The English version of this Decree was prepared in order to help comprehension by non-Italian mother tongue users, but it is NOT an official document. Please, refer to the Italian version for the only official document.

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Decree 21st December 2007

Directions for submitting the request for authorisation of a clinical trial on a medicinal product for human use to the Competent Authority, for communicating substantial amendments, for declaring the end of the trial and for the request of an opinion to the Ethics Committee.

THE MINISTER OF HEALTH

Having regard to the legislative decree 24th June 2003 n. 211, published in the ordinary supplement n. 130/L to the Official Journal n. 184 of 9th August 2003, concerning the transposition of Directive 2001/20/EC relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use;

Having regard in particular to the letters a), b) and c) of section 11 of article 9 of the above mentioned decree establishing that a decree of the Ministry of health provides respectively the form and the content of the application for authorisation, the form and the content of the proposal for substantial amendments and the declaration of end of the trial to submit to the Competent Authorities;

Having regard in particular to article 8, section 1, of the above mentioned decree establishing that a decree of the Ministry of health provides the form and the documentation required to submit the request for an opinion of the Ethics Committee;

Having regard to the ministerial decree 17th December 2004, published in the Official Journal n. 43 of 22nd February 2005 concerning “General prescriptions and conditions, relating to the conduction of clinical trials with medicines with special reference to those designed to enhance clinical practice, as an integral part of health and medical care”.

Having regard to the detailed guidance issued by the European Commission on October 2005 (ENTR/F2/BL D2003 - Revision 2 Volume 10 Eudralex) about the content of the application and the documents to submit to the Competent Authorities for the request of authorisation of a clinical trial on a medicinal product for human use, the communication of substantial amendments and the declaration of end of a trial;

Having regard to the detailed guidance issued by the European Commission on February 2006 (ENTR/CT2 - Revision 1- Volume 10 Eudralex) about the content of the application and the documents to submit to an Ethics Committee for the evaluation of a clinical trial on medicinal products for human use;

HEREBY ISSUES:

Article 1

The form and the content of a request for authorisation of a clinical trial, the form and the content of a proposal for substantial amendments to the clinical protocol, the declaration of end or of early termination as specified in article 9, section 11 of the legislative decree 24th June 2003, n.

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211, to be forwarded to the Competent Authority, must be submitted in compliance with the provisions outlined in the attachment 1 to this decree.

Article 2

The application as of article 8, section 1 of legislative decree 24th June 2003, n. 211 to submit to the Ethics Committee in order to obtain the relative opinion about a clinical trial, must be prepared in compliance with the provisions outlined in attachment 2 to this decree.

Article 3

1. The Competent Authority as specified in article 2, section 1, letter t), item 1 of legislative decree 24th June 2003, n. 211 may, completely or partially, appoint the Ethics Committee concerned to the assessment of documentation as of attachment 1 to this decree; anyway, the application form, properly filled in compliance with appendix 5 to this decree, must be always forwarded to the Competent Authority.

2. The operative procedures for the implementation of what provided in the above mentioned section 1, included any electronic submission, are established with a decision of the Competent Authority whereof the same section.

Article 4

1. In order to fulfil the obligations connected with the National Monitoring Centre of Clinical

Trials with Medicines, the sponsors of trials and the technical-scientific secretariats send to the same National Monitoring Centre the data of competence as of appendixes 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12 and 15 to this decree according to the time frames here indicated.

2. The technical-scientific secretariats of the Ethics Committees granting the single opinion, as well as the Italian Medicines Agency or the Italian National Health Institute, for those clinical trials within their competence, validate the data notified by the sponsor.

3. The data notified through the National Monitoring Centre are transferred to the European registry of clinical trials (EudraCT) by the Italian Medicines Agency, in compliance with what provided in the European Community Guidelines.

Article 5

The data and documentation, transmitted to the Competent Authorities and Ethics Committees in order to obtain the authorisation for a clinical trial, must be handled as confidential and must not be accessible to staff not involved in the sponsorship, conduct and monitoring of the clinical trial.

Article 6

In order to import medicines to be utilized in clinical trials, the import dossier must be

supported by a copy of the single opinion of the Ethics Committee as well as the authorisation by the Italian Medicines Agency or Higher Health Institute Italian National Health Institute, in the prescribed cases. This documentation must be forwarded to the competent peripheral or central offices of the Ministry of Health, as provided in current regulations, or to the Italian Medicines Agency in case of import of blood derivatives.

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Article 7

The sponsor must send the medicines to be employed in a clinical trial to the pharmacy of

the health facility participating in the trial which will provide for their registration, suitable storage and delivery to the investigator.

Article 8

1. The attachments 1 and 2 and the appendixes from 1 to 15 are integral parts of this decree. 2. The appendixes to this decree are available on the National Monitoring Centre of Clinical

Trials website (https://oss-sper-clin.agenziafarmaco.it/) as well as the application forms. 3. Any update of and modification to the attachments to this decree and to the notification

procedures are established by provisions of the Director General of the Italian Medicines Agency, in compliance with the regulations of the European Community.

4. Revisions of appendixes to this decree, in accordance with any possible revisions of detailed guidance issued by the European Commission, will be directly available on the National Monitoring Centre of Clinical Trials website and it is mandatory to comply with the procedures since the date of the publication of the revised forms in the website itself.

Article 9

The ministerial circulars of 10th July 1997 n. 8 and 5th October 2000, n. 15 concerning

“Revision of ministerial circular n. 8 of 10th July 1997 relating to the clinical trials with medicines” have been abrogated.

Article 10

1. This ministerial decree enters into force on the hundred twentieth day after its publication in the Official Journal of the Italian Republic. It does not apply to the applications and documentation already submitted to the Competent Authority and local Ethics Committees within the above mentioned time frame, even though not evaluated yet.

2. Between the sixtieth and the hundred twentieth day following the publication of this decree in the Official Journal, the sponsors may submit the documents to the Competent Authorities and the Ethics Committees in compliance with the provisions established in this decree; in this case, the Competent Authorities and the Ethics Committees are obliged to assess the above mentioned documents.

Rome, 21st December 2007 The Minister: Turco

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Attachment 1

Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the Competent Authority, communication of substantial amendments and declaration of the end of the trial.

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Table of contents Page Glossary of acronyms “ 6 1. Legal basis …………………………………………………………………………………….. “ 7 2. Scope ………………………………………………………………………………………….. “ 7 3. Definitions ……………………………………………………………………………………. “ 7 4. Format and content of applications and information to submit ……………………………… “ 9 4.1 Request for a clinical trial authorisation ………………………………………………... “ 9 4.1.1 Covering letter …………………………………………………………………. “ 11 4.1.2 Allocation of the EudraCT number ……………………………………………. “ 11 4.1.3 Application form (CTA form) ………………………………………………… “ 11 4.1.4 Protocol ………………………………………………………………………... “ 11 4.1.4.1 First in human clinical trials …………………………………………. “ 12 4.1.5 Investigator’s Brochure ……………………………………………………….... “ 12 4.1.6 IMP and PeIMP related data ………………………………………………….... “ 13 4.1.6.1 Investigational Medicinal Product Dossier (IMPD) …………………. “ 14 4.1.6.1.1 Quality data ……………………………………………..... “ 15 4.1.6.1.2 Non clinical pharmacology and toxicology data ………..... “ 16 4.1.6.1.3 Previous clinical trial and human experience data ……….. “ 17 4.1.6.1.4 Overall risk and benefit assessment …………………….... “ 17 4.1.6.2 Simplified IMPD ………………………………………....................... “ 17 4.1.6.2.1 When to use a simplified IMPD ………………………...... “ 17 4.1.6.2.2 IMPD for marketed products ……………………………….. “ 18 4.1.7 Non-investigational Medicinal Products ReTNIMPs and PeIMPs …………….. “ 19 4.2 Communication or notification of amendments ……………………………………......... “ 20 4.2.1 Scope ………………………………………………………………………….... “ 20 4.2.2 Non-substantial amendments …………………………………………………... “ 20 4.2.3 Substantial amendments ………………………………………………………… “ 20 4.2.3.1 Guidance for the definition of a substantial amendment ……………... “ 20 4.2.3.2 Amendments to protocol ……………………………………………… “ 21 4.2.3.3 Amendments to initial scientific documents supporting the Clinical

Trial Authorisation (CTA) ……………………………………..............“

21 4.2.3.4 Amendments to the initial CTA application form …………………..... “ 21 4.2.4 Procedure for submission ……………………………………………………..... “ 22 4.2.5 Format and content of submission ……………………………………………... “ 23 4.2.6 Implementation ……………………………………………………………......... “ 23 4.2.7 Time for amendments authorisation …………………………………………….... “ 23 4.2.8 Urgent amendments ……………………………………………………………. “ 23 4.2.9 Suspension or definitive interruption of a trial by the Competent Authority ….. “ 24 4.2.10 Infringements ………………………………………………………………….... “ 25 4.3 Declaration of the end of a clinical trial ………………………………………………..... “ 25 4.3.1 Legal basis and scope …………………………………………………………… “ 25 4.3.2 Procedure for declaring the end of the trial …………………………………….. “ 25 4.3.2.1 Premature end of a trial ……………………………………………..... “ 25 4.3.2.2 Temporary halt of a trial ……………………………………………... “ 25 4.3.2.3 Clinical trial report ………………………………………………….... “ 26 4.3.2.4 Follow up …………………………………………………………….. “ 26 4.3.3 Format and content ……………………………………………………………... “ 26 5. Access to clinical trials data by Regions and independent Provinces …………………………. “ 27 6. Additional information to notify by Monitoring of Clinical Trials Centre (Osservatorio) …..... “ 27

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Glossary of the acronyms AIFA: Agenzia Italiana del Farmaco (Italian Medicines Agency) CTA: Clinical Trial Application EEA: European Economic Area According to Directive 2001/20, references to the European Community, the European Union or to the Member States include the EEA States, island, Norway and Lichtenstein. EMEA: European Medicines Agency EudraCT: European Clinical Trials Database GCP: Good Clinical Practice GMP: Good Manufacturing Practice IB: Investigator’s Brochure IMP: Investigational Medicinal Product IMPD: Investigational Medicinal Product Dossier ISS: Istituto Superiore di Sanità (Italian National Health Institute) MA: Marketing Authorisation NIMP: Non-Investigational Medicinal Product OsSC: Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (National Monitoring Centre on Clinical Trials with Medicines) PeIMP: Product equivalent to the Investigational Medicinal Product (from a regulatory perspective) ReTNIMP: Regardless to Trial Non Investigational Medicinal Product SmPC: Summary of Product Characteristics TSE: Transmissible Spongiform Encephalopathy

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1. Legal Basis The legal basis of this attachment is the legislative decree of 24th June 2003, n. 211 “Transposition of Directive 2001/20/EC relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for clinical use” - in particular, the article 9, section 11 – to be read in conjunction with this attachment. Article 9, section 11 of the above mentioned legislative decree requires the Ministry of health, with a decree, transposing the guidance of the European Commission into the national legislation, to draw up and publish detailed guidance on: (a) the format and contents of the request to conduct a clinical trial on a medicinal product for human use as well as the documentation to be submitted to support that request on the quality and manufacture of the investigational medicinal product, any toxicological and pharmacological tests, the protocol and clinical information on the investigational medicinal product including the investigator's brochure; (b) the presentation and content of notifications of substantial proposed amendments to the protocol; (c) the declaration of the end of the clinical trial. 2. Scope This detailed attachment is intended to provide advice on the application format and contents of a request to the Competent Authority in Italy for: • authorisation of a clinical trial on a medicinal product for human use; • notifications of substantial proposed amendments; • declaration of the end of the clinical trial. Legislative decree 24th June 2003, n. 211 applies to all investigational medicinal products, including the following types of product: • chemical entities; • biotechnology products; • cell therapy products; • gene therapy products; • plasma derived products; • other extractive products; • immunological medicinal products (such as: vaccines, allergens, immune sera); • herbal medicinal products; • radiopharmaceutical products; • homeopathic products. 3. Definitions The definitions of legislative decree 24th June 2003, n. 211 are applicable. Article 2, section 1, letter d) of the legislative decree defines an “investigational medicinal product” - from now on in the text defined “IMP” - as:

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“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.” Some clinical trial protocols require the use of non investigational medicinal products (NIMPs) which are not defined in the legislative decree such as:

1. background standard therapy, administered to all patients regardless of their participation in the trial or from the randomization group, to treat the indication which is the object of the study. Furthermore, the protocol may require that the test medicine plus the standard care medicine(s) is compared with a placebo or a active comparator plus the standard care medicines(s);

2. concomitant therapy that is medicinal products given to clinical trial participants as part of their standard care for a condition which is not indication for which the IMP is being tested, and is therefore not the object of the trial;

3. supporting therapy (see Table I); 4. challenge agents, that is products used to induce a physiological response; 5. medicines which contribute with the IMP to assess end-points in the clinical trial; 6. medicines necessary to prevent and treat the reactions connected with standard therapy, as

provided by the Summary of Product Characteristics. These medicines, defined Non Investigational Medicinal Products (NIMPs), are subdivided into two distinct categories, according to the regulatory and financial aspects:

a) ReTNIMPs (Regardless Trial NIMPs, ) that is NIMPs which, in any case, would be administered to the patients regardless of their participation in the trial.

b) PeIMPs (Products equivalent to the IMPs) that is NIMPs, equivalent to the IMP according to regulatory aspect, which are administered to the patients in virtue of their participation in the trial.

In the first case, it deals with non investigational medicinal products, with a marketing authorisation in Italy used in clinical trials according to the Summary of Product Characteristics, for preventive, diagnostic or therapeutic reasons and/or needed to ensure that adequate medical care is provided for the subject (see Table I). The RetNIMPs will be supplied to all the patients participating in the trial who would have taken them, regardless of their participation in the trial. The RetNIMPs will be charged to the National Health Service, if applicable. In the second case, the PeIMPs1 will be on charge of the sponsor of the trial (see Table I). In both cases, the sponsors should provide details of these NIMPs and of their proposed use in the trial protocol and ensure that they are of the necessary quality for human use after seeking advice and/or involvement of a Qualified Person2 of the manufacturing site, if these products do not have a marketing authorisation in any Member States (see also section 4.1.7).

1 Please, note: all the rules provided for the IMP should be applied to the PeIMP included the obligation of submitting the same information; therefore, only in the headings of this attachment and of the appropriate Annexes the abbreviation “PeIMP” is quoted next to the abbreviation “IMP” each time it occurs as memorandum, while it is not repeated during the text because it is implicit that wherever the abbreviation IMP occurs it refers to the PeIMP as well. 2 It refers to the definition contained in the chapter IV, section 52 of the legislative decree n. 219 of 24th April 2006 “Implementation of the directive 2001/83/EC (and following modifications) on the Community code relating to medicinal products for human use, as well as the Directive 2003/94/EC”.

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Table I

IMP NIMP ReTNIMP PeIMP

A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial (see definition on page 8). Financial burden is charged on sponsor.

a) Non investigational medicinal products required in the protocol, with a marketing authorisation in Italy, to be administered to all the patients regardless of their participation in the trial and of the randomization group (e.g. background therapies, concomitant therapies, medication necessary to prevent and cure the reactions connected with standard therapy, as provided in the SmCP as well);

b) Medications with a marketing authorisation in Italy identified in the protocol as those that may be administered to the patients when the efficacy of the IMP is not satisfactory (rescue therapy).

Financial burden is charged on the National Health Service according to the Italian law about the classification and the reimbursement, if provided. See the law 537/93 and modifications.

Medications not directly investigated in the clinical trial but provided by the clinical protocol which can be: a) a medicinal product with a marketing

authorisation (MA) in Italy and used according to the conditions specified in the authorisation compulsory provided by the protocol as a necessary treatment for the correct conduction of the trial (e.g. products used to assess clinical trial end-point) included possible treatments necessary to prevent and cure adverse drug reactions related to the IMP;

b) a medicinal product with a MA in Italy but used outside the conditions of the MA;

c) a medicinal product without a MA in Italy but with a MA in a member state of EEA or in one of the countries in the footnote below, even though used outside the conditions of the MA;

d) challenge agents, namely substances used to produce physiological response that is necessary before the pharmacological action of the IMP can be assessed. They may be substances without a MA, provided that they have a long tradition of clinical use.

Financial burden is charged on sponsor.

Footnote: USA, Canada, Japan, Australia, New Zealand, Switzerland.

4. Format and content of applications and information to submit 4.1 Request for a clinical trial authorisation The sponsor of a clinical trial or its delegate (henceforward defined as sponsor) must submit a valid request for authorisation to the Competent Authority. If the applicant is not the sponsor, they should enclose a letter from the sponsor authorising the applicant to act on their behalf.

The sponsor should provide the Competent Authority of the clinical site where the Ethics Committee gives its single opinion, or AIFA or the Istituto Superiore di Sanità when Competent Authorities, with a list of Competent Authorities of the other Member States in EU and/or extra EU countries to which they have already made the same application. This list should contain the details of the decisions of the Competent Authorities in the other countries updated at the time of the submission and a copy of the opinion of the Ethics Committee as of article 7 of the Legislative

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decree n. 211 of 24th June 2003 (single opinion). If at the time of the request the single opinion is not available, the sponsor should send it to Competent Authority as soon as possible . In case of a single opinion not favourable, the sponsor should inform the concerned Competent Authority and send it a copy of this opinion.

If an application is not valid the Competent Authority will inform the applicant within 7 working days, specifying which parts have to be modified. The application as of this attachment does not exempt the applicant from requesting other possible authorisations provided by the current regulations for special categories of drugs, such as drugs containing GMO 3, radiopharmaceuticals4, narcotics5. The sponsor has the power to withdraw a request for authorisation before the Competent Authority has reached its decision about authorisation and in this case the fees already paid will not be refunded. The application for authorisation can be submitted only to carry on clinical trials at health facilities authorised to this purpose according to the current regulations. In particular, clinical trials with medicines can be performed: § in public hospitals or in those ones made equivalent to them (according to the Law 23th

December 1978, n. 833, article 41); § in research institutes (according to the Law 23rd December 1978, n.833, section 40); § in universities and in institutes of research and care, both public and private (according to

the ministerial decrees 27th April 1992 and 13th May 1999); § in public consulting rooms of the local health units, only for phase II and III clinical trials

when their carry out is not feasible or appropriate in hospitals and universities, and provided that these facilities have been recognised suitable for clinical trials by the health direction of the health unit itself. The above mentioned facilities should possess the minimum requirements as of the decree of the President of the Republic 14th January 1997. Each time one of these facilities carries out a clinical trial, the general director of the local health unit concerned has to notify AIFA (according to the ministerial decree 13th May 1999 article 2, section 2);

§ in the private sites recognised suitable for clinical trials by the competent local health unit, according to the ministerial decree 19th March 1998. Article 1 of the above mentioned decree fixes the criteria which the private facilities have to meet in order to carry out phase I trials with healthy volunteers, bioequivalence and bioavailability trials, while article 2 establishes which private sites may perform phase I clinical trials with healthy volunteers and phase II and III.

As for phase IV clinical trials, according to the ministerial decree 4th December 1990, these may be conducted out of public hospitals and institutes only for demands of public health valid to motivate an explicit request to this purpose by the Ministry of health.

3 Legislative decree 8th July 2003, n. 224 “Implementation of Directive 2001/18/CE concerning the deliberate release into the environment of genetically modified organisms.” 4 Legislative decree 17th March 1995, n. 230 “Implementation of directives 86/618/EURATOM, 90/641/EURATOM, 92/3/EURATOM on ionizing radiation” and legislative decree 26th May 2000, n. 187 “Implementation of directive 97/43/EURATOM on health protection of individuals against the dangers of ionizing radiation in relation to medical exposure” modified by the Financial Law 1st March 2002, n. 39, article 39, section 2, letter b). 5 Decree of the President of the Republic 9th October 1990, n. 309, article 49 “Integral text of the laws concerning the regulation of the narcotics and psychotropic substances, prevention, care and rehabilitation of the relative conditions of drug addiction” and following modifications.

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Finally, phase III and IV clinical trials can be conducted in the outpatients of the general physicians and paediatricians, as provided by the ministry decree 10th May 2001.

4.1.1 Covering Letter The applicant should submit and sign a covering letter with the application. Its heading should contain the EudraCT number and the sponsor protocol code with a title of the trial and any other information considered relevant. 4.1.2 Allocation of the EudraCT number Before submitting an application to the Competent Authority, the sponsor should obtain a unique EudraCT number. The EudraCT number (defined by the European Commission in Detailed Guideline about the European clinical trials database – European database) will identify the protocol for a trial whether conducted at a single site or at multiple sites in one or more Member States. To obtain the EudraCT number automatically from the database the applicant will follow the instructions described in the website of the Osservatorio (http://oss-sper-clin.agenziafarmaco.it). 4.1.3 Application form (CTA form) The application form contained in fac-simile in the Appendix 5 should uniquely identify the clinical trial and the organisations and key individuals responsible for the conduct of the trial. The applicant should connect with the OsSC complete the form, print, sign and date it, and finally send it as part of the application to the Competent Authority and the Ethics Committee. The applicant's signature will confirm that the sponsor is satisfied that, a) the information provided is complete, b) the attached documents contain an accurate account of the information available, c) in their opinion it is reasonable for the proposed clinical trial to be undertaken, and d) any information provided to both the Competent Authority and the Ethics Committee concerned is based on the same data. The application form and the documents attached (as in the check lists I.a and I.b of the Appendix 5) have to be submitted both to the Competent Authority and to the Ethics Committee. 4.1.4 Protocol The content and format of the protocol should comply with the Good Clinical Practice rules as of the ministerial decree 15th July 1997, concerning “The implementation of Good clinical practice guidelines of the European Union in the conduct of clinical trials on medicinal products for human use”. The protocol version submitted should include all the amendments made at the time of the submission and a definition of the end of the trial. The protocol should be identified by: § a title; § a sponsor’s code number specific for all versions of it; § a number and date of version that will be updated when it is amended; § any short title or name assigned to it.

The protocol should be signed by the sponsor at the time of its submission and by the principal investigator before the trial initiation.

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The protocol or other documents should include among other things: § an evaluation of the anticipated benefits and risks; § an ethical evaluation of the trial; § the procedure to follow to propose the informed consent with specific elements for those

subjects who are, temporarily or permanently, incapable of giving their consent or when the presence of an impartial witness is required;

§ a justification for including subjects who are incapable of giving informed consent or other special populations;

§ if applicable, a list of sub-studies and of the involved sites in which these will be conducted.

When necessary, the protocol should include a description of the plan for the provision of any additional care of the subjects once their participation in the trial has ended, where it differs from what is normally expected according to the subject’s medical condition. Furthermore, a protocol synopsis in Italian should be submitted along with the full version of the complete protocol. 4.1.4.1 First in human clinical trials The safety of participants in first- in-human clinical trials can be enhanced by identification and planned mitigation of factors associated with risk. A protocol planning the administration of a medicinal product in human beings for the first time should describe the strategies to identify and mitigate the risks and take into consideration all the pre-clinical available data and the factors of risk identified. In order to design and prepare the protocol sponsors should follow a specific detailed guidance6 about the strategies to mitigate the risks of ‘first in human’ clinical trials issued by the Committee for Human Medicinal Products for Human Use (CHMP) at EMEA. This guidance provides information about key aspects of a trial, designed to mitigate those risk factors, including: § choice of subjects; § route and rate of administration; § estimation of the first dose in human; § precautions to apply between doses within a cohort; § precautions to apply between cohorts; § dose escalation schemes; § dose escalation increments; § stopping rules and decision making; § monitoring and communication of adverse events/reactions; § characteristics of clinical facilities and personnel involved.

4.1.5 Investigator’s Brochure The content, format and procedures for updating the Investigator’s Brochure (from now on in the text defined IB) should comply with the good clinical practice rules as provided by the ministerial

6 Guideline on strategies to identify and mitigate risks for first in human clinical trials with investigational medicinal products. EMEA/CHMP/SWP/28367/07, 19th July 2007.

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decree 15th July 1997. IB should be prepared from all available information and evidence that supports the rationale for the proposed clinical trial and the safe use of the IMP in the trial. The approved Summary of Product Characteristics (from now on in the text defined SmPC) will replace the IB provided tha t the IMP is authorised in any Member State, and it is used according to the terms of the marketing authorisation (from now on in the text defined MA). But when the conditions of use in the clinical trial differ from those authorised, the SmPC should be complemented with a summary of relevant non-clinical and clinical data that support the use of the IMP in the clinical trial. When the IMP is identified in the protocol only by its active substance, as documents supporting the application, the sponsor should elect one SPC as equivalent to the IB for all medicinal products that contain that active substance and are used at any clinical trial site. For an international trial where the medicinal product to be used in each Member State is the one authorised at a national level and the SmPC varies among Member States, the sponsor should choose one SmPC to replace the IB for the whole clinical trial. The current IB or SmPC, when applicable, will be the reference document for the assessment of the expectedness of any adverse reaction that might occur during the clinical trial. 4.1.6 IMP and PeIMP related data The information and data required to support the quality of the IMP should be provided in the following documents: § Investigator’s brochure (see 4.1.5); § Investigational Medicinal Product Dossier (IMPD) (see 4.1.6.1); § simplified IMPD for known products (see 4.1.6.2 and table I); § Summary of Product Characteristics (SmPC) (for products with a marketing authorisation in

the European Union) (see 4.1.6.2.2); § examples of the label in Italian; § a copy of the manufacturing authorisation referred to in Article 13, section 1 of the

legislative decree 24th June 2004, n. 211 and of the Directive 2001/20/CE, if the IMP does not have a marketing authorisation in the European Union and is manufactured in the European Union or in extra European Union countries according to mutual recognition on manufacturing medicinal products of the same typology as those ones used in the trial;

§ if the IMP is not manufactured in the European Union, does not have a marketing authorisation in the European Union and does not fall within the typology of medicinal products object of mutual recognition on manufacturing:

- certification of the Qualified Person (QP) of a Member State that a) the manufacturing site works in compliance with GMP at least equivalent to EU GMP or b) that each production batch has undergone all relevant analyses, tests or checks necessary to confirm its quality; - certification of the GMP status of any active biological substance; - copy of the importer’s manufacturing authorisation in the Member State and of the manufacturing authorisation of manufacturing site of the third country from which the IMP is imported as referred to in article 13 of the legislative decree 24th June 2004 n. 211 and of the Directive 2001/20/CE. Furthermore, where applicable, it is necessary to submit: § certificate of analysis in exceptional cases where impurities are not justified by the

specification or when unexpected impurities (not covered by the specification) are detected;

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§ Viral safety studies and data; § TSE Certificate, if materials containing bovine origin ingredients are used as well as what

provided in the ministerial decree 20th January 1999 “Measures concerning the marketing authorisation and clinical trials with medicinal products containing bovine origin ingredients”, modified by the ministerial decree 28th December 2000 “Measures aiming at the minimization of risk of human transmission of agents causing the bovine spongiform encephalopathy through medicines;

§ NIMPs dossier (see section 4.1.7).

The IMPD should give information to justify the quality of any IMP to be used in the clinical trial, including reference products and placebos. It should also provide data from non-clinical studies and the previous clinical use of the IMP or justify in the application why information is not provided. The applicant may either provide a stand alone IMPD or cross-refer to the IB for the pre-clinical and clinical parts of the IMPD. In the latter case, the summaries of pre-clinical information and clinical information should include data, preferably in tables, providing sufficient detail to allow assessors to reach a decision about the potential toxicity of the IMP and the safety of its use in the proposed trial. If there is some special aspect of the pre-clinical data or clinical data that requires a detailed expert explanation or discussion beyond what would usually be included in the IB, the sponsor should submit the pre-clinical and clinical information as part of the IMPD. 4.1.6.1 Investigational Medicinal Product Dossier (IMPD) The sponsor should submit a full IMPD when they have not previously submitted any information about that chemical or biological product to the Competent Authority concerned and cannot cross-refer to information submitted by another sponsor. For instance, when the sponsor does not have a marketing authorisation for the IMP in any Member State of the European Union and the Competent Authority concerned has not granted them a CTA previously and they cannot cross-refer to the relevant information in another sponsor’s application for the same product. If a sponsor cross-refers to information submitted by another sponsor he should present the authorisation provided by this latter. A full IMPD should include summaries of information related to the quality, manufacture and control of the IMP, data from non-clinical studies and from its clinical use. It is preferable to present data in tabular form accompanied by the briefest narrative highlighting the main salient points. Sponsors should preface the IMPD with a detailed table of contents and a glossary of terms. Where possible data should be provided under the headings and arranged in the order given in the Appendix 1, 2 and 3. If there is no appropriate heading a new section may be added. In addition, the relevant Community guideline or European Commission decision should be followed for specific types of investigational medicinal product, clinical trial, or patient group. This type of information is available at the European Medicines Agency (EMEA from now on in the text) website www.emea.europa.eu . In particular, innovative medicinal products used for gene therapy and somatic cell therapy often require a definition of identity which cannot be reduced to its chemical formula. The definition of identity for this type of products should base on the characteristics of the physical object and/or of the manufacturing process and/or the function aiming at characterizing the IMP in an unequivocal way.

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For these innovative medicinal products the identity can be obtained through the characterisation of a sequence of nucleic acid or amino acids and relating secondary modifications; from a whole of antigens, from biological measurable functions, from a specific manufacturing process or from their combination according to what is necessary from their clinical application. The IMPD with the information as in this section 4.1.6.1 and relating subsections must be submitted:

1) to the general director or legal officer of the health facility where the coordinating investigator in Italy works (or principal investigator for a monosite trial), if this is the Competent Authority according to the article 2, section 1, letter t) point 1 of the legislative decree 24th June 2003, n. 211;

2) to the Italian Medicines Agency, from now on in the text defined as AIFA, when it is Competent Authority according to article 2, section 1, letter t) point 2 of the legislative decree 24th June 2003, n. 211;

3) to the Istituto Superiore di Sanità, from now on in the text defined as ISS, when it is Competent Authority according to article 2, section 1, letter t) point 3 of the legislative decree 24th June 2003, n. 211.

4.1.6.1.1 Quality data The sponsor has to submit summaries of chemical, pharmaceutical and biological data on any IMP with the application. Furthermore, the sponsor has to supply information as of the headings listed in Appendix 1, when applicable. Applicants should refer to the guideline of the European Commission of March 2006 “Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning Investigational Medicinal Products in clinical trials” (CHMP/QWP/185401 final) where applicable. The legislative decree 24th June 2003, n. 211 and the Directive 2001/20/CE require sponsors to supply IMPs for a clinical trial whose manufacture complies with the principles of Good Manufacturing Practice (GMP) set out in Directive 2003/94/EC7 and the guidance on application of the principles set out in Annex 13 (revised July 2003) to the Community Guide to GMP8. To document this requirement the applicant should provide a copy of the manufacturing authorisation if the IMP does not have a marketing authorisation in the European Union and is manufactured in the European Union or in extra European Union countries with mutual recognition of manufacture of IMPs falling within the same typology as of those used in the trial. If the IMP is not manufactured in the European Union, does not have a marketing authorisation in the European Union, and does not fall within the typology of IMPs in mutual recognition of manufacture, the sponsor has to provide: - Certification of the Qualified Person (QP) in a Member State that a) the manufacturing site works in compliance with GMP at least equivalent to EU GMP or

7 “Implementation of the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use in compliance with Directive 2003/94/EC of the Commission of 8th October 2003.” (Official Journal 18th November 2004, n. 271) implemented in legislative decree 24th April 2006, n. 219. 8 Annex 13 to Volume 4 of “Rules Governing Medicinal Products in the European Community”.

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b) each production batch has undergone all relevant analyses, tests or checks necessary to confirm its quality; - Certification of the GMP status of any active biological substance; - Copy of the importer’s authorisation in the Member State and of the manufacturer’s authorisation in the Third Country from where the IMP is imported as referred to in Article13 of the legislative decree 24th June 2003, n. 211 and of the Directive 2001/20/CE). Moreover, where applicable, it is necessary to supply: § certificate of analysis in exceptional cases where impurities are not justified by the

specification or when unexpected impurities (not covered by the specification) are detected; § Viral safety studies and data; § TSE Certificate, if materials containing bovine origin ingredients are used as well as what

provided in the ministerial decree 20 January 1999 “Measures concerning the marketing authorisation and clinical trials with medicinal products containing bovine origin ingredients”, modified by the Ministerial decree 28th December 2000 “Measures aiming at the minimization of risk of human transmission of agents causing the bovine spongiform encephalopathy through medicines.

4.1.6.1.2 Non-clinical pharmacology and toxicology data The sponsor should also provide summaries of non-clinical pharmacology and toxicology data for any IMP to be used in the clinical trial or justify why they have not. They should also provide a reference list of studies conducted and appropriate literature references. Full data from the studies and copies of the references should be made available on request. Wherever appropriate it is preferable to present data in tabular form accompanied by the briefest narrative highlighting the main salient points. The summaries of the studies conducted should allow an assessment of the adequacy of the study and whether the study has been conducted according to an acceptable protocol. Sponsors should as far as possible provide the non-clinical information in the full IMPD under the headings in Appendix 2. Sponsors should provide a critical analysis of the available data, including justification for deviations and omissions from this attachment and an assessment of the safety of the product in the context of the proposed clinical trial. The studies needed as a basis for the non-clinical section of the IMPD are outlined in the relevant Community guidelines9 available from the EMEA website www.emea.europa.eu. All studies should meet the requirements of Good Laboratory Practice guidelines where appropriate. The sponsor should justify any deviations from these guidelines. The test material used in the toxicity studies should be representative of that proposed for clinical trial use in terms of qualitative and quantitative impurity profiles. The preparation of the test material should be subject to appropriate controls to ensure this and thus support the validity of the study. 9 Community guideline “Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (CPMP/ICH/286/95).

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4.1.6.1.3 Previous clinical trial and human experience data In this section the sponsor should provide summaries of all available data from previous clinical trials and human experience with the proposed IMP(s). They should as far as possible provide the information under the headings in Appendix 3, where applicable, to be integrated if necessary. If the clinical trial to submit aims at obtaining a MA, it is necessary that all the previous studies have been conducted in accordance with the rules of Good Clinical Practice (Ministerial decree 15th July 1997). If the clinical trial to submit is non profit instead, the previous studies have to be at least compliant with the principles of Good Clinical Practice according to the Ministerial decree 17th December 200410. This should be confirmed by the sponsor in a statement of the GCP status of all studies of previous phases. Applicants should take account of the general guidance on clinical trials in the development of a medicinal product in the Community guideline (CPMP/ICH/291/95)11. These and other relevant guidelines are available from the EMEA website www.emea.europa.eu. Information to provide according to this section has to be submitted to the Competent Authority of each clinical site participating a multi-site clinical trial but only to ISS and to AIFA, central Competent Authorities, in case of trials falling within their competence.. 4.1.6.1.4 Overall risk and benefit assessment This section should provide a brief integrated summary that critically analyses the non-clinical and clinical data in relation to the potential risks and benefits of the proposed trial. The text should identify any studies that were terminated prematurely and discuss the reason(s). As for studies on minors or incapacitated adults it is necessary to comply with the provisions set out in articles 4 and 5 of the legislative decree 24th June 2003, n. 211. The aim of the non-clinical pharmacology and toxicity testing is to indicate the principal hazards of a new medicinal product. The sponsor should use the relevant pharmacology, toxicology and kinetic results as the basis of extrapolation to indicate possible risks in humans. As a guide to what may occur in humans, the sponsor should integrate all the available data, analyse the pharmacological and toxic actions of the IMP and use the results to suggest possible mechanisms and the exposure required to produce them. Where appropriate, they should discuss safety margins in terms of relative systemic exposure to the IMP. Information to provide according to this section has to be submitted to the Competent Authority of each clinical site participating a multi-site clinical trial but only to ISS or to AIFA, central Competent Authorities, in case of trials falling within their competence. 4.1.6.2 Simplified IMPD 4.1.6.2.1 When to use a simplified IMPD A simplified IMPD may be submitted if information related to the IMP has been assessed previously as part of a marketing authorisation in any Member State of the European Union or as

10 Prescriptions and conditions of a general nature referring to the conduct of clinical trials of medicines, with special reference to those designed to enhance clinical practice as an integral part of health and medical care. Published in the Official Journal 22nd February 2005, n. 43. 11 Note for a Guidance on general considerations for clinical trials (CPMP/ICH/291/95).

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part of a clinical trial application to the Competent Authority concerned. Information on a placebo may also be provided as a simplified IMPD. The text should include a discussion of the potential risks and benefits of the proposed trial (see section 4.1.6.1.4). Table II provides a guidance on the types of information for IMPs known to submit to the Competent Authority of the site where the coordinating investigator works in a multi-site trial (principal investigator of the site for a mono-site trial) or to ISS or AIFA as for clinical trials falling within their competence. Information about clinical data (see Table II) and discussion of the risk/benefit ratio has to be submitted to the local Competent Authorities of the clinical sites except that for trials authorised by AIFA or ISS. Where appropriate, sponsors are allowed to cross-refer to the IMPD submitted by another applicant and held by the Competent Authority. This may require a letter from the other applicant to authorise the Competent Authority to cross-refer to their data.

Table II. Reduced information requirements for IMPs known.

Types of previous assessment

Quality data Non-clinical data

Clinical data

The IMP has a MA in any EU Members State and is used in the trial: 1. within the condition of the SmPC 2. outs ide the conditions of the SmPC 3. After it has been blinded

SmPC SmPC P+A

SmPC IMPD or IB, if containing the data relating the investigational use proposed. As in points 1 e 2, according to the case.

SmPC IMPD or IB, if containing the data relating the investigational use proposed. As in points 1 e 2, according to the case.

Another pharmaceutical form or strength of the IMP has a MA in any EU Member State and the IMP is supplied by the MA holder

P+A

IMPD

IMPD

IMP is a placebo.

P+A

No

No

N.B.: In case of no-profit trials, sponsors are allowed to cross-refer to the documents submitted for the same IMP to the same Competent Authority by other applicants, provided that they are able to attach a letter by the other applicant which authorizes to cross refer to their data. When the same sponsor requests the authorisation of a Competent Authority which had previously authorised the same IMP, they may cross-refer to the documents already presented transmitting only any possible new data.

Legenda: SmPC: Summary of Product Characteristics. P: drug product data as Appendix 1. A: Appendices of the IMPD.

4.1.6.2.2 IMPD for marketed products The sponsor may submit the current version of the SmPC as the IMPD if an IMP has a marketing authorisation in any Member State in the EU and is being used in the same form, in the same administration route, for the same indications and with a dosing regimen covered by the SmPC. The SmPC must be understandable by the concerned Competent Authorities, so that translation in Italian or into English at least is required. It will also be sufficient for studies of dosing regimens

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not covered by the SmPC when the sponsor can show that the information in the SmPC justifies the safety of the proposed new regimen. Otherwise they should submit additional non-clinical data and/or clinical data to support the safety of its use in the new indication, new patient population and/or the new dosing regimen as appropriate. If the applicant is the marketing authorisation holder and he has submitted an application to vary the SmPC, which has not yet been authorised, the nature of the variation and the reason for it should be explained in the covering letter. There are situations where the IMP to be used in the clinical trial has a MA in Italy, is marketed under different brands and with the same characteristics and the protocol allows that any brand of the IMP may be administered to the trial subjects. In those situations, providing that the IMP is not modified e.g. over-encapsulated, it is acceptable that IMPs to be used are only identified by the active substance name or ATC code. Here below are reported the cases as follows:

a) a sponsor may wish to conduct a trial with an active substance that is available in Italy in a number of medicines with MAs and different trade names. In which case, the protocol may define the treatment in terms of the active substance only and not specify the trade name of each product. This is to allow investigators to administer any brand name of these products that contains the active substance in the required pharmaceutical form. To notify this, they should complete section D.2.2.1 of the application form (Appendix 5); in section D.3.1 (Appendix 5) they should provide the name routinely used to describe the product in the protocol under ‘Product Name’ and the name of the active substance. When the IMP is defined in the protocol in terms of its active substance, the sponsor should elect one medicine and submit its Italian SmPC (or if necessary of EU country in case of a EU clinical trial) as equivalent to the IMPD for all medicinal products that contain that active substance used at any of the clinical trial sites.

b) In some trials the sponsor may wish to allow investigators in the same multi-site trial to

administer different regimens of IMPs, e.g. groups of anticancer drugs, according to local clinical practice at each Italian clinical site. They should define the acceptable treatment regimens in the protocol and notify this in the application form by completing Section D.2.2.2 (Appendix 5). In Section D.3.1 (Appendix 5) they should provide the name routinely used to describe the regimen in the protocol under ‘Product Name’ and the name of each active substance in D.3.8 or D.3.9.

c) In other trials the sponsor may wish to study the effect of a number of medical treatments on

a specific illness without specifying the IMPs to be used except that they have a MA in Italy. To achieve this he should identify the treatment using its ATC Code (level 3-5) in the protocol and complete Section D.2.2.3 and D.3.3 of the application form.

When the IMP is defined in the protocol in terms of its ATC code, the sponsor could replace the IMPD by one representative SmPC for each active substance pertaining to that ATC group. Alternatively, he could provide a collated document containing information equivalent to that in the representative SmPCs for each active substance that could be used as an IMP in the clinical trial. 4.1.7. Non-investigational medicinal products ReTNIMPs and PeIMPs There are situations where the protocol may require the use of Non IMPs (see also Section 3 and Table I).

a) ReTNIMPs products with a MA in Italy;

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b) PeIMPs, the use of products with a MA in Italy is strongly recommended for these purposes.

As for the documents to attach to the CTA form, this should include: 1) SmPC, for products with a MA in the EEA and used in compliance with this; 2) the same information provided for the IMPs, in all the other cases.

4.2 Communication or notification of amendments 4.2.1 Scope Article 10 of the legislative decree 24th June 2003, n. 211 allows amendments to be made to the conduct of a clinical trial after its commencement. Substantial amendments, as provided by the above mentioned article, must be communicated to the Competent Authority and Ethics Committee concerned for approval while the non substantial amendments must be simply notified to the ethics committees only. Yet, when a sponsor and/or investigator must take urgent safety measures to protect the trial subjects from immediate hazard, article 10 allows them to do so before submitting the Competent Authority and the Ethics Committees, but they must notify them as soon as possible. 4.2.2 Non-substantial amendments The sponsor does not have to notify non-substantial amendments to the Competent Authority but to the Ethics Committee only. However, they should be recorded and be available on request for inspection at the trial site and/or the sponsors premises as appropriate. 4.2.3 Substantial amendments 4.2.3.1 Guidance for the definition of a substantial amendment Article 10, section 1, letter a) of the legislative decree 24th June 2004, n. 211 defines substantial amendments as those amendments “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 in relation to the clinical conduct of the trial”. Substantial amendments to the conduct of the clinical trial may arise from changes to the protocol or from new information relating to the scientific documents in support of the trial. Amendments to the trial are regarded as “substantial” by the sponsor where they are likely to have a significant impact on: § the safety or physical or mental integrity of the subjects; § the scientific value of the trial; § the conduct or management of the trial; § the quality or safety of any IMP used in the trial.

In all cases, an amendment is only to be regarded as “substantial” when one or more of the above criteria are met. Appendix 4 provides headings of aspects of a trial to which a sponsor might need to make a substantial amendment. The list is not exhaustive; a substantial amendment might occur in some other aspect of a trial. Not all amendments to those aspects of a trial need to be notified, only those that meet the criteria of “substantial” above.

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In particular, as for substantial amendments, these must be submitted to the Competent Authorities (see artic le 10 of the legislative decree 24th June 2003, n. 211) and to the Ethics Committee where the coordinating investigator of the clinical trial works responsible for giving an opinion on the amendment; this opinion will be then accepted or refused by the other Ethics Committees. Yet, in the cases provided in the Appendix 4, section 2, the amendment has to be submitted to the Competent Authority and to the Ethics Committee of the coordinating site only; as for the case reported in Appendix 4, section 3, the amendment has to be submitted to the Competent Authority and Ethics Committee of the participating site concerned only; as for the cases reported in Appendix 4, section 4, the amendment has to be notified to the Competent Authority and to Ethics Committees concerned but, even though substantial, there is no need of the Ethics Committee’s opinion to implement it. 4.2.3.2 Amendments to protocol When the sponsor intends to make a substantial amendment to the protocol that would make a significant impact on the criteria in section 4.2.3.1 he has to request the authorisation to the concerned Competent Authority and the opinion to the relevant Ethics Committee. For instance reducing the number of clinic visits might impact on the safety or physical or mental integrity of the subjects. Introducing a new monitoring procedure or a change in the principal investigator might significantly affect the conduct or management of the trial respectively. The use of a new measurement for the primary endpoint could alter the scientific value of the trial. Altering the procedure for reconstitution or administration of an IMP could affect the safe use of an IMP in the trial. These types of changes would be considered substantial amendments. 4.2.3.3 Amendments to initial scientific documents supporting the Clinical Trial Authorisation (CTA) The sponsor has to notify a substantial amendment to the scientific documents submitted to support the request for a CTA when certain new information becomes available: for instance, data from additional studies of pharmacology, toxicology or clinical use of an IMP used in the trial which might alter the initial risk to benefit evaluation of the supporting documents in relation to the criteria in section 4.2.3.1; or any change to the IB that alters the product safety profile in such a way that the pharmacovigilance reporting will be altered. 4.2.3.4 Amendments to the initial CTA application form Some information key to the criteria of a substantial amendment in section 4.2.3.1 may be documented only in the CTA application form – for instance a change to the legal representative of the sponsor in the EU, the revocation, suspension or substantial relevant amendment of the MA of the IMP or transfer of sponsor responsibilities to a new individual or organisation. Changes to this type of key information in the form should be notified as a substantial amendment. If sponsor intends to add new clinical sites in a multi-sites trial after receiving a single opinion favourable, they have to notify this amendment to the ethics committee which has given the single opinion. A copy of the CTA form updated has to be attached to a transmission letter with the reasons of the amendment.

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4.2.4 Procedure for submission. The sponsor should first assess on a case-by-case basis whether or not an amendment is substantial using criteria from 4.2.3.1 above. Substantial amendments to the information supporting the initial authorisation of the trial or to the protocol has to be submitted to the Competent Authorities and ethics committees using the Amendment Application Form at Appendix 912. This form is available in the Osservatorio website (https://oss-sper-clin.agenziafarmaco.it/). Sponsors have to connect with the web site, using their credentials and fill in the form in detail before sending it, with date and signature, as part of the amendment application to the Competent Authorities and to the Ethics Committees. The applicant should also submit a covering letter and sign it. Its heading should contain the EudraCT number and the sponsor protocol number with the title of the trial and an amendment code number. The text should draw attention to any special issues related to the amendment and indicate where the relevant information or text is in the original application. When a sponsor proposes to change the principal investigator at a trial site he should notify to the Competent Authority and to the Ethics Committee by the Amendment Application Form at Appendix 9. This amendment can be applied if the opinion of the Ethics Committee is favourable and the Competent Authorities have raised no grounds for non-acceptance of the above-mentioned substantial amendment by 35 days. In the meanwhile the investigator identified by the sponsor will guarantee the necessary clinical trial activities. When a sponsor proposes to change the co-ordinating investigator for valid and reasonable grounds the should follow this procedure:

a) if the new coordinating investigator works in the same site, the sponsor notifies the change to the Competent Authority and the relevant Ethics Committee of the site by submitting the Amendment Application Form at Appendix 9 and if the opinion of the Ethics Committee is favourable and the Competent Authorities have raised no grounds for non-acceptance of the above-mentioned substantial amendment by 35 days, the sponsor may notify all the Competent Authorities and Ethics Committees concerned;

b) if the new coordinating investigator works in a site different from that one where the previous coordinating investigator worked, the sponsor has to submit the amendment by Appendix 9 to: § the Ethics Committee and the Competent Authority of the coordinating investigator

who is going to be changed; § the Ethics Committee and the Competent Authority of the site where the new

coordinating investigator works. If the opinion of the Ethics Committee is favourable and the Competent Authorities have raised no grounds for non-acceptance of the above-mentioned substantial amendment by 35 days, the sponsor may notify all the Competent Authorities and Ethics Committees concerned. In both cases, until the procedure has been completed the coordinating investigator identified by the sponsor will guarantee the necessary activity of coordination.

12 This procedure should also be followed to report substantial amendments both to the Competent Authorities and to the relevant Ethics Committee concerned. To this purpose consult the Attachment 2 to this decree, about the application form and supporting documents to submit to the Ethics Committees for the request for an opinion.

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4.2.5 Format and content of submission The submission of a substantial amendment should include the following information:

a) Covering letter, including reason for qualification as a substantial amendment. b) Application form (Appendix 9) that contains: § identification of CT (title, EudraCT number, sponsor’s protocol code number); § identification of applicant; § identification of the amendment (sponsor’s amendment number and date). One amendment

could refer to several changes in the protocol or scientific supporting documents; § a description of the amendment and the reason for it.

c) An extract of the modified documents showing previous and new wording, where applicable. d) The new version of modified documents where the changes are so widespread and/or substantial that they justify a new version, identified with updated number of version and date. e) Supporting information including, where applicable: § summaries of data; § an updated overall risk benefit assessment; § possible consequences for subjects already included in the trial; § possible consequences for the evaluation of the results.

f) Where applicable, if a substantial amendment changes the application form data (CTA form), the sponsor should update the data in the OsSC filling the electronic Amendment form reported in fac-simile in the Appendix 9. The application for substantial amendment should identify the fields to be changed, by attaching a print out of the revised CTA form showing the amended fields highlighted. 4.2.6 Implementation The sponsor may implement a substantial amendment when the Ethics Committee opinion is favourable and the Competent Authority has raised no grounds for non-acceptance. 4.2.7 Time for amendments authorisation If the Competent Authority has raised no grounds for non-acceptance within 35 days by the receipt of the application and the Ethics Committee has expressed a favourable opinion within the same period the sponsor may implement the substantial amendment. In the cases provided in article 9, sections 5 and 6 of the legislative decree 24th June 2003, n. 211, the sponsor must obtain a written authorisation before implementing the substantial. This authorisation must be given in the period set out in article 9, section 4 of the above mentioned legislative decree. 4.2.8 Urgent Amendments Article 10 of the legislative decree 24th June 2003, n. 211 requires a sponsor and investigator to take appropriate urgent safety measures to protect subjects against any immediate hazard where

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new events relating to the conduct of the trial or the development of the IMP are likely to affect the safety of the subjects. These safety measures such as temporarily halting of the trial may be taken without prior authorisation from the Competent Authority or favourable opinion of the Ethics Committee. In these cases, the sponsor must inform the Competent Authority and the ethics committee concerned of the new events, the measures taken and their plan for further action as soon as possible. This notification should be sent immediately by using the fastest means of communication in the first place followed by a written report. When for serious reasons such as problems of safety or lack of efficacy the sponsor halts a clinical trial (stops recruitment of new subjects and/or interrupts the treatment of subjects already included in the trial), they have to notify the Competent Authority and Ethics Committee concerned as soon as possible and not later than 15 days as a substantial amendment by the fac-simile form as in Appendix 9. In this case, the opinion of the Ethics Committee is not provided except that safety measures have to be taken when necessary to protect the health of the subjects involved. The sponsor may not recommence the trial halted for serious reasons until: § they will not have submitted a request for a substantial amendment to recommence the trial

(form in Appendix 9); § the Ethics Committee of the coordinating site have given a favourable opinion (which has to

be accepted or refused by the other Ethics committees of the participating sites, if a multisites clinical trial) and the Competent Authorities have not raised grounds for non-acceptance.

If urgent circumstances occur that may justify the immediate restart of the trial according to the above mentioned article 10 of the legislative decree 24th June 2003, n. 211, the substantial amendment has to be notified immediately to the Competent Authorities and Ethics committees, using the form as in the Appendix 9. 4.2.9 Suspension or definitive interruption of a trial by the Competent Authority An authorised clinical trial may be suspended or interrupted definitely by:

1) AIFA, irrespective of it is Competent Authority according to article 2, section 1, letter t, point 2 of the legislative decree 24th June 2003 n. 211, may revoke the authorisation where it has objective grounds for considering that the conditions in the authorisation are not being met or has doubts about the safety or scientific validity of the clinical trial already authorised. This provision may cause the temporary suspension of the clinical trial or its definite interruption.

2) ISS, when Competent Authority according to article 2, section 1, letter t, point 3 of the

legislative decree 24th June 2003 n. 211, a may revoke its authorisation where it has objective grounds for considering that the conditions in the authorisation are not being met or has doubts about the safety or scientific validity of the clinical trial already authorised. This provision may cause the temporary suspension of the clinical trial or its definite interruption. AIFA must be notified about this provision within 3 working days.

3) The Director-General or the Legal Officer of the health facilities when Competent Authority

according to article 2, section 1, letter t, point 1 of the legislative decree 24th June 2003 n. 211, where it has objective grounds for considering that the conditions in the authorisation are not being met or has doubts about the safety or scientific validity of the clinical trial already authorised. Therefore, they may revoke their authorisation in the single clinical site temporarily or definitively. This provision may cause the temporary suspension of the

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clinical trial or its definite interruption. These measures have to be adopted, except where there is imminent risk, after consulting the Ethics Committee concerned and the Competent Authorities of the other clinical sites. AIFA must be informed about the adoption of such provisions within 3 working days.

Before they reach their decision, they must inform the sponsor, except where there is imminent risk, and ask the sponsor and/or the investigator for their opinion. The sponsor should immediately investigate the grounds for suspension or prohibition and provide a report within one week addressing the issues raised and any exceptional circumstances that might have led to those conditions not being met. When that period has elapsed the Competent Authority shall take its decisions independently and notifies the Ethics Committees and the other Competent Authorities concerned. When a clinical trial is terminated following a suspension, the sponsor must notify AIFA, the other Competent Authorities, the Ethics Committees concerned, using the form in fac-simile in Appendix 12, to declare the end of the trial. 4.2.10 Infringements Where AIFA and the Competent Authorities have objective grounds for considering that the sponsor or investigator or any other person involved in the conduct of the trial no longer meets the obligations laid down, the Competent Authority may set a course of action as provided by article 12, sections 5 and 6 of the legislative decree 24th June 2003, n. 211 4.3 Declaration of the end of a clinical trial 4.3.1 Legal basis and scope Article 10, section 2 and article 11, section 1 letter e) of the legislative decree 24th June 2003 n. 211 requires the sponsor of a clinical trial to notify AIFA, regional Authorities and the Competent Authorities and Ethics Committees concerned that the clinical trial has ended. 4.3.2 Procedure for declaring the end of the trial The definition of the end of the trial should be provided in the protocol and any change to this definition for whatever reason should be notified as a substantial amendment. In most cases it will be the date of the last visit of the last patient undergoing the trial. Any exceptions to this should be justified in the protocol. The sponsor should make an end of trial declaration connecting with the Osservatorio web database and filling the form for the conclusion data in detail, whose fac-simile is available in Appendix 12. Then the sponsor must print the end declaration directly from the Osservatorio database and send it with date and signature to AIFA. The sponsor must notify AIFA of the end of the trial within 90 days specifying: • the date of the end of the trial in Italy; • the date of the completion of the trial in the last participating sites in the world. 4.3.2.1 Premature end of a trial Whenever a trial is terminated early (premature end) for whatever reason the sponsor must notify the local Ethics Committees, the Competent Authorities (of the single sites or ISS when Competent

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Authorities) and AIFA immediately and at least within 15 days from when the trial is halted and clearly explain the reasons. The sponsor should notify this as a Declaration of End of Trial using the electronic form available in the Osservatorio web database and at Appendix 12. Notification of a premature end of a trial must be made to the health facilities and, obviously to the investigators involved, with a transmission letter specifying the sponsor’s protocol code, the EudraCT number and a brief explanation about the decision taken along with a description of the necessary treatments to protect the health of the subjects included in the trial. 4.3.2.2 Temporary halt of a trial When a sponsor halts the trial temporarily for serious reasons such as safety problems or lack of efficacy, he should notify the concerned Competent Authorities, Ethics Committees and investigators immediately and at least within 15 days from when the trial is temporarily halted. This should be as a substantial amendment using the form at Appendix 9 as described in section 4.2.3 and clearly explain the reasons and scope e.g. stopping recruitment and/or interrupting treatment of subjects already included. The sponsor should also describe the necessary treatments to protect the health of the subjects included in the trial. To restart the trial he should make the request as a substantial amendment using the form at Appendix 9 and providing evidence that it is safe to restart the trial. If the sponsor decides not to recommence a temporarily halted trial he should notify AIFA, the Competent Authorities and the Ethics Committees concerned within 15 days of his decision, using the form at Annex 12 and providing a brief explanation of the reasons for ending the trial. 4.3.2.3 Clinical trial report As required by the regulatory requirement(s) and to comply with the Community guideline on Good Clinical Practice the sponsor should also provide a summary of the clinical trial report within one year of the end of the trial in the world 13, entering these data into the specific section “Results” in the database of the Osservatorio. The format of this summary should comply as much as possible with annex 1 of the Community guideline on the Structure and Content of Clinical Study Reports (CPMP/ICH/137/95). 4.3.2.4 Follow up If a new event occurs after the termination of the trial that is likely to change the risk/benefit analysis of the trial and could still have an impact on the trial participants, the sponsor should notify AIFA and Ethics Committee concerned and provide a proposed course of action. 4.3.3 Format and content The declaration of the end of the trial should be notified using the electronic form printed from the Osservatorio database and available in fac-simile in the Appendix 12. To this purpose the following information should be provided: § name and address of the sponsor or his legal representative in the European Union; § title of the trial; § EudraCT number; § sponsor’s protocol code number; § date of end of trial in Italy;

13 If not otherwise specified in the protocol, the conclusion of a trial refers to the last visit of the last patient enrolled in all the countries participating the trial, both European and ext ra European.

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§ date of end of complete trial in all participating sites in all countries when available. When the trial is terminated early, the end of clinical trial report should also provide the following information: § justification of the premature ending or of the temporary halt of the trial; § number of patients still receiving treatment at time of study termination; § proposed management of patients receiving treatment at time of halt or study termination; § consequences for the evaluation of results.

5. Access to clinical trials data by Regions and independent Provinces According to article 11 of the legislative decree 24th June 2003, n. 21114, the Authorities of the Regions and of the independent Provinces may access, through the Osservatorio, to the information of all the clinical trials conducted within their territory, including the information related to the opinion of the Ethics Committees, the commencement, the possible early termination and regular end of the trial as well as the data about the results obtained and the reasons of possible interruption. This function guarantees that sponsors notify clinical trials data to Regions and independent Provinces, as provided in the above mentioned article 11. 6. Additional information to notify by Monitoring Clinical Trials Centre (Osservatorio) The sponsor of a clinical trial must notify electronically by Osservatorio: commencement of the trial in each clinical site within 30 days (a fac-simile of the electronic form is available in Appendix 10); the end of the trial in each single clinical site within 30 days from the last visit of the last patient, if the end is not otherwise specified in the protocol (a fac-simile of the electronic form is available in the Appendix 11).

14 Modified by the law 24th November 2003, n. 326 “Conversion into law, with modifications of the law –decree 30th September 2003, n. 269, concerning urgent provisions to promote the development and the correction of the trend of public accounts.”

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Attachment 2 Detailed guidance about the content of 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.

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Table of contents Page Glossary of the acronyms ……………………………………………………………………. “ 30 1. Introduction …………………………………………………………………………………..... “ 31 2. Legal basis ……………………………………………………………………………………... “ 31 3. Scope …………………………………………………………………………………………... “ 31 4. Definitions ……………………………………………………………………………………... “ 31 5. Procedures to obtain the opinion of the Ethics Committee …………………………………..... “ 31 6. Format and content of the application for an opinion of the Ethics Committee ……………..... “ 32 6.1 Before commencing a clinical trial ……………………………………………….. “ 32 6.1.1 “ 32 6.1.2

Request for an opinion of the Ethics Committee ……………………………… Information to submit ………………………………………………………….. “ 32

6.1.2.1 The application form ………………………………………………... “ 33 6.1.2.2 Information concerning the Investigational Medicinal Product (IMP

and PeIMP) …………………………………………………………. “

33 6.1.2.3 The clinical trial protocol ……………………………………………. “ 33 6.1.2.4 Recruitment arrangements ………………………………………….. “ 34 6.1.2.5 Subject information and the informed consent procedure …………... “ 35 6.1.2.6 Suitability of the investigator …………………………….………….. “ 36 6.1.2.7 Insurance …………………………………………………………….. “ 36 6.1.2.8 Financial arrangements ……………………………………………… “ 37 6.1.2.9 Involvement of other sites and/or countries …………………………. “ 37 6.1.2.10 Information concerning the outcomes of the inspections GCP

received by the sponsor ……………………………………………... “

37 6.2. During the carrying out of a clinical trial ……………………………………………… “ 37 6.2.1 Amendments ……………………………………………………………………. “ 38 6.2.2 Safety measures and serious adverse reactions…………………………………. “ 39 6.2.3 Revocation of the opinion by the Ethics Committee ………………………….... “ 39 6.3 Notification after end or an early termination of the trial ………………………………. “ 39 7. Role of the technical-scientific secretarial office of the Ethics Committee in the management

of the notifications to the Osservatorio ………………………………………………………... “

40

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Glossary of the acronyms AIFA: Agenzia Italiana del Farmaco (Italian Medicines Agency) CTA: Clinical Trial Application EEA: European Economic Area EMEA: European Medicines Agency EudraCT: European Clinical Trials Database GCP: Good Clinical Practice GMP: Good Manufacturing Practice IB: Investigator’s Brochure IMP: Investigational Medicinal Product IMPD: Investigational Medicinal Product Dossier ISS: Istituto Superiore di Sanità (Italian National Health Institute) MA: Marketing Authorisation NIMP: Non-Investigational Medicinal Product OsSC: Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (National Monitoring Centre on Clinical Trials with Medicines) PeIMP: Product equivalent to the Investigational Medicinal Product (from a regulatory perspective) ReTNIMP: Regardless to Trial Non Investigational Medicinal Product SmPC: Summary of Product Characteristics TSE: Transmissible Spongiform Encephalopathy

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1. Introduction

This detailed guidance should be read in conjunction with the legislative decree of 24th June 2003, n. 211 “Transposition of Directive 2001/20/EC relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for clinical use” which establishes that clinical trial on a medicinal product for human use may not start until the appropriate Ethics Committee has issued a favourable opinion. This detailed guidance is intended to provide advice on the format and content of a clinical trial application to be submitted to an Ethics Committee. The ministerial decree 15th July 1997 “Implementation of the guideline of the European Union concerning the good clinical practice in the conduct of clinical trials with medicines” provides a further useful guidance on the responsibilities of the Ethics Committees and other relevant issues as well as the ministerial decree 12th May 2006 “Minimum requirements for establishment, organisation and operation of Ethics Committees for clinical trials on medicinal products”.

2. Legal basis Article 8 of the Legislative Decree 24th June 2003, n. 211 requires the Ministry of Health to establish the application format and appropriate documentation to be submitted in an application for an Ethics Committee opinion on a clinical trial on a medicinal product for human use. For multi-centre clinical trial, article 7 of the legislative decree 24th June 2003, n. 211 requires the sponsor to request a single opinion to the Ethics Committee competent for the health facility where the coordinating investigator works and that the Ethics Committees of the other participating sites accept or refuse such opinion.

3. Scope This attachment provides the application form for a clinical trial to be submitted to an Ethics Committee and, for multi-centre clinical trials, to both the Ethics Committee who expresses the single opinion and the Ethics Committees who have to accept or refuse this opinion. This attachment applies to the format and accompanying documentation of the application for an Ethics Committee opinion on a clinical trial on a medicinal product for human use before commencing a trial, during the conduct and at the termination of the trial to allow the Ethics Committee to fulfil its obligations according to the legislative decree 24th June 2003, n. 211 and the principles of Good Clinical Practice (GCP). It also covers the documentation concerning possible proposals of substantial amendments to make to the trial to be forwarded to the Ethics Committee.

4. Definitions

The definitions used in this attachment are the same as those provided in the legislative decree 24th June 2003 n. 211, and where applicable, in the Good Clinical practice. 5. Procedures to obtain the opinion of the Ethics Committee The procedures to obtain the single opinion as well as the acceptance or refusal of it by the Ethics Committees of the collaborating sites, are established in the legislative decree 24th June 2003 n.

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211. The Ethics Committee expresses its own opinion within the limits of its liabilities, as defined in the above mentioned decree. The technical-scientific secretarial office of the Ethics Committee who granted the single opinion will communicate its decision by the National Monitoring Centre database conveying the information of the form reported in facsimile in Appendix 6. This form once printed and signed by the president of the Ethics Committee has to be forwarded to AIFA within 30 days upon the decision. The entering the data of the single opinion in the National Monitoring Centre database guarantees the notification of the opinion to the other collaborating sites, for multi-centre trials. 6. Format and content of the application for an opinion of the Ethics Committee

6.1. Before commencing a clinical trial 6.1.1. Request for an opinion to the Ethics Committee The request of an opinion to the Ethics Committee has to be submitted by the sponsor of the clinical trial. The application should be initially checked by the technical- scientific secretaria l office of the Ethics Committee which has to establish if it is valid. The application is considered to be valid if all required documents are complete. The omission of required documents must be properly motivated by the applicant. The application submitted to the Ethics Committee is considered to be valid if it meets the requirements listed in this attachment; if the application is considered not valid the scientific secretarial office of the Ethics Committee will inform the applicant of the deficiencies within 7 working days from the receipt of it. The application should be signed by the applicant. The documents, to be forwarded to both the Ethics Committee and the Competent Authority, have to be submitted in the same version, in five paper copies and one electronic copy (for example on CD-rom). If an applicant withdraws an application before the single opinion has been granted and submits it to another Ethics Committee it has to justify this to the above mentioned Ethics Committees and to AIFA. AIFA can issue regulations with regard to this.

6.1.2 Information to submit The applicant should submit and sign a covering letter with the application. Its heading should contain the EudraCT number and the sponsor protocol number with a title of the trial. All documents will report date and number of current version, besides the identifying elements of the trial. The information described in this section and summarized in the application form (Appendix 5) grant an adequate evaluation of the clinical trial by the Ethics Committees. If the Ethics Committee responsible for granting the single opinion recognizes deficiencies in the information received, it may request integration only once (according to article 6, section 4, of the legislative decree 24th June 2003, n. 211) in compliance with the documents provided in this decree. The Ethics Committee of the collaborating site may request changes only about the informed consent limited to the subjects enrolled in the trial at the concerning clinical site (according to article 7, section 3 of the legislative decree 24th June 2003, n. 211).

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6.1.2.1. The application form

The clinical trial application form is reported in facsimile in Appendix 5. The technical-scientific secretaria l office will check that the application data are complete and that a cover page reporting the EudraCT number, printed from the National Monitoring Centre database is attached to the application form. This one represents the receipt of the electronic data entering. 6.1.2.2 Information concerning the Investigational Medicinal Product (IMP/PeIMP)15 The following information must be submitted to the Ethics Committees:

1) the following listed documents must be submitted to the Ethics Committee where the coordinating investigator works (or the principal investigator when single centre trial). This documentation refers to what is reported in Attachment 1 (in brackets the references):

§ Investigator’s Brochure (IB) (s. paragraph 4.1.5) § Investigational medicinal product Dossier (IMPD) (s.paragraph 4.1.6 and 4.1.6.1)

- Quality data (s. paragraph 4.1.6.1.1) - Non clinical pharmacology and toxicology data (s. paragraph 4.1.6.1.2) - Clinical trial and previous human experience data (s. paragraph 4.1.6.1.3) - Overall risk benefit analysis (s. paragraph 4.1.6.1.4)

§ Simplified IMPD, when applicable (s.paragraph4.1.6. and 4.1.6.2).

If Non-Investigational-Medicinal-Products (NIMPs) are used in the trial it is required to refer to the rules established in the paragraph 4.1.7 in Attachment 1.

2) The documentation listed as it follows must be submitted to the other Ethics Committees of

the multi-centre trial that have to accept or refuse the single opinion. This documentation refers to what is reported in Attachment 1 (in brackets the references):

§ Investigator’s Brochure (IB) (s. paragraph 4.1.5) § Clinical trial and previous human experience data (s.paragraph 4.1.6.1.3) § Overall risk benefit analysis, if not included in the IB (s.paragraph 4.1.6.1.4).

If the IMP has a MA in any Member State in the Community and the product is to be used as authorised, the Investigator’s Brochure could be substituted by the authorised SmPC. This SmPC shall be translated into Italian or, at least, in English.

6.1.2.3 The clinical trial protocol

The content and format of the protocol should comply with the Good Clinical Practice rules as of the ministerial decree 15th July 1997 concerning “Implementation of the guideline of the European Union on the good clinical practice in the conduct of clinical trials with medicines”. The version submitted to the Ethics Committee should include all currently established amendments and a definition of the end of the trial. If this is not the last visit of the last subject undergoing the trial, the reason should be given by the sponsor. 15 For PeIMP (Product equivalent to the IMP) see paragraphs 3 and 4.1.7 as well as table I of Attachment 1 of this decree.

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The protocol has to be identified by: § the title ; § a sponsor’s protocol code number specific for all versions of it; § a number and date of version that will be updated when it is amended; § any short title or name assigned to it.

The protocol has to be signed by the sponsor upon the submission of the application for an opinion and by the principal investigator before the commencing of the trial. Among other things, the clinical trial protocol has to include:

§ the evaluation of the anticipated benefits and risks; § a justification for the selection of trial subjects, especially when including subjects

whoare incapable to giving informed consent or other special populations (i.e. minors); § when necessary, a description of the plan for the provision of any additional care of the

subjects once their participation in the trial has ended, where it differs from what is normally expected according to the subject’s medical condition;

§ a description of the recruitment and informed consent procedures, especially when subjects who are (temporarily or permanently) incapable of giving informed consent are included or when a procedure with witnessed consent is to be used;

§ a description of ethical consideration on the clinical trial which should not be restricted to a declaration of compliance with the ethical principles but should go into any ethical problems connected with the trial in more depth.

Besides a complete protocol edited in Italian or in English a summary of it in Italian should be submitted. A protocol may include one or more sub-studies to be conducted at all trial sites or only at specific sites. The covering letter of the application to the Ethics Committee should draw attention to any sub-studies and information should be provided in the proper section of the application form (Appendix 5) and supporting documents. 6.1.2.4 Recruitment arrangements The procedures for enrolment of subjects as well as the reasons for selection of particular subject groups should be described in detail in the trial protocol. When recruitment of subjects is planned to be by advertisement, copies of the material to be used should be appended, including any printed materials, recordings or videotapes. These forms of recruitment:

a) must specify the site where the trial is going to be performed; b) must be previously approved by the Ethics Committee of this site; c) must not mention the name of the medicine and/or the investigational substance; d) must comply with the current rules regulating the advertisement of medicines.

Furthermore, the procedures proposed for handling the responses to the advertisement(s) should be outlined. This includes the planned arrangements for information and/or advice to the respondents found not to be suitable for inclusion in the trial.

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Whether the material for recruitment by public information is disclosed by means of communication with high circulation (e.g. publication in newspapers or magazines distributed throughout national territory) the competent Ethics Committee is that one which grants the single opinion. The Ethics Committee of the collaborating site has to assess the material for public information to be used locally, within the health facility of competence. Further guidance and information on issues that might be relevant to consider depending on the type of trial and advertisement are given in Appendix 13. 6.1.2.5 Subject information and the informed consent procedure Article 4 and 5 of the legislative decree 24th June 2003, n. 211 define the information to be provided to the subjects (and/or, where appropriate, the parent(s)/legal representative) before their decision to participate or abstain from participation should be submitted together with the form for written informed consent. The information should be based on the elements set out in the ministerial decree 15th July 1997 concerning “Implementation of the guideline of the European Union on the good clinical practice in the conduct of clinical trials with medicines”. There should also be a description of the arrangements for taking care of the subjects after their participation in the trial has ended, where there is additional care necessary because of the subjects’ participation in the trial and where it differs from that normally expected according to the medical condition. The information sheets given to the subject and/or the parent(s)/legal representative should be kept short, clear, , and understandable. The measures taken to safeguard the subject’s privacy and the protection of personal data should be described as is required according to the legislative decree 3030th June 2003, n. 196. There should be information on: § how the identity of the subject, biological material obtained from the subject, and any

recorded data will be coded, stored and protected; § the person(s) who will have access to the code list, where the list will be kept and for how

long, and who will be responsible for keeping it according to the above mentioned decree. Furthermore, the information should address the right of the subject to ask for updated information on what data are recorded, to require corrections of errors, and to know who will be responsible for keeping the data and who will have access to them in keeping. The subject should be informed of the possibility to withdraw consent without giving any reason and to require that all previously retained identifiable samples will be destroyed to prevent future analyses. The information should include a statement that the consequence of the subject’s withdrawal of consent will be that no new information will be collected from the subject and added to existing data or a database. Information should be provided on a contact person from who additional information can be obtained about the trial and the right of the trial subjects and whom to contact in the event of trial related injury.

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If a procedure with witnessed consent is to be used, relevant information on the reason for using a witness, on the selection of the witness and on the procedure for obtaining consent should be provided. In case of temporarily incapacitated patients the procedure for obtaining the consent of the legal representative should be described. The procedure should be outlined that will be used to obtain/confirm consent if/when the patient regains the capacity to consent and the information to be given to the patient in that case. The form to be used to verify that information has been given and that the trial subject has consented (the informed consent form) should contain at least three elements:

§ consent to participate in the trial; § consent to make confidential personal information available (direct access) for quality

control and quality assurance by relevant personnel from the sponsor, a nominated research organisation on behalf of the sponsor (whereof article 20, section 3 of legislative decree 24 June 2003, n. 211) and for inspection by AIFA or other Competent Authorities;

§ consent to archive coded information, and for its transmission outside Italy or outside the Community if applicable.

Appendix 14 provides more guidance and gives examples of items that might be addressed in the subject information leaflet depending on the type of trial. 6.1.2.6 Suitability of the investigator The qualification of the principal investigator should be described in a current curriculum vitae and/or other relevant documents. Any previous training in the principles of GCP or experience obtained from work with clinical trials and patient care should be described. Furthermore, any conditions, such as economic interests, that might be suspected to influence the impartiality of the investigator should be presented. To this aim, a facsimile form for the declaration on the conflict of interests is provided in the Appendix 15; this form may be used as reference. The Ethics Committee should give an opinion on these aspects as well as on the quality of the facilities (including the availability of adequate resources, personnel and laboratory facilities). In order to have the Ethics Committee evaluate the suitability of the clinical site and of investigators, the principal investigator should submit the Ethics Committee, if available, the inspection minutes and the relating summary letter of AIFA or of other Inspectorates EU/Third Countries, including any prescriptions received in the last three years, except the necessary measures for possible safeguard of regulations on confidentiality. In order to allow the sponsor to the evaluation of the compliance with the Good Clinical Practice rules of the clinical sites before their involvement in the trial, the sponsor may require the principal investigator the summary reports of AIFA or other Inspectorates EuropeanUnion/Third Countries, if available, concerning any inspections at the same investigational site or however, at the same investigator in the last three years, except the necessity by the investigator of encrypting the elements that may lead to the identification of other sponsors. 6.1.2.7 Insurance Documents testifying indemnity or compensation arrangements in case of injury or death of a trial subject have to be attached with the application to the Ethics Committee, as well as the insurance or indemnity arrangements to cover the liability of the sponsor and investigator.

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6.1.2.8 Financial arrangements It is the responsibility of the Ethics Committee in order to grant its opinion to take into consideration the suitability of the arrangements for rewarding or compensating investigator(s) / sites and any compensation to trial subjects as well as the relevant aspects of any agreement between the sponsor and the site. It is pointed out that any compensation for loss of earning is allowed only for healthy volunteers participating in a trial. As for any reimbursement of the expenses incurred by patients to go to the investigational site concerned, this is expected only if the clinical trial is carried out in high specialization sites (in some Regions only) and investigates particular or rare pathologies, causing the patients to cover long journeys. In this case, the eventuality of an economical cover for the out-of-pocket expenses incurred and certified by the patients involved in the trial may be taken into consideration except the necessity that the reimbursement procedure is processed by the administration office of the facility and is being previously approved by the Ethics Committee. 6.1.2.9 Involvement of other sites and/or countries The sponsor must submit in the application form (CTA form) the list of the participating sites, the name and qualifications of the main investigators and the number of subjects to be included in the trial in Italy in addition to brief information about the inclusion of sites in other Member states or in Third countries. If the sponsor decides to involve other clinical sites after the grant of a favourable single opinion, a non substantial amendment will be notified to the Ethics committee of the site which has granted the single opinion. A copy of the CTA form updated has to be attached with the cover letter reporting the reasons of the amendment. 6.1.2.10 Information concerning the outcomes of the GCP inspections received by sponsor In order to have the Ethics Committee which grants the single opinion to evaluate the reliability of the sponsor and of the data of clinical trials referred to in the documents submitted, the sponsor must submit when applicable:

1. summary letters issued by AIFA inclusive of any recommendations of AIFA itself concerning the inspections reports received in the last three years about the clinical trials concerning the clinical development of an IMP, wherever it is has been investigated;

2. summary letters issued by AIFA inclusive of any recommendations concerning the quality system inspections received in the sponsor’s site in the last three years;

3. if all duties and functions of the sponsor are assigned to a Contract Research Organization (CRO), as of article 20, section3 of the legislative decree 24th June 2003 n. 211, this is obliged to submit all the documents received by AIFA as of the items 1 and 2.

6.2 During the carrying out of a clinical trial The legislative decree 24th June 2003, n. 211 describes the information arising during the conduct of a trial that must be submitted to the Ethics Committee for review or information This includes new events relating to the conduct of the trial or the development of the investigational medicinal product where that event is likely to affect the safety of the subjects, reports of adverse reactions, and when the trial is halted or terminated early by the sponsor.

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In addition, the Ethics Committee may request the investigator and/or sponsor to submit any other information necessary to fulfil the requirement of continuing review of the trial according to the Good Clinical Practice rules implemented in the ministerial decree 15th July 1997.

6.2.1. Amendments The sponsor is obliged by article 10 of legislative decree 24th June 2003 n. 211 to inform the Ethics Committee about substantial amendments to the protocol and to submit all relevant documents in support of such amendments according to the procedures described in the Attachment 1. The sponsor may not implement such amendments without a favourable opinion of the Ethics Committee, unless the changes consist of urgent safety measures to protect the trial subjects (see section 4.2.8 of Attachment 1). Yet, in the cases described in Appendix 4, item 2, the amendment has to be submitted solely to the Ethics Committee that has granted the single opinion; in the case described in Appendix 4, item 3, the amendment has to be submitted solely to the Ethics Committee of the collaborating site concerned in the change; in the cases reported in Appendix 4, item 4, the amendment has to be notified to the Ethics Committees involved but even though substantial it may be implemented without a favourable opinion of the Ethics Committee. Criteria for considering an amendment as substantial, the format and content of the application to make such an amendment are given in the sections 4.2.3 and 4.2.4 of Attachment 1 of this decree as well as in Appendix 4. An application of amendments identified as substantial should be submitted to both the Ethics Committee and the Competent Authority in parallel using the same form (Appendix 9) . The substantial amendment should be identified (by sponsor’s amendment number, version and date) and signed by the sponsor. In addition, the reasons for the amendment must be indicated and all the documents in their updated version must be submitted, included each new version of the investigator’s brochure (or the SmPC in the cases listed in the section 4.1.5 in Attachment 1 to this decree) and an updated risk benefit assessment, where applicable. Only the relevant new documents must be submitted with clear references to those ones already sent. Changes to the protocol might lead to a modification of the subject information sheet and any new subject information should be appended. If there is a need to obtain new consent from the subjects, the procedure should be described. When necessary, the amendment has to be submitted with a description of the possible consequences for the evaluation of the results for the subjects already included and a report about the validity and usefulness of data recorded and stored up then. The non-substantial amendments should be handled as outlined in Attachment 1 (see section 4.2.2) Documentation of the changes should be kept at the sponsor and at the site and be made available on request and for inspection.

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6.2.2 Safety measures and serious adverse reactions. The sponsor shall ensure that all relevant information about serious unexpected adverse reactions and all the problems likely to affect the safety of the subjects and the regular conduct of the trial are reported to the Ethics Committee in accordance with the obligations outlined in article 17 of the legislative decree 24th June 2003, n. 211. Information relating adverse events (and namely those events which are not considered serious unexpected suspected adverse reactions) must not be reported to the Ethics Committee. In case of death of a subject participating the trial, the investigator notifies the sponsor and the Ethics committee providing any further information relevant for the assessment of the safety profile of IMP (see article 16 of the legislative decree 24th June 2003, n. 211). 6.2.3 Revocation of the opinion by the Ethics Committee. a) Revocation of single opinion The Ethics Committee of the clinical site, where the coordinating investigator works, that has granted the single opinion may revoke the above mentioned opinion, temporarily or permanently if it has objective grounds for considering that the conditions in the request of opinion are no longer met or has information raising doubts about the ethical aspects or the safety and the scientific validity of clinical trials already authorised. The Ethics Committee shall notify the sponsor of the revocation and, except where there is imminent risk, ask the sponsor and/or the investigator for their opinion. The Ethics Committee has to notify also the Competent Authority of the site where it works of its revocation and this, in its turn, shall revoke its own authorisation according to the procedures outlined in the section 4.2.9 of attachment 1. Revocation of single opinion makes the acceptance of this opinion by the other Ethics Committees of the sites participating the trial to elapse and causes the automatic revocation of all the authorisations in each single site. In case of urgency, to the aims above mentioned, the Ethics Committee that has granted the single opinion and then revokes it shall inform AIFA and each Ethics Committee of the sites participating. When the Competent Authority that has authorised the trial is the ISS the Ethics Committee is obliged to inform this authority about the revocation of the favourable opinion. The Ethics Committee of the clinical site that has revoked the single opinion enters into the OsSC the specific information concerning the revocation, filling the form reported in facsimile in the Appendix 7. This form must be printed and sent to AIFA within 30 days of the decision of Ethics Committee. b) Revocation of acceptance of the single opinion Analogue procedure described in section a) must be followed when the acceptance of the single opinion is revoked by the collaborating Ethics Committees. The consequences of this revocation are limited to the site concerned. 6.3 Notification after end or an early termination of the trial According to Article 10 of legislative decree 24th June 2003 n. 211 at the end of the trial, intended as last patient’s last visit (if intended differently it must be defined in the protocol) the sponsor

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should notify the Ethics Committees within 90 days, entering the data reported in Appendix 12 into the OsSC database. In case of an early termination (premature end) of the trial or temporary halt by the sponsor the Ethics Committee should be notified within 15 days of the termination or halt by mail. When for serious reasons, such as problems of safety or lack of efficacy, a trial is temporary halted by the sponsor (interruption of the treatment of the subjects involved or of the enrolment of new subjects) the Ethics Committee should be notified as soon as possible but at least within 15 days of the termination by the form for the communication of substantial amendments reported in Appendix 9. At the end of the trial the sponsor should provide the Ethics Committee and AIFA with a summary of the clinical trial report entering the information in the section “Risultati” (Results) of the Osservatorio as soon as it is available and anyway within 12 months of the end of the trial worldwide16. If after the termination of a trial the risk/ benefit analyses have changed, the new evaluation should be provided in case it will have an impact on the planned follow up of the subjects who have participated in the trial. If so, the actions needed to protect the subjects should be described.

7. Role of the technical-scientific secretarial office of the Ethics Committee in the management of the notifications to the Osservatorio. The technical-scientific secretaria l office adopts the most suitable measures to spread information concerning the activities of the Ethics Committee, even through the use of a notice board available in the Osservatorio website, for example to store, update and spread the requirements relating the informed consent or any other information or useful document for the sponsors in order to prepare the application for the opinion. Within 30 days upon the decision the technical-scientific secretaria l office must enter the data relating the opinion into the Osservatorio, and specifically the data relating to: § favourable or unfavourable single opinion and revocation of single opinion (Appendix 6 and

7); § acceptance or refusal of the single opinion, or revocation of acceptance by the collaborating

Ethics Committee; § opinion about substantial amendment (Appendix 4, see also section 6.2.1).

The technical-scientific secretaria l office of the Ethics Committee that grants the single opinion checks that the information entered into Osservatorio are consistent with the paper documents provided by the sponsor. In this way the technical-scientific secretariat guarantees the validation of the data notified in electronic format, in particular: § the information included in the application form (Appendix 5) and the documents attached

(see the check list I.a of Appendix 5); § the information contained in the notification form for substantial amendments (Appendix 9)

and any documents attached (i.e. the new version of the protocol, where the changes have been so wide and/or substantial to justify a new version).

16 If not otherwise specified in the protocol, the conclusion of a trial refers to the last visit of the last patient enrolled in all the countries participating the trial, both European and ext ra European.

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In addition, the technical-scientific secretaria l office of each Ethics Committee has the duty to verify that the sponsor has entered the start-up and end data of the trial in each clinical site concerned into the Osservatorio (Appendix 10 and 11), according to the obligations outlined in section 5 of Attachment 1 of this decree. In case of no profit trials, the legal representative of the sponsor has to identify a person responsible for the transmission of the information within the competence of the sponsor into the Osservatorio. When the trial is sponsored by a heath facility and a person responsible for data entry into the Osservatorio has not been identified within the technical-scientific secretarial office of the Ethics Committee, this person has to be selected by the legal representative of the facility through a request of a specific password for sponsor’s profile. The procedure to apply for a password is described in detail in the Osservatorio website (https://oss-sper-clin.agenziafarmaco.it/nuovi_utenti.htm). With regard to the national registry of the Ethics Committees, the technical-scientific secretaria l office must guarantee the updating of all the specific information of the Ethics Committee and of its composition, within 20 days of its establishment, in the Osservatorio website as well as the communication about any discontinuance of the activity of the Ethics Committee, according to the conditions outlined in the website itself.

List of appendixes

Appendix 1 Section adapted from Common Technical Document – CTD Headings for IMP/PeIMP data quality

Appendix 2 Section adapted from Common Technical Document – CTD Headings for IMP/PeIMP non clinical pharmacology and toxicology data

Appendix 3 Section adapted from Common Technical Document – CTD Headings for IMP/PeIMP clinical trial and previous human experience data

Appendix 4 Headings for aspects of a trial that might involve a substantial amendment

Appendix 5 Application form for authorisation of a clinical trial on medicinal products for human use to the competent authorities and for opinion of the ethics committees

Appendix 6 Form for communicating the favourable or unfavourable single opinion

Appendix 7 Form for communicating the revoke of the single opinion

Appendix 8 Form for communicating the sponsor the decision of the ethics committee of the collaborating clinical site about the single opinion (acceptance or refusal or revoke of the acceptance)

Appendix 9 Application form for the request of a substantial amendment of a clinical trial on medicinal products for human use to the competent authorities for authorisation and to the ethics committees for opinion

Appendix 10 Form for declaring the opening/withdrawal of a single clinical site

Appendix 11 Form for declaring the end of the trial in a single site

Appendix 12 Form for declaring the end of a clinical trial on medicinal products for human use to the competent authority and the ethics committee

Appendix 13 Advertising for trial subjects enrolment and additional procedures to communicate to the ethics committees

Appendix 14 Subject information content

Appendix 15 Public declaration of interests and confidentiality undertaking by the investigator

page 1 of 3

Appendix 1

SECTION ADAPTED FROM COMMON TECHNICAL DOCUMENT1 – CTD

HEADINGS FOR IMP / PeIMP2 DATA QUALITY

This appendix has to be used as a reference for the completion of the IMPD (IMP Dossier) in compliance with paragraph 4.1.6.1.1 of Attachment 1. When applicable the sponsor should refer to the Guidance of the European Commission of march 2006 “Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning Investigational Medicinal Products in clinical trials (CHMP/QWP/185401 final).”

2.1.S Drug substance

2.1.S.1 General information

2.1.S.1.1 Nomenclature 2.1.S.1.2 Structure3 2.1.S.1.3 General properties

2.1.S.2 Manufacture

2.1.S.2.1 Manufacturer(s) 2.1.S.2.2 Description of manufacturing process and process controls 2.1.S.2.3 Control of materials 2.1.S.2.4 Controls of critical steps and intermediates 2.1.S.2.5 Process validation and/or evaluation 2.1.S.2.6 Manufacturing process development

2.1.S.3 Characterisation4

2.1.S.3.1 Elucidation of structure and other characteristics 2.1.S.3.2 Impurities

2.1.S.4 Control of active substance

2.1.S.4.1 Specifiche 2.1.S.4.2 Analytical procedures 2.1.S.4.3 Validation of analytical procedures 2.1.S.4.4 Batch analysis 2.1.S.4.5 Justification of specification

1 Rules regulating the medicinal products in the European Union – Volume 2B: Notice to applicants. Detailed and updated

information is available on the website of the European commission: http://pharmacos.eudra.org. 2 Please, note: in compliance with paragraph 4.1.7 of Attachment 1, all the rules provided for the IMP apply to the PeIMP, included

the necessity of granting the same information. 3 The word ”structure” or ”structural” for gene therapy products or cell therapy products is used with the meaning of ”identity” as

defined in paragraph 4.1.6.1 of attachment 1. 4 The word ”characterisation” for gene therapy products or cell therapy products refers to the whole of the characteristics of

”identity” used to define the product.

- Appendix 1 -

page 2 of 3

2.1.S.5 Reference standards or materials

2.1.S.6 Container closure systems

2.1.S.7 Stability

2.1.P Medicinal product

2.1.P.1 Description and composition of the medicinal product

2.1.P.2 Pharmaceutical development

2.1.P.2.1 Components of the medicinal product 2.1.P.2.1.1 Drug substance 2.1.P.2.1.2 Excipients

2.1.P.2.2 Medicinal product 2.1.P.2.2.1 Formulation development 2.1.P.2.2.2 Overages 2.1.P.2.2.3 Psychochemical and biological properties

2.1.P.2.3 Manufacturing process development 2.1.P.2.4 Container closure systems 2.1.P.2.5 Microbiological attributes 2.1.P.2.6 Compatibility

2.1.P.3 Manufacture

2.1.P.3.1 Manufacturer(s) 2.1.P.3.2 Batch formula 2.1.P.3.3 Description of manufacturing process and process controls 2.1.P.3.4 Controls of critical steps and intermediates 2.1.P.3.5 Process validation an/or evaluation

2.1.P.4 Control of excipients

2.1.P.4.1 Specification(s) 2.1.P.4.2 Analytical procedures 2.1.P.4.3 Validation of analytical procedures 2.1.P.4.4 Justification of specification 2.1.P.4.5 Excipients of human or animal origin 2.1.P.4.6 Novel excipients

2.1.P.5 Control of medicinal product

2.1.P.5.1 Specification(s) 2.1.P.5.2 Analytical procedure 2.1.P.5.3 Validation of analytical procedures 2.1.P.5.4 Batch analyses 2.1.P.5.5 Characterisation of impurities 2.1.P.5.6 Justification of specification(s)

2.1.P.6 Reference standards or materials

2.1.P.7 Container closure systems

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2.1.P.8 Stability

2.1.A Appendices

2.1.A.1 Facilities and equipment

2.1.A.2 Adventitious agents safety evaluation

2.1.A.3 Novel excipients

2.1.A.4 Solvents for reconstitutions and diluents

page 1 of 2

Appendix 2

SECTION ADAPTED FROM COMMON TECHNICAL DOCUMENT1– CTD HEADINGS FOR IMP / PeIMP NON CLINICAL PHARMACOLOGY AND

TOXICOLOGY DATA2

This appendix can be used as a reference for the completion of the IMPD (IMP Dossier) in compliance with paragraph 4.1.6.1.2 of Attachment 1.

2.2.1 Pharmacodynamics

2.2.1.1 Brief summary

2.2.1.2 Primary pharmacodynamics

2.2.1.3 Secondary pharmacodynamics

2.2.1.4 Pharmacology safety

2.2.1.5 Pharmacodynamic interactions

2.2.1.6 Discussion and conclusion

2.2.2 Farmacokinetics

2.2.2.1 Brief summary

2.2.2.2 Methods of analysis

2.2.2.3 Absorption

2.2.2.4 Distribut ion

2.2.2.5 Metabolism

2.2.2.6 Excretion

2.2.2.7 Pharmacokinetic drug interactions

2.2.2.8 Other pharmacokinetic studies

2.2.2.9 Discussion and conclusions including evaluation of toxicokinetics

2.2.3 Toxicology

2.2.3.1 Brief summary

2.2.3.2 Single dose toxicity

2.2.3.3 Repeat-dose toxicity3

1 Rules regulating the medicinal products in the European Union – Volume 2B: Notice to applicants. Detailed and updated

information is available on the website of the European Commission: http://pharmacos.eudra.org. 2 Please, note: in compliance with paragraph 4.1.7 of Attachment 1, all the rules provided for the IMP apply to the PeIMP, included

the necessity of granting the same information. 3 These headings should be supported by toxicokinetic evaluations.

- Appendix 2 -

pag. 2 di 2

2.2.3.4 Genotoxicity4

2.2.3.4.1 In vitro 2.2.3.4.2 In vivo2

2.2.3.5 Carcinogenicity2 2.2.3.6 Reproductive and development toxicity2 2.2.3.7 Local tolerance 2.2.3.8 Other toxicity studies5 2.2.3.9 Discussion and conclusions

4 For gene therapy, insertional mutagenesis. 5 For gene therapy, biodistribution studies, persistence and integration and assessment of the involuntary germ-line transmission of

vectors. Immunotoxicity studies, for cell therapy and gene therapy.

page 1 of 1

Appendix 3

SECTION ADAPTED FROM COMMON TECHNICAL DOCUMENT1– CTD HEADINGS FOR IMP/PeIMP2 CLINICAL TRIAL AND PREVIOUS HUMAN

EXPERIENCE DATA

This appendix can be used as a reference for the completion of the IMPD (IMP Dossier) in compliance with paragraph 4.1.6.1.3 of Attachment 1.

2.3.1 Clinical pharmacology

2.3.1.1 Brief summary

2.3.1.2 Mechanism of primary action

2.3.1.3 Secondary pharmacological effects

2.3.1.4 Pharmacodynamic interactions

2.3.2 Clinical pharmacokinetics

2.3.2.1 Brief summary

2.3.2.2 Absorption

2.3.2.3 Distribution

2.3.2.4 Elimination

2.3.2.5 Pharmacokinetics of active metabolites

2.3.2.6 Plasma concentration-effect relationship

2.3.2.7 Dose and time-dependencies

2.3.2.8 Special patient populations

2.3.2.9 Interactions

2.3.3 Human exposure

2.3.3.1 Brief summary

2.3.3.2 Overview of safety and efficacy

2.3.3.3 Healthy subject studies

2.3.3.4 Patient study

2.3.3.5 Previous human experience

2.3.4 Benefits and risks assessment

3 Appendixes

1 Rules regulating the medicinal products in the European Union – Volume 2B: Notice to applicants. Detailed and updated

information is available on the website of the European commission: http://pharmacos.eudra.org. 2 Please, note: in compliance with paragraph 4.1.7 of Attachment 1, all the rules provided for the IMP apply to the PeIMP, included

the necessity of granting the same information.

pag. 1 di 3

Appendix 4

HEADINGS FOR ASPECTS OF A TRIAL THAT MIGHT INVOLVE A SUBSTANTIAL

AMENDMENT

This appendix has to be used as a reference for any trial amendments in compliance with paragraph 4.2.3 of Attachment 1. Substantial amendments to the conduct of the clinical trial may arise from changes to the protocol or from new information relating to the scientific documents in support of the trial. Amendments to the trial are regarded as “substantial” by sponsor when they are likely to have a significant impact on one or more of the following aspects: § the safety or physical or mental integrity of the subjects and ethical aspects of the trial; § the scientific value of the trial; § the conduct or management of the trial; § the quality or safety of each IMP1 used in the trial.

The following lists report some aspects of a trial that might involve a substantial amendment. These lists are divided into four different groups according to the different authorisation procedures which they have to follow in order to be applied. The list is not exhaustive because a substantial amendment might occur in some other aspect of a trial. Not all the amendments to those aspects of a trial need to be submitted to the Competent Authority for authorisation and to the Ethics Committee for opinion, only those that meet the criteria of “substantial” above; those that do not meet the criteria of “substantial” should be simply notified to the Ethics Committee without waiting for an opinion. 1. To submit to the Competent Authority and to the Ethics Committee of the clinical site

where the coordinating investigator works and to the Competent Authorities and the Ethics Committees of the participating sites. The coordinating Ethics Committee gives its opinion on these amendments; the opinion of the Ethics Committee will be accepted or refused by the other Ethics Committees.

1.1 Amendments related to the protocol

– Ethical aspects – Protection of the rights, health and well-being of subjects – Procedures for quality data – Pur pose of trial – Design of trial – Informed consent – Recruitment procedure

1 Please, note: in compliance with paragraph 4.1.7 of Attachment 1, all the rules provided for the IMP apply to the PeIMP, included the necessity of granting the same information.

- Appendix 4 -

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– Measures of efficacy – Schedule of samples – Addition or deletion of tests or measures – Number of participants – Age range of participants – Inclusion criteria – Exclusion criteria – Safety monitoring – Change of safety criteria to interrupt the investigational treatment – Duration of exposure to the investigational medicinal product(s) – Change of posology of the investigational medicinal product(s) – Change of comparator – Statistical analysis – Change of the definition of the end of the trial – Changes to the protocol to solve the problems of safety or lack of efficacy occurred during

the trial

1.2 Changes to clinical trial and human experience data where this is relevant to the ongoing trials with particular reference to the altered risk/benefit assessment (the headings here listed concern changes to the information previously submitted to the Ethics Committee for giving its opinion; therefore, in these cases, after assessing new information if substantial, the Ethics Committees will express about maintaining the favourable opinion previously given).

– Safety related to a clinical trial or human experience with the investigational medicinal product

– Results of new clinical pharmacology tests – New interpretation of existing clinical pharmacology tests – Results of new clinical studies – New interpretations of existing clinical trial data – New data from human experience with the investigational medicinal product – New interpretation of existing data from human experience with the investigational

medicinal product 2. To submit to the Competent Authority and to the Ethics Committee where the

coordinating investigator works. The coordinating Ethics Committee only gives its opinion on these amendments.

2.1 Amendments related to the IMP

– Changes to IMP quality data – Change of name or code of IMPs – Immediate packaging material – Manufacturer(s) of active substance – Manufacturing process of active substance – Specifications of active substance – Manufacture of the medicinal product – Specification of the medicinal product – Specification of excipients where these may affect product performance – Major change to the formulation

- Appendix 4 -

page 3 of 3

– Storage conditions – Test procedures of active substance – Test procedures of the medicinal product – Test procedures of non-pharmacopoeial excipients

2.2 Changes to non-clinical pharmacology and toxicology data when this is relevant to the

ongoing trials (the headings here listed concern changes to the information previously submitted to the Ethics Committee for giving its opinion; therefore, in these cases, after assessing new information if substantial, the Ethics Committees will express about maintaining the favourable opinion previously given).

– Results of new pharmacological tests – New interpretations of existing pharmacology tests – Results of new toxicity tests – New interpretation of existing toxicity tests – Results of new interaction studies

2.3 Change of the coordinating investigator

3. To submit to the Competent Authority and to the Ethics Committee of the coordinating

site concerned. The Ethics Committee of the clinical site gives its opinion on this amendment.

– Change of the principal investigator 4. To submit to the Competent Authorities and to the Ethics Committees concerned but

even though substantial they do not need the opinion of the Ethics Committee for their implementation.

4.1 Amendments related to the trial arrangements

– Change of the sponsor or legal representative

– Change of the CRO assigned significant tasks

4.2 Urgent amendments

– Urgent safety measures to protect the subjects partic ipating in the trial (see section 4.2.8 of Attachment 1).

page 1 of 18

Appendix 5

APPLICATION FORM FOR AUTHORISATION OF A CLINICAL TRIAL ON MEDICINAL

PRODUCTS FOR HUMAN USE TO THE COMPETENT AUTHORITIES AND FOR OPINION OF THE ETHICS COMMITTEES

Fill in and print this form from the OsSC website: https://oss-sper-clin.agenziafarmaco.it For official use by Competent Authority and Ethics Committee: Date of receiving the request

|__|__|/|__|__|/|__|__|__|__| Date of request for information to make it valid:

|__|__|/|__|__|/|__|__|__|__|

Date of request for additional information

|__|__|/|__|__|/|__|__|__|__|

Grounds for non acceptance/negative opinion: Date:

|__|__|/|__|__|/|__|__|__|__|

o

Date of valid application: |__|__|/|__|__|/|__|__|__|__| Date of start of procedure

|__|__|/|__|__|/|__|__|__|__|

Date of receipt of additional/ amended information: |__|__|/|__|__|/|__|__|__|__|

Authorisation/positive opinion Date: |__|__|/|__|__|/|__|__|__|__|

o

Registration number or equivalent: Withdrawal of application Date: |__|__|/|__|__|/|__|__|__|__|

o

To be filled in by the applicant : APPLICATION FOR AUTHORISATION TO THE COMPETENT AUTHORITY o REQUEST FOR OPINION TO THE ETHICS COMMITTEE o The investigational medicinal product is used along with a medical device YES |__| NO |__| If YES, the medical device is made in EC YES |__| NO |__| If it is not branded EC, the relating authorisations that regulate the trials of medical devices have been obtained YES |__| NO |__| In negative case, the Sponsor undertakes to obtain the authorisations before the trial starts.

- Appendix 5 -

page 2 of 18

A. TRIAL IDENTIFICATION

A.1 EudraCT number

A.2 Full title of the trial

A.3 Sponsor’s protocol code, version and date

A.4 Name or abbreviated title of the trial (if available)

A.5 ISRCTN number (if available) B. IDENTIFICATION OF THE SPONSOR RESPONSIBLE FOR THE REQUEST

B.1 Sponsor

B.1.1 Name of organisation

B.1.2 Name of the person to contact

B.1.3 Address

B.1.4 Telephone number

B.1.5 Fax number

B.1.6 E-mail

B.2 Legal Representative1 of the Sponsor in EU for the purpose of this trial (if different from the Sponsor)

B.2.1 Institute

B.2.2 Name and surname of the reference person

B.2.3 Address

B.2.4 Phone number

B.2.5 Fax number

B.2.6 E-mail

B.3 Status of the Sponsor

B.3.1 Profit o

B.3.2 Non profit o

B.3.2.1 The sponsor declares that the non profit trial is in compliance with the requirements fixed in the ministerial decree 17 December 2004.2

yes o no o

B.3.2.2 The sponsor declares that the measures provided to ensure the quality of the trial are guaranteed:

a) by trial specific measures or

b) by the quality system of the health facility

o o

1 In accordance with article 20 of Legislative decree 211/2003. 2 Ministerial decree 17 december 2004 ”Prescriptions and conditions of a general nature referring to the conduct of clinical trials of

medicines, with special reference to those designed to enhance clinical practice as an integral part of health and medical care.”

- Appendix 5 -

page 3 of 18

C. APPLICANT IDENTIFICATION (responsible for submitting the clinical trial form to the Ethics Committee and to the Competent Authority )

C.1 Sponsor o

C.2 Person or organisation authorised by the sponsor to make the application o

C.3 Complete the details of the applicant below:

C.3.1 Organisation

C.3.2 Name of contact person

C.3.3 Address

C.3.4 Telephone number

C.3.5 Fax number

C.3.6 E-mail

C.4 Request to receive an .xml copy of CTA data3

C.4.1 Requesto to receive an .xml copy of CTA data transmitted to EudraCT EudraCT

yes o no o

C.4.1.1 If yes, provide the e-mail address(es) to which it should be sent (up to 5 addresses):

C.4.1.2 Request to receive this via password protected link(s)4 yes o no o

C.4.1.2.1 If the option selected above is “no”, the .xml file will be transmitted by less secure e-mail link(s)

D. INFORMATION ON EACH IMP/PeIMP5

Information on each ‘bulk product’ before the trial-specific operations (blinding, trial specific packaging and labelling) are provided in this section for each investigational medicinal product (IMP) being tested including each comparator and each placebo, if applicable. If the trial is performed with several products, in the database a sequential number will be assigned to each product automatically. If the product is a combination product, information should be given for each active substance. If applicable, information about placebo is reported in section D.7.

D.1 IMP IDENTIFICATION (provide the following information for each IMP to be used in the trial)

D.1.1 (This refers to the sequential number assigned to the IMP by the OsSC database system)

D.1.2 IMP being tested o

D.1.3 IMP used as comparator o

D.1.4 For placebo go directly to section D.7

3 This utility depends on the European register EudraCT. 4 This option requires a EudraLink account (See http://eudract.emea.eu.int/ for details). 5 Please note: as provided in section 4.1.7. of attachment 1 of this decree, all the rules to be followed for the IMP have to

be followed for the PeIMP, including the necessity of providing the same information; therefore, in the title only of this section the acronym PeIMP is indicated next to that of IMP as memo, while along the text this acronym is not repeated because it is implicit that anywhere the acronym IMP recurs, the same information is required for the PeIMP as well.

- Appendix 5 -

page 4 of 18

D.2 STATUS OF THE IMP (If the IMP has a marketing authorisation (MA) in Italy but the trade name and marketing authorisation holder are not fixed in the protocol go to section D.2.2)

D.2.1 The IMP to be used in the trial has a marketing authorisation yes o no o

D.2.1.1 If yes to D.2.1, specify for the product to be used in the trial:

D.2.1.1.1 Trade name6

D.2.1.1.2 Name of the MA holder6

D.2.1.1.3 National MA number 6

D.2.1.1.4 Indicate if the IMP has been modified in relation to its MA

yes o no o

D.2.1.1.4.1 If yes, please specify:

D.2.1.1.5 Specify wich country granted the MA

D.2.1.1.5.1 Italy yes o no o

D.2.1.1.5.2 If another Member State, please specify:

D.2.1.1.5.3 If Third Country, please specify:

D.2.2 The IMP to be used in the trial has a MA in Italy with different names and with the same characteristics (indication, dosages, pharmaceutical form) and the protocol allows that any brand of the IMP be administered to the trial subjects.

yes o no o

If yes, please specify:

D.2.2.1 In the protocol the treatment is defined only by active substance

yes o no o

D.2.2.1.1 If yes, describe active substance in D.3.8 or D.3.9

D.2.2.2 In the protocol treatment regimens allow different combinations of marketed products used according to local clinical practice at some or all investigator sites

yes o no o

D.2.2.2.1 If yes, describe active substance in D.3.8 o D.3.9

D.2.2.3 The products to be administered as IMPs are defined as belonging to an ATC group.

yes o no o

D.2.2.3.1 If yes, give the ATC group of the applicable authorised codes in the ATC code field (level 3 or the level that can be defined) in D.3.3

D.2.2.4 If other, please specify:

D.2.3 IMPD submitted:

D.2.3.1 Full IMPD yes o no o

D.2.3.2 Simplified IMPD7 yes o no o

6 Available in the Summary of Prodcut Characteristics (SmPC).

- Appendix 5 -

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D.2.3.3 Summary of product characteristics (SmPC) only

yes o no o

D.2.4 The use of IMP has been previously authorised in a clinical trial conducted by the Sponsor in EU

yes o no o

D.2.4.1 If yes, specify which Member States:

D.2.5 The IMP has been designated in this indication as an orphan drug in the Community

yes o no o

D.2.5.1 If yes, give the orphan drug designation number8:

D.2.6 The IMP has been the subject of scientific advice related to this clinical trial

yes o no o

D.2.6.1 If yes, please indicate source of advice and provide a copy in the CTA request:

D.2.6.1.1 From CHMP at EMEA yes o no o

D.2.6.1.2 From a Member State Competent Authority yes o no o

D.2.6.1.2.1 If yes, specify:

D.3 Description of the IMP

D.3.1 Product name (where applicable)9

D.3.2 Product code (where applicable)10

D.3.3 ATC code, if officially registered 11

D.3.4 Pharmaceutical form (use standard terms)

D.3.5 Maximum duration of treatment of a subject according to the protocol

D.3.6 Maximum dose allowed (specify: per day or total dose; units and route of administration)

D.3.7 Route of administration (use standard terms)

D.3.8 Name of each active substance (INN or proposed INN, if available)

D.3.9 Other available name for each active substance (CAS12, current sponsor code(s), other descriptive name, etc. provide all available)

D.3.10 Strength (specify all strengths to be used) - concentration number - concentration type

7 Provide justification for using simplified dossier in the covering letter (see Attachment 1, section 4.1.6.2.1 and table 1). 8 According to the Community register on orphan medicinal product (Regulation (EC) n° 141/2000):

http://ec.europa.eu/enterprise/pharmaceuticals/register/index.htm . 9 To be provided only when there is no trade name. This is the name routinely used by a sponsor to identify the IMP in the clinical

trial documentation (protocol, investigator’s brochure ...). 10 To be provided only when there is no trade name. This is a code designated by the sponsor which represents the name routinely

used by the sponsor to identify the product in the CT documentation. For example, a code may be used for combinations of drugs or drugs and devices.

11 Available from the Summary of Product Characteristics (SmPC). 12 Chemical Abstracts Service.

- Appendix 5 -

page 6 of 18

D.3.11 Type of IMP Does the IMP contain an active substance:

D.3.11.1 of chemical origin yes o no o

D.3.11.2 of biological / biotechnological nature yes o no o

This is a:

D.3.11.3 Cell therapy medicinal product yes o no o

D.3.11.4 Gene therapy edicinal product yes o no o

D.3.11.5 Radiopharmaceutical medicinal product yes o no o

D.3.11.6 Immunological medicinal product (such as vaccine allergen, immune serum)

yes o no o

D.3.11.7 Plasma derived medicinal product yes o no o

D.3.11.8 Other extractive medicinal product yes o no o

D.3.11.9 Herbal medicinal product yes o no o

D.3.11.10 Homeopathic medicinal product yes o no o

D.3.11.11 Medicinal product containing genetically modified organisms If yes,

yes o no o

D.3.11.11.1 The authorisation for contained use or release has been granted

yes o no o

D.3.11.11.2 It is pending yes o no o

D.3.11.12 Another type of medicinal product, if yes specify:

D.4 Biological / Biotechnological investigational medicinal products (including vaccines) If yes to question D.3.11.2 , specify the type of product

D.4.1 Type of product

D.4.1.1 Extractive yes o no o

D.4.1.2 Recombinant yes o no o

D.4.1.3 Vaccine yes o no o

D.4.1.4 GMO yes o no o

D.4.1.5 Plasma derived products yes o no o

D.4.1.6 Other, specify:

D.5 Somatic cell therapy investigational medicinal (no genetic modification) If yes to question D.3.11.3, specify the origin and the type of cells

D.5.1 Origin of cells

D.5.1.1 Autologous yes o no o

D.5.1.2 Allogeneic yes o no o

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D.5.1.3 Xenogeneic yes o no o

D.5.1.3.1 If yes, specify species of origin:

D.5.2 Type of cells

D.5.2.1 Stem cells yes o no o

D.5.2.2 Differentiated cells yes o no o

D.5.2.2.1 If yes, specify the type (eg. keratinocytes, fibroblasts, chondrocyes, ecc.):

D.5.2.3 Others, specify:

D.6 Gene Therapy Investigational Medicinal Products If the answer to section D.3.11.4 is yes, specify:

D.6.1 Gene(s) of interest

D.6.2 In vivo gene therapy yes o no o

D.6.3 Ex vivo gene therapy yes o no o

D.6.4 Type of gene transfer product

D.6.4.1 Nucleic acid (e.g. plasmid) If yes, specify:

yes o no o

D.6.4.1.1 naked yes o no o

D.6.4.1.2 complexed yes o no o

D.6.4.2 Viral vector yes o no o

D.6.4.2.1 If yes, specify the type: adenovirus, retrovirus, adeno-associated virus.):

D.6.4.3 If others, specify:

D.6.5 Genetically modified cells: If yes, specify – origin of the cells:

yes o no o

D.6.5.1 Autologous yes o no o

D.6.5.2 Allogeneic yes o no o

D.6.5.3 Xenogeneic yes o no o

D.6.5.3.1 If yes, specify the species of origin:

D.6.5.4 Other type of cells (e.g. haematopoietic stem cells), specify:

D.6.6 Comments on novel aspects of gene therapy investigational product if any (free text):

D.7 Information on placebo (if relevant; repeat as necessary)

D.7.1 Is there a placebo: yes o no o

D.7.2 This refers to placebo number:

- Appendix 5 -

page 8 of 18

D.7.3 Pharmaceutical form:

D.7.4 Route of administration:

D.7.5 Which IMP is it placebo for? Specify IMP number(s) from D.1.1:

D.7.5.1 Composition apart from the active substance(s):

D.7.5.2 Is it otherwise identical to the IMP? yes o no o

D.7.5.2.1 If not, specify the major ingredients:

D.8 Site where the qualified person certifies bathc release:13 This section is dedicated to finished IMPs, i.e. medicinal products randomised, packaged, labelled and certified for use in the clinical trial. If there is more than one site or more than one IMP is certified use extra pages and give each IMP its number from section D.1.1 or D.7.2. In the case of multiple sites indicate the product certified by each site. Where the product does not have a MA in EU, but it is supplied in bulk and final packaging and labelling for local use is carried out in accordance with Article 9.2. of Directive 2005/28/EC (GCP Directive) then enter the site where the product was finally certified for release by the Qualified Person for use in clinical trial at D.8.2 above.

D.8.1 Do not fill in section D.8.2 for an IMP that meets all the following conditions: - has a MA in the European Union, and - is sourced from the EU market, and - is used in the trial without modification (e.g. not overencapsulated), and - the packaging and labelling is carried out for local use only as per Article 9.2.

of the Directive 2005/28/EC (GCP Directive)

D.8.2 Site respons ible in the EU for certification of the finished IMP This site is responsible for certification of (list the number(s) of each IMP, including placebo from sections D.1.1 and D.7.2):

D.8.2.1 Manufacturer yes o no o

D.8.2.2 Importer yes o no o

D.8.2.3 Name of the organisation

D.8.2.3.1 Address

D.8.2.4 Manufacturing authorisation number

D.8.2.4.1 If no authorisation, specify the reasons:

E. GENERAL INFORMATION ON THE TRIAL

This section should be used to provide information about the aims, scope and design of the trial. When the protocol includes a sub-study in the MS concerned section E.2.3 should be completed providing information about each sub-study.

E.1 MEDICAL CONDITION OR DISEASE UNDER INVESTIGATION

E.1.1 Specify the medical condition(s) to be investigated (free text)14:

13 In accordance with paragraph 38 of Annex 13 of Volume 4 of the “Rules Governing Medicinal Products in the European Union”. 14 In the case of healthy volunteer trials, the intended indication for the product under developement should be provided.

- Appendix 5 -

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E.1.2 MedDRA version, level, term and classification code15 (repeat as necessary)

E.1.3 Is any of the conditions being studied a rare disease16 yes o no o

E.2 Objective of the trial

E.2.1 Main objective:

E.2.2 Secondary objectives:

E.2.3 Are there any sub-studies: yes o no o

E.2.3.1 If yes, give the full title, date and version of each sub-study and their relating objectives:

E.3 Main inclusion criteria (list the most important )

E.4 Main exclusion criteria (list the most important )

E.5 Primary end-point(s)

E.6 Scope of the trial (Tick all boxes where applicable))

E.6.1 Diagnosis o

E.6.2 Prophylaxis o

E.6.3 Therapy o

E.6.4 Safety o

E.6.5 Efficacy o

E.6.6 Pharmacokinetic o

E.6.7 Pharmacodynamic o

E.6.8 Bioequivalence o

E.6.9 Dose-response o

E.6.10 Pharmacogenetic o

E.6.11 Pharmacogenomic o

E.6.12 Pharmacoeconomic o

E.7 Trial type and phase17

E.7.1 Human pharmacology (Phase I) It is:

o

E.7.1.1 First administration to humans o

E.7.1.2 Bioequivalence study o

E.7.1.3 Other, specify:

15Applicants are encouraged to provide the MedDRA lower level term if applicable and classification code. 16 Points to consider on the calculation and reporting of the prevalence of a condition for Orphan drug designation: COM/436/01

(www.emea.eu.int/htms/human/comp/orphaapp.htm). 17 The descriptions of the trial types provided are those reccommended in preference to Phases. See page 5 of Community guideline

CPMP/ICH/291/95.

- Appendix 5 -

page 10 of 18

E.7.2 Therapeutic exploratory (Fase II) o

E.7.3 Therapeutic confirmatory (Fase III) o

E.7.4 Therapeutic use (Fase IV) o

E.8 Design of the trial

E.8.1 Controlled If yes, specify:

yes o no o

E.8.1.1 randomised yes o no o

E.8.1.2 open yes o no o

E.8.1.3 single blind yes o no o

E.8.1.4 double blind yes o no o

E.8.1.5 parallel groups yes o no o

E.8.1.6 cross-over yes o no o

E.8.1.7 other, specify:

E.8.1.8 If controlled specify the comparator:

E.8.1.8.1 other medicinal products yes o no o

E.8.1.8.2 placebo yes o no o

E.8.1.8.3 other, specify:

E.8.2 Single site in Italy (see also section G) yes o no o

E.8.3 Multiple site in Italy (see also section G) yes o no o

E.8.3.1 Number of sites antic ipated in Italy

E.8.4 The trial involves general practitioners and paediatricians 18 yes o no o

E.8.5 The trial involves other Member States yes o no o

E.8.5.1 Number of clinical sites in EU

E.8.6 The trial involves countries outside the EU yes o no o

E.8.7 The trial has a Data Review Monitoring Committee yes o no o

E.8.8 Definition of the end of the trial, and justification in the case where it is not the last visit of the last subject undergoing the trial:19 (free text):

E.8.9 Initial estimate of the duration of the trial20 (years, months and days)

E.8.9.1 In Italy years months days

E.8.9.2 In all countries concerned by the trial years months days

18 According to the ministerial decree 10th May 2001 ”Controlled clinical trials in general medicine and paediatrics” . 19 If not provided in the protocol. 20 From the first inclusion up to the last visit of the last subject.

- Appendix 5 -

page 11 of 18

F. POPULATION OF TRIAL SUBJECTS

F.1 Age span

F.1.1 Less than 18 years If yes, specify:

yes o no o

F.1.1.1 in utero yes o no o

F.1.1.2 preterm newborn infants (up to gestational = 37 weeks) yes o no o

F.1.1.3 newborn (0-27 days) yes o no o

F.1.1.4 infant and toddler (28 days-23 months) yes o no o

F.1.1.5 children (2-11 years) yes o no o

F.1.1.6 adolescents (12-17 years) yes o no o

F.1.2 Adult (18-44 years) yes o no o

F.1.3 Adult (45-65 years) yes o no o

F.1.4 Elderly (> 65 years) yes o no o

F.2 Gender

F.2.1 Female o

F.2.2 Male o

F.3 Group of trial subjects

F.3.1 Healthy volunteers yes o no o

F.3.2 Patients yes o no o

F.3.3 Specific vulnerable population yes o no o

F.3.3.1 Women of child bearing potential yes o no o

F.3.3.2 Women of child bearing potential using contraception yes o no o

F.3.3.3 Pregnant women yes o no o

F.3.3.4 Nursing women yes o no o

F.3.3.5 Emergency situation yes o no o

F.3.3.6 Subjects incapable of giving consent personally yes o no o

F.3.3.6.1 If yes, specify:

F.3.3.7 Others yes o no o

F.3.3.7.1 If yes, specify:

F.4 Planned number of subjects to be included

F.4.1 In Italy

F.4.2 For a multinational trial

F.4.2.1 In the European Union

- Appendix 5 -

page 12 of 18

F.4.2.2 In the whole clinical trial

F.5 When necessary, specify the plans for treatment or care after a subject has ended his/her participation in the trial21, if different from the expected normal treatment of that condition (free text):

G. CLINICAL SITES INVOLVED IN THE TRIAL IN ITALY

G.1 Coordinating investigator (for multicenter trial) or principal investigator (for single centre trial)

G.1.1 Name

G.1.2 Family name

G.1.3 Qualification

G.1.4 Clinico site

G.1.4.1 Name

G.1.4.2 Address

G.1.5 Ethics Committee concerned

G.2 Principal investigator (complete a form for each collaborating clinical site participating the trial)

G.2.1 Name

G.2.2 Family name

G.2.3 Qualification

G.2.4 Clinical site

G.2.4.1 Name

G.2.4.2 Address

G.2.5 Ethics Committee concerned

21 If not already provided in the protocol.

- Appendix 5 -

page 13 of 18

G.3 Central technical facilities to be used in the conduct of the trial (laboratory or other

technical facility, in which the measurement or assessment of the main evaluation criteria are centralised (repeat as needed for multiple organisations).

G.3.1 Organisation

G.3.2 Name of contact person

G.3.3 Address

G.3.4 Telephone number

G.3.5 Duties subcontracted

G.4 Organisations to whom the sponsor has transferred trial related duties and functions (repeat as needed for multiple organisations).

G.4.1 The sponsor has transferred any major or all the sponsor’s trial related duties and functions to another organisation or third party If yes, please specify:

yes o no o

G.4.1.1 Organisation

G.4.1.2 Address

G.4.1.3 Telephone number

G.4.1.4 Name of contact person

In addition, specify the transferred trial related duties

G.4.1.5 All the sponsor’s trial related duties o

G.4.1.6 Any sponsor’s trial related duties specificare:

o

G.4.1.6.1 Monitoring yes o no o

G.4.1.6.2 Regulatory (e.g. preparation of applications to Competent Authorities and EthicsCommittees)

yes o no o

G.4.1.6.3 Investigator recruitment yes o no o

G.4.1.6.4 IVRS22 – treatment randomisation yes o no o

G.4.1.6.5 Data management yes o no o

G.4.1.6.6 E-data capture yes o no o

G.4.1.6.7 SUSARs reporting yes o no o

G.4.1.6.8 Quality assurance auditing yes o no o

G.4.1.6.9 Statistica analysis yes o no o

G.4.1.6.10 Medical writing yes o no o

G.4.1.6.11 Other duties subcontracted yes o no o

G.4.1.6.11.1 If yes to other please specify:

22 Interactive Voice Response System: commonly used for randomisation of treatment and controlling the shipment of stock of product.

- Appendix 5 -

page 14 of 18

H. SIGNATURE OF THE APPLICANT

H.1 I hereby confirm that/confirm on behalf of the sponsor that: (delete which is not applicable)

• the above information given on this request is correct;

• the trial will be conducted according to the protocol, national regulation and the principles of good clinical practice;

• it is reasonable for the proposed clinical trial to be undertaken;

• I will submit reports of suspected unexpected serious adverse reactions and safety reports to the Competent Authority and the Ethics Committee concerned according to current regulation;

• I will submit through Osservatorio a summary of the final study as soon as available within a maximum 1 year deadline after the end of the study in all the participating countries.

H.2 Applicant of the request

H.2.1 Date |__|__|/|__|__|/|__|__|__|__|

H.2.2 Signature

H.2.3 Name

H.2.4 Family name

- Appendix 5 -

page 15 of 18

I.a CHECK LIST OF THE INFORMATION ATTACHED TO THE APPLICATION (tick

the appropriate boxes)

Information to submit to the Competent Authority (CA23) and to the Ethics Committee (EC) of the clinical site where the coordinating investigator works (Principal Investigator in case of single site trial)

1. General information

o 1.1 Cover printed from the OsSC database and containing the EudraCT number

o 1.2 Covering letter

o 1.3 Application form printed from OsSC

o 1.4 List of Competent Authorities within Community to which the application has been submitted and details of decisions (if available)

o 1.5 Copy / summary of any scientific advice

o 1.6 If the applicant is not the sponsor, a letter of authorisation enabling the applicant to act on behalf of the sponsor

2. Subject related

o 2.1 Informed consent form, date and version number

o 2.2 Subject information leaflet, date and version number

o 2.3 Arrangements for recruitment of subjects

o 2.4 Material to be given to the subjects (diaries, questionnaires, etc)

3. Protocol related

o 3.1 Clinical trial protocol, date and version number

o 3.2 Summary of the protocol in Italian, date and version number

o 3.3 Peer Review of trial (when available)

o 3.4 If not in the protocol, risk-benefit assessment, foreseeable risks of treatment and procedures to be used (including pain, discomfort, violation of physical and mental integrity of subjects and means to avoid and/or take care of unfo reseen or unwanted events) reason for including persons from vulnerable groups (i.e. minors, temporarily or permanently incapacitated subjects etc.)

o 3.5 Ethical assessment made by the principal / coordinating investigator, if not given in the protocol

4. IMP/PeIMP related

o 4.1 Investigator’s Brochure, date and version number

o 4.2 Investigational Medicinal Product Dossier (IMPD)

o 4.3 Simplified IMPD for known products (see table I, attachment 1)

o 4.4 Summary of Product Characteristics (SmPC) (for products with marketing authorisation in the Community used according to the MA, the SmPC may take the place of IMPD and IB)

23 As for clinical trials of central competence, the Competent Authority is AIFA or ISS, as referred to in article 2, section 1, letter t,

of the Legislative Decree 211/2003.

- Appendix 5 -

page 16 of 18

o 4.5 Outline of all active trials with the same IMP

4.6 If IMP manufactured in EU and if no marketing authorisation in UE:

o 4.6.1 Copy of the manufacturing authorisation referred to in art. 13, section 1 of the Legislative Decree 211/2003 and of Directive 2001/20/CE

4.7 If IMP not manufactured in European Union and if no marketing authorisation in EU:

o 4.7.1 Certification of the QP of a Member State that: a) the manufacturing site works in compliance with GMP at least

equivalent to EU GMP, or b) each production batch has undergone all relevant analyses, tests or

checks necessary to confirm its quality

o 4.7.2 Certification of GMP status of active biological substance

o 4.7.3 Copy of the importers manufacturing authorisation in the member State and of manufacturing authorisation of the manufacturer in the Third Country form which the IMP has been imported, according to art. 13, section 1 of the Legislative Decree 211/2003 and Directive 2001/20/CE

4.8 Certification of analysis for test product in exceptional cases:

o 4.8.1 Where impurities are not justified by the specification or when unexpected impurities (not covered by specification) are detected

o 4.9 Viral safety studies (when applicable)

o 4.10 Applicable authorisations to cover trial or products with special characteristics (if available) e.g. GMOs, radio-pharmaceuticals, narcotics

o 4.11 Examples of the label in Italian

o 4.12 TSE certificate when applicable

5. Facilities and staff related information

o 5.1 Facilities for the trial

o 5.2 CV of the coordinating / principal investigator

o 5.3 Information about supporting staff, if present

6. Finance related24

o 6.1 Provision for indemnity or compensation in the event of injury or death attributable to the clinical trial

o 6.2 Any insurance or indemnity to cover the liability of the sponsor or investigator

o 6.3 Any compensation for loss of earning or any reimbursement of the expenses incurred by patients to go to the investigational site

o 6.4 Proposal of agreement between the sponsor and the trial site

24 When the Competent Authority is AIFA or ISS, finance related information should not been attached to the application form.

- Appendix 5 -

page 17 of 18

I.b CHECK LIST OF THE INFORMATION ATTACHED TO THE APPLICATION (tick

the appropriate boxes)

Information to submit to the Competent Authority (CA25) and to the Ethics Committee (EC) of the clinical site where the collaborating investigator works.

1. General information

o 1.1 Cover printed from the OsSC database and containing the EudraCT number

o 1.2 Covering letter

o 1.3 Application form, printed from OsSC

o 1.4 If the applicant is not the sponsor, a letter of authorisation enabling the applicant to act on behalf of the sponsor

2. Subject related information

o 2.1 Informed consent form, date and version number

o 2.2 Subject information leaflet, date and version number

o 2.3 Arrangements for recruitment of subjects

o 2.4 Material to be given to the subjects (diaries, questionnaires, etc)

3. Protocol related information

o 3.1 Clinical trial protocol, date and version number

o 3.2 Summary of the protocol in Italian, date and version number

o 3.3 Peer Review of trial (when available)

o 3.4 If not in the protocol, risk-benefit assessment, foreseeable risks of treatment and procedures to be used (including pain, discomfort, violation of physical and mental integrity of subjects and means to avoid and/or take care of unforeseen or unwanted events) reason for including persons from vulnerable groups (i.e. minors, temporarily or permanently incapacitated subjects etc.)

o 3.5 Ethical assessment made by the principal / coordinating investigator, if not given in the protocol

4. IMP/PeIMP related information

o 4.1 Investigator’s Brochure, date and version number (for products with marketing authorisation in the Community used according to the MA, the SmPC may take the place of IMPD and IB)

o 4.2 Outline of all active trials with the same IMP

o 4.3 Absolute risk benefit assessment, if not given in the IB

5. Facilities and staff related information

25 As for clinical trials of central competence, the Competent Authority is AIFA or ISS, as referred to in article 2, section 1, letter t,

of the Legislative Decree 211/2003.

- Appendix 5 -

page 18 of 18

o 5.1 Facilities for the trial

o 5.2 CV of the principal investigator

o 5.3 Information about supporting staff, if present

6. Finance related information

o 6.1 Provision for indemnity or compensation in the event of injury or death attributable to the clinical trial

o 6.2 Any insurance or indemnity to cover the liability of the sponsor or investigator

o 6.3 Any compensation for loss of earning or any reimbursement of the expenses incurred by patients to go to the investigational site

o 6.4 Proposal of agreement between the sponsor and the trial site

page 1 of 5

Appendix 6

FORM FOR COMMUNICATING THE FAVOURABLE OR UNFAVOURABLE SINGLE

OPINION1

Fill in and print this form from the OsSC website: https://oss-sper-clin.agenziafarmaco.it For official use by AIFA: Registration number of AIFA: Date of receiving: |__|__|/|__|__|/|__|__|__|__| To be filled by the Ethics Committee which has given its single opinion: A. TRIAL IDENTIFICATION

A.1 EudraCT number

A.2 Full title of the trial

A.3 Code, version and date of the clinical protocol B. ETHICS COMMITTEE IDENTIFICATION

(established according to the Ministerial Decree 12 May 2006) B.1 Name of the Ethics Committee

B.2 Name of the President

B.3 Address of the Ethics Committee

B.4 Telephone number

B.5 Fax number

B.6 E-mail C. COORDINATING INVESTIGATOR IDENTIFICATION

(PRINCIPAL INVESTIGATOR, IF SINGLE SITE) C.1 First name

C.2 Family name

C.3 Clinical site

C.4 Clinical site address

C.5 Ward

1 To be filled, printed and sent to AIFA, by the Ethics Committee which has given its favourable/unfavourable opinion within 30

days from the decision.

- Appendix 6 -

page 2 of 5

D. DOCUMENTS EXAMINED

D. 1 Date of the covering letter |__|__|/|__|__|/|__|__|__|__|

D. 2 Date of receiving the application |__|__|/|__|__|/|__|__|__|__|

D. 3 Date of receiving integrating information (where applicable) |__|__|/|__|__|/|__|__|__|__|

D. 4 CTA form o

D. 5 Documents reported in the check list I.a of the CTA form o

D. 6 Clinical trial file in the Osservatorio in compliance with the information of the application form

o

E. ITEMS CONSIDERED (select “n.a.” when the information is not applicable)

E.1 IMP/PeIMP quality data

§ The information and the data supporting the IMP quality are adequate o § The sponsor has certified that the products used in the trial are prepared,

managed and stored in compliance with the applicable Good Manufacturing Practice (GMP)

o

E.1.1 Any possible critical aspects noticed (free text)

E.2 Non clinical pharmacology and toxicology data § Sound and relevant suppositions justifying the start up of trial exist o

E.2.1 Any possible critical aspects noticed (free text)

E.3 Clinical data § There are sound and relevant suppositions which justify the start up of

trial (not applicable for phase I and II trials) o o n.a.

§ The trial will allow to acquire further information on the IMP, to improve prophylactic diagnostic and therapeutic procedures or the comprehension of the etiology and the pathogenesis of diseases.

o

E.3.1 Any possible critical aspects noticed (free text) E.4 Protocol

§ Objectives are consistent with the scientific rational o

§ The trial design is pertinent and relevant o The following aspects have been examined:

Lack of control group o o n.a. Open design o o n.a.

Lack of randomisation o o n.a.

Use of placebo as control group o o n.a. Design of equivalence or non inferiority o o n.a.

§ The IMP treatment scheme is adequate (administration route, dosage treatment duration)

o

§ The control treatment and scheme are adequate o o n.a.

§ Inclusion/exclusion criteria are appropriate, clear and well defined o

- Appendix 6 -

page 3 of 5

§ The exams, the visits and the procedures planned (especially if invasive) are suitable to verify the effects of treatment

o

§ The measure of primary outcome is clinically relevant or correlable with a measure clinically relevant

o o n.a.

§ The methods to point out the measure of primary outcome are adequate o o n.a. § The schedule planned for the survey of efficacy parameters is adequate o o n.a.

§ The parameters selected for the safety assessment are suitable o

§ The follow-up has an adequate duration with reference to the scope of the trial

o

§ The sample size has been calculated as a function of the measure of the primary outcome declared

o o n.a.

§ The calculation of the sample size is correct with reference to the power expected for the trial

o o n.a.

§ The statistical plan of data analysis is consistent with the objectives o

§ The expected difference between the compared treatments is significant o o n.a.

§ For equivalence or non inferiority trials the difference considered is sufficiently restricted and acceptable

o o n.a.

§ The protocol is compliant with the EMEA guideline on the matter o o n.a.

If yes on the previous item, specify the references (free text) E.4.1 Any possible critical aspects noticed (free text)

E.5 Ethical aspects

§ The sponsor has certified that the trial is being conducted in compliance with the ethical principles established in the Declaration of Helsinki and with the GCP and applicable regulations

o

§ The risks and the foreseen setbacks have been weighed up with respect to the benefits for the subject included in the trial and for other current and future patients

o

§ The Ethics Committee has come to the conclusion that the benefits expected from the trial, both therapeutic and in the matter of pubblic health, may justify the risks

o

§ The rights, the safety and the well-being of the subjects in the trial have been primarily considered and have prevailed on the interests of the science and of the society

o

§ Research with persons incapable of giving their consenti is justified o o n.a.

§ Possibile direct benefits for the subject are expected o o n.a.

§ Possibile benefits for the community are expected o o n.a. E.5.1 Any possible critical aspects noticed (free text)

E.6 Subjects information and procedures for informed consent

§ Subjects information is complete and comprehensible o § Procedures description in the protocol is exhaustive o

§ Discomforts and risks which are likely to occur to the patients are well described

o

§ Procedures to obtain the informed consent are well described o

- Appendix 6 -

page 4 of 5

§ Procedures to recruit healthy volunteers are adequate o o n.a. § Procedures used to protect the privacy of the subject and of the

recorded data are adequate in compliance with current rules o

§ Procedures to inform the general practitioner are correct and complete o o n.a. E.6.1 Any possible critical aspects noticed (free text)

E.7 Financial aspects and information concerning facilities and personnel

§ The financial agreement proposal between the sponsor and the clinical site has been evaluated appropriately

o o n.a.

§ The insurance guarantees an appropriate protection of the subjects o

§ The amount, the procedures for remuneration or compensation of any kind provided by the competent administration for the investigators are compliant with the current rules and appropriate with respect to the commitment required and not so important to be considered a decisive factor for the conduction of the trial

o o n.a.

§ The consistency of any possible compensation for healthy volunteers has been considered which must not be so decisive for the participation in the trial

o o n.a.

§ The suitability of the investigators and sub- investigators has been examined

o

§ The health facility where the trial is going to take place is appropriate o

§ It thas been verified that the sponsor declares that a correct and rapid circulation of the information acquired by the trial is guaranteed

o

E.7.1 Any possible critical aspects noticed (free text) F. DECISION OF THE ETHICS COMMITTEE

F.1 Favourable single opinion o F.1.1 In case of request of opinion about a non profit clinical trial the

Ethics Committee has verified the possession of the requirements in compliance with the Ministerial Decree 17th December 20042

yes o no o

F.2 Unfavourable single opinion o

F.3 Clinical trial to conduct at: F.3.1 The same health facility o

F.3.2 Another health facility o F.4 Planned number of patients in the site

G. ANY POSSIBLE COMMENTS ABOUT PARTICULAR ASPECTS OF THE TRIAL CONSIDERED IN GIVING THE SINGLE OPINION (free text)

H. REASONS OF THE UNFAVOURABLE SINGLE OPINION

2 Ministerial Decree 17th December 2004, published in the Official Journal n. 43 of 22nd February 2005 concerning “Prescriptions

and conditions of a general nature referring to the conduct of clinical trials of medicines, with special reference to those designed to enhance clinical practice as an integral part of health and medical care.”

- Appendix 6 -

page 5 of 5

(tick more than one box if applicable )

H.1 Protocol o H.2 Subjects information and procedures for informed consent o

H.3 Ethical aspects o H.4 Clinical data o

H.5 Non clinical pharmacology and toxicology data o H.6 Investigational medicinal product quality data o

H.7 Need for assessment by Istituto Superiore di Sanità (art. 3, subsection 1, letter b, of Presidential Decree 439/2001)

o

H.8 Other, specify: I. DESCRIPTION OF THE REASONS FOR UNFAVOURABLE SINGLE OPINION

(free text) L. ETHICS COMMITTEE SESSION

L.1 Date of the session |__|__|/|__|__|/|__|__|__|__| L.2 Number of the register of opinions of EC

L.3 EC members present and qualifications L.4 External consultants present and qualification (where applicable)

L.5 EC members present who have not voted (where applicable) M. SIGNATURE OF THE PRESEIDENT OF THE ETHICS COMMITTEE M.1 The Ethics Committee has given its single opinion:

• verified the existence of the legal number, being present members n. ____ out of n. _____

• having considered any possible comments received by the participating Ethics Committees within the following date: |__|__|/|__|__|/|__|__|__|__|

Please find attached to this opinion a copy of the CTA form containing the list of the examined documents (check list I.a).

M.2 Name and surname

M.3 Date |__|__|/|__|__|/|__|__|__|__| M.4 Signature

Page 1 of 2

Appendix 7

FORM FOR COMMUNICATING THE REVOKE OF THE SINGLE OPINION1

Fill in and print this form from the OsSC website: https://oss-sper-clin.agenziafarmaco.it For official use by AIFA: AIFA registration number: Date of receiving the communication: |__|__|/|__|__|/|__|__|__|__| To be filled in by the Ethics Committee which has given its single opinion: A. TRIAL IDENTIFICATION

A.1 EudraCT number

A.2 Full title of the clinical trial

A.3 Sponsor’s protocol code, version and date

A.4 Trial conducted at:

A.4.1 Same health facility A.4.2 Another health facility

o o

B. ETHICS COMMITTEE IDENTIFICATION

(established according to the Ministerial Decree of 12 May 2006) B.1 Name of the Ethics Committee

B.2 Name and family name of the president

B.3 Address of the Ethics Committee

B.4 Telephone number

B.5 Fax number

B.6 E-mail

1 To be filled, printed and sent to AIFA within 30 days from the decision of the Ethics Committee.

C. COORDINATING PRINCIPAL INVESTIGATOR IDENTIFICATION (PRINCIPAL INVESTIGATOR IF SINGLE SITE TRIAL)

C.1 Name

C.2 Family name

C.3 Clinical site

C.4 Clinical site address

C.5 Ward

Page 2 of 2

D. SESSION OF THE ETHICS COMMITTEE

D.1 Date of the session |__|__|/|__|__|/|__|__|__|__|

D.2 Ethics Committee’s opinions registration number

D.3 Members of the Ethics Committee present and qualification

D.4 External consultants present and qualification (where applicable)

D.5 Members of the Ethics Committees present who have not expressed their vote (where applicabile)

E. EXAMINED DOCUMENTATION

E.1 Single opinion references

E.2 Specify the documents evaluated (date - version)

F. REASONS OF THE REVOKE OF THE SINGLE OPINION (select more than one option)

F.1 Protocol o

F.2 Subject information and procedure for obtaining the informed consent o

F.3 Ethical aspects o

F.4 Clinical data o

F.5 Non clinical pharmacology and toxicology data o

F.6 IMP quality data o

F.7 Other, specify:

G. DESCRIPTION OF THE REASONS OF THE REVOKE OF THE SINGLE OPINION (free text)

H. SIGNATURE OF THE PRESIDENT OF THE ETHICS COMMITTEE

H.1 The Ethics Committee has revoked the single opinion: • granted the legal number, being present

member n. ____ out of n. ____ H.2 Name and family name

H.3 Date |__|__|/|__|__|/|__|__|__|__|

H.4 Signature

page 1 of 3

Appendix 8

FORM FOR COMMUNICATING THE SPONSOR THE DECISION OF THE ETHICS COMMITTEE OF THE COLLABORATING CLINICAL SITE ABOUT THE SINGLE

OPINION (ACCEPTANCE OR REFUSAL OR REVOKE OF THE ACCEPTANCE1)

Fill in and print this form from the OsSC website: https://oss-sper-clin.agenziafarmaco.it To be completed and printed by the Ethics Committee of the collaborating clinical site which has accepted /refused the single opinion or has revoked a previous acceptance of the single opinion: A. TRIAL IDENTIFICATION

A.1 EudraCT number

A.2 Full title of the trial

A.3 Sponsor’s protocol code, version and date B. ETHICS COMMITTEE IDENTIFICATION

(established according to the Ministerial Decree 12 May 2006) B.1 Name of the Ethics Committee

B.2 Name and family name of the president

B.3 Address of the Ethics Committee

B.4 Telephone number

B.5 Fax number

B.6 E-mail C. PRINCIPAL INVESTIGATOR IDENTIFICATION

C.1 Name

C.2 Family name

C.3 Clinical site

C.4 Address of the clinical site

C.5 Ward

1 To be transmitted to AIFA, within 30 days from the decision of the Ethics Committee, exclusively through the OsSC database.

- Appendix 8 -

page 2 of 3

D. DOCUMENTS EXAMINED

D. 1 Date of the application covering letter |__|__|/|__|__|/|__|__|__|__|

D. 2 Date of receiving the request |__|__|/|__|__|/|__|__|__|__|

D. 3 CTA form o

D. 4 Documents referred to in the check list I.b of the CTA form o E. DECISION OF THE ETHICS COMMITTEE

E.1 Single opinion references

E.2 Acceptance of the single opinion o

E.2.1 Date of transmission of comments to the coordinating Ethics Committee (where applicable)

|__|__|/|__|__|/|__|__|__|__|

E.2.2 If non-profit trial request, the Ethics Committee has verified the compliance with the requirements of the Ministerial Decree 17 December 20042

yes o no o

E.3 Refusal of the single opinion o

E.3.1 Date of transmission of comments to the coordinating EC (where applicable)

|__|__|/|__|__|/|__|__|__|__|

E.4 Revoke of the acceptation of the single opinion previously expressed o

E.5 Trial to be conducted at:

E.5.1 Same health facility o

E.5.2 Another health facility o

E.6 Number of patients planned for the site F. PARTICULAR ASPECTS OF THE TRIAL CONSIDERED BY THE PARTICPATING

SITE IN THE ACCEPTATION OF THE SINGLE OPINION (free text)

2 Ministerial Decree 17 December 2004, published in the Official Gazette n. 43 of 22 February 2005 concerning “Prescriptions and

conditions of a general nature, referring to the conduct of clinical trials of medicines with special reference to those designed to enhance clinical practice as an integral part of health and medical care”.

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G. REASONS FOR THE REFUSAL OF THE SINGLE OPINION OR THE REVOKE OF THE ACCEPTANCE OF THE SINGLE OPINION BY THE PARTICIPATING ETHICS COMMITTEE (select more than one option )

G.1 Protocol o

G.2 Subjects information and procedure for obtaining the informed consent (clinical site specific)

o

G.3 Ethical aspects o

G.4 Clinical data o

G.5 Non clinical pharmacology and toxicology o

G.6 IMP qualità data o

G.7 Other, specify: H. DESCRIPTION OF THE REASONS OF THE COLLABORATING ETHICS

COMMITTEE FOR THE REFUSAL OF THE SINGLE OPINION OR THE REVOKE OF THE ACCEPTANCE OF THE SNGLE OPINION (free text)

I. SESSION OF THE ETHICS COMMITTEE

I.1 Date of the session |__|__|/|__|__|/|__|__|__|__|

I.2 Registration number of the Ethics Committee

I.3 Members of the Ethics Committee present and qualification

I.4 External consultants present and qualification (where applicable)

I.5 Members of the Ethics Committee present who have not expressed their vote(where applicable)

L. SIGNATURE OF THE PRESIDENT OF THE ETHICS COMMITTEE

L.1 The Ethics Committee has expressed its opinion about the trial:

• granted the legal number, being present members n. ____ out of n. ____

In attachment, please find a copy of the CTA form containing the documents examined (check list I.b).

L.2 Name and family name

L.3 Date |__|__|/|__|__|/|__|__|__|__|

L.4 Signature

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Appendix 9

APPLICATION FORM FOR THE REQUEST OF A SUBSTANTIAL AMENDMENT OF A

CLINICAL TRIAL ON MEDICNAL PRODUCTS FOR HUMAN USE TO THE COMPETENT AUTHORITIES FOR AUTHORISATION AND TO THE ETHICS

COMMITTEES FOR OPINION

Fill in and print this form from the OsSC website: https://oss-sper-clin.agenziafarmaco.it For official use by Competent Authority and Ethics Committee: Date of receiving the request |__|__|/|__|__|/|__|__|__|__|

Grounds for non acceptance /negative opinion Date |__|__|/|__|__|/|__|__|__|__|

o

Date of start of procedure |__|__|/|__|__|/|__|__|__|__|

Authorisation / favourable opinion Data |__|__|/|__|__|/|__|__|__|__|

o

Registration number or equivalent Withdrawal of amendment application Date |__|__|/|__|__|/|__|__|__|__|

o

To be filled by the applicant: APPLICATION FOR AUTHORISATION TO THE COMPETENT AUTHORITY o REQUEST FOR OPINION TO THE ETHICS COMMITTEE o The investigational medicinal product is used along with a medical device YES |__| NO |__| If YES, the medical device is made in EC YES |__| NO |__| If it is not branded EC, the relative authorisations which regulate the trials of medical devices have been obtained YES |__| NO |__| In negative case, the Sponsor undertakes to obtain the authorisations before the trial starts. A. TRIAL IDENTIFICATION

A.1 EudraCT Number

A.2 Full trial title

A.3 Sponsor’s protocol code, version and date

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B. IDENTIFICATION OF THE SPONSOR RESPONSIBLE FOR THE REQUEST

B.1 Sponsor

B.1.1 Organisation

B.1.2 Name of person to contact

B.1.3 Address

B.1.4 Number of telephone

B.1.5 Number of fax

B.1.6 E-mail

B.2 Legal representative1 of the sponsor in the EU for the purpose of this trial (if different from the sponsor)

B.2.1 Organisation

B.2.2 Name of person to contact

B.2.3 Address

B.2.4 Number of telephone

B.2.5 Numbero of fax

B.2.6 E-mail

B.3 Status of the sponsor

B.3.1 Profit o

B.3.2 Non profit o C. APPLICANT IDENTIFICATION

C.1 Sponsor o

C.2 Person or organisation authorised by the sponsor to make the application o

C.3 Complete the details of the applicant below:

C.3.1 Organisation

C.3.2 Name of the contact person

C.3.3 Address

C.3.4 Number of telephone

C.3.5 Number of fax

C.3.6 E-mail

1 As stated in article 20 of Legislative Decree 211/2003.

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D. SUBSTANTIAL AMENDMENT IDENTIFICATION

D.1 Substantial amendment code, version and date

D.2 Type of substantial amendment

D.2.1 Amendment to information in the CT application form yes o no o

D.2.2 Amendment to the protocol yes o no o

D.2.3 Amendment to other documents appended to the initial application form

yes o no o

D.2.3.1 If yes, specify:

D.2.4 Amendment to other documents or information yes o no o

D.2.4.1 If yes, specify:

D.2.5 This amendment concerns mainly urgent safety measures already implemented

yes o no o

D.2.6 This amendment is to notify a temporary halt of the trial yes o no o

D.2.7 This amendment is to request the restart of the trial yes o no o

D.3 Reasons for the subs tantial amendment

D.3.1 Changes in safety, rights, well-being or integrity of trial subjects yes o no o

D.3.2 Changes in interpretation of scientific documents/value of the trial yes o no o

D.3.3 Changes in quality of IMP(s) yes o no o

D.3.4 Changes in conduct or management of the trial yes o no o

D.3.5 Change of principal investigator(s), coordinating investigator (multiple trial)

yes o no o

D.3.6 Change of sponsor, legal representative, applicant yes o no o

D.3.7 Change in transfer of major trial related duties yes o no o

D.3.7.1 If yes, please specify:

D.3.8 Other change yes o no o

D.3.8.1 If yes, please specify:

D.4 Information on temporary halt of the trial

D.4.1 Date of temporary halt |__|__|/|__|__|/|__|__|__|__|

D.4.2 Recruitment has been stopped yes o no o

D.4.3 Treatment has been stopped yes o no o

D.4.4 Number of patients still receiving treatment at time of the temporary halt

D.4.5 Justification for the temporary halt of the trial

D.4.5.1 Safety yes o no o

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D.4.5.2 Lack of efficacy yes o no o

D.4.5.3 Other, specify:

D.4.6 Briefly describe (free text): § Justification for a temporary halt of the trial § The proposed management of patients receiving therapy at time of the halt

(free text) § Evaluation of the consequences of the temporary halt for the evaluationof

the results and for overall risk benefit assessment of the IMP (free text)

E. BRIEF DESCRIPTION OF THE PROPOSED AMENDMENT (free text)

F. BRIEF DESCRIPTION OF THE CHANGES (free text)

G. CHANGE OF THE INVESTIGATOR (coordinating or principal) / CLINICAL SITE

G.1 Type of substantial amendment

G.1.1 Change of the coordinating investigator (provide the details of the new coordinating investigator and of the clinical site where he/she works)

G.1.1.1 Name

G.1.1.2 Family name

G.1.1.3 Qualifications

G.1.1.4 Address of the clinical site

G.1.1.5 Ethics Committee of competence

G.1.1.6 Name and family name of the previous coordinating investigator

G.1.2 Change of the principal investigator of a clinical site

G.1.2.1 Name

G.1.2.2 Family name

G.1.2.3 Qualifications

G.1.2.4 Address of the clinical site

G.1.2.5 Name and family name of the previous coordinating investigator

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H. CHANGE OF INSTRUCTIONS FOR FEEDBACK FROM EUDRACT REGISTRY 2

H.1 Change of e-mail contact for feedback on application yes o no o

H.1.1 Change to request to receive an .xml copy of CTA data saved on EudraCT registry

yes o no o

H.1.1.1 If yes, provide the e-mail address(es) to which it should be sent (up to 5 addresses)

H.1.2 Specify if you want to receive this via password protected link(s)3 yes o no o

If you selct no to item H.1.2 the .xml file will be trasmitted by less secure e-mail link(s)

H.1.3 Specify if you want to stop messages to an email for which they were previously requested

yes o no o

H.1.3.1 If yes, provide the e-mail address(es) to which feedback should no longer be sent:

I. LIST OF THE DOCUMENTS APPENDED TO THE AMENDMENT APPLICATION

FORM

Please submit only relevant documents and/or when applicable make clear references to the ones already submitted. Make clear references to any changes of separate pages and submit old and new texts. Tick the appropriate box(es).

I.1 Covering letter stating the type of amendment and the reason(s) o

I.2 Summary of the proposed amendment o

I.3 List of modified documents (identity, version, date) o

I.4 If applicable, pages with previous and new wording o

I.5 Supportive information o

I.6 Comments on any novel aspect of the amendment if any o

2 This function depends on the EudraCT Registry. 3 This requires a EudraLink account (see http://eudract.emea.europa.eu/ for details).

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L. SIGNATURE OF THE APPLICANT

L.1 I hereby confirm that/confirm on behalf of the sponsor that: § The above information given on this request is correct; § The trial will be conducted in according to the protocol, national regulation

and the principles of good clinical practice; § It is reasonable for the proposed amendment to be undertaken.

L.2 Applicant of the request

L.2.1 Date |__|__|/|__|__|/|__|__|__|__|

L.2.2 Signature

L.2.3 Name

L.2.4 Family name

page 1 of 2

Appendix 10

FORM FOR DECLARING THE OPENING/ WITHDRAWAL OF A SINGLE CLINICAL

SITE

Fill in and print this form from the OsSC website: https://oss-sper-clin.agenziafarmaco.it To be filled in by the applicant: A. TRIAL IDENTIFICATION

A.1 EudraCT number

A.2 Full title of the trial

A.3 Sponsor’s protocol code, version and date B. CLINICAL SITE IDENTIFICATION

B.1 Name

B.2 Address

B.3 Ethics Committee of competence

B.4 Principal investigator identification

B.4.1 Name

B.4.2 Family

B.4.3 Qualification (MD, .…………… ……) C. APPLICATION WITHDRAWAL IN A COLLABORATING SITE(where applicable)1

C.1 The applicant has withdrawn the application before obtaining the opinion of the Ethics Committee

yes o no o

1 The application withdrawal has to be notified when the applicant intends to withdraw the application in a collaborating site. If the

applicant has not the intention of going on with the trial in all the clinical sites, including the site where the Ethics Committee is responsible for the single opinion, the applicant has not to fill in this section but it has to use the function “Ritiro delle richieste di valutazione” (Withdraw the requests of assessment) available in Osservatorio.

- Appendix 10 -

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D. CLINICAL SITE OPENING2

(to be filled in only if the Ethics Committee has approved the trial)

D.1 The clinical site has been opened yes o no o

D.1.1 If yes, specify:

D.1.1.1 Opening date |__|__|/|__|__|/|__|__|__|__|

D.1.1.2 Date of the authorisation of the Competent Authority or of the expiry of the deadline for silence-assent, where applicable

|__|__|/|__|__|/|__|__|__|__|

D.1.1.3 Date of contract signing between sponsor and clinical site, where applicable

|__|__|/|__|__|/|__|__|__|__|

D.1.2 If not, specify:

D.1.2.1 Reason for the non-opening of the site

D.2 First subject has been enrolled (signature on informed consent) yes o no o

D.2.1 If yes, specify the date |__|__|/|__|__|/|__|__|__|__|

D.3 Number of subjects expected in the site

2 To be filled in within 30 days from the opening of the site. A site is intended ”opened” after authorisation and favourable opinion

as well as the completion of the organisational procedures which allow the enrolment of patients.

page 1 of 2

Appendix 11

FORM FOR DECLARING THE END OF THE TRIAL IN A SINGLE SITE1

Fill in and print this form from the OsSC website: https://oss-sper-clin.agenziafarmaco.it To be filled in by the applicant: A. TRIAL IDENTIFICATION

A.1 EudraCT number

A.2 Full title of the trial

A.3 Sponsor’s protocol code, version and date B. CLINICAL SITE IDENTIFICATION

B.1 Name

B.2 Address

B.3 Ethics Committee of competence

B.4 Principal investigator identification

B.4.1 Name

B.4.2 Family name

B.4.3 Qualification (MD.…………… ……) C. TRIAL END

C.1 Date of end |__|__|/|__|__|/|__|__|__|__|

C.2 Type of conclusion

C.2.1 Regular end of the trial yes o no o

C.2.2 Premature ending of the trial If yes, please specify the reasons:

yes o no o

C.2.2.1 safety yes o no o

C.2.2.2 lack of efficacy yes o no o

C.2.2.3 premature completion of the enrolment yes o no o

1 To be filled in within 30 days from the end of the trial in the site (”end of the trial” refers to last patient’s last visit in the site

concerned, if not otherwise specified in the protocol). If no patient has been enrolled, ”end of the trial” refers to the date in which the applicant has formally closed the site (e.g. closure visit).

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C.2.2.4 difficulties in enrolment yes o no o

C.2.2.5 renuncia tion of the investigator yes o no o

C.2.2.6 other, specify:

C.3 End of the enrolment

C.3.2 Number of subjects enrolled in the site (included in the trial)

page 1 of 3

Appendix 12

FORM FOR DECLARING THE END OF A CLINICAL TRIAL ON MEDICINAL

PRODUCTS FOR HUMAN USE TO THE COMPETENT AUTHORITY AND THE ETHICS COMMITTEE1

Fill in and print this form from the OsSC website: https://oss-sper-clin.agenziafarmaco.it For official use by Competent Authority and Ethics Committee:

Registration number or equivalent :

Date of receipt: |__|__|/|__|__|/|__|__|__|__|

To be filled in by the applicant: DECLARATION FOR AIFA / COMPETENT AUTHORITY (to be notified via mail in the appropriate cases1)

o

DECLARATION FOR ETHICS COMMITTEE (to be notified via mail in the appropriate cases1)

o

A. TRIAL IDENTIFICATION

A.1 EudraCT number

A.2 Full title of the trial

A.3 Sponsor’s protocol code, version and date

1 To be notified via mail: a) to AIFA (Italian Agency of Medicines), in all the cases; b) to the Competent Authorities, of each single

clinical site, who have authorised the trial or to ISS (Istituto Superiore di Sanità, when competent Authority) as well as to the Ethics Committees concerned, in the cases of early conclusion or an interruption following a temporary halt.

- Appendix 12 -

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B. APPLICANT IDENTIFICATION

B.1 Sponsor o

B.2 Person or organisation authorised by the sponsor to make the application o

B.3 Legal representative of the sponsor in the EU for the purpose of this trial o

B.4 Complete below

B.4.1 Organisation

B.4.2 Name of person to contact

B.4.3 Address

B.4.4 Telephone number

B.4.5 Fax number

B.4.6 E-mail

C. END OF TRIAL

C.1 Date of the end of the trial in Italy 2 |__|__|/|__|__|/|__|__|__|__|

C.1.1 End of the enrolment (date of the enrolment of the last patient)

|__|__|/|__|__|/|__|__|__|__|

C.1.2 Number of subjects (included in the trial) enrolled in Italy

C.2 The end of the complete trial in all countries concerned yes o no o

C.2.1 Date of the complete trial (or expected date) |__|__|/|__|__|/|__|__|__|__|

C.3 Premature ending of the trial yes o no o

C.3.1 If yes, give the date: |__|__|/|__|__|/|__|__|__|__|

C.3.2 Reasons of the premature ending:

C.3.2.1 Safety yes o no o

C.3.2.2 Lack of efficacy yes o no o

C.3.2.3 The trial has not commenced yes o no o

C.3.2.4 Definitive revoke of the authorisation by AIFA yes o no o

C.3.2.5 Definitive revoke of the authorisation by ISS yes o no o

C.3.2.6 Definitive revoke of the single opinion yes o no o

C.3.2.7 Other yes o no o

2 With “end” is meant the last patient’s last visit, if not otherwise specified in the protocol.

If no patient has been enrolled, “end” refers to the date when the applicant has formally closed the last clinical site (i.e. closure visit). If the trial has never started, even though a favourable single opinion by the Ethics Committee and/or the authorisation by AIFA or ISS have been obtained, “end” refers to the date of the decision of the applicant to withdraw the trial in Italy.

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C.3.2.8 If “yes” to any of the above questions, describe:

C.3.2.8.1 the justification for premature ending of the trial (brief text)

C.3.2.8.2 number of patients still receiving treatment at time of premature termination and their proposed management (brief text)

C.3.2.8.3 the consequences of early termination for the evaluation of the results and for overall risk benefit assessment of the investigational medicinal product (brief text)

D. SIGNATURE OF THE APPLICANT

D.1 I hereby confirm that/confirm on behalf of the sponsor that (delete which is not applicable): § the above information given on this request is correct;

§ I will submit a summary of the final study through Osservatorio, as soon as available within a maximum 1 year deadline after the end of the study in all the participating countries.

D.2 Applicant for the Competent Authority /AIFA

D.2.1 Date |__|__|/|__|__|/|__|__|__|__|

D.2.2 Signature

D.2.3 Name

D.2.4 Family name

D.3 Applicant for the Ethics Committee

D.3.1 Date |__|__|/|__|__|/|__|__|__|__|

D.3.2 Signature

D.3.3 Name

D.3.4 Family name

- Appendix 13 -

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Appendix 13

ADVERTISING FOR TRIAL SUBJECTS ENROLMENT AND ADDITIONAL

PROCEDURES TO COMMUNICATE TO THE ETHICS COMMITTEES

This appendix is intended to provide guidance on items that might be relevant to consider when advertising for subjects who will be asked to participate in a clinical trial in compliance with section 6.1.2.4 of Attachment 2. Yet, the items listed do not comprise a complete list and could be modified according to the type of trial. ADVERTISING FOR TRIAL SUBJECTS ENROLMENT

All advertisements for trial subjects have to be included in the submission documents and application to the Ethics Committee.

The advertisements might contain information on the following topics:

1. the research nature of the project; 2. the scope of the trial; 3. type/group of subjects to be included; 4. the investigator responsible for the trial; 5. the person to contact for information (specify name, address, qualification,

organisation and address); 6. the possibility of registration for the responding subjects; 7. the procedure to contact the interested subjects; 8. any possibile compensation for expenses in the cases expected; 9. the clarification that the response to the advertisement on the part of a potential subject

only signifies interest to obtain further information. ADDITIONAL PROCEDURES TO BE COMMUNICATED TO THE ETHICS COMMITTEES

In addition to the copies of the advertising to be distributed, information should be provided to the Ethics Committees on the procedures to handle the answers to the advertisement as well as on the procedures to provide information to and take care of those patients not suitable for inclusion in the planned trial. If there is a screening procedure to evacuate the suitability of the respondent two different information leaflet might be used: § a leaflet providing information about the procedures and the screening methods explaining

what the consequences might be in case of a certain outcome of the screening (for example, in case of exclusion following a diagnostic exam, there might be a description of how the patient will be given therapy or care);

§ a leaflet providing detailed information on the trial according to the usual requirements; In the only case of healthy volunteers, the procedures providing a compensation for loss of earning should be described; as for the patients, only in the cases provided in section 6.1.2.8 of Attachment 2, the procedures for reimbursement of the expenses and its amount should be described. In addition, the sponsor should describe the procedure for informing the subject responding the advertisement on how he/she may be eliminated from the register as of section 6.

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Appendix 14

SUBJECT INFORMATION CONTENT

This appendix is intended to provide further guidance on items that might be of relevance for the subject information leaflet according to section 6.1.2.5 of Attachment 2. It is not intended to provide a complete list of items which should be included, but to give some examples of items that might be considered if relevant. 1. Trial specific and genera l explanatory information to subjects. In order to improve the comprehension of subjects involved in a clinical trial, it might be useful to divide the information to be provided in two parts. 1.1 Trial specific information One part should contain the information necessary for the subject to decide whether or not to participate in the planned trial. To this purpose, the leaflet should state clearly the justification for the trial, its relevance and objective and should contain at least all the items listed in the specific section of Good Clinical Practice (section 4.8.10 of Attachment 1 to the Ministerial Decree 15 July 1997). In addition, written information should be provided on: § the names and addresses of the investigator, study nurse who are responsible for taking care

of the included subjects; § any planned procedures for follow up after the end of the trial (for example for trials

involving gene transfer medicinal products) and/or plans for additional care that might be needed due to findings during follow up;

§ the positive opinion of the Ethics Committee.

1.2 General information on clinical trials (privacy, insurance). The second part should contain general information rather than trial specific information necessary to guarantee the rights, the well-being and the safety of the subjects involved in a trial. Therefore, this section should contain a description of: § the subject’s rights to privacy and the means taken to ensure protection of personal data

according to current regulations;

- Appendix 14 -

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§ the right of the subject (or parent or legal representative) to obtain updated information

about what is recorded as well as the right to require corrections of errors; § the fact that in the event of the withdrawal of consent to participate in the trial, no new data

will be added to the database and that, according to current provisions, the subject (or parent or legal representative) may require all previously retained identifiable samples to be destroyed to prevent further analysis;

§ the right of the subject (parent or legal representative) to be informed of any plans for new

analyses on retained identifiable material that were not foreseen when the subject consented to participate in the trial. In this case the investigator might have to ask for new consent and the subject has the right to refuse further analyses;

§ the reasons for source data verification of the trial;

§ the provisions for compensation in case of injury to the subjects caused by procedures

connected with the trial, in order to cover the liability of the sponsor and the investigator. 2. Information in pharmacogenetic trials In clinical trials where genetic testing is included, this has to be clearly explained to the subjects. The information should give the background and purpose of the genetic tests, the planned analyses and whether the samples will be kept to make future analyses possible in conjunction with planned project. Where applicable, information about the genetic part of the trial might be separate form the information on the other part. The subjects should be informed on the possibility to abstain from the genetic testing but still be able to participate in the non-genetic part of the trial. In addition, the subjects should express their will of obtaining any critical information for their health conditions, coming from the outcomes of pharmacogenetic studies.

page 1 of 2

Appendix 15

PUBLIC DECLARATION OF INTERESTS AND CONFIDENTIALITY UNDERTAKING

BY THE INVESTIGATOR

First name (block letters) ………………………………………………………………………….

Family name (block letters) …...………………………………………………………….………….

Qualification ………………………………………………………………………….

Organisation …………………………………………………………………………. Employment in a pharmaceutical company over the last 5 years1: List each possible interest in the pharmaceutical industry (use additional forms, if necessary) ………………………………………………………………………………………………………… ………………………………………………………………………………………………………… ………………………………………………………………………………………………………… § Financial interests in a pharmaceutical company:

- Name of the company: ………………………………………………………………… - Type of share: ….…………………………………………...…………………. - Number of shares: .…………………………………………………………………………

§ Other relationships with the pharmaceutical industry2:

…………………………………………………………………………………………………….. …………………………………………………………………………………………………….. …………………………………………………………………………………………………….. ……………………………………………………………………………………………………..

Any other interests or facts that should be made known to the public, including elements relating family members (family members are: the spouse, the partner, children dependent on the person concerned): (it is not necessary to provide the names of these persons) ………………………………………………………………………………………………………… …………………………………………………………………………………………………………

1 All the activities performed (directly or indirectly) for pharmaceutical companies (or on their behalf; in this case, specify the role

and the activities performed, the name of the product, and the type of the activity performed) whether these activities have required regular or occasional compensation in money or in kind, among which:

§ participation in a decision-making process in a pharmaceutical company (e.g. member of the board of directors, participation in

the executive or non executive management); § employ of a pharmaceutical company with a permanent or a temporary contract. Other activities performed in a pharmaceutical

company must be declared (e.g. training). § consulting or other type of activities let out on contract by pharmaceutical companies.

2 Each type of assistance and support received by the industry during the previous 5 years, including financial or material benefits, direct or indirect, such as grants or research funding fellowship or sponsorships subsidized by the pharmaceutical industry.

- Appendix 15 -

page 2 of 2

I do hereby declare that, to the best of my knowledge, the only direct or indirect interests I have in the pharmaceutical interests are those listed above. Should there be any new or additional interests to be made known to the public, I shall promptly complete a new declaration of interests detailing the changes. Signature……………………….… Date………….…………………………