MEDICINES (MARKETING AUTHORISATION) REGULATIONS (sl_458.34) | MT

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Preamble — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

SUBSIDIARY LEGISLATION 458.34

MEDICINES (MARKETING AUTHORISATION)

REGULATIONS

26th October, 2007

LEGAL NOTICE 324 of 2007, as amended by Legal Notices 231 of 2008,

252 of 2010, 373 of 2012, 349 of 2013, 234 of 2022 and 61 of 2024.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 1 Citation. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

The title of these regulations is the Medicines (Marketing

Authorisation) Regulations.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Schedule — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

Added by

L.N. 252 of 2010.

ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLINICAL STANDARDS

AND PROTOCOLS IN RESPECT OF THE TESTING OF MEDICINAL

PRODUCTS

TABLE OF CONTENTS

Introduction and general principles

Standardised marketing authorisation dossier requirements

1. Module 1: Administrative information

Table of contents

Application form

Summary of product characteristics, labelling and package leaflet

Summary of product characteristics

Labelling and package leaflet

Mock-ups and specimens

Summaries of product characteristics already approved in the Member

States

Information about the experts

Specific requirements for different types of applications

Environmental risk assessment

2. Module 2: Summaries

Overall table of contents

Introduction

Quality overall summary

Non-clinical overview

Clinical overview

Non-clinical summary

Clinical Summary

3. Module 3: Chemical, pharmaceutical and biological information for

medicinal products containing chemical and/or biological active

substances

Format and presentation

Content: basic principles and requirements

Active substance(s)

General information and information related to the starting and raw

materials

Manufacturing process of the active substance(s)

Characterisation of the active substance(s)

Control of active substance(s)

Reference standards or materials

Container and closure system of the active substance

Stability of the active substance(s)

Finished medicinal product

Description and composition of the finished medicinal product

Pharmaceutical development

Manufacturing process of the finished medicinal product

Control of excipients

Control of the finished medicinal product

Reference standards or materials

Container and closure of the finished medicinal product

Stability of the finished medicinal product

4. Module 4: Non-clinical reports

Format and Presentation

Content: basic principles and requirements

Pharmacology

Pharmaco-kinetics

Toxicology

5. Module 5: Clinical study reports

Format and Presentation

Content: basic principles and requirements

Reports of bio-pharmaceutics studies

Reports of studies pertinent to pharmaco-kinetics using human bio-

materials

Reports of human pharmaco-kinetic studies

Reports of human pharmaco-dynamic studies

Reports of efficacy and safety studies

Study Reports of Controlled Clinical Studies Pertinent to the Claimed

Indication

Study reports of uncontrolled clinical studies reports of analyses of data

from more than one study and other clinical study reports

Reports of post-marketing experience

Case reports forms and individual patient listings

Part II: Specific marketing authorisation dossiers and requirements

1. Well-established medicinal use

2. Essentially similar medicinal products

3. Additional data required in specific situations

4. Similar biological medicinal products

5. Fixed combination medicinal products

6. Documentation for applications in exceptional circumstances

7. Mixed marketing authorisation applications

Part III: Particular medicinal products

1. Biological medicinal products

Plasma-derived medicinal product

Vaccines

2. Radio-pharmaceuticals and precursors

Radio-pharmaceuticals

Radio-pharmaceutical precursors for radio-labelling purposes

3. Homeopathic medicinal products

4. Herbal medicinal products

5. Orphan Medicinal Products

Part IV: Advanced therapy medicinal products

1. Introduction

2. Definitions

Gene therapy medicinal products

Somatic cell therapy medicinal products

3. Specific requirements regarding Module 3

Specific requirements for all advanced therapy medicinal products

Specific requirements for gene therapy medicinal products

Introduction: finished product, active substance and starting materials

Specific requirements

Specific requirements for somatic cell therapy medicinal products and

tissue engineered products

Introduction: finished product, active substance and starting materials

Specific requirements

Specific requirements for advanced therapy medicinal products

containing devices

Advanced therapy medicinal products containing devices referred to in

Article 7 of Regulation (EC) 1394/2007

Combined advanced therapy medicinal products as defined in Article

2(1)(d) of Regulation (EC) 1394/2007

4. Specific requirements regarding Module 4

Specific requirements for all advanced therapy medicinal products

Specific requirements for gene therapy medicinal products

Pharmacology

Pharmacokinetics

Toxicology

4.3.

Specific requirements for somatic cell therapy medicinal products and

tissue engineered products

4.3.1.

Pharmacology

4.3.2.

Pharmacokinetics

4.3.3.

Toxicology

5. Specific requirements regarding Module 5

5.1.

Specific requirements for all advanced therapy medicinal products

5.2.

Specific requirements for gene therapy medicinal products

5.2.1.

Human pharmacokinetic studies

5.2.2.

Human pharmacodynamic studies

5.2.3.

Safety studies

5.3.

Specific requirements for somatic cell therapy medicinal products

5.4.

Specific requirements for tissue engineered products

5.4.1.

Pharmacokinetic studies

5.4.2.

Pharmacodynamic studies

5.4.3.

Safety studies

Introduction and general principles

(1) The particulars and documents accompanying an application for marketing

authorisation pursuant to Articles 8 and 10 (1) shall be presented in accordance with

the requirements set out in this Schedule and shall follow the guidance published by

the Commission in The rules governing medicinal products in the European

Community,Volume 2 B, Notice to applicants, Medicinal products for human use,

Presentation and content of the dossier, Common Technical Document (CTD).

(2) The particulars and documents shall be presented as five modules: Module 1

provides European Community specific administrative data; Module 2 provides

quality, non-clinical and clinical summaries, Module 3 provides chemical,

pharmaceutical and biological information, Module 4 provides non-clinical reports

and Module 5 provides clinical study reports. This presentation implements a

common format for all ICH regions (European Community, United States of

America, Japan). These five Modules shall be presented in strict accordance with the

format, content and numbering system delineated in details in Volume 2 B of the

Notice to Applicants referred to above.

(3) The European Community-CTD-presentation is applicable for all types of

marketing authorisation applications irrespective of the procedure to be applied (i.e.

centralised, mutual recognition or national) and of whether they are based on a full

or abridged application. It is also applicable for all types of products including new

chemical entities (NCE), radio-pharmaceuticals, plasma derivatives, vaccines,

herbal medicinal products, etc.

(4) In assembling the dossier for application for marketing authorisation,

applicants shall also take into account the scientific guidelines relating to the quality,

safety and efficacy of medicinal products for human use as adopted by the

Committee for Proprietary Medicinal Products (CPMP) and published by the

European Medicine Evaluation Agency (EMEA) and the other pharmaceutical

Community guidelines published by the Commission in the different volumes of the

rules governing medicinal products in the European Community.

(5) With respect to the quality part (chemical, pharmaceutical and biological) of

the dossier, all monographs including general monographs and general chapters of

the European Pharmacopoeia are applicable.

(6) The manufacturing process shall comply with the requirements of

Commission Directive 91/356/EEC laying down the principles and guidelines of

Good Manufacturing Practice (GMP) for medicinal products for human use and with

the principles and guidelines on GMP, published by the Commission in the rules

governing medicinal products in the European Community, Volume 4.

(7) All information, which is relevant to the evaluation of the medicinal product

concerned, shall be included in the application, whether favourable or unfavourable

to the product. In particular, all relevant details shall be given of any incomplete or

abandoned pharmaco-toxicological or clinical test or trial relating to the medicinal

product and/or completed trials concerning therapeutic indications not covered by

the application.

(8) All clinical trials, conducted within the European Community, must comply

with the requirements of Directive 2001/20/EC of the European Parliament and of

the Council on the approximation of the laws, regulations and administrative

provisions of the Member States relating to the implementation of good clinical

practice in the conduct of clinical trials on medicinal products for human use. To be

taken into account during the assessment of an application, clinical trials, conducted

outside the European Community, which relate to medicinal products intended to be

used in the European Community, shall be designed, implemented and reported on

what good clinical practice and ethical principles are concerned, on the basis of

principles, which are equivalent to the provisions of Directive 2001/20/EC. They

shall be carried out in accordance with the ethical principles that are reflected, for

example, in the Declaration of Helsinki.

(9) Non-clinical (pharmaco-toxicological) studies shall be carried out in

conformity with the provisions related to Good Laboratory Practice laid down in

Council Directives 87/18/EEC on the harmonisation of regulations and

administrative provisions relating to the application of the principles of good

laboratory practice and the verification of their application for tests in chemical

substances and 88/320/EEC on the inspection and verification of good laboratory

practice (GLP).

(10) Member States shall also ensure that all tests on animals are conducted in

accordance with Council Directive 86/609/EEC of 24 November 1986 on the

approximation of laws, regulation and administrative provisions of the Member

States regarding the protection of animals for experimental and other scientific

purposes.

(11) In order to monitor the benefit/risk assessment, any new information not in

the original application and all pharmaco-vigilance information shall be submitted to

the competent authority. After marketing authorisation has been granted, any change

to the data in the dossier shall be submitted to the competent authorities in

accordance with the requirements of Commission Regulations (EC) No 1084/2003

and (EC) No 1085/2003 of the Commission or, if relevant, in accordance with

national provisions, as well as the requirements in Volume 9 of Commission

publication The rules governing medicinal products in the European Community.

This Schedule is divided in four different parts

-

Part I describes the application format, the summary of product

characteristics, the labelling, the leaflet and presentation requirements

for standard applications (Modules 1 to 5).

-

Part II provides derogation for ‘Specific applications’, i.e. well-

established medicinal use, essentially similar products, fixed

combinations, similar biological products, exceptional circumstances

and mixed applications (part bibliographic and part own studies).

-

Part III deals with ‘Particular application requirements’ for biological

medicinal products (Plasma Master File; Vaccine Antigen Master File),

radio-pharmaceuticals, homeopathic medicinal products, herbal

medicinal products and orphan medicinal products.

-

Part IV deals with ‘Advanced therapy medicinal products’ and concerns

specific requirements for gene therapy medicinal products (using

human autologous or allogeneic system, or xenogeneic system) and cell

therapy medicinal products both of human or animal origin and

xenogeneic transplantation medicinal products.

PART I

STANDARDISED MARKETING AUTHORISATION DOSSIER REQUIREMENTS

1. MODULE 1: ADMINISTRATIVE INFORMATION

1.1.

Table of contents

A comprehensive table of contents of Modules 1 to 5 of the dossier submitted for

marketing authorisation application shall be presented.

1.2.

Application form

The medicinal product, which is the subject of the application, shall be identified

by name and name of the active substance(s), together with the pharmaceutical form,

the route of administration, the strength and the final presentation, including

packaging.

The name and address of the applicant shall be given, together with the name and

address of the manufacturers and the sites involved in the different stages of the

manufacture (including the manufacturer of the finished product and the

manufacturer(s) of the active substance(s)), and where relevant the name and address

of the importer.

The applicant shall identify the type of application and indicate what samples, if

any, are also provided. Annexed to the administrative data shall be copies of the

manufacturing authorisation as defined in Article 40, together with a list of countries

in which authorisation has been granted, copies of all the summaries of product

characteristics in accordance with Article 11 as approved by Member States and a

list of countries in which an application has been submitted.

As outlined in the application form, the applicants shall provide, inter alia, details

of the medicinal product subject of the application, the legal basis of the application,

the proposed marketing authorisation holder and manufacture(s), information on

orphan medicinal product status, scientific advice and paediatric development

program.

1.3.

Summary of product characteristics, labelling and package leaflet

1.3.1.

Summary of product characteristics

The applicant shall propose a summary of the product characteristics, in

accordance with Article 11.

1.3.2.

Labelling and package leaflet

A proposed labelling text for immediate and outer packaging as well as for the

package leaflet shall be provided. These shall be in accordance with all mandatory

items listed in Title V on the labelling of medicinal products for human use (Article

63) and on package leaflet (Article 59).

1.3.3.

Mock-ups and specimens

The applicant shall provide specimen and/or mock-ups of the immediate and outer

packaging, labels and package leaflets for the medicinal product concerned.

1.3.4.

Summaries of product characteristics already approved in the Member

States

Annexed to the administrative data of the application form shall be copies of all

the summaries of product characteristics in accordance with Articles 11 and 21 as

approved by Member States, where applicable and a list of countries in which an

application has been submitted.

1.4.

Information about the experts

In accordance with Article 12(2) experts must provide detailed reports of their

observations on the documents and particulars which constitute the marketing

a u t h o r i sa t i o n d o s s i e r a n d i n p a r t i c u l a r o n M o d u l e s 3 , 4 a n d 5 ( c h e m i ca l ,

pharmaceutical and biological documentation, non-clinical documentation and

clinical documentation, respectively). The experts are required to address the critical

points related to the quality of the medicinal product and of the investigations

carried out on animals and human beings and bring out all the data relevant for

evaluation.

These requirements shall be met by providing a quality overall summary, a non-

clinical overview (data from studies carried out in animals) and a clinical overview

that shall be located in Module 2 of the marketing authorisation application dossier.

A declaration signed by the experts together with brief information on their

educational background, training and occupational experience shall be presented in

Module 1. The experts shall have suitable technical or professional qualifications.

The professional relationship of the expert to the applicant shall be declared.

1.5.

Specific requirements for different types of applications

Specific requirements for different types of applications are addressed in Part II of

this Schedule.

1.6.

Environmental risk assessment

Where applicable, applications for marketing authorisations shall include a risk

assessment overview evaluating possible risks to the environment due to the use and/

or disposal of the medicinal product and make proposals for appropriate labelling

provisions. Environmental risk connected with the release of medicinal products

containing or consisting of GMOs (Genetically Modified Organisms) within the

meaning of Article 2 of Directive 2001/18/EC of the European Parliament and of the

Council of 12March 2001 on the deliberate release into the environment of modified

organisms and repealing Council Directive 90/220/EEC (1) shall be addressed.

Information pertaining to the environmental risk shall appear as an appendix to

Module 1.

The information shall be presented in accordance with the provisions of Directive

2001/18/EC, taking into account any guidance documents published by the

Commission in connection with the implementation of the said Directive.

The information shall consist of

an introduction;

a copy of any written consent or consents to the deliberate release into

the environment of the GMO(s) for research and development purposes

according to Part B of Directive 2001/18/EC;

the information requested in Annexes II to IV of the Directive 2001/18/

EC, including detection and identification methods as well as unique

code of the GMO, plus any additional information on the GMO or the

product of relevance to evaluating the environmental risk;

an environment risk assessment (ERA) report prepared on basis of the

information specified in Annexes III and IV of Directive 2001/18/EC

and in accordance with Annex II of Directive 2001/18/EC;

taking into account the above information and the ERA, a conclusion

which proposes an appropriate risk management strategy which

includes, as relevant to the GMO and product in question, a post market

monitoring plan and the identification of any special particulars which

need to appear in the Summary of Product Characteristics, labelling and

package leaflet;

appropriate measures in order to inform the public.

A dated signature of the author, information on the author’s educational, training

and occupational experience, and a statement of the author’s relationship with the

applicant, shall be included.

2. MODULE 2: SUMMARIES

This Module aims to summarise the chemical, pharmaceutical and biological data,

the non-clinical data and the clinical data presented in Modules 3, 4 and 5 of the

dossier for marketing authorisation, and to provide the reports/overviews described

in Article 12 of this Directive.

Critical points shall be addressed and analysed. Factual summaries including

tabular formats shall be provided. Those reports shall provide cross-references to

tabular formats or to the information contained in the main documentation presented

in Module 3 (chemical, pharmaceutical and biological documentation), Module 4

(non-clinical documentation) and Module 5 (clinical documentation).

Information contained in Module 2 shall be presented in accordance with the

format, content and numbering system delineated in the Volume 2 of the Notice to

Applicants. The overviews and summaries shall comply with the basic principles and

requirements as laid down herewith

Overall table of contents

Module 2 shall contain a table of contents for the scientific documentation

submitted in Modules 2 to 5.

Introduction

Information on the pharmacological class, mode of action and proposed clinical

use of the medicinal product for which a marketing authorisation is requested shall

be supplied.

Quality overall summary

A review of the information related to the chemical, pharmaceutical and biological

data shall be provided in a quality overall summary.

Key critical parameters and issues related to quality aspects shall be emphasised

as well as justification in cases where the relevant guidelines are not followed. This

document shall follow the scope and outline of the corresponding detailed data

presented in Module 3.

2.4.

Non-clinical overview

An integrated and critical assessment of the non-clinical evaluation of the

medicinal product in animals/in vitro shall be required. Discussion and justification

of the testing strategy and of deviation from the relevant guidelines shall be

included.

Except for biological medicinal products, an assessment of the impurities and

degradation products shall be included along with their potential pharmacological

and toxicological effects. The implications of any differences in the chirality,

chemical form, and impurity profile between the compound used in the non-clinical

studies and the product to be marketed shall be discussed.

For biological medicinal products, comparability of material used in non-clinical

studies, clinical studies, and the medicinal product for marketing shall be assessed.

Any novel excipient shall be the subject of a specific safety assessment.

The characteristics of the medicinal product, as demonstrated by the non-clinical

studies shall be defined and the implications of the findings for the safety of the

medicinal product for the intended clinical use in humans shall be discussed.

2.5.

Clinical overview

The clinical overview is intended to provide a critical analysis of the clinical data

included in the clinical summary and Module 5. The approach to the clinical

development of the medicinal product, including critical study design, decisions

related to and performance of the studies shall be provided.

A brief overview of the clinical findings, including important limitations as well

as an evaluation of benefits and risks based on the conclusions of the clinical studies

shall be provided. An interpretation of the way the efficacy and safety findings

support the proposed dose and target indications and an evaluation of how the

summary of product characteristics and other approaches will optimise the benefits

and manage the risks is required.

Efficacy or safety issues encountered in development and unresolved issues shall

be explained.

2.6.

Non-clinical summary

The results of pharmacology, pharmaco-kinetics and toxicology studies carried out

in animals/in vitro shall be provided as factual written and tabulated summaries

which shall be presented in the following order

-

Introduction

-

Pharmacology Written Summary

-

Pharmacology Tabulated Summary

-

Pharmaco-kineticsWritten Summary

-

Pharmaco-kinetics Tabulated Summary

-

Toxicology Written Summary

-

Toxicology Tabulated Summary.

2.7.

Clinical Summary

A detailed, factual summary of the clinical information on the medicinal product

included in Module 5 shall be provided. This shall include the results of all bio-

pharmaceutics studies, of clinical pharmacology studies, and of clinical efficacy and

safety studies. A synopsis of the individual studies is required.

Summarised clinical information shall be presented in the following order

-

Summary of Bio-pharmaceutics and Associated Analytical Methods

-

Summary of Clinical Pharmacology Studies

-

Summary of Clinical Efficacy

-

Summary of Clinical Safety

-

Synopses of Individual Studies

3. MODULE 3: CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL

INFORMATION FOR MEDICINAL PRODUCTS CONTAINING CHEMICAL

AND/OR BIOLOGICAL ACTIVE SUBSTANCES

3.1.

Format and presentation

The general outline of Module 3 is as follows

-

Table of contents

-

Body of data

-

Active substance

General Information

-

Nomenclature

-

Structure

-

General Properties

Manufacture

-

Manufacturer(s)

-

Description of Manufacturing Process and Process Controls

-

Control of Materials

-

Controls of Critical Steps and Intermediates

-

Process Validation and/or Evaluation

-

Manufacturing Process Development

Characterisation

-

Elucidation of Structure and other Characteristics

-

Impurities

-

Control of Active Substance

-

Specification

-

Analytical Procedures

-

Validation of Analytical Procedures

-

Batch Analyses

-

Justification of Specification

Reference Standards or Materials

Container Closure System

Stability

-

Stability Summary and Conclusions

-

Post-approval Stability Protocol and Stability Commitment

Stability Data

Finished Medicinal Product

Description and Composition of the Medicinal Product

Pharmaceutical Development

Components of the Medicinal Product

Active Substance

Excipients

Medicinal Product

Formulation Development

Overages

Physicochemical and Biological Properties

Manufacturing Process Development

Container Closure System

Microbiological Attributes

Compatibility

Manufacture

Manufacturer(s)

Batch Formula

Description of Manufacturing Process and Process Controls

Controls of Critical Steps and Intermediates

Process Validation and/or Evaluation

Control of Excipients

Specifications

Analytical Procedures

Validation of Analytical Procedures

Justification of Specifications

Excipients of Human or Animal Origin

Novel Excipients

Control of Finished Medicinal Product

Specification(s)

Analytical Procedures

Validation of Analytical procedures

Batch Analyses

Characterisation of Impurities

Justification of Specification(s)

Reference Standards or Materials

Container Closure System

Stability

Stability Summary and Conclusion

Post-approval Stability Protocol and Stability Commitment

Stability Data

Appendices

Facilities and Equipment (Biological Medicinal Products

only)

-

Adventitious Agents Safety Evaluation

-

Excipients

-

European Community Additional Information

-

Process Validation Scheme for the Medicinal Product

-

Medical Device

-

Certificate(s) of Suitability

-

Medicinal products containing or using in the

manufacturing process materials of animal and/or human

origin (TSE procedure)

-

Literature References

3.2.

Content: basic principles and requirements

(1) The chemical, pharmaceutical and biological data that shall be provided

shall include for the active substance(s) and for the finished medicinal product all of

relevant information on: the development, the manufacturing process, the

characterisation and properties, the quality control operations and requirements, the

stability as well as a description of the composition and presentation of the finished

medicinal product.

(2) Two main sets of information shall be provided, dealing with the active

substance(s) and with the finished medicinal product, respectively.

(3) This Module shall in addition supply detailed information on the starting

and raw m aterials used during the manufacturing operat ions of the active

substance(s) and on the excipients incorporated in the formulation of the finished

medicinal product.

(4) All the procedures and methods used for manufacturing and controlling the

active substance and the finished medicinal product shall be described in sufficient

details to enable them to be repeated in control tests, carried out at the request of the

competent authority. All test procedures shall correspond to the state of scientific

progress at the time and shall be validated. Results of the validation studies shall be

provided. In the case of test procedures included in the European Pharmacopoeia,

this description shall be replaced by the appropriate detailed reference to the

monograph(s) and general chapter(s).

(5) The monographs of the European Pharmacopoeia shall be applicable to all

substances, preparations and pharmaceutical forms appearing in it. In respect of

other substances, each Member State may require observance of its own national

pharmacopoeia.

H o w e v e r, w h e r e a m a t e r i a l i n t h e E u r o p e a n P h a r m a c o p o e i a o r i n t h e

pharmacopoeia of a Member State has been prepared by a method liable to leave

impurities not controlled in the pharmacopoeia monograph, these impurities and

their maximum tolerance limits must be declared and a suitable test procedure must

be described. In cases where a specification contained in a monograph of the

European Pharmacopoeia or in the national pharmacopoeia of a Member State might

be insufficient to ensure the quality of the substance, the competent authorities may

request more appropriate specifications from the marketing authorisation holder. The

competent authorities shall inform the authorities responsible for the pharmacopoeia

in question. The marketing authorisation holder shall provide the authorities of that

pharmacopoeia with the details of the alleged insufficiency and the additional

specifications applied.

In the case of analytical procedures included in the European Pharmacopoeia, this

description shall be replaced in each relevant section by the appropriate detailed

reference to the monograph(s) and general chapter(s).

(6) In case where starting and raw materials, active substance(s) or excipient(s)

are described neither in the European Pharmacopoeia nor in the pharmacopoeia of a

Member State, compliance with the monograph of a third country pharmacopoeia

can be accepted. In such cases, the applicant shall submit a copy of the monograph

accompanied by the validation of the analytical procedures contained in the

monograph and by a translation where appropriate.

(7) Where the active substance and/or a raw and starting material or excipient(s)

are the subject of a monograph of the European Pharmacopoeia, the applicant can

apply for a certificate of suitability that, where granted by the European Directorate

for the Quality of Medicines, shall be presented in the relevant section of this

Module. Those certificates of suitability of the monograph of the European

Pharmacopoeia are deemed to replace the relevant data of the corresponding sections

described in this Module. The manufacturer shall give the assurance in writing to the

applicant that the manufacturing process has not been modified since the granting of

the certificate of suitability by the European Directorate for the Quality of

Medicines.

(8) For a well-defined active substance, the active substance manufacturer or

the applicant may arrange for the

(i)

detailed description of the manufacturing process,

(ii) quality control during manufacture, and

(iii) process validation

to be supplied in a separate document directly to the competent authorities by the

manufacturer of the active substance as an Active Substance Master File.

In this case, the manufacturer shall, however, provide the applicant with all of the

data, which may be necessary for the latter to take responsibility for the medicinal

product. The manufacturer shall confirm in writing to the applicant that he shall

ensure batch to batch consistency and not modify the manufacturing process or

specifications without informing the applicant.

Documents and particulars supporting the application for such a change shall be

supplied to the competent authorities; these documents and particulars will be also

supplied to the applicant when they concern the open part of the active substance

master file.

(9) Specific measures concerning the prevention of the transmission of animal

spongiform encephalopathies (materials from ruminant origin): at each step of the

manufacturing process, the applicant must demonstrate the compliance of the

materials used with the Note for Guidance on Minimising the Risk of Transmitting

Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates,

published by the Commission in the Official Journal of the European Union.

Demonstration of compliance with the said Note for Guidance can be done by

submitting either, preferably a certificate of suitability to the relevant monograph of

the European Pharmacopoeia that has been granted by the European Directorate for

the Quality of Medicines or by the supply of scientific data to substantiate this

compliance.

(10) For adventitious agents, information assessing the risk with respect to

potential contamination with adventitious agents, whether they are non-viral or viral,

as laid down in relevant guidelines as well as in relevant general monograph and

general chapter of the European Pharmacopoeia, shall be provided.

(11) Any special apparatus and equipment, which may be used at any stage of the

manufacturing process and control operations of the medicinal product, shall be

described in adequate details.

(12) Where applicable and if needed, a CE marking which is required by

Community legislation on medical devices shall be provided. Special attention shall

be paid to the following selected elements.

3.2.1.

Active substance(s)

3.2.1.1.

General information and information related to the starting and raw

materials

(a) Information on the nomenclature of the active substance shall be provided,

including recommended International Non-proprietary Name (INN), European

Pharmacopoeia name if relevant, chemical name(s).

The structural formula, including relative and absolute stereo-chemistry, the

molecular formula, and the relative molecular mass shall be provided. For

biotechnological medicinal products if appropriate, the schematic amino acid

sequence and relative molecular mass shall be provided.

A list shall be provided of physicochemical and other relevant properties of the

active substance, including biological activity for biological medicinal products.

(b) For the purposes of this Schedule, starting materials shall mean all the

materials from which the active substance is manufactured or extracted.

For biological medicinal products, starting materials shall mean any substance of

biological origin such as micro-organisms, organs and tissues of either plant or

animal origin, cells or fluids (including blood or plasma) of human or animal origin,

and biotechnological cell constructs (cell substrates, whether they are recombinant

or not, including primary cells).

A biological medicinal product is a product, the active substance of which is a

biological substance.

A biological substance is a substance that is produced by or extracted from a

biological source and that needs for its characterisation and the determination of its

quality a combination of physicochemical-biological testing, together with the

production process and its control. The following shall be considered as biological

medicinal products: immunological medicinal products and medicinal products

derived from human blood and human plasma as defined, respectively in paragraphs

(4) and (10) of Article 1; medicinal products falling within the scope of Part A of the

Annex to Regulation (EEC) No 2309/93; advanced therapy medicinal products as

defined in Part IV of this Schedule.

Any other substances used for manufacturing or extracting the active substance(s)

but from which this active substance is not directly derived, such as reagents, culture

media, foetal calf serum, additives, and buffers involved in chromatography, etc. are

known as raw materials.

3.2.1.2.

Manufacturing process of the active substance(s)

(a) The description of the active substance manufacturing process represents the

applicant’s commitment for the manufacture of the active substance. To adequately

describe the manufacturing process and process controls, appropriate information as

laid down in guidelines published by the Agency shall be provided.

(b) All materials needed in order to manufacture the active substance(s) shall be

listed, identifying where each material is used in the process. Information on the

quality and control of these materials shall be provided. Information demonstrating

that materials meet standards appropriate for their intended use shall be provided.

Raw materials shall be listed and their quality and controls shall also be

documented.

The name, address, and responsibility of each manufacturer, including contractors,

and each proposed production site or facility involved in manufacturing and testing

shall be provided.

(c) For biological medicinal products, the following additional requirements

shall apply. The origin and history of starting materials shall be described and

documented. Regarding the specific measures for the prevention of the Transmission

of animal Spongiform Encephalopathies, the applicant must demonstrate that the

active substance complies with the Note for Guidance on Minimising the Risk of

Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products

and its updates, published by the Commission in the Official Journal of the European

Union.

When cell banks are used, the cell characteristics shall be shown to have remained

unchanged at the passage level used for the production and beyond.

Seed materials, cell banks, pools of serum or plasma and other materials of

biological origin and, whenever possible, the materials from which they are derived

shall be tested for adventitious agents.

If the presence of potentially pathogenic adventitious agents is inevitable, the

corresponding material shall be used only when further processing ensures their

elimination and/or inactivation, and this shall be validated.

Whenever possible, vaccine production shall be based on a seed lot system and on

established cell banks. For bacterial and viral vaccines, the characteristics of the

infectious agent shall be demonstrated on the seed. In addition, for live vaccines, the

stability of the attenuation characteristics shall be demonstrated on the seed; if this

proof is not sufficient, the attenuation characteristics shall also be demonstrated at

the production stage.

For medicinal products derived from human blood or plasma, the origin and the

criteria and procedures for collection, transportation and storage of the starting

material shall be described and documented in accordance with provisions laid down

in Part III of this Schedule.

The manufacturing facilities and equipment shall be described.

(d) Tests and acceptance criteria carried out at every critical step, information

on the quality and control of intermediates and process validation and/or evaluation

studies shall be provided as appropriate.

(e) If the presence of potentially pathogenic adventitious agents is inevitable,

the correspondent material shall be used only when further processing ensures their

elimination and/or inactivation and this shall be validated in the section dealing with

viral safety evaluation.

(f)

A description and discussion of the significant changes made to the

manufacturing process during development and/or manufacturing site of the active

substance shall be provided.

3.2.1.3.1. Characterisation of the active substance(s)

Data highlighting the structure and other characteristics of the active substance(s)

shall be provided.

Confirmation of the structure of the active substance(s) based on any physico-

chemical and/or immunochemical and/or biological methods, as well as information

on impurities shall be provided.

3.2.1.3.2. Control of active substance(s)

Detailed information on the specifications used for routine control of active

substance(s), justification for the choice of these specifications, methods of analysis

and their validation shall be provided. The results of control carried out on

individual batches manufactured during development shall be presented.

3.2.1.3.3. Reference standards or materials

Reference preparations and standards shall be identified and described in detail.

Where relevant, chemical and biological reference material of the European

Pharmacopoeia shall be used.

Container and closure system of the active substance

A description of the container and the closure system(s) and their specifications

shall be provided.

Stability of the active substance(s)

(a)

The types of studies conducted, protocols used, and the results of the

studies shall be summarized

(b)

Detailed results of the stability studies, including information on the

analytical procedures used to generate the data and validation of these procedures

shall be presented in an appropriate format

(c)

The post authorisation stability protocol and stability commitment shall

be provided

Finished medicinal product

Description and composition of the finished medicinal product

A description of the finished medicinal product and its composition shall be

provided. The information shall include the description of the pharmaceutical form

and composition with all the constituents of the finished medicinal product, their

amount on a per-unit basis, the function of the constituents of

the active substance(s),

the constituent(s) of the excipients, whatever their nature or the quantity

used, including colouring matter, preservatives, adjuvants, stabilisers,

thickeners, emulsifiers, flavouring and aromatic substances, etc.,

the constituents, intended to be ingested or otherwise administered to

the patient, of the outer covering of the medicinal products (hard

capsules, soft capsules, rectal capsules, coated tablets, films-coated

tablets, etc.),

these particulars shall be supplemented by any relevant data concerning

the type of container and, where appropriate, its manner of closure,

together with details of devices with which the medicinal product will

be used or administered and which will be delivered with the medicinal

product.

The ‘usual terminology’, to be used in describing the constituents of medicinal

products, shall mean, notwithstanding the application of the other provisions in

Article 8 (3)(c)

in respect of substances which appear in the European Pharmacopoeia

or, failing this, in the national pharmacopoeia of one of the Member

States, the main title at the head of the monograph in question, with

reference to the pharmacopoeia concerned,

-

in respect of other substances, the international non-proprietary name

(INN) recommended by the World Health Organisation, or, failing this,

the exact scientific designation; substances not having an international

non-proprietary name or an exact scientific designation shall be

described by a statement of how and from what they were prepared,

supplemented, where appropriate, by any other relevant details,

-

in respect of colouring matter, designation by the ‘E’ code assigned to

them in Council Directive 78/25/EEC of 12 December 1977 on the

approximation of the rules of the Member States concerning the

colouring matters authorised for use in medicinal products and/or

European Parliament and Council Directive 94/36/EC of 30 June 1994

on colours for use in foodstuffs.

In order to give the ‘quantitative composition’ of the active substance(s) of the

finished medicinal products, it is necessary, depending on the pharmaceutical form

concerned, to specify the mass, or the number of units of biological activity, either

per dosage-unit or per unit of mass or volume, of each active substance.

Active substances present in the form of compounds or derivatives shall be

designated quantitatively by their total mass, and if necessary or relevant, by the

mass of active entity or entities of the molecule.

For medicinal products containing an active substance, which is the subject of an

application for marketing authorisation in any Member State for the first time, the

quantitative statement of an active substance, which is a salt or hydrate shall be

systematically expressed in terms of the mass of the active entity or entities in the

molecule. All subsequently authorised medicinal products in the Member States

shall have their quantitative composition stated in the same way for the same active

substance.

Units of biological activity shall be used for substances, which cannot be defined

molecularly. Where an International Unit of biological activity has been defined by

the World Health Organisation, this shall be used. Where no International Unit has

been defined, the units of biological activity shall be expressed in such a way as to

provide unambiguous information on the activity of the substances by using where

applicable the European Pharmacopoeia Units.

3.2.2.2.

Pharmaceutical development

This chapter shall be devoted to information on the development studies

conducted to establish that the dosage form, the formulation, manufacturing process,

container closure system, microbiological attributes and usage instructions are

appropriate for the intended use specified in the marketing authorisation application

dossier.

The studies described in this chapter are distinct from routine control tests

conducted according to specifications.

Critical parameters of the formulation and process attributes that can influence

batch reproducibility, medicinal product performance and medicinal product quality

shall be identified and described. Additional supportive data, where appropriate,

shall be referenced to the relevant chapters of Module 4 (Non Clinical Study

Reports) and Module 5 (Clinical Study Reports) of the marketing authorisation

application dossier.

(a) The compatibility of the active substance with excipients as well as key

physicochemical characteristics of the active substance that can influence the

performance of the finished product or the compatibility of different active

s u b s t a n c e s w i t h e a c h o t h e r i n t h e c a s e o f co m b i n a t i o n p r o d u c t s , s h a l l b e

documented.

(b) The choice of excipients, in particular relative to their respective functions

and concentration shall be documented.

(c) A description of the development of the finished product shall be provided,

taking into consideration the proposed route of administration and usage.

(d)

Any overages in the formulation(s) shall be warranted.

(e) As far as the physiochemical and biological properties are concerned, any

parameter relevant to the performance of finished product shall be addressed and

documented.

(f)

The selection and optimisation of the manufacturing process as well as

differences between the manufacturing process(es) used to produce pivotal clinical

batches and the process used for manufacturing the proposed finished medicinal

product shall be provided.

(g) The suitability of the container and closure system used for the storage,

shipping and use of the finished product shall be documented. A possible interaction

between medicinal product and container may need to be considered.

(h) The microbiological attributes of the dosage form in relation with non-

sterile and sterile products shall be in accordance with and documented as prescribed

in the European Pharmacopoeia.

(i)

In order to provide appropriate and supportive information for the labelling

the compatibility of the finished product with reconstitution diluent(s) or dosage

devices shall be documented.

3.2.2.3.

Manufacturing process of the finished medicinal product

(a) The description of the manufacturing method accompanying the application

for Marketing Authorisation pursuant to Article 8(3)(d), shall be drafted in such a

way as to give an adequate synopsis of the nature of the operations employed.

For this purpose it shall include at least

-

mention of the various stages of manufacture including process controls

and corresponding acceptance criteria, so that an assessment can be

made of whether the processes employed in producing the

pharmaceutical form might have produced an adverse change in the

constituents,

-

in the case of continuous manufacture, full details concerning

precautions taken to ensure the homogeneity of the finished product,

-

experimental studies validating the manufacturing process, where a

non-standard method of manufacture is used or where it is critical for

the product,

-

for sterile medicinal products, details of the sterilisation processes and/

or aseptic procedures used,

-

a detailed batch formula.

The name, address, and responsibility of each manufacturer, including contractors,

and each proposed production site or facility involved in manufacturing and testing

shall be provided.

(b) Particulars relating to the product control tests that may be carried out at an

intermediate stage of the manufacturing process, with a view to ensuring the

consistency of the production process shall be included.

These tests are essential for checking the conformity of the medicinal product with

the formula when, exceptionally, an applicant proposes an analytical method for

testing the finished product which does not include the assay of all the active

substances (or of all the excipient constituents subject to the same requirements as

the active substances).

The same applies where the quality control of the finished product depends on in-

process control tests, particularly if the medicinal product is essentially defined by

its method of preparation.

(c) Description, documentation, and results of the validation studies for critical

steps or critical assays used in the manufacturing process shall be provided.

3.2.2.4.

Control of excipients

(a) All the materials needed in order to manufacture the excipient(s) shall be

listed identifying where each material is used in the process. Information on the

quality and control of these materials shall be provided. Information demonstrating

that materials meet standards appropriate for their intended use shall be provided.

Colouring matter shall, in all cases, satisfy the requirements of Directives 78/25/

EEC and/or 94/36/EC. In addition, colouring matter shall meet purity criteria as laid

down in Directive 95/45/EC, as amended.

(b) For each excipient, the specifications and their justifications shall be

detailed. The analytical procedures shall be described and duly validated.

(c) Specific attention shall be paid to excipients of human or animal origin.

Regarding the specific measures for the prevention of the Transmission of animal

Spongiform Encephalopathies, the applicant must demonstrate also for excipients

that the medicinal product is manufactured in accordance with the Note for Guidance

on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents

via Medicinal Products and its updates, published by the Commission in the Official

Journal of the European Union. Demonstration of compliance with the

aforementioned Note for Guidance can be done by submitting either preferably a

certificate of suitability to the relevant monograph on Transmissible Spongiform

Encephalopathies of the European Pharmacopoeia, or by the supply of scientific data

to substantiate this compliance.

(d)

Novel excipients

For excipient(s) used for the first time in a medicinal product or by a new route of

administration, full details of manufacture, characterisation, and controls, with cross

references to supporting safety data, both non-clinical and clinical, shall be provided

according to the active substance format previously described.

A document containing the detailed chemical, pharmaceutical and biological

information shall be presented. This information shall be formatted in the same order

as the chapter devoted to Active Substance(s) of Module 3.

Information on novel excipient(s) may be presented as a stand-alone document

following the format described in the former paragraphs. Where the applicant differs

from the novel excipient manufacturer the said stand-alone document shall be made

available to the applicant for submission to the competent authority.

Additional information on toxicity studies with the novel excipient shall be

provided in Module 4 of the dossier.

Clinical studies shall be provided in Module 5.

3.2.2.5.

Control of the finished medicinal product

For the control of the finished medicinal product, a batch of a medicinal product is

an entity which comprises all the units of a pharmaceutical form which are made

from the same initial quantity of material and have undergone the same series of

manufacturing and/or sterilisation operations or, in the case of a continuous

production process, all the units manufactured in a given period of time.

Unless there is appropriate justification, the maximum acceptable deviation in the

active substance content of the finished product shall not exceed ± 5% at the time of

manufacture.

Detailed information on the specifications, (release and shelf life) justification for

their choice, methods of analysis and their validation shall be provided.

3.2.2.6.

Reference standards or materials

Reference preparations and standards used for testing of the finished medicinal

product shall be identified and described in detail, if not previously provided in the

section related to the active substance.

3.2.2.7.

Container and closure or the finished medicinal product

A description of the container and the closure system(s) including the identity of

each immediate packaging material and their specifications shall be provided. The

specifications shall include description and identification. Non-pharmacopoeial

methods (with validation) shall be included where appropriate.

For non-functional outer packaging materials only a brief description shall be

provided. For functional outer packaging materials additional information shall be

provided.

3.2.2.8.

Stability of the finished medicinal product

(a) The types of studies conducted, protocols used, and the results of the studies

shall be summarized;

(b) Detailed results of the stability studies, including information on the

analytical procedures used to generate the data and validation of these procedures

shall be presented in an appropriate format; in case of vaccines, information on

cumulative stability shall be provided where appropriate;

(c) The post authorisation stability protocol and stability commitment shall be

provided.

4. MODULE 4: NON-CLINICAL REPORTS

4.1.

Format and Presentation

The general outline of Module 4 is as follows

-

Table of contents

-

Study reports

-

Pharmacology

-

Primary Pharmaco-dynamics

-

Secondary Pharmaco-dynamics

-

Safety Pharmacology

-

Pharmaco-dynamic Interactions

-

Pharmaco-kinetics

-

Analytical Methods and Validation Reports

-

Absorption

-

Distribution

-

Metabolism

-

Excretion

-

Pharmaco-kinetic Interactions (non-clinical)

-

Other Pharmaco-kinetic Studies

-

Toxicology

-

Single-Dose Toxicity

-

Repeat-Dose Toxicity

-

Genotoxicity

- In vitro

- In

vivo

(including

supportive

toxico-kinetics

evaluations)

-

Carcinogenicity

- Long-term studies

- Short- or medium-term studies

- Other studies

-

Reproductive and Developmental Toxicity

- Fertility and early embryonic development

- Embryo-fetal development

- Prenatal and postnatal development

- Studies in which the offspring (juvenile animals) are

dosed and/or further evaluation

-

Local Tolerance

-

Other Toxicity Studies

-

Antigenicity

-

Immuno-toxicity

-

Mechanistic studies

-

Dependence

-

Metabolites

-

Impurities

-

Other

-

Literature references

Content: basic principles and requirements

Special attention shall be paid to the following selected elements.

(1)

The pharmacological and toxicological tests must show

(a) the potential toxicity of the product and any dangerous or undesirable

toxic effects that may occur under the proposed conditions of use in

human beings; these should be evaluated in relation to the pathological

condition concerned;

(b) the pharmacological properties of the product, in both qualitative and

quantitative relationship to the proposed use in human beings. All

results must be reliable and of general applicability.

Whenever appropriate, mathematical and statistical procedures shall be used in

designing the experimental methods and in evaluating the results. Additionally, it is

necessary for clinicians to be given information about the therapeutic and

toxicological potential of the product.

(2) For biological medicinal products such as immunological medicinal

products and medicinal products derived from human blood or plasma, the

requirements of this Module may have to be adapted for individual products;

therefore the testing program carried out shall be justified by the applicant.

In establishing the testing program, the following shall be taken into

consideration

all tests requiring repeated administration of the product shall be

designed to take account of the possible induction of, and interference

by, antibodies;

examination of reproductive function, of embryo/foetal and peri-natal

toxicity, of mutagenic potential and of carcinogenic potential shall be

considered. Where constituents other than the active substance(s) are

incriminated, validation of their removal may replace the study.

(3) The toxicology and pharmaco-kinetics of an excipient used for the first time

in the pharmaceutical field shall be investigated.

(4) Where there is a possibility of significant degradation during storage of the

medicinal product, the toxicology of degradation products must be considered.

4.2.1.

Pharmacology

Pharmacology study shall follow two distinct lines of approach.

-

Firstly, the actions relating to the proposed therapeutic use shall be

adequately investigated and described. Where possible, recognised and validated

assays, both in vivo and in vitro, shall be used.

Novel experimental techniques must be described in such detail as to allow them

to be reproduced.

The results shall be expressed in quantitative terms using, for example, dose-effect

curves, timeeffect curves, etc.

Wherever possible, comparisons shall be made with data relating to a substance or

substances with a similar therapeutic action.

-

Secondly, the applicant shall investigate the potential undesirable pharmaco-

dynamic effects of the substance on physiological functions. These investigations

shall be performed at exposures in the anticipated therapeutic range and above.

The experimental techniques, unless they are standard procedures, must be

described in such detail as to allow them to be reproduced, and the investigator must

establish their validity. Any suspected modification of responses resulting from

repeated administration of the substance shall be investigated.

For the pharmaco-dynamic medicinal product interaction, tests on combinations of

active substances may be prompted either by pharmacological premises or by

indications of therapeutic effect. In the first case, the pharmaco-dynamic study shall

demonstrate those interactions, which might make the combination of value in

therapeutic use. In the second case, where scientific justification for the combination

is sought through therapeutic experimentation, the investigation shall determine

whether the effects expected from the combination can be demonstrated in animals,

and the importance of any collateral effects shall at least be investigated.

4.2.2.

Pharmaco-kinetics

Pharmaco-kinetics means the study of the fate of the active substance, and its

met aboli tes, w ith in t he organism , and co vers t he stud y of th e absorp tion ,

distribution, metabolism (bio-transformation) and excretion of these substances.

The study of these different phases may be carried mainly by means of physical,

chemical or possibly by biological methods, and by observation of the actual

pharmaco-dynamic activity of the substance itself. Information on distribution and

elimination shall be necessary in all cases where such data are indispensable to

determine the dosage for humans, and in respect of chemo-therapeutic substances

(antibiotics, etc.) and substances whose use depends on their non-pharmaco-dynamic

effects (e.g. numerous diagnostic agents, etc.).

In vitro studies also can be carried out with the advantage of using human material

for comparison with animal material (i.e. protein binding, metabolism, drug-drug

interaction).

Pharmaco-kinetic investigation of all pharmacologically active substances is

necessary. In the case of new combinations of known substances, which have been

investigated in accordance with the provisions of this Directive, pharmaco-kinetic

studies may not be required, if the toxicity tests and therapeutic experimentation

justify their omission.

The pharmaco-kinetic program shall be design to allow comparison and

extrapolation between animal and human.

4.2.3.

Toxicology

(a)

Single-dose toxicity

A single-dose toxicity test shall mean a qualitative and quantitative study of the

toxic reactions, which may result from a single administration of the active

substance or substances contained in the medicinal product, in the proportions and

physico-chemical state in which they are present in the actual product.

The single-dose toxicity test must be carried out in accordance with the relevant

guidelines published by the Agency.

(b)

Repeat-dose toxicity

Repeated dose toxicity tests are intended to reveal any physiological and/or

anatomo-pathological changes induced by repeated administration of the active

substance or combination of active substances under examination, and to determine

how these changes are related to dosage.

Generally, it is desirable that two tests be performed: one short term, lasting two to

four weeks, the other long-term.

The duration of the latter shall depend on the conditions of clinical use. Its

purpose is to describe potential adverse effects to which attention should be paid in

clinical studies. The duration is defined in the relevant guidelines published by the

Agency.

(c)

Geno-toxicity

The purposes of the study of mutagenic and clastogenic potential is to reveal the

changes which a substance may cause in the genetic material of individuals or cells.

Mutagenic substances may present a hazard to health since exposure to a mutagen

carries the risk of inducing germ-line mutation, with the possibility of inherited

disorders, and the risk of somatic mutations including those leading to cancer. These

studies are obligatory for any new substance.

(d)

Carcino-genicity

Tests to reveal carcinogenic effects shall normally be required

1. These studies shall be performed for any medicinal product whose

expected clinical use is for a prolonged period of a patient’s life, either

continuously or repeatedly in an intermittent manner.

2. These studies are recommended for some medicinal products if there is

concern about their carcinogenic potential, e.g. from product of the

same class or similar structure, or from evidence in repeated dose

toxicity studies.

3. Studies with unequivocally geno-toxic compounds are not needed, as

they are presumed to be trans-species carcinogens, implying a hazard to

humans. If such a medicinal product is intended to be administered

chronically to humans a chronic study may be necessary to detect early

tumorigenic effects.

(e)

Reproductive and developmental toxicity

Investigation of possible impairment of male or female reproductive function as

well as harmful effects on progeny shall be performed by appropriate tests.

These tests comprise studies of effect on adult male or female reproductive

function, studies of the toxic and teratogenic effects at all stages of development

from conception to sexual maturity as well as latent effects, when the medicinal

product under investigation has been administered to the female during pregnancy.

Omission of these tests must be adequately justified.

Depending on the indicated use of the medicinal product, additional studies

addressing development when administering the medicinal product of the offspring

may be warranted. Embryo/foetal toxicity studies shall normally be conducted on

two mammalian species, one of which shall be other than a rodent. Peri- and

postnatal studies shall be conducted in at least one species. If the metabolism of a

medicinal product in particular species is known to be similar to that in man, it is

desirable to include this species. It is also desirable that one of the species is the

same as in the repeated dose toxicity studies.

The state of scientific knowledge at the time when the application is lodged shall

be taken into account when determining the study design.

(f)

Local tolerance

The purpose of local tolerance studies is to ascertain whether medicinal products

(both active substances and excipients) are tolerated at sites in the body, which may

come into contact with the medicinal product as a result of its administration in

clinical use. The testing strategy shall be such that any mechanical effects of

a d m i n i s t r a t i o n o r p u r e l y p h y s i c o - c h e m i c a l a c t i o n s o f t h e p r o d u ct c a n b e

distinguished from toxicological or pharmaco-dynamic ones.

Local tolerance testing shall be conducted with the preparation being developed

for human use, using the vehicle and/or excipients in treating the control group(s).

Positive controls/reference substances shall be included where necessary.

The design of local tolerance tests (choice of species, duration, frequency and

route of administration, doses) will depend upon the problem to be investigated and

the proposed conditions of administration in clinical use. Reversibility of local

lesions shall be performed where relevant. Studies in animals can be substituted by

validated in vitro tests provided that the test results are of comparable quality and

usefulness for the purpose of safety evaluation.

For chemicals applied to the skin (e.g. dermal, rectal, vaginal) the sensitising

potential shall be evaluated in at least one of the test systems currently available (the

guinea pig assay or the local lymph node assay).

5. MODULE 5: CLINICAL STUDY REPORTS

Format and Presentation

The general outline of Module 5 is as follows

Table of contents for clinical study reports

Tabular listing of all clinical studies

Clinical study reports

Reports of Bio-pharmaceutical Studies

- Bio-availability Study Reports

- Comparative Bio-availability and Bio-equivalence Study

Reports

- In vitro - In vivo Correlation Study Report

- Reports of Bio-analytical and Analytical Methods

Reports of Studies Pertinent to Pharmaco-kinetics Using Human

Bio-materials

- Plasma Protein Binding Study Reports

- Reports of Hepatic Metabolism and Interaction Studies

- Reports of Studies Using Other Human Bio-materials

Reports of Human Pharmaco-kinetic Studies

- Healthy subjects Pharmaco-kinetics and Initial Tolerability

Study Reports

- Patient Pharmaco-kinetics and Initial Tolerability Study

Reports

- Intrinsic Factor Pharmaco-kinetics Study Reports

- Extrinsic Factor Pharmaco-kinetics Study Reports

- Population Pharmaco-kinetics Study Reports

Reports of Human Pharmaco-dynamic Studies

- Healthy Subject Pharmaco-dynamic and Pharmaco-kinetics/

Pharmaco-dynamic Study Reports

- Patient Pharmaco-dynamic and Pharmaco-kinetics/Pharmaco-

dynamic Studies Study Reports

Reports of Efficacy and Safety Studies

- Study Reports of Controlled Clinical Studies Pertinent to the

Claimed Indication

- Study Reports of Uncontrolled Clinical Studies

- Reports of Analyses of Data from More than One Study

including any formal integrated analyses, meta-analyses and

bridging analyses

- Other Study Reports

Reports of Post-marketing Experience

Literature references

Content: basic principles and requirements

Special attention shall be paid to the following selected elements.

(a) The clinical particulars to be provided pursuant to Articles 8(3)(i) and 10(1)

must enable a sufficiently well-founded and scientifically valid opinion to be formed

as to whether the medicinal product satisfies the criteria governing the granting of a

marketing authorisation. Consequently, an essential requirement is that the results of

all clinical trials should be communicated, both favourable and unfavourable.

(b) Clinical trials must always be preceded by adequate pharmacological and

toxicological tests, carried out on animals in accordance with the requirements of

Module 4 of this Schedule. The investigator must acquaint himself with the

conclusions drawn from the pharmacological and toxicological studies and hence the

applicant must provide him at least with the investigator’s brochure, consisting of all

the relevant information known prior to the onset of a clinical trial including

chemical, pharmaceutical and biological data, toxicological, pharmaco-kinetic and

pharmaco-dynamic data in animals and the results of earlier clinical trials, with

adequate data to justify the nature, scale and duration of the proposed trial; the

complete pharmacological and toxicological reports shall be provided on request.

For materials of human or animal origin, all available means shall be employed to

ensure safety from transmission of infectious agents prior to the commencement of

(c) Marketing authorisation holders must arrange for essential clinical trial

documents (including case report forms) other than subject’s medical files, to be

kept by the owners of the data

for at least 15 years after completion or discontinuation of the trial,

or for at least two years after the granting of the last marketing

authorisation in the European Community and when there are no

pending or contemplated marketing applications in the European

Community,

or for at least two years after formal discontinuation of clinical

development of the investigational product.

Subject’s medical files should be retained in accordance with applicable

legislation and in accordance with the maximum period of time

permitted by the hospital, institution or private practice.

The documents can be retained for a longer period, however, if required

by the applicable regulatory requirements or by agreement with the

sponsor. It is the responsibility of the sponsor to inform the hospital,

institution or practice as to when these documents no longer need to be

retained.

The sponsor or other owner of the data shall retain all other

documentation pertaining to the trial as long as the product is

authorised. This documentation shall include: the protocol including the

rationale, objectives and statistical design and methodology of the trial,

with conditions under which it is performed and managed, and details of

the investigational product, the reference medicinal product and/or the

placebo used; standard operating procedures; all written opinions on the

protocol and procedures; the investigator’s brochure; case report forms

on each trial subject; final report; audit certificate(s), if available. The

final report shall be retained by the sponsor or subsequent owner, for

five years after the medicinal product is no longer authorised.

In addition for trials conducted within the European Community, the

marketing authorisation holder shall make any additional arrangements

for archiving of documentation in accordance with the provisions of

Directive 2001/20/EC and implementing detailed guidelines.

Any change of ownership of the data shall be documented.

All data and documents shall be made available if requested by relevant

authorities.

(d) The particulars of each clinical trial must contain sufficient detail to allow

an objective judgment to be made

the protocol, including the rationale, objectives and statistical design

and methodology of the trial, with conditions under which it is

performed and managed, and details of the investigational medicinal

product used

audit certificate(s), if available

the list of investigator(s), and each investigator shall give his name,

address, appointments, qualifications and clinical duties, state where the

trial was carried out and assemble the information in respect of each

patient individually, including case report forms on each trial subject

final report signed by the investigator and for multi-centre trials, by all

the investigators or the coordinating (principal) investigator.

(e) The particulars of clinical trials referred to above shall be forwarded to the

competent authorities. However, in agreement with the competent authorities, the

applicant may omit part of this information. Complete documentation shall be

provided forthwith upon request.

The investigator shall, in his conclusions on the experimental evidence, express an

opinion on the safety of the product under normal conditions of use, its tolerance, its

efficacy and any useful information relating to indications and contra-indications,

dosage and average duration of treatment as well as any special precautions to be

taken during treatment and the clinical symptoms of over dosage. In reporting the

results of a multi-centre study, the principal investigator shall, in his conclusions,

express an opinion on the safety and efficacy of the investigational medicinal

product on behalf of all centres.

(f)

The clinical observations shall be summarised for each trial indicating

(1) the number and sex of subjects treated;

(2) the selection and age-distribution of the groups of patients being

investigated and the comparative tests;

(3) the number of patients withdrawn prematurely from the trials and the

reasons for such withdrawal;

(4) where controlled trials were carried out under the above conditions,

whether the control group

-

received no treatment

-

received a placebo

-

received another medicinal product of known effect

-

received treatment other than therapy using medicinal products;

(5) the frequency of observed adverse reactions;

(6) details concerning patients who may be at increased risk, e.g. elderly

people, children, women during pregnancy or menstruation, or whose

physiological or pathological condition requires special consideration;

(7) parameters or evaluation criteria of efficacy and the results in terms of

these parameters;

(8) a statistical evaluation of the results when this is called for by the

design of the trials and the variable factors involved.

(g)

In addition, the investigator shall always indicate his observations on

(1) any signs of habituation, addiction or difficulty in weaning patients

from the medicinal product;

(2) any interactions that have been observed with other medicinal products

administered concomitantly;

(3) the criteria determining exclusion of certain patients from the trials;

(4) any deaths which occurred during the trial or within the follow-up

period.

(h) Particulars concerning a new combination of medicinal substances must be

identical to those required for new medicinal products and must substantiate the

safety and efficacy of the combination.

(i)

Total or partial omission of data must be explained. Should unexpected

results occur during the course of the trials, further pre clinical toxicological and

pharmacological tests must be undertaken and reviewed.

(j)

If the medicinal product is intended for long-term administration, particulars

shall be given of any modification of the pharmacological action following repeated

administration, as well as the establishment of long-term dosage.

5.2.1.

Reports of bio-pharmaceutics studies

Bio-availability study reports, comparative bio-availability, bio-equivalence study

reports, reports on in vitro and in vivo correlation study, and bio-analytical and

analytical methods shall be provided.

In addition, an assessment of bio-availability shall be undertaken where necessary

to demonstrate bioequivalence for the medicinal products referred to in Article

10(1)(a).

5.2.2.

Reports of studies pertinent to pharmaco-kinetics using human bio-

materials

For the purposes of this Schedule, human bio-materials shall mean any proteins,

cells, tissues and related materials derived from human sources that are used in vitro

or ex vivo to assess pharmaco-kinetics properties of drug substances.

In this respect, reports of plasma protein binding study, hepatic metabolism and

active substance interaction studies and studies using other human bio-materials

shall be provided.

5.2.3.

Reports of human pharmaco-kinetic studies

(a)

The following pharmaco-kinetic characteristics shall be described

-

absorption (rate and extent),

-

distribution,

-

metabolism,

-

excretion.

Clinically significant features including the implication of the kinetic data for the

dosage regimen especially for patients at risk, and differences between man and

animal species used in the pre clinical studies, shall be described.

In addition to standard multiple-sample pharmaco-kinetics studies, population

pharmaco-kinetics analyses based on sparse sampling during clinical studies can

also address questions about the contributions of intrinsic and extrinsic factors to the

variability in the dose- pharmaco-kinetics response relationship. Reports of

pharmaco-kinetic and initial tolerability studies in healthy subjects and in patients,

reports of pharmaco-kinetic studies to assess effects of intrinsic and extrinsic

factors, and reports of population pharmaco-kinetic studies shall be provided.

(b) If the medicinal product is normally to be administered concomitantly with

other medicinal products, particulars shall be given of joint administration tests

performed to demonstrate possible modification of the pharmacological action.

Pharmaco-kinetic interactions between the active substance and other medicinal

products or substances shall be investigated.

5.2.4.

Reports of human pharmaco-dynamic studies

(a) The pharmaco-dynamic action correlated to the efficacy shall be

demonstrated including

-

the dose-response relationship and its time course,

-

justification for the dosage and conditions of administration,

-

the mode of action, if possible.

The pharmaco-dynamic action not related to efficacy shall be described.

The demonstration of pharmaco-dynamic effects in human beings shall not in

itself be sufficient to justify conclusions regarding any particular potential

therapeutic effect.

(b) If the medicinal product is normally to be administered concomitantly with

other medicinal products, particulars shall be given of joint administration tests

performed to demonstrate possible modification of the pharmacological action.

Pharmaco-dynamic interactions between the active substance and other medicinal

products or substances shall be investigated.

5.2.5.

Reports of efficacy and safety studies

5.2.5.1.

Study Reports of Controlled Clinical Studies Pertinent to the Claimed

In general, clinical trials shall be done as ‘controlled clinical trials’ if possible,

randomised and as appropriate versus placebo and versus an established medicinal

product of proven therapeutic value; any other design shall be justified. The

treatment of the control groups will vary from case to case and also will depend on

ethical considerations and therapeutic area; thus it may, in some instances, be more

pertinent to compare the efficacy of a new medicinal product with that of an

established medicinal product of proven therapeutic value rather than with the effect

of a placebo.

(1) As far as possible, and particularly in trials where the effect of the product

cannot be objectively measured, steps shall be taken to avoid bias, including

methods of randomisation and blinding.

(2) The protocol of the trial must include a thorough description of the

statistical methods to be employed, the number and reasons for inclusion of patients

(including calculations of the power of the trial), the level of significance to be used

and a description of the statistical unit. Measures taken to avoid bias, particularly

methods of randomisation, shall be documented. Inclusion of a large number of

subjects in a trial must not be regarded as an adequate substitute for a properly

controlled trial.

The safety data shall be reviewed taking into account guidelines published by the

Commission, with particular attention to events resulting in changes of dose or need

for concomitant medication, serious adverse events, events resulting in withdrawal,

and deaths. Any patients or patient groups at increased risk shall be identified and

particular attention paid to potentially vulnerable patients who may be present in

small numbers, e.g., children, pregnant women, frail elderly, people with marked

abnormalities of metabolism or excretion etc. The implication of the safety

evaluation for the possible uses of the medicinal product shall be described.

5.2.5.2. Study reports of uncontrolled clinical studies reports of analyses of data

from more than one study and other clinical study reports

These reports shall be provided.

5.2.6.

Reports of post-marketing experience

If the medicinal product is already authorised in third countries, information shall

be given in respect of adverse reactions of the medicinal product concerned and

medicinal products containing the same active substance(s), in relation to the usage

rates if possible.

5.2.7.

Case reports forms and individual patient listings

When submitted in accordance with the relevant Guideline published by the

Agency, case report forms and individual patient data listings shall be provided and

presented in the same order as the clinical study reports and indexed by study.

PART II

SPECIFIC MARKETING AUTHORISATION DOSSIERS ANDREQUIREMENTS

Some medicinal products present specific features which are such that all the

requirements of the marketing authorisation application dossier as laid down in Part

I of this Schedule need to be adapted. To take account of these particular situations,

an appropriate and adapted presentation of the dossier shall be followed by

applicants.

1. WELL-ESTABLISHED MEDICINAL USE

For medicinal products the active substance(s) of which has/have a ‘well-

established medicinal use’ as referred to Article 10(1)(a)(ii), with recognised

efficacy and an acceptable level of safety, the following specific rules shall apply.

The applicant shall submit Modules 1, 2 and 3 as described in part I of this

Schedule.

For Modules 4 and 5, a detailed scientific bibliography shall address non-clinical

and clinical characteristics.

The following specific rules shall apply in order to demonstrate the well-

established medicinal use

(a) Factors which have to be taken into account in order to establish a well-

established medicinal use of constituents of medicinal products are

-

the time over which a substance has been used,

-

quantitative aspects of the use of the substance,

-

the degree of scientific interest in the use of the substance (reflected in

the published scientific literature) and

-

the coherence of scientific assessments.

Therefore different periods of time may be necessary for establishing well-

established use of different substances. In any case, however, the period of time

required for establishing a well established medicinal use of a constituent of a

medicinal product must not be less than one decade from the first systematic and

documented use of that substance as a medicinal product in the Community.

(b) The documentation submitted by the applicant should cover all aspects of

the safety and/or efficacy assessment and must include or refer to a review of the

relevant literature, taking into account pre and post-marketing studies and published

scientific literature concerning experience in the form of epidemiological studies and

in particular of comparative epidemiological studies. All documentation, both

favourable and unfavourable, must be communicated. With respect to the provisions

on ‘well established medicinal use’ it is in particular necessary to clarify that

‘bibliographic reference’ to other sources of evidence (post marketing studies,

epidemiological studies, etc.) and not just data related to tests and trials may serve as

a valid proof of safety and efficacy of a product if an application explains and

justifies the use of these sources of information satisfactorily.

(c) Particular attention must be paid to any missing information and

justification must be given why demonstration of an acceptable level of safety and/or

efficacy can be supported although some studies are lacking.

(d) The non-clinical and/or clinical overviews must explain the relevance of any

data submitted which concern a product different from the product intended for

marketing. A judgment must be made whether the product studied can be considered

as similar to the product, for which application for a marketing authorisation has

been made in spite of the existing differences.

(e) Post-marketing experience with other products containing the same

constituents is of particular importance and applicants should put a special emphasis

on this issue.

2. ESSENTIALLY SIMILAR MEDICINAL PRODUCTS

(a) Applications based upon Article 10(1)(a)(i) (essentially similar products)

shall contain the data described in Modules 1, 2 and 3 of Part I of this Schedule

provided the applicant has been granted the consent of the holder of the original

marketing authorisation to cross refer to the content of his Modules 4 and 5.

(b) Applications based upon Article 10(1)(a)(iii) (essentially similar products

i.e. generics) shall contain the data described in Modules 1, 2 and 3 of Part I of this

Schedule together with data showing bioavailability and bio-equivalence with the

original medicinal product provided the latter is not a biological medicinal product

(see Part II, 4 Similar biological medicinal products).

F o r t h e s e p r o d u c t s t h e n o n- c l i n i c a l / c l i n i c a l o v e r v i e w s / s u m m ar i e s sha l l

particularly focus on the following elements

-

the grounds for claiming essential similarity;

-

a summary of impurities present in batches of the active substance(s) as

well as those of the finished medicinal product (and where relevant

decomposition products arising during storage) as proposed for use in

the product to be marketed together with an evaluation of these

impurities;

-

an evaluation of the bio-equivalence studies or a justification why

studies were not performed with respect to the guideline on

‘Investigation of Bio-availability and Bio-equivalence’;

-

an update of published literature relevant to the substance and the

present application. It may be acceptable for articles in ‘peer review’

journals to be annotated for this purpose;

-

every claim in the summary of product characteristics not known from

or inferred from the properties of the medicinal product and/or its

therapeutic group should be discussed in the non clinical/clinical

overviews/summaries and substantiated by published literature and/or

additional studies.

-

if applicable, additional data in order to demonstrate evidence on the

equivalence of safety and efficacy properties of different salts, esters or

derivatives of an authorised active substance should be provided by the

applicant when he claims essential similarity.

3. ADDITIONAL DATA REQUIRED IN SPECIFIC SITUATIONS

Where the active substance of an essentially similar medicinal product contains

the same therapeutic moiety as the original authorised product associated with a

different salt/ester complex/derivative evidence that there is no change in the

pharmaco-kinetics of the moiety, pharmaco-dynamics and/or in toxicity which could

change the safety/efficacy profile shall be demonstrated. Should this not be the case,

this association shall be considered as a new active substance.

Where a medicinal product is intended for a different therapeutic use or presented

in a different pharmaceutical form or to be administered by different routes or in

different doses or with a different posology, the results of appropriate toxicological

and pharmacological tests and/or of clinical trials shall be provided.

4. SIMILAR BIOLOGICAL MEDICINAL PRODUCTS

The provisions of Article 10(1)(a)(iii) may not be sufficient in the case of

biological medicinal products.

If the information required in the case of essentially similar products (generics)

does not permit the demonstration of the similar nature of two biological medicinal

products, additional data, in particular, the toxicological and clinical profile shall be

provided.

When a biological medicinal product as defined in Part I, paragraph 3.2 of this

Schedule, which refers to an original medicinal product having been granted a

m a r k e t i n g a u t h o r i s a t i o n i n t h e C o m m u n i t y, i s s u b m i t t e d f o r a m ar k e t i n g

authorisation by an independent applicant after the expiry of data protection period,

the following approach shall be applied.

-

Information to be supplied shall not be limited to Modules 1, 2 and 3

(pharmaceutical, chemical and biological data), supplemented with bio-

equivalence and bio-availability data. The type and amount of

additional data (i.e. toxicological and other non-clinical and appropriate

clinical data) shall be determined on a case by case basis in accordance

with relevant scientific guidelines.

-

Due to the diversity of biological medicinal products, the need for

identified studies foreseen in Modules 4 and 5, shall be required by the

competent authority, taking into account the specific characteristic of

each individual medicinal product.

The general principles to be applied are addressed in a guideline taking into

account the characteristics of the concerned biological medicinal product published

by the Agency. In case the originally authorised medicinal product has more than

one indication, the efficacy and safety of the medicinal product claimed to be similar

has to be justified or, if necessary, demonstrated separately for each of the claimed

indications.

5. FIXED COMBINATION MEDICINAL PRODUCTS

Applications based upon Article 10(1)(b) shall relate to new medicinal products

made of at least two active substances not previously authorised as a fixed

combination medicinal product.

For those applications a full dossier (Modules 1 to 5) shall be provided for the

fixed combination medicinal product.

Where applicable, information regarding the manufacturing sites and the

adventitious agents, safety evaluation shall be provided.

5. DOCUMENTATION

FOR

APPLICATIONS

IN

EXCEPTIONAL

CIRCUMSTANCES

When, as provided for in Article 22, the applicant can show that he is unable to

provide comprehensive data on the efficacy and safety under normal conditions of

use, because

the indications for which the product in question is intended are

encountered so rarely that the applicant cannot reasonably be expected

to provide comprehensive evidence, or

in the present state of scientific knowledge, comprehensive information

cannot be provided, or

it would be contrary to generally accepted principles of medical ethics

to collect such information,

marketing authorisation may be granted subject to certain specific obligations.

These obligations may include the following

the applicant shall complete an identified programme of studies within a

time period specified by the competent authority, the results of which

shall form the basis of a reassessment of the benefit/risk profile,

the medicinal product in question may be supplied on medical

prescription only and may in certain cases be administered only under

strict medical supervision, possibly in a hospital and in the case of a

radio-pharmaceutical, by an authorised person,

the package leaflet and any medical information shall draw the attention

of the medical practitioner to the fact that the particulars available

concerning the medicinal product in question are as yet inadequate in

certain specified respects.

7. MIXED MARKETING AUTHORISATION APPLICATIONS

Mixed marketing-authorisation applications shall mean marketing-authorisation

application dossiers where Module 4 and/or 5 consists of a combination of reports of

limited non-clinical and/or clinical studies carried out by the applicant and of

bibliographical references. All other Module(s) are in accordance with the structure

described in Part I of this Schedule. The competent authority shall accept the

proposed format presented by the applicant on a case by case basis.

PART III

PARTICULAR MEDICINAL PRODUCTS

This Part lays down specific requirements related to the nature of identified

medicinal products.

1. BIOLOGICAL MEDICINAL PRODUCTS

1.1. Plasma-derived medicinal product

For medicinal products derived from human blood or plasma and by derogation

from the provisions of Module 3, the dossier requirements mentioned in

‘Information related to the starting and raw materials’, for starting materials made of

human blood/plasma may be replaced by a Plasma Master File certified in

accordance with this Part.

(a)

Principles

For the purposes of this Schedule

Plasma Master File shall mean a stand-alone documentation, which is

separate from the dossier for marketing authorisation which provides all

relevant detailed information on the characteristics of the entire human

plasma used as a starting material and/or a raw material for the

manufacture of sub/intermediate fractions, constituents of the excipient

and active substance(s), which are part of medicinal products or medical

devices referred to in Directive 2000/70/EC of the European Parliament

and of the Council of 16 November 2000 amending Council Directive

93/42/EC as regards medical devices incorporating stable derivatives of

human blood or human plasma.

Every centre or establishment for fractionation/processing of human

plasma shall prepare and keep updated the set of detailed relevant

information referred to in the Plasma Master File.

The Plasma Master File shall be submitted to the Agency or to the

competent authority by the applicant for a marketing authorisation or

the holder of the marketing authorisation. Where the applicant for a

marketing authorisation or the marketing authorisation holder differs

from the holder of the Plasma Master File, the Plasma Master File shall

be made available to the applicant or marketing authorisation holder for

submission to the competent authority. In any case, the applicant or

marketing authorisation holder shall take responsibility for the

medicinal product.

The competent authority that is evaluating the marketing authorisation

shall await for the Agency to issue the certificate before deciding on the

application.

Any marketing authorisation dossier containing a human plasma-

derived constituent shall refer to the Plasma Master File corresponding

to the plasma used as a starting/raw material.

(b)

Content

In accordance with the provisions of Article 109, as amended by Directive 2002/

98/EC, which refers to the requirements for donors and the testing of donations, the

Plasma Master File shall include information on the plasma used as starting/raw

material, in particular

(1) Plasma origin

(i)

information on centres or establishments in which blood/plasma

collection is carried out, including inspection and approval, and

epidemiological data on blood transmissible infections.

(ii) information on centres or establishments in which testing of

donations and plasma pools is carried out, including inspection

and approval status.

(iii) selection/exclusion criteria for blood/plasma donors.

(iv) system in place which enables the path taken by each donation to

be traced from the blood/ plasma collection establishment through

to finished products and vice versa.

(2) Plasma quality and safety

(i)

compliance with European Pharmacopoeia Monographs.

(ii) testing of blood/plasma donations and pools for infectious agents,

including information on test methods and, in the case of plasma

pools, validation data on the tests used.

(iii) technical characteristics of bags for blood and plasma collection,

including information on anticoagulants solutions used.

(iv) conditions of storage and transport of plasma.

(v) procedures for any inventory hold and/or quarantine period.

(vi) characterisation of the plasma pool.

(3) System in place between the plasma-derived medicinal product

manufacturer and/or plasma fractionator/processor on the one hand, and

blood/plasma collection and testing centres or establishments on the

other hand, which defines the conditions of their interaction and their

agreed specifications.

In addition, the Plasma Master File shall provide a list of the medicinal

products for which the Plasma Master File is valid, whether the

medicinal products have been granted a marketing authorisation or are

in the process of being granted such an authorisation, including

medicinal products referred to in Article 2 of Directive 2001/20/EC of

the European Parliament and of the Council relating to the

implementation of good clinical practice in the conduct of clinical trials

on medicinal products for human use.

(c)

Evaluation and Certification

For medicinal products not yet authorised, the marketing authorisation

applicant shall submit a full dossier to a competent authority, which

shall be accompanied by a separate Plasma Master File where one does

not already exist.

The Plasma Master File is subject to a scientific and technical

evaluation carried out by the Agency. A positive evaluation shall result

in a certificate of compliance with Community legislation for the

Plasma Master File, which shall be accompanied by the evaluation

report. The certificate issued shall apply throughout the Community.

The Plasma Master File shall be updated and re-certified on an annual

basis.

Changes subsequently introduced to the terms of a Plasma Master File

must follow evaluation procedure laid down by Commission Regulation

(EC) No 542/95 concerning the examination of variations to the terms

of a marketing authorisation falling within the scope of Council

regulation (EEC) No 2309/93 of 22 July 1993 laying down Community

procedures for the authorisation and supervision of medicinal products

for human and veterinary use and establishing a European Agency for

the Evaluation of Medicinal Products. Conditions for the assessment of

these changes are laid down by Regulation (EC) No 1085/2003.

As a second step to the provisions in the first, second, third and fourth

indents, the competent authority that will grant or has granted the

marketing authorisation shall take into account the certification, re-

certification or variation of the Plasma Master File on the concerned

medicinal product(s).

By derogation from the provisions of the second indent of the present

point (evaluation and certification), where a Plasma Master File

corresponds only to blood/plasma-derived medicinal products the

marketing authorisation of which is restricted to a single Member State,

the scientific and technical evaluation of the said Plasma Master File

shall be carried out by the national competent authority of that Member

State.

1.2. Vaccines

For vaccines for human use and by derogation from the provisions of Module 3 on

‘Active substance(s)’, the following requirements when based on the use of a

Vaccine Antigen Master File system shall apply. The marketing authorisation

application dossier of a vaccine other than human influenza vaccine, shall be

required to include a Vaccine Antigen Master File for every vaccine antigen that is

an active substance of this vaccine.

(a)

Principles

For the purposes of this Schedule

Vaccine Antigen Master File shall mean a stand-alone part of the

marketing authorisation application dossier for a vaccine, which

contains all relevant information of biological, pharmaceutical and

chemical nature concerning each of the active substances, which are

part of this medicinal product. The stand-alone part may be common to

one or more monovalent and/or combined vaccines presented by the

same applicant or marketing authorisation holder.

A vaccine may contain one or several distinct vaccine antigens. There

are as many active substance(s) as vaccine antigen(s) present in a

vaccine.

A combined vaccine contains at least two distinct vaccine antigens

aimed at preventing a single or several infectious diseases.

A monovalent vaccine is a vaccine, which contains one vaccine antigen

aimed at preventing a single infectious disease.

(b)

Content

The Vaccine Antigen Master File shall contain the following information extracted

from the relevant part (Active substance) of Module 3 on ‘Quality Data’ as

delineated in Part I of this Schedule

Active Substance

1. General Information, including compliance

with

the

relevant

monograph(s) of the European Pharmacopoeia.

2. Information on the manufacture of the active substance: this heading

must cover the manufacturing process, information on the starting and

raw materials, specific measures on TSEs and adventitious agents safety

evaluation and facilities and equipment.

3. Characterisation of the active substance

4. Quality control of the active substance

5. Reference standard and materials

6. Container and closure system of the active substance

7. Stability of the active substance.

(c)

Evaluation and Certification

For novel vaccines, which contain a novel vaccine antigen, the applicant

shall submit to a competent authority a full marketing-authorisation

application dossier including all the Vaccine Antigen Master Files

corresponding to each single vaccine antigen that is part of the novel

vaccine where no master file already exists for the single vaccine

antigen.A scientific and technical evaluation of each Vaccine Antigen

Master File shall be carried out by the Agency. A positive evaluation

shall result in a certificate of compliance to the European legislation for

each Vaccine Antigen Master File, which shall be accompanied by the

evaluation report. The certificate shall apply throughout the

Community.

The provisions of the first indent shall also apply to every vaccine,

which consists of a novel combination of vaccine antigens, irrespective

of whether or not one or more of these vaccine antigens are part of

vaccines already authorised in the Community.

Changes to the content of a Vaccine Antigen Master File for a vaccine

authorised in the Community shall be subject to a scientific and

technical evaluation carried out by the Agency in accordance with the

procedure laid down in Commission Regulation (EC) No 1085/2003. In

the case of a positive evaluation the Agency shall issue a certificate of

compliance with Community legislation for the Vaccine Antigen Master

File. The certificate issued shall apply throughout the Community.

By derogation from the provisions of the first, second and third indents

of the present point (evaluation and certification), where a Vaccine

Antigen Master File corresponds only to a vaccine which is the subject

of a marketing authorisation which has not been/will not be granted

according to a Community procedure, and, provided the authorised

vaccine includes vaccine antigens which have not been evaluated

through a Community procedure, the scientific and technical evaluation

of the said Vaccine Antigen Master File and its subsequent changes,

shall be carried out by the national competent authority that has granted

the marketing authorisation.

As a second step to the provisions in the first, second, third and fourth

indents, the competent authority that will grant or has granted the

marketing authorisation shall take into account the certification, re-

certification or variation of the Vaccine Antigen Master File on the

concerned medicinal product(s).

2. RADIO-PHARMACEUTICALS AND PRECURSORS

2.1. Radio-pharmaceuticals

For the purposes of this chapter, applications based upon Articles 6(2) and 9 shall

provide a full dossier in which the following specific details shall be included

Module 3

(a) In the context of a radio-pharmaceutical kit, which is to be radio-labelled

after supply by the manufacturer, the active substance is considered to be that part of

the formulation which is intended to carry or bind the radio-nuclide. The description

of the manufacturing method of radiopharmaceutical kits shall include details of the

manufacture of the kit and details of its recommended final processing to produce

the radioactive medicinal product. The necessary specifications of the radio-nuclide

shall be described in accordance, where relevant, with the general monograph or

specific monographs of the European Pharmacopoeia . In addition, any compounds

essential for the radio-labelling shall be described. The structure of the radio-

labelled compound shall also be described.

For radio-nuclides, the nuclear reactions involved shall be discussed.

In a generator, both mother and daughter radio-nuclides shall be considered as

active substances.

(b) Details of the nature of the radio-nuclide, the identity of the isotope, likely

impurities, the carrier, the use and the specific activity shall be provided.

(c)

Starting materials include irradiation target materials.

(d) Considerations on chemical/radiochemical purity and its relationship to bio-

distribution shall be provided.

(e) Radio-nuclide purity, radiochemical purity and specific activity shall be

described.

(f)

For generators, details on the testing for mother and daughter radio-nuclides

are required. For generator eluates, tests for mother radio-nuclides and for other

constituents of the generator system shall be provided.

(g) The requirement to express the content of active substances in terms of the

mass of active entities shall only apply to radio-pharmaceutical kits. For radio-

nuclides, radioactivity shall be expressed in Becquerels at a given date and, if

necessary, time with reference to time zone. The type of radiation shall be indicated.

(h) For kits, the specifications of the finished product shall include tests on

performance of products after radiolabelling. Appropriate controls on radiochemical

and radio-nuclidic purity of the radiolabelled compound shall be included. Any

material essential for radio-labelling shall be identified and assayed.

(i)

Information on stability shall be given for radio-nuclide generators, radio-

nuclide kits and radiolabelled products. The stability during use of radio-

pharmaceuticals in multi-dose vials shall be documented.

Module 4

It is appreciated that toxicity may be associated with a radiation dose. In

diagnosis, this is a consequence of the use of radio-pharmaceuticals; in therapy, it is

the property desired. The evaluation of safety and efficacy of radio-pharmaceuticals

shall, therefore, address requirements for medicinal products and radiation

dosimetry aspects. Organ/tissue exposure to radiation shall be documented.

Absorbed radiation dose estimates shall be calculated according to a specified,

internationally recognised system by a particular route of administration.

Module 5

The results of clinical trials shall be provided where applicable otherwise justified

in the clinical overviews.

2.2. Radio-pharmaceutical precursors for radio-labelling purposes

In the specific case of a radio-pharmaceutical precursor intended solely for radio-

labelling purposes, the primary objective shall be to present information which

would address the possible consequences of poor radio-labeling efficiency or in vivo

dissociation of the radio-labeled conjugate, i.e. questions related to the effects

produced in the patient by free radio-nuclide.

In addition, it is also necessary to present relevant information relating to

o c c u p a t i o n a l h a z a r d s , i . e . r a d i at i o n e x p o s u r e t o h o s p i t a l s t a ff a n d t o t h e

environment.

In particular, the following information where applicable shall be provided

Module 3

The provisions of Module 3 shall apply to the registration of radio-pharmaceutical

precursors as defined above (indents (a) to (i)), where applicable.

Module 4

Concerning single dose and repeat dose toxicity, the results of studies carried out

in conformity with the provisions related to good laboratory practice laid down in

Council Directives 87/18/EEC and 88/320/EEC shall be provided, unless otherwise

justified.

Mutagenicity studies on the radio-nuclide are not considered to be useful in this

particular case.

Information relating to the chemical toxicity and disposition of the relevant ‘cold’

nuclide shall be presented.

Module 5

Clinical information generated from clinical studies using on the precursor itself is

not considered to be relevant in the specific case of a radio-pharmaceutical precursor

intended solely for radio-labelling purposes.

H o w e v e r, i n f o r m a t i o n d e m o n s t r a t i n g t h e c l i n i c a l u t i l i t y o f t h e r a d i o -

pharmaceutical precursor when attached to relevant carrier molecules shall be

presented.

3. HOMEOPATHIC MEDICINAL PRODUCTS

This section sets out specific provisions on the application of Modules 3 and 4 to

homeopathic medicinal products as defined in Article 1(5).

Module 3

The provisions of Module 3 shall apply to the documents submitted in accordance

with Article 15 in the simplified registration of homeopathic medicinal products

referred to in Article 14(1) as well as to the documents for authorisation of other

homeopathic medicinal products referred to in Article 16(1) with the following

modifications.

(a)

Terminology

The Latin name of the homeopathic stock described in the marketing authorisation

application dossier must be in accordance with the Latin title of the European

Pharmacopoeia or, in absence thereof, by an official pharmacopoeia of a Member

State. Where relevant the traditional name(s) used in each Member State shall be

provided.

(b)

Control of starting materials

The particulars and documents on the starting materials, i.e. all of the materials

used including raw materials and intermediates up to the final dilution to be

incorporated into the finished medicinal product, accompanying the application shall

be supplemented by additional data on the homeopathic stock.

The general quality requirements shall apply to all of the starting and raw

materials as well as intermediate steps of the manufacturing process up to the final

dilution to be incorporated into the finished medicinal product. If possible, an assay

is required if toxic components are present and if the quality cannot be controlled on

final dilution to be incorporated because of the high dilution degree. Every step of

the manufacturing process from the starting materials up to the final dilution to be

incorporated into the finished medicinal product must be fully described.

In case dilutions are involved, these dilution steps should be done in accordance

with the Homeopathic manufacturing methods laid down in the relevant monograph

of the European Pharmacopoeia or, in absence thereof, by an official pharmacopoeia

of a Member State.

(c)

Control tests on the finished medicinal product

The general quality requirements shall apply to the homeopathic finished

medicinal products, any exception needs to be duly justified by the applicant.

Identification and assay of all the toxicologically relevant constituents shall be

carried out. If it can be justified that an identification and/or an assay on all the

toxicologically relevant constituents is not possible e.g. due to their dilution in the

finished medicinal product the quality shall be demonstrated by complete validation

of the manufacturing and dilution process.

(d)

Stability tests

The stability of the finished medicinal product must be demonstrated. Stability

data from the homeopathic stocks are generally transferable to dilutions/triturations

obtained thereof. If no identification or assay of the active substance is possible due

to the degree of dilution, stability data of the pharmaceutical form may be

considered.

Module 4

The provisions of Module 4 shall apply to the simplified registration of

homeopathic medicinal products referred to in Article 14(1) with the following

specifications.

Any missing information must be justified, e.g., justification must be given why

demonstration of an acceptable level of safety can be supported although some

studies are lacking.

4. HERBAL MEDICINAL PRODUCTS

Applications for herbal medicinal products shall provide a full dossier in which

the following specific details shall be included.

Module 3

The provisions of Module 3, including compliance with monograph(s) of the

European Pharmacopoeia, shall apply to the authorisation of herbal medicinal

products. The state of scientific knowledge at the time when the application is

lodged shall be taken into account.

The following aspects specific to herbal medicinal products shall be considered

(1)

Herbal substances and herbal preparations

For the purposes of this Schedule the terms ‘herbal substances and preparations’

shall be considered equivalent to the t erm s ‘herbal drugs and herbal drug

preparations’, as defined in the European Pharmacopoeia.

With respect to the nomencRlature of the herbal substance, the binomial scientific

name of plant (genus, species, variety and author), and chemotype (where

applicable), the parts of the plants, the definition of the herbal substance, the other

names (synonyms mentioned in other Pharmacopoeias) and the laboratory code shall

be provided.

With respect to the nomenclature of the herbal preparation, the binomial scientific

name of plant (genus, species, variety and author), and chemotype (where

applicable), the parts of the plants, the definition of the herbal preparation, the ratio

of the herbal substance to the herbal preparation, the extraction solvent(s), the other

names (synonyms mentioned in other Pharmacopoeias) and the laboratory code shall

be provided.

To document the section of the structure for herbal substance(s) and herbal

preparation(s) where applicable, the physical form, the description of the

constituents with known therapeutic activity or markers (molecular formula, relative

molecular mass, structural formula, including relative and absolute stereo-chemistry,

t h e m o l e c u l a r f o r m u l a , a nd t h e r e l a t i v e m o l e c ul a r m as s ) a s w e l l a s o t h e r

constituent(s) shall be provided.

To document the section on the manufacturer of the herbal substance, the name,

address, and responsibility of each supplier, including contractors, and each

proposed site or facility involved in production/collection and testing of the herbal

substance shall be provided, where appropriate.

To document the section on the manufacturer of the herbal preparation, the name,

address, and responsibility of each manufacturer, including contractors, and each

proposed manufacturing site or facility involved in manufacturing and testing of the

herbal preparation shall be provided, where appropriate.

With respect to the description of manufacturing process and process controls for

the herbal substance, information shall be provided to adequately describe the plant

production and plant collection, including the geographical source of the medicinal

plant and cultivation, harvesting, drying and storage conditions.

With respect to the description of manufacturing process and process controls for

the herbal preparation, information shall be provided to adequately describe the

manufacturing process of the herbal preparation, including description of the

processing, solvents and reagents, purification stages and standardisation.

With respect to the manufacturing process development, a brief summary

describing the development of the herbal substance(s) and herbal preparation(s)

where applicable shall be provided, taking into consideration the proposed route of

administration and usage. Results comparing the phyto-chemical composition of the

herbal substance(s) and herbal preparation(s) where applicable used in supporting

bibliographic data and the herbal substance(s) and herbal preparation(s), where

applicable, contained as active substance(s) in the herbal medicinal product applied

for shall be discussed, where appropriate.

With respect to the elucidation of the structure and other characteristics of the

herbal substance, information on the botanical, macroscopical, microscopical,

phyto-chemical characterisation, and biological activity if necessary, shall be

provided.

With respect to the elucidation of the structure and other characteristics of the

herbal preparation, information on the phyto- and physicochemical characterisation,

and biological activity if necessary, shall be provided.

The specifications for the herbal substance(s) and herbal preparation(s) where

applicable shall be provided.

The analytical procedures used for testing the herbal substance(s) and herbal

preparation(s) where applicable shall be provided.

With respect to the validation of analytical procedures, analytical validation

information, including experimental data for the analytical procedures used for

testing the herbal substance(s) and herbal preparation(s) where applicable shall be

provided.

With respect to batch analyses, description of batches and results of batch analyses

for the herbal substance(s) and herbal preparation(s) where applicable shall be

provided, including those for pharmacopoeial substances.

Justification for the specifications of the herbal substance(s) and herbal

preparation(s) where applicable shall be provided.

Information on the reference standards or reference materials used for testing of

the herbal substance(s) and herbal preparation(s) where applicable shall be provided.

Where the herbal substance or the herbal preparation is the subject of a

monograph, the applicant can apply for a certificate of suitability that was granted

by the European Directorate for the Quality of Medicines.

(2)

Herbal Medicinal Products

With respect to the formulation development, a brief summary describing the

development of the herbal medicinal product should be provided, taking into

consideration the proposed route of administration and usage. Results comparing the

phyto-chemical composition of the products used in supporting bibliographic data

and the herbal medicinal product applied for shall be discussed, where appropriate.

5. ORPHAN MEDICINAL PRODUCTS

-

In the case of an orphan medicinal product in the meaning of Regulation

(EC) No 141/2000, general provisions of Part II-6 (exceptional circumstances) can

be applied. The applicant shall then justify in the non-clinical and clinical

summaries the reasons for which it is not possible to provide the complete

information and shall provide a justification of the benefit/risk balance for the

orphan medicinal product concerned.

-

When an applicant for an marketing authorisation for an orphan medicinal

product invokes the provisions of Article 10 (1)(a)(ii) and Part II-1 of this Schedule

(well-established medicinal use), the systematic and documented use of the

concerned substance can refer - as way of derogation - to the use of that substance in

accordance with the provisions of Article 5.

PART IV

ADVANCED THERAPY MEDICINAL PRODUCTS

1. INTRODUCTION

Marketing authorisation applications for advanced therapy medicinal products, as

defined in point (a) of Article 2(1) of Regulation (EC) No 1394/2007, shall follow

the format requirements (Modules 1, 2, 3, 4 and 5) described in Part I of this

Schedule.

The technical requirements for Modules 3, 4 and 5 for biological medicinal

products, as described in Part I of this Schedule, shall apply. The specific

requirements for advanced therapy medicinal products described in sections 3, 4 and

5 of this part explain how the requirements in Part I apply to advanced therapy

medicinal products. In addition, where appropriate and taking into account the

specificities of advanced therapy medicinal products, additional requirements have

been set.

Due to the specific nature of advanced therapy medicinal products, a risk-based

approach may be applied to determine the extent of quality, non-clinical and clinical

data to be included in the marketing authorisation application, in accordance with

the scientific guidelines relating to the quality, safety and efficacy of medicinal

products referred to in point 4 of the “Introduction and general principles”.

The risk analysis may cover the entire development. Risk factors that may be

considered include: the origin of the cells (autologous, allogeneic, xenogeneic), the

ability to proliferate and/or differentiate and to initiate an immune response, the

level of cell manipulation, the combination of cells with bioactive molecules or

structural materials, the nature of the gene therapy medicinal products, the extent of

replication competence of viruses or micro-organisms used in vivo, the level of

integration of nucleic acids sequences or genes into the genome, the long time

functionality, the risk of oncogenicity and the mode of administration or use.

Relevant available non-clinical and clinical data or experience with other, related

advanced therapy medicinal products may also be considered in the risk analysis.

Any deviation from the requirements of this Schedule shall be scientifically

justified in Module 2 of the application dossier. The risk analysis described above,

when applied, shall also be included and described in Module 2. In this case, the

methodology followed, the nature of the identified risks and the implications of the

risk based approach for the development and evaluation program shall be discussed

and any deviations from the requirements of this Schedule resulting from the risk

analysis shall be described.

2. DEFINITIONS

For the purposes of this Schedule, in addition to the definitions laid down in

Regulation (EC) No 1394/2007, the definitions set out in sections 2.1 and 2.2 shall

apply.

2.1.

Gene therapy medicinal product

Gene therapy medicinal product means a biological medicinal product which has

the following characteristics

(a) it contains an active substance which contains or consists of a

recombinant nucleic acid used in or administered to human beings with

a view to regulating, repairing, replacing, adding or deleting a genetic

sequence;

(b) its therapeutic, prophylactic or diagnostic effect relates directly to the

recombinant nucleic acid sequence it contains, or to the product of

genetic expression of this sequence. Gene therapy medicinal products

shall not include vaccines against infectious diseases.

2.2.

Somatic cell therapy medicinal product

Somatic cell therapy medicinal product means a biological medicinal product

which has the following characteristics

(a) contains or consists of cells or tissues that have been subject to

substantial manipulation so that biological characteristics, physiological

functions or structural properties relevant for the intended clinical use

have been altered, or of cells or tissues that are not intended to be used

for the same essential function(s) in the recipient and the donor;

(b) is presented as having properties for, or is used in or administered to

human beings with a view to treating, preventing or diagnosing a

disease through the pharmacological, immunological or metabolic

action of its cells or tissues.

For the purposes of point (a), the manipulations listed in Annex I to Regulation

( E C ) N o 1 3 9 4 / 2 0 0 7 , i n p a r t i c u l a r, s h a l l n o t b e c o n s i d e r e d a s s u b s t a n t i a l

manipulations.

3. SPECIFIC REQUIREMENTS REGARDING MODULE 3

3.1.

Specific requirements for all advanced therapy medicinal products

A description of the traceability system that the marketing authorisation holder

intends to establish and maintain to ensure that the individual product and its starting

and raw materials, including all substances coming into contact with the cells or

tissues it may contain, can be traced through the sourcing, manufacturing,

packaging, storage, transport and delivery to the hospital, institution or private

practice where the product is used, shall be provided.

The traceability system shall be complementary to, and compatible with, the

requirements established in Directive 2004/23/EC of the European Parliament and of

the Council, as regards human cells and tissues other than blood cells, and Directive

2002/98/EC, as regards human blood cells.

3.2.

Specific requirements for gene therapy medicinal products

3.2.1.

Introduction: finished product, active substance and starting materials

3.2.1.1. Gene therapy medicinal product containing recombinant nucleic acid

sequence(s) or genetically modified microorganism(s) or virus(es).

The finished medicinal product shall consist of nucleic acid sequence(s) or

genetically modified microorganism(s) or virus(es) formulated in their final

immediate container for the intended medical use. The finished medicinal product

may be combined with a medical device or active implantable medical device.

The active substance shall consist of nucleic acid sequence(s) or genetically

modified microorganism(s) or virus(es).

3.2.1.2.

Gene therapy medicinal product containing genetically modified cells

The finished medicinal product shall consist of genetically modified cells

formulated in the final immediate container for the intended medical use. The

finished medicinal product may be combined with a medical device or active

implantable medical device.

The active substance shall consist of cells genetically modified by one of the

products described in section 3.2.1.1 above.

3.2.1.3. In the case of products consisting of viruses or viral vectors, the starting

materials shall be the components from which the viral vector is obtained, i.e. the

master virus vector seed or the plasmids used to transfect the packaging cells and the

master cell bank of the packaging cell line.

3.2.1.4. In the case of products consisting of plasmids, non-viral vectors and

genetically modified microorganism(s) other than viruses or viral vectors, the

starting materials shall be the components used to generate the producing cell, i.e.

the plasmid, the host bacteria and the master cell bank of recombinant microbial

cells.

3.2.1.5. In the case of genetically modified cells, the starting materials shall be

the components used to obtain the genetically modified cells, i.e. the starting

materials to produce the vector, the vector and the human or animal cells. The

principles of good manufacturing practice shall apply from the bank system used to

produce the vector onwards.

3.2.2.

Specific requirements

In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of this

Schedule, the following requirements shall apply

(a) information shall be provided on all the starting materials used for the

manufacture of the active substance, including the products necessary

for the genetic modification of human or animal cells and, as applicable,

subsequent culture and preservation of the genetically modified cells,

taking into consideration the possible absence of purification steps;

(b) for products containing a microorganism or a virus, data on the genetic

modification, sequence analysis, attenuation of virulence, tropism for

specific tissues and cell types, cell cycle dependence of the

microorganism or virus, pathogenicity and characteristics of the

parental strain shall be provided;

(c) process-related impurities and product-related impurities shall be

described in the relevant sections of the dossier, and in particular

replication competent virus contaminants if the vector is designed to be

replication incompetent;

(d) for plasmids, quantification of the different plasmid forms shall be

undertaken throughout the shelf life of the product;

(e) for genetically modified cells, the characteristics of the cells before and

after the genetic modification, as well as before and after any

subsequent freezing/storage procedures, shall be tested.

For genetically modified cells, in addition to the specific requirements for gene

therapy medicinal products, the quality requirements for somatic cell therapy

medicinal products and tissue engineered products (see section 3.3) shall apply.

Specific requirements for somatic cell therapy medicinal products and

tissue engineered products

Introduction: finished product, active substance and starting materials

The finished medicinal product shall consist of the active substance formulated in

its immediate container for the intended medical use, and in its final combination for

combined advanced therapy medicinal products.

The active substance shall be composed of the engineered cells and/or tissues.

A d d i t i o n a l s u b s t a n c e s ( e . g . s c a ff o l d s , m a t r i c e s , d e v i c e s , b i o m a t e r i a l s ,

biomolecules and/or other components) which are combined with manipulated cells

of which they form an integral part shall be considered as starting materials, even if

not of biological origin.

Materials used during the manufacture of the active substance (e.g. culture media,

growth factors) and that are not intended to form part of the active substance shall be

considered as raw materials.

Specific requirements

In addition to the requirements set out in sections 3.2.1 and 3.2.2 of Part I of this

Schedule, the following requirements shall apply

Starting materials

(a) Summary information shall be provided on donation, procurement and

testing of the human tissue and cells used as starting materials and made

in accordance with Directive 2004/23/EC. If non-healthy cells or tissues

(e.g. cancer tissue) are used as starting materials, their use shall be

justified.

(b) If allogeneic cell populations are being pooled, the pooling strategies

and measures to ensure traceability shall be described.

(c) The potential variability introduced through the human or animal tissues

and cells shall be addressed as part of the validation of the

manufacturing process, characterisation of the active substance and the

finished product, development of assays, setting of specifications and

stability.

(d) For xenogeneic cell-based products, information on the source of

animals (such as geographical origin, animal husbandry, age), specific

acceptance criteria, measures to prevent and monitor infections in the

source/donor animals, testing of the animals for infectious agents,

including vertically transmitted microorganisms and viruses, and

evidence of the suitability of the animal facilities shall be provided.

(e) For cell-based products derived from genetically modified animals, the

specific characteristics of the cells related to the genetic modification

shall be described. A detailed description of the method of creation and

the characterisation of the transgenic animal shall be provided.

(f)

For the genetic modification of the cells, the technical requirements

specified in section 3.2 shall apply.

(g) The testing regimen of any additional substance (scaffolds, matrices,

devices, biomaterials, biomolecules or other components), which are

combined with engineered cells of which they form an integral part,

shall be described and justified.

(h) For scaffolds, matrices and devices that fall under the definition of a

medical device or active implantable medical device, the information

required under section 3.4 for the evaluation of the combined advanced

therapy medicinal product shall be provided.

Manufacturing process

(a) The manufacturing process shall be validated to ensure batch and

process consistency, functional integrity of the cells throughout

manufacturing and transport up to the moment of application or

administration, and proper differentiation state.

(b) If cells are grown directly inside or on a matrix, scaffold or device,

information shall be provided on the validation of the cell culture

process with respect to cell-growth, function and integrity of the

combination.

Characterisation and control strategy

(a) Relevant information shall be provided on the characterisation of the

cell population or cell mixture in terms of identity, purity (e.g.

adventitious microbial agents and cellular contaminants), viability,

potency, karyology, tumourigenicity and suitability for the intended

medicinal use. The genetic stability of the cells shall be demonstrated.

(b) Qualitative and, where possible, quantitative information on product-

and process-related impurities, as well as on any material capable of

introducing degradation products during production, shall be provided.

The extent of the determination of impurities shall be justified.

(c) If certain release tests cannot be performed on the active substance or

finished product, but only on key intermediates and/or as in-process

testing, this shall be justified.

(d) Where biologically active molecules (such as growth factors, cytokines)

are present as components of the cell based product, their impact and

interaction with other components of the active substance shall be

characterised.

(e) Where a three-dimensional structure is part of the intended function, the

differentiation state, structural and functional organisation of the cells

and, where applicable, the extracellular matrix generated shall be part

of the characterisation for these cell-based products. Where needed,

non-clinical investigations shall complement the physicochemical

characterisation.

3.3.2.4.

Excipients

For excipient(s) used in cell or tissue-based medicinal products (e.g. the

components of the transport medium), the requirements for novel excipients, as laid

down in Part I of this Schedule, shall apply, unless data exists on the interactions

between the cells or tissues and the excipients.

3.3.2.5.

Developmental studies

The description of the development program shall address the choice of materials

and processes. In particular, the integrity of the cell population as in the final

formulation shall be discussed.

3.3.2.6.

Reference materials

A reference standard, relevant and specific for the active substance and/or the

finished product, shall be documented and characterised.

3.4.

Specific requirements for advanced therapy medicinal products

containing devices

3.4.1.

Advanced therapy medicinal product containing devices as referred to in

Arti cle 7 of Regul ation (EC) N o 139 4/200 7 A d escriptio n of the p hysical

characteristics and performance of the product and a description of the product

design methods shall be provided.

The interaction and compatibility between genes, cells and/or tissues and the

structural components shall be described.

3.4.2.

Combined advanced therapy medicinal products as defined in Article

2(1)(d) of Regulation (EC) No 1394/2007

For the cellular or tissue part of the combined advanced therapy medicinal

product, the specific requirements for somatic cell therapy medicinal products and

tissue engineered products set out in section 3.3 shall apply and, in the case of

genetically modified cells, the specific requirements for gene therapy medicinal

products set out in section 3.2 shall apply.

The medical device or the active implantable medical device may be an integral

part of the active substance.

Where the medical device or active implantable medical device is combined with

the cells at the time of the manufacture or application or administration of the

finished products, they shall be considered as an integral part of the finished

product.

Information related to the medical device or the active implantable medical device

(which is an integral part of the active substance or of the finished product) which is

relevant for the evaluation of the combined advanced therapy medicinal product

shall be provided. This information shall include

(a) information on the choice and intended function of the medical device

or implantable medical device and demonstration of compatibility of the

device with other components of the product;

(b) evidence of conformity of the medical device part with the essential

requirements laid down in Annex I to Council Directive 93/42/EEC, or

of conformity of the active implantable device part with the essential

requirements laid down in Annex 1 to Council Directive 90/385/EEC;

(c) where applicable, evidence of compliance of the medical device or

implantable medical device with the BSE/TSE requirements laid down

in Commission Directive 2003/32/EC;

(d) where available, the results of any assessment of the medical device part

or the active implantable medical device part by a notified body in

accordance with Directive 93/42/EEC or Directive 90/385/EEC.

The notified body which has carried out the assessment referred to in point (d) of

this section shall make available on request of the competent authority assessing the

application, any information related to the results of the assessment in accordance

with Directive 93/42/EEC or Directive 90/385/EEC. This may include information

and documents contained in the conformity assessment application concerned, where

necessary for the evaluation of the combined advanced therapy medicinal product as

a whole.

4. SPECIFIC REQUIREMENTS REGARDING MODULE

4.1.

Specific requirements for all advanced therapy medicinal products

The requirements of Part I, Module 4 of this Schedule on the pharmacological and

toxicological testing of medicinal products may not always be appropriate due to

unique and diverse structural and biological properties of advanced therapy

medicinal products. The technical requirements in sections 4.1, 4.2 and 4.3 below

explain how the requirements in Part I of this Schedule apply to advanced therapy

medicinal products. Where appropriate and taking into account the specificities of

advanced therapy medicinal products, additional requirements have been set.

The rationale for the non-clinical development and the criteria used to choose the

relevant species and models (in vitro and in vivo) shall be discussed and justified in

the non-clinical overview. The chosen animal model(s) may include immuno-

compromised, knockout, humanised or transgenic animals. The use of homologous

models (e.g. mouse cells analysed in mice) or disease mimicking models shall be

considered, especially for immunogenicity and immunotoxicity studies.

I n a d d i t i o n t o t h e r e q u i r e m e n t s o f P a r t I , t h e s a f e t y, s u i t a b i l i t y a n d

biocompatibility of all structural components (such as matrices, scaffolds and

devices) and any additional substances (such as cellular products, biomolecules,

biomaterials, and chemical substances), which are present in the finished product,

shall be provided. Their physical, mechanical, chemical and biological properties

shall be taken into account.

4.2.

Specific requirements for gene therapy medicinal products

In order to determine the extent and type of non-clinical studies necessary to

determine the appropriate level of non-clinical safety data, the design and type of the

gene therapy medicinal product shall be taken into account.

4.2.1.

Pharmacology

(a) In vitro and in vivo studies of actions relating to the proposed

therapeutic use (i.e. pharmacodynamic “proof of concept” studies) shall

be provided using models and relevant animal species designed to show

that the nucleic acid sequence reaches its intended target (target organ

or cells) and provides its intended function (level of expression and

functional activity). The duration of the nucleic acid sequence function

and the proposed dosing regimen in the clinical studies shall be

provided.

(b) Target selectivity: When the gene therapy medicinal product is intended

to have a selective or target-restricted functionality, studies to confirm

the specificity and duration of functionality and activity in target cells

and tissues shall be provided.

Pharmacokinetics

(a) Biodistribution studies shall include investigations on persistence,

clearance and mobilisation. Biodistribution studies shall additionally

address the risk of germline transmission.

(b) Investigations of shedding and risk of transmission to third parties shall

be provided with the environmental risk assessment, unless otherwise

duly justified in the application on the basis of the type of product

concerned.

Toxicology

(a) Toxicity of the finished gene therapy medicinal product shall be

assessed. In addition, depending on the type of product, individual

testing of active substance and excipients shall be taken into

consideration, the in vivo effect of expressed nucleic acid sequence-

related products which are not intended for the physiological function

shall be evaluated.

(b) Single-dose toxicity studies may be combined with safety pharmacology

and pharmacokinetic studies, e.g. to investigate persistence.

(c) Repeated dose toxicity studies shall be provided when multiple dosing

of human subjects is intended. The mode and scheme of administration

shall closely reflect the planned clinical dosing. For those cases where

single dosing may result in prolonged functionality of the nucleic acid

sequence in humans, repeated toxicity studies shall be considered. The

duration of the studies may be longer than in standard toxicity studies

depending on the persistence of the gene therapy medicinal product and

the anticipated potential risks. A justification for the duration shall be

provided.

(d) Genotoxicity shall be studied. However, standard genotoxicity studies

shall only be conducted when they are necessary for testing a specific

impurity or a component of the delivery system.

(e) Carcinogenicity shall be studied. Standard lifetime rodent

carcinogenicity studies shall not be required. However, depending on

the type of product, the tumourigenic potential shall be evaluated in

relevant in vivo/in vitro models.

(f)

Reproductive and developmental toxicity: Studies on the effects on

fertility and general reproductive function shall be provided. Embryo-

foetal and perinatal toxicity studies and germline transmission studies

shall be provided, unless otherwise duly justified in the application on

the basis of the type of product concerned.

(g) Additional toxicity studies

-

Integration studies: integration studies shall be provided for any

gene therapy medicinal product, unless the lack of these studies is

scientifically justified, e.g. because nucleic acid sequences will

not enter into the cell nucleus. For gene therapy medicinal

products not expected to be capable of integration, integration

studies shall be performed, if biodistribution data indicate a risk

for germline transmission.

-

Immunogenicity and immunotoxicity: potential immunogenic and

immunotoxic effects shall be studied.

Specific requirements for somatic cell therapy medicinal products and

tissue engineered products

Pharmacology

(a) The primary pharmacological studies shall be adequate to demonstrate

the proof of concept. The interaction of the cell-based products with the

surrounding tissue shall be studied.

(b) The amount of product needed to achieve the desired effect/the effective

dose, and, depending on the type of product, the frequency of dosing

shall be determined.

(c) Secondary pharmacological studies shall be taken into account to

evaluate potential physiological effects that are not related to the

desired therapeutic effect of the somatic cell therapy medicinal product,

of the tissue engineered product or of additional substances, as

biologically active molecules besides the protein(s) of interest might be

secreted or the protein(s) of interest could have unwanted target sites.

Pharmacokinetics

(a) Conventional pharmacokinetic studies to investigate absorption,

distribution, metabolism and excretion shall not be required. However,

parameters such as viability, longevity, distribution, growth,

differentiation and migration shall be investigated, unless otherwise

duly justified in the application on the basis of the type of product

concerned.

(b) For somatic cell therapy medicinal products and tissue engineered

products, producing systemically active biomolecules, the distribution,

duration and amount of expression of these molecules shall be studied.

Toxicology

(a) The toxicity of the finished product shall be assessed. Individual testing

of active substance(s), excipients additional substances and any

process-related impurities shall be taken into consideration.

(b) The duration of observations may be longer than in standard toxicity

studies and the anticipated lifespan of the medicinal product, together

with its pharmacodynamic and pharmaco-kinetic profile, shall be taken

into consideration. A justification of the duration shall be provided.

(c) Conventional carcinogenicity and genotoxicity studies shall not be

required, except with regard to the tumourigenic potential of the

product.

(d) Potential immunogenic and immunotoxic effects shall be studied.

(e) In the case of cell-based products containing animal cells, the

associated specific safety concerns such as transmission to humans of

xenogeneic pathogens shall be addressed.

5. SPECIFIC REQUIREMENTS REGARDING MODULE 5

Specific requirements for all advanced therapy medicinal products

The specific requirements in this section of Part IV are additional

requirements to those set in Module 5 in Part I of this Schedule.

5.1.2.

Where the clinical application of advanced therapy medicinal products

requires specific concomitant therapy and involve surgical procedures, the

therapeutic procedure as a whole shall be investigated and described. Information on

t h e s t a n d a r d i s a t i o n a n d o p t i m i s a ti o n o f t h o s e p r o c e d u r e s d u r i n g c l i n i c a l

development shall be provided.

Where medical devices used during the surgical procedures for application,

implantation or administration of the advanced therapy medicinal product may have

an impact on the efficacy or safety of the advanced therapy product, information on

these devices shall be provided.

Specific expertise required to carry out the application, implantation,

administration or follow-up activities shall be defined. Where necessary, the training

plan of he alth care professiona ls o n t he u s e , a p p li c a ti o n, i mp lan ta ti o n o r

administration procedures of these products shall be provided.

5.1.3.

Given that, due to the nature of advanced therapy medicinal products,

their manufacturing process may change during clinical development, additional

studies to demonstrate comparability may be required.

5.1.4.

During clinical development, risks arising from potential infectious

agents or the use of material derived from animal sources and measures taken to

reduce such risk shall be addressed.

5.1.5.

Dose selection and schedule of use shall be defined by dose-finding

studies.

5.1.6.

The efficacy of the proposed indications shall be supported by relevant

results from clinical studies using clinically meaningful endpoints for the intended

use. In certain clinical conditions, evidence of long-term efficacy may be required.

The strategy to evaluate long-term efficacy shall be provided.

5.1.7.

A strategy for the long-term follow-up of safety and efficacy shall be

included in the risk management plan.\

5.1.8.

For combined advanced therapy medicinal products, the safety and

efficacy studies shall be designed for and performed on the combined product as a

whole.

5.2.

Specific requirements for gene therapy medicinal products

5.2.1.

Human pharmacokinetic studies

Human pharmacokinetic studies shall include the following aspects

(a) shedding studies to address the excretion of the gene therapy medicinal

products;

(b) biodistribution studies;

(c) pharmacokinetic studies of the medicinal product and the gene

expression moieties (e.g. expressed proteins or genomic signatures).

5.2.2.

Human pharmacodynamic studies

Human pharmacodynamic studies shall address the expression and function of the

nucleic acid sequence following administration of the gene therapy medicinal

product.

5.2.3.

Safety studies

Safety studies shall address the following aspects

(a) emergence of replication competent vector;

(b) emergence of new strains;

(c) reassortment of existing genomic sequences;

(d) neoplastic proliferation due to insertional mutagenicity.

5.3.

Specific requirements for somatic cell therapy medicinal products

5.3.1.

Somatic cell therapy medicinal products where the mode of action is

based on the production of defined active biomolecule(s)

For somatic cell therapy medicinal products where the mode of action is based on

the production of defined active biomolecule(s), the pharmacokinetic profile (in

particular distribution, duration and amount of expression) of those molecules shall

be addressed, if feasible.

5.3.2.

Biodistribution, persistence and long-term engraftment of the somatic

cell therapy medicinal product components The biodistribution, persistence and

long-term engraftment of the somatic cell therapy medicinal product components

shall be addressed during the clinical development.

5.3.3.

Safety studies

Safety studies shall address the following aspects

(a) distribution and engrafting following administration;

(b) ectopic engraftment;

(c) oncogenic transformation and cell/tissue lineage fidelity.

5.4.

Specific requirements for tissue engineered products

5.4.1.

Pharmacokinetic studies

Where conventional pharmacokinetic studies are not relevant for tissue engineered

products, the biodistribution, persistence and degradation of the tissue engineered

product components shall be addressed during the clinical development.

5.4.2.

Pharmacodynamic studies

Pharmacodynamic studies shall be designed and tailored to the specificities of

tissue engineered products. The evidence for the “proof of concept” and the kinetics

of the product to obtain the intended regeneration, repairing or replacement shall be

provided. Suitable pharmacodynamic markers, related to the intended function(s)

and structure shall be taken into account.

5.4.3.

Safety studies

Section 5.3.3 shall apply.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 2 Interpretation. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1)

For the purposes of these regulations -

''abuse of medicinal products'' means persistent or sporadic,

intentional excessive use of medicinal products which is

accompanied by harmful physical or psychological effects;

''advanced therapy medicinal product'' means a product as

defined in Article 2 of Regulation (EC) No 1394/2007 of the

European Parliament and of the Council of 13 November 2007 on

advanced therapy medicinal products

''Annex I'' means Annex I of Directive 2001/83/EC as

subsequently amended and as appearing in the Schedule;

''the Act'' means the Medicines Act;

''the Agency'' means the European Medicines Agency established

by Regulation (EC) No 726/2004;

''the Authority'' means the Medicines Authority established under

article 4 of the Act;

''the Commission'' means the Commission in accordance with

Council Decision 1999/468/EC of 28 June, 1999;

''the Community'' means the European Union, previously referred

to as the European Community and the European Economic

Community;

''common name'' is the international non-proprietary name

recommended by the World Health Organisation, or if it does not

exist, the usual common name;

''co-ordination group'' means the co-ordination group set up in

accordance with Article 27 of Directive 2001/83/EC as amended by

Directive 2004/27/EC;

''global marketing authorisation'' means the marketing

authorisations containing the initial marketing authorisation and all

variations and extensions thereof, as well as any additional

strengths, pharmaceutical forms, administration routes or

presentations authorised through separate procedures and under a

different name, granted to the marketing authorisation holder of the

initial authorisation;

''homeopathic medicinal product'' means any medicinal product

prepared from substances called homeopathic stocks in accordance

with a homeopathic manufacturing procedure described by the

European Pharmacopoeia or, in the absence thereof, by the

pharmacopoeias currently used officially in the Member States. A

homeopathic medicinal product may contain a number of

principles;

''Licensing Authority'' means the Licensing Authority referred to

in article 3 of the Act;

''medicinal product'' shall have the same meaning as defined by

the Act;

''Member State'' means a State, which is a member of the

European Union, and shall also include Iceland, Norway and

Liechtenstein;

"Pharmacovigilance system" means a system used by the

marketing authorisation holder and by Member States to fulfil the

tasks and responsibilities listed in these regulations and designed to

monitor the safety of authorised medicinal products and detect any

change to their risk-benefit balance;

"Pharmacovigilance system master file" means a detailed

description of the pharmacovigilance system used by the marketing

authorisation holder with respect to one or more authorised

medicinal products;

"post-authorisation safety study" means any study relating to an

authorised medicinal product conducted with the aim of identifying,

characterising or quantifying a safety hazard, confirming the safety

profile of the medicinal product, or of measuring the effectiveness of

risk management measures;

''reference Member State'' means the Member State which, for a

given medicinal product, has produced the assessment report,

which serves as the basis for the mutual recognition procedure and

the decentralised procedure;

''representative of the marketing authorisation holder'' means the

person commonly known as local representative, designated by the

marketing authorisation holder to represent him in the Member

State concerned;

''risk-benefit balance'' means an evaluation of the positive

therapeutic effects of the medicinal product in relation to the risks

relating to the quality, safety and efficacy of the medicinal product

as regards patients’ health or public health;

"risk management system" means a set of pharmacovigilance

activities and interventions designed to identify, characterise,

prevent or minimise risks relating to a medicinal product, including

t h e a s s e s s m e n t of t h e e ff e c t iv e ne s s o f t h o s e a c t i v it i e s a n d

interventions;

"risk management plan" means a detailed description of the risk

management system;

''risks related to use of the medicinal product'' means any risk

relating to the quality, safety or efficacy of the medicinal product as

regards patients’ health or public health or any risk of undesirable

effects on the environment;

''strength of the medicinal product'' means the content of the

active substances expressed quantitatively per dosage unit, per unit

of volume or weight according to the dosage form;

''the Superintendent'' means the Superintendent of Public Health.

(2)

The provisions of these regulations shall not apply to

(a) any medicinal product prepared in a pharmacy in

accordance with a medical prescription for an

individual patient (commonly known as the magistral

formula);

(b) any medicinal product which is prepared in a

pharmacy in accordance with the prescriptions of a

pharmacopoeia and is intended to be supplied directly

to the patients served by the pharmacy in question,

(commonly known as the officinal formula);

(c) medicinal products intended for research and

development trials but without prejudice to the

provisions of the Clinical Trials Regulations or of

Directive 2001/20/EC of the European Parliament and

of the Council of the 4th April 2001 on the

approximation of the laws, regulations and

administrative provisions of the Member States

relating to the implementation of good clinical practice

in the conduct of clinical trials on medicinal products

for human use;

(d)

intermediate products intended for further processing

by an authorised manufacturer;

(e) any radionuclides in the form of sealed sources;

(f)

whole blood, plasma or blood cells of human origin,

except for plasma which is prepared by a method

involving an industrial process;

(g) medicinal products supplied in response to a bona fide

unsolicited order, formulated in accordance with the

specifications

of

an

authorised

health-care

professional and for use by an individual patient under

his direct personal responsibility;

(h) any advanced therapy medicinal product, as defined in

Regulation (EC) No 1394/2007, which is prepared on a

non-routine basis according to specific quality

standards, and used in Malta in a hospital under the

exclusive professional responsibility of a medical

practitioner, in order to comply with an individual

medical prescription for a custom-made product for an

individual patient. The manufacturing of these

products shall be authorised by the Licensing

Authority in Malta.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 2A List of medicinal products to be published. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) The Licensing Authority shall establish, notify to the

Commission and publish on its website a list of medicinal products

to which it has applied or intends to apply the derogations as set out

in Directive (EU) 2022/642 of the European Parliament and of the

Council of 12 April 2022;

(2) The Licensing Authority shall ensure that the list referred

to in sub-regulation (1) is updated and managed in an independent

manner, at least on a six-monthly basis.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 3 Applicability. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) The provisions of these regulations shall apply to

medicinal products for human use intended to be placed on the

market in Malta and either prepared industrially or manufactured

by a method involving an industrial process.

(2) In cases of doubt, where, taking into account all its

characteristics, a product may fall within the definition of a

''medicinal product'' and within the definition of a product covered

by other community legislation, the provisions of these regulations

shall apply.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 4 Authorisation for placing on the market. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1)(a) Subject to the following provisions of this regulation,

no medicinal product may be placed on the market in

Malta unless there is in respect of that product a valid

marketing authorisation issued by the Licensing

Authority in accordance with these regulations or in

accordance with procedures laid down in Regulation

(EC) No 726/2004 of the European Parliament and of

the Council of 31 March 2004 laying down Community

procedures for the authorisation and supervision of

medicinal products for human and veterinary use and

establishing a European Medicines Agency), read in

conjunction with Regulation (EC) No 1901/2006 of the

European Parliament and of the Council of 12

December 2006 on medicinal products for paediatric

u se , a n d R e g u l a t i o n ( E C ) N o . 1 3 9 4 / 2 0 0 7 o f t h e

European Parliament and of the Council of the 13th

N o v e m b e r 2 0 0 7 o n a d v a n c e d t h e r a p y m e d i ci n a l

products and such placing on the market is in

accordance with the terms and conditions of such

marketing authorisation.

(b) When a medicinal product has been granted an initial

marketing authorisation in accordance with the

preceding paragraph, any additional strengths,

pharmaceutical

forms,

administration

routes,

presentations, as well as any variations and extensions

shall only be granted an authorisation in accordance

with the preceding paragraph or be included in the

initial marketing authorisation. All these marketing

authorisations shall be considered as belonging to the

same global marketing authorisation, in particular for

the purpose of the application of regulation 7(1).

(c) The provisions of paragraphs (a) and (b) shall also

apply to radionuclide generators, kits, radionuclide

precursor radiopharmaceuticals and industrially

prepared radiopharmaceuticals.

(d) A marketing authorisation shall not be required in the

case of a radiopharmaceutical prepared at the time of

its use by a person or by an establishment duly

authorised to use such medicinal products in an

approved health care establishment exclusively from

authorised

radionuclide

generators,

kits

or

radionuclide precursors in accordance with the

manufacturer’s instructions.

(e) The Licensing Authority may, in exceptional cases,

subject to any condition it deems fit, allow the use of a

medicinal product which does not have a marketing

authorisation.

(f)

The Licensing Authority may temporarily authorise

the distribution of an unauthorised medicinal product

in response to the suspected or confirmed spread of

pathogenic agents, toxins, chemical agents or nuclear

radiation any of which could cause harm.

(g) The marketing authorisation holder shall be responsible

for marketing the medicinal product and the designation

of a representative shall not relieve the marketing

authorisation holder of his legal responsibility. The

holder of a marketing authorisation for a medicinal

product and the distributors of the said medicinal product

actually placed on the market in Malta shall, within the

limits of their responsibilities, ensure appropriate and

continued supplies of that medicinal product to

pharmacies and persons authorised to supply medicinal

products so that the needs of patients in Malta are

covered.

(2)

(a) In the absence of a marketing authorisation or of a

pending application for a medicinal product which is

authorised in another Member State in accordance with

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

any amendments thereto, the Licensing Authority may

for justified public health reasons authorise the placing

of the said medicinal product on the market in Malta.

(b) The medicinal product referred to in paragraph (a) has

to comply in particular with the requirements of the

provisions regarding the classification of medicinal

products, laid down in the Act, and any regulations

made thereunder, and the following regulations

(i)

the

Medicinal

Products

(Advertising)

Regulations;

(ii) the Medicinal Products

(Labelling

and

Packaging) Regulations;

(iii) the Pharmacovigilance Regulations; and

(iv)

the Wholesale Distribution

of

Medicinal

Products Regulations.

The Authority may decide that regulation 10(1) and (2) of

the Medicinal Products (Labelling and Packaging)

Regulations and Article 63(1) and (2) of Directive 2001/

83/EC shall not apply to medicinal products authorised

MEDICINES (MARKETING AUTHORISATION)

under paragraph (a).

(c) Any authorisation issued under this regulation shall for

the purposes of articles 99 to 104 of the Act be deemed

to be a marketing authorisation.

(d) Before granting such an authorisation the Licensing

Authority shall

(i)

notify the marketing authorisation holder in the

Member State in which the medicinal product

concerned is authorised, of its intention to grant

an authorisation under subregulation (2), and

(ii) request the competent authority in that Member

State to furnish a copy of the assessment report,

and of the marketing authorisation in force.

(e)

(i) The medicinal product to be placed on the

market in Malta shall be that authorised by the

Member State referred to in paragraph (a).

(ii) An authorisation under this subregulation cannot

be used as the basis for a licence in terms of the

Parallel Importation of Medicinal Products

Regulations.

(iii) An authorisation under this subregulation cannot

be used as a reference for an application

submitted in accordance with regulation 7.

(f)

The holder of the authorisation in Malta granted in

accordance with this subregulation, shall ensure that

(i)

the medicinal product is in accordance with the

marketing authorisation issued by the Member

State referred to above, and includes any

variations in particular those affecting the

summary of product characteristics, labelling

and package leaflet of the medicinal product as

approved in the said Member State, and submits

the updated documentation to the Medicines

Authority;

(ii) he implements without any delay actions

relating to issues concerning the medicinal

product which have resulted in a product or

batch recall as may apply to the medicinal

product authorised in the Member State referred

to above.

(g) In the case of a medicinal product, where the

wholesale distributor is not the authorisation holder

for the medicinal product in Malta, the distributor

shall, in respect of the product he is distributing in

Malta, furnish to the Medicines Authority an

authenticated copy of the said authorisation together

with a letter of access issued by the authorisation

holder granting the wholesale distributor the use of

such an authorisation.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 4A Derogation for products from the United Kingdom. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) By way of derogation from regulation 4(2), until the

31st December 2024, in the absence of a marketing authorisation or

of a pending application for a marketing authorisation, the

Licensing Authority may authorise for justified public health

reasons the placing on the market of a medicinal product authorised

in parts of the United Kingdom other than Northern Ireland

Provided that the Licensing Authority may also maintain

in force or, until the 31st December 2024, extend marketing

authorisations that were granted pursuant to this sub-regulation before

the 20th April 2022 which authorise the placing on the market of a

medicinal product authorised in parts of the United Kingdom other than

Northern Ireland

Provided further that authorisations that are granted,

extended or maintained in force pursuant to the provisions of this sub-

regulation shall not be valid after the 31st December 2026.

(2)

By way of derogation from regulation 5(1)(b), the

Licensing Authority may grant marketing authorisations as referred to in

regulation 4(2), to marketing authorisation holders established in parts

of the United Kingdom other than Northern Ireland.

(3)

Where the Licensing Authority grants or extends a

marketing authorisation as referred to in sub-regulation (1), it shall

ensure compliance with the requirements of this regulation.

(4)

Before granting a marketing authorisation pursuant to sub-

regulation (1), the Licensing Authority

(a) shall notify the marketing authorisation holder in parts

of the United Kingdom other than Northern Ireland of

the proposal to grant a marketing authorisation or to

extend a marketing authorisation under this regulation

in respect of the medicinal product concerned;

(b) may request the competent authority in the United

Kingdom to submit the relevant information regarding

the marketing authorisation of the medicinal product

concerned.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 5 Grant or renewal of marketing authorisation. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) A marketing authorisation may only be granted or

renewed if the general conditions applicable to authorisations and

the conditions set out under Directive 2001/83/EC on the

Community code relating to medicinal products for human use and

subsequent amendments thereto, are fulfilled as follows

(a) an application for marketing authorisation shall be

made to the Licensing Authority which shall refer such

application to the Authority for processing;

(b) a marketing authorisation may only be granted to an

applicant established in the Community

Provided that by way of derogation from the above,

marketing authorisations may be granted until the 31st

December 2024, by the Licensing Authority in

accordance with the mutual recognition or the

decentralised procedure laid down under regulation 22

to marketing authorisation holders established in parts

of the United Kingdom other than Northern Ireland

Provided further that until the 31st December 2024 the

Licensing

Authority

may

extend

marketing

authorisations already granted prior to the 20th April

2022 to marketing authorisation holders established in

parts of the United Kingdom other than Northern

Ireland

Provided further that marketing authorisations granted

or extended by the Licensing Authority in accordance

with the preceding two provisos shall cease to be valid

at the latest on the 31st December 2026.

(c) the application shall be accompanied by the following

documents and particulars to be submitted in

accordance with Annex I

(i)

the name or corporate name and permanent

address of the applicant and, where applicable,

of the manufacturer;

(ii) the name of the medicinal product;

(iii) qualitative and quantitative particulars of all the

constituents of the medicinal product, including

the reference to its international non-proprietary

name (INN) recommended by the World Health

Organisation, where an INN for the medicinal

product exists, or a reference to the relevant

chemical name;

(iv) evaluation of the potential environmental risks

posed by the medicinal product. This impact

shall be assessed and, on a case-by-case basis,

specific arrangements to limit it shall be

envisaged;

(v) a description of the manufacturing method;

(vi) therapeutic indications, contra-indications and

adverse reactions;

(vii)

posology, pharmaceutical form, method and

route of administration and expected shelf life;

(viii) reasons for any precautionary and safety

measures to be taken for the storage of the

medicinal product, its administration to patients

and for the disposal of waste products, together

with an indication of potential risks presented by

the medicinal product for the environment;

(ix) description of the control methods employed by

the manufacturer;

(x)

a written confirmation that the manufacturer of

the medicinal product has verified compliance of

the manufacturer of the active substance with

principles and guidelines of good manufacturing

practice by conducting audits, in accordance

with regulation 5 of the Good Manufacturing

Practice in respect of Medicinal Products,

Active Substances and Investigational Medicinal

Products for Human Use Regulations. The

written confirmation shall contain a reference to

the date of the audit and a declaration that the

outcome of the audit confirms that the

manufacturing complies with the principles and

guidelines of good manufacturing practice;

(xi)

results of pharmaceutical (physico-chemical,

biological or microbiological) tests, pre-clinical

(toxicological and pharmacological) tests,

clinical trials;

(xii)

a summary of the applicant’s pharmacovigilance

system which shall include the following

elements

- proof that the applicant has at his disposal a

qualified

person

responsible

for

pharmacovigilance,

- the Member States in which the qualified

person resides and carries out his tasks,

- the contact details of the qualified person,

- a statement signed by the applicant to the

effect that the applicant has the necessary

means to fulfil the tasks and responsibilities

listed in Title IX of Directive 2001/83/EC as

amended,

- a reference to the location where the

pharmacovigilance system master file for the

medicinal product is kept;

(xiii) the risk management plan describing the risk

management system which the applicant will

introduce for the medicinal product concerned,

together with a summary thereof of the risk

management system which the applicant will

introduce;

(xiv)

a statement to the effect that clinical trials

carried out outside the European Union meet the

ethical requirements of the Clinical Trials

Regulations and of Directive 2001/20/EC of the

European Parliament and of the Council of the

4th April, 2001 on the approximation of the

laws, regulations and administrative provisions

of the Member States relating to the

implementation of good clinical practice in the

conduct of clinical trials on medicinal products

on human use;

(xv)

a summary, in accordance with regulation 8, of

the product characteristics, a mock-up of the

outer packaging, containing the details provided

for in the Medicinal Products (Labelling and

Packaging) Regulations, and of the immediate

packaging of the medicinal product, containing

the details provided for in those regulations,

together with a package leaflet in accordance

with those same regulations;

(xvi) a document showing that the manufacturer is

authorised in his own country to produce

medicinal products;

(xvii) copies of the following

- any authorisation, obtained in another

Member State or in a third country, to place

the medicinal product on the market, a

summary of the safety data including the

data contained in the periodic safety update

reports, where available, and suspected

adverse reactions reports, together with a list

of those Member States in which an

application for authorisation submitted in

accordance with the provisions of Directive

2001/83/EC, as amended, is under

examination,

-

the summary of the product characteristics

proposed by the applicant in accordance with

regulation 8 or approved by the competent

authorities of the Member State in

accordance with regulation 16 and the

package leaflet proposed in accordance with

the Medicinal Products (Labelling and

Packaging) Regulations, or as approved by

the competent authorities of the Member

State in accordance with the Medicinal

Products

(Labelling

and

Packaging)

Regulations,

- details of any decision to refuse

authorisation, whether in the Community or

in a third country, and the reasons for such a

decision;

(xviii) a copy of any designation of the medicinal

product as an orphan medicinal product under

Regulation (EC) No 141/2000 of the European

Parliament and of the Council of 16 December

on

orphan

medicinal

products,

accompanied by a copy of the relevant Agency

opinion.

(2) The documents and information concerning the results of

the pharmaceutical and pre-clinical tests and the clinical trials

referred to in sub-regulation (1)(c)(x) shall be accompanied by

detailed summaries in accordance with regulation 9.

(3) The risk management system referred to in sub-regulation

(1)(c)(xii) shall be proportionate to the identified risks and the

potential risks of the medicinal product, and the need for post-

authorisation safety data.

(4) The information in sub-regulation (1) shall be updated

where and when appropriate.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 5A Obligations of the authorisation holder. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

The derogations set out in regulations 4A and 5(1) (b),

regulations 4 and 22 of the Pharmacovigilance Regulations, and

regulations 11A, 11B, 11C and 11D of the Manufacture and Importation

of Medicinal Products for Human Use Regulations shall not affect the

obligations of the marketing authorisation holder to ensure the quality,

safety and efficacy of the medicinal product placed on the market as laid

down in these regulations.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 6 Application for radionuclide generator. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

In the case of an application for a marketing authorisation

for a radionuclide generator, in addition to the requirements set out

in regulations 5 and 7(1), the application shall also contain

(a) a general description of the system together with a

detailed description of the components of the system

which may affect the composition or quality of the

daughter nucleid preparation; and

(b) qualitative and quantitative particulars of the eluate or

the sublimate.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 7 Details to be provided. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) (a)

(i)

By way of derogation from regulation 5(1)(c)(x),

and without prejudice to the law relating to the

protection of industrial and commercial

property, the applicant shall not be required to

provide the results of pre-clinical tests and of

clinical trials if he can demonstrate that the

medicinal product is a generic of a reference

medicinal product which is or has been

authorised under regulation 4(1) for not less than

eight years in a Member State or in the

C o m m u n i t y. A g e n e r i c m e d i c i n a l p r o d u c t

authorised pursuant to this provision shall not be

placed on the market until ten years have elapsed

from the initial authorisation of the reference

product

Provided that the said ten-year period shall be

extended to a maximum of eleven years if,

during the first eight years of those ten years, the

marketing authorisation holder obtains an

authorisation for one or more therapeutic

indications which, during the scientific

evaluation prior to their authorisation, are held

to bring a significant clinical benefit in

comparison with existing therapies.

(ii) Subregulation (1)(a)(i) shall also apply if the

reference medicinal product was not authorised

in Malta. In this case, the applicant shall

indicate in the application form the name of the

Member State in which the reference medicinal

product is or has been authorised. At the request

of the Licensing Authority, the competent

authority of the other Member State shall

transmit within a period of one month, a

confirmation that the reference medicinal

product is or has been authorised, together with

the full composition of the reference product and

if necessary other relevant documentation

Provided that the Licensing Authority shall within one

month provide any information requested by the

competent authority of another Member State in

respect of a reference medicinal product authorised in

Malta

Provided further that for the purposes of this

regulation

''reference medicinal product'' means a medicinal

product authorised under regulation 4(1), in

accordance with the provisions of regulation 5 or

authorised under Article 8 of Directive 2001/83/EC as

amended;

''generic medicinal product'' means a medicinal

product which has the same qualitative and

quantitative composition in active substances and the

same pharmaceutical form as the reference medicinal

product, and whose bioequivalence with the reference

medicinal product has been demonstrated by

appropriate bioavailability studies. The different salts,

esters, ethers, isomers, mixtures of isomers, complexes

or derivatives of an active substance shall be

considered to be the same active substance, unless they

differ significantly in properties with regard to safety

and, or efficacy. In such cases, additional information

providing proof of the safety and, or efficacy of the

various salts, esters or derivatives of an authorised

active substance must be supplied by the applicant.

The various immediate-release oral pharmaceutical

forms shall be considered to be one and the same

pharmaceutical form. Bioavailability studies need not

be required of the applicant if he can demonstrate that

the generic medicinal product meets the relevant

criteria as defined in the appropriate detailed

guidelines.

(b) In cases where the medicinal product does not fall

within the definition of a generic medicinal product as

provided above or where the bioequivalence cannot be

demonstrated through bioavailability studies or in case

of changes in any active substance, therapeutic

indications, strength, pharmaceutical form or route of

administration, vis-à-vis the reference medicinal

product, the results of the appropriate pre-clinical tests

or clinical trials shall be provided.

(c) Where a biological medicinal product which is similar

to a reference biological product does not meet the

conditions in the definition of generic medicinal

products, owing to, in particular, differences relating

to raw materials or differences in manufacturing

processes of the biological medicinal product and the

reference biological medicinal product, the results of

appropriate pre-clinical tests or clinical trials relating

to these conditions must be provided. The type and

quantity of supplementary data to be provided must

comply with the relevant criteria stated in Annex I and

the related detailed guidelines.

The results of other tests and trials from the reference

medicinal product’s dossier shall not be provided.

(d) In addition to the provisions laid down in paragraph

(a), where an application is made for a new indication

for a well-established substance, a non-cumulative

period of one year of data exclusivity shall be granted,

provided that significant pre-clinical or clinical studies

were carried out in relation to the new indication.

(e) Conducting the necessary studies and trials with a

view to the application of paragraphs (a), (b), and (c)

and the consequential practical requirements shall not

be regarded as contrary to patent rights or to

supplementary protection certificates for medicinal

products.

(f)

The periods of protection provided for in paragraphs

(a), (b), (c) and (d) shall not apply to reference

medicinal products for which an application for

authorisation has been submitted before the date of

coming into force of these regulations.

(2) By way of derogation from regulation 5(1)(c)(x), and

without prejudice to the law relating to the protection of industrial

and commercial property, the applicant shall not be required to

provide the results of pre-clinical tests or clinical trials if he can

demonstrate that the active substances of the medicinal product

have been in well-established medicinal use within the Community

for at least ten years, with recognised efficacy and an acceptable

level of safety in terms of the conditions set out in Annex I. In that

event, the test and trial results shall be replaced by appropriate

scientific literature.

(3) In the case of medicinal products containing active

substances used in the composition of authorised medicinal

products but not hitherto used in combination for therapeutic

purposes, the results of new pre-clinical tests or new clinical trials

relating to that combination shall be provided in accordance with

regulation 5(1)(c)(x), but it shall not be necessary to provide

scientific references relating to each individual active substance.

(4) Following the granting of a marketing authorisation, the

authorisation holder may allow use to be made of the

pharmaceutical, pre-clinical and clinical documentation contained

in the file on the medicinal product, with a view to examining

subsequent applications relating to other medicinal products

possessing the same qualitative and quantitative composition in

terms of active substances and the same pharmaceutical form.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 8 Summary of product characteristics. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) The summary of the product characteristics shall

contain, in the order indicated below, the following information

(a) name of the medicinal product followed by the

strength and the pharmaceutical form;

(b) qualitative and quantitative composition in terms of

the active substances and constituents of the excipient,

knowledge of which is essential for proper

administration of the medicinal product. The usual

common name or chemical description shall be used;

(c) pharmaceutical form;

(d) clinical particulars

(i) therapeutic indications,

(ii) posology and method of administration for

adults and, where necessary for children,

(iii) contra-indications,

(iv) special warnings and precautions for use and, in

the case of immunological medicinal products,

any special precautions to be taken by persons

handling such products and administering them

to patients, together with any precautions to be

taken by the patient,

(v) interaction with other medicinal products and

other forms of interactions,

(vi) use during pregnancy and lactation,

(vii) effects on ability to drive and to use machines,

(viii) undesirable effects,

(ix) overdose (symptoms, emergency procedures,

antidotes);

(e) pharmacological properties

(i) pharmacodynamic properties,

(ii) pharmacokinetic properties,

(iii) preclinical safety data;

(f)

pharmaceutical particulars

(i) list of excipients,

(ii) major incompatibilities,

(iii) shelf life, when necessary after reconstitution of

the medicinal product or when the immediate

packaging is opened for the first time,

(iv) special precautions for storage,

(v) nature and contents of container,

(vi) special precautions for disposal of a used

medicinal product or waste materials derived

from such medicinal product, if appropriate;

(g) marketing authorisation holder;

(h) marketing authorisation numbers;

(i)

date of the first authorisation or renewal of the

authorisation;

(j)

date of revision of the text;

(k) for radiopharmaceuticals

(i) full details of internal radiation dosimetry;

(ii) additional

detailed

instructions

for

extemporaneous preparation and quality control

of such preparation and, where appropriate,

maximum storage time during which any

intermediate preparation such as an eluate or the

ready-touse pharmaceutical will conform with

its specifications.

(2) For the authorisations referred to under regulation 7, those

parts of the summary of product characteristics of the reference

medicinal product referring to indications or dosage forms which

were still covered by patent law at the time when a generic

medicine was marketed need not be included.

(3) For medicinal products included in the list referred to in

Article 23 of Regulation (EC) No 726/2004, the summary of

product characteristics shall include the statement: "This medicinal

product is subject to additional monitoring". This statement shall

be preceded by the black symbol referred to in Article 23 of

Regulation (EC) No 726/2004 and followed by an appropriate

standardised explanatory sentence.

For all medicinal products, a standard text shall be included

expressly asking healthcare professionals to report any suspected

adverse reaction in accordance with the national spontaneous reporting

system. Different ways of reporting, including electronic reporting,

shall be available in compliance with the second subparagraph of

Article 107a(1) of Directive 2001/83/EC as amended.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 9 Experts to formulate and sign documents. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) The applicant shall ensure that, before the detailed

summaries referred to in the regulation 5(3) are submitted to the

Licensing Authority, they have been drawn up and signed by

experts with the necessary technical or professional qualifications,

which shall be set out in a brief curriculum vitae.

(2) Persons having the technical and professional qualifications

referred to in the preceding subregulation shall justify any use

made of scientific literature under regulation 7(2) in accordance

with the conditions set out in Annex I.

(3) The detailed summaries shall form part of the file which the

applicant submits to the Licensing Authority.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 10 Specific provisions applicable to homeopathic medicinal products. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) The Authority shall ensure that homeopathic medicinal

products manufactured and placed on the market within the

Community are registered or authorised in accordance with this

regulation and regulation 11. In case of registrations, regulation

22(1)(a) to (f) shall apply.

(2) The Authority shall establish a special simplified

registration procedure for the homeopathic medicinal products

referred to in subregulation (3).

(3) Only homeopathic medicinal products which satisfy all of

the following conditions may be subject to a special, simplified

registration procedure

(a) they are administered orally or externally;

(b) no specific therapeutic indication appears on the

labelling of the medicinal product or in any

information relating thereto;

(c) there is a sufficient degree of dilution to guarantee the

safety of the medicinal product; in particular, the

medicinal product may not contain either more then

one part per 10 000 of the mother tincture or more than

1/100th of the smallest dose used in allopathy with

regard to active substances whose presence in an

allopathic medicinal product results in the obligation

to submit a doctor’s prescription.

The classification for the dispensing of the medicinal product,

shall be determined by the Authority at the time of registration.

The criteria and rules of procedure provided for in regulations

12, 17, 18, 19, 20 and 21, and Articles 4(4), 112, 116 and 125 of

Directive 2001/83/EC, as amended, shall apply by analogy to the

special, simplified re gistration procedure for homeopathic

medicinal products with the exception of the proof of therapeutic

efficacy.

(4) An application for special, simplified registration may

cover a series of medicinal products derived from the same

homeopathic stock or stocks. The following documents shall be

included with the application in order to demonstrate, in particular,

the pharmaceutical quality and the batch-to-batch homogeneity of

the products concerned

(a) scientific name or other name given in a

pharmacopoeia of the homeopathic stock or stocks,

together with a statement of the various routes of

administration, pharmaceutical forms and degree of

dilution to be registered;

(b) dossier describing how any homeopathic stock or

stocks is obtained and controlled, and justifying its

homeopathic use, on the basis of an adequate

bibliography;

(c) manufacturing and control file for each pharmaceutical

form and a description of the method of dilution and

potentization;

(d) manufacturing authorisation for the medicinal product

concerned;

(e) copies of any registrations or authorisations obtained

for the same medicinal product in other Member

States;

(f)

one or more mock-ups of the outer packaging and the

immediate packaging of the medicinal products to be

registered;

(g) data concerning the stability of the medicinal product.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 11 Saving. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

Homeopathic medicinal products, other than those referred

to in regulation 10(3), shall be authorised and labelled in

accordance with regulations 5, 7 and 8.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 12 Processing of application. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

It shall be the duty of the Authority to ensure that the

procedure for granting a marketing authorisation for medicinal

products is completed within a maximum of two hundred and ten

days after the submission of a valid application

Provided that applications for marketing authorisations in

two or more Member States in respect of the same medicinal

product shall be submitted in accordance with the mutual

recognition and decentralised procedures.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 13 Application already under examination in a Member State. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

Where the Authority notes that another marketing

authorisation application for the same medicinal product is being

examined in another Member State, the Authority shall decline to

assess the application and shall advise the applicant that the mutual

recognition and decentralised procedures apply.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 14 Duties of the Authority on receiving the report. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

Where the Authority is informed in accordance with

regulation 5(1)(c)(xiii) that another Member State has authorised a

medicinal product, which is the subject of a marketing

authorisation application in Malta, it shall reject the application

unless it was submitted in compliance with the mutual recognition

or decentralised procedures.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 15 Examination of application. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) In order to examine the application submitted in

accordance with regulations 5 and 7, the Authority -

(a) shall verify whether the particulars submitted by the

applicant are in terms of the provisions of these

regulations and examine whether the conditions for

issuing a marketing authorisation are complied with;

(b) may submit the medicinal product, its starting

materials and, if need be, its intermediate products or

other constituent materials, for testing by an Official

Medicines Control Laboratory or by a laboratory

designated for that purpose by the Authority in order

to ensure that the control methods employed by the

manufacturer and described in the particulars

accompanying the application in accordance with

regulation 5(1)(c)(ix) are satisfactory;

(c) may, where appropriate, require the applicant to

supplement the particulars accompanying the

application in respect of the items listed under

regulations 5(1)(c) and 7, in which case, the two

hundred and ten days referred to under regulation 12

shall be suspended until such time as the

supplementary information required has been

MEDICINES (MARKETING AUTHORISATION)

provided. Likewise, these time limits shall be

suspended when the applicant is given the opportunity

of providing an oral or written explanation.

(2)

The Authority

(a) shall verify that manufacturers and importers of

medicinal products coming from third countries are

able to carry out manufacture in compliance with the

particulars supplied pursuant to regulation 5(1)(c)(v)

and, or to carry out controls according to the methods

described in the particulars accompanying the

application in accordance with regulation 5(1)(c)(ix);

(b) may allow manufacturers and importers of medicinal

products coming from third countries, in justifiable

cases, to have certain stages of manufacture and, or

certain of the controls referred to in paragraph (a)

carried out by third parties; in such cases, the

verifications by the Authority shall also be made in the

establishment designated.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 16 Information to holder. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(a) When the marketing authorisation is issued it shall be

subject to the conditions as specified in the Marketing

Authorisation, the Act and any regulations made

t h e r e u nd e r as w e l l as t o a ny co nd i ti o ns t ha t t he

Licensing Authority may deem necessary, and the

holder shall be informed by the Authority of the

summary of the product characteristics as approved by

it.

(b) The Authority shall

(i)

take all necessary measures to ensure that the

information given in the summary is in

conformity with that accepted when the

marketing

authorisation

is

issued

or

subsequently;

(ii) make publicly available without delay the

marketing authorisation together with the

summary of the product characteristics for each

medicinal product which it has authorised;

(iii) shall, without delay, make publicly available the

marketing authorisation together with the package

leaflet, the summary of the product characteristics

and any conditions established in accordance with

article 23 of the Medicines Act and paragraph (c)

and regulation 17(a) and (b), and together with any

deadlines for the fulfilment of those conditions for

each medicinal product which they have

authorised;;

(iv) shall draw up an assessment report and make

comments on the file as regards the results of the

pharmaceutical and pre-clinical tests, the clinical

trials, the risk management system and the

pharmacovigilance system of the medicinal

product concerned. The assessment report shall be

updated whenever new information becomes

available which is important for the evaluation of

the quality, safety or efficacy of the medicinal

product concerned.

The Authority shall make the assessment report

publicly accessible without delay, together with the

reasons for their opinion, after deletion of any

information of a commercially confidential nature.

The justification shall be provided separately for each

indication applied for.

The public assessment report shall include a summary

written in a manner that is understandable to the

public. The summary shall contain, in particular, a

section relating to the conditions of use of the

medicinal product.

(c) In addition to the provisions laid down in regulation

15, a marketing authorisation for a medicinal product

may be granted subject to one or more of the following

conditions

(i)

to take certain measures for ensuring the safe

use of the medicinal product to be included in

the risk management system;

(ii) to conduct post-authorisation safety studies;

(iii) to comply with obligations on the recording or

reporting of suspected adverse reactions which

are stricter than those referred to in Title IX of

Directive 2001/83/EC as amended;

(iv) any other conditions or restrictions with regard

to the safe and effective use of the medicinal

product;

(v) the existence of an adequate pharmacovigilance

system;

(vi) to conduct post-authorisation efficacy studies

where concerns relating to some aspects of the

efficacy of the medicinal product are identified

and can be resolved only after the medicinal

product has been marketed. Such an obligation

to conduct such studies shall be based on the

delegated acts adopted pursuant to Regulation

17 of these regulations, while taking into

account the scientific guidance referred to in

Article 108a of Directive 2001/83/EC as

amended.

The marketing authorisation shall lay down deadlines

for the fulfilment of these conditions where necessary.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 17 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(a) In

exceptional

circumstances

and

following

Exceptional

circumstances.

consultation with the applicant, the marketing

Substituted by

authorisation may be granted subject to certain

L.N. 373 of 2012.

conditions, in particular relating to the safety of the

medicinal product, notification to the Authority of any

incident relating to its use, and action to be taken.

The marketing authorisation may be granted only

when the applicant can show that he is unable to

provide comprehensive data on the efficacy and safety

of the medicinal product under normal conditions of

use, for objective, verifiable reasons and it should be

based on one of the grounds set out in Schedule I.

Continuation of the marketing authorisation shall be

linked to the annual reassessment of these conditions.

(b) After the granting of a marketing authorisation, the

Licensing Authority may impose an obligation on the

marketing authorisation holder

(i)

to conduct a post-authorisation safety study if

there are concerns about the risks of an

authorised medicinal product. If the same

concerns apply to more than one medicinal

product, the Authority shall, following

consultation with the Pharmacovigilance Risk

Assessment

Committee,

encourage

the

marketing authorisation holders concerned to

conduct a joint post-authorisation safety study;

(ii) to conduct a post-authorisation efficacy study

when the understanding of the disease or the

clinical methodology indicate that previous

efficacy evaluations might have to be revised

significantly. The obligation to conduct the post-

authorisation efficacy study shall be based on

the guidelines or Regulations published by the

Commission pursuant to Article 22b of Directive

2001/83/EC as amended, while taking into

account the scientific guidance referred to in

Article 108a of Directive 2001/83/EC as

amended.

The imposition of such an obligation shall be duly

justified, notified in writing, and shall include the

objectives and timeframe for submission and conduct

of the study.

The Authority shall provide the marketing

authorisation holder with an opportunity to present

written observations in response to the imposition of

the obligation within a time limit which it shall

specify, if the marketing authorisation holder so

requests within thirty days of receipt of the written

notification of the obligation.

On the basis of the written observations submitted by

the marketing authorisation holder, the Licensing

Authority shall withdraw or confirm the obligation.

Where the Licensing Authority confirms the

obligation, the marketing authorisation shall be varied

to include the obligation as a condition of the

marketing authorisation and the risk management

system shall be updated accordingly.

(c) The marketing authorisation holder shall incorporate

any conditions referred to in paragraphs (a) and (b)

and in regulation 16(b), in his risk management

system.

(d) The Member States shall inform the Agency of the

marketing authorisations that they have granted subject

to conditions pursuant to paragraphs (a) or (b) or in

regulation 16(c).

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 18 Duties of authorisation holder. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) After a marketing authorisation has been granted, the

marketing authorisation holder shall, in respect of the methods of

manufacture and control provided for in regulation 5(1)(c)(v) and

(ix), take account of scientific and technical progress and introduce

any changes that may be required to enable the medicinal product

to be manufactured and checked by means of generally accepted

scientific methods.

Those changes shall be subject to the approval of the

Licensing Authority.

(2) The marketing authorisation holder shall forthwith provide

the national competent authority with any new information which

might entail the amendment of the particulars or documents

referred to in regulation 5(1)(c), regulation 7(1), (2) and (3), and

regulation 8 , or Article 32(5), or Annex I of Directive 2001/83/EC

as amended.

In particular, the marketing authorisation holder shall

forthwith inform the national competent authority of any

prohibition or restriction imposed by the competent authorities of

any country in which the medicinal product is marketed and of any

other new information which might influence the evaluation of the

benefits and risks of the medicinal product concerned. The

information shall include both positive and negative results of

clinical trials or other studies in all indications and populations,

whether or not included in the marketing authorisation, as well as

data on the use of the medicinal product where such use is outside

the terms of the marketing authorisation.

(3) The marketing authorisation holder shall ensure that the

product information is kept up to date with the current scientific

knowledge, including the conclusions of the assessment and

recommendations made public by means of the European medicines

web-portal established in accordance with Article 26 of Regulation

(EC) No 726/2004.

(4) In order to be able to continuously assess the risk-benefit

balance, the national competent authority may at any time ask the

marketing authorisation holder to forward data demonstrating that

the risk-benefit balance remains favourable. The marketing

authorisation holder shall answer fully and promptly any such

request.

The national competent authority may at any time ask the

marketing authorisation holder to submit a copy of the

pharmacovigilance system master file. The marketing authorisation

holder shall submit the copy at the latest seven days after receipt of

the request.

(5) After a marketing authorisation has been granted, the

holder of the authorisation shall inform the Authority of the date of

actual marketing of the medicinal product for human use in Malta,

taking into account the various presentations authorised.

If the product ceases to be placed on the Maltese market, either

temporarily or permanently, the marketing authorisation holder shall

notify the Medicines Authority. Such notification shall, other than in

exceptional circumstances, be made no less than two months before

the interruption in the placing on the market of the product. The

marketing authorisation holder shall inform the Medicines Authority

of the reasons for such action in accordance with regulation 23(7).

(6) Upon request by the Authority, particularly in the context of

pharmacovigilance, the marketing authorisation holder shall provide it

with all data relating to the volume of sales of the medicinal product,

and any data in his possession relating to the volume of prescriptions.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 19 Validity of marketing authorisation. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) Without prejudice to sub-regulations (5) and (6), a

marketing authorisation shall be valid for five years.

(2) The marketing authorisation may be renewed after five

years on the basis of a re-evaluation of the risk-benefit balance by

the Authority.

(3) To this end, the marketing authorisation holder shall

provide the Authority with a consolidated version of the file in

respect of quality, safety and efficacy, including the evaluation of

data contained in suspected adverse reactions reports and periodic

safety update reports submitted in accordance with Title IX of

Directive 2001/83/EC as amended, and information on all

variations introduced since the marketing authorisation was

granted, at least nine months before the marketing authorisation

ceases to be valid in accordance with sub-regulation (1).

(4) Once renewed, the marketing authorisation shall be valid

for an unlimited period, unless the national competent Authority

decides, on justified grounds relating to pharmacovigilance,

including exposure of an insufficient number of patients to the

medicinal product concerned, to proceed with one additional five-

year renewal in accordance with sub-regulation (2).

(5) Any authorisation granted by the Authority which within

three years of its granting is not followed by the actual placing on

the market of the authorised product in Malta shall cease to be

valid.

(6) When an authorised product previously placed on the

market in Malta is no longer actually present on the market for a

period of three consecutive years, the authorisation for that product

shall cease to be valid.

(7) The Authority may, in exceptional circumstances and on

public health grounds, grant exemptions from sub-regulations (4) and

(5) provided that such exemptions are duly justified.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 20 Civil and criminal liability. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

An authorisation or licence for placing a medicinal product

on the market shall not affect the civil and criminal liability of the

manufacturer and, where applicable, of the marketing authorisation

holder who has placed such medicinal product on the market in any

European Union or European Economic Area state. Such

manufacturer or marketing authorisation holder shall in particular

remain liable for any deficiencies in quality, safety and efficacy of

such medicinal products.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 21 Refusal of marketing authorisation. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) The marketing authorisation of a medicinal product

shall be refused if, after verification of the particulars and

documents listed in regulations 5 and 7 it is clear that

(a) the risk-benefit balance is not considered to be

favourable, or

(b) the therapeutic efficacy of the medicinal product is

insufficiently substantiated by the applicant, or

(c) the qualitative and quantitative composition of the

medicinal product is not as declared.

(2) Authorisation shall likewise be refused if any particulars or

documents submitted in support of the application do not comply

with the provisions of regulations 5 and 7.

(3) The applicant or the holder of a marketing authorisation

shall be responsible for the accuracy of the documents and the data

submitted.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 22 Mutual recognition and decentralised procedure. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(a) With a view to the granting of a marketing

authorisation for a medicinal product in more than one

Member State, including Malta, an applicant shall

submit an application to the Authority, based on a

dossier identical to that submitted in the other Member

States. The dossier shall contain the information and

documents referred to in regulations 5, 7 and 8. The

documents submitted shall include a list of Member

States concerned by the application.

The applicant shall request one Member State to act as

''reference Member State'' and to prepare an

assessment report on the medicinal product in

accordance with paragraphs (b) and (c).

(b) Where the medicinal product has already received a

marketing authorisation at the time of application, if

Malta is a concerned Member State, the Authority

shall recognise the marketing authorisation granted by

the reference Member State. To this end, the marketing

authorisation holder shall request the reference

Member State either to prepare an assessment report

on the medicinal product or, if necessary, to update any

existing assessment report. If Malta is the reference

Member State, the Authority shall prepare or update

the assessment report within ninety days of receipt of a

valid application. The assessment report together with

the approved summary of product characteristics,

labelling and package leaflet shall be sent to the

MEDICINES (MARKETING AUTHORISATION)

concerned Member States and to the applicant.

(c) In cases where the medicinal product has not received

a marketing authorisation at the time of application,

the applicant shall request the reference Member State

to prepare a draft assessment report, a draft summary

of product characteristics and a draft of the labelling

and package leaflet. If Malta is the Reference Member

State, the Authority shall prepare these draft

documents within one hundred and twenty days after

receipt of a valid application and shall send them to

the concerned Member States and to the applicant.

(d) If Malta is a concerned Member State, within ninety

days of receipt of the documents referred to in

paragraphs (b) and (c), the Authority shall approve the

assessment report, the summary of product

characteristics and the labelling and package leaflet

and shall inform the reference Member State

accordingly. If Malta is the reference Member State,

the Authority shall record the agreement of all parties,

close the procedure and inform the applicant

accordingly.

(e) The Authority shall adopt a decision in conformity

with the approved assessment report, the summary of

product characteristics and the labelling and package

leaflet as approved, within thirty days after

acknowledgement of the agreement.

(f)

If, within the period laid down in paragraph (d), the

Authority cannot approve the assessment report, the

summary of product characteristics, the labelling and

the package leaflet on the grounds of potential serious

risk to public health, it shall give a detailed exposition

of the reasons for its position to the reference Member

State, to the other Member States concerned and to the

applicant. The points of disagreement shall be

forthwith referred to the co-ordination group. Within

such co-ordination group, the Authority shall use its

best endeavours to reach agreement on the action to be

taken and it shall allow the applicant the opportunity

to make his point of view known orally or in writing.

If, within sixty days of the communication of the

points of disagreement, all Member States reach an

agreement, if Malta is the Reference Member State,

the Authority shall record the agreement, close the

procedure and inform the applicant accordingly and

paragraph (e) shall apply

Provided that if Member States fail to reach an

agreement within the co-ordination group, within such

sixty-day period, and if the Authority has approved the

assessment report, the draft summary of product

characteristics and the labelling and package leaflet of

the reference Member State, the Authority may, at the

request of the applicant, authorise the medicinal

product without waiting for the outcome of the

procedure laid down in Article 32 of Directive 2001/

83/EC as amended by Directive 2004/27/EC. In that

event, the authorisation granted shall be without

prejudice to the outcome of that procedure.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 23 Referral to Committee for Medicinal Products for Human Use. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) If two or more applications submitted in accordance

w i t h r e g u l a t i o n s 5 , 7 a n d 8 h a v e b e e n m ad e f o r m a r k e t i n g

authorisation for a particular medicinal product, and if Member

States have adopted divergent decisions concerning the

authorisation of the medicinal product or its suspension or

revocation, the Authority, the Commission or the applicant or the

mark eting auth orisati on h older may ref er th e mat ter t o th e

Committee for Medicinal Products for Human Use, hereinafter

referred to as the Committee, for the application of the procedure

laid down in Articles 32, 33 and 34 of Directive 2001/83 as

amended by Directive 2004/27.

(2) In order to promote harmonisation of authorisations for

medicinal products authorised in the Community, the Authority

shall, each year, forward to the coordination group a list of

medicinal products for which a harmonised summary of product

characteristics should be drawn up.

(3) The Authority or the Commission, in agreement with the

Agency and taking into account the views of interested parties, may

refer these products to the Committee in accordance with

subregulation (1).

(4) The Member States, the Commission, the applicant or the

marketing authorisation holder shall, in specific cases where the

interests of the European Union are involved, refer the matter to the

Committee for application of the procedure laid down in Articles

32, 33 and 34 of Directive 2001/83/EC as amended before any

decision is reached on an application for a marketing authorisation

or on the suspension or revocation of a marketing authorisation, or

on any other variation of the marketing authorisation which appears

necessary.

Where the referral results from the evaluation of data

relating to pharmacovigilance of an authorised medicinal product,

the matter shal l be referred to t he P harmacovigilance Risk

Assessment Committee and Article 107j(2) of Directive 2001/83/

EC may be applied. The Pharmacovigilance Risk Assessment

C o m m i t t e e s h a l l i ss u e a r e c o m m e n d a t i o n a c c o r d i n g t o t h e

procedure laid down in Article 32 of Directive 2001/83/EC as

amended. The final recommendation shall be forwarded to the

Committee for Medicinal Products for Human Use or to the

coordination group, as appropriate, and the procedure laid down in

regulation 65 of the Pharmacovigilance Regulations shall apply.

However, where one of the criteria listed in regulation

57(1)(a)(i) of the Pharmacovigilance Regulations is met, the procedure

laid down in regulation 57 thereof applies.

(5) The Authority or the Commission shall clearly identify the

question which is referred to the Committee for consideration and

shall inform the applicant or the marketing authorisation holder.

(6) The Authority and the applicant or the marketing

authorisation holder shall supply the Committee with all available

information relating to the matter in question.

(7)

(a) Where the referral to the Committee concerns a range

of medicinal products or a therapeutic class, the

Agency may limit the procedure to certain specific

parts of the authorisation. In that event, regulation 24

shall apply to those medicinal products only if they

were covered by the authorisation procedures referred

to in regulations 22 and 23.

(b) Where the scope of the procedure initiated under

regulations 22 and 23 concerns a range of medicinal

products or a therapeutic class, medicinal products

authorised in accordance with Regulation (EC) No

726/2004 which belong to that range or class shall also

be included in the procedure.

(8) Without prejudice to sub-regulation (4), the Licensing

Authority may, where urgent action is necessary to protect public

health at any stage of the procedure, suspend the marketing

authorisation and prohibit the use of the medicinal product

concerned in Malta until a definitive decision is adopted. It shall

inform the Commission, the Agency and the other Member States,

no later than the following working day, of the reasons for its

action.

(9) Where the scope of the procedure initiated in accordance

with sub-regulation (7) includes medicinal products authorised in

accordance with Regulation (EC) No 726/2004, the Commission

may, where urgent action is necessary to protect public health, at

any stage of the procedure, suspend the marketing authorisations

and prohibit the use of the medicinal products concerned until a

definitive decision is adopted. The Commission shall inform the

Agency and the Licensing Authority no later than the following

working day of the reasons for its action.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 24 Application for variation. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

A marketing authorisation holder may apply to vary the

marketing authorisation, which has been granted in accordance

with regulations 22 and 23, and such application shall be submitted

to the Authority and to all other Member States which have

previously authorised the medicinal product concerned.

This regulation shall apply by analogy to medicinal

products authorised by the Authority following an opinion of the

Committee given in accordance with Article 4 of Directive 87/22/

EEC before 1 January, 1995.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 25 Applications to be considered in accordance with regulation (EC) No 726/2004. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

Applications for marketing authorisations which have been

referred to the Committee for Proprietary Medicinal Products

before the 1 January, 1995 in accordance with Article 2 of

Directive 87/22/EEC and in respect of which the Committee

concerned has not given an opinion by 1 January, 1995, shall be

considered in accordance with Regulation (EC) No 726/2004.

Regulation 22(1)(f) second paragraph, regulation 23 and

Articles 32 to 34 of Directive 2001/83/EC and its subsequent

amendments, shall not apply to homeopathic medicinal products

referred to in regulation 10(1), (2) and (3).

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 26 Classification of medicinal products. into: — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) When a marketing authorisation is granted, the

Authority shall specify the classification of the medicinal product

(a) a medicinal product subject to medical prescription,

(b) a medicinal

product

not

subject

to

medical

prescription.

To this end, the criteria laid down in regulation 27(1) shall

apply.

(2) The Authority may fix sub-categories for medicinal

products which are available on medical prescription only. In that

case, they shall refer to the following classification

(a) medicinal products on medical prescription for

renewable or non-renewable delivery;

(b) medicinal products

subject

to

special

medical

prescription;

(c) medicinal

products

on

''restricted''

medical

prescription, reserved for use in certain specialised

areas

Provided that where the Authority does not designate

medicinal products into sub-categories, it shall nevertheless take

into account the criteria referred to in regulation 27(2) and (3) in

determining whether any medicinal product shall be classified as a

prescription-only medicine.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 27 Medicinal products subject to medical prescription. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) Medicinal products shall be subject to medical

prescription where they -

(a) are likely to present a danger either directly or

indirectly, even when used correctly, if utilized

without medical supervision, or

(b) are frequently and to a very wide extent used

incorrectly, and as a result are likely to present a direct

or indirect danger to human health, or

(c) contain substances or preparations thereof, the activity

and any adverse reactions of which require further

investigation, or

(d) are normally prescribed by a doctor to be administered

parenterally.

(2) For the sub-category of medicinal products subject to

special medical prescription, the Authority shall take account of the

following factors

(a) the medicinal product contains, in a non-exempt

quantity, a substance classified as a narcotic or a

psychotropic substance within the meaning of the

international conventions in force, such as the United

Nations Conventions of 1961 and 1971, or

(b) the medicinal product is likely, if incorrectly used, to

present a substantial risk of medicinal abuse, to lead to

addiction or be misused for illegal purposes, or

(c) the medicinal product contains a substance which, by

reason of its novelty or properties, could be considered

as belonging to the group envisaged in paragraph (b),

as a precautionary measure.

(3) For the sub-category of medicinal products subject to

restricted prescription, the Authority shall take account of the

following factors

(a) the medicinal product, because of its pharmaceutical

characteristics or novelty or in the interests of public

health, is reserved for treatments which can only be

followed in a hospital environment;

(b) the medicinal product is used in the treatment of

conditions which must be diagnosed in a hospital

environment or in institutions with adequate

diagnostic facilities, although administration and

follow-up may be carried out elsewhere, or

(c) the medicinal product is intended for out-patients but

its use may produce very serious adverse reactions

requiring a prescription drawn up as required by a

specialist and special supervision throughout the

treatment.

(4) The Authority may waive application of subregulations (1),

(2) and (3) having regard to

(a) the maximum single dose, the maximum daily dose,

the strength, the pharmaceutical form, certain types of

packaging; and, or

(b) other circumstances of use which it has specified.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 28 Medicinal products not subject to a prescription. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

Medicinal products not subject to prescription shall be

those which do not meet the criteria listed in regulation 27.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 29 List of medicinal products. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

The Authority shall draw up a list of the medicinal

products subject to medical prescription, specifying, if necessary,

the category of classification, and it shall update this list annually.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 30 Amendment of classification. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) When new facts are brought to its attention, the

Authority shall examine and, as appropriate, amend the

classification of a medicinal product by applying the criteria listed

in regulation 27.

(2) Where a change of classification of a medicinal product has

been authorised on the basis of significant pre-clinical tests or

clinical trials, the Authority shall not refer to the results of those

tests or trials when examining an application by another applicant

or holder of marketing authorisation for a change of classification

of the same substance for one year after the initial change was

authorised.

Laws of Malta — Subsidiary Legislation 458.34 — MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Reg. 31 Informing the Agency of the actions taken. — MEDICINES (MARKETING AUTHORISATION) REGULATIONS Open official source

(1) The Medicines Authority shall take all the appropriate

measures to ensure that decisions authorising marketing, refusing

or revoking a marketing authorization, cancelling a decision

refusing or revoking a marketing authorization, prohibiting supply,

or withdrawing a product from the market, together with the

reasons on which such decisions are based, are brought to the

attention of the Agency forthwith.

(2) The marketing authorisation holder shall be obliged to

notify the Medicines Authority forthwith of any action taken by the

holder to suspend the marketing of a medicinal product, to

withdraw a medicinal product from the market, to request the

withdrawal of a marketing authorisation or not to apply for the

renewal of a marketing authorisation, together with the reasons for

such action. The marketing authorisation holder shall in particular

declare if such action is based on any of the grounds set out in

article 28(1) of the Medicines Act.

(3) The marketing authorisation holder shall also make the

notification pursuant to sub-regulation (2) in cases where the action

is taken in a third country and where such action is based on any of

the grounds set out in article 28(1) of the Medicines Act.

(4) The marketing authorisation holder shall furthermore notify

the Agency where the action referred to in sub-regulation (2) is

based on any of the grounds referred to in article 28 of the

Medicines Act.

(5) The Medicines Authority shall ensure that appropriate

information about action taken pursuant to sub-regulations (1) and

(2) which may affect the protection of public health in third

countries is forthwith brought to the attention of the World Health

Organization, with a copy to the Agency.

(6) The marketing authorisation holder shall notify the Medicines

Authority before the commencement of any recall of medicinal product

from the local market, and to submit all pertinent and required

information.

MEDICINES (MARKETING AUTHORISATION) REGULATIONS

Table of Provisions (36)

Statutory Text (36 Articles)

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