. If at the time of submitting the application in Italy and in other Member States, the medicinal product has not obtained the AIC, AIFA, upon request by the applicant, prepares, within one hundred and twenty days from the date of receipt of the application recognized as valid, a draft assessment report, a draft summary of product characteristics and a draft labeling and package leaflet and sends them to the Member States concerned and to the applicant.
4. In the cases envisaged by paragraphs 2 and 3, AIFA, after ninety days from the date of communication of receipt, by the Member States involved, of the documentation referred to in the same paragraphs, having acquired the favorable evaluations of the same, ascertains the consent of all parties, closes the procedure and informs the applicant of the outcome.
5. If AIFA receives, within the term referred to in paragraph 4, from a Member State involved the communication of not being able to approve, due to a potentially serious risk to public health, the evaluation report, the summary of the characteristics of the product, the labeling and the package leaflet prepared, the procedure referred to in Article 29 of Directive 2001/83/EC applies.
6. In the hypothesis envisaged by paragraph 2, within thirty days of ascertaining the consent of all the parties referred to in paragraph 4, AIFA updates, if necessary, the AIC of the medicinal product as well as the summary of product characteristics, labeling and package leaflet. In the hypothesis envisaged by paragraph 3, within thirty days of obtaining consent, AIFA issues the AIC complete with evaluation report, summary of product characteristics, approved labeling and leaflet.
Article 43.
Hypothesis in which Italy acts as interested State
1. If the applicant who submits an application in several Member States of the European Community, pursuant to Article 28 of Directive 2001/83/EC, does not request that the Italian State act as the reference Member State and at the time of the application the medicinal has already obtained a marketing authorization in another Member State, AIFA recognizes, within ninety days of receiving the evaluation report, the summary of product characteristics, labeling and package leaflet prepared by the Member State concerned , the marketing authorization issued by that member state on the basis of the evaluation report prepared or updated by the same state. If at the time of application the medicinal product has not already obtained a marketing authorization in another Member State, AIFA approves it within ninety days of receiving the evaluation report, the summary of product characteristics, the labeling and the leaflet prepared by the Member State concerned, the evaluation report, the summary of product characteristics, the labeling and the package leaflet prepared by the reference Member State, and, within thirty days of the verification, by the reference Member State, of the general consensus, the AIFA adopts, with regard to the requested authorization, a decision in accordance with the approved evaluation report, summary of product characteristics, labeling and package leaflet.
2. If AIFA, due to a potentially serious risk to public health, deems it unable to approve the assessment report, the summary of product characteristics, the labeling and the package leaflet prepared by the reference Member State, communicate, within the deadline set by Article 28(4) of Directive 2001/83/EC, the detailed justification of its position to the reference Member State, to the other Member States concerned and to the applicant.
3. If AIFA receives, within the term referred to in paragraph 2, from a Member State involved, the communication of not being able to approve, due to a potentially serious risk to public health, the evaluation report, the draft of the summary of product characteristics, the labeling and the package leaflet prepared, at the request of the applicant, can in any case authorise, on a provisional basis, the medicinal product pending the outcome of the procedure referred to in article 32 of directive 2001/83/ THERE IS.
Article 44.
Hypothesis of lack of agreement between the Member States concerned on the issue of the authorisation
1. In the cases envisaged by paragraphs 2 and 3 of article 43 and in any other case of failure to reach an agreement between the Member States that have received a request pursuant to article 28 of directive 2001/83/EC, the procedures for referred to in Article 29 of Directive 2001/83/EC. If the community procedures referred to in articles 32, 33 and 34 of the same directive have been completed, AIFA adopts a measure in conformity with the decision taken by the European Commission within thirty days of notification of the decision itself.
Article 45.
Hypothesis of different evaluations of the Member States
1. When the same medicinal product has been the subject of two or more marketing authorization applications in the European Community in compliance with the provisions of Directive 2001/83/EC and the Member States concerned have adopted diverging decisions regarding the authorization of said medicinal product or the suspension or the revocation of the same, AIFA, also at the request of the Ministry of Health, or the applicant or holder of the AIC, may appeal to the Committee for Medicinal Products for Human Use, hereinafter referred to in this chapter as the "Committee", for the application of the procedure of articles 32, 33 and 34 of the aforementioned directive. After completing this procedure, AIFA adjusts, where necessary, its decisions to the Commission's decision, within thirty days of its notification. The provision referred to in the previous period also applies when the Committee is referred to by the Commission or by another Member State or by the applicant or the marketing authorization holder in another Member State.
2. In order to promote the harmonization of medicinal product authorizations in the European Community, every year AIFA proposes, pursuant to article 30, paragraph 2, of Directive 2001/83/EC, a list of medicinal products for which, in your opinion, it seems appropriate to draw up a harmonized summary of product characteristics.
Article 46.
Particular cases of Community interest to appeal to the Committee
1. In particular cases involving the interests of the European Community, AIFA or the applicant or holder of the marketing authorization may appeal to the Committee, for the application of the procedure set out in articles 32, 33 and 34 of directive 2001/83 /EC, before a decision is taken on the application, suspension or withdrawal of the authorization or on any other modification of the authorization which appears necessary, in particular, to take account of the information collected under Title IX.
2. AIFA clearly identifies the matter submitted to the Committee and informs the applicant or the MA holder.
3. AIFA, the applicant or the marketing authorization holder send the Committee all available information regarding the matter.
4. After the completion of the procedure referred to in articles 32, 33 and 34 of Directive 2001/83/EC, AIFA adopts its own decisions or, where necessary, adapts the decisions already adopted, in compliance with the decision of the European Commission, within thirty days of its notification.
Article 47.
Variations of mutual recognition and decentralized authorizations
1. The holder of a marketing authorization issued in accordance with the provisions of this chapter, who requests changes to the authorization itself, must also submit the application to the other Member States which have authorized the medicinal product. Also in this case, if the procedures set out in articles 32, 33 and 34 of Directive 2001/83/EC are completed, AIFA adopts its decisions in compliance with the decision of the European Commission, within thirty days of its notification.
2. If AIFA deems it necessary, for the protection of public health, to modify a marketing authorization issued in accordance with the provisions of this chapter, or to suspend or revoke the authorisation, it shall immediately inform the EMEA of this assessment, for the purpose of applying of the procedures referred to in Articles 32, 33 and 34 of Directive 2001/83/EC.
3. In exceptional cases, when the adoption of an urgent measure to protect public health is indispensable and until a definitive decision has been taken pursuant to the procedure referred to in paragraph 2, AIFA may suspend the release marketing and use of the medicinal product concerned. AIFA informs the Commission and the other Member States, no later than the working day following the adoption of the measure, of the reasons which led it to take this decision.
Article 48.
Medicinal products authorized under Directive 87/22/EEC
1. Article 47 also applies to medicinal products authorized by the Member States of the European Community in accordance with the provisions of article 4 of Directive 87/22/EEC.
Article 49.
Homeopathic medicines
1. This title does not apply to homeopathic medicinal products referred to in article 20.
2. For other homeopathic medicinal products, this title applies with the limitations deriving from article 39 of directive 2001/83/EC.
TITLE IV
PRODUCTION AND IMPORT
Chapter I
PRODUCTION AND IMPORT AUTHORIZATIONS
Article 50.
Authorization for the production of medicines
1. No one can produce a medicinal product on the national territory, even for the sole purpose of export, without the authorization of AIFA, which is issued after an inspection aimed at ascertaining that the applicant has qualified personnel and technical-industrial means. compliant with the provisions of letters b) and c) of paragraph 2.
2. To obtain the production authorisation, the applicant is required to:
a) specify the medicines and pharmaceutical forms that it intends to produce or import, as well as the place of production and controls;
b) have, for the production or importation of the medicinal products themselves, adequate and sufficient premises, technical equipment and facilities and control possibilities, both for the production and control, and for the conservation of the medicinal products;
c) have at least one qualified person pursuant to article 52 of this decree.
3. Within ninety days from the date of receipt of the application, accompanied by information aimed at proving possession of the requirements set out in paragraph 1 and compliance with the conditions indicated in paragraph 2, AIFA adopts its own decisions. The authorization issued can be supplemented by the imposition of obligations to ensure compliance with the requirements set out in paragraph 1. The refusal of the authorization must be notified to the interested party, complete with justification.
4. The term referred to in paragraph 3 is suspended if AIFA requests further information on the establishment or indicates to the interested party the conditions necessary to make the premises and equipment suitable for production, assigning a term for the relative fulfilment.
5. For any modification of the conditions on the basis of which the authorization was issued, an application must be submitted to AIFA, which decides on the same within the term of thirty days, which can be extended up to ninety days in exceptional cases, without prejudice to the application of paragraph 4.
6. When the modification concerns the sudden need to replace the qualified person, the new appointee can carry out his/her duties while waiting for AIFA to pronounce itself pursuant to paragraph 5.
7. In justified cases, the holder of the authorization referred to in this article may be authorized by AIFA, subject to the consent of the person responsible for placing the medicinal product on the market, if different from the aforementioned holder, to carry out stages of production in another authorized workshop and controls. In these hypotheses, the responsibility for the production and control phases concerned is assumed not only by the qualified person of the customer, but also by the qualified person of the plant that carries out the requested operations.
8. AIFA sends the EMEA a copy of the authorizations issued pursuant to this article. AIFA publishes the list of establishments that are authorized for the production and control of medicinal products in the Official Gazette of the Italian Republic as of 30 June of each year.
Article 51.
Obligations of the manufacturer
Compliance with good manufacturing standards
1. The production authorization holder is required to:
a) have adequate personnel for the production and checks it carries out;
b) sell the authorized medicines, in compliance with this decree and with the other laws and regulations in force;
c) allow AIFA-designated inspectors access to its premises at any time;
d) make available to the qualified person referred to in article 52 all the means necessary to allow him to carry out his duties;
e) comply with the principles and guidelines on good manufacturing practices for medicinal products, referred to in chapter II of this title, and with the additional directives in this regard issued by the European Community and use only substances produced according to the guidelines as pharmacologically active raw materials details on good manufacturing practices for raw materials.
Article 52.
Qualified personnel which the holder of the production authorization must have
1. The holder of the authorization for the production of medicinal products must make use of at least one qualified person and of the additional qualified personnel referred to in paragraph 10.
2. The qualified person carries out his activity on an ongoing basis under the company's employ. The holder of the production authorization can also perform the functions of a qualified person if he has the requisites required by this article.
3. AIFA recognizes the suitability of the qualified person who possesses the following requirements:
a) is in possession of the degree pursuant to the law of 19 November 1990, n. 341, or specialist degree pursuant to the decree of the Minister of University and Scientific and Technological Research November 3, 1999, n. 509, or master's degree pursuant to the decree of the Minister of Education, University and Research 22 October 2004, n. 270, in one of the following disciplines or in one of the scientific-disciplinary sectors to which the declarations of the same disciplines refer chemistry and pharmaceutical technology, pharmacy, chemistry, industrial chemistry, biological sciences, medicine and surgery, veterinary medicine; university-level training must include the theoretical and practical teaching of the following basic disciplines and the passing of the related exams: experimental physics, general and inorganic chemistry, organic chemistry, analytical chemistry, pharmaceutical chemistry, including drug analysis, general biochemistry and applied, physiology, microbiology, pharmacology, pharmaceutical technology, toxicology, pharmacognosy;
b) has carried out practical activity concerning qualitative analysis of medicinal products, quantitative analysis of active substances, tests and verifications necessary to guarantee the quality of medicinal products, for a period of at least two years in companies authorized to produce medicinal products; in cases of preparation or production of medicinal products for advanced therapies, the practical activity of two years must be carried out in the same type of production for which the qualified person must perform his duties; in the latter case, the reduction referred to in paragraph 4 does not apply;
c) is qualified to practice the profession and is registered in the professional register.
4. The period referred to in letter b) of paragraph 3 is reduced by one year when the interested party has completed a university training cycle lasting at least five years; and reduced by eighteen months where the cycle itself had a duration of at least six years.
5. For the purposes of this article, the diplomas referred to in letter a) of paragraph 3, obtained on the basis of courses other than those indicated therein, are declared valid, in relation to the required requisites, by AIFA, subject to a favorable opinion expressed by the Ministry of Education, University and Research, after consultation with the National University Council, when the interested party demonstrates the acquisition, after obtaining the degree, of sufficient knowledge in subjects not included in the course of study.
6. The technical directors of production workshops, already recognized by AIFA or by the Ministry of Health at the time of entry into force of this decree, can continue to carry out the same activity with the function of qualified person.
7. Those who, on the date of entry into force of this decree, carry out the activity referred to in this article on the basis of the previous legislation in force, can continue the same activity in workshops of the same type of production, even in the absence of the requisites envisaged from paragraph 3.
8. The qualified person:
a) supervises that each batch of medicines is produced and checked in compliance with the provisions of the law and the conditions imposed in the authorization to place the medicine on the market;
b) checks that, in the case of medicinal products originating from countries not belonging to the European Economic Community, each imported production batch is subjected to a complete qualitative analysis, a quantitative analysis of at least all the active substances and any other test and verification necessary to guarantee the quality of the medicines in compliance with the conditions set for the AIC, without prejudice to what is established by any mutual recognition agreements;
c) certify the operations referred to in letters a) and b) in appropriate documentation;
d) is responsible, in accordance with the provisions of chapter II of this title, for keeping the documentation referred to in letter c), and is obliged to show it at the request of the health authority;
e) immediately inform AIFA and the head of the company on which it depends any substantial irregularity detected in the medicinal product that has already been placed on the market;
f) actively collaborates in the inspections carried out by the health authority pursuant to this decree and carries out the operations requested by the same;
g) supervises the general conditions of hygiene of the premises for which he is responsible.
9. The qualified person cannot carry out the same function in several workshops, unless it is a workshop constituting a detached department of the main workshop.
10. The qualified person is assisted at least by the qualified personnel envisaged by chapter II of this title and by the good manufacturing standards.
Article 53.
Investigations on the production of medicines
1. AIFA can:
a) proceed, at any time, even without notice, where necessary for the purpose of verifying compliance with the provisions of this decree and, in particular those of chapter II of this title, to inspect the establishments and premises where the production, control and storage of medicines and active substances used as raw materials in the production of medicines;
b) take samples of medicines and, if necessary, of other substances necessary for the analyses;
c) take note and, if necessary, acquire a copy of all the documents relating to the object of the inspections.
2. During inspections of immunological drug production workshops, AIFA verifies that the production processes used are duly validated and allow for continuous compliance of the batches to be ensured.
3. The inspections of the production plants and control laboratories referred to in paragraph 1 are periodically renewed.
4. Such inspections may also take place at the request of the European Commission, the EMEA or another Member State.
5. AIFA can proceed with the inspection of a producer of raw materials also upon specific request of the same.
6. Without prejudice to any agreements concluded between the European Community and third countries, AIFA may ask the producer established in a third country to submit to the inspection referred to in paragraph 1.
7. At the end of each inspection, a report is drawn up on the manufacturer's compliance with the principles and guidelines of the good manufacturing practices for medicinal products referred to in chapter II of this title and the additional directives issued in this regard by the European Community. The content of the report is communicated to the producer and to any competent authority of another Member State of the European Community which makes a reasoned request.
8. In the ninety days following the inspection referred to in paragraph 1, if the inspection ascertains compliance by the manufacturer with the principles and guidelines of the good manufacturing practices established by Community legislation, the manufacturer is issued a certificate compliance with good manufacturing practices.
9. AIFA enters the certificates of conformity with good manufacturing standards issued by it in a community database kept by the EMEA on behalf of the European Community.
10. If the inspection referred to in paragraph 1 ascertains the manufacturer's failure to comply with the principles and guidelines of good manufacturing practices established by Community legislation, this information is entered in the Community database referred to in paragraph 9.
11. For the purposes of the checks referred to in this article, AIFA may make use of its own personnel, the Higher Institute of Health, the Higher Institute for Prevention and Safety at Work, local health units, and other structures institutions recognized as suitable by AIFA, provided they possess the professional requisites established by AIFA itself, through agreements with other institutes.
12. Technicians from the 'Higher Institute of Health in possession of specific experience in the sector.
13. The expenses required for inspections of pharmaceutical companies, both before and after the issue of production authorisations, aimed at verifying compliance with the provisions of this decree, shall be borne by the inspected companies.
14. The personnel who carry out the checks referred to in this article are due a fee including travel allowance, to be established by decree of the Minister of Health, in agreement with the Minister of Economy and Finance, to be adopted within no later than sixty days from the date of entry into force of this decree.
15. AIFA, having consulted the Higher Institute of Health and the Technical-Scientific Advisory Commission, establishes the annual control program of the compositions of medicinal products whose analyzes are carried out by the Higher Institute of Health.
Article 54.
Specification of the scope of application of the regulation relating to the authorization to produce medicines
1. The provisions of articles 50, 51, 52 and 53 also govern the execution of partial operations of preparation, division and packaging and presentation of medicinal products, as well as the execution of quality controls of medicinal products in the cases provided for by law .
2. This title also applies to the production activities of active substances used as raw materials for the production of medicinal products, with reference both to the total or partial production phases and to the importation of an active substance, even if used itself as a prior to the production or extraction of other active substances, as defined in Annex I, part I, point 3.2.1.1.b), or to the various operations of dividing, packaging or presentation preceding the incorporation of the starting material into the medicinal product, including repackaging and relabelling by a raw material wholesale distributor.
3. For raw materials, including those imported from third countries, a certificate of compliance with good manufacturing practices must be available, issued to the production workshop by the competent authorities of a Member State of the European Union. For marketing authorization applications submitted pursuant to chapter V, title III of this decree and pursuant to regulation (EC) no. 726/2004, the provision of the certificate is not mandatory, except as provided by the relevant guidelines. This is without prejudice to any mutual recognition agreements of the inspection systems entered into by the European Union with third countries. For the operating procedures, reference will be made to the provisions of the text of these agreements. The activities envisaged by this paragraph are carried out within the limits of the human and instrumental resources available under current legislation and without new or greater burdens for public finance.
4. The possession by the manufacturer of raw materials of a certificate of conformity with good manufacturing practices issued by a competent authority within the European Community does not exempt the importer or manufacturer of the finished medicinal product from the responsibility for carrying out checks on raw materials and checks on the producer.
Article 55.
Authorization to import medicines
1. The provisions of articles 50, 51, 52 and 53 of this decree also apply to the importation of medicinal products from third countries.
2. Articles 50, 51 and 52 do not apply when it comes to medicinal products that come from countries with which the European Community has concluded agreements aimed at guaranteeing that the manufacturer applies good manufacturing standards at least equivalent to those established by the Community and that the checks referred to in article 52, paragraph 8, letter b), have been carried out in the exporting country, without prejudice to the provisions of mutual recognition agreements.
Article 56.
Special cases of medicinal products from other Member States
1. When medicinal products from another Member State are produced by third countries, each batch of medicinal product must be accompanied by a certificate from the person in charge of controls according to the legislation of the Community State of origin.
2. The obligation referred to in paragraph 1 also applies in cases in which the medicinal product was produced in a member state of the European Community, but then exported and re-imported in the same or in another member state.
Article 57.
Homeopathic medicines
1. The provisions of this title also apply to homeopathic medicines.
Chapter II
GUIDELINES ON GOOD MANUFACTURING STANDARDS
Article 58.
Scope
1. This chapter establishes the principles and guidelines relating to the standards of good manufacturing practice for medicinal products for human use whose production is subject to the authorization referred to in Article 50 and for experimental medicinal products for human use whose production subject to the authorization referred to in article 13 of the legislative decree 24 June 2003, n. 211.
Article 59.
Definitions
1. For the purposes of this chapter, the following definitions apply:
a) experimental medicinal product: a pharmaceutical form of an active ingredient or a placebo tested as an experimental medicinal product or as a control in a clinical trial, including medicinal products which have already obtained a marketing authorization but which are used or prepared (according to the master formula or packaged ) in a form other than the authorized form, or are used for unauthorized indications or to obtain further information on the authorized form;
b) pharmaceutical quality assurance: the sum of all precautions taken to ensure that medicinal products or investigational medicinal products have the quality required for their intended use;
c) good manufacturing practice: the technical rules relating to quality assurance which guarantee that medicinal products are manufactured and controlled according to quality standards appropriate to their intended use;
d) intentional obscuring of the identity of an experimental medicinal product according to the instructions of the promoter of the experimentation, as defined in paragraph 1, letter e), of article 2 of legislative decree 24 June 2003, n. 211;
e) unmasking revealing the identity of a masked medicinal product.
2. In this chapter, the term medicinal product without further specifications means the medicinal product other than the experimental medicinal product, as defined in paragraph 1, letter a).
Article 60.
Community guidelines
1. To interpret the principles and guidelines of good manufacturing practice, manufacturers and competent authorities shall take into account the detailed guidelines referred to in Article 47, second paragraph, of Directive 2001/83/EC, published by the Commission in "Guide to good manufacturing practice for medicinal products and investigational medicinal products".
Article 61.
Compliance with good manufacturing standards
1. The manufacturer ensures that the manufacturing operations comply with good manufacturing practice and manufacturing approval. This provision also applies to medicines intended exclusively for export.
2. For medicines and experimental medicines imported from third countries, the importer guarantees that they comply with production standards at least equivalent to those in force in the Community. The importer of medicines also guarantees that these medicines are produced by duly authorized manufacturers for the purpose. The importer of experimental medicinal products guarantees that these medicinal products are produced by manufacturers notified to the competent authorities and approved by them for the purpose.
Article 62.
Marketing Authorization Compliance
1. The manufacturer ensures that all the manufacturing operations of medicinal products subject to a marketing authorization are carried out in compliance with the information provided in the relevant application for authorization approved by AIFA. For experimental medicinal products, the manufacturer ensures that all production operations respond to the information provided by the promoter of the experimentation pursuant to article 9, paragraph 2, of legislative decree 24 June 2003, n. 211, and accepted by the competent authorities.
2. The manufacturer reviews its production methods at regular intervals in the light of technical and scientific progress and the development of investigational medicinal products. When a modification of the AIC dossier or of the application referred to in article 9, paragraph 2, of the legislative decree 24 June 2003, n. 211, the modification request is submitted to AIFA.
Article 63.
Quality assurance system
1. The manufacturer establishes and operates an effective pharmaceutical quality assurance system, which involves the active participation of management and employees in all different activities of production, documentation and control.
Article 64.
Personal
1. At each manufacturing site, the manufacturer has sufficient personnel with the appropriate skills and qualifications to achieve the objective of pharmaceutical quality assurance.
2. The duties of the managerial and supervisory staff, including the qualified person responsible for the application and implementation of good manufacturing practices, are specified in specific job descriptions. The levels of responsibility are defined in an organization chart. Organization charts and job descriptions are approved in accordance with the manufacturer's internal procedures.
3. The personnel referred to in paragraph 2 are given the necessary powers for the correct exercise of their functions.
4. Personnel shall receive initial and ongoing training, the effectiveness of which is verified, focusing in particular on the theory and practice of quality assurance and good manufacturing practices and possibly on specific requirements for the production of investigational medicinal products.
5. Hygiene courses appropriate to the activities to be carried out are organized and followed. These mainly concern the health, hygiene and clothing of the staff.
Article 65.
Establishments and facilities
1. In compliance, however, with the regulations in force on town planning, the environment, safety and health, the location, design, construction, expansion, restructuring and maintenance of the establishments and production plants are appropriate to the activities to be performed there.
2. The establishments and production plants are organised, designed and operated in such a way as to minimize the risk of error and to allow for effective cleaning and maintenance in order to avoid contamination, cross-contamination and, in general, deleterious effects on the quality of the product.
3. The establishments and plants to be used in phases of the production process which are decisive for the quality of the products are subject to qualification and validation, as regulated in the publication referred to in article 60.
Article 66.
Documentation
1. The manufacturer establishes and maintains a documentation system based on specifications, production formulas, processing and packaging instructions, procedures and records for each production operation performed. The documentation is clear, truthful, updated. The manufacturer keeps available pre-established procedures and conditions of the general production and the documents specific to the production of each batch. This set of documents makes it possible to reconstruct the production process of each batch and the changes introduced during the development of an experimental drug. The documentation on the lots of a medicinal product is kept for at least one year from the expiry date of the lots to which it refers or for at least five years from the issue of the certificates referred to in article 52, paragraph 8, letter c), if this term and ' longer. For investigational medicinal products, batch documentation is kept for at least five years after the completion or formal suspension of the last clinical trial in which the batch was used. The promoter of the trial or, if different, the marketing authorization holder is responsible for keeping the documents necessary for this authorization pursuant to Annex I of this decree if necessary for a subsequent authorization.
2. If, instead of written documents, photographic, electronic processing or other documentation systems are used, the manufacturer validates the systems in advance, proving that the data will be adequately stored for the intended period. The data stored by these systems are made available in a simple and readable form and provided to the competent authorities upon their request. The data stored in electronic form are protected against loss or damage, for example by methods such as duplication or the production of reserve copies transferred to other storage systems; moreover, a trace of the changes made to the data is kept.
Article 67.
Production
1. The various production operations are carried out according to pre-established instructions and procedures and in accordance with good manufacturing practices. Adequate and sufficient resources are allocated to controls during production. Deviations from procedures and manufacturing defects are documented and thoroughly investigated.
2. Appropriate technical-organizational measures are taken to avoid cross-contamination and mixing. For investigational medicinal products, particular attention is paid to the handling of the products during and after each masking operation.
3. For medicines, every new production or major change to the production of a medicine is validated. Critical stages of production processes are regularly re-validated.
4. For investigational medicinal products, the entire production process is possibly validated taking into account the product development phase. At least the most important steps, for example sterilization, are validated. All the design and development phases of the production process are meticulously documented.
Article 68.
Quality control
1. The manufacturer establishes and maintains a quality control system under the responsibility of a suitably qualified person who is independent of production. This person has or has access to one or more quality control laboratories adequately staffed and equipped to analyze and test raw materials, packaging materials and intermediate and final products.
2. For medicinal products, including those imported from third countries, external laboratories may be used, pursuant to the following article and the second sentence of paragraph 2 of article 30.
3. For experimental medicines, the promoter of the experimentation ensures that the external laboratory complies with the requirements described in the application for authorization of the experimentation, referred to in article 9, paragraph 2, of the legislative decree of 24 June 2003, n. 211. When the products are imported from third countries, the analyzes are not mandatory, without prejudice to the responsibility of the importer to verify that they are produced and controlled according to standards at least equivalent to those established by Community regulations.
4. During the final control of the finished product, before distribution or placing on the market or use for clinical trials, the quality control system takes into account not only the results of the analyzes but also essential information such as the conditions of production, the controls during the process, the examination of the production documents, the conformity of the product to the specifications and of the final packaging.
5. Samples of each batch of finished medicinal product are kept for at least one year from the expiry date. For investigational medicinal products, sufficient samples of each bulk product lot and of the major packaging components used for each finished product lot are retained, for at least two years after completion or formal suspension of the last clinical trial in which the lot is ' been used, whichever is longer. Samples of raw materials used in the manufacturing process, excluding solvents, gases or water, are kept for at least two years after the batch release of the medicinal product. This period can be shortened if the stability period of the raw material, indicated in the specification that concerns it, is shorter. All samples are kept at the disposal of the competent authorities. With the approval of AIFA, other sampling and conservation conditions can be defined for raw materials and certain medicinal products when they are produced individually or in small quantities, or their storage raises particular problems.
Article 69.
Operations contract
1. Each production operation or related operation, contractually entrusted to third parties, is the subject of a written contract.
2. The contract clearly defines the responsibilities of the parties and in particular the contractor's obligation to comply with good manufacturing practices and the way in which the qualified person, responsible for the certification of each batch, has to carry out his duties.
3. The contractor may not subcontract any work entrusted to him without written authorization from the customer.
4. The contractor respects the principles and guidelines of good manufacturing practice and submits to the inspections carried out by the competent authorities referred to in Article 53, paragraph 1, letter a), and in Article 15 of the Legislative Decree of 24 June 2003, no. 211.
Article 70.
Complaints, drug withdrawals and emergency demasking
1. For medicines, the manufacturer puts in place a system of registering and examining complaints and an effective system of rapid withdrawal, at any time, of medicines already in the distribution network. He registers and examines every complaint relating to defects and informs AIFA of all defects that may give rise to withdrawals from the market, to abnormal limitations on supplies and, as far as possible, indicates the countries of destination. Withdrawals from the market are carried out in compliance with the provisions of article 34, paragraph 7.
2. For investigational medicinal products, the manufacturer shall set up, together with the trial sponsor, a system for registering and examining complaints and an effective system for rapid withdrawal, at any time, of already distributed investigational medicinal products. He registers and examines every complaint regarding defects and informs AIFA of all defects that may give rise to withdrawals or abnormal limitations of supplies. For investigational medicines, all the trial centers and, as far as possible, also the countries of destination are indicated. In the case of an investigational medicinal product for which marketing authorization has been granted, the manufacturer of this medicinal product, together with the sponsor of the trial, informs the marketing authorization holder of any possible defect in the authorized medicinal product.
3. If necessary to speed up a withdrawal referred to in paragraph 2, the trial promoter prepares a procedure for the urgent unmasking of masked medicines. The procedure ensures that the identity of the masked medicine is revealed only to the extent necessary.
Article 71.
Self-inspection
1. Within the quality assurance system, the manufacturer carries out repeated self-inspections to check the application and observance of the good manufacturing practices and propose the necessary corrective measures. Self-inspections are logged as are all subsequent correctives.
Article 72.
Labeling
1. The labeling of an experimental medicinal product must guarantee the protection of the subject and traceability, must allow the identification of the medicinal product and of the clinical study and allow the appropriate use of the experimental medicinal product.
TITLE V
LABELING AND PACKAGE LEAFLET
Article 73.
Labeling
1. The external packaging or, in the absence thereof, the immediate packaging of medicinal products shall bear the following indications:
(a) the name of the medicinal product, followed by the strength and pharmaceutical form, adding where appropriate the term 'babyhood', 'children' or 'adults'; when the medicine contains up to three active substances, and only when the denomination is an invented name, it is followed by the common denomination;
b) the qualitative and quantitative composition in terms of active substances per dosage unit or, in relation to the pharmaceutical form, for a given volume or weight, reported using the common names;
c) the pharmaceutical form and the contents of the package expressed in weight, volume or dosage units;
d) a list of excipients, with known action or effect, included in guidelines published pursuant to Article 65 of Directive 2001/83/EC; however, if it is an injectable product or a topical or ocular preparation, all excipients must be reported;
e) the method of administration and, if necessary, the route of administration; in correspondence with this indication, a space must be reserved on which to indicate the dosage prescribed by the doctor;
f) the warning: "Keep the medicine out of the reach and sight of children";
g) any special warnings necessary for the medicine in question with particular reference to the contraindications caused by the interaction of the medicine with alcoholic beverages and spirits, as well as any danger to driving deriving from taking the same medicine;
h) the month and year of expiry, indicated with words or numbers;
i) the special conservation precautions, if foreseen;
l) if necessary, the special precautions to be taken for the disposal of the unused medicinal product or waste derived from the same, as well as a reference to the appropriate existing collection systems;
m) the name and address of the MA holder, preceded by the expression "MA Holder";
n) the marketing authorization number;
o) the production batch number;
p) for non-prescription medicinal products, the therapeutic indications and main instructions for use of the medicinal product;
q) the supply system according to the provisions of Title VI of this decree;
r) the price to the public of the medicinal product, which, limited to the medicinal products referred to in article 96, must be indicated in compliance with the provisions of article 1, paragraph 5, of decree law no. 87, converted, with amendments, by law 26 July 2005, n. 149;
s) the indication of the reimbursement conditions by the National Health Service.
2. In addition to the indications provided for in paragraph 1, with prior authorization from AIFA, the name and address of whoever, on the basis of a specific agreement with the marketing authorization holder, sees to the effective marketing of the medicine on the whole national territory. These indications, as well as any symbols and emblems relating to the same distributor, must not prevent the clear reading of the indications, symbols and emblems relating to the MA holder.
3. The provisions of this article are without prejudice to the provisions in force concerning the adoption of systems capable of guaranteeing the authenticity and traceability of the medicinal products referred to in the decree of the Minister of Health dated 2 August 2001, published in the Official Gazette of the Republic of November 20, 2001, n. 270 and the decree of the Minister of Health dated 15 July 2004, published in the Official Gazette of the Italian Republic dated 4 January 2005, n. 2, as well as those concerning the labeling of medicines dispensed at the expense of the National Health Service. The Minister of Health adopts appropriate initiatives aimed at preventing the application of the rules concerning the marking and traceability of medicines from causing excessive costs for low-cost medicines.
4. AIFA ensures compliance with the detailed indications provided for by article 65 of directive 2001/83/EC, also for medicinal products authorized according to the provisions of regulation (EC) no. 726/2004.
Article 74.
Labeling for small blisters and primary packaging
1. Primary packaging other than those provided for in paragraphs 2 and 3 bear the indications referred to in article 73.
2. Provided they are contained in an external packaging that complies with the provisions of articles 73 and 79, primary packaging that comes in the form of blister packs may only bear the following indications:
a) the name of the medicinal product pursuant to Article 73(a);
b) the name of the marketing authorization holder;
c) the month and year of expiry indicated with words or numbers;
d) the production batch number.
3. Small primary packaging, on which it is impossible to mention the information referred to in articles 73 and 79, bear at least the following indications:
a) the name of the medicinal product, in accordance with Article 73(a), and, if necessary, the route of administration;
b) the method of administration;
c) the month and year of expiry indicated with words or numbers;
d) the production batch number;
e) the content by weight, by volume or in dosage units.
Article 75.
Special provisions in favor of the blind and visually impaired
1. With the exception of the medicinal products referred to in articles 92 and 94, as well as other hypotheses possibly identified at Community level, the name of the medicinal product followed by the dosage and the pharmaceutical form and any other essential information are also shown in Braille characters on the outer packaging . The marketing authorization holder guarantees that the package leaflet is made available, at the request of patient associations, in formats suitable for the blind and the visually impaired.
2. The Ministry of Health, in agreement with the representatives of the pharmaceutical industry and of blind and visually impaired subjects, defines by 31 December 2006 the procedures for informing blind and visually impaired subjects on the month and year of expiry of the product and any conventional signs for particular conditions of use or storage, to be reported on the outer packaging or in a folding card, or in any case to be made easily accessible to the blind or visually impaired in another way, inserted in the package.
3. By decree of the Minister of Health, with the procedure referred to in paragraph 2, the methods of implementation of the second period of paragraph 1 are established, also taking into account voluntary experiences already implemented on part of the national territory. Pending the issuance of the ministerial decree, the guidelines issued by the European Commission are observed.
Article 76.
Leaflet requirement
1. It is mandatory to include, in the external packaging of medicinal products, an illustrative leaflet, except in the case in which all the information required by articles 74 and 77 appear directly on the external packaging or on the primary packaging.
Article 77.
Contents of the leaflet
1. The package leaflet is drawn up in accordance with the summary of product characteristics; it contains, in the following order:
a) for the identification of the medicinal product:
1) the name of the medicinal product, followed by the dosage and the pharmaceutical form, and possibly whether it is indicated for early childhood, children or adults; when the medicinal product contains a single active substance and bears an invented name, the common name must appear;
2) the pharmacotherapeutic category or the type of activity, written in terms easily understood by the patient;
b) the therapeutic indications;
c) a list of information to know before taking the medicine:
1) contraindications;
2) appropriate precautions for use;
3) interactions with other medicines and other forms of interaction (for example with alcohol, tobacco, food), which can affect the action of the medicine;
4) special warnings;
d) the necessary and usual instructions for correct use and, in particular:
1) dosage;
2) method and, if necessary, route of administration;
3) frequency of administration, specifying, if necessary, the appropriate time at which the medicinal product can or should be administered, and if necessary, in relation to the nature of the product;
4) duration of the treatment, if it needs to be limited;
5) actions to be taken in the event of an overdose (eg description of recognition symptoms and first aid intervention);
6) conduct to be followed in the event that one or more doses have been omitted;
7) indication, if necessary, of the risk of effects following suspension of the medicinal product;
8) specific recommendation to contact the doctor or pharmacist to obtain appropriate clarifications on the use of the medicine;
e) a description of the undesirable effects that may occur with normal use of the medicinal product and, if necessary, of the measures to be taken; the patient should be expressly invited to communicate to his doctor or pharmacist any undesirable effect not described in the package leaflet;
(f) a reference to the expiry date appearing on the label, followed by the elements specified below:
1) a warning against using the medicine after that date;
2) if necessary, the special precautions to be taken for the storage of the medicinal product;
3) where appropriate, a warning regarding particular visible signs of deterioration;
4) the complete qualitative composition, in terms of active substances and excipients, as well as the quantitative composition in terms of active substances, provided using the common names, for each presentation of the medicinal product;
5) the pharmaceutical form and the content by weight, volume or dosage units, for each presentation of the medicinal product;
6) the name and address of the marketing authorization holder;
7) the name and address of the manufacturer;
g) when the medicinal product is authorized pursuant to Chapter V of Title III under different names in the Member States of the European Community concerned, a list with the name authorized in each of the Member States;
h) the date on which the package leaflet was last revised.
2. In addition to the indications provided for in paragraph 1, it is lawful to report, with prior authorization from AIFA, the name and address of whoever, on the basis of a specific agreement with the MA holder, sees to the effective marketing of the medicine throughout the country. These indications, as well as any symbols and emblems relating to the same distributor, must be smaller in size than the indications, symbols and emblems relating to the MA holder.
3. The list referred to in paragraph 1, letter c):
a) takes into account the particular situation of certain categories of users (children, pregnant or breastfeeding women, the elderly, patients with certain pathological conditions);
b) mention, if necessary, the possible effects on the ability to drive a vehicle or operate machinery;
c) contains the list of at least all the excipients which it is important to know for an effective and safe use of the medicinal product and which are foreseen in the guidelines published pursuant to article 65 of directive 2001/83/EC.
4. The package leaflet reflects the results of surveys carried out on targeted groups of patients, in order to ensure that it is legible, clear and easy to use.
5. AIFA verifies compliance with the provision referred to in paragraph 4 on the occasion of the issuance of the AIC, as well as on the occasion of subsequent variations that involve a significant modification of the leaflet.
Article 78.
Changes to the labeling and package leaflet compatible with the summary of product characteristics.
1. Any proposed change to an element relating to the labeling or package leaflet which does not imply a change in the summary of product characteristics is deemed approved if AIFA does not pronounce itself against the draft change within ninety days of application submission date. In any case, AIFA's failure to pronounce does not exclude the producer's and the MA holder's liability, including criminal liability.
2. The Ministry of Health, on a proposal from AIFA, having consulted the categories concerned, identifies ways to make the approved amendments to the package leaflet immediately available to the consumer within the limits of the human and instrumental resources available under current legislation and without new or greater charges for public finance.
Article 79.
Signs or pictograms
1. The outer packaging and the package leaflet may, with the prior authorization of AIFA, carry signs or pictograms aimed at making certain information referred to in articles 73 and 77, paragraph 1 more explicit, as well as other information compatible with the summary of characteristics of the product, useful for the patient, to the exclusion of any element of a promotional nature.
Article 80.
Language used
1. At least the indications referred to in articles 73, 77, 79 are drawn up in Italian and, limited to medicinal products on the market in the province of Bolzano, also in German. However, they must be compatible with the summary of product characteristics. The German language version of the package leaflet can be made available to the purchaser in the pharmacy upon sale of the medicine according to procedures to be established by decree of the Minister of Health, also taking into account voluntary experiences already implemented on part of the national territory .
2. For some orphan medicinal products, upon reasoned request by the applicant, AIFA may authorize that the indications referred to in article 73 be drawn up only in one of the official languages of the Community.
3. The complementary use of foreign languages is permitted provided that the relative texts correspond exactly to those in the Italian language. The marketing authorization holder of the medicinal product who intends to make use of this option must notify AIFA in advance and keep the sworn translation of the texts in foreign languages at his disposal.
4. If the medicinal product is not intended to be supplied directly to the patient, AIFA may dispense with the obligation to include certain indications on the labeling and on the package leaflet and to draw up the package leaflet in Italian and, for medicinal products on the market in the province of Bolzano, also in German.
Article 81.
General characteristics of the information contained in the package leaflet and on the labels
1. The information referred to in this title is reported in such a way as to be easily legible, clearly understandable and indelible.
2. The package leaflet, in particular, must allow the user to use the medicinal product correctly, if necessary with the help of health professionals.
Article 82.
Consequences in case of non-compliance with the provisions on the labeling and package leaflet
1. In the event of non-compliance with the provisions of this title, AIFA, with a reasoned provision, notifies the MA holder of the adaptation of the labeling or the package leaflet, setting a deadline for compliance. In the event of non-compliance within the indicated deadline, AIFA may suspend the marketing authorization of the medicinal product until fulfilment. The suspension is notified to the interested party with an indication of the means of redress envisaged by the legislation in force and of the term within which they can be proposed.
2. Without prejudice to the obligation to adapt the labeling and leaflet of new production batches to the requirements of this decree, packs already on the market that comply with the previous provisions may be sold until the expiry date, without prejudice to the measures adopted to protect public health.
Article 83.
Special provisions for the labeling of medicinal products containing radionuclides
1. The outer packaging and container of medicinal products containing radionuclides are labeled in accordance with the regulations on the safety of transport of radioactive materials issued by the International Atomic Energy Agency. Furthermore, the labeling complies with paragraphs 2 and 3.
2. The labeling of the protective armored container must bear the information required by Article 73. Furthermore, the labeling of the protective container must clearly explain all the codes used on the vial, indicating, if necessary, for a given time and date, the total or unitary amount of radioactivity and the number of capsules or, for liquids, the number of milliliters contained in the container.
3. The container labeling must include the following information:
(a) the name or code of the medicinal product, including the name or chemical symbol of the radionuclide;
b) lot identification and expiry date;
c) the international symbol for radioactivity;
d) the name and address of the producer;
e) the amount of radioactivity as specified in paragraph 2.
Article 84.
Package leaflet of radiopharmaceuticals, radionuclide generators, radionuclide kits, radionuclide precursors.
1. The competent authority shall verify that a package leaflet containing detailed instructions is included in the packaging of radiopharmaceuticals and radionuclide generators, kits and precursors. The text of this leaflet is drawn up in accordance with Article 77. It also reports the precautions that the operator and the patient must take during the preparation and administration of the medicinal product, as well as the special precautions to be taken for the disposal of the packaging and unused contents.
Article 85.
Special provisions for the labeling and package leaflet of homeopathic medicines
1. Without prejudice to the provisions of paragraph 2, homeopathic medicinal products are labeled in compliance with this title and distinguished by the indication of their homeopathic nature affixed in clear and legible characters.
2. The labeling and possibly the package leaflet of the homeopathic medicinal products referred to in articles 16 and 20 must contain the following indications only:
a) Wording: "homeopathic medicine" prominently, followed by the phrase: "without approved therapeutic indications";
b) scientific denomination of the homeopathic strain or strains or, failing this, the scientific denomination of the starting material or materials for homeopathic preparations or other denomination appearing in a pharmacopoeia, accompanied by the denomination proper to the homeopathic tradition followed by the degree of dilution , expressed with the symbols of the pharmacopoeia used in accordance with article 1, paragraph 1, letter d); if the homeopathic medicinal product is made up of two or more homeopathic strains, their scientific denomination may be completed by an invented name on the labelling;
c) name and address of the registration holder and, if different, of the producer;
d) method of administration and, if necessary, route of administration;
e) month and year of expiry indicated with words or numbers;
f) pharmaceutical form;
g) contents of the package, by weight, volume or in administration units;
h) any special precautions to be taken for the storage of the medicinal product;
i) special warning, if the medicinal product requires it;
l) production batch number;
m) registration number;
n) a warning to the user to consult a doctor if symptoms persist;
o) price of the medicinal product;
p) wording: «medicine not paid for by the National Health Service».
Article 86.
Updated labeling and package leaflet provisions
1. The provisions of this title concerning the contents of the labeling and leaflet of medicinal products can be updated upon proposal or after consultation with AIFA, by decree of the Minister of Health, in compliance with Community provisions.
TITLE VI
CLASSIFICATION OF MEDICINES FOR THE PURPOSE OF SUPPLY
Article 87.
Classes of medicines for supply purposes
1. Upon release of the marketing authorization or subsequently, subject to a new evaluation by AIFA, also upon request of the applicant, medicinal products are classified in one or more of the following categories:
a) medicines subject to medical prescription;
b) medicines subject to medical prescription to be renewed each time;
c) medicines subject to special medical prescription;
d) medicines subject to restricted medical prescription, including:
1) medicines that can be sold to the public on prescription from hospitals or specialists;
2) medicines that can only be used in a hospital environment or in an environment similar to it;
3) medicines that can only be used by the specialist;
e) medicines not subject to medical prescription including:
1) over-the-counter or self-medication medicines;
2) remaining non-prescription medicines.
Article 88.
Medicinal products subject to medical prescription
1. Medicines are subject to medical prescription when
a) may present a danger, directly or indirectly, even under normal conditions of use, if they are used without medical supervision;
b) are often used, and to a very large extent, incorrectly and, consequently, with the risk of a direct or indirect danger to health;
c) contain substances or preparations of substances whose activity or adverse reactions require further investigation;
d) are intended to be administered parenterally, subject to the exceptions established by the Ministry of Health, upon proposal or after consultation with AIFA.
2. The medicinal products referred to in paragraph 1, when they do not have the characteristics of the medicinal products referred to in articles 89, 92 and 94, must bear on the external packaging or, failing that, on the immediate packaging the phrase: «To be sold upon presentation of medical prescription".
3. The repeatability of the sale of medicinal products referred to in paragraph 2 is permitted, unless otherwise indicated by the prescribing doctor, for a period not exceeding six months from the date on which the prescription is compiled and in any case not more than ten times. The indication by the doctor of a number of packs higher than the unit excludes the repeatability of the sale. In any case, the various prescriptions established, with reference to particular types of medicines, by decree of the Minister of Health are reserved.
Article 89.
Medicinal products subject to medical prescription to be renewed each time
1. Medicinal products which, by presenting one or more of the characteristics envisaged by article 88, paragraph 1, may cause, with continued use, toxic states or may in any case involve particularly high for health.
2. The medicinal products referred to in paragraph 1 must bear on the outer packaging or, failing that, on the primary packaging the phrase «To be sold upon presentation of a medical prescription that can be used only once».
3. Medical prescriptions relating to the medicines referred to in paragraph 1 are valid for thirty days; they must be collected by the pharmacist, who is required to keep them for six months, if he does not deliver them to the competent authority for reimbursement of the price charged to the National Health Service. Once this period has elapsed, the pharmacist destroys the prescriptions in a manner designed to exclude third party access to the data contained therein.
4. The doctor is required to indicate the patient's tax code on the prescription relating to medicinal products governed by this article; in cases where provisions of a special nature require confidentiality of processing, the relative procedures apply.
5. The prescription, which must in any case contain, printed or affixed with a stamp, the clear indication of the prescribing doctor and of the structure on which he depends, is not valid if it lacks the elements referred to in paragraph 4 or the date, signature of the doctor and data relating to the exemption.
Article 90.
Medicinal products subject to special medical prescription
1. Medicinal products subject to special medical prescription are medicinal products for which the consolidated text of the laws concerning the regulation of narcotic drugs and psychotropic substances, prevention, treatment and rehabilitation of the related states of drug addiction, approved by decree of the President of the Republic of 9 October 1990, no. 309, and subsequent amendments, provides for specific methods of distribution and prescription.
2. Without prejudice to the provisions of the consolidated text referred to in paragraph 1, medicinal products subject to special medical prescriptions may also be subject to other limitations provided for by this decree and by the provisions which ensure their implementation.
Article 91.
Medicinal products subject to restricted medical prescription
1. Medicinal products subject to restricted medical prescription are medicinal products whose prescription or use is limited to certain doctors or certain environments, in accordance with the provisions of articles 92, 93 and 94.
Article 92.
Medicines that can only be used in hospitals or similar structures
1. Medicinal products that can be used exclusively in hospitals are medicinal products which, due to their pharmacological characteristics, or because of their innovative nature, method of administration or for other reasons of public health protection, cannot be used in conditions of sufficient safety outside hospital facilities.
2. Taking into account the characteristics of the medicinal products, AIFA may establish that the use of the medicinal products referred to in paragraph 1 is limited to certain hospital centers or, on the other hand, is also permitted in private hospitalization structures.
3. The medicinal products regulated by this article must bear on the outer packaging or, failing this, on the primary packaging the phrases: «Use reserved for hospitals. Not for sale to the public.' In the cases envisaged by paragraph 2, the first sentence is modified in relation to the authorized use of the medicinal product.
4. The medicines governed by this article are supplied by the manufacturers and wholesalers directly to the structures authorized to use them or to the bodies on which they depend.
Article 93.
Medicines that can be sold to the public on prescription from hospitals or specialists
1. Medicines that can be sold to the public on prescription from hospital centers or specialists are medicines which, although they can also be used in home treatments, require that the diagnosis be carried out in hospital environments or in centers that have adequate means of diagnosis, or that the diagnosis itself and, possibly, monitoring during treatment are reserved to the specialist.
2. The medicinal products referred to in paragraph 1 must bear on the outer packaging or, failing this, on the primary packaging, after the sentences: «To be sold upon presentation of a medical prescription», or «To be sold upon presentation of a usable medical prescription only once», the specification of the type of institution or specialist authorized to prescribe.
Article 94.
Medicines to be used only by the specialist
1. Medicines that can only be used by the specialist in the outpatient clinic are medicines which, due to their pharmacological characteristics and methods of use, are intended to be used directly by the specialist during the outpatient visit.
2. The specialist may use a medicine referred to in paragraph 1 at the patient's home, only if the administration of the same does not require particular outpatient equipment.
3. The medicinal products governed by this article must bear on the external packaging or, failing this, on the primary packaging the following sentences: «Reserved use for…», with specification of the specialist authorized to use the medicinal product, and «Sale prohibited to the public".
4. The medicinal products governed by this article may be supplied by manufacturers and wholesalers directly to specialists authorized to use them.
Article 95.
Checks on compliance with classification provisions
1. The local health authorities check compliance by pharmacists with the provisions of this title on a sample basis, informing the Ministry of Health and AIFA of the outcome of the check.
Article 96.
Non-prescription medicines
1. Non-prescription medicinal products are those which do not meet the criteria set out in articles 88 to 94.
2. The pharmacist can give advice to the customer, in the pharmacy, on the medicines referred to in paragraph 1. The same medicines can be advertised to the public if they meet the requirements established by the regulations in force on the subject and provided that the limits and the conditions established by the same rules.
3. If the medicinal product is classified in class c-bis referred to in article 8, paragraph 10, of the law of 24 December 1993, n. 537, the words "self-medication medicine" must be reported on the label. In the remaining cases, the wording "medicine not subject to medical prescription" must be reported.
4. The external packaging of the medicinal products referred to in this article bears an identification stamp which allows for clear identification by the consumer, in compliance with the decree of the Minister of Health dated 1 February 2002, published in the Official Gazette of the Italian Republic no. 33 of 8 February 2002.
Article 97.
Publication of the list of medicines according to the classification for supply purposes
1. Within the month of February of each year, AIFA proceeds with the publication in the Official Gazette of the Italian Republic of all the medicinal products whose placing on the market is authorised, with the specification for each of them of the envisaged class of belonging from this title.
2. Every year, AIFA notifies the European Commission and the other Member States of the European Community of the changes made to the list referred to in paragraph 1, limited to medicinal products whose supply is subject to the obligation of medical prescription, specifying their classification .
Article 98.
Protection of tests and trials aimed at changing the classification
1. When a change in the classification of a medicinal product has been authorized on the basis of significant preclinical tests or clinical trials, AIFA, for one year from the date of such authorisation, does not take into account such preclinical or experimental tests for the purposes of examination of the application for classification of another medicinal product based on the same substance presented by a different applicant or holder.
TITLE VII
WHOLESALE DISTRIBUTION OF MEDICINAL PRODUCTS
Article 99.
Scope of
1. This title regulates the wholesale distribution of medicinal products for human use, as well as pharmacologically active raw materials.
2. The wholesale distribution activity on the national territory of medicinal products can only concern medicinal products for which a marketing authorization has been issued pursuant to this decree or to (EC) regulation no. 726/2004.
3. Any distributor, who is not the marketing authorization holder, who intends to import a medicinal product from another Member State shall notify the marketing authorization holder, the Ministry of Health and AIFA at least forty-five days before proceeding with the distribution of said medicine.
Article 100.
Authorization for the wholesale distribution of medicines
1. The wholesale distribution of medicinal products is subject to the possession of an authorization issued by the region or autonomous province or by the other competent authorities identified by the legislation of the regions or autonomous provinces.
2. The wholesale distribution of medicines and the supply of medicines to the public in pharmacies are incompatible with each other.
3. The authorization referred to in paragraph 1 is not required if the interested party is in possession of the production authorization referred to in article 50, provided that wholesale distribution is limited to medicinal products, including raw materials pharmacologically active, subject to this authorisation.
4. The possession of the authorization to exercise the activity of wholesaler of medicinal products does not dispense with the obligation to possess the production authorization obtained in accordance with title IV, and to comply with the conditions established in this regard, even when the activity of production or importation is carried out as a collateral activity.
5. The activity of wholesale trade intermediation which does not involve the purchase or sale of wholesale medicines is excluded from the scope of application of this title.
6. Cylinders and other containers of oxygen, and possibly other medicinal gases to be identified by decree of the Minister of Health, can be supplied directly to patients' homes, under the conditions established by regional provisions.
Article 101.
Requirements for obtaining the authorisation
1. To obtain the authorization, the applicant must meet the following conditions:
a) have suitable premises, installations and equipment, sufficient to ensure proper storage and distribution of medicinal products;
b) have adequate personnel as well as a responsible person, in possession of a degree in pharmacy or chemistry or pharmaceutical chemistry and technology or industrial chemistry, who has not been convicted of crimes against property or in any case connected to the trade in medicinal products that does not comply with the provisions of this decree, nor definitive criminal sentences of at least two years for intentional crimes;
c) undertake to comply with the obligations to which he is subject pursuant to article 104.
2. The responsible person referred to in letter b) of paragraph 1 must carry out his/her activity on a continuous basis in the office indicated in the authorization with a timetable compatible with the needs deriving from the size of the distribution activity carried out.
3. Responsibility for several warehouses belonging to the same owner may be entrusted to the same person, provided that the activity carried out by the latter in each warehouse is compatible with the provisions of paragraph 2.
Article 102.
Wholesale distribution exercised in multiple warehouses
1. To carry out wholesale distribution through several warehouses, located in different regions, the interested party must obtain separate authorizations, by forwarding an application to each competent authority.
Article 103.
Authorization procedure
1. Within ninety days of submitting the application for authorisation, the competent authority shall notify the interested party of the outcome of the same. If the data provided by the interested party are not sufficient to demonstrate compliance with the conditions set out in article 101, the same authority may request the necessary additions; in this case, the ninety-day term is suspended until the presentation of the requested additional data.
2. The authorisation, to be issued after inspection of the warehouse, must specify:
a) the location of the warehouse;
b) the personal details of the responsible person, pursuant to article 101;
c) the medicinal products or the type of medicinal products which may be the object of the wholesale distribution activity, in relation to the equipment available to the warehouse;
d) the geographical territory within which the wholesaler has declared that he is able to operate in compliance with the provisions of paragraph 2 of article 105.
3. Simultaneously with the notification to the interested party, the competent authority sends a copy of the authorization to the Ministry of Health.
4. In the event of refusal of authorisation, which must in any case be motivated, the means of recourse envisaged by the legislation in force and the term within which the recourse can be brought are communicated to the interested parties.
Article 104.
Obligations and powers of the authorization holder
1. The holder of the authorization for the wholesale distribution of medicinal products is required to:
a) make the premises, installations and equipment referred to in Article 101, paragraph 1, letter a), accessible at all times to the agents responsible for inspecting them;
b) obtain medicinal products only from persons or companies who themselves possess the authorization or who are exempt from the obligation to possess it pursuant to article 100, paragraph 3; this obligation also concerns supplies from other countries of the European Community, compatibly with the legislation in force therein;
c) to supply medicines only to persons, companies or entities which themselves hold the authorization for the wholesale distribution of medicines, or are authorized or authorized for other reasons to obtain medicines;
d) have an emergency plan which ensures the effective application of any action to withdraw from the market ordered by AIFA or initiated in cooperation with the manufacturer or marketing authorization holder of the medicinal product in question;
e) keep documentation, in the form of invoices, or in computerized form or in any other suitable form, which shows, for each entry and exit operation, at least the following information:
1) date;
2) name of the medicinal product;
3) quantity received or supplied;
4) lot number for each entry operation; this number must be indicated on the delivery note for the goods supplied to the wholesaler;
5) name and address of the supplier or consignee, as applicable;
f) keep the documentation referred to in letter e) at the disposal of the competent authorities, for inspection purposes, for a period of five years;
g) make use, both in the procurement phase and in the distribution phase of medicines, of suitable means to guarantee the correct conservation of the same during transport, in compliance with any technical standards adopted by the Ministry of Health, also ensuring compliance by third parties;
h) comply with the principles and guidelines on good practice in the distribution of medicines pursuant to the decree of the Minister of Health dated 6 July 1999, published in the Official Gazette of the Italian Republic no. 190 of 14 August 1999;
i) fulfill the obligations set out in article 105.
Article 105.
Minimum equipment and supply of medicines
1. With the exception of those who import medicinal products and for those who exclusively distribute pharmacologically active raw materials or medicinal gases or medicinal products governed by articles 92 and 94, or medicinal products for which they hold the marketing authorization or the sales concession, the holder of the distribution authorization wholesale is required to hold at least
a) the medicines listed in table 2 attached to the official pharmacopoeia of the Italian Republic;
b) ninety percent of medicinal products in possession of a marketing authorisation, including homeopathic medicinal products authorized pursuant to article 18; this percentage must also be respected in the context of generic medicines only.
2. The holder of a marketing authorization for a medicinal product and the distributors of such medicinal product actually placed on the market shall ensure, within the limits of their responsibilities, appropriate and continuous supplies of such medicinal product to pharmacies and persons authorized to deliver medicinal products in a way that meets the needs of patients.
3. The supply to pharmacies, including hospital pharmacies, or to other subjects authorized to supply medicines to the public, of the medicines with which the distributor is provided must take place with the utmost promptness and, in any case, within the twelve working hours following the request, in the territorial area indicated in the declaration referred to in article 103, paragraph 2, letter d).
4. The marketing authorization holder is obliged to supply within forty-eight hours, at the request of pharmacies, including hospital pharmacies, a medicinal product that is not available in the regional distribution network.
5. For each transaction, the wholesale distributor must give the recipient a document showing, in addition to his name and address,
a) the date;
b) the name and pharmaceutical form of the medicinal product;
c) the quantity supplied to the consignee;
d) the name and address of the consignee.
Article 106.
Provisions concerning particular medicinal products
1. Radiopharmaceuticals may be sold by manufacturers and wholesalers only to wholesalers who are authorized to hold radioactive substances, to university institutes or to hospital departments of nuclear medicine.
2. Where immunological medicinal products or blood-derived medicinal products are produced and marketed in quantities insufficient to optimally satisfy the therapeutic needs, the Ministry of Health, having consulted AIFA, may adopt provisions aimed at ensuring the best use of the available quantities .
3. The provisions on wholesale trade contained in the consolidated text of the laws concerning the regulation of narcotic drugs and psychotropic substances, prevention, treatment and rehabilitation of the related states of drug addiction, approved by decree of the President of the Republic October 9, 1990, n. . 309, and subsequent modifications.
Article 107.
Identification of distribution channels for medicines
1. Pharmacies open to the public, hospital pharmacies and other facilities that hold medicinal products directly intended for use on the patient must be able to promptly communicate to the competent authorities who request it, the information which makes it possible to identify the distribution channel of each medicinal.
Article 108.
Medicines depositories
1. The provisions of this title with the exception of article 105, paragraphs 1 and 3, govern, to the extent applicable, also the activity of those who hold, for subsequent distribution, medicinal products for human use on the basis of stipulated deposit contracts with the medicinal product marketing authorization holders or their representatives.
Article 109.
Inspections by the Ministry of Health and AIFA
1. Without prejudice to the powers entrusted by this decree to the regions and autonomous provinces, the Ministry of Health and AIFA may carry out inspections at any time at the warehouses and other locations where medicines are stored, for checks relating to profiles of own competence.
2. At the request of the Ministry of Health and AIFA, the inspections referred to in paragraph 1 can be carried out by the regions and autonomous provinces.
Article 110.
Guidelines on good distribution practice
1. By decree of the Minister of Health, the good practices for the distribution of medicinal products referred to in article 104, paragraph 1, letter h) are updated in accordance with new Community provisions.
Article 111.
Reporting obligations
1. The competent authority which has granted the authorization referred to in paragraph 1 of article 100, if it modifies, suspends or revokes the same, as the requirements on the basis of which said authorization was granted have no longer met, shall immediately inform the Ministry of Health by sending a copy of the suspension or revocation provision.
2. The Ministry of Health, having acquired a copy of the suspension or revocation provisions referred to in paragraph 1, adopted by the regions and autonomous provinces or by the authorities delegated by them, shall inform the European Commission and the other member States.
3. At the request of the European Commission or of a Member State, the Ministry of Health provides any useful information relating to the authorization referred to in Article 100.
Article 112.
Homeopathic medicines
1. The provisions of this title also apply to distributors of homeopathic medicines.
TITLE VIII
ADVERTISING
Article 113.
Definition of advertising of medicines and scope of application
1. For the purposes of this title, "advertising medicinal products" means any information, customer research or solicitation action intended to promote the prescription, supply, sale or consumption of medicinal products; it includes in particular the following:
a) advertising of medicines to the public;
(b) advertising of medicinal products to persons authorized to prescribe or dispense them, including the following aspects:
1) visits by scientific representatives to persons authorized to prescribe or supply medicines;
2) the provision of samples of medicines;
3) the incitement to prescribe or to supply medicines through the granting, the offer or the promise of pecuniary advantages or in kind, with the exception of objects of negligible intrinsic value;
4) the sponsorship of promotional meetings attended by persons authorized to prescribe or supply medicinal products;
5) sponsorship of scientific congresses attended by persons authorized to prescribe or supply medicinal products, in particular the payment of their travel and subsistence expenses on such occasions.
2. The following does not form the subject of this title:
a) the labeling and package leaflet, subject to the provisions of Title V;
b) correspondence necessary to respond to a precise and unsolicited request for information on a particular medicinal product;
c) factual information and reference documents concerning, for example, changes in packaging, warnings on undesirable effects in the context of pharmacovigilance, sales catalogs and price lists, provided that they do not include information on the medicinal product;
d) information relating to human health or human diseases, provided that they do not contain any reference, even indirect, to a medicinal product.
Article 114.
Fundamental principles of the discipline
1. Any advertising of a medicinal product for which a marketing authorization has not been issued, in conformity with this decree, with regulation (EC) n. 726/2004 or other binding community provisions.
2. All elements of the advertising of a medicinal product must comply with the information contained in the summary of product characteristics.
3. Advertising for a medicine:
a) must favor the rational use of the medicinal product, presenting it objectively and without exaggerating its properties;
b) cannot be deceptive.
Article 115.
Limits of advertising to the public
1. Medicinal products may be advertised to the public which, due to their composition and therapeutic objective, are designed and manufactured to be used without the intervention of a doctor for diagnosis, prescription or monitoring during treatment and, if necessary, with the advice of the pharmacist.
2. Advertising to the public of medicinal products which can only be supplied upon presentation of a medical prescription or which contain psychotropic or narcotic substances is prohibited; as an exception to this prohibition, the Ministry of Health can authorize vaccination campaigns promoted by pharmaceutical companies.
3. The distribution of medicines to the public for promotional purposes is prohibited.
4. Without prejudice to the provisions of the second part of paragraph 2 of this article, the advertising to the public of medicinal products, the dispensing of which burdens, even if not totally, the National Health Service, as well as of the medicinal products referred to in the letters a), b) and c) of article 3, paragraph 1, and in article 5.
5. In printed publications, radio-television broadcasts and in non-advertising messages in any case disseminated to the public, it is forbidden to show a medicinal product or its name in images in a context that may favor the consumption of the product.
Article 116.
Characteristics and minimum content of advertising to the public
1. Without prejudice to the provisions of article 115, the advertising of a medicinal product to the public
a) it is made in such a way that the advertising nature of the message is evident and the product is clearly identified as a medicinal product;
b) includes at least
1) the name of the medicinal product and the common name of the active substance; the indication of the latter is not mandatory if the medicinal product is made up of several active substances;
2) the essential information for correct use of the medicinal product;
3) an explicit and clear invitation to carefully read the warnings appearing, as appropriate, on the package leaflet or on the outer packaging; in written advertising, the invitation must be easily legible from the normal vantage point; in advertising in the daily and periodical press it must, in any case, be written in characters no smaller than nine-point in size.
Article 117.
Advertising content not allowed
1. Advertising of a medicinal product to the public may not contain any element which:
a) makes a doctor's consultation or surgery appear unnecessary, in particular by offering a diagnosis or proposing treatment by mail;
b) leads to the belief that the efficacy of the medicinal product has no undesirable effects or is superior or equal to another treatment or another medicinal product;
c) induces the belief that the medicinal product can improve the normal state of good health of the subject;
d) induces the belief that not using the medicinal product could have prejudicial effects on the normal state of good health of the subject; this prohibition does not apply to the vaccination campaigns referred to in article 115, paragraph 2;
e) is aimed exclusively or mainly at children;
f) includes a recommendation from scientists, health professionals or people widely known to the public;
g) assimilates the medicinal product to a food product, a cosmetic product or another consumer product;
h) leads to the belief that the safety or efficacy of the medicinal product is due to the fact that it is a "natural" substance;
i) may lead to an erroneous self-diagnosis;
l) refers improperly, impressively or misleadingly to claims of healing;
m) uses in an improper, impressive or deceptive way visual representations of changes in the human body due to disease or injury, or of the action of a medicine on the human body or on a part of it.
2. Likewise, in accordance with the provisions of article 116, paragraph 1, letter a), the disclosure of messages and texts whose advertising intent is hidden by the redundancy of other information is not permitted.
3. By decree of the Minister of Health it may be established that the advertising messages authorized pursuant to article 118 contain the marketing authorization number of the medicinal product.
Article 118.
Permission to advertise to the public
1. No advertising of medicines to the public may be carried out without authorization from the Ministry of Health, with the exception of advertisements in the daily or periodical press which, without prejudice to the provisions of article 116, paragraph 1, are limited to reproduce in full and without changes the indications, contraindications, appropriate precautions for use, interactions, special warnings, undesirable effects described in the package leaflet, with the possible addition of a photograph or a graphic representation of the outer packaging or primary packaging of the medicine.
2. The authorization is issued by the Ministry of Health, having consulted the Commission of experts envisaged by article 201 of the consolidated text of the health laws referred to in the royal decree of 27 July 1934, n. 1265, and subsequent modifications.
3. The Commission referred to in paragraph 2, appointed by the Minister of Health, is made up of:
a) the Minister himself or his delegate, who presides over it;
b) two members belonging to the Ministry of Health, of which one representative of the General Directorate responsible for medical devices, a member representing the Ministry of Productive Activities, a member designated by AIFA, one belonging to the Higher Institute of Health, two designated by the Permanent Conference for relations between the State, the regions and the autonomous provinces. Participation in the work of the Commission does not give the right to the payment of any emolument, indemnity, compensation or reimbursement of expenses;
c) four doctors, three of whom are first or second tier university professors;
d) two pharmacists, one of whom is designated by the Federation of Italian Pharmacists' Orders.
4. The Commission is renewed every three years.
5. Secretarial functions are ensured by the Ministry of Health.
6. The Commission's opinion is not mandatory in the following cases:
a) if the advertising message cannot be authorised, resulting in evident conflict with the provisions of articles 114, 115 and 116, paragraph 1, letter b), and of article 117, paragraph 1, letters c) and f);
b) if the message is intended to be published in the daily or periodical press, or to be broadcast by radio, and has been approved by a self-regulatory institute formed by the most representative associations interested in the dissemination of advertising of recognized self-medication medicines by the Ministry of Health;
c) if the message forms part of another already authorized on the opinion of the Commission.
7. The Minister of Health, having verified the correctness of the Institute's assessments referred to in paragraph 6, letter b), with a decree to be published in the Official Gazette of the Italian Republic, extends the procedure referred to in the aforementioned paragraph 6, letter b), to television and film advertisements.
8. After forty-five days from the presentation of the application aimed at obtaining authorization to advertise a medicinal product, failure by the Ministry of Health to notify the applicant of the non-acceptability of the application constitutes, to all effects, release of the authorization request. Consequently, the advertising message must contain the indication: «authorisation upon request by …» followed by the date on which the request for authorization was received by the Ministry of Health.
9. If, within the forty-five days envisaged by paragraph 8, the Ministry of Health informs the applicant that the health advertising object of the application can only be accepted with the modifications specified in the ministerial communication, the applicant is authorized to divulge a compliant advertising message to the changes indicated by the Office. In this case, the message must contain the indication «authorisation of …» followed by the date of the ministerial communication.
10. Any provisions of the Ministry of Health aimed at requesting the modification of the messages authorized pursuant to paragraphs 8 and 9 must be adequately motivated.
11. Messages broadcast by radio are exempt from the obligation to report the details of the authorization in accordance with the provisions of paragraphs 8 and 9.
12. Authorizations for health advertising of medicines are valid for twenty-four months, without prejudice to the possibility of the Ministry of Health to establish, with justification, a shorter period of validity, in relation to the characteristics of the message disclosed. The period of validity starts from the date, in any case no more than six months after that of the application, indicated by the applicant for the start of the advertising campaign; in the absence of such indication, the period of validity starts from the date of the authorisation. Authorizations valid on the date of entry into force of this decree, for which a term of validity has not been established, expire 24 months from that date.
13. If advertising to the public is carried out in violation of the provisions of this decree, the Ministry of Health:
a) orders the immediate cessation of advertising;
b) orders the dissemination, at the offender's expense, of a correction and clarification press release, according to methods established by the same Ministry, without prejudice to the provisions of article 7 of law no. 175.
14. The provisions of paragraphs 8, 9, 10, 11, 12 and 13 also apply to medical devices, including in vitro diagnostics that can be used without prescription or assistance from a doctor or other health professional, as well as to other products other than medicines for human use, subject to the discipline established by article 201, third paragraph, of the consolidated text of the health laws referred to in the royal decree of 27 July 1934, n. 1265, and subsequent modifications.
Article 119.
Advertising to healthcare professionals
1. The healthcare professionals to whom the advertising of a medicinal product may be addressed are exclusively those authorized to prescribe or dispense it.
2. Without prejudice to the provisions of this title, scientific information to healthcare professionals must be carried out in compliance with the criteria and guidelines adopted by AIFA, subject to agreement with the Permanent Conference for relations between the State, the regions and the autonomous provinces of Trento and Bolzano after consultation with the pharmaceutical industry associations.
3. The advertising of a medicinal product to healthcare professionals must always include the summary of the characteristics of the product which is authorized at the time of dissemination of the advertisement, specify the classification of the medicinal product for the purpose of supply and indicate the selling price and the conditions of the possible dispensing of the medicine with the burden borne by the National Health Service.
4. By way of derogation from the provisions of paragraph 3, the advertising of a medicinal product to healthcare professionals may be limited to the sole name of the medicinal product, with the specification of the common name of the substance or active substances which compose it. To these indications can be added the name of the marketing authorization holder followed, in the case envisaged by paragraph 5, by the name of the person responsible for the actual marketing of the product.
5. The implementation of advertising among healthcare professionals can be carried out, also jointly with the marketing authorization holder of the medicinal product, but in any case on the basis of a specific agreement with this, by another pharmaceutical company, which is the owner of other AIC or an authorization to produce medicinal products. In such hypotheses, however, both the obligations and responsibilities of the company that holds the MA of the medicinal product remain unchanged, with regard to the information activity carried out by the other company, and the obligation referred to in article 122, paragraph 3.
6. If the promotional information to healthcare professionals is carried out in violation of the provisions and criteria and directives adopted by AIFA pursuant to paragraph 2, the Agency itself:
a) orders the immediate cessation or suspension of the promotional information;
b) orders the dissemination, at the offender's expense, of a correction and clarification press release, the drafting of which will be handled according to the methods established by AIFA. This press release may be inserted by AIFA in the Bulletin of information on drugs and on the institutional website of the same and, by and at the expense of the Company, on the latter's website or even in national newspapers.
7. The provisions of paragraphs 1, 3, 4 and 5 and the provisions of articles 121 and 125 are applied without prejudice to what is regulated by the regions pursuant to paragraph 21 of article 48 of the decree-law of 30 September 2003, n. 269, converted, with amendments, by law 24 November 2003, n. 326.
Article 120.
Special provisions on advertising to doctors
1. The documentation on the medicinal product, with the exception of the summary of the product characteristics, approved pursuant to article 8, paragraph 3, letter o), must be filed with AIFA before the start of the advertising campaign and can be provided to the doctor from the pharmaceutical company if ten days have passed since the filing date. The filing date must be indicated in the disclosed material.
2. AIFA may, at any time, with a motivated provision, also taking into account the guidelines referred to in paragraph 2 of article 119, prohibit or suspend the disclosure of the documentation referred to in paragraph 1, if it deems it to be in conflict with the provisions and principles of this decree.
3. All the information contained in the documentation referred to in paragraph 1 must be exact, updated, verifiable and sufficiently complete to allow the recipient to be adequately informed on the therapeutic effect and on the characteristics of the medicine. The information itself must comply with the documentation submitted for the purpose of issuing the marketing authorization of the medicinal product or its updates.
4. Articles, tables and other illustrations taken from medical journals or scientific works must be reproduced integrally and faithfully, with the exact indication of the source. Quotations which, detached from the context from which they are taken, may be partial or distortive are not permitted.
5. Advertising aimed at doctors can also be achieved through visits by the same to the laboratories and research centers of pharmaceutical companies, provided that they are oriented towards the development of knowledge in the sectors of chemistry, pharmaceutical technology, pharmacology, toxicology, biotechnology and biochemistry.
Article 121.
Special provisions on advertising to pharmacists
1. Advertising to pharmacists of medicines that can be sold on presentation of a medical prescription is limited to the information contained in the summary of the characteristics of the medicine. The limitation does not apply to hospital pharmacists.
2. For medicines that can be sold without a prescription, advertising may include other useful documentation to allow the pharmacist to provide the customer with advice on using the product, if necessary.
3. The documentation which does not consist in the simple reproduction of the summary of the characteristics of the product is subject to the provisions of article 120.
4. The discipline referred to in paragraph 3 does not apply to information of exclusively commercial content.
Article 122.
Requirements and activities of scientific representatives
1. Information on medicinal products can be provided to the doctor and pharmacist by scientific representatives. In January of each year, each pharmaceutical company must notify AIFA, on a regional basis, of the number of healthcare professionals visited by its scientific representatives in the previous year, specifying the average number of visits made. To this end, within the month of January of each year, each pharmaceutical company must communicate to AIFA the list of scientific representatives employed during the previous year, with an indication of the qualification and type of employment contract with the pharmaceutical company.
2. Without prejudice to the situations regularly in place on the date of entry into force of this decree, scientific representatives must be in possession of the degree referred to in the law of 19 November 1990, n. 341, or specialist degree pursuant to the decree of the Minister of University and Scientific and Technological Research November 3, 1999, n. 509, or master's degree pursuant to the decree of the Minister of Education, University and Research 22 October 2004, n. 270, in one of the following disciplines or in one of the scientific-disciplinary sectors to which the declaratory statements refer to medicine and surgery, biological sciences, organic or biological chemistry, pharmacy, pharmaceutical chemistry and technology or veterinary medicine. Alternatively, scientific representatives must possess a university diploma in scientific information on drugs pursuant to the decree of the Minister of University and Scientific and Technological Research of 30 June 1993, published in the Official Gazette of the Italian Republic no. 87 of 15 April 1994, or the corresponding degree referred to in the aforementioned ministerial decrees of 3 November 1999, n. 509, and 22 October 2004, n. 270. The Minister of Health may, after hearing the Ministry of Education, University and Research, by decree, recognize other degrees as suitable for the purposes of this article, specifying the teachings essential for training purposes. In all cases, scientific reps must receive adequate training from the companies they depend on, so as to be in possession of sufficient scientific knowledge to provide accurate and as complete information on the medicines presented. The companies holding marketing authorization ensure the constant updating of the technical and scientific training of scientific representatives.
3. The activity of scientific representatives is carried out on the basis of an employment relationship established with a single pharmaceutical company. By decree of the Minister of Health, on the proposal of the AIFA, derogations from the provisions set out in the previous period may be envisaged, due to the size and characteristics of the companies.
4. At each visit, reps must deliver to the doctor, for each medicinal product presented, the summary of product characteristics, complete with information on the price and, where applicable, the conditions under which the medicinal product can be prescribed with the cost borne by the National Health Service.
5. The fulfillment referred to in paragraph 4 is not necessary if the doctor is in possession of a publication that reproduces the texts of the summaries of the characteristics of the products authorized by AIFA and if, for the medicinal product presented by the scientific rep, the summary of product characteristics has not changed from the text included in the aforementioned publication.
6. Scientific representatives must report to the scientific service referred to in article 126, on which they depend, and to the head of the pharmacovigilance service referred to in paragraph 4 of article 130, all information on the undesirable effects of medicinal products, attaching, where possible, a copy of the reporting forms used by the doctor in accordance with Title IX.
Article 123.
Concession or promise of prizes or advantages, pecuniary or in kind
1. In the context of the information and presentation of medicinal products carried out with doctors or pharmacists, it is forbidden to grant, offer or promise prizes, pecuniary or in-kind advantages, unless they are of negligible value and are in any case connected to the activity carried out by the doctor and the pharmacist.
2. Information material for scientific or work consultation, not specifically pertaining to the medicinal product, may be transferred free of charge only to public health facilities.
3. Doctors and pharmacists cannot solicit or accept any incentive prohibited under paragraph 1.
Article 124.
Conventions or congresses and other meetings concerning medicines
1. Every pharmaceutical company in possession of the authorizations provided for in title III or in title IV, or which, on the basis of a specific agreement with the marketing authorization holder, carries out the effective marketing of medicinal products, which it organizes or contributes to realizing, through funding or the provision of other benefits, even indirect ones, in Italy or abroad, a congress, convention or meeting on issues related to the use of medicines produced or marketed by the same company, must send to the competent AIFA office, at least sixty days before the start date of the congress or meeting, a communication, with authenticated signature, containing the following elements:
a) its name or company name, tax code and registered office;
b) venue and date of the event;
c) addressees of the initiative;
d) object of the topic dealt with, existing correlation between this and the medicines owned by the company, program and scientific rationale for the event;
e) professional and scientific qualification of the speakers;
f) analytical estimate of expenses; when the company limits itself to providing a contribution to the organizers, the amount and methods of the same must be indicated, as well as any rights or powers granted by the organizers as consideration.
2. When several pharmaceutical companies contribute to the realization of the same congress, convention or meeting, the communications referred to in paragraph 1 must be sent jointly, through the organisers, with a summary table of the participating companies. Communications sent in breach of the provisions of this paragraph are ineffective.
3. The events referred to in paragraphs 1 and 2 must comply with criteria of a strictly technical nature and be oriented towards the development of knowledge in the sectors of chemistry, pharmaceutical technology, biochemistry, physiology, pathology and clinics and must be carried out in compliance with the provisions of this decree and the criteria and guidelines established by AIFA pursuant to paragraph 2 of article 119. The participation of pharmaceutical companies in trade union conventions or meetings is prohibited.
4. In the context of the events referred to in paragraphs 1 and 2, any charges for travel or hospitality expenses must be limited to qualified sector operators and cannot be extended to any accompanying persons. Furthermore, hospitality cannot exceed the period of time between the twelve hours preceding the start of the congress and the twelve hours following the conclusion of the same, nor present characteristics such as to prevail over the technical-scientific purposes of the event. General practitioners and paediatricians of free choice are allowed to participate in conferences and congresses with ECM accreditation of an educational nature on pertinent topics, subject to notification to the competent health facility. A register with data relating to participation in the events in question is deposited at this facility; such data must be accessible to the Regions and AIFA.
5. The pharmaceutical company can carry out or contribute to carrying out the congress, convention or meeting if, within forty-five days of the communication referred to in paragraph 1, AIFA communicates its favorable opinion, having consulted the Region where the event. The pharmaceutical company or, in the case governed by paragraph 2, the organizers of the event, must send AIFA the analytical balance of the expenses.
6. For exhibitions that take place abroad and for those which involve, for the pharmaceutical company, an expense exceeding 25,822.85 euros, the company itself must obtain express authorization from AIFA, which adopts its decisions within forty-five days from the communication referred to in paragraph 1, accompanied by the certification of payment of the tariff referred to in article 158, paragraph 8, letter b). The provisions of the second period of paragraph 5 apply to the aforementioned events.
7. In any case, within the congress or convention, or side by side with it, no form of distribution or display of samples of medicinal products or illustrative material of medicinal products may be carried out, with the exception of the summary of product characteristics, proceedings of congresses and scientific papers, provided that they are integral and duly filed with AIFA pursuant to article 120, paragraph 1. Only for international congresses, the dissemination, in the original languages, of information material compliant with the AIC of the medicinal product is permitted issued in other countries, provided that doctors from the latter are present at the event.
8. The provisions of this article apply to congresses, conventions and meetings of pharmacists on topics related to medicinal products.
9. The pharmaceutical companies referred to in paragraph 1 which organize or contribute to the realization through financing, even indirectly, in Italy or abroad, of a congress, convention or meeting on subjects which do not pertain to medicines produced or marketed by them are not subject to the provisions of this article, without prejudice to the prohibition for them to carry out any advertising of their medicines to health professionals on the occasion of the events.
10. If the events referred to in this article are carried out in violation of the provisions of this decree and of the criteria and directives established by AIFA, the Agency itself may prohibit the holding of the event.
Article 125.
Free samples
1. Free samples of a medicine for human use can only be given to doctors authorized to prescribe it and must be delivered only through scientific representatives. Physicians must ensure storage according to the instructions indicated on the package or on the package leaflet.
2. Samples cannot be delivered without a written request bearing the date, stamp and signature of the recipient.
3. Scientific reps may deliver two samples per visit to each healthcare professional for each dosage or pharmaceutical form of a medicinal product exclusively in the eighteen months following the date of first marketing of the product and within the maximum limit of eight samples per year for each dosage or form.
4. Without prejudice to the provisions of paragraph 2, scientific representatives may also deliver to the doctor no more than four samples per visit, within the maximum limit of ten samples per year, chosen from the company list of medicinal products on the market for more than eighteen months.
5. The quantitative limits of paragraphs 3 and 4 also apply to medicines that can be sold to the public in pharmacies and are not dispensed with costs borne by the National Health Service.
6. Each sample must be graphically identical to the smallest package on the market. Its content may be lower, in number of dosage units or in volume, than that of the package on the market, provided it is therapeutically suitable; the non-correspondence of the content and, possibly, of the primary packaging to the authorized package must be expressly referred to on the label.
7. The summary of the product characteristics must always be delivered together with the samples, except in the case provided for by paragraph 5 of article 122.
8. Except in the case of obvious technical difficulties, on the outer packaging, on the primary packaging and, where appropriate, on the self-adhesive stamp used for dispensing the medicinal product at the expense of the National Health Service, the indication "free sample - not to be sold" or other similar expression.
9. No sample of the medicines governed by the consolidated text referred to in the decree of the President of the Republic of 9 October 1990, n. 309.
10. Pharmaceutical companies are required to ensure that any storage conditions indicated on the external packaging or on the primary packaging of the medicinal product are respected until the sample is delivered to the doctor. In particular, companies will have to provide their scientific representatives with all the necessary information relating to the methods of correct conservation and distribution of medicines envisaged by current legislation, equipping them with the appropriate stowage tools for free samples for their transport. Scientific reps must be given free samples in quantities proportional to the number of visits scheduled for a given period, generally every fifteen days.
11. The delivery of samples to the hospital doctor is subject to the provisions of this article.
12. Pharmaceutical companies are required to withdraw from the scientific representatives any medical request referred to in paragraph 2 and to keep, for eighteen months, suitable documentation to prove that the delivery of samples took place in compliance with the provisions of this decree.
13. The Minister of Health, on the proposal of AIFA, taking into account the trend in the consumption of medicines, may, by decree, reduce the number of samples that can be delivered by scientific representatives pursuant to this article or provide for specific further limitations for certain categories of medicines.
Article 126.
Scientific service
1. Every company that holds a marketing authorization for medicinal products must have a scientific service in charge of providing information on the medicinal products it places on the market. The service is directed by a graduate in possession of a degree in medicine and surgery or in pharmacy or in pharmaceutical chemistry and technology pursuant to the law of 19 November 1990, n. 341, or in possession of a specialist or master's degree belonging to the specialist or master's degree classes to which the scientific-disciplinary sectors of the above-mentioned degree diplomas refer, medicine and surgery, pharmacy, chemistry and pharmaceutical technology. The scientific service must be independent from the marketing service of the pharmaceutical company.
2. For medicinal products whose marketing authorization holder is based abroad, the requirement set out in paragraph 1 must be satisfied by the company which represents the authorization holder in Italy or which, in any case, arranges for the importation and distribution of medicinal products .
3. The marketing authorization holder and the subjects referred to in paragraph 2:
a) ensure that the pharmaceutical advertising of their company complies with the provisions of this decree;
b) verify that the scientific reps they employ are in possession of adequate training and comply with the obligations imposed by this decree;
c) provide AIFA with any information and assistance required for the exercise of its powers;
d) ensure that the provisions adopted by the Ministry of Health and AIFA pursuant to this decree are immediately and fully complied with.
4. The fulfilments indicated in paragraphs 1 and 3 must be satisfied both by the marketing authorization holder and by whoever sees to the effective marketing of the medicinal product, in compliance with the conditions set out in paragraph 5 of article 119.
Article 127.
Advertising to healthcare professionals carried out irregularly
1. In the event of irregular advertising carried out at healthcare professionals, AIFA adopts, if necessary, the measures indicated in article 118, paragraph 13.
Article 128.
Special provisions for the advertising of homeopathic medicines
1. The advertising of homeopathic medicinal products referred to in article 16, paragraph 1, is subject to the provisions of this title, with the exception of article 114, paragraph 1; however, only the information referred to in Article 85 may be used in the advertising of such medicinal products.
2. Any form of advertising to the public of the homeopathic medicinal products referred to in article 20, paragraph 1 is prohibited.
TITLE IX
PHARMACOVIGILANCE
Article 129.
National Pharmacovigilance System
1. The national pharmacovigilance system belongs to AIFA.
2. AIFA, in accordance with the methods agreed at Community level and defined by the EMEA:
a) collects and evaluates useful information for the monitoring of medicinal products with particular regard to adverse reactions, improper use and abuse of the same, also taking into account data relating to their consumption;
b) promotes the process of computerization of all the data flows necessary for pharmacovigilance by managing and coordinating, in particular, the national pharmacovigilance telematic network, which connects healthcare facilities, regions and pharmaceutical companies; it also collaborates with the EMEA, with the competent bodies of the Member States of the European Community and with the European Commission in the establishment and management of a European computerized network to facilitate the exchange of information relating to the pharmacovigilance of medicines marketed in the European Community to allow all competent authorities to share information simultaneously;
c) promotes and coordinates, also in collaboration with the Higher Institute of Health, studies and research on pharmacoutilisation, active pharmacovigilance and pharmacoepidemiology;
d) adopts, assisted by the regions, initiatives aimed at promoting spontaneous reporting by health professionals;
e) promote suitable initiatives for the correct communication of information relating to pharmacovigilance to citizens and healthcare professionals;
f) prepares the annual report to Parliament on pharmacovigilance with the help of the Technical-Scientific Commission and in collaboration with the Superior Health Council.
3. The Regions, individually or in agreement with each other, collaborate with AIFA in the pharmacovigilance activity, providing elements of knowledge and evaluation to integrate the data received by AIFA pursuant to article 131. The Regions provide, in within its sphere of competence, the dissemination of information to healthcare personnel and the training of operators in the field of pharmacovigilance. Regions also work together to provide data on drug consumption through regional drug prescription monitoring programmes. The Regions can also make use of specific Pharmacovigilance Centers for their activities.
4. AIFA organizes, with the participation of the Higher Institute of Health, periodic meetings with the pharmacovigilance managers in the regions to agree on the operating procedures relating to the management of pharmacovigilance.
5. On the proposal of AIFA, having consulted the Higher Institute of Health, by decree of the Minister of Health, in agreement with the Permanent Conference for relations between the State, the regions and the autonomous provinces of Trento and Bolzano, they can further specific guidelines on pharmacovigilance, aimed at operators in the sector, and in any case compliant with the Community guidelines, must be drawn up.
Article 130.
Provisions concerning the marketing authorization holder
1. The marketing authorization holder is required to record in detail all the suspected adverse reactions from medicinal products observed in Italy, in the European Union or in a third country. The marketing authorization holder is also required to register and notify with the utmost urgency, and in any case within fifteen days of receiving news of it, any suspected serious adverse reaction from medicinal products that occurred in Italy and reported to him by health personnel, to the health care to which the reporter belongs and, if it is not possible to identify this structure, to AIFA. The marketing authorization holder is also required to notify AIFA as a matter of urgency, and in any case within fifteen days of receiving news of it, of any other suspected serious adverse reactions from medicinal products of which he has become aware.
2. The marketing authorization holder shall ensure that all suspected serious and unexpected adverse reactions and the presumed transmission of infective agents through a medicinal product which have occurred in the territory of a third country and reported by healthcare personnel, are as urgently and in any case within fifteen calendar days from when it received news, notified to AIFA according to the procedures set out in the guidelines referred to in paragraph 2 of article 129.
3. For medicines to which the mutual recognition and decentralized procedures have been applied and for which Italy is the reference member country, the MA holder also provides to notify AIFA, according to the methods and established in accordance with it, any suspected serious adverse reaction occurring in the European Community. AIFA is responsible for analyzing and monitoring these adverse reactions.
4. The marketing authorization holder for medicinal products must have, on a permanent and continuous basis, a person in charge of the pharmacovigilance service, who possesses, without prejudice to situations regularly in place on the date of entry into force of this decree, a degree in medicine and surgery or in pharmacy, or in pharmaceutical chemistry and technology, pursuant to the law of 19 November 1990, n. 341, or respective specialist degrees referred to in the aforementioned ministerial decree of 3 November 1999, n. 509, or master's degrees referred to in the aforementioned ministerial decree of 22 October 2004, n. 270. Degree diplomas pursuant to law no. 1990 of 19 November 1990 are also considered valid. 341, a specialist degree and a master's degree in biological sciences or organic-biological chemistry provided that the study plan includes at least one annual exam in pharmacology or 12 training credits in the related scientific-disciplinary sector. The person in charge of the pharmacovigilance service must be a different person from the person in charge of the scientific service envisaged by article 111 of this decree, and must be able to use all the data of this service. The responsibility of the person in charge extends to all medicines whose marketing authorization is held by the company he employs, even if marketed by other companies.
5. Without prejudice to any other prescriptions which condition the granting of the authorisation, the marketing authorization holder is obliged to submit to the competent authorities information on suspected adverse reactions in the form of periodic safety update reports (PSUR). These periodic reports are sent to AIFA at least every six months starting from the granting of the authorization and up to the time of placing on the market. The periodic safety update reports are also presented immediately upon request or at least every six months in the first two years following the first placing on the market and then once a year for the following two years. Thereafter, reports are submitted every three years, or immediately upon request. The periodic safety update reports should include a scientific assessment of the benefit/risk balance of the medicinal product.
6. After the marketing authorization has been issued, the holder may request a modification of the times specified in this article, by submitting an application for variation, pursuant to regulation (EC) n. 1084/2003.
7. The periodic safety update reports – PSURs – are presented according to the set deadline, based on operating procedures established by AIFA.
8. In accordance with the guidelines, the MAHs use internationally agreed medical terminology for reporting adverse reactions.
9. The marketing authorization holder cannot communicate information on pharmacovigilance problems relating to his authorized medicinal product to the public without first or simultaneously notifying the competent authorities. However, the marketing authorization holder ensures that this information is presented in an objective and not misleading manner.
10. The marketing authorization holder is obliged to disseminate the information notes and updates on the safety of medicinal products to the prescribing physicians, according to the indications, times and methods established by AIFA, whenever new information emerges relating to the tolerability profile of the medicinal product .
11. The companies that hold marketing authorizations for medicinal products are required to transmit the data on the sale of medicinal products electronically on a quarterly basis. Until AIFA indicates with a specific provision the procedure envisaged for this transmission, the managerial decree of 24 May 2002, published in the Official Gazette of the Italian Republic n. 132 of 7 June 2002.
12. The obligation envisaged in paragraph 11 is extended to companies responsible for the marketing of medicines.
Article 131.
Responsible for the pharmacovigilance service
1. The person in charge of the pharmacovigilance service referred to in paragraph 4 of article 130 resides in a member country of the European Community; he assures:
a) the establishment and functioning of a system capable of guaranteeing that information on all alleged adverse reactions communicated to company personnel and medical-scientific representatives are collected, sorted and accessible in a single place;
b) that all information relating to the safety of medicinal products, subsequent to the act of authorisation, is brought to the attention of healthcare personnel quickly, including through the contacts of the scientific information service of their company;
c) the preparation of the reports referred to in paragraph 5 of article 130, to be submitted to the competent authorities according to the methods established by AIFA, which takes into account the indications of the competent international and community bodies;
d) the transmission to the pertinent healthcare facility of reports of suspected serious or unexpected adverse reactions that occurred on the national territory received directly from the reporter and not through the national pharmacovigilance network;
e) the rapid and exhaustive transmission, upon each request from AIFA, of supplementary information for the purpose of assessing the benefits and risks of a medicinal product, including information regarding the sales or prescription volumes of the same;
f) the submission to AIFA of any other relevant information for the purposes of assessing the benefits and risks relating to a medicinal product, including the appropriate information on post-authorisation safety studies.
Article 132.
Obligations of healthcare facilities and operators and subsequent AIFA fulfilments
1. Local health authorities, hospitals, public and private scientific hospitalization and treatment institutes, public and private university polyclinics and other similar health facilities must appoint a pharmacovigilance manager of the facility, who registers to the national pharmacovigilance network for the purpose of obtaining the qualification necessary for the management of reports. The pharmacovigilance manager of the facility must meet the requirements referred to in paragraph 4 of article 130. Private healthcare facilities, other than those referred to in the first period, in order to fulfill the pharmacovigilance tasks, refer to the pharmacovigilance manager of the company competent local health authority for the territory.
2. Physicians and other healthcare professionals are required to report all suspected serious or unexpected adverse reactions they become aware of in the course of their work. However, all suspected adverse reactions observed, serious, non-serious, expected and unexpected, from all vaccines and medicines placed under intensive monitoring and included in lists periodically published by AIFA must be reported.
3. The provisions of the legislative decree of 24 June 2003, n. 211.
4. Doctors and other healthcare professionals must promptly transmit reports of suspected adverse reactions, using the appropriate form, to the pharmacovigilance manager of the healthcare facility they belong to. Doctors and other health professionals working in private health facilities must promptly send reports of suspected adverse reactions, using the appropriate form, to the pharmacovigilance manager of the competent local health authority, directly or, if required, through the Health Department. The pharmacovigilance managers provide, after verifying the completeness and adequacy of the data, the insertion of the report, within and no later than seven days from the date of receipt of the same, in the database of the national pharmacovigilance network and the verification of the effective forwarding of the message, relating to the insertion, the region and the pharmaceutical company concerned. If it is impossible to transmit the message, the healthcare facilities will send the recipients, who could not be reached electronically, a copy of the report bearing the numerical code issued by the system. Pharmacovigilance managers facilitate the active search by the pharmacovigilance service managers of pharmaceutical companies for additional information on reports.
5. The original report forms will be kept in the healthcare facility that received them and a copy forwarded to AIFA, to the region to which they belong or to the Pharmacovigilance Center identified by the region where requested by them.
6. Updates of suspected adverse reactions can be requested from the reporter by the pharmacovigilance manager of the healthcare facility to which they belong or by his delegate, or by AIFA staff, in all cases where this is deemed necessary. However, updates must be requested in the event of serious adverse reactions, unless the original report is already complete with updated information or cannot be further updated. The requesting party enters the acquired data into the network by updating the entered form. The pharmacovigilance manager is in any case required to acquire a detailed clinical report from the reporter, to be sent to AIFA within fifteen calendar days, for all cases of adverse reactions with a fatal outcome.
7. Any additions to the operating procedures regarding the management and updating of reports of suspected adverse reactions, referred to in paragraphs 4, 5 and 6, may be included in the guidelines referred to in paragraph 5 of the article.
8. AIFA ensures that all reports of suspected serious adverse reactions from medicinal products that have occurred on the national territory and the information subsequently acquired in this regard are immediately made available to the marketing authorization holder and in any case within fifteen calendar days from the date of receipt of communication.
9. AIFA ensures that all reports of suspected serious adverse reactions from medicinal products that have occurred in the national territory are made available to the EMEA and the other Member States of the European Community within fifteen calendar days from the date of receipt of their communication. AIFA also gives timely notice to the public, via the website, of the content of such reports.
Article 133.
Suspension, revocation or modification of a marketing authorization for pharmacovigilance reasons
1. If, following the evaluation of the pharmacovigilance data, AIFA deems it necessary to suspend, revoke or modify a marketing authorization in accordance with the guidelines referred to in article 106, paragraph 1, of directive 2001/83/EC, it shall immediately inform the EMEA, the other Member States of the European Community and the marketing authorization holder.
2. When urgent action is required to protect public health, AIFA may suspend the marketing authorization of a medicinal product, provided that it informs the EMEA, the European Commission and the other Member States of the European Community within the first working day following.
3. AIFA revokes or modifies, if necessary, its provision in compliance with the decisions of the European Commission pursuant to article 107 of directive 2001/83/EC.
4. AIFA makes the decisions taken pursuant to this article known to the public, using the most appropriate means.
Article 134.
Checks on compliance with pharmacovigilance regulations
1. AIFA ensures compliance with the provisions of this title by inspecting the premises, records and documents of the MA holders in relation to the activities referred to in this title.
2. At the conclusion of each inspection, a report on compliance with the provisions of this title shall be drawn up.
3. The provisions of paragraphs 13 and 14 of article 53 apply to the inspections envisaged by this article.
TITLE X
SPECIAL PROVISIONS CONCERNING MEDICINAL PRODUCTS DERIVED FROM HUMAN BLOOD OR PLASMA AND IMMUNOLOGICAL MEDICINAL PRODUCTS
Article 135.
Collection and control of human blood and plasma
1. The provisions of the legislative decree of 19 August 2005, n. 191, transposing directive 2002/98/EC of 27 January 2003, which establishes standards of quality and safety for the collection, control, processing, conservation and distribution of human blood and its components and which modifies the Directive 2001/83/EC.
2. The implementation provisions of the aforementioned legislative decree no. 191 of 2005 must provide, for the collection and control of human blood and its components intended for the production of blood products, requirements and criteria equivalent to those envisaged for blood and blood components intended for transfusion; the assessment of this equivalence must, however, take into account the guarantees that can be obtained through the production processes of blood products.
Article 136.
Community self-sufficiency in human blood and plasma
1. The Ministry of Health and AIFA take all the necessary measures to achieve the self-sufficiency of the European Community in the field of human blood and plasma. To this end, they shall encourage voluntary and unpaid donations of blood or blood components and take all necessary measures to develop the production and use of products derived from human blood or plasma resulting from voluntary and unpaid donations. The measures taken are notified to the European Commission.
Article 137.
Reports of analysis checks
1. AIFA may require manufacturers of immunological medicinal products or medicinal products derived from human blood or plasma to send copies of all control reports signed by the qualified person, in accordance with article 52, paragraph 8.
Article 138.
Status control of immunological medicinal products
1. Before being distributed, they are subjected to batch-by-batch status checks
a) live vaccines;
b) immunological medicinal products used for active immunization of children or other risk groups;
c) immunological medicinal products used in collective active immunization programmes;
d) limited to a transitional period, normally established in the AIC, new immunological medicinal products or medicinal products prepared with the aid of new or modified techniques, or which are innovative for the manufacturer.
2. With a decree of the Minister of Health, having consulted the Higher Institute of Health and the Higher Health Council, within six months from the date of entry into force of this decree, prescriptions and technical procedures are dictated for the execution of the checks envisaged by the paragraph 1, which, carried out by the Higher Institute of Health, must be completed within sixty days of receipt of the samples.
3. In the manner indicated in paragraph 2:
a) immunological medicinal products other than those indicated in paragraph 1 may be subjected to state control, taking into account the directives of the European Community, when particular needs for the protection of public health so require;
b) it can be established that, for certain products, the state check is carried out, rather than on samples of the medicines, on the documentation relating to the checks carried out by the manufacturer;
c) immunological medicinal products which offer sufficient guarantees of safety and uniformity may be exempted from state control.
4. State control is not required when the lot has already been subjected to a similar control by the health authority of another member state of the European Community or of a state with which bilateral agreements exist.
Article 139.
Status monitoring of medicines derived from human blood or plasma
1. The Minister of Health, having consulted the Higher Institute of Health and the Higher Health Council, may subject medicines derived from human blood or plasma, in bulk or ready-to-use, to state control, even limited to individual types for use; the same procedure dictates prescriptions and methods for carrying out this check, which must be completed within sixty days of receiving the samples.
Article 140.
Elimination of pathogenic viruses susceptible to transmission with medicinal products derived from human blood or plasma
1. For the purpose of issuing marketing authorization for medicinal products derived from human blood or plasma, the manufacturer must demonstrate that the production and purification processes adopted, suitably validated, make it possible to constantly obtain homogeneous batches, as well as guarantee, as far as allowed by the developments of the technique, the absence of specific viral contaminants, as well as pathogens susceptible to be transmitted; the documentation on the production and purification processes, together with the validation documentation, must be submitted to AIFA, which acquires the technical judgment of the Higher Institute of Health in this regard.
TITLE XI
SUPERVISION AND SANCTIONS
Article 141.
Suspension, revocation and ex officio modification of a marketing authorization
1. The marketing authorization for a medicinal product, issued by AIFA, can be revoked.
2. The revocation, which entails the definitive withdrawal from the market of the medicinal product, is ordered when, in the justified opinion of the AIFA:
a) the medicinal product is harmful under normal conditions of use;
b) the medicinal product does not allow to obtain the therapeutic effect or the effect for which it was authorised;
c) the risk/benefit ratio is not favorable under normal conditions of use;
d) the medicinal product does not have the declared qualitative and quantitative composition.
3. The authorization may also be revoked if it is found that the information in the dossier pursuant to Article 8 or Articles 10, 11, 12, 13 and 14 is incorrect or has not been modified pursuant to the article 33, or when the checks on the finished product, or on the components and intermediate products of production, based on the methods adopted for the marketing authorization have not been carried out, as well as in cases where the trials presented in support of the marketing authorization request have been conducted without respecting the principles and guidelines of the rules of good clinical practice established by Community legislation.
4. The revocation is arranged upon notification of the facts to the marketing authorization holder, who has the right to present his observations, in writing or at the appropriate hearing, within fifteen days of the notification itself. The provision is adopted by AIFA. Against the revocation provision adopted by AIFA, an opposition may be lodged on which AIFA decides, having heard the Higher Health Council.
5. If, in the cases envisaged by paragraph 2, it is advisable to acquire further elements on the characteristics of the medicinal product, AIFA suspends the authorisation. The suspension is ordered in the event of slight irregularities referred to in paragraph 2, which can be remedied in a suitable period of time. However, the suspension entails a ban on sales for the entire duration of its duration. 6. Instead of revocation or suspension, AIFA shall, in the cases envisaged by paragraph 2, amend the AIC. 7. With the provision of modification of the AIC referred to in paragraph 6, AIFA establishes the deadline within which the unmodified packages must be withdrawn from the market.
Article 142.
Prohibition of sale and use withdrawal from the market and seizure of the medicinal product
1. AIFA prohibits the sale and use of the medicinal product and orders its withdrawal from the market, even limited to individual lots, if in its justified opinion, one of the conditions referred to in paragraph 2 of article 141 occurs or that checks have not been carried out on the finished product, or on the components and intermediate products of production, or that the obligations and conditions imposed upon the issue of the production authorization or subsequently have not been observed, or the medicinal product has quality defects potentially dangerous for public health.
2. AIFA may also order the seizure of the medicinal product, even limited to individual lots, when there are elements to believe that only the removal of the material availability of the medicinal product can ensure effective protection of public health.
3. The provisions referred to in paragraphs 1 and 2 also extend, to the extent applicable, to pharmacologically active raw materials.
Article 143.
General prescriptions relating to medicines
1. AIFA can establish, in compliance with the directives and recommendations of the European Community, conditions and prescriptions of a general nature relating to all medicinal products or to particular groups of them, including provisions on the labeling and packaging of medicinal products and on the methods of prescription and use.
Article 144.
Provisions of the administrative authority in the event of irregularities in the trade of medicines
1. In the event of the sale of a medicinal product for which the marketing authorization has not been issued or confirmed or which has been suspended or revoked, or of a medicinal product having a declared composition other than that authorised, AIFA shall order immediate withdrawal from the market and may, where there is also the responsibility of the manufacturer, provide for the immediate closure, partial or total, of the plant in which the medicinal product is produced. The withdrawal from the market order is optional if the change in composition does not appear to be relevant from a health point of view.
2. AIFA may also order the seizure of the medicinal product when there are elements to believe that only the removal of the material availability of the medicinal product can ensure effective protection of public health.
3. In the cases referred to in paragraph 1, the competent administrative authority pursuant to regional legislation may order the closure, for a period of time from fifteen to thirty days, of the pharmacy where the medicinal products were offered for sale or held for sale, despite the prohibition imposed by AIFA.
4. If the events envisaged in paragraph 1 are subsequently repeated, at least twice, at the same pharmacy, the competent administrative authority orders the forfeiture of the practice.
Article 145.
Publication and notification of measures
1. The revocation provisions, including the revocation upon renunciation pursuant to article 38, paragraph 9, of suspension or modification of the office, as well as the prohibition of sale and use pursuant to article 142, are published by extract or by press release in the Official Gazette of the Italian Republic within three days of issue. The same provisions are notified to the authorization holders.
Article 146.
Suspension and revocation of the production authorisation
1. AIFA suspends or revokes the production authorization for a category of preparations or for all of these when compliance with one of the conditions set out in article 50, paragraphs 1 and 2 has ceased.
2. AIFA, without prejudice to the provisions of article 142, in the event that the obligations of articles 50, 51 and 52, paragraph 8 have not been observed, or in cases in which the obligations and conditions imposed by AIFA at the time of granting the authorization or subsequently or the principles and guidelines of the rules of good manufacturing practice for medicinal products established by Community legislation have not been respected, or finally in the case in which the marketing authorization holder and , if necessary, the holder of the production authorization does not provide proof of the execution of the checks carried out on the medicinal product and/or on the components, as well as on the intermediate products of the production, based on the methods adopted for the AIC, can suspend the production or import of medicinal products from third countries or suspend or withdraw the production authorization for a category of preparations or for all of them.
3. Except in cases of absolute urgency, the suspension and revocation measures of the authorization envisaged by article 50 are issued after the facts have been notified to the holder, who has the right to present his observations within fifteen days; the provisions themselves are notified to the holders of the authorizations and published in extract form in the Official Gazette of the Italian Republic.
4. AIFA can provide for the closure of the workshop permanently or for the duration of the suspension of the authorisation.
5. Holders of production authorizations are required to notify AIFA of the temporary or definitive closure of the production site.
Article 147.
Criminal penalties
1. The owner or legal representative of the company which begins the production of medicines or pharmacologically active raw materials without obtaining the authorization referred to in article 50, or continues it despite the revocation or suspension of the authorization itself is punished with imprisonment from six months to one year and a fine ranging from ten thousand to one hundred thousand euros. The same penalties also apply to anyone who imports medicines or pharmacologically active raw materials in the absence of the authorization envisaged by article 55 or who does not carry out or does not have the quality checks referred to in article 52, paragraph 8, carried out on the medicinal products, letter b). These penalties also apply to those who continue the authorized activity despite the absence of the qualified person referred to in article 50, paragraph 2, letter c), or the supervening unsuitability of essential equipment to produce and control medicines under the conditions and with the authorized requirements.
2. Unless the fact constitutes a crime, whoever places medicinal products on the market for which the authorization referred to in article 6 has not been issued or confirmed or has been suspended or revoked, or medicinal products having a declared composition different from the authorized one, is punished with imprisonment up to one year and with a fine ranging from two thousand to ten thousand euros. The penalties are reduced by half when the difference between the declared composition and the authorized one concerns only the excipients and has no toxicological significance.
3. The pharmacist who has offered for sale or who holds to sell medicinal products for which the authorization referred to in article 6 has not been issued or confirmed, or medicinal products whose sale has in any case been prohibited, as having a composition declared different from the authorized one, is punished with a fine ranging from eight hundred to two thousand four hundred euros and with the suspension of the professional exercise for up to one month. In the event of specific recidivism, the penalty is imprisonment from two to eight months, a fine from one thousand six hundred to four thousand euros and suspension from practicing the profession for a period of two to six months. The penalties are reduced by half when the difference between the declared composition and the authorized one concerns only the excipients and has no toxicological significance.
4. The owner or legal representative of the company which begins the wholesale distribution of medicinal products without obtaining the authorization referred to in article 100, or continues it despite the revocation or suspension of the authorization itself, and ' punished with imprisonment from six months to one year and a fine of between ten thousand and one hundred thousand euros. These penalties also apply to those who continue the authorized activity without having the responsible person referred to in article 101.
5. Whoever, in violation of article 123, paragraph 1, grants, offers or promises prizes, pecuniary or kind advantages, is punished with imprisonment of up to one year and with a fine ranging from four hundred to one thousand euros. The same penalties apply to the doctor and pharmacist who, in violation of article 123, paragraph 3, request or accept prohibited incentives. The conviction entails suspension from the practice of the profession for a period of time equal to the duration of the imposed sentence. In case of violation of paragraph 2 of article 123, the sanction of a fine ranging from four hundred to one thousand euros is applied.
6. The penalties referred to in paragraphs 2, first sentence, and 3, first and second sentences, also apply in the event of violation of the provisions adopted by AIFA pursuant to paragraph 1 of article 142.
7. The manufacturer of medicinal products or the marketing authorization holder who places on the market medicinal products without the requirement of sterility when prescribed or medicinal products referred to in title X which contain pathogenic agents liable to be transmitted, is subject to the penalties provided for by the article 443 of the penal code increased by one third.
Article 148.
Administrative penalties
1. Unless the fact constitutes a crime, in the event of violation of the provisions referred to in article 34, paragraph 7, the person responsible for placing the medicinal product on the market is subject to an administrative sanction ranging from three thousand to eighteen thousand euros. The marketing authorization holder who makes a modification to a medicinal product, or to its packaging or to the printed matter without the authorization provided for in article 35, is subject to the same administrative sanction.
2. Unless the fact constitutes a crime, the producer who, following the notification by AIFA of the report referred to in paragraph 7 of article 53, does not comply with the provisions contained in the notification provision within the times established therein is subject to an administrative fine ranging from ten thousand euros to fifty thousand euros.
3. Unless the fact constitutes a crime, in the event of non-compliance with the obligations set out in article 52, paragraph 8, the qualified person is subject to an administrative fine ranging from two hundred to one thousand two hundred euros. The sanction is doubled in case of violation of the obligation referred to in letter e) of the aforementioned paragraph.
4. Unless the fact constitutes a crime, an administrative fine of between ten thousand euros and fifty thousand euros is applied to the marketing authorization holder who fails to request the changes necessary to include the information of security referred to in Article 34, paragraph 3.
5. Unless the act constitutes a crime, if a medicinal product is placed or kept on the market with labeling or leaflet different from those approved by AIFA, or with label or leaflet not modified according to the provisions issued by the same Agency, or without the pharmaceutical sticker provided for by article 5-bis of the legislative decree 30 December 1992, n. 540, the marketing authorization holder is subject to an administrative fine ranging from ten thousand to sixty thousand euros.
6. In the case envisaged by paragraph 5, AIFA, with a reasoned provision, notifies the MA holder of the adaptation of the labeling or the leaflet, establishing a deadline for compliance. In the event of non-compliance within the indicated deadline, AIFA may suspend the marketing authorization of the medicinal product until fulfilment. The suspension is notified to the interested party with an indication of the means of redress envisaged by the legislation in force and of the term within which they can be proposed.
7. Unless the fact constitutes a crime, the pharmacist who sells a medicine referred to in paragraph 2 of article 88 without presenting a medical prescription is subject to an administrative fine ranging from three hundred to one thousand eight hundred euros. The pharmacist who violates the provisions of paragraph 3 of article 88 or does not affix the stamp certifying the sale of the product on the recipes is subject to an administrative fine ranging from two hundred to one thousand two hundred euros.
8. Unless the fact constitutes a crime, the pharmacist who sells a medicinal product governed by article 89 without presentation of a medical prescription or upon presentation of a prescription that is invalid is subject to an administrative fine ranging from five hundred to three thousand euros. The competent administrative authority may order the closure of the pharmacy for a period of time ranging from fifteen to thirty days.
9. Unless the fact constitutes a crime, the doctor who prescribes a medicine referred to in paragraph 1 of article 89 without complying with the procedures referred to in paragraph 4 of the same article is subject to an administrative fine ranging from three hundred to one thousand eight hundred euros.
10. Unless the fact constitutes a crime, the pharmacist who sells to the public or to an unauthorized establishment a medicinal product governed by article 92 is subject to the sanctions and administrative consequences provided for by paragraph 11.
11. Unless the fact constitutes a crime, the pharmacist who sells a medicine governed by article 93 without presenting a prescription from a medical center authorized to prescribe is subject to an administrative fine ranging from five hundred to three thousand euros. The competent administrative authority may order the closure of the pharmacy for a period of time ranging from fifteen to thirty days.
12. Unless the fact constitutes a crime, the pharmacist who sells to the public or to a doctor who is not authorized to use a medicinal product governed by article 94 is subject to the sanctions and administrative consequences provided for by paragraph 11.
13. Anyone who violates the provisions of title VII other than those provided for in paragraph 4 of article 147 is subject to an administrative sanction ranging from three thousand euros to eighteen thousand euros, without prejudice to any penal sanctions that may be applicable.
14. Whoever violates the prohibition referred to in paragraph 5 of article 115 is subject to an administrative fine ranging from ten thousand to sixty thousand euros.
15. Whoever advertises to the public in violation of the provisions of this decree is subject to an administrative fine ranging from two thousand six hundred to fifteen thousand six hundred euros.
16. Whoever violates the provisions of paragraph 8 of article 125 is subject to an administrative fine ranging from five thousand to thirty thousand euros. In case of violation of the remaining provisions of the same article 125, the provisions of article 127 apply.
17. Whoever violates the provisions of article 126 is subject to an administrative fine ranging from fifty thousand to three hundred thousand euros.
18. Violation of the provisions of this decree on advertising to healthcare professionals entails the application of an administrative fine ranging from two thousand six hundred to fifteen thousand six hundred euros.
19. For medicines included in the list of medicines which can be dispensed at the expense of the National Health Service, the violation referred to in paragraph 18 may also lead to the suspension of the medicine from the aforementioned list for a period of time from ten days to two years, taking into account the seriousness of the fact. The suspension provision is adopted after contesting the fact to the MA holder, who can send counter-arguments to AIFA within fifteen days of the contestation itself.
20. The marketing authorization holder for medicinal products who violates the obligations set out in article 130 is subject to a payment sanction ranging from thirty thousand to one hundred and eighty thousand euros. The amount of the fine is increased by a variable amount from 0.1 percent to 1 percent of the turnover of the medicinal product for which the violation has been found.
21. The marketing authorization holder for medicinal products who violates the obligations set out in article 130 is also obliged, in the event of news of significant interest to patients, to publish, at his own expense, for three consecutive days in the main national newspapers corrections, agreed with AIFA, of previously disclosed information.
22. The pharmacovigilance manager of the pharmaceutical company, who violates the obligations of article 131, is subject to the sanction of payment of the sum from twenty thousand euros to one hundred and twenty thousand euros.
23. Whoever violates the obligation provided for by article 130, paragraph 12, is subject to the sanction of payment of the sum from ten thousand euros to sixty thousand euros.
24. Failure to comply with the provisions envisaged for those in charge of pharmacovigilance in healthcare facilities entails the establishment in the competent offices of proceedings for the disbursement of disciplinary sanctions, according to legislative and contractual provisions.
Article 149.
Extension of the provisions of this title to centrally authorized medicinal products
1. With the exception of the power to revoke the marketing authorization, the provisions of this title also apply to medicinal products authorized pursuant to regulation (EC) no. 726/2004. In this case, AIFA, when it adopts precautionary measures, makes the communications and performs the other fulfilments envisaged by the aforementioned regulation.
Article 150.
Extension of the provisions of the title to homeopathic medicines
1. The provisions of this title also apply to homeopathic medicines.
TITLE XII
ADDITIONAL PROVISIONS
Article 151.
Compliance with reporting obligations within the community
1. The Ministry of Health verifies that AIFA complies with all the communication obligations within the Community envisaged by this decree.
2. AIFA normally accepts the conclusions of an inspection carried out in another Member State, pursuant to the provisions of Directive 2001/83/EC, which concern medicinal products marketed in Italy. In exceptional circumstances, however, when for public health reasons AIFA cannot accept the conclusions of an inspection, it immediately informs the Commission, the EMEA and the Ministry of Health.
Article 152.
Reporting obligations to the World Health Organization
1. AIFA immediately communicates to the World Health Organization adequate information on decisions concerning medicinal products on the market which may affect health protection in third countries.
2. A copy of the communication referred to in paragraph 1 is sent to the EMEA and to the Ministry of Health.
Article 153.
Mandatory nature of cases relating to restrictive measures
1. AIFA may refuse, suspend or revoke the AIC only for the reasons specified in this decree.
2. Decisions to suspend the production or import of medicines from third countries, to ban the sale and to withdraw a medicine from the market can be taken, respectively, only for the reasons indicated in articles 146 and 142.
Article 154.
Extension of certain provisions on pharmacovigilance
1. The provisions of Title IX which envisage obligations for operators and healthcare facilities and the related sanctions envisaged in Title XI also apply to adverse reactions resulting from the use of a medicinal product for an indication or route of administration o a method of administration or use other than that authorized, in accordance with the provisions of article 3, paragraph 2, of the decree-law of 17 February 1998, n. 23, converted, with modifications, by law 8 April 1998, n. 94.
2. The Minister of Health can prohibit the use of medicines, even prepared in pharmacies, considered dangerous for public health.
Article 155.
Measures aimed at ensuring the independence and transparency of evaluations and better coordination between the activities of AIFA and the Ministry of Health.
1. AIFA and, to the extent of its competence, the Ministry of Health, the Regions and the authorities delegated by them, adopt adequate measures so that their personnel, the rapporteurs and the experts in charge of evaluations concerning the authorizations envisaged by this decree and drug surveillance have no financial or personal interest in the pharmaceutical industry that could affect their impartiality. The aforementioned subjects issue a declaration on their financial interests every year. Untruthful declarations that conceal interests included in the first sentence of this paragraph entail the immediate removal of the subject from the activities envisaged by this decree, without prejudice to any other legal consequence.
2. AIFA makes its internal regulations and those of its collegial bodies that intervene in the matters governed by this decree, as well as the agendas of the related meetings, accessible to the public, in ways to be published on the website. Upon request, it provides the minutes of the aforementioned meetings, accompanied by the decisions taken and information concerning the votes and their reasons, including the opinions of the minority.
3. A representative of the competent General Directorate of the Ministry of Health participates, with the power to present the position of the Ministry of Health on particular issues, in the meetings of the collegial bodies of AIFA governed by articles 19 and 20 of the decree of the Minister of Health dated 20 September 2004, no. 245. Participation in the meetings of the collegiate bodies of AIFA does not give the right to the payment of any emolument, indemnity, compensation or reimbursement of expenses.
Article 156.
Certifications concerning the production of medicines
1. AIFA certifies, at the request of the manufacturer, the exporter or the authorities of an importing third country, the possession by the manufacturer of the authorization for the production of medicines and pharmacologically active raw materials. When issuing the certificate, AIFA:
a) take into account the provisions of the World Health Organisation;
b) provides, for medicinal products already authorized and intended for export, the summary of product characteristics.
2. The producer who is not in possession of a marketing authorization is required to provide AIFA, for the purpose of issuing the certificate referred to in paragraph 1, the reasons for the lack of such authorization, as well as a copy of the marketing authorization in the country of destination, or the application for authorization submitted to the authorities of that country.
Article 157.
Collection systems for unused or expired medicines
1. Without prejudice to the provisions regarding the management of medical waste by the decree of the President of the Republic of 15 July 2003, n. 254, by decree of the Minister of Health, in concert with the Minister of the Environment and Protection of the Territory and the Minister of Productive Activities, subject to the opinion of the Permanent Conference for relations between the State, the regions and the autonomous provinces of Trento and Bolzano, suitable collection systems for unused or expired medicines are established at the expense of the operators. These systems can also be based on agreements, at national or territorial level, between the parties interested in the collection. The same decree identifies methods that make it possible for non-profit organizations to use unused, correctly stored and still valid medicines.
TITLE XIII
FINAL PROVISIONS
Article 158.
repeals; effects of the authorizations adopted on the basis of the repealed provisions; confirmation of specific provisions.
1. Without prejudice to the provisions of article 10, paragraph 10, the legislative decrees of 29 May 1991, n. 178, 30 December 1992, n. 538, 30 December 1992, no. 539, with the exception of article 12, 30 December 1992, n. 540, with the exception of article 5-bis, 30 December 1992, n. 541, 17 March 1995, no. 185, 18 February 1997, n. 44, 8 April 2003, no. 95, and their subsequent modifications. The provisions on medicines contained in the law of 14 December 2000, n. 376, and related implementing provisions, as well as any other provision in force which imposes constraints and conditions for the trade of medicines for specific public health protection needs.
2. The powers attributed to AIFA by this decree also apply to previous and still existing legal relationships and situations, established under the provisions of the repealed legislative decrees which attributed corresponding or similar powers to the Ministry of Health or Health.
3. When provisions contained in the repealed legislative decrees are referred to in current legislation, such references are understood to refer to the corresponding provisions contained in this decree.
4. The holders of the authorizations issued by the competent bodies established by the regional legislation in accordance with what has already been regulated by the legislative decree of 30 December 1992, n. 538, who, on the basis of the previous legislation, carried out import operations of pharmacologically active raw materials for which an authorization pursuant to title IV is now required, can continue the same operations on condition that they obtain within twelve months from the date of entry into force of this decree the authorization provided by it.
5. To allow for the preparation of the documentation required by chapter IV of title III, for medicinal products whose expiry date of the authorization falls within the six months following the date of entry into force of this decree, the deadline for submitting applications for renewal or for the updating of applications still in progress, is extended by three months.
6. The provisions of the decree of the Minister of Health dated 11 February 1997, containing modalities for the importation of proprietary medicinal products registered abroad, published in the Official Gazette of the Italian Republic no. 72 of 27 March 1997, and subsequent amendments. These medicines are used only for indications approved in the country of origin and in accordance with the relevant summary of product characteristics. The maritime, air, border and internal customs offices of the Ministry of Health transmit to AIFA, notifying the General Directorate of Medicines and Medical Devices of the Ministry of Health, the data indicated in article 4 of the aforementioned ministerial decree .
7. The provisions of the decree of the Minister of Health dated 29 August 1997, concerning the authorization procedures for the parallel importation of medicinal products for human use, published in the Official Gazette of the Italian Republic no. 235 of 8 October 1997, without prejudice to the attribution to AIFA of the responsibilities referred therein to the Ministry of Health.
8. Upon entry into the national territory, the traveler has the right to bring with him medicines registered in other countries, provided they are intended for a therapeutic treatment not exceeding thirty days, with the exception, limited to narcotics and psychotropic substances of referred to in the consolidated text referred to in the decree of the President of the Republic 9 October 1990, n. 309, and subsequent amendments, the conditions and procedures that can be established by decree of the Minister of Health.
9. The provisions referred to in the ministerial decrees referred to in paragraphs 6 and 7, may be modified by decree of the Minister of Health, on the proposal of AIFA or after consulting it. In any case, the need for ministerial authorization remains unaffected for the introduction into the national territory, in the hypotheses envisaged by paragraphs 6 and 7, of medicines subject to the discipline of the consolidated text referred to in the decree of the President of the Republic of 9 October 1990, n. 309, and subsequent modifications.
10. By decree of the Minister of Health, to be adopted within one hundred and twenty days from the date of entry into force of this decree, also taking into account the EMEA guidelines for the compassionate use of medicines, the criteria and methods for the use of medicines without a marketing authorization in Italy, including the use outside the summary of the characteristics of the product authorized in the country of origin and the compassionate use of medicines not yet registered. Until the date of entry into force of the aforementioned ministerial decree, the ministerial decree of 8 May 2003, published in the Official Gazette of the Italian Republic no. 173 of 28 July 2003.
11. Are confirmed:
a) the tariffs in force on the date of entry into force of this decree, concerning the services rendered by the Ministry of Health at the request and utility of the interested parties, on the basis of the provisions of article 5, paragraph 12, of the law of 29 December 1990, no. 407;
b) the tariffs already envisaged by article 12, paragraph 7, of the legislative decree of 30 December 1992, n. 541.
c) the fees established for the examination of marketing authorization applications for medicinal products and for applications for modification and renewal of the authorizations themselves, in application of article 5, paragraph 1, of legislative decree no. 44.
12. The tariffs envisaged by paragraph 11 are updated, within the month of March of each year, on the basis of the annual variations of the Istat cost of living index referring to December of the previous year. Limited to the tariffs referred to in letter c) of paragraph 11, the amounts, by decree of the Minister of Health on the proposal of the AIFA, are updated, in proportion to the changes in the tariffs due to the EMEA. In any case, the fees referred to in paragraph 11, letter c), cannot be less than one fifth of the amounts of the fees established by the Community regulations for the corresponding EMEA services.
13. In the event of non-payment of the due fees, if as a result of tacit consent procedures, the company concerned has acquired the required authorisation, no other application concerning the same medicinal product can be taken into consideration unless the fee has been paid initially unpaid.
Article 159.
financial provisions
1. The implementation of this decree must not result in new or greater burdens for the public finance.
2. The Public Administrations involved carry out the obligations set out in this decree within the limits of the financial, human and instrumental resources available under current legislation.
Article 160.
Compliance clause
1. In relation to the provisions of article 117, fifth paragraph, of the Constitution, articles 102, 119 and 125 shall apply until the date of entry into force of the implementing legislation of directive 2001/83/EC, and subsequent amendments, adopted by each region and autonomous province, in compliance with the constraints deriving from the Community legal system and the fundamental principles deducible from this decree.
ANNEX I
STANDARDS AND ANALYTICAL, TOXIC-PHARMACOLOGICAL PROTOCOLS
AND CLINICS IN THE MATTER OF TESTING OF MEDICINAL PRODUCTS
INDEX
Introduction and general principles
Part I
STANDARDIZED MARKETING AUTHORIZATION DOSSIER REQUIREMENTS
1. Module 1: Administrative Information
1.1. Index
1.2. Application form
1.3. Summary of product characteristics, labeling and package leaflet
1.3.1. Summary of product characteristics
1.3.2. Labeling and leaflet
1.3.3. Specimens and samples
1.3.4. Summaries of Product Characteristics already approved in Member States
1.4. Information about the experts
1.5. Specific requirements for different types of questions
1.6. Environmental risk assessment
2. Module 2: Summaries
2.1. General index
2.2. Introduction
2.3. General summary related to quality
2.4. Review related to the non-clinical part
2.5. Review related to the clinical part
2.6. Summary related to the non-clinical part
2.7. Summary of the clinical part
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 fundamental principles and requirements
3.2.1. Active substance(s).
3.2.1.1. General information and related to raw materials and subsidiary materials
3.2.1.2. Manufacturing process of the active substance(s).
3.2.1.3. Characterization of the active substance(s).
3.2.1.4. Control of the active substance(s).
3.2.1.5. Reference standards or materials
3.2.1.6. Containers and closure system of the active substance
3.2.1.7. Stability of the active substance(s).
3.2.2. Finished medicine
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. Checking the finished medicine
3.2.2.6. Reference standards or materials
3.2.2.7. Container and closure of the finished medicine
3.2.2.8. Stability of the finished medicinal product
4. Module 4: Non-clinical relationships
4.1. Format and presentation
4.2. Content fundamental principles and requirements
4.2.1. Pharmacology
4.2.2. Pharmacokinetics
4.2.3. Toxicology
5. Module 5: Clinical Trial Reports
5.1. Format and presentation
5.2. Content fundamental principles and requirements
5.2.1. Biopharmaceutical study reports
5.2.2. Reports on studies carried out in the pharmacokinetic field with the use of human biomaterials
5.2.3. Reports of human pharmacokinetic studies
5.2.4. Reports of human pharmacodynamic studies
5.2.5. Reports of efficacy and safety studies
5.2.5.1. Reports of controlled clinical trials relating to the claimed indication
5.2.5.2. Uncontrolled clinical trial reports, data analysis reports from more than one study, and other clinical trial reports
5.2.6. Post-marketing experience reports
5.2.7. Forms for «case reports» the report of trials and lists of individual patients
Part II
SPECIFIC MARKETING AUTHORIZATION DOSSIERS
1. Well known medical use
2. Essentially similar medicines
3. Complementary data required in specific situations
4. Medicinal products of similar biological origin
5. Fixed combination medicinal products
6. Documentation for claims in exceptional circumstances
7. Mixed Marketing Authorization Applications
Part III
PARTICULAR MEDICINAL PRODUCTS
1. Medicinal products of biological origin
1.1. Medicinal products derived from plasma
1.2. Vaccines
2. Radiopharmaceuticals and precursors
2.1. Radiopharmaceuticals
2.2. Radiopharmaceutical precursors for radiolabelling purposes
3. Homeopathic medicines
4. Herbal medicines
5. Orphan drugs
Part IV
MEDICINES FOR ADVANCED THERAPIES
1. Gene therapy medicinal products (human and xenogenic)
1.1. Diversity of gene therapy medicinal products
1.2. Module specific requirements 3
2. Somatic cell therapy medicinal products (human and xenogenic)
3. Specific requirements for gene therapy and somatic cell therapy medicinal products (human and xenogenic) related to modules 4 and 5
3.1. Form 4
3.2. Form 5
3.2.1. Human pharmacology and efficacy studies
3.2.2. Safety
4. Specific statement on xenotransplantation medicinal products
Introduction and general principles*
*As a rule, this annex mentions both the EU directive and the corresponding Italian implementing legislation. Only if the directives refer to matters not exclusively pertaining to the pharmaceutical sector (e.g. GMOs, dyes, etc.) is the mention of the corresponding national legislation omitted.
(1) The information and documents attached to the application for marketing authorization pursuant to Article 8 and 10, paragraph 1 of this Decree (Articles 8 and 10, paragraph 1 of Directive 2001/83/EC), must be presented in accordance with the provisions of this annex and must comply with the guide published by the Commission in the collection "Regulations relating to medicinal products of the European Community", volume 2 B, guide for use by applicants, medicinal products for human use, presentation and content of the dossier, Common Technical Document (CTD).
(2) The submission of information and documents is to be done through five modules: module 1 provides specific administrative data for the European Community; module 2 summaries relating to the quality part, the non-clinical part and the clinical part; module 3 chemical, pharmaceutical and biological information; module 4, non-clinical reports and module 5, clinical study reports. This presentation constitutes the implementation of a format common to all ICH areas (European Community, USA, Japan). The five forms must be submitted in strict accordance with the format, content and numbering system specified in Volume 2B, Guide for Applicants, cited above.
(3) The submission in the European Community CTD format applies to all types of marketing authorization applications, irrespective of the envisaged procedure (centralised, mutual recognition or national) and whether the application is complete or simplified . It is also applicable to all kinds of products, including new chemicals (NCE: New Chemical Entities), radiopharmaceuticals, plasma derivatives, vaccines, herbal medicines, etc.
(4) When preparing the marketing authorization application dossier, applicants should also take into account the scientific guidelines/guidelines on the quality, safety and efficacy of medicinal products for human use, adopted by the Committee for Medicinal Products ( CPMP: Committee for Proprietary Medicinal Products) and published by the European Medicines Evaluation Agency (EMEA) and other guidelines in the pharmaceutical field established by the Community, published by the Commission in the various volumes of the collection «The legislation relating to medicinal products in the European Community".
(5) As regards the quality part of the dossier (chemical, pharmaceutical and biological), all the monographs, including the general ones, and the general chapters of the European Pharmacopoeia apply.
(6) The manufacturing process must comply with the requirements of Commission Directive 2003/94/EC (Chapter II of Title IV of this decree), which establishes the principles and guidelines of good manufacturing practice (GMP: Good Manufacturing Practices) relating to medicinal products for human use and medicinal products for human use in the investigational phase, and to the principles and guidelines on GMP published by the Commission in the collection "The regulation relating to medicinal products in the European Community" volume 4.
(7) The application must contain all the information necessary for the evaluation of the medicinal product in question, whether it is favorable or unfavorable for the medicinal product. In particular, it will contain all the information relating to incomplete or abandoned pharmaco-toxicological or clinical trials or trials relating to the medicinal product/s, and/or completed trials concerning therapeutic indications not considered in the application.
(8) All clinical trials carried out in the European Community must comply with the requirements of the legislative decree 24 June 2003, n. 211 (Directive 2001/20/EC of the European Parliament and of the Council, concerning the approximation of the laws, regulations and administrative provisions of the Member States relating to the application of good clinical practice in the execution of clinical trials on medicines for human use). To be considered during the assessment of an application, clinical trials performed outside the European Community - concerning medicinal products intended for use in the European Community - must be designed, implemented and described according to good clinical practice and relevant ethical principles, on the basis of principles equivalent to the provisions of the aforementioned legislative decree no. 211/2003 (directive 2001/20/EC). The trials must be carried out in accordance with the ethical principles contained, for example, in the Declaration of Helsinki.
(9) Non-clinical (pharmaco-toxicological) studies must be carried out in accordance with the provisions relating to good laboratory practice set out in Council Directive 87/18/EEC on the approximation of laws, regulations and administrative provisions relating to the application of principles of good laboratory practice and the control of their application for tests on chemical substances, and to the legislative decree 27 January 1992, n. 120, and subsequent additions (Directive 2004/9/EC of the European Parliament and of the Council concerning the inspection and verification of good laboratory practice - GLP).
(10) All animal tests are carried out according to the provisions of the legislative decree of 27 January 1992, n. 116 (Directive 86/609/EEC of the Council of 24 November 1986), concerning the approximation of the laws, regulations and administrative provisions of the Member States relating to the protection of animals used for experimental or other scientific purposes.
(11) For the purpose of continuous monitoring of the benefit/risk assessment, all new information not contained in the original application and all pharmacovigilance information should be submitted to the competent authorities. After the granting of the marketing authorisation, any changes to the data in the dossier must be submitted to the competent authorities in accordance with the requirements of Regulations (EC) Nos. 1084/2003 and (CE) n. 1085/2003 of the Commission or, possibly, pursuant to national regulations as well as the requirements of volume 9 of the Commission's collection "Regulations relating to medicinal products in the European Community".
This annex is divided into four parts:
– Part I describes the application format, summary of product characteristics, labelling, package leaflet and submission requirements for standard applications (modules 1 to 5).
– Part II provides for a derogation for «Specific Applications», i.e. relating to well-known medical use, essentially similar products, fixed combinations, similar biological products, exceptional circumstances and mixed applications (partly bibliographic and partly based on his own studies).
– Part III deals with the 'Requirements for special applications' relating to medicinal products of biological origin (plasma master file; vaccine antigen master file), radiopharmaceuticals, homeopathic medicinal products, herbal medicinal products and orphan medicinal products.
– Part IV deals with 'Advanced therapy medicinal products' and concerns in particular the specific requirements relating to gene therapy medicinal products (using the human autologous or allogeneic system, or the xenogenic system) and cell therapy medicinal products of human or animal, as well as medicines for xenogenic transplants.
PART I
REQUIREMENTS RELATING TO THE STANDARDIZED MARKETING AUTHORIZATION DOSSIER.
1. MODULE 1: ADMINISTRATIVE INFORMATION
1.1. Index
A complete table of contents of Modules 1 to 5 of the Marketing Authorization Application dossier should be submitted.
1.2. Application form
The medicinal product covered by the application must be identified by its name, the name of the active substance(s), the pharmaceutical form, the route of administration, the dosage and the final presentation, including the packaging.
In addition, the name and address of the applicant, name and address of the manufacturer(s) and sites of the different manufacturing steps (including the manufacturer of the finished product, the manufacturer(s) of the active substance(s)) and, if applicable, name and address of the importer.
The applicant must also specify the type of application and indicate any samples presented. The administrative data must be accompanied by copies of the manufacturing authorizations according to the provisions of article 50, paragraph 1 of this decree (article 40 of directive 2001/83/EC), together with the list of countries for which the authorization was issued. authorization, copies of all the summaries of product characteristics according to the provisions of article 14 of this decree (article 11 of directive 2001/83/EC) approved by the Member States and finally the list of countries in which it was presented an application for authorisation. As indicated in the application form, applicants should inter alia provide detailed information on the medicinal product being applied for, the legal basis of the application, the marketing authorization holder and the proposed manufacturing plant(s). i, as well as information on the orphan drug situation, scientific opinions and pediatric development programmes.
1.3. Summary of product characteristics, labeling and package leaflet
1.3.1. Summary of product characteristics
The applicant proposes a summary of the product characteristics as required by article 8, paragraph 3, letter o) of this decree and by article 11 of directive 2001/83/EC and subsequent amendments.
1.3.2. Labeling and leaflet
The proposed text for the labeling of the immediate packaging and the outer packaging as well as the package leaflet must be submitted. The texts must comply with all the mandatory items listed, for the labeling of medicinal products for human use, articles 73 and 74 of this decree (title V, article 63 of directive 2001/83/EC) and for the package leaflet from article 77 of this decree (article 59 of directive 2001/83/EC).
1.3.3. Specimens and samples
The applicant must submit samples and models of the immediate packaging, outer packaging, labels and package leaflets of the medicinal product in question.
1.3.4. Summaries of Product Characteristics already approved in Member States
Copies of all summaries of product characteristics must be attached to the administrative data of the application form - pursuant to article 8, paragraph 3 of this decree and article 11 of directive 2001/83/EC and subsequent amendments and of the article 31, paragraph 1 of this decree (article 21 of directive 2001/83/EEC) – approved by the member states, as well as a list of the countries in which the application has been presented.
1.4. Information about the experts
Pursuant to article 15, paragraph 1 of this decree (article 12, paragraph 2 of directive 2001/83/EEC), the experts must provide detailed reports of their findings relating to the documents and information which make up the authorization dossier for the placing on the market, and in particular relating to modules 3, 4 and 5 (respectively chemical, pharmaceutical and biological documentation, non-clinical documentation and clinical documentation). The experts must address the critical aspects concerning the quality of the product and the studies carried out on animals and humans, reporting all the data useful for an evaluation.
To meet these requirements, an overall quality summary, a non-clinical review (data from animal studies) and a clinical review must be provided and placed in module 2 of the marketing authorization application dossier. In module 1, a declaration signed by the experts is presented together with a brief description of their training, qualifications and professional activities. Experts must have appropriate technical or professional qualifications. The professional relationship existing between the expert and the applicant must also be indicated.
1.5. Specific requirements for different types of questions
The specific requirements for different types of applications are dealt with in Part II of this Annex.
1.6. Environmental risk assessment
Where appropriate, applications for marketing authorization must include a comprehensive assessment of any risks to the environment associated with the use and/or disposal of the medicinal product, and formulate any proposals for appropriate labelling. The environmental risks associated with the release of medicinal products containing or consisting of GMOs (Genetically Modified Organisms) in accordance with Article 2 of Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release need to be addressed in the environment of genetically modified organisms and repealing Council Directive 90/220/EEC. The information on environmental risk is presented in an appendix to module 1. The presentation of the information must comply with the provisions of Directive 2001/18/EC, taking into account any guidance documents published by the Commission with reference to the implementation of this Directive .
The information will contain
– an introduction;
– a copy of the written consent or written consents to the deliberate release into the environment of GMOs for research and development purposes, pursuant to part B of Directive 2001/18/EC;
– the information required in Annexes II to IV of Directive 2001/18/EC, such as the methods of detection and identification as well as the unique code of the GMO and any other additional information on the GMOs or on the product, concerning risk assessment environmental;
– an environmental risk assessment report (ERA) drafted on the basis of the information referred to in Annexes III and IV of Directive 2001/18/EC and pursuant to Annex II of the same directive;
– a conclusion, which, based on this information and the VRA, proposes an appropriate risk management strategy, including a post-marketing control plan, all details which should appear in the summary of product characteristics, in the labeling and in the package leaflet, due to their importance for the GMOs and for the product in question;
– adequate public information measures.
Also required are the date and signature of the author, a description of his education, qualifications and professional experience, as well as a statement of his professional relationship with the applicant.
2. MODULE 2: SUMMARY
This module summarizes the chemical, pharmaceutical and biological data, non-clinical data and clinical data presented in Modules 3, 4 and 5 of the Marketing Authorization Application dossier, and provides the reports/overviews referred to in the article 15, paragraph 1 of this decree (article 12 of directive 2001/83/EC). Critical points are analyzed and addressed, and factual summaries are presented, including tabular formats. The reports should contain references to tabular formats or to information contained in the main documentation submitted in Module 3 (Chemical, Pharmaceutical and Biological Documentation), Module 4 (Non-Clinical Documentation) and Module 5 (Clinical Documentation).
The information contained in Form 2 must be submitted in accordance with the format, content and numbering system specified in Volume 2, Guide for Applicants. Reviews and abstracts should adhere to the following basic principles and requirements:
2.1. General index
Module 2 must include an index of the scientific documentation presented in modules 2 to 5.
2.2. Introduction
Information on the pharmacological class, mode of action and proposed clinical use of the medicinal product for which marketing authorization is being sought must be provided.
2.3. General summary on the quality part
A comprehensive quality summary should provide information regarding chemical, pharmaceutical and biological data.
Key critical parameters and quality issues should be highlighted, as well as reasons where relevant guidance/guidelines have not been followed. This document should conform to the scope and approach of the corresponding details presented in module 3.
2.4. Review related to the non-clinical part
An integrated and critical assessment of the non-clinical animal/in vitro evaluation of the medicinal product is required. This should include discussion and justification of the testing strategy and any deviation from the relevant guidance/guideline.
Except for medicinal products of biological origin, an assessment of impurities and breakdown products, with their potential pharmacological or toxicological effects, should be included. The consequences of any differences in chirality, chemical form and impurity profile between the compound used for non-clinical studies and the product to be marketed should be discussed. For medicinal products of biological origin, the comparability between the materials used for non-clinical and clinical studies and the medicinal product to be marketed must be assessed.
Each new excipient must undergo a specific safety evaluation. The characteristics of the medicinal product, demonstrated by non-clinical studies, should be defined, and the consequences of these results for the safety of the medicinal product with reference to the proposed clinical use should be discussed.
2.5. Review related to the clinical part
The clinical review should provide a critical analysis of the clinical data included in the clinical summary and Form 5. The clinical development approach of the medicinal product, including critical study design, related decisions and study design, should be clarified.
A brief review of the clinical results, including significant limitations, as well as an assessment of the benefits and risks based on the conclusions of the clinical studies should be provided. How efficacy and safety findings support the proposed dose and indications should be interpreted, and an assessment of how the Summary of Product Characteristics and other measures maximize benefits and control risks is required.
Efficacy and safety issues raised during development, as well as unresolved issues should be explained.
2.6. Summary related to the non-clinical part
The results of animal/in vitro pharmacological, pharmacokinetic and toxicological studies should be presented as factual summaries in written and tabulated form in the following order:
- Introduction
– Written summary of pharmacology
– Tabular summary of pharmacology
– Written summary of pharmacokinetics
– Tabulated summary of pharmacokinetics
– Written summary of toxicology
– Tabular summary of toxicology.
2.7. Summary of the clinical part
A detailed factual summary of the clinical information on the medicinal product contained in Module 5 should be provided. The results of all biopharmaceutical and clinical pharmacology studies, as well as clinical efficacy and safety studies should be included. A summary of individual studies is required.
The summarized clinical information should be presented in the following order:
– Summary of biopharmaceuticals and related analytical methods
– Summary of clinical pharmacology studies
– Summary of clinical efficacy
– Summary of clinical safety
– Summary of individual studies.
3. MODULE 3: CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL INFORMATION FOR MEDICINAL PRODUCTS CONTAINING CHEMICAL AND/OR BIOLOGICAL ACTIVE SUBSTANCES
3.1. Format and presentation
The general setting of module 3 is the following:
- Index
– Set of data
– Active substance
General informations
– Nomenclature
- Structure
– General properties
Manufacturing
– Manufacturer(s).
– Description of the manufacturing process and the controls to which it is subject
– Control of materials
– Control of critical phases and intermediate products
– Validation and/or evaluation of the process
– Development of the manufacturing process
Characterization
– Explanation of the structure and other characteristics
– Impurities
Control of the active substance
– Specifications
– Analytical procedures
– Validation of analytical procedures
– Batch analysis
– Justification of the specifications
– Standards or reference subjects
– Container locking system
– Stability
– Stability summary and conclusions
– Stability Protocol and commitments made on stability following its approval
– Stability data
– Out of medicine
– Description and composition of the medicinal product
– Pharmaceutical development
– Components of the medicinal product
– Active substance
– Excipients
– Medicinal
– Formulation development
– Overdoses
– Physico-chemical and biological properties
– Development of the manufacturing process
– Container locking system
– Microbiological characteristics
– Compatibility
Manufacturing
– Manufacturer(s).
– Batch formula
– Description of the manufacturing process and the controls to which it is subject
– Control of critical phases and intermediate products
– Validation and/or evaluation of the process
Control of excipients
– Specifications
– Analytical procedures
– Validation of analytical procedures
– Justification of the specifications
– Excipients of human or animal origin
– New excipients
Checking the finished medicine
– Specify(s).
– Analytical procedure
– Validation of analytical procedures
– Batch analysis
– Characterization of impurities
– Justification of the specification(s).
Reference standards or materials
Container locking system
Stability
– Stability summary and conclusion
– Stability Protocol and commitments made on stability following its approval
– Stability data
– Appendices
– Plant and equipment (only for medicinal products of biological origin)
– Safety assessment of adventitious agents
– Excipients
– Additional information for the European Community
– Process validation program for the medicinal product
- Medical device
– Certificate(s) of eligibility
– Medicines that contain or use in the manufacturing process materials of animal and/or human origin (TSE procedure: transmissible spongiform encephalopathy)
- Bibliography
3.2. Content fundamental principles and requirements
(1) For the active substance(s) and the finished medicinal product the chemical, pharmaceutical and biological data to be provided shall include all relevant information regarding the development, manufacturing process, characterization and properties, operations and requirements for quality control, stability, as well as a description of the composition and presentation of the finished medicinal product.
(2) Two main sets of information should be provided, respectively on the active substance(s) and on the finished product.
(3) This module should also provide details on the raw materials used in the manufacturing operations of the active substance(s) and on the excipients incorporated in the formulation of the finished medicinal product.
(4) All procedures and methods used for manufacturing and testing the active substance and the finished medicinal product must be described in detail, so that they can be reproduced in control tests at the request of the competent authorities. All the procedures followed for the tests must comply with the latest developments in scientific progress and must be validated. The results of the validation studies should be submitted. If the procedures for carrying out the tests are already included in the European Pharmacopoeia, the description can be replaced by suitable detailed references to the monograph(s) and to the general chapter(s).
(5) The monographs of the European Pharmacopoeia are applicable to all substances, preparations and pharmaceutical forms appearing in the European Pharmacopoeia. For other substances, each Member State can enforce compliance with the national pharmacopoeia.
However, if a material, listed in the European Pharmacopoeia or in that of a Member State, has been prepared by a method which leaves impurities uncontrolled in the Pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a description must be given. adequate procedure for carrying out tests. In cases where a specification contained in a monograph of the European Pharmacopoeia or in the national pharmacopoeia of a Member State is insufficient to guarantee the quality of the substance, the competent authorities may ask the marketing authorization holder for more appropriate specifications. The competent authorities will inform the authorities responsible for the pharmacopoeia in question. The MAH will provide the authorities of that pharmacopoeia with details of the alleged insufficiency and the additional specifications applied.
In case the test procedures are already included in the European Pharmacopoeia, in each of the relevant sections the description can be replaced by suitable detailed references to the monograph(s) and to the general chapter(s).
(6) If the starting materials and auxiliary materials, the active substance(s) or the excipient(s) are neither described in the European Pharmacopoeia nor in a national Pharmacopoeia, reference to the monograph may be permitted of the pharmacopoeia of a third country. In such cases, the applicant shall submit a copy of the monograph accompanied, where appropriate, by the validation of the analytical procedures contained in the monograph and by the translation.
(7) If the active substance and/or a starting material and ancillary material or the excipient(s) are the subject of a monograph of the European Pharmacopoeia, the applicant may request a certificate of suitability, which, if issued by the Management Quality Control Committee for Medicines, must be submitted in the relevant section of this form. These certificates of suitability of the European Pharmacopoeia monograph may replace the relevant data of the corresponding sections described in this form. The manufacturer will guarantee the applicant in writing that the manufacturing process has not been modified after the issue of the certificate of suitability by the European Directorate for the Quality of Medicinal Products.
(8) In the case of a well-defined active substance, the manufacturer of the active substance or the applicant may establish that
(i) the detailed description of the manufacturing process,
(ii) quality control during manufacture, e
(iii) process validation
are provided in a separate document directly to the competent authorities by the active substance manufacturer as an active substance master file.
In this case, however, the manufacturer communicates to the applicant all relevant data so that the latter assumes responsibility for the medicinal product. The manufacturer confirms in writing to the applicant that he ensures conformity between the various batches and that he will not make any changes to the manufacturing process or specifications without informing the applicant. All documents and details regarding any modification request must be submitted to the competent authorities; these documents and details are also provided to the applicant if they concern the open part of the master file.
(9) Specific measures for the prevention of transmission of spongiform encephalopathies of animal origin (materials derived from ruminants): at each stage of the manufacturing process the applicant shall demonstrate that the materials used comply with the guiding principles for actions to minimize the risk of transmitting etiological agents of animal spongiform encephalopathies through medicinal products and related updates, published by the Commission in the Official Journal of the European Union. Compliance with these guiding principles can be demonstrated by preferably presenting a certificate of compliance with the relevant monograph of the European Pharmacopoeia issued by the European Directorate for the Quality of Medicines, or scientific data demonstrating such suitability.
(10) As regards adventitious agents, information on the risk assessment relating to the potential for contamination by adventitious, non-viral or viral agents should be submitted, in accordance with the indications given in the corresponding guidelines, as well as in the general monograph and in the relevant general chapter of the European Pharmacopoeia.
(11) All special installations and equipment, which may be used at any stage of the manufacturing process and control operations of the medicinal product, must be adequately described.
(12) Where applicable, any CE marking required by Community legislation on medical devices must be presented. Particular attention should be paid to the elements identified below.
3.2.1. Active substance(s).
3.2.1.1. General information and related to raw materials and subsidiary materials
a) Information on the nomenclature of the active substance should be provided, including the recommended international non-proprietary name (INN), the European Pharmacopoeia name if relevant and the chemical name(s).
The structural formula, including relative and absolute stereochemistry, molecular formula and relative molecular mass, must be provided. Where relevant, for biotechnological medicinal products, the schematic representation of the amino acid sequence and relative molecular mass should be provided.
A list of the physicochemical properties of the active substance as well as other significant properties including biological activity for medicinal products of biological origin should be provided.
b) For the purposes of this Annex, starting materials are understood to mean all materials from which the active substance is manufactured or extracted.
With regard to medicinal products of biological origin, starting materials are understood to mean all substances of biological origin, such as microorganisms, organs and tissues of plant or animal origin, cells or biological liquids (including blood or plasma) of human or animal origin and biotechnological cellular constructs (cellular substrates, recombinant or not, including primary cells).
A biological medicinal product is a product whose active ingredient is a biological substance. A biological substance is a substance produced, or extracted, from a biological source and which requires for its characterization and determination of its quality a series of physical-chemical-biological tests, as well as indications on the production process and the his control. The following are considered biological medicinal products: immunological medicinal products and medicinal products derived from human blood and human plasma, respectively defined in article 1, paragraph 1, letter c) and letter i) of this decree (paragraphs (4) and (10) of the Article 1 of Directive 2001/83/EC); medicinal products falling within the scope of application of paragraph 1 of the annex to Regulation (EEC) no. 726/2004; advanced therapy medicinal products, as defined in Part IV of this Annex. All other substances as well as any other material used to manufacture or extract the active substance(s), but from which the active substance is not obtained directly, such as reagents, culture media, fetal calf serum, additives, buffers used in chromatography, etc., are known as raw materials.
3.2.1.2. Manufacturing process of the active substance(s).
a) The description of the manufacturing process of the active substance constitutes the commitment by the applicant regarding the manufacturing of the active substance. In order to adequately describe the manufacturing process and the controls to which it is subject, appropriate information must be provided in accordance with the guidelines published by the Agency.
b) All materials used to manufacture the active substance(s) shall be listed, indicating precisely where each material is used in the process. Information on the quality and control of such materials shall be provided, as well as information demonstrating that they conform to standards appropriate to their intended use.
Subsidiary materials must be listed, and their quality and the controls to which they are subjected must be documented.
The name, address and responsibility of each manufacturer, including contractors, as well as all production sites or facilities involved in manufacturing and testing shall be indicated.
c) The following additional requirements apply to medicinal products of biological origin.
The origin and history of raw materials must be described and documented. With regard to the specific prevention of the transmission of animal spongiform encephalopathies, the applicant shall demonstrate that the active substance complies with the explanatory note on the reduction of the risk of transmission of animal spongiform encephalopathies agents via medicinal products for human and veterinary use and its updates published by the Commission in the Official Journal of the European Union.
In the case of using cell banks, it must be demonstrated that the cellular characteristics have not changed during the passages carried out in the production phase and subsequently. Tests should be carried out to ascertain the absence of adventitious agents in starting materials, such as seed, cell banks, serum or plasma mixtures and other materials of biological origin and, if possible, in the materials from which they were derived.
If the presence of potentially pathogenic adventitious agents is unavoidable, the corresponding material can be used only if subsequent processing guarantees their elimination and/or inactivation. The deletion and/or inactivation must be validated. Whenever possible, vaccine production should be based on a seed lot system and pre-established cell banks. In the case of bacterial and viral vaccines, the characteristics of the infectious agent must be demonstrated in the seed. Furthermore, in the case of live vaccines, the stability of the attenuation characteristics must be demonstrated on the seed, if this demonstration is not sufficient, the attenuation characteristics of the infectious agents must be demonstrated during production.
In the case of medicinal products derived from human blood or plasma, it is necessary to describe and document the source, criteria and methods of collection, transport and conservation of the starting material, in accordance with the requirements set out in part III of the this annex.
Manufacturing facilities and equipment shall be described.
d) Tests and acceptance criteria used in all critical stages, information on quality and control of intermediate products, process validation and/or evaluation studies shall be appropriately communicated.
e) If the presence of potentially pathogenic adventitious agents is unavoidable, the corresponding material can be used only if subsequent processing guarantees their elimination and/or inactivation. Elimination and/or inactivation should be validated in the section dealing with viral safety assessment.
f) A description and discussion of the significant changes made to the manufacturing process during the development and/or at the manufacturing site of the active substance should be provided.
3.2.1.3. Characterization of the active substance(s).
Data evidencing the structure and other characteristics of the active substance(s) shall be provided.
Confirmation of the structure of the active substance(s) by physicochemical and/or immunochemical and/or biological methods shall be given, and information on impurities shall be provided.
3.2.1.4. Control of the active substance(s).
Details of the specifications used for the routine monitoring of the active substance(s), the justification for the choice of these specifications, the methods of analysis and their validation shall be submitted.
The results of the check carried out on the individual batches manufactured during development must be presented.
3.2.1.5. Reference standards or materials
Reference preparations and materials should be identified and described in detail. If relevant, chemical and biological reference materials from the European Pharmacopoeia should be used.
3.2.1.6. Containers and closure system of the active substance
A description of the container and closure system(s) and their specifications shall be provided.
3.2.1.7. Stability of the active substance(s).
a) The types of studies performed, the protocols used and the results obtained should be summarized.
b) Detailed results of the stability studies, including information on the analytical procedures used to compile the data and the validation of these procedures, shall be presented in an appropriate format.
c) The stability protocol and the stability commitment following the approval must be submitted.
3.2.2. Finished medicine
3.2.2.1. Description and composition of the finished medicinal product
A description of the finished medicinal product and its composition must be submitted. The information must include the description of the pharmaceutical form and composition with all the constituent elements of the finished medicinal product, their quantity per unit, the function of the components:
– of the active substance(s),
– excipients, whatever their nature or quantity used, including colourings, preservatives, adjuvants, stabilizers, thickeners, emulsifiers, taste correctors, flavourings, etc.,
– of the components of the outer coating of medicinal products intended to be ingested or otherwise administered to the patient (hard and soft capsules, rectal capsules, coated tablets, film-coated tablets, etc.),
– these indications must be completed with any useful details about the type of container and, if necessary, about its closure system, together with the specification of the devices used for use or administration supplied with the medicinal product.
"Usual terms" used to designate the components of the medicinal product must be understood, without prejudice to the application of the other indications referred to in article 8, paragraph 3 letter c) of this decree (article 8, paragraph 3, letter c of directive 2001/ 83/CE)
– for substances listed in the European Pharmacopoeia or, if not listed in the European Pharmacopoeia, in the national Pharmacopoeia of a Member State, only the principal name used in the relevant monograph, with reference to the Pharmacopoeia in question,
– for other substances, the international non-proprietary name (INN: International non-proprietary name) recommended by the World Health Organization or, failing that, the exact scientific name; for substances without an international non-proprietary name or an exact scientific name, the origin and production method must be indicated, providing any other useful details if necessary,
– for coloring substances, the designation by means of the "E" code attributed to them in Council Directive 78/25/EEC of 12 December 1977 on the approximation of the laws of the Member States relating to substances which may be added to medicinal products for of their coloring and/or in Directive 94/36/EC of the European Parliament and of the Council of 30 June 1994 on coloring substances intended for use in foodstuffs.
To indicate the "quantitative composition" of the active substance(s) of the finished medicinal product, it is necessary, according to the pharmaceutical form concerned, to specify for each active substance the weight or the number of units of biological activity, or per unit dose, or per unit of weight or volume.
The quantities of active substances present in the form of compounds or derivatives are to be designated quantitatively by the total mass and, if necessary and relevant, by the mass of the active entity(ies) of the molecule.
For medicines that contain an active substance, the subject of an application for marketing authorization for the first time in a Member State, the declaration of the quantities of an active substance that is a salt or a hydrate must always be expressed in terms of mass of the entity(ies) in the molecule. The quantitative composition of all medicinal products subsequently authorized in the Member States must be declared in the same way as the active substance.
The units of biological activity are to be used for molecularly undefinable substances. In cases where the World Health Organization has defined an international unit of biological activity, this international unit will be followed. Where, on the other hand, no international unit has been defined, the units of biological activity must be expressed in such a way as to provide clear and unambiguous information on the activity of the substances, resorting where possible to the units of the European Pharmacopoeia.
3.2.2.2. Pharmaceutical development
This chapter deals with information on the development studies carried out to establish that the dosage form, formula, manufacturing process, container closure system, microbiological characteristics and instructions for use are appropriate for the intended use, indicated in the marketing authorization application dossier.
The studies in this chapter are distinguished from routine checks performed in accordance with the specifications. Critical formulation parameters and process characteristics that may affect batch reproducibility, efficacy and quality of the medicinal product should be identified and described. If appropriate, additional supporting data should be submitted with reference to the relevant chapters of Module 4 (Non-Clinical Study Reports) and Module 5 (Clinical Study Reports) of the Marketing Authorization Application dossier.
a) The compatibility of the active substance with the excipients, the basic physicochemical characteristics of the active substance which may influence the activity of the finished product, or the mutual compatibility of different active substances in case of combination products, must be documented.
b) The choice of excipients should be documented, especially in relation to their respective functions and concentrations.
c) A description of the development of the finished product must be presented, taking into account the proposed methods of administration and use.
d) Any overdoses in the formulation(s) must be justified.
e) As for the physicochemical and biological properties, all the parameters that influence the activity of the finished product must be treated and documented.
f) The selection and optimization of the manufacturing process as well as the differences between the manufacturing process(es) used to produce pilot clinical batches and the process used to manufacture the proposed finished medicinal product shall be presented.
g) The suitability of the container and closure system used to store, ship and use the finished product must be documented. Possible interaction between medicinal product and container should be taken into account.
h) The microbiological characteristics of the form of administration in relation to non-sterile and sterile products must comply with the European Pharmacopoeia and be documented according to its requirements.
i) In order to provide useful and appropriate labeling information, the compatibility of the finished product with the reconstitution diluent(s) or administration devices should be documented.
3.2.2.3. Manufacturing process of the finished medicinal product
a) The description of the manufacturing method, to be submitted together with the application for marketing authorization pursuant to article 8, paragraph 3, letter e) of this decree (article 8, paragraph 3, letter d) of the 2001 directive /83/EC), must be drafted in such a way as to provide an adequate summary of the nature of the operations performed.
To this end, it must contain at least
– an indication of the various manufacturing stages, including the control procedures and related acceptability criteria, which makes it possible to evaluate whether the processes used to create the pharmaceutical form could have given rise to alterations of the components,
– in the case of continuous manufacture, any indication of the precautions taken to ensure the homogeneity of the finished product,
– experimental studies to demonstrate the validity of the production process in cases where the production method used is non-standard or critical for the product,
– in the case of sterile medicinal products, details of the sterilization process and/or processes carried out under aseptic conditions,
– a detailed batch formula.
The name, address and responsibility of each manufacturer, including contractors, as well as all proposed production sites or facilities involved in manufacturing and testing shall be disclosed.
b) Information relating to product controls that may be carried out in the intermediate stages of manufacturing, in order to ascertain the consistency of the production process, shall be submitted.
These tests are indispensable to allow the control of the conformity of the medicinal product to the formula, when the applicant has exceptionally submitted an analytical test method of the finished product which does not involve the dosage of all the active substances (or of the excipient components which must meet the same requirements set for active substances).
This also applies when the controls carried out during manufacturing affect the quality control of the finished product, especially when the medicinal product is essentially defined by its manufacturing process.
c) The description, documentation and results of validation studies relating to the critical steps or critical dosages used during the manufacturing process shall be submitted.
3.2.2.4. Control of excipients
a) All materials used in manufacturing the excipient(s) shall be listed, indicating precisely where each material is used in the process. Information on the quality and control of such materials shall be provided, as well as information demonstrating that they conform to standards appropriate to their intended use.
In any case, the coloring substances must satisfy the requirements established by directives 78/25/EEC or 94/36/EEC. The dyes must also meet the purity criteria set out in the amended Directive 95/45/EC.
b) The specifications and related justifications must be specified for each excipient. Analytical procedures must be described and duly validated.
c) Particular attention should be paid to excipients of human or animal origin.
As for the specific measures for the prevention of the transmission of spongiform encephalopathies of animal origin, also for the excipients the applicant must demonstrate that the medicinal product is manufactured in compliance with the guidelines/guiding principles for interventions aimed at minimizing the risk of transmitting etiological agents of animal spongiform encephalopathies through medicinal products and their updates, published by the Commission in the Official Journal of the European Union.
Compliance with these guidelines/guiding principles can be demonstrated by submitting preferably a certificate of suitability in relation to the relevant European Pharmacopoeia monograph, or scientific data demonstrating such compliance.
d) New excipients.
For excipient(s) used for the first time in a medicinal product, or for a new route of administration, full information on manufacturing, characterization and controls should be provided – according to the active substance format described above, with references to supporting safety data, both non-clinical and clinical. A document must be submitted containing detailed chemical, pharmaceutical and biological information arranged in a format compliant with that of the chapter on the active substance(s) of module 3.
The information on the new excipient(s) can be presented as a stand-alone document in accordance with the format described in the previous paragraph. If the applicant is different from the manufacturer of the new excipient, this separate document must be made available to the applicant for presentation to the competent authorities.
Further information on the toxicity studies relating to the new excipient should be presented in module 4 of the dossier.
Clinical studies should be presented in module 5.
3.2.2.5. Checking the finished medicine
For the purposes of checking the finished medicinal product, a medicinal product manufacturing batch means all the units of a pharmaceutical form which come from the same initial quantity and have been subjected to the same series of manufacturing and/or sterilization operations or , in the case of a continuous production process, the set of manufacturing units in a given period of time.
Unless duly justified, the maximum tolerances in active substance content in the finished product cannot exceed 5% at the time of manufacture.
Detailed information on the specifications, justifications (release and validity period) of the choice, methods of analysis and their validation must be provided.
3.2.2.6. Reference standards or materials
If not previously provided for in the active substance section, the preparations and reference standards used for testing the finished medicinal product should be identified and described in detail.
3.2.2.7. Container and closure of the finished medicine.
A description of the container and closure(s) must be provided, including the identity of all immediate packaging materials and their specifications, in turn accompanied by description and identification. If necessary, non-pharmacopoeia methods (with validation) should be exposed.
Only a brief description should be submitted for non-functional outer packaging materials, and additional information is required for functional outer packaging materials.
3.2.2.8. Stability of the finished medicinal product
a) The types of studies performed, the protocols used and the results obtained should be summarized;
b) The detailed results of the stability studies, including information on the analytical procedures used to compile the data and the validation of these procedures, shall be presented in an appropriate format; in the case of vaccines, information on cumulative stability should be provided where appropriate;
c) The stability protocol and the commitments undertaken regarding stability to be fulfilled after approval must be presented.
4. MODULE 4: NON-CLINICAL REPORTS
4.1. Format and presentation.
The general setting of module 4 is the following:
- Index
– Study reports
– Pharmacology
– Primary pharmacodynamics
– Secondary pharmacodynamics
– Safety Pharmacology
– Pharmacodynamic interactions
– Pharmacokinetics
– Analytical methods and validation reports
– Absorption
– Distribution
– Metabolism
– Excretion
– Pharmacokinetic interactions (non-clinical)
– Other pharmacokinetic studies
– Toxicology
– Toxicity for single administration
– Toxicity for repeated administration
– Genotoxicity
– In vitro
– In vivo (including supporting toxicokinetic 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 offspring (juvenile animals) are dosed and/or evaluated
– Local tolerance
– Other toxicological studies
– Antigenicity
– Immunotoxicity
– Mechanism studies
- Dependence
– Metabolites
– Impurities
- Other
- Bibliography
4.2. Basic principles and requirements
Particular attention should be paid to the following items.
(1) Toxicological and pharmacological tests must highlight:
a) the potential toxicity of the product, its possible harmful or unwanted toxic effects under the conditions of use envisaged in man, which must be evaluated according to the pathological state;
b) the pharmacological properties of the product in relation to the proposed use for humans from a quantitative and qualitative point of view. All results must be reliable and suitable for generalisation. For this purpose, where appropriate, mathematical and statistical procedures will be applied, both in the elaboration of experimental methods and in the evaluation of the results. It is also necessary for the clinician to be shown the therapeutic and toxicological potential of the product.
(2) In the case of medicinal products of biological origin, such as immunological medicinal products and medicinal products derived from human blood or plasma, the requirements of this module may require adaptation to individual products; for this reason the applicant must justify the program of the tests performed.
In defining this programme, the following elements will be taken into account:
all tests involving repeated administration of the product must take into account the possible induction of antibodies and interference from antibodies;
evaluation of the opportunity to examine reproductive function, embryo-foetal and perinatal toxicity, mutagenic and carcinogenic potential. In case the offending constituents are not the active substance(s), the study can be replaced by validation of the elimination of the constituents in question.
(3) The toxicity and pharmacokinetics of an excipient used for the first time in the pharmaceutical field should be examined.
(4) If there is a possibility of significant degradation of the medicinal product during storage, the toxicology of the degradation products should be investigated.
4.2.1. Pharmacology
The pharmacology study must be conducted following two distinct approaches.
– In the first, the actions relating to the proposed therapeutic use must be investigated and adequately described. Where possible, recognized and validated determinations, both in vivo and in vitro, should be used. New experimental techniques must be described in detail, so that they can be repeated. Results should be presented in quantitative form, using e.g. dose-effect curves, time-effect curves, etc. Comparisons with data relating to one or more substances with similar therapeutic action should be made whenever possible.
– In the second, the applicant must investigate the potential undesirable pharmacodynamic effects of the substance on physiological functions. The investigations must be performed with exposures within the prescribed therapeutic limits and above them. The experimental techniques, where they are not those usually used, must be described in detail so that they can be repeated and the experimenter must demonstrate their validity. Any suspected change in responses resulting from repeated administration of the substance should be investigated.
With regard to the pharmacodynamic interaction of medicinal products, tests on combinations of active substances can arise from pharmacological premises or from indications of therapeutic effect. In the first case, the pharmacodynamic study must highlight the interactions that make the combination itself recommendable for therapeutic use. In the second case, since the scientific justification of the association must be provided by the therapeutic experimentation, it must be verified whether the effects expected from the association are verifiable on the animal, and at least check the importance of the side effects.
4.2.2. Pharmacokinetics
By pharmacokinetics we mean the study of the fate that the active substance and its metabolites undergo in organisms. It includes the study of absorption, distribution, metabolism (biotransformation) and excretion of these substances.
The study of these different phases can be carried out above all with physical, chemical or possibly biological methods, as well as by detecting the effective pharmacodynamic activity of the substance itself.
Information relating to distribution and elimination is required in all cases where such indications are indispensable for establishing the dose for humans, as well as for chemotherapeutic substances (antibiotics, etc.) and for those products whose use is based on non-pharmacodynamic effects (e.g. numerous diagnostic means, etc.).
In vitro studies can be favored by the possibility of using human material to compare it with animal material (protein binding, metabolism, drug-drug interaction). Pharmacokinetic testing is required for all pharmacologically active substances. In the case of new combinations of substances known and studied in accordance with the provisions of this Directive, pharmacokinetic investigations may not be required if the toxicological tests and therapeutic trials justify it.
The pharmacokinetic program should be designed to allow comparison and extrapolation between humans and animals.
4.2.3. Toxicology
a) Toxicity for single administration
A single administration toxicity test is a qualitative and quantitative study of the toxic reactions which may result from a single administration of the active substance or substances contained in the medicinal product, in the proportions and in the chemical-physical state in which they are present in the product itself. The single dose toxicity test shall be performed in accordance with the relevant guidelines published by the Agency.
b) Toxicity for repeated administrations
Toxicity tests for repeated administrations are used to highlight the functional and/or anatomical-pathological alterations resulting from repeated administration of the substance or combination of active substances under test, and to establish the relationship of these alterations with the dosage.
In general it is useful that two trials be carried out, one short-term, lasting between two and four weeks, and one long-term, depending on the conditions of clinical use. The latter evidence serves to describe potentially adverse effects that need to be looked out for in clinical trials. The duration is set out in the relevant guidelines/guidelines published by the Agency.
c) Genotoxicity
The study of the mutagenic and clastogenic potential aims to reveal any changes produced by a substance on the genetic material of individuals or cells. Mutagenic substances can constitute a health hazard, because exposure to them can induce germ line mutations, with the possibility of congenital dysfunctions and the risk of somatic mutations, including carcinogenic ones. These studies are mandatory for any new substance.
d) Carcinogenicity Experiments aimed at revealing carcinogenic effects are usually required:
1. These studies must be performed for each drug whose clinical use is expected for a long period of the patient's life, whether constant or repeated intermittently.
2. These studies are recommended for some medicinal products, where there are concerns of carcinogenic effects, for example from products of the same class or of a similar structure, or from findings from studies on repeated dose toxicity.
3. Studies of unequivocally genotoxic compounds are not necessary, because they are considered cross-species carcinogens and risk factors for humans. If a drug of this type is to be administered chronically to humans, a chronic study may be necessary to detect early carcinogenic effects.
e) Reproductive and developmental toxicity
Investigations into any harmful effects on male and female fertility as well as on the offspring must be carried out with adequate tests.
They include studies of the effects on adult male or female fertility, studies of toxic and teratogenic effects at all stages of development, from conception to sexual maturity, as well as studies of the latent effects, when the medicinal product under test is administered to the female during pregnancy .
Failure to carry out these tests must be duly justified.
Depending on the medicinal product's indications for use, further developmental studies may be permitted when administering the medicinal product to offspring.
Embryo-foetal toxicity studies should normally be conducted in two mammalian species, one of which is a non-rodent. Peri- and postnatal studies should be conducted in at least one species. Where a given species exhibits a metabolism similar to humans for a given medicinal product, it would be appropriate to include this species in the trial. One of the species used should also correspond to the species used for the repeated dose toxicity studies.
The study design is determined taking into account the state of scientific knowledge at the time the application is submitted.
f) Local tolerance
Local tolerance studies should identify whether medicinal products (both active substances and excipients) are tolerated at points of the body that may come into contact with the medicinal product following its administration in clinical use. The tests carried out must guarantee a distinction between the mechanical effects of administration, or a purely physico-chemical action of the product, and the toxicological or pharmacodynamic effects.
Local tolerance tests should be performed with the preparation developed for human use, using the vehicle and/or excipients to treat the control group(s). If necessary, positive controls and reference substances should be included.
Local tolerance trials (choice of species, duration, frequency, route of administration, doses) must be designed taking into account the problem to be investigated and the administration conditions proposed for clinical use. If relevant, the reversibility of local lesions should be checked.
Animal studies may be replaced by validated in vitro tests, provided that the test results are of equivalent quality and utility for the safety assessment.
For chemicals applied to the skin (e.g. cutaneous, rectal, vaginal) the sensitizing potential should be assessed by at least one of the currently available methods (guinea pig test or local lymph node test).
5. MODULE 5: CLINICAL STUDY REPORTS
5.1. Format and presentation
The general setting of module 5 is the following:
– Index of clinical study reports
– Tabular listing of all clinical studies
Clinical study reports
– Reports of biopharmaceutical studies
– Reports of bioavailability studies
– Reports of comparative studies of bioavailability and bioequivalence
– Reports of in vitro-in vivo correlation studies
– Reports of bioanalytical and analytical methods
Reports of studies in the field of pharmacokinetics with the use of human biomaterials
– Reports of plasma protein binding studies
– Reports of hepatic metabolism and interaction studies
– Reports of studies with use of other human biomaterials
Reports of human pharmacokinetic studies
– Reports of pharmacokinetic and initial tolerability studies in healthy subjects
– Reports of pharmacokinetic and initial tolerability studies on patients
– Reports of pharmacokinetic studies on intrinsic factor
– Reports of pharmacokinetic studies on extrinsic factor
– Reports of population pharmacokinetic studies
Reports of human pharmacodynamic studies
– Reports of pharmacodynamic and pharmacokinetic/pharmacodynamic studies in healthy subjects
– Reports of pharmacodynamic and pharmacokinetic/pharmacodynamic studies on patients
Reports of studies on efficacy and safety
– Reports of controlled clinical trials relating to the claimed indication
– Reports of uncontrolled clinical trials
– Analysis reports of data from more than one study, including formal integrated analyses, meta-analyses and linkage analyses
– Other study reports
Post-market experience reports
- Bibliography
5.2. Content fundamental principles and requirements
Particular attention should be paid to the following items.
a) The clinical information to be provided pursuant to article 8, paragraph 3 letter l), number 3 of this decree (article 8, paragraph 3, letter i) of Directive 2001/83/EC) and article 10, paragraph 1 of this decree (article 10, paragraph 1, of directive 2001/83/EC) must allow for the formation of a sufficiently well-founded and scientifically valid opinion on the compliance of the medicinal product with the criteria established for the release of the marketing authorisation. For this reason it is essential that the results of all the clinical trials carried out, both favorable and unfavourable, are communicated.
b) Clinical trials must always be preceded by sufficient toxicological and pharmacological tests performed on animals in accordance with the provisions of module 4 of this annex. The investigator must be aware of the conclusions of the pharmacological and toxicological examination and therefore the applicant must at least provide him with the investigator's file, including all relevant information known before the execution of the clinical trial, including any chemical, pharmacological and biological data as well as toxicological, pharmacokinetic and pharmacodynamic data derived from animals, and the results of previous clinical trials with data capable of justifying the type, size and duration of the proposed trial; complete pharmacological and toxicological reports must be provided upon request. In the case of material of human or animal origin, all necessary means must be used to ensure that the material is free from the transmission of infectious agents before the start of the experiment.
c) Marketing authorization holders shall ensure that important clinical trial documents (especially case report forms), other than subject medical records, are maintained by the data owners:
– for at least 15 years after completion or discontinuation of the trial,
– for at least 2 years after the granting of the most recent marketing authorization in the European Community and if no marketing applications are pending or envisaged in the European Community,
– for at least 2 years after the clinical development of the investigational product is officially discontinued.
The medical records of the subjects will be kept in accordance with the applicable legislation and for the maximum period foreseen by the hospital, institute or private laboratory.
However, the documents can be kept for longer periods, if required by the applicable regulatory requirements or by an agreement with the sponsor, who is responsible for notifying the hospital, institute or laboratory when it is no longer necessary to keep the documents. documents.
The sponsor or other data owner maintains all trial documentation for the duration of product authorization. This documentation includes: the protocol, including the rationale, objectives and statistical model, as well as the methodology for carrying out the experiment, with the conditions in which it was carried out together with detailed indications regarding: the product being tested , the reference medicinal product and/or placebo used; standard operating procedures; all written opinions on the protocol and procedures; the investigator's file; the case report forms for each trial subject; the final report; any certificate(s) verifying the study. The sponsor or subsequent owner must retain the final report for a period of five years after the medicinal product's authorization has expired.
Furthermore, for trials carried out in the European Community, the holder of the marketing authorization must take further measures to file the documentation in accordance with the provisions of Legislative Decree 24 June 2003, n. 211 (directive 2001/20/EC and related guidelines/detailed implementation guidelines).
All changes in data ownership must be documented.
All data and documents must be immediately available upon request by the competent authorities.
d) The information relating to each clinical trial must contain sufficient detail to enable an objective judgment to be formed, such as:
– the protocol, including the rationale, objectives and statistical model, as well as the methodology of the experiment, the conditions in which it was carried out, together with detailed indications regarding the product being tested
– any certificate(s) verifying the study
– list of the investigator(s); for each investigator, name, address, titles, qualifications and clinical duties must be provided, as well as where the test was performed and separate information must be submitted for each individual patient, including the case report form for each subject tested trial
– the final report signed by the investigator and, in the case of multi-centre trials, by all investigators or the coordinating (principal) investigator.
e) The detailed data of the clinical trials referred to above must be transmitted to the competent authorities. However, in agreement with the latter, the applicant may leave out part of the above information. However, complete documentation will be provided immediately upon request.
Finally, the investigator will have to draw his own conclusions by pronouncing, within the framework of the trial, the safety of the product under normal conditions of use, tolerance, efficacy, with any useful clarification regarding indications and contraindications, dosage and average duration. of the treatment, as well as possibly the special precautions for use and the clinical symptoms for overdose. The principal investigator presenting the results of a multicentre study must formulate in his conclusions an opinion on behalf of all the centers regarding the safety and efficacy of the medicinal product under study.
f) Clinical observations should be summarized for each trial indicating
1) the number of subjects treated, broken down by gender;
2) the choice and composition by age of the groups of patients undergoing trials and the comparative trials;
3) the number of patients who interrupted the trial before the end, as well as the reasons for the interruption;
4) in the case of controlled trials, carried out under the conditions indicated above, if the control group
– has not undergone any therapeutic treatment
– has received a placebo
– have received another medicine with a known effect
– has received non-pharmacological treatment
5) the frequency of the observed negative side effects;
6) clarifications on subjects at greater risk, for example the elderly, children, pregnant or menstruating women, or subjects whose particular physiological or pathological state must be taken into consideration;
7) parameters or criteria for assessing effectiveness and the results expressed according to these parameters;
8) the statistical evaluation of the results, when it is consequent to the programming of the tests, and the variables involved.
g) The investigator must also always report the observations made on:
1) Any phenomena of addiction, drug dependence or withdrawal syndrome;
2) established interactions with other drugs administered at the same time;
3) the criteria by which certain patients were excluded from trials;
4) any cases of death that occurred during the trial or in the subsequent period.
h) The information relating to a new combination of medicinal substances must be identical to that prescribed for a new medicinal product and justify the combination from the point of view of safety and efficacy.
i) The total or partial lack of data must be justified. When unexpected effects occur during trials, further preclinical, toxicological and pharmacological tests must be performed and analysed.
j) In the case of medicinal products intended for prolonged administration, information on any changes that have occurred in the pharmacological action after repeated administration, as well as on the establishment of the long-term dosage, must be provided.
5.2.1. Biopharmaceutical study reports
Reports on comparative studies of bioavailability, bioequivalence, as well as reports of in vitro and in vivo correlation studies and bioanalytical and analytical methods should be submitted.
Where necessary, an assessment of bioavailability should also be carried out to demonstrate bioequivalence between medicinal products referred to in Article 10(1)(a).
5.2.2. Reports on studies carried out in the pharmacokinetic field with the use of human biomaterials
For the purposes of this Annex, human biomaterials means proteins, cells, tissues and related materials of human origin used in vitro or ex vivo to evaluate the pharmacokinetic properties of pharmaceutical substances.
In this respect, reports on studies of plasma protein binding, hepatic metabolism and interaction of active substances, as well as studies using other human biomaterials should be submitted.
5.2.3. Reports of human pharmacokinetic studies
a) The following pharmacokinetic characteristics shall be described:
– absorption (speed and quantity),
– distribution,
– metabolism,
– excretion.
Clinically significant characteristics should be described, including the implications of the kinetic data on the dosing regimen, particularly for patients at risk, as well as differences between humans and the animal species used in the preclinical studies.
In addition to standard multiple-sample pharmacokinetic studies, small sampling-based population pharmacokinetic analyzes during clinical trials may also be helpful in addressing issues of the contribution of intrinsic and extrinsic factors to variability in the pharmacokinetic dose/response relationship. Reports of pharmacokinetic and initial tolerability studies in healthy subjects and patients, pharmacokinetic study reports evaluating intrinsic and extrinsic factors, as well as population pharmacokinetic study reports shall be submitted.
b) If the medicinal product is to be used correctly simultaneously with other medicinal products, information on joint administration tests carried out to highlight any modification of the pharmacological action must be provided.
Pharmacokinetic interactions between the active substance and other medicinal products or substances should be investigated.
5.2.4. Reports of human pharmacodynamic studies
a) The pharmacodynamic action correlated with efficacy should be demonstrated, including
– the dose-response relationship and its development over time,
– the justification for the dosage and conditions of administration,
– if possible, the methods of action.
The pharmacodynamic action unrelated to efficacy should be described.
Evidence of pharmacodynamic effects in humans is not sufficient by itself to draw conclusions about a particular potential therapeutic effect.
b) If the medicinal product is normally to be used concomitantly with other medicinal products, information on the joint administration tests carried out to highlight any modification of the pharmacological action must be provided.
Pharmacodynamic interactions between the active substance and other medicinal products or substances should be investigated.
5.2.5. Reports of efficacy and safety studies
5.2.5.1. Reports of controlled clinical trials relating to the claimed indication
In general, clinical trials should be conducted in the form of 'controlled clinical trials' if possible, randomized and if appropriate against placebo and against a known medicinal product of recognized therapeutic value; each different study design must be justified. The treatment of the control groups varies on a case-by-case basis and also depends on ethical considerations and the therapeutic area; thus it can sometimes be more interesting to compare the effectiveness of a new medicine with that of an established medicine with proven therapeutic value, rather than with the effect of a placebo.
(1) As far as possible, but especially when it comes to trials in which the effect of the medicinal product is not objectively measurable, the necessary means must be put in place to avoid bias, including by resorting to randomization and methods in Czech.
(2) The trial protocol should include a full description of the statistical methods to be used, the number and reasons justifying the inclusion of patients (including study power calculations), the significance level to be used and the description of the statistical unit. Measures taken to avoid bias, especially methods of randomisation, should be documented. The participation of a large number of patients in a trial should in no case be considered as a substitute for an adequately controlled trial.
The safety data should be verified taking into account the guidelines/guidelines published by the Commission, paying particular attention to events resulting in changes in posology or the need for simultaneous administration of medicinal products, serious adverse events, events leading to discontinuations and deaths. Patients or groups of patients at greatest risk should be identified and particular attention should be paid to potentially vulnerable patients who may be present in small numbers, e.g. children, pregnant women, vulnerable elderly people with evident abnormalities of metabolism or excretion, etc. The implication of the safety assessment on the possible uses of the medicinal product should be described.
5.2.5.2. Uncontrolled clinical trial reports, data analysis reports from more than one study, and other clinical trial reports.
You must provide these relationships.
5.2.6. Post-marketing experience reports
If the medicinal product is already authorized in third countries, information on adverse reactions to this medicinal product and to other medicinal products containing the same active substance(s), possibly with reference to usage rates, should be provided.
5.2.7. Forms for «case reports» the report of trials and lists of individual patients
When submitted in accordance with the relevant guidelines published by the Agency, case report forms and individual patient data lists should be provided and submitted in the same order as clinical study reports and categorized by study.
PART II
SPECIFIC MARKETING AUTHORIZATION DOSSIERS – SPECIFIC REQUIREMENTS
Some medicinal products have specific characteristics such that all the requirements relating to the application for marketing authorisation, set out in Part I of this Annex, need to be adapted. In order to take account of these particular situations, applicants must comply with an adequate and adapted presentation of the dossier.
1. WELL KNOWN MEDICAL USE
For medicinal products whose active substance(s) has/have had a «well-known medical use» within the meaning of article 11 of this decree (article 10 bis of directive 2004/27/EC amending directive 2001/ 83) and have recognized efficacy and an acceptable level of safety, the following specific rules apply.
The applicant submits forms 1, 2 and 3 described in part I of this annex.
As for modules 4 and 5, a detailed scientific bibliography must address the clinical and non-clinical characteristics.
To prove the well-known medical use, the following rules apply:
a) The factors to be considered in establishing that the components of a medicinal product are of well-known medical use are
– the length of time during which a substance has been used,
– the quantitative aspects of the use of the substance,
– the degree of scientific interest in the use of the substance (based on the published scientific literature), e
– the consistency of scientific assessments.
Therefore, different times may be required to establish the well-known medical uses of different substances. In any case, however, the minimum period necessary to establish whether a component of a medicinal product has a well-known medical use is at least 10 years from the first systematic and documented use in the Community of the substance in question as a medicinal product.
b) The documentation submitted by the applicant shall cover every aspect of the safety and/or efficacy assessment and shall contain, or be based on, a review of the relevant literature, including pre- and post-marketing studies and published scientific contributions relating to to epidemiological studies, in particular of a comparative type. All existing documentation, whether favorable or unfavourable, must be submitted. With regard to the rules on "well-known medical use", it is in particular necessary to clarify that the "bibliographic references" to other evidentiary sources (post-marketing studies, epidemiological studies, etc.) and not only to data relating to tests and trials can provide valid evidence of the safety and efficacy of a product if an application satisfactorily explains and justifies the use of such sources of information.
c) Particular attention should be paid to any gaps in the information and explain why the efficacy of the product can be considered acceptable in terms of safety and/or efficacy despite the absence of some studies.
d) Non-clinical and/or clinical reviews must explain the relevance of any data presented relating to a product other than the intended product. It has to be judged whether this product can be considered similar to the one to be authorized despite the existing differences.
e) Post-marketing experience gained with other products containing the same components is of particular importance and applicants should attach particular importance to it.
2. ESSENTIALLY SIMILAR MEDICINAL PRODUCTS
a) Applications pursuant to article 13 of this decree (article 10 quater of directive 2001/83/EC as amended by directive 2004/27/EC) must contain the data referred to in modules 1, 2 and 3 of part I of this Annex, provided that the original marketing authorization holder has allowed the applicant to refer to the content of his Modules 4 and 5.
b) Applications pursuant to article 10 of this decree (article 10 of directive 2001/83/EC as amended by directive 2004/27/EC generic medicines) must contain the data referred to in forms 1, 2 and 3 of part I of this annex, together with data demonstrating bioavailability and bioequivalence with the original medicinal product, provided that the latter is not a medicinal product of biological origin (see part II, module 4, similar medicinal products of biological origin).
For these products, the clinical and non-clinical overviews and summaries should particularly highlight the following elements:
– the reasons why the essentially similar nature is asserted;
– a summary of the impurities present in batches of the active substance(s) and in the finished medicinal product (and, if relevant, the breakdown products formed during storage), which are proposed to be used in the product to be co-marketed an evaluation of such impurities;
– an evaluation of the bioequivalence studies or the reason why such studies were not performed with reference to the guideline "Bioavailability and bioequivalence study";
– an update on the published literature affecting the substance and the application in question. For this purpose, articles from recognized journals can be commented on;
– any statement reported in the summary of product characteristics not known or not inferred from the properties of the medicinal product and/or its therapeutic category must be discussed in the non-clinical/clinical reviews/summaries and must be substantiated by advertising literature and/or complementary studies ;
– possibly, additional data demonstrating the equivalence in terms of safety and efficacy of different salts, esters or derivatives of an authorized active substance, to be provided by the applicant claiming essentially similar nature to the existing active substance.
3. ADDITIONAL DATA REQUIRED IN SPECIFIC SITUATIONS
If the active substance of an essentially similar medicinal product contains the same therapeutically active moiety of the original authorized medicinal product associated with a different salt/ester compound/derivative, it must be demonstrated that there is no change in the pharmacokinetics of the active moiety, pharmacodynamics and/or toxicity which could change the safety/efficacy profile. If this does not occur, this combination should 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 administered by different routes or in different doses or with a different posology, the results of the relevant toxicological, pharmacological and/or clinical trials must be provided.
4. MEDICINAL PRODUCTS OF SIMILAR BIOLOGICAL ORIGIN
The provisions referred to in article 10, paragraph 7 of this decree (article 10, paragraph 4 of directive 2001/83/EC as amended by directive 2004/27/EC) may not be sufficient in the case of medicinal products of biological origin. If the information required in the case of essentially similar products (generic medicines) does not allow demonstrating that two medicinal products of biological origin are similar, additional data, particularly relating to the toxicological and clinical profile, must be provided.
If a biological medicinal product, as defined in Part I, paragraph 3.2 of this Annex, which refers to an original medicinal product which had obtained a marketing authorization in the Community, is the subject of a marketing authorization application from an independent applicant after the expiry of the data protection period, the following setting should be followed.
– The information to be provided should not be limited to modules 1, 2 and 3 (pharmaceutical, chemical and biological data), supplemented by bioequivalence and bioavailability data. The type and amount of data to be added (toxicological, other non-clinical data and appropriate clinical data) should be determined on a case-by-case basis according to the relevant scientific guidelines/guidelines.
– Given the diversity of medicinal products of biological origin, the need for certain studies under Modules 4 and 5 must be determined by the competent authority, taking into account the specific characteristics of each individual medicinal product.
The general principles to be applied are contained in guidelines/guidelines published by the Agency, which take into account the characteristics of the biological medicinal product concerned. If the originally authorized medicinal product has more than one indication, the efficacy and safety of the medicinal product claimed to be similar must be confirmed or, if necessary, demonstrated separately for each of the claimed indications.
5. FIXED ASSOCIATION MEDICINAL PRODUCTS
Applications pursuant to article 12 of this decree (article 10 ter of directive 2001/83/EC as amended by directive 2004/27/EC) must refer to new medicinal products composed of at least two active substances not previously authorized as a combination medicinal product fixed. For these applications, you need to submit a complete dossier (forms 1 to 5) for fixed combination medicines. Where possible, information on manufacturing sites and the safety assessment for adventitious agents should be submitted.
6. DOCUMENTATION FOR APPLICATIONS IN EXCEPTIONAL CIRCUMSTANCES
When, as provided for by article 33 of this decree (article 22 of directive 2001/83/EC), the applicant can demonstrate that he is unable to provide complete data on the efficacy and safety of the medicinal product under normal conditions of use in quantity
– the cases for which the medicinal products in question are indicated are so rare that the applicant cannot reasonably be expected to provide complete evidence, or
– the current stage of development of scientific knowledge does not allow for the collection of complete information, or
– generally accepted principles of medical ethics prohibit the collection of such information,
the marketing authorization can be granted under some specific conditions:
– the applicant must complete a given study program within a time period set by the competent authority; based on the results obtained, a new evaluation of the risk/benefit profile is carried out,
– the medicinal product in question must be sold only on medical prescription and in some cases its administration can only take place under strict medical supervision, possibly in a hospital environment and, in the case of radiopharmaceuticals, by an authorized person,
– the package leaflet and all other medical information must draw the attention of the attending physician to the fact that the knowledge available on the medicinal product in question is not yet sufficient in certain respects.
7. MIXED MARKETING AUTHORIZATION APPLICATIONS
Mixed Marketing Authorization Applications means Marketing Authorization Applications where Forms 4 and/or 5 consist of a combination of non-clinical and/or limited clinical study reports performed by the applicant, and bibliographic references . The composition of all the other modules complies with the indications of part I of this annex. The competent authority decides on a case-by-case basis whether to accept the format presented by the applicant.
PART III
PARTICULAR MEDICINAL PRODUCTS
This part contains the specific provisions relating to the nature of properly identified medicinal products.
1. MEDICINAL PRODUCTS OF BIOLOGICAL ORIGIN
1.1. Medicinal products derived from plasma
For medicinal products derived from human blood or plasma and by way of derogation from the provisions of module 3, the requirements in the "Information concerning starting materials and subsidiary materials" for starting materials composed of human blood/plasma may be replaced by a plasma master file certified under this part.
a) Principles
For the purposes of this attachment
– Plasma master file means a stand-alone documentation separate from the marketing authorization dossier, which provides any detailed information pertinent to the characteristics of all human plasma used as raw material and/or subsidiary for manufacturing of intermediate fractions/subfractions components of the excipient and of the active substance/s, which are part of the medicines or medical devices referred to in the legislative decree of 24 February 1997, n. 46 as amended by Legislative Decree 31 October 2002, n. 271 (directive 2000/70/EC of the European Parliament and of the Council, of 16 November 2000, which modifies directive 93/42/EEC of the Council as regards medical devices incorporating stable derivatives of human blood or plasma). Each human plasma fractionation/processing center or facility should maintain and maintain the set of detailed and pertinent information referenced in the plasma master file.
– The plasma master file must be presented to the European Agency or to the competent national authority – the Italian Medicines Agency (AIFA) – according to the procedures indicated by the same by the person requesting the marketing authorization or by the holder of such authorisation. If the applicant and the holder of such an authorization are not the same as the holder of the plasma master file, the plasma master file shall be made available to the applicant or the authorization holder for submission to the competent authority. However, the Applicant or Marketing Authorization Holder assumes responsibility for the medicinal product.
– The competent authority evaluating the marketing authorization waits for the European Agency to issue the certificate before taking a decision on the application.
– Each marketing authorization dossier, which contains a human plasma derivative as a component, must refer to the plasma master file corresponding to the plasma used as starting/subsidiary material.
b) Content
In accordance with Article 109 of Directive 2001/83/EC as amended by Directive 2002/98/EC as it relates to donor requirements and donation testing, the plasma master file must contain information on the plasma used as raw/subsidiary material, dealing specifically with:
(1) Plasma origin
(i) information on blood/plasma collection centers or establishments, with related inspections and authorizations, and epidemiological data on blood-borne infections.
(ii) information on the centers or establishments where tests on donations and plasma pools are performed, with related inspections and authorisations.
(iii) selection/exclusion criteria for blood/plasma donors.
(iv) an operational system that allows the path of each donation to be identified from the blood/plasma collection plant to the finished products and vice versa.
(2) Plasma quality and safety
(i) compliance with European Pharmacopoeia monographs.
(ii) tests on blood/plasma donations and mixtures to detect infectious agents, with related information on the method of analysis and, in the case of "plasma pool", validation data of the tests used.
(iii) technical characteristics of the blood and plasma collection bags, with relative information on the anticoagulant solutions used.
(iv) plasma storage and transport conditions.
(v) procedures relating to inventory keeping and/or the quarantine period.
(vi) characterization of the «plasma pool».
(3) System operating between the manufacturer of plasma-derived medicinal products and/or plasma fractionator/processor on the one hand, and blood/plasma collection and testing centers or establishments on the other hand, which defines the conditions of their mutual interactions and the established specifications.
The plasma master file must also provide a list of the medicinal products relating to it - whether they have obtained marketing authorization or whether the authorization process is in progress - including the medicinal products referred to in Legislative Decree .vo 24 June 2003, n. 211, article 2 (article 2 of directive 2001/20/EC of the European Parliament and of the Council concerning the application of good clinical practice in the execution of clinical trials of medicines for human use).
c) Evaluation and certification
– For medicines that have not yet been authorised, the person applying for marketing authorization submits a complete dossier to a national competent authority, in any manner indicated by the same, to which he attaches a separate plasma master file, if it does not already exist .
– The European Agency subjects the plasma master file to scientific and technical evaluation. A positive assessment results in the issue of a certificate of conformity with Community legislation of the plasma master file, to which the assessment report will be attached. This certificate applies throughout the Community. For the plasma master file certification procedure, reference is made to the guideline CPMP/BWP/4463/03 of February 26, 2004.
– Plasma master file will be updated and recertified every year.
– Subsequent changes to the terms of a plasma master file shall follow the evaluation procedure set out in Regulation (EC) No 542/95 of the Commission concerning the examination of the modifications of the terms of an authorization to place on the market which falls under the regulation (EEC) n. 726/2004. The conditions for the assessment of these modifications are established by Regulation (EC) No. 1085/2003.
– In a second step with respect to the first, second, third and fourth indents, the competent authority that will grant or has granted the marketing authorization shall take into account the certification, recertification or modification of the relevant plasma master file to the medicinal product(s) concerned.
– By way of derogation from the provisions of the second indent of this letter (evaluation and certification), if a plasma master file corresponds only to medicinal products derived from blood/plasma whose marketing authorization is limited to a single Member State, the scientific and technical evaluation of that plasma master file shall be performed by the competent national authority of that Member State.
1.2. Vaccines
For vaccines for human use, by way of derogation from the provisions of Module 3 on 'Active Substance(s)', the following requirements apply if based on the use of a vaccine antigen master file system.
The marketing authorization application dossier for a vaccine other than human influenza vaccine must contain a vaccine antigen master file for each antigen that is an active substance of the vaccine.
a) Principles.
For the purposes of this attachment
– Vaccine Antigen Master File is a self-contained part of the marketing authorization application dossier for a vaccine, which contains all relevant biological, pharmaceutical and chemical information relating to each active substance which is part of the medicine. The separate part may be common to one or more monovalent and/or polyvalent vaccines presented by the same applicant or marketing authorization holder.
– A vaccine may contain one or more distinct antigens. There are as many active substances in a vaccine as there are vaccine antigens.
– A multivalent vaccine contains at least two distinct antigens intended to prevent one or more infectious diseases.
– A monovalent vaccine contains a single antigen intended to prevent a single infectious disease.
b) Content.
The Vaccine Antigen Master File contains the following information from the corresponding part (active substance) of Module 3 on Quality Data described in Part I of this Annex.
Active substance
1. General information, including compliance with the relevant European Pharmacopoeia monograph.
2. Information on the manufacture of the active substance: Under this heading should include the manufacturing process, information on raw materials and subsidiary materials, specific measures on safety assessments for TSEs and adventitious agents, facilities and equipment.
3. Characterization of the active substance
4. Quality control of the active substance
5. Standards and reference materials
6. Container and closure system of the active substance
7. Stability of the active substance.
c) Evaluation and certification.
– For new vaccines, containing a new antigen, the applicant shall submit to the national competent authority a complete marketing authorization application dossier including all vaccine antigen master files corresponding to each individual antigen which is part of the of the new vaccine, if no master file exists yet for the single vaccine antigen. The European Agency will carry out a scientific and technical evaluation of each vaccine antigen master file. In the event of a positive evaluation, it will issue a certificate of conformity to European legislation for each vaccine antigen master file, to which the evaluation report will be attached. This certificate is valid throughout the Community. For the certification procedure of the vaccine antigen master file, reference is made to the guideline EMEA/CPMP/4548/03/Final of 26 February 2004.
– The provisions of the first indent also apply to all vaccines consisting of a new combination of vaccine antigens, whether or not one or more of these antigens are part of vaccines already authorized in the Community.
– Changes to the content of a Vaccine Antigen Master File for a vaccine authorized in the Community are subject to scientific and technical evaluation by the Agency in accordance with the procedure set out in Regulation (EC) No 1924/2006. 1085/2003 of the Commission. In the event of a positive evaluation, the Agency issues a certificate of conformity with Community legislation relating to the vaccine antigen master file. This certificate is valid throughout the Community.
– Notwithstanding the provisions of the first, second and third indents of this letter (evaluation and certification), where a vaccine antigen master file corresponds only to a vaccine whose marketing authorization has not been/will not be issued in accordance with a Community procedure, and the authorized vaccine also includes vaccine antigens that have not been evaluated in accordance with a Community procedure, the scientific and technical evaluation of this vaccine antigen master file and its subsequent modifications shall be performed by the competent national authority which has issued the marketing authorisation.
– In a second step with respect to the provisions of the first, second, third and fourth indents, the competent authority which will issue or has granted the marketing authorisation, will take into account the certification, recertification or modification of the master file of the vaccine antigen related to the medicinal product(s) concerned.
2. RADIO PHARMACEUTICALS AND PRECURSORS
2.1. Radiopharmaceuticals
For the purposes of this chapter, the applications for the drugs referred to in articles 6, paragraph 4 and 9 of this decree (article 6, paragraph 2, and article 9 of directive 2001/83/EC) must consist of a complete dossier, which must understand the specific clarifications that follow
Form 3
a) In the case of a radiopharmaceutical kit which must be radiolabelled after supply by the manufacturer, the active substance is the part of the formulation intended to carry or bind the radionuclide. The description of the manufacturing method of the radiopharmaceutical kit will contain information on the manufacture of the kit and its final treatment which is recommended to produce the radioactive medicinal product. Where appropriate, the necessary specifications of the radionuclide should be described in accordance with the general monograph or specific monographs of the European Pharmacopoeia. Any other compounds essential for radiolabelling and the structure of the radiolabelled compound should also be specified.
For radionuclides, the nuclear radiation involved should be discussed.
In the case of a generator, both the parent radionuclide and the descendant radionuclide are understood to be active substances.
b) Details on the nature of the radionuclide, the identity of the isotope, the probable impurities, the carrier element, as well as the use and specific activity must be provided.
c) Raw materials include radiation target materials.
d) Considerations on chemical/radiochemical purity and its relation to biodistribution shall be presented.
e) It is necessary to describe the purity of the radionuclides, the radiochemical purity and the specific activity.
f) In the case of generators, details of the parent and child radionuclide tests must be provided. In the case of generating eluates, tests for the parent radionuclide and other components of the generating system should be carried out.
g) The requirement to express the content of active substances in terms of the weight of the active fractions applies only to radiopharmaceutical kits. In the case of radionuclides, radioactivity must be expressed in Becquerels at a given date and, where appropriate, time with reference to the time zone. The type of radiation must be indicated.
h) The specifications of the finished product include, in the case of kits, product efficiency tests after radio-marking. Such tests shall include adequate checks of the radiochemical and radionuclide purity of the radiolabelled compound. It is necessary to identify and dose all the materials necessary for radio-labelling.
i) Information on the stability of radionuclide generators, radionuclide kits and radiolabelled products shall be provided. In-use stability of radiopharmaceuticals in multidose vials should be documented.
Form 4
It is known that toxicity can be associated with a given radiation dose. In the diagnosis it is a consequence of the use of radiopharmaceuticals; in therapy it is instead a sought-after property. The evaluation of the safety and efficacy of radiopharmaceuticals must therefore concern the rules concerning the medicinal product and the dosimetric aspects of the radiation. Radiation exposure of organs/tissues should be documented. Estimates of absorbed radiation dose must be calculated according to a specific, internationally recognized system for a given route of administration.
Module 5
Where possible, results of clinical trials should be provided, otherwise they should be justified in the overviews of the clinical part.
2.2. Radiopharmaceutical precursors for radiolabelling purposes
In the specific case of a radiopharmaceutical precursor intended exclusively for radiolabelling purposes, the aim must essentially be to present information on the possible consequences of the poor efficiency of the radiolabelling or of the in vivo dissociation of the radiolabelled conjugate, i.e. on the problems of the effects produced on the patient by free radionuclides. It is also necessary to present the relevant information relating to occupational risks, i.e. radiation exposure of hospital staff and the environment.
If applicable, the following information must be provided:
Form 3
The provisions of module 3 – defined in letters a) to i) above – apply, if applicable, to the registration of radiopharmaceutical precursors.
Form 4
With regard to toxicity from single or repeated administration, unless there are justified reasons, the results of studies carried out in accordance with the principles of good laboratory practice set out in Council Directive 87/18/EEC on the approximation of legislative provisions must be presented, regulatory and administrative relating to the application of the principles of good laboratory practice and to the control of their application for tests on chemical substances, and to the legislative decree 27 January 1992, n. 120, and subsequent additions (directive 2004/9/EC of the European Parliament and of the Council).
In this specific case, mutagenicity studies on the radionuclide are not considered useful. Information concerning the chemical toxicity and disposition of the relevant 'cold' nuclide shall be submitted.
Module 5
Clinical information deriving from clinical studies relating to the precursor itself is not considered significant in the specific case of a radiopharmaceutical precursor intended exclusively for radiolabelling purposes.
However, any information demonstrating the clinical utility of radiopharmaceutical precursors when linked to the relevant carrier molecules should be submitted.
3. HOMEOPATHIC MEDICINES
This section contains specific provisions on the application of modules 3 and 4 to homeopathic medicinal products referred to in article 1, paragraph 1, letter d) of this decree (article 1, no. 5 of directive 2001/83/EC).
Form 3
The provisions of form 3 apply to documents submitted pursuant to article 17 of this decree (article 15 of directive 2001/83/EC) in the simplified registration of homeopathic medicinal products referred to in article 16 of this decree (article 14, paragraph 1 of Directive 2001/83/EC), as well as documents relating to the authorization of homeopathic medicinal products other than those referred to in Article 18 of this decree (Article 16, paragraph 1 of Directive 2001/83/EC) with the following amendments .
a) Terminology.
The Latin name of the homeopathic stock given in the marketing authorization application dossier must conform to the Latin title of the European Pharmacopoeia or, in its absence, of an official pharmacopoeia of a Member State. If applicable, indicate the traditional name(s) used in each Member State.
b) Control of raw materials.
The information and documents on the starting materials - ie on everything that is used including the subsidiary and intermediate materials, up to the final dilution to be incorporated into the finished medicinal product - attached to the application must be supplemented by complementary data on the starting material.
The general quality requirements apply to all raw materials and subsidiary materials, as well as intermediate stages of the manufacturing process, up to the final dilution to be incorporated into the finished medicinal product. If possible, a test should be carried out in the presence of toxic components and if the high degree of dilution prevents quality control in the final dilution. All steps of the manufacturing process, from raw materials to the final dilution to be incorporated into the finished medicinal product, must be fully described.
If dilutions are required, they must be carried out in accordance with the homeopathic manufacturing methods contained in the relevant monograph of the European Pharmacopoeia, or in its absence, in an official pharmacopoeia of a Member State.
c) Checks of the finished medicinal product.
The finished homeopathic medicines must comply with the general quality requirements. Any exceptions must be duly motivated by the applicant.
All toxicologically relevant components must be identified and tested. If it proves impossible to identify and/or test all toxicologically relevant constituents, for example due to their dilution in the finished medicinal product, the quality must be demonstrated by a full validation of the manufacturing and dilution process.
d) Stability tests.
The stability of the finished medicinal product must be demonstrated. The stability data of the homeopathic starting materials are normally transmissible to the dilutions/triturations obtained from them. If the identification and dosage of the active substance is not possible due to the degree of dilution, the stability data of the pharmaceutical form can be used.
Form 4
The provisions of module 4 apply to the simplified registration of homeopathic medicinal products referred to in article 16 of this decree (article 14, paragraph 1 of directive 2001/83/EC) with the following clarifications.
Any missing information must be justified: p. eg. it must be explained why the demonstration of an acceptable level of safety is accepted even in the absence of some studies.
4. HERBAL MEDICINES
In the case of applications for herbal medicines, a complete dossier must be submitted, in which the following particulars must be included.
Form 3
The provisions of module 3, including compliance with the monograph(s) of the European and/or national Pharmacopoeia apply to the authorization of herbal medicines. The state of scientific knowledge at the time the application is submitted must be taken into account.
The following characteristic aspects of herbal medicines should be considered:
(1) Herbal substances and preparations
For the purposes of this Annex, the terms 'herbal substances and preparations' are equivalent to the terms 'herbal medicinal products' as defined in the European Pharmacopoeia.
Regarding the nomenclature of the herbal substance, the binomial scientific name of the plant (genus, species, variety and author), the chemotype (if applicable), the parts of the plant, the definition of the herbal substance, the other names (synonyms listed in pharmacopoeias) and the laboratory code.
Regarding the nomenclature of the herbal preparation, the binomial scientific name of the plant (genus, species, variety and author), the chemotype (if applicable), the parts of the plant, the definition of the herbal preparation, the amount of herbal substance in the preparation, the extraction solvent(s), the other names (synonyms given in other pharmacopoeias) and the laboratory code.
To document the section on the structure of the substance(s) or possibly of the herbaceous preparation(s), it is necessary to provide, where applicable, the physical form, the description of the components with recognized therapeutic properties or of the markers (molecular formula, relative molecular mass , structural formula, including relative and absolute stereochemistry, molecular formula and relative molecular mass), as well as other component(s).
To document the section on the manufacturer of the herbal substance, the name, address and responsibility of each supplier, including contractors, as well as all production sites or facilities proposed to be involved in manufacturing/harvesting and testing of the herbal substance should be provided. herbal substance, where appropriate.
To document the section on the manufacturer of the herbal preparation, the name, address and responsibility of each manufacturer, including contractors, as well as all production sites or facilities proposed to be involved in the manufacturing and testing of the herbal preparation should be provided. herbal, where appropriate.
As for the description of the manufacturing process of the herbal substance and the controls to which it is subject, information must be provided which adequately presents the production and harvesting of the plant, including the place of origin of the medicinal plant and the conditions of cultivation, harvesting, drying and storage.
As for the description of the manufacturing process of the herbal preparation and the controls to which it is subject, information must be provided which adequately presents the manufacturing process of the herbal preparation, including the description of the processing, solvents and reagents , purification steps and standardization.
With respect to the manufacturing process development, where possible a brief summary of the development of the substance(s) and herbal preparation(s) should be provided, taking into account the proposed routes of administration and use. Where appropriate, the results of the comparison between the phytochemical composition of the substance(s) and possibly the herbal preparation(s) used in the supporting bibliographic data, and the substance(s) and possibly the preparation(s) are discussed. herbal medicines contained as active substance(s) in the herbal medicinal product covered by the application.
With respect to the explanation of the structure and other characteristics of the herbal substance, information on botanical, macroscopic, microscopic and phytochemical characterization and biological activity, where appropriate, should be provided.
With respect to the explanation of the structure and other characteristics of the herbal preparation, information on the phytochemical and physicochemical characterization, as well as on the biological activity, where necessary, should be provided.
Specifications of the substance(s) and possibly of the herbal preparation(s) must be provided.
The analytical procedures used for testing the substance(s) and possibly the herbal preparation(s) must be presented.
Regarding the validation of analytical procedures, information on the analytical validation should be submitted, including experimental data relating to the analytical procedures used for testing the substance(s) and possibly the herbal preparation(s).
Concerning batch analyses, a description of the batches and the results of the batch analyzes for the herbal substance(s) and herbal preparation(s), including those for pharmacopoeial substances, should be provided.
Justification of the specifications of the substance(s) and possibly of the herbal preparation(s) should be provided, if applicable.
Where applicable, information on standards or reference materials used for testing the substance(s) and herbal preparation(s) shall be provided.
If the substance or herbal medicinal product is the subject of a Pharmacopoeia monograph, the applicant may request a certificate of suitability issued by the European Directorate for the Quality of Medicines.
(2) Herbal medicines
Concerning the development of the formula, a brief summary should be presented describing the development of the herbal medicinal product, taking into account the proposed routes of administration and use. Where appropriate, the results of the comparison of the phytochemical composition of the products used in the supporting bibliographic data, and the herbal medicinal product covered by the application are discussed.
5. ORPHAN DRUGS
– To an orphan medicinal product within the meaning of Regulation (EC) No. 141/2000, it is possible to apply the general provisions referred to in part II, module 6 (exceptional circumstances). The applicant will then explain in the clinical and non-clinical summaries the reasons why it is not possible to provide complete information and explain the balance of risks and benefits of the orphan medicinal product concerned.
– If the applicant for a marketing authorization for an orphan medicinal product invokes the requirements of article 11 of this decree (article 10-bis of directive 2001/83/EC as amended by directive 2004/27) and in part II, paragraph 1 of this annex (well-known medical use) the systematic and documented use of the substance concerned may refer – by way of derogation – to the use of this substance pursuant to the provisions of article 5, paragraph 1 of this decree (Article 5, paragraph 1 of Directive 2001/83/EC as amended by Directive 2004/27/EC).
PART IV
MEDICINES FOR ADVANCED THERAPIES
Advanced therapy medicinal products are based on manufacturing processes centered on various biomolecules produced by gene transfer and/or advanced therapy biologically modified cells as active substances or part of active substances.
For these medicinal products, the presentation of the marketing authorization application dossier must comply with the format requirements set out in Part I of this Annex.
Modules 1 to 5 apply. For genetically modified organisms, deliberately released into the environment, the persistence of the GMO in the receptor and the possible replication/modification of the GMO once released into the environment must be taken into account. Information on environmental risks must be inserted in the attachment to module 1.
1. GENE THERAPY MEDICINAL PRODUCTS (HUMAN AND XENOGENIC)
For the purposes of this Annex, gene therapy medicinal product means the product of a series of manufacturing processes aimed at the transfer of a prophylactic, diagnostic or therapeutic gene (i.e. a fraction of nucleic acid) - to be performed in vivo or ex vivo - to human/animal cells and its subsequent expression in vivo. Gene transfer involves an expression system that is contained in a transmission system known as a vector that can be of either viral or non-viral origin. The vector can also be included in a human or animal cell.
1.1. Diversity of gene therapy medicinal products
a) Gene therapy medicinal products based on allogeneic or xenogeneic cells.
The vector is prepared and stored for subsequent transfer into host cells.
The cells have been obtained previously and can be treated as a cell bank (collection bank or bank established for the procurement of primary cells) with limited viability.
The cells genetically modified by the vector constitute an active substance.
Additional operations may be performed to obtain the finished medicine. A medicinal product of this type is by definition 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 prepared vectors, stored before its transfer into autologous cells.
Additional operations may be performed to obtain the finished medicine.
These medicines are made with cells obtained from an individual patient. The cells are then genetically modified using prepared vectors containing the suitable gene, which have been previously prepared and constitute the active substance. The preparation is reinjected into the patient and is by definition intended for a single patient. The entire production process – from collection of cells from the patient to reinjection into the patient – should be considered a single operation.
c) Administration of vectors prepared with inserted genetic material (prophylactic, diagnostic or therapeutic).
The active substance is a batch of prepared carriers.
Additional operations may be performed to obtain the finished medicine. This type of medicinal product is intended to be administered to various patients.
The transfer of the genetic material can be carried out by direct injection into the recipients of the prearranged vector.
1.2. Module specific requirements 3
Gene therapy medicines include
– the naked nucleic acid
– complexed nucleic acid or non-viral vectors
– viral vectors
– genetically modified cells.
As for other medicinal products, the three main elements of the manufacturing process can be identified, namely:
– raw materials: materials from which the active substance is manufactured, such as the reference gene, expression plasmids, cell banks and virus stocks or non-viral vectors;
– active substance: recombinant vectors, viruses, naked or complex plasmids, cells that produce viruses, cells genetically modified in vitro;
– medicinal product as an active substance formulated in its definitive primary container for the intended medical use. Depending on the type of gene therapy medicinal product, protocol, route of administration and conditions of use may require ex vivo treatment of the patient's cells.
Particular attention should be paid to the following points:
a) Information on the relevant characteristics of the gene therapy medicinal product, including its expression in the target cell population, shall be provided. Information relating to the origin, construction, characteristics and verification of the genetic coding sequence, including its integrity and stability, shall be provided. In addition to the therapeutic gene, the complete sequence of other genes, regulatory elements and the backbone vector must be provided.
b) Information relating to the characterization of the vector used to transfer and deliver the gene shall be provided. Its physicochemical and/or biological/immunological characterization must be understood.
For medicinal products that use microorganisms such as bacteria or viruses to facilitate the transfer of genes (biological gene transfer), data on the pathogenesis of the parental strain and its tropism for specific tissue and cell types, as well as cycle dependence should be submitted. of the cells of the interaction.
For medicinal products that use non-biological means to facilitate gene transfer, the physicochemical properties of individual and associated components should be reported.
c) The principles that apply to cell banking or to the establishment and characterization of seed lots should eventually be applied to gene transfer medicinal products.
d) The origin of the cells hosting the recombinant vector must be indicated.
The characteristics of the human source, such as age, gender, microbiological and viral test results, exclusion criteria, and country of origin should be documented.
For cells of animal origin, detailed information on the following points shall be provided:
– Origin of animals
– Breeding and animal care
– Transgenic animals (creation methods, characterization of transgenic cells, nature of the inserted gene)
– Measures to prevent and control infections of source/donor animals
– Tests for infectious agents
- Installations
– Control of raw materials and subsidiary materials.
The method of harvesting the cells should be described, including location, tissue type, operating process, transport, storage and traceability, as well as the controls performed during the harvesting operation.
e) The evaluation of the viral safety and the traceability of the products from the donor to the finished medicinal product are an essential part of the documentation to be submitted. Go, Fr. eg, excluding the presence of replicating viruses in non-replicating viral vector strains.
2. MEDICINAL PRODUCTS FOR SOMATIC CELL THERAPY (HUMAN AND XENOGENIC)
For the purposes of this Annex, somatic cell therapy medicinal product means the use in humans of autologous (from the patient himself), allogeneic (from another human being), or xenogeneic (from animals) living somatic cells, whose biological characteristics have been substantially modified following manipulation to obtain a therapeutic, diagnostic or preventive effect by metabolic, pharmacological and immunological means. Manipulation includes the expansion or activation of autologous cell populations ex vivo (adoptive immunotherapy), the use of allogeneic and xenogeneic cells combined with medical devices for ex vivo or in vivo use (microcapsules, intrinsic matrix structures, biodegradable or not).
Specific requirements for cell therapy medicinal products related to module 3
Medicinal products for somatic cell therapy include
– Cells manipulated to modify their immunological, metabolic or other functional properties from a qualitative or quantitative point of view;
– Cells separated, selected, manipulated and subsequently subjected to a manufacturing process to obtain the finished medicine;
– Cells manipulated and associated with non-cellular components (for example biological or inert matrices or medical devices) which exert the essential action envisaged 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 entire manufacturing process – from harvesting the cells from the patient (autologous situation) to reinjecting them into the patient – should be considered a single operation.
As for other medicines, the three elements of the manufacturing process:
– raw 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 used in association with inert matrices and medical devices;
– finished medicines: active substance formulated in its definitive primary container for the intended medical use.
a) General information on the active substance(s).
The active substances of medicinal products for cell therapy consist of cells which, following in vitro treatment, have prophylactic, diagnostic or therapeutic properties different from their original physiological and biological properties.
This section describes the cell type and culture involved. The tissues, organs or biological fluids from which the cells are derived, as well as the autologous, allogeneic or xenogenic nature of the donation and its geographical origin must be documented. Cell collection, sampling and storage prior to further processing should be described. For allogeneic cells, particular attention should be paid to the very early stages of the process, relating to donor selection. The type of manipulation performed, as well as the physiological function of the cells used as active substance, must be explained.
b) Information concerning the starting materials of the active substance(s).
1. Human somatic cells
Human somatic cell therapy medicinal products are composed of a defined number (pool) of viable cells, which by means of a manufacturing process are obtained from organs or tissues harvested from a human being, or from a well-defined cell bank system, in which the cell pool can rely on continuous cell lines. For the purposes of this chapter, active substance means the human cell seed pool and finished medicinal product means the human cell seed pool formulated for the intended medical use.
The raw materials and each stage of the manufacturing process must be accurately documented, emphasizing the aspects of viral safety.
(1) Organs, tissues, body fluids and cells of human origin
The characteristics of the human source, such as age, gender, microbiological and viral status, exclusion criteria and country of origin, must be documented.
A description of the sampling should be provided, including site, type, operating process, mixing, transport, storage and traceability, as well as the controls performed on the sampling.
(2) Cell banking systems
For the preparation and quality control of cell banking systems, the requirements of Part I apply. This is essentially the case for allogeneic and xenogeneic cells.
(3) Ancillary medical materials or devices
Information on the use of all starting materials (cytokines, growth factors, culture media) or possible ancillary medical products or devices (such as cell separation devices, biocompatible polymers, matrices, fibres, biocompatibility and functionality beads) should be provided. as well as on the risks of infectious agents).
2. Animal somatic cells (xenogenic)
Detailed information on the following points should be provided:
– Origin of animals
– Breeding and animal care
– Genetically modified animals (methods of creation, characterization of transgenic cells, nature of the inserted or excluded gene (knock-out)
– Measures to prevent and control infections of source/donor animals
– Tests for infectious agents, including vertically transmitted microorganisms (including endogenous retroviruses)
- Installations
– Cell banking systems
– Control of raw materials and subsidiary materials.
a) Information on the manufacturing process of the active substance(s) and of the finished medicinal product.
The different steps of the manufacturing process (organ/tissue dissociation; selection of the relevant cell population; in vitro cell culture; cell transformation by physicochemical agents or gene transfer) shall be documented.
b) Characterization of the active substance(s).
All relevant information on the characterization of the relevant cell population in terms of identity (species of origin, grouping cytogenetics, morphological analysis), purity (adventitious microbial agents and cellular contaminants), efficacy (defined biological activity ) and suitability (karyology and carcinogenicity tests) for the intended medicinal use.
c) Pharmaceutical development of the finished drug.
In addition to the specific method of administration used (intravenous injection, injection on site, surgical transplantation), information on the use of any auxiliary medical devices (matrix, biocompatible polymers, fibres, granules) must be provided in terms of biocompatibility and durability.
d) Traceability.
A detailed flow diagram must be presented, which ensures 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 XENOGENIC) MEDICINAL PRODUCTS RELATED TO MODULES 4 AND 5
3.1. Form 4
It is recognized that for somatic cell and gene therapy medicinal products the conventional requirements contained in Module 4 for non-clinical testing of medicinal products may not always be adequate, due to the unique and diverse structural and biological properties of the products concerned, including the degree species specificity, subject specificity, immunological barriers and pleiotropic response differences.
The rationale underlying the non-clinical development and the criteria used to choose the relevant species and models will be given adequate space in module 2.
It may be necessary to identify or develop new animal models to help extrapolate specific findings relating to functional endpoints and in vivo toxicity of the product to humans. Scientific justification for the use of these animal models of disease should be provided to support safety and proof of concept efficacy.
3.2. Form 5
The efficacy of advanced therapy medicinal products must be demonstrated according to the indications in module 5. However, for some products and for some therapeutic indications it may be impossible to carry out conventional clinical trials. Any deviation from the guidelines/guidelines in force must be justified in module 2.
The clinical development of advanced cell therapy medicinal products has some special characteristics due to the complex and labile nature of the active substances. Issues related to the viability, proliferation, migration and differentiation of cells (somatic cell therapy), the special clinical circumstances in which drugs are used or the special mode of action through gene expression (somatic gene therapy) require further attention.
In the application for the marketing authorization of medicinal products for advanced therapies, it is necessary to deal with the particular risks associated with these products, which derive from the possible contamination by infectious agents. On the one hand, particular attention should be paid to the early stages of development, including the choice of donors in the case of cell therapy medicinal products and, on the other hand, to the therapeutic intervention as a whole, including the suitability of handling and administration of the product. If necessary, form 5 of the application must also contain data on measures for the observation and control of the functions and development of living cells in the recipient, to prevent the transmission of infectious agents to the recipient and to minimize any risks to public health.
3.2.1. Human pharmacology and efficacy studies
Studies of human pharmacology must provide information on the expected mode of action, the expected efficacy points on the basis of justified "end-points", on the biodistribution, on the adequate dose, on the times and methods of administration or on the method of use, that are significant for efficacy studies.
Conventional pharmacokinetic studies may not be meaningful for some advanced therapy medicinal products. Studies in healthy volunteers are sometimes not feasible and it will be difficult to establish doses and kinetics in clinical trials. However, it is necessary to study the distribution and in vivo behavior of the product, including cell proliferation and long-term function, as well as the amount and distribution of the gene product and the duration of the desired gene expression. Appropriate tests should be used, and if necessary developed, to trace the cell product or cell expressing the desired gene in the human body, and to monitor the functioning of the administered or transfected cells.
Evaluation of the efficacy and safety of an advanced therapy medicinal product must include a thorough description and evaluation of the therapeutic procedure as a whole, including special modes of administration (such as ex vivo cell transfection, in vitro manipulation or use of invasive techniques), as well as evidence of possible associated regimens (including immunosuppressive, antiviral and cytotoxic treatments).
The whole procedure must be verified with clinical trials and described in the product information.
3.2.2. Safety
Safety concerns arising from immune response to medicinal products or expressed proteins, immune rejection, immunosuppression, and failure of immune isolation devices should be addressed.
Certain advanced gene therapy and somatic cell therapy medicinal products (such as xenogenic cell therapy and some gene transfer products) may contain replication-capable particles and/or infectious agents. It is possible that the patient should be monitored for the development of possible infections and/or their pathological consequences during the pre- and/or post-authorisation phases; this surveillance must also be able to be extended to subjects in close contact with the patient, including healthcare professionals.
In the use of certain somatic cell therapy medicinal products and certain gene transfer products, the risk of contamination with potentially transmissible agents cannot be completely eliminated, but can nevertheless be minimized by the appropriate measures described in module 3.
The measurements that are part of the manufacturing process must be supplemented with auxiliary test methods, quality control processes and suitable means of surveillance, which must be described in module 5.
The use of certain advanced somatic cell therapy medicinal products may be limited, temporarily or permanently, to centers that have well-documented expertise and facilities to ensure specific monitoring of patient safety. Such an approach may also be relevant for some gene therapy medicinal products subject to potential risk from infectious agents capable of replication. If applicable, monitoring issues related to the occurrence of late complications should be addressed and addressed in the application.
If appropriate, the applicant shall submit a detailed risk management plan including clinical and laboratory data of the patient, the emerging epidemiological data and, where appropriate, archival data of tissue samples from the donor and the recipient. This system must ensure the traceability of the medicinal product and the rapid response to suspicious signals of adverse events.
4. SPECIFIC STATEMENT REGARDING XENOTRANSPLANT MEDICINAL PRODUCTS
For the purposes of this Annex, xenotransplantation means any procedure involving the transplantation, implantation or infusion into a human recipient of live tissues or organs derived from animals, or of human body fluids, cells, tissues or organs subjected ex vivo to contact with live animal cells, tissues or organs of the non-human kind.
Particular attention should be paid to raw materials.
In this regard, detailed information relating to the following points must be provided, in accordance with precise guidelines/guidelines:
– Origin of animals
– Breeding and animal care
– Genetically modified animals (methods of creation, characterization of transgenic cells, nature of the inserted or knocked out gene)
– Measures to prevent and control infections of source/donor animals
– Tests for infectious agents
- Installations
– Control of raw materials and subsidiary materials
– Traceability.
ANNEX 2
Provided for by article 14, paragraph 1
SUMMARY OF PRODUCT CHARACTERISTICS
1. Name of the medicinal product followed by the strength and pharmaceutical form.
2. Qualitative and quantitative composition in terms of active substances and excipients the knowledge of which is necessary for correct administration of the medicinal product. The usual common name or chemical description is used.
3. Pharmaceutical form:
4. Clinical Information:
4.1 Therapeutic indications;
4.2 Posology and method of administration for adults and, if necessary, for children;
4.3 Contraindications;
4.4 Special warnings and precautions for use and, for immunological medicinal products, special precautions for persons handling said medicinal products and administering them to patients, as well as any precautions to be taken by the patient;
4.5 Interactions with other medicinal products and other forms of interaction;
4.6 Pregnancy and lactation;
4.7 Effects on ability to drive and use machines;
4.8 Undesirable effects;
4.9 Overdose (symptoms, first aid procedures, antidotes).
5. Pharmacological properties:
5.1 Pharmacodynamic properties;
5.2 Pharmacokinetic properties;
5.3 Preclinical safety data.
6. Pharmaceutical Information:
6.1 List of excipients;
6.2 Incompatibility;
6.3 Shelf life, if necessary specify the shelf life after reconstitution of the medicinal product or after the immediate packaging has been opened for the first time;
6.4 Special precautions for storage;
6.5 Nature of immediate packaging and contents of the package;
6.6 Any special precautions to be taken for the disposal of the used medicinal product and waste products derived from this medicinal product.
7. MA holder.
8. MA number or MA numbers.
9. Date of the first authorization or of the renewal of the authorisation.
10. Text revision date.
11. For radiopharmaceuticals, complete internal radiation dosimetry data.
12. For radiopharmaceuticals, further detailed instructions on impromptu preparation and quality control of the preparation and, if applicable, the maximum storage period during which any intermediate preparation, such as an eluate, or the ready-to-use radiopharmaceutical will keep complies with the specified specifications.