A 4.5 Validity Period of a Marketing Authorisation

104 A 4.5 Examples of situations in which the notification procedure according to Art. 61(3) of the Community Code will apply are as follows: Minor changes to the package leaflet resulting from readability testing, not requiring a change to the SPC. Changes to the order of information in the package leaflet arising from the implementation of Art. 59 of the Community Code. A change in user instructions in the package leaflet, not resulting in a change in the SPC. A change in storage instructions or arrangements, not resulting in a change in the SPC. A change in expression of side effects in the package leaflet, not resulting in a specific SPC change. A 4.5 Validity Period of a Marketing Authorisation The Review provisions provided for a new system of validity of the MA. The former provisions of Art. 24 ( of the Community Code and Art. 13 ( of Reg. 2309/93 had provided for a validity period of five years, renewable for 5-year-periods on the respective application of the MAH at least 3 months before the expiry date of the MA. The new provisions introduced several new aspects of validity. A 4.5.1 Renewal and Unlimited Validity The new provisions generally provide for an initial validity of 5 years and an unlimited validity of the MA after the first renewal. Only in exceptional circumstances the competent authority may decide on the requirement of one additional renewal based on reasons related to pharmacovigilance, Art. 24( to (3) of the Community Code and Art. 14 ( to (3) of Reg. 726/2004 2). The renewal shall be granted on a renewal application submitted by the MAH at least six months before the MA ceases to be valid. This application shall be accompanied by a consolidated version of the file in respect of quality, safety and efficacy, including all variations which have been made since the MA was granted. After the five-year-renewal has been granted, the MA shall be valid for an unlimited period. However, the competent authority may decide to request an additional five-year renewal, based on safety concerns, i.e. justified reasons emanating from the pharmacovigilance data, Art. 24(3) of the Community Code, Art. 14 (3) of Reg. 726/ 2004. For the additional renewal the same principles apply as for the first renewal. It has to be submitted at least six months prior to the cessation of the validity of the MA. The renewal application has to be accompanied again by a consolidated version of the file with respect to the quality, safety and efficacy part. Even if the competent authority decides that an additional five-year-renewal is necessary the MA will benefit from an unlimited period of validity after the additional renewal. It will be interesting to see how the Commission will interpret the starting of the validity period of five years after the first renewal in case an additional renewal has been decided. This will strongly depend on the question whether the respective competent authorities will be able to grant the renewal within the first five-year-validity of the MA. The question will be, whether the second five-year-validity will be counted from the day of the first MA. In this case the application for the second renewal would have to be submitted at least six months prior to the OJ No. L 214, 24.8.1993, p. 1 2) OJ No. L 136, 30.4.2004, p. 1

A 4.5 105 10th anniversary of the MA. In case the second five-year-validity would count from the date of the renewal decision the second renewal application would have to be submitted at least six months prior to the fifth anniversary of the renewal decision. However, in this respect the situation in Germany should be taken into account: In Germany for years the interpretation regarding the determination of the deadline for submission of the renewal application has always been counted by jurisdiction and authorities from the date of the first granting of the MA. This interpretation has now been changed by a decision of the Bundesverwaltungsgericht. It ruled, that the deadline for the submission of the renewal application always starts at the date of the renewal decision. As the German authority often granted the renewal decision a respectable time after the end of the five-year-validity, this change in interpretation has great consequences on former decisions of the competent authority deciding that MAs would have ceased due to failure to submit the renewal application within the deadline determined in accordance with the former interpretation. Consequently, the MAH may only be advised to determine the deadline for the second renewal application in relation to the date which ever is the earlier. A A 4.5.2 Special Case: MA granted under Conditions in Accordance with Art. 14 (7) of Reg. 726/2004 Recital 33 of Reg. 726/2004 expresses the necessity to introduce temporary authorisations subject to special annually reviewable obligations / conditions, which is then laid down in Art. 14 (7) of Reg. 726/2004. Consequently, an exception from the principle of a five-year-validity of the MA is contained in Art.14 (7) of Reg. 726/2004. According to this provision a MA, which is granted subject to certain specific obligations, is valid for one year, on a renewable basis. The observance of the specific obligations, therefore, is annually reviewed by the EMEA. Commission Regulation (EC) No. 507/2006 of 29 March 2006 lays down the rules on the socalled conditional marketing authorisation falling within the scope of Reg. 726/2004. The renewal application has to be submitted to the EMEA at least six months before the expiry of the conditional MA. Even though the EMEA shall ensure that the opinion of the CHMP is given within 90 days, Art. 6 (4) of the Commission Regulation 507/2006 provides that the validity of a conditional MA is only subject to a valid renewal application until a decision has been taken in accordance with Art. 10 of Reg. 726/2004. Consequently, even in case the Commission decision is granted after the one-year-validity period elapsed, the prior conditional MA remains valid until such decision. As soon as all specific obligations have been fulfilled, the Committee may at any time adopt an opinion in favour of the granting of a MA in accordance with Art. 14 ( of Reg. 726/2004, i.e. with a 5-year validity. The period of unlimited validity of the MA will then start after the five-year- renewal, unless the Commission decides that an additional five-yearrenewal is necessary due to pharmacovigilance reasons. A 4.5.3 Requirement of Actual Marketing of the Authorised Product for Maintenance of the Validity of the MA A new requirement for the maintenance of the validity of the MA has been introduced. According to Art. 24 (4) and (5) of the Community Code and Art. 14 (4) and (5) of Reg. 726/2004 the actual marketing of the authorised product within a specific period is a requirement for the maintenance of validity of the MA. OJ No. L 92, 30.3.2006, p. 6

106 A 4.5 The medicinal product has to be actually placed on the market within three years after the MA has been granted, Art. 24 (4) of the Community Code and Art. 14(4) of Reg. 726/2004. The marketing of an authorised medicinal product which has previously been placed on the market in the Member State of authorisation must not be interrupted for a period of three consecutive years, Art. 24 (5) of the Community Code and Art. 14 (5) of Reg. 726/2004. If both requirements are not complied with the MA ceases to be valid. The MAH, however, may apply to the Commission for an exemption from the requirement to actually market the medicinal product. Such an exemption may only be based on exceptional circumstances which have to be duly justified, Art. 14 (6). In the NTA, Volume 2A, Chapter 1 in the version of November 2005 (http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/a/vol2a_chap1_2005-11.pdf) the Commission gives guidance on the interpretation of these new provisions relating to the requirement of marketing of the product. A 4.5.3.1 Start of the 3-Year Period from the Granting of the MA The three-year-period after the granting of the MA shall start on the date when the medicinal product can actually be marketed by the MAH. When determining this date, market exclusivity periods and other protection rules have to be taken into account. A 4.5.3.2 Determination of the Notion Marketing Authorisation Furthermore, for the purpose of this provision the notion of the global MA is essential. It will be sufficient for the maintenance of the MA if at least one presentation of the MA is placed on the market and if at least one pack-size for the presentation is marketed. Consequently, for the purpose of application of these rules the notion of the global MA is the determining factor in relation to the MA. A 4.5.3.3 Definition of "Placed on the Market" The term placed on the market shall be interpreted as release into the distribution chain. This shall be the date when the medicinal product comes out of the control of the MA. The medicinal product must be placed on the market of the competent authority which granted the MA. For nationally authorised medicinal products this is the market of the Member State which granted the MA, irrespective whether it has been granted on a merely national basis or via MRP/DCP. In case of medicinal products which have been granted a Community MA it shall be sufficient if one pack-size of one presentation is marketed in one Member State. A 4.5.3.4 Information to be provided from the MAH to the Competent Authority For the purpose of enabling the competent authorities to apply the new provisions the MAH has to provide them with all information relating to the actual marketing of the medicinal product. Art. 23a of the Community Code and Art. 13 (4) of Reg. 726/2004 provide that the MAH has to notify the competent authority of the date of actual marketing of the medicinal product in relation to each of the presentations,

A 4.6 107 any interruption of the marketing of the medicinal product, irrespective whether this interruption is temporarily or permanently. This notification has to be made at least 2 months prior to the intended starting date of the interruption. Furthermore, the MAH has substantial information obligations on request of the competent authority. He is obliged to provide the competent authority with all available data relating to the volume of sales and volume of prescription. A A 4.5.3.5 Transitional Agreements The Commission provides for transitional agreements regarding the application of the starting date of the 3-year-period with respect to the interruption of the marketing of a medicinal product. In relation to the interruption of the marketing the 3-year-period will only be counted from the date of the application of the new provisions in each Member State. A 4.5.3.6 Granting of Exemptions from Application of the Reasons for Cessation Art. 24 (6) of the Community Code and Art. 14 (6) of Reg. 726/2004 provide for an exemption from the application of the reasons for cessation of a MA. On justified request from the MAH, i.e. in exceptional circumstances and based on grounds of public health the competent authorities (Member States in case of national MAs, the Commission in case of Community MAs) may grant exemptions from the application of Art. 24 (4) and (5) of the Community Code. With regard to the request it has to be taken into account that the MA automatically ceases when the 3-year periods either since the granting of the MA or the 3-year period of consecutive interruption has elapsed. It is not necessary that the competent authority issues a decision on the cessation. Therefore, it is extremely important that the request for exemption from the rule is submitted to the competent authority as early as possible to enable either that the competent authority may grant an exemption from the obligation to place on the market before the 3-year period elapsed to prevent the MA from ceasing to be valid. A 4.6 Compassionate Use An exemption from the general principle that a MA has to be granted to a medicinal product prior to the placing on the market is made for those products which fall under the special case of compassionate use as defined in Art. 83 of Reg. 726/2004, Art. 126a and Art. 5 of the Community Code. In case of justified public health reasons Member States may make available medicinal products for compassionate use (Art. 83 of Reg. 726/2004) or authorise the placing on the market of an unauthorised medicinal product (Art. 126a of the Community Code) or temporarily authorise the distribution of unauthorised medicinal product in response to the suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation (Art. 5 (2) of the Community Code). A 4.6.1 Compassionate Use according to Art. 83 of Reg. 726/2004 Definition, Requirements and Procedure The definition of compassionate use in the sense of Art. 83 is contained in Art. 83(2). It is defined as making a medicinal product qualifying for the Centralised Procedure (CP) according to Art. 3 ( or (2) of Reg. 726/2004 available for a group of patients with a chronically or seriously debilitating disease or whose disease is considered to be lifethreatening, and who can not be

A 10.2 / 10.3 253 A 10.2 Marketing Authorisations to which the Regulations are Applicable The regulations define the kind of MAs to the amendments of which they apply. A A 10.2.1 Commission Reg. 1084/03/EC Commission Regulation No. 1084/03/EC concerning the examination of variations to the terms of a marketing authorisation granted by a competent authority of a Member State defines its scope of applicability in its Arts. 1 and 2. According to Art. 1 the Regulation is applicable to the examination of notifications and applications for variations to marketing authorisations of medicinal products the national marketing authorisation of which has been granted within the scope of Directive 87/22/EEC or through a MRP or DCP according to the Community Code, medicinal products for which there has been a referral as set out in Arts. 32, 33 and 34 of the Community Code. As a conclusion all marketing authorisations granted through a procedure mentioned above may only be varied consistently, the marketing authorisation holder being obliged to in principle submit variations to marketing authorisations in all Member States which have previously authorised the medicinal product concerned, Art. 35 ( of Dir. 2001/83/EC. In principle, separate variations in the sense of this regulation of such a MA are no longer possible, if a procedure has taken place to harmonise the SPC. All MAs granted through a harmonising procedure (concertation procedure, MRP, DCP, referral) share the same destiny and have a consistent development. The Reg. does not apply to those MA which have been granted separately before 1998. A 10.2.2 Commission Reg. 1085/03/EC Commission Reg. 1085/03/EC concerning the examination of variations to the terms of a marketing authorisation falling within the scope of Council Regulation (EEC) No 2309/93 only applies to variations of Community MAs according to Council Regulation No. 2309/93/EEC and now also applies to those Community MAs which have been granted according to Council Regulation 726/2004/EC. It is irrelevant, whether the centralised procedure had been applied obligatorily or voluntarily. A 10.3 Definition of "Variation" and Types of Variations Both Commission Regulations contain similar provisions in relation to the definition and classification of variations as well as the amendment procedures. However, the differences in the respective procedures also entail differences in the course of the procedures. A 10.3.1 General Definition of "Variation" Art. 3 no. 1 of both Regulations defines the key term variation. It is defined in Reg. No. 1084/ 03 as OJ No. L 15, 17.1.1987, p. 38

254 A 10.3 an amendment to the contents of the documents referred to in Articles 8 12 of Directive 2001/ 83/EC for human medicinal products and Arts. 12 15 of Dir. 2001/82/EC for veterinary medicinal products. Art. 3 no. 1 of Reg. No. 1085/03 defines the key term variation as an amendment to the contents of the documents referred to in Article 6 ( and (2) or Article 28 ( and (2) of Regulation (EEC) No. 2309/93 (now Article 6 ( and (2) of Reg. 726/04/EC annotation from author), such as they existed at the moment the decision on the marketing authorisation was adopted, in accordance with Art. 10 or Art. 32 of that Regulation or after approval of any previous variations. A 10.3.2 Types of Variations Variations in the term of the Regulations may be divided into minor variations of Type IA, minor variations of Type IB, major variations of Type II, and urgent safety restrictions. A 10.3.2.1 Minor Variations of Type IA or IB Minor variations of Type IA or IB are positively defined by the enumeration contained in Annex I of the regulations. These types of variations are defined in the respective Article 3 no. 2 as a variation listed in Annex I which fulfils the conditions set out therein. The respective Annex I of the regulations contains the definite enumeration of those variations classified as minor. The annexes of both regulations are nearly identical in their wording. Minor variation may principally be characterized as such amendments which, for instance, refer to mearly administrative amendments, such as e.g. change of name and/ or address of the MAH (Annex I (), minor changes to the manufacturing process or test procedures and changes which do not have consequences in relation to the specifications, the quality, or e.g. the dissolution profile of the medicinal product. Details are contained in Annex I. In the course of the replacement of Commission Reg. No. 541/95/EEC and No. 542/95/EEC by the new regulations No. 1084/03/EC and 1085/03/EC an extensive revision of Annex I has taken place. The minor variations which had been listed in the Annex are now divided into minor variations of Type IA and of Type IB. Whereas Annex I of the initial regulations consisted of 33 points, Annex I of the new regulations consists of 46 points in Reg. No. 1084/03/EC and 47 points in Reg. No. 1085/ 03/EC for the centralised procedure. The manufacture of the product is of great importance in this Annex, detailed provisions deal with this issue, partly variations are added which had not expressly been dealt with or had been classified as another variation before. Some changes which had been mentioned in the Annex I of the initial regulations are now subdivided. Classifications differ with respect to type IA and type IB dependent on the respective step of manufacture and/ or the pharmaceutical form. Guidance for documentation which has to be submitted for Type IA or Type IB variations is given in the Guideline on Dossier Requirements for Type IA and Type IB Notifications http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm. This Guideline has been recently updated. Amendments especially relate to the addition of a requirement for a declaration by the qualified person in variation 7, 8, 14 and 15 according to Article 41 of the Community Code, Dir. 2001/83. In Variation 42 a footnote is added for clarification of the acceptance of pilot scale batches.

A 10.4 255 However, special provisions have to be observed for biological medicinal products including medicinal products derived from human blood or plasma. To this end, biological medicinal product is defined as 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 for which a combination of physico-chemical-biological testing and the production process and its control is needed for its characterisation and the determination of its quality." As a consequence, for the purpose of the variation regulations biological medicinal products shall be considered immunological medicinal products and medicinal products derived from human blood and human plasma as defined in Articles 1(4) and 1(10) of the Community Code, respectively; medicinal products falling within the scope of the Annex to Council Regulation (EEC) No 726/2004; advanced therapy medicinal products as defined in part IV of Annex I to the Community Code. For these medicinal products part of the variations listed in Annex I expressly contain the condition that this change does not refer to a biological substance or a biological excipient (e.g. the numbers 7, 8, 10-14, 17-19, 24, 29, 32, 33, 37, 42 of Annex I). Therefore the respective variations may not be classified as minor variations of biological medicinal products but fulfil the criterion for a major variation Type II. For details please refer to Annex I of the variation regulations. A 10.3.2.2 Major Variations of Type II According to Art. 3 no. 3 of the regulations major variations of Type II are those variations which do neither satisfy the criteria of Annex I nor the criteria of Annex II of the regulations concerning extensions. This is the case e.g. for those changes which are described in Annex I but do not satisfy the conditions set out in this Annex or changes which are neither listed in Annex I nor listed in Annex II. The extensions defined in Annex II require a new application. A 10.3.2.3 Urgent Safety Restrictions (USR) Art. 3 no. 5 of the regulations defines urgent safety restrictions (USR). They represent an interim change to the product information which particularly concerns one or more of the key items of the SPC, the indications, posology, contraindications, warnings, target species in veterinary medicinal products, withdrawal periods. They result from new information which has a bearing on the safe use of the medicinal product. It may be initiated by the MAH or the competent authorities. In case of an USR the MAH or a competent authority may, due to the overwhelming interest of public health, implement changes in the product information (outer packaging, patient information leaflet, information for professionals) which is followed by the respective Type II-variation procedure afterwards. A A 10.4 Changes to Marketing Authorisations which are not Variations in the Sense of the Variation Regulations Certain changes to MA are not classified as variations in the sense of the regulations and therefore the variation regulations do not apply. These amendments are extensions of MAs which fulfil the conditions set out in Annex II of the respective Regulation, Art. 2 (a) of the regulations,

B 1.3 381 trally authorised medicinal products "placed on the Community market" means that the medicinal product is at least marketed in one Member State of the Community. For nationally authorised products "placed on the market in the authorising Member State" means that the medicinal product is on the market of the Member State which has granted the marketing authorisation. This is independent of the authorisation procedure used (decentralised, mutual recognition or purely national procedure)'. As soon as the authorisation holder ceases to release the medicinal product in the distribution chain, it ceases to be placed on the market. The marketing authorisation holder has to inform the competent authority/ies about placing his medicinal product on the market (see Regulation (EC) 726/2004, Article 13(4) and Directive 2001/83/EC as amended, Article 23a). 'Any authorisation which within three years of its granting is not followed by the actual placing on the market of the authorised product in the authorising Member State or on the Community market shall cease to be valid' (according to Regulation (EC) No 726/2004, Article 14(4) to (6) and Directive 2001/83/EC as amended Article 24(4) to (6)). 'The marketing authorisation will remain valid if at least one presentation of the marketing authorisation is placed on the market and if at least one pack-size of the existing pack-sizes for that presentation is marketed' (quotation from ). For special transitional arrangements see. B B 1.3 Marketing Authorisation Procedures and Community Referrals Within the European Community different procedures for submitting a marketing authorisation application to a competent authority can be distinguished, 2), 3) : (Independent) national procedure Procedures that are based on the recognition by national competent authorities: -Mutual Recognition procedure (MRP) -Decentralised procedure (DCP) Centralised (or Community) procedure -Conditional marketing authorisation -Centralised procedure for orphan medicinal products Procedure according to article 129a of Directive 2001/83/EC as amended Registration procedures for -Homeopathic medicinal products -Registration procedure and for traditional herbal medicinal products ('traditional-use registration') Figure B1.3-1 gives an overview of these procedures. EudraLex Vol 2A Chapter 1 - Marketing Authorisation (updated version November 2005) 2) EudraLex Vol 1 - Consolidated 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 as amended by Directive 2002/98/EC, Directive 2004/24/EC and Directive 2004/27/ EC. 3) EudraLex Vol 1 - 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 establishin a European Medicines Agency

382 B 1.3 Figure B1.3-1: Marketing Authorisation Procedures Independent National Procedure For the national procedure, the marketing authorisation application (MAA) has to be sent to the national competent authority. Since 1 January 1998 national procedures are strictly limited to 'the inital phase of mutual recognition (granting of the marketing authorisation by the Reference Member State) and to medicinal products which are not to be authorised in more than one Member State' (see ). Procedures based on the Recognition by National Competent Authorities (Mutual Recogniition Procedure and Decentralised Procedure) In cases where a marketing authorisation shall be obtained in more than one Member State, one of the procedures based on the recognition by national competent authorities, the Mutual Recognition procedure (MRP) or the decentralised procedure (DCP), has to be used. Except are those medicinal products that have to follow the centralised procedure (for details see 'Centralised Procedure' as mentioned below). EudraLex Vol 2A Chapter 1 - Marketing Authorisation (updated version November 2005)

B 1.3 383 Directive 2001/83/EC amended by Directive 2004/27/EC 2) contain the legal provisions covering both the MRP and the DCP. The former 'conventional Mutual Recognition Procedure' was revised 'in order to improve the opportunities for cooperation between Member States. Therefore, Directive 2004/27/EC 2) has introduced the decentralised procedure and the coordination group (the Mutual Recognition Facilitation Group, see http://heads.medagencies.org 3) ), which is responsible to settle any disagreement arising from the decentralised and mutual recognition procedures' 4). Both procedures, the MRP and the DCP, 'are based on the recognition by national competent authorities of a first assessment performed by the authorities in one Member State' 4), aiming at 'facilitating access to a single market by relying upon the principle of mutual recognition' 3). Chapter 4 of Directive 2001/83/EC amended by Directive 2004/27/EC 2) introduce both procedures that are based on mutual recognition: 'With a view to the granting of a marketing authorisation for a medicinal product in more than one Member State, an applicant shall submit an application based on an identical dossier in these Member States. The dossier shall contain the information and documents referred to in Articles 8, 10, 10a, 10b, 10c and 11. 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 2 or 3 (see article 28 of Directive 2004/27/EC 2) ). The mutual recognition procedure (MRP) has to be used when the medicinal product in question has already received a marketing authorisation in any Member State at the time of application (see also article 28, paragraph 2 of Directive 2004/27/EC 2) ), the decentralised procedure (DCP) has to be used in those cases, where a marketing authorsation has not yet been received in any Member State at the time of application ( 3), see also article 28, paragraph 3 of Directive 2004/27/EC 2) ; for an overview see figure B1.3-2). The mutual recognition (MRP or DCP) can either be triggered by a Member State (MS) or can be initiated by the Marketing Authorisation Holder (MAH) in case of the MRP or the applicant in case of the DCP (see figure B1.3-2). In general, the mutual recognition procedure is divided into six steps, while the decentralised procedure is divided into five steps (see figure B1.3-3). B EudraLex Vol 1 - 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 2) EudraLex Vol 1 - Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004, amending Directive 2001/83/EC on the Community code relating to medicinal products for human use 3) EudraLex Vol 2A Chapter 2 - Mutual Recognition (updated version - November 2005) 4) EudraLex Vol 2A Chapter 1 - Marketing Authorisation (updated version November 2005)

B 10.1 879 B 10 Investigational Medicinal Product Dossier (IMPD) B 10.1 Commencement of Clinical Trials Introduction When applying for a marketing authorisation, the application has among others to be accompanied by results of clinical trials. The results of clinical study reports have to provided in Module 5 CTD ( Clinical Study Reports ) of the application dossier. Additionally, a detailed factual summarisation of the clinical information has to be documented in the Clinical Summary (Module 2.7 CTD) and a critical analyses of the clinical data and information, drawn up and signed by experts, has to be provided in the Clinical Overview (Module 2.5 CTD). According to Annex I, article 8 of Directive 2003/73/EC (replacing Annex I of Directive 2001/ 83/EC as amended), All clinical trials, conducted within the European Community, must comply with the requirements of Directive 2001/20/EC 2) 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. For the latter a statement to the effect that the clinical trials carried out outside the European Union meets the ethical requirements of Directive 2001/20/EC has to be provided in the application documents submitted to the competent authority/ies (see Directive 2001/83/ EC as amended, article 8 (3) (ib)). A clinical trial (CT) is defined as any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy; this includes clinical trials carried out in either one site or multiple sites, whether in one or more than one Member State (see Directive 2001/20/EC, article 2(a); see also Questions and Answers - Clinical Trials Documents, April 2006 3) ). B Commission Directive 2003/63/EC of 25th June 2003 (Official Journal of the European Union, L 159/46, dated: 27.06.2003) 2) EudraLex Vol 1 - Directive 2001/20/EC of the European Parliament and of the Council of 4 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 3) Questions and Answers - Clinical Trial Documents, April 2006

880 B 10.1 An Investigational Medicinal Product (IMP) is defined as a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form (see Directive 2001/20/EC, article 2(d)). (For the differentiation between IMP (Investigational Medicinal Product) and NIMP (Non Investigational Medicinal Product see *) ). A compilation of legislative and guidance documents in the field of clinical trials was recently published as EudraLex Volume 10 Clinical Trials **). Obligations before conducting a Clinical Trial - Request for a Clinical Trial Authorisation (CTA) and an Ethics Committee Opinion According to article 3(2) of Directive 2001/20/EC a clinical trial may be undertaken only if, in particular: (a) the foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients (...). A clinical trial may therefore only be initiated, if the competent authority has granted a clinical trial application (CTA), AND if the Ethics Committee has given a favourable opinion (see article 9, Directive 2001/20/EC). In order to apply for a CTA and an Ethics Committee opinion, the sponsor a) has to send an application for a clinical trial authorisation to the competent authority of the EU Member State in which the sponsor plans to conduct the CT AND b) has to submit an application for an Ethics Committee to the responsible Ethics Committee (see Directive 2001/20/EC, article 9). Information about the quality, manufacture and control of the investigational medicinal product (IMP) as well as data from non-clinical studies and from its clinical use have to be provided in an Investigational Medicinal Product Dossier (IMPD) that is part of the application for a clinical trial authorisation. The EU guidance document ENTR/CT1 provides advice on the application format and contents of an application for a CT including the IMPD. EU document ENTR/CT2 2) provides guidance for the application for an Ethics Committee opinion (ENTR/CT2). Both documents can be downloaded from the EudraCT website http://eudract.emea.eu.int. Figure B10.1-1 gives an overview of the approval procedure for clinical trials. *) Drafted Notice to Applicants Definition of Investigational Medicinal Products (IMPs) - Definiton of Non Investigational Medicinal Products (NIMPs) that will be included in the rules governing medicinal products in the European Union, Volume 10 Clinical Trials, Chapter V Addition Information - Questions and Answers after approval. http://ec.europa.eu/enterprise/pharmaceuticals/pharmacos/docs/doc2006/07_2006/ def_imp_2006_07_27.pdf **) EudraLex Vol 10 - Clinical trials (Medicinal products for human use in clinical trials (investigational medicinal products; first edition, July 2006). http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev10.htm ENTR/CT1, Revision 2, Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial, October 2005 2) ENTR/CT2, Revision 1, Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use, February 2006

B 10.1 881 B Figure B10.1-1 Approval Procedure for Clinical Trials - An Overview Obligations of Investigator and Sponsor during/after the conduct of a Clinical Trial Substantial Amendments, SUSARs, End of the Clinical Trial Substantial amendments of clinical trials that are likely to have an impact on the safety of the trial subjects or to change the interpretation of the scientific documents in support of the conduct of the trial, or if they are otherwise significant have to be notified to the competent authorities of the Member States or Member States concerned of the reasons for, and content of, these amendments and to the Ethics Committee (article 10(a), (b) of Directive 2001/20/EC). Non-substantial amendments do NOT require notification, but nevertheless have to be recorded and made being available on request for inspections. Within a period of 90 days of the end of the CT the sponsor has to notify the end of a clinical trial to the competent authorities of the Member State or Member States concerned AND to the Ethics Committee (article 10(c) of Directive 2001/20/EC). EU document ENTRA/CT1 gives guidance on both, the notification of substantial amendments and the declaration of the end of the trial. Furthermore, the investigator has to report all serious adverse events to the sponsor of the clinical trial, who has to keep records about it. These records have to be submitted to the Member States concerned if being requested for (see article 16 of Directive 2001/20/EC). All information related to suspected unexpected serious adverse reactions (SUSARs) have to be reported as soon as possible to the competent authorities in all the Member States concerned as

882 B 10.1 well as to the Ethics Committee (see article 17 ( of Directive 2001/20/EC). As laid down in article 17 (2) and (3) of Directive 2001/20/EC the sponsor shall provide the Member States in whose territory the clinical trial is being conducted and the Ethics Committee once a year throughout the clinical trial (...) with a listing of all suspected serious adverse reactions which have occurred over this period and a report of the subjects' safety. The EU document ENTR/CT3 gives guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use. EUDRACT Database and Eudravigilance Clinial Trial Module According to article 17(3a) of Directive 2001/20/EC Each Member State shall see to it that all suspected unexpected serious adverse reactions to an investigational medicinal product which are brought to its attention are immediately entered in a European database to which, in accordance with Article 11(, only the competent authorities of the Member States, the Agency and the Commission shall have access (to that database). ENTR/CT4 2) gives detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (SUSARs) (Eudravigilance Clinical Trial Module). This database about SUSARs is interfaced with another CT database, the European clinical trials database (Eudract) that gives authorities an overview of clinical trials being conducted in the Community. EU Document ENTR/CT5 3) gives detailed guidance on the Eudract database (see table B10.1-. Both databases are necessary to facilitate communication on CTs and SUSARs between the authorities. The legal basis for both databases are provided in articles 11 and 17 of Directive 2001/ 20/EC. The Commission's website gives an overview of all implementing texts for Directive 2001/20/EC (http://ec.europa.eu/enterprise/pharmaceuticals/pharmacos/dir200120ec.htm). For additional information see also EudraCT website (http://eudract.emea.eu.int). Table B10.1-1 gives an overview of the EU guidance documents related to clinical trials, the ENTR/CTx-document family and its attachments. ENTR/CT3, Revision 1 Adverse Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use, April 2004 2) ENTR/CT4, Revision 1 Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance Clinical Trial Module), April 2004 3) ENTR/CT5 Detailed guidance on the European clinical trials database (EUDRACT Database) April 2003; this guidance has been replaced by the document CT 5.1 Amendment describing the Development of EudraCT- Lot 1 for 1 May 2004 and CT 5.2 EudraCT core dataset

936 C 1.1 C 1.1 Definition of Medicinal Product Derived from Human Blood or Human Plasma and Applicable Provisions Medicinal products which contain or are made of blood and/ or blood components deserve special attention. Art. 1 no. 10 of the Community Code defines the term medicinal product derived from human blood or human plasma (in the following: blood products ) as Medicinal products based on blood constituents which are prepared industrially by public or private establishments, such medicinal products including,in particular, albumin, coagulating factors and immunoglobulins of human origin. Consequently, all provisions relating to medicinal products as such also apply to blood products. This principle refers to the application of the provision of the Community Code and its Annex as well as Reg. 726/2004 in the same way as to the principles set out by GMP-Directive 2003/ 94 2). Blood products are a sub-group of biological medicinal products as defined in. I, 3.2.1.1 of the Annex of Dir. 2003/63 3) as a product, the active substance of which is a biological substance. They are expressly mentioned in this definition as being considered as biological medicinal product. Consequently, the provisions of the Annex of the Community Code apply to blood products, in particular the provisions relating to starting and raw materials in I, 3.2.1, III, 1.1 of the Annex which deals with provisions for plasma-derived products, i.e. the Plasma Master File (PMF). When used as starting materials, blood and blood components have to comply with the requirements of GMP as provided for in Art. 47 of the Community Code. However, due to the extreme consequences which derive from viral contamination of blood used as starting material special provisions have to be complied with in addition to the application of the general provisions. Title X, Arts. 109 and 110 of Dir. 2001/83 provide that for the collection and testing of human blood and human plasma, Dir. 2002/98 has to be complied with 4). Consequently, also Directives enacted for implementation of the principles laid down in Dir. 2002/98 have to be complied with. Actually (31.10.2005) the Commission enacted the implementing Directives Dir. 2004/33 5) regarding technical requirements for blood and blood components, Dir. 2005/61 6) regarding traceability requirements and notification of serious adverse reactions and events and Dir. 2005/62 7), regarding Community standards and specifications relating to a quality system for blood establishments which have to be complied with. An overview of the development and the content of the provisions is given in C, Chapters 1.2 and subchapters. OJ No. L 136, 30.4.2004, p. 34 2) OJ No. L 262, 14.10.2003, p. 22 3) OJ No. L 159, 27.6.2003, p. 46 4) OJ No. L 33, 8.2.2003, p.30 5) OJ No. L 91, 30.3.2004, p. 25 6) OJ No. L 256, 1.10.2005, p. 32 7) OJ No. L 256, 1.10.2005, p. 41

C 1.2 937 C 1.2 Development of Special Provisions The provisions governing the manufacture, marketing, distribution and use of medicinal products, contained in the European Directives 65/65 and 75/319 from the beginning on also applied to medicinal products deriving from human blood or human plasma. This was due to the fact, that Art. 1 of Dir. 65/65 provided that medicinal product was defined as any substance or combination of substances presented for treating or preventing disease in human beings or animals or any substance or combination of substances which may be administered to human beings or animals with a view to making a medical diagnoses or to restoring, correcting or modifying physiological functions in human beings or in animals. The term substance itself was defined as any matter which could also be of human origin, e.g. human blood and human blood products. The principle objective of the provisions governing the manufacture, marketing and use of medicinal products, formerly mainly contained in Dir. 65/65 and 75/319 was to ensure a high level of protection of public health. Before 1989, the provisions governing the standards for blood donation were based on national provisions, if existing at all. In 1989, the first Dir. was introduced aiming at harmonising the standards for medicinal products derived from human blood or human plasma, applicable in addition to the general provisions of Dir. 65/65 and 75/319. This Dir. mainly aimed at abolishing the hindrances in inter Community trade existing between the MS due to the difference in national legislation. In the 1990s, the upcoming of HIV infections and incidences of contaminated blood and blood products, led to an increased interest and necessity of effective measures to safeguard public health and safety. The blood scandals showed that the existing provisions were insufficient and inadequate with regard to these special products. Provisions had to be introduced to guarantee the correct quality of such special medicinal products to eliminate as far as possible the danger of causing severe infections through blood transfusion. In 2002, the so-called Blood Directive was implemented setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components, amending the Community Code in this respect. In parallel, provisions governing the quality and safety for the collection and use of human tissue and cells were implemented (Dir. 2004/23, see Chapter C 2). C C 1.2.1 Directive 89/381/EC The first step to introduce such special provisions was made by Dir. 89/381. This Directive aimed at extending the scope of the existing main Directives 65/65 and 75/319 and laying down special provisions for medicinal products derived from human blood or human plasma. The scope of application of this Directive was provided for as follows: the scope was positively defined as applying to medicinal products based on blood constituents which are prepared industrially by public or private establishments. including albumin, coagulating factors and immunoglobulins of human origin. This was at the same time the definition of medicinal product derived from human blood or human plasma, Art. 1 ( Dir. 89/381; the scope was negatively defined as not applying to whole blood, plasma or blood cells of human origin, Art. 1 (2) Dir. 89/381. OJ No. L 181, 28.6.1989, p. 44

938 C 1.2 The central point of this Dir. was the aim to guarantee correct and stable quality in the manufacture of medicinal products falling within the scope of this Dir., i.e. medicinal products for which human blood or human plasma is used as starting material. It introduces the principle, that before a MA for a medicinal product falling within the scope of this Dir. was granted, the manufacturer had to demonstrate his ability to guarantee a batch-to-batch consistency and the absence of special viral contamination. To this end, Art. 3 of this Dir. committed MS to take the necessary measures to prevent the transmission of infectious diseases via medicinal products, especially by referring to the application of the selection and testing measures included in the monographs of the European Pharmacopoeia, the measure recommended by the Council of Europe and the WHO, to ensure that donors and donation centres are clearly identifiable. Furthermore, MS had to guarantee the proper validation of manufacturing and purifying processes as well as the absence of specific viral contamination. This should be achieved by imposing on manufacturers the obligation to notify the competent authorities of the MS of the methods used to reduce or eliminate pathogenic viruses and to enable competent authorities to test samples of the bulk and/ or finished product at a State laboratory or another laboratory designated for these purposes, to require manufacturers to submit copies of all control reports signed by the qualified person. Member States had to comply with the provisions of this Dir. before 1 January 1992. When all existing legal texts relating to the manufacture, marketing, distribution and use of medicinal products were integrated into the Community Code, the special provisions governing medicinal products derived from human blood and human plasma were integrated into the Community Code in Title X, Arts. 109 and 110. The details of the requirements for blood and blood products were additionally incorporated in the Annex to the Directive. C 1.2.2 Directive 2002/98/EC and Implementing Directives As mentioned above in C, Chapter 1.2.1, in the first step of Dir. 89/381 the whole blood, plasma and blood cells were expressly excluded from the scope of application. However, upcoming scandals involving viral contamination of blood with HIV and Hepatitis in the 1990s intensively increased the interest in guaranteeing the quality and safety of blood and blood components used for transfusion as well as the products derived from blood and plasma. Numerous actions were taken as a consequence: On 21.12.1994 the Commission published a Communication indentifying the need for a strategy to safeguard public health by guaranteeing the quality and safety of blood and blood products, reinforcing the confidence in safety of the blood transfusion chain and to promote Community self-sufficiency to reduce the need for importation of blood from third countries outside the EU. Commission Communication COM (94) 652 (final)

C 1.3 939 Council and European Parliament passed a series of resolutions and recommendations on blood safety and quality issues including the necessity of self-sufficiency in blood (e.g. Council Resolutions of 2 June 1995, of 12 November 1996 2). In its Recommendation of 29 June 1998 on the suitability of blood and plasma donors and the screening of donated blood in the European Community 3) the Council expressed the urgent need for provisions regarding the selection of donors, screening of donations and securing of self-sufficiency for the supply of blood in the Community. The Amsterdam Treaty, which entered into force on 1 January 1999, introduced the provision of Art. 152 (4) (a) in the EC-Treaty, according to which the Council was enabled to adopt measures setting high standards of quality and safety of organs and substances of human origin, blood and blood derivatives. However, these measures should only represent the minimum standard as the Treaty furthermore expressly provides that these measures shall not prevent any Member State from maintaining or introducing more stringent protective measures. All these activities resulted in Dir. 2002/98, the Blood Directive. This Dir. aimed at ensuring a high level of quality and safety of blood and blood products by filling the gap which had occurred through the fact that the existing Directive 89/381 did not cover whole blood, plasma and blood cells. The transformation period for this Dir. was set until 8 February 2005, Art. 32. In 2004 and 2005, three Directives implementing the provisions of Dir. 2002/98 regarding certain technical requirements for blood and blood components (Dir. 2004/33), the traceability requirements, the notification of serious adverse events (Dir. 2005/6 as well as Community standards for the quality systems of blood establishments (Dir. 2005/62) were also enacted. C C 1.3 Details of Directive 2002/98/EC The provisions of Dir. 2002/98 aim at ensuring a high level of human health protection in connection with the application of blood and its constituents. It is the basis for the definition of standards of quality and safety of human blood and blood components, Art. 1. Dir. 2002/98 mainly contains provisions 1. imposing obligations on MS in relation to designation, authorisation, accreditation or licensing of blood establishments, inspection. They shall designate the national authorities competent for the obligation in the field of blood products. 2. Defining requirements for blood establishments with respect to responsible persons, quality management, OJ No. C 164, 30.6.1995 2) OJ No. C 374, 11.12.1996, p. 1 3) OJ No. L 203, 21.7.1998, p. 14

Terms and Definitions 1047 Grading of toxicity Grade Definition 0 No toxicity 1 Mild toxicity (usually transient, requiring no special treatment and generally not interfering with usual daily activities, e.g., colds) 2 Moderate toxicity (usually ameliorated by simple therapeutic maneuvers, and impairs usual activities, e.g., pneumonia treated as an out-patient) 3 Severe toxicity (requires vigorous therapeutic intervention, interrupts usual activities. Hospitalization may or may not be required (e.g., pneumonia requiring hospitalization or intravenous antibiotics). 4 Life-threatening toxicity (requires hospitalization, e.g., immediate risk of death from event and not reactions that had it occurred in a more serious form, might have caused death) http://ctep.cancer.gov/reporting/ctc.html, http://ctep.cancer.gov/forms/ctcaev3.pdf Guidelines Guidelines are texts convering technical topics, their legal status may differ: Guidelines resultung from a formal request laid down in a Community Directive of Regulation are binding when those acts so provide, and must be complied with when the corresponding Directive or Regulation is implemented. The Commission publishes them, e.g. the "Note forguidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products". Guidelines spontaneously drawn up by the scientific committees are not legally binding; they present the best or more appropriate way to fulfil an obligation laid down in the Community rules EudraLex Vol. 2A, Procedures for marketing authorisation, Chapter 1 Marketing Authorisation, February 2004 Health Care Professional For the purposes of reporting suspected adverse reactions, health care professionals are defined as physicians, dentists, pharmacists, nurses and coroners. When reports originate from healthcare professionals other than physicians and dentists, further information about the case should be obtained from a medically-qualified person if possible. Herbal Drug Preparations Preparations obtained by subjecting herbal drug to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. CHMP/QWP/297/97 Rev 1 corr Summary of requirements for active substances in the quality part of the dossier Terms + Defs Herbal Drugs Many whole, fragmented or cut, plants, parts of plants, algae, fungi, lichen in an unprocessed state, usually in dried form but sometimes fresh. CHMP/QWP/297/97 Rev 1 corr Summary of requirements for active substances in the quality part of the dossier Herbal Medicinal Products Vegetable medicinal products: are medicinal products containing as active substances exclusively herbal drugs or herbal drug preparations. CPMP/QWP/2820/00