Agenzia Italiana del Farmaco

Summary of the administrative procedures to conduct a clinical trial.

Submission of Clinical Trial Application data.

Ethics Committee opinion and financial agreement.

List of documents required for Clinical Trial Application.

1. Submission of Clinical Trial Application data

Submission of the clinical trial application data and supporting documents must be done through the National Clinical Trials Database (Osservatorio – OsSC). The sponsor must submit these data mainly in Italian except for some fields where English language is required. Information required are compliant with the Appendix 5 of the Ministerial decree 21st December 2007 "Modalità di inoltro della richiesta di autorizzazione all'Autorità competente, per la comunicazione di emendamenti sostanziali e la dichiarazione di conclusione della sperimentazione clinica e per la richiesta di parere al comitato etico" (available at this link: https://oss-sper-clin.agenziafarmaco.it/normativa/direttive_OsSC-000097-000096.pdf).

CTA application, printed from the OsSC database, and supporting documents must be submitted to the local Competent Authorities and Ethics Committee concerned.

Both electronic and paper submission are maintained for the moment.

To access the OsSC, the sponsor/C.R.O. should obtain an user ID/password.
To request the user ID/password, it is necessary to connect with the web-site here below and follow the instructions:

https://oss-sper-clin.agenziafarmaco.it/index_ingl.htm

The registration of the trial data and documents within the OsSC complies with the Italian and European requirements (EudraCT DB) for Clinical Trial electronic data transmission to the Competent Authority.

Blank copies of the CTA form to apply for authorisation and Ethics Committee opinion are available in the OsSC (direttive_OsSC-000097-000096.pdf).

A complete printable Clinical Trial Application form can be obtained via the OsSC.

Substantial amendments data can be entered into OsSC since 2^nd July 2008.

The OsSC database is required to be updated as additional information becomes available. For example, the sponsor/ C.R.O. is required to enter initiation and closure data for each Italian clinical site and closure data of the trial as a whole in Italy.

2. Competent Authority authorisation

2.1 The Italian Medicines Agency – AIFA - is the Competent Authority for clinical trials with gene therapy, somatic cells therapy and IMPs containing GMO.
Paper application and supporting documents can be sent to the following address:

Agenzia Italiana del Farmaco - AIFA
Ufficio Ricerca e Sperimentazione
Via del Tritone, 181
00187 Roma - Italy
E-mail: sperimentazione.clinica@aifa.gov.it

2.2 The National Institute of Health (Istituto Superiore di Sanità - ISS) is the Competent Authority for phase I clinical trials.
Further information and contact details are available at the following web-site: http://www.iss.it/scf1/serv/cont.php?id=22&lang=1&tipo=3
Paper application and documents have to be sent to the following address :

Istituto Superiore di Sanità
Dipartimento del farmaco
V.le Regina Elena, 299
00161 Roma - Italy
E-mail: segreteria.commac@iss.it

2.3 For all the other clinical trials, and namely, for those that are neither phase I trials nor trials testing gene/somatic cells/GMO therapies, authorisation has to be requested from the local Competent Authority of each clinical site (that is the legal Officer: i.e. director general of the Hospital). The legal Officer can authorise the trial within 60 days. If the legal Officer has not informed the applicant of any grounds for non-acceptance within 60 days, the trial is considered authorised, provided that the opinion of the Ethics Committee is favourable. Timeframe is reduced to 35 days for the authorisation/no grounds for non acceptance of any substantial amendment. Practically, the local Competent Authority is involved in administrative evaluation of the financial agreement. The local Competent Authority (the legal Officer of each clinical site) usually delegates the complete scientific assessment of the trial to the Ethics Committee of its facility.

The central Competent Authority (AIFA) performs only a marginal assessment of all the clinical trials employing therapies which do not fall within its competence (see section 2.1) involving only a check of the data before transmission to EudraCT database and a check of suspected serious adverse reactions (SUSARs). The assessment of the complete clinical trial application and documents is performed by accredited Ethics Committees
(https://oss-sper-clin.agenziafarmaco.it/consultazione_ce_pub.htm).

3. Ethics Committee opinion and financial agreement

In addition to obtaining competent authority approval, the sponsor needs to obtain:

the Ethics Committee’s approval (single opinion) at the clinical site of the coordinating/principal investigator. For a multi-centre trial, the acceptance of the single opinion by the Ethics Committee of each participating site is required.
where applicable, the financial agreement between the legal Officer of each clinical site, or a person appointed by him, and the trial sponsor.

4. Current Legislation Reference

The main current legislation references for clinical trials with medicines to be conducted in Italy are as follows:

- the Legislative Decree 24th June 2003 n.211, which has enforced into Italian regulations the principles of the European directive 2001/20. (It is available at: decreto_24062003_inglese.pdf);
- the Ministerial Decree 21st December 2007 for a more detailed guidance on practical aspects such as the request for authorisation and Ethics Committee's opinion, "Modalità di inoltro della richiesta di autorizzazione all'autorità competente, per la comunicazione di emendamenti sostanziali e la dichiarazione di conclusione della sperimentazione clinica e per la richiesta di parere al comitato etico." This decree transposes partially two Guidances of the European Commission:

"Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human", October 2005;
"Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion", February 2006.

5. Scheme of the procedure

CA = Competent Authority:
1)pursuant to current legislation, the Director-General or legal representative of the public health structures where the clinical trial is conducted, or equivalent facilities, as defined by decree no. 211;
2)the AIFA in the cases of > Phase I clinical trials involving medicinal products for gene therapy, somatic cell therapy (including xenogenic cell therapy) and all medicinal products containing genetically modified organisms (GMOs);
3) the National Health Institute (ISS, Istituto Superiore di Sanità) in the cases of newly introduced drugs referred to in the Presidential decree no. 439 of September 21st, 2001 (all phase I studies).

6. List of supporting documents required for Clinical Trial Application.

The documents enlisted above have to be submitted to the local Competent Authorities as well, provided that these have not delegated complete assessment to the Ethics Committees (coordinating and participating ones).
In the case of clinical trials falling within the competence of AIFA or ISS, finance related documents have not to be submitted with the application.

Part II
General frequently asked questions about the use of the OsSC.

Data access.
OsSC registration.
Data input.
The role of C.R.O.s within Osservatorio OsSC.
The connection with the European database - EudraCT.
Printing section.
Questions and answers concerning the ministerial decree 31st March 2008 regulating the CROs.

1. Data Access

1.1 Is OsSC a public database?
The OsSC database is a public and a private database. The public area does not allow entries to be made. The private area is accessible through a password, where information in relation to the clinical trial is entered and stored.

1.2 Who should register in order to access the private area?
The following bodies should register in OsSC:
with the profile of sponsor:

the sponsors of clinical trials or the applicants who operate on behalf of sponsors (Italian affiliates of pharmaceutical corporation):
1. pharmaceutical companies;
2. health facilities (such as Hospitals, Local Health Units, Universities, Scientific Associations, Foundations and so on) sponsoring no profit clinical trials;

with the profile of C.R.O.:

C.R.O.s – Contract Research Organizations – charged by the sponsors to enter the data into OsSC;

with the profile of Local Ethics Committees:

the technical-scientific secretariats of the Local Ethics Committees which release their opinion on clinical trials;

with the profile of ASL (Local Heath Unit):

the public local health facilities which have created the Registry of General Practitioners and General Paediatricians authorised to carry out a clinical trial in their consulting rooms; this register has to be updated every six months at least according to the Ministerial Decree of 10th May 2001;

Regions and autonomous provinces may request a new password or ask for changing the old one with the profile Regions in order to:

validate the data of the Ethics Committees accredited within their region (according to the Ministerial Decree 12^th May 2006);
consult the information of all the trials ongoing within the Region, the opinions of the Ethics Committees, the beginning of the trial, the possible early conclusion and regular conclusion as well as the data of the results and the possible interruption of the trial.

1.3 How can public be informed about the Local Ethics Committees recognised by AIFA (Italian Medicines Agency) able to release an opinion about a clinical trial?
Through consultation of the “Registro dei comitati etici” (Register of local Ethics Committees), available through the link “Dati” in the Home page. The Local Ethics Committees are sorted by region and town.

1.4 How can public be informed about whether a private clinical site has the requirements to participate in a multi-center clinical trial?
Through consultation of the “Registro dei centri privati” (Register of private clinical sites) established according to the Ministerial Decree n. 274, October 7^th 1998, available through the link “Dati” in the Home page.

1.5 How can public be informed about whether a Contract Research Organisation (C.R.O.) has the requirements to follow a clinical trial on behalf of a sponsor?
Through consultation of the list of the C.R.O.s satisfying the requirements according to the Ministerial Decree 31st March 2008, available through the link “Dati” in the Home page.

2. OsSC Registration

2.1 Is a password required to access the private area of the OsSC?
Yes, a password is necessary.

2.2.Who should request the password?
The legal officer for the body involved in a clinical trial at different levels (as a sponsor, CRO, Ethics Committee, Local Health Unit for the update of the Register of General Practitioners and Paediatricians). The legal officer of the body should appoint a person in the organization responsible for entering the clinical trial data into the OsSC database according to what provided in the Ministerial decree of 21st December 2007.

2.3. Who issues user ID and password to access OsSC?
The Clinical Trial Office (Ufficio Sperimentazione Clinica) of the Agenzia Italiana del Farmaco – AIFA issues a user ID and password on request.

2.4. What is the procedure to request the password to access the OsSC
To request a password it is necessary to access the link "Nuovi utenti" (New users), available in the Home Page of the OsSC website. The appropriate, on-line form should be filled and printed through the function "Stampa questa pagina" (Print this page) then signed by both the legal officer of the organization and the person appointed to notify the information and sent to the Agenzia Italiana del Farmaco- AIFA. Following the print, the same on-line form has to be sent via web, selecting the button "Invia" (Send). Instructions are available in the link itself both in Italian and in English.

How to request a password

2.5 Should sponsors from countries external to the European Union, who intend to conduct clinical trials in Italy access the OsSC?
Yes, in order to obtain a password to access OsSC, sponsors external to EU should submit a password request with an attached declaration that the sponsor has established a legal representative in a Member State of the EU, according to article 20, section 1, of the Legislative Decree 211 of 24th June 2003.

2.6 When the person appointed to enter the data into the OsSC changes, is it necessary to obtain a new password?
Yes, in this case, the user enters the confidential database user ID and password through the link "Utenti abilitati", in the Home Page of the OsSC website; then in the section "Servizi" (Facilities) of the menu page fills in an on-line form for the request of changing the person appointed to enter the data. Instructions in English are available in the link itself. The old password will be cancelled.

2.7 How can the clinical trials sponsored by two different pharmaceutical companies be managed, within OsSC, after the merging of these companies into one company?
Each user ID and password of the two companies will be maintained active in the OsSC, in order to complete the data transmission relating to these clinical trials which have been sponsored by each of the two companies and have already commenced . A new password will be assigned, upon request, to the new company originated by the merging of the previous ones for the new trials.

3. Data input

3.1 Who inputs the data into the OsSC?
Clinical trial data should be inputted by:

sponsors, profit or no-profit, or the applicants delegated by the sponsors (Italian affiliated, CROs). They have to enter the initial Clinical Trial Application data, substantial amendments data, initiation and conclusion data for each single site and of the trial as a whole, in Italy and in the other countries, a synthesis of the results and references of possible publications;
local Ethics Committees (technical-scientific secretariats). They have to:
- enter the favourable/non favourable single and opinion data, acceptation/refusal of the favourable single opinion and opinion about the possible substantial amendments (section available since July 2008);
- update the Registry of local Ethics Committees.
AIFA, when Competent Authority, enters the authorization data (initial clinical trial application and possible subsequent substantial amendments) for clinical trials with gene therapy, somatic cell therapy, GMO drugs.
Istituto Superiore di Sanità - ISS, when Competent Authority, enters the authorization data (initial clinical trial application and possible subsequent substantial amendments) for phase I clinical trials.

3.2. What type of data should be entered into OsSC database?
The OsSC database collects:

the data relating the institution and composition of the Local Ethics Committees working in Italy, entered by Ethics Committees;
the data of initial CT application entered by sponsors or by the applicants delegated;
the data of any withdrawal of the initial CTA form before the expression of the opinion entered by the sponsor or the applicant appointed to this;
the data of the suspension of the decision about the opinion waiting for integrations or changes to the CTA form and supporting documents entered by Ethics committees;
the data of the opinions (single opinion and acceptance/refusal of single opinion) for each trial entered by Ethics Committees;
the data of AIFA authorisation/refusal/suspension for clinical trials with gene therapy, somatic cell therapy and GMO drugs entered by AIFA;
the data of ISS authorisation/refusal/suspension for phase I trials, entered by ISS;
the data of the initiation of the trial in each single clinical site entered by sponsors or by the applicants delegated;
the data for the request of authorisation of possible amendments, entered by sponsors or by applicants delegated (section available since July 2008);
the data of favourable or unfavourable opinion/authorisation of substantial amendments entered by Ethics Committees and AIFA/ISS for trials within their competence (section available since July 2008);
the data upon the regular conclusion of the trial in each single clinical site entered by sponsors or by applicants delegated;
the data of the completion, or possible early conclusion or interruption of the trial in Italy and as a whole, the synopsis of the results and references of eventual publications entered by sponsors or by applicants delegated;
the data of the private clinical sites accredited to conduct clinical trials with medicines entered by AIFA (Register of private clinical sites);
the data of general practitioners and paediatricians of the public national health service authorised to conduct clinical trials with medicines entered by the local health unit (Register of general practitioners and paediatricians).

3.3 Is it mandatory to enter clinical trials data?
Yes, it is mandatory as established in the Decree 25^th May 2000 “Trasmissione per via telematica dei dati inerenti le sperimentazioni cliniche” (Clinical trial data transmission via web) and in the Legislative Decree nr. 211, 24^th June 2003, article 11.

3.4 Should clinical trials data be inputted into OsSC before submitting the initial Clinical Trial Application and following possible substantial amendments to competent Authority and Ethics Committee?
Yes. The Ethics Committees responsible for giving their single opinion, or AIFA/ISS for the trials of competence, have to verify and validate that the CTA data and the attached documents have been entered into the OsSC database and that these are complete and consistent with the paper dossier received.

3.5 Is entering the clinical trials data into OsSC sufficient to obtain a printed application form to submit to competent Authority and Ethics Committee?
Yes, after entering the data into OsSC and saving them in the central database, they can be printed in the application form, with a cover. Once this has been signed by the applicant, this can be submitted to both the competent Authority and to the Ethics Committee.

3.6 Is entering the clinical trials data into the OsSC sufficient to obtain a printed request form in English language (Clinical Trial Application form) or in another language different from Italian to submit to the competent Authority of other Member States involved in the trial?
No, in this case, entering the data into OsSC is not sufficient. In order to make an application in English or in another language, it is necessary to use the web-facility available on the website EMA. This Clinical Trial Application form filled, printed, signed and sent to the competent Authority of the Member State involved, should be submitted also on CD-rom or floppy disk. Consequently, the competent Authority validates the clinical trial application and uploads its data in EudraCT database. Therefore, in this case, the sponsor has to enter the data twice: once into OsSC for Italy and once through the EudraCT web facility for the other Member States involved.

3.7 3.7. May the check list I.b (relating the supporting documents to be submitted to the collaborating Ethics Committees) be attached to the electronic CTA form?
No, the electronic CTA form includes the list I.a only, the list I. b should be submitted in the only paper version.

3.8 What is the procedure to follow when an applicant intends to withdraw a CTA form before receiving the single opinion of the coordinating Ethics Committee/authorisation of the central competent Authority (ISS or AIFA)?
The CTA form withdrawal has to be notified through the function “Ritiro della richiesta parere unico/autorizzazione” (Withdraw the request for single opinion/authorisation) available through the link “Richieste di valutazione della sperimentazione”. The application will be withdrawn in all the Italian clinical sites in which it has been submitted. Following the withdrawal of the application, the clinical trial data will be available in the section Progress report.

3.9 What is the procedure to follow when an applicant intends to withdraw a CTA form in a collaborating clinical site before receiving the opinion of the concerned Ethics committee?
The applicant must notify the coordinating Ethics committee of the withdrawal through the function “Ritiro della domanda” (Withdraw the application) available in the clinical sites list next to each site and select the site concerned. The reasons of the withdrawal must be specified.

3.10 May the Ethics Committees accept CT applications non compliant with the Ministerial decree 21st December 2007?
No, according to the current legislation (legislative decree 24th June 2003 n. 211 and the ministerial decree 21st December 2007):

the CT application must be submitted in compliance with the above mentioned decrees and the technical-scientific secretariat of each Ethics Committee has to accept it since 1st July 2008, when the ministerial decree enters into force;
the application has to submitted at the same time to all the Ethics committees participating a multicentre trial.

3.11 Is the technical-scientific secretariat of the Ethics committee responsible for checking the formal validity of the applications submitted and of the documents attached to it and to defer the Ethics Committee the assessment of the content and possible request of integrating documents during the board meeting?
According to the spirit of the ministerial decree 21 December 2007, the technical- scientific secretariat of the Ethics committee plays the key role of verifying that the application is complete with all the information necessary for a correct assessment by the Ethics committee during the board meeting. So, the secretariat may go into the documentation and request – if necessary – to integrate the application in order to make it valid, before the Ethics committee meets.

3.12 As for those clinical trials which have obtained a favourable opinion before the Ministerial decree 21^st December 2007 entered into force and which are submitted to the Ethics committees of the participating sites involved in the trial after that date, may the sponsor follow the old procedure in order to request opinion and authorisation?
No, since 1^st July 2008, the procedure to request the authorisation to the competent Authority and an opinion to the Ethics committee to conduct a clinical trial must be compliant with the ministerial decree 21^st December 2007, even though the procedure has begun before the above mentioned date.

3.13 Are the applicants required to notify AIFA the initiation of the trial the early conclusion, the withdrawal/interruption and completion in each single site and of the trial as a whole via mail, even though they have already sent these notifications electronically through the OsSC?
Applicants are required to notify AIFA only the conclusion of the trial as a whole, according to the ministerial decree 21^st December 2007. This can be made by printing the information data entered into OsSC according to the format contained in the Appendix 12 of the decree.

3.14 Upon initiation of the site, what specific information is required in the field "Data di apertura dello studio" (Date of trial initiation) of the electronic form to be filled?
The date of the initiation visit by the monitor or of the completion of all the procedures necessary, at the site, for the enrolment of patients is required to be entered in this form.

3.15 Upon conclusion of the trial in each single site, what specific information is required in the field "Data di chiusura dello studio" (Date of trial completion) of the electronic form?
It is required the date of the last patient's last visit at the site, if not otherwise specified in the protocol.

3. 16 In the electronic form to fill to notify the conclusion of the trial as a whole, what specific information is required in the field "Data di chiusura dello studio" (Date of trial closure)?
It is required the date of the last patient's last visit in the last clinical site participating in the trial, if not otherwise specified in the protocol.

3.17 Is it necessary to enter trial substantial amendment data into OsSC database?
Yes, it is. The section to collect the amendment data into the OsSC has been developed and published on line in two steps in July and in September 2008.

3.18. How to manage the clinical trial amendments in the OsSC system?
According to the ministerial decree of 21st December 2007, the amendments to a trial can be distinguished into substantial amendments and non substantial amendments (see sub-section 4.2 of the Attachment 1 to the above mentioned decree).
Since 2nd July 2008 the substantial amendments to the information contained in the CTA form and in documents attached may be entered into the OsSC after that a favourable single opinion has been given. Amendments information has then to be printed in a form as of Appendix 9 of the decree to be submitted for approval/ authorisation.
Since 9th September 2008 substantial amendments concerning:

Temporary halt of the trial;
Restart of the trial after a temporary halt;
Change of the coordinating investigator;
Change of the principal investigator of a participating site.

In the section of amendments a Guide for data entering is available (in English language also). In order to make non substantial amendments to the CTA form, sponsors have to send an e-mail to the help desk (ossc_help@cineca.it) and in carbon copy to AIFA (info_sperclin@aifa.gov.it).

How to manage the substantial amendments

3.19 How to change the CTA form data and the attached documents when the single opinion and/or the authorisation by ISS or by AIFA, if applicable, are not in the OsSC database?
Applicants may request the CINECA Help Desk for the re-opening of the electronic file. This opportunity must be considered an exception and adequate reasons must be given. The above mentioned procedure applies also to the substantial amendments submission.
In any case, applicants have to send an e-mail to CINECA Help Desk (ossc_help@cineca.it) and in carbon copy to the OsSC contact person for the Ethics Committee of the coordinating site and to the OsSC contact person for ISS or AIFA, when ISS or AIFA are competent Authorities.

3.20 Which data may be changed through the function “Richiedi una nuova e- query” (Request for a new e-query)?

The applicant may change an incorrect association clinical site/competent Ethics Committee - in the case of a collaborating site, even after the single opinion has been given.
The Ethics Committee may modify the name of a clinical site or may urge the applicant to select the appropriate competent Ethics Committee.

3.21 What is the correct procedure to change the CTA form and/or the attached documents, when the Ethics Committee responsible for the single opinion requires integrations or changes in collegiate session?
The Ethics Committee suspends its decision and enters the relating data into the OsSC database. This causes the re-opening of the CTA file and allows the applicant to make any possible changes in the CT application form. These amendments may concern the whole CT application.

3.22 How to manage the request of substantial amendments submitted by mail (transmission letter subsequent 17^th July 2008) after the implementation of the amendment section in the OsSC system?
The data of the substantial amendments submitted to competent Authorities and Ethics committees after the section has been implemented in the OsSC system must be entered into the OsSC and then printed in as of the Appendix 9 of the decree 21^st December 2007.

3.23 What is required when entering the substantial amendment data to a trial in the OsSC proper section, recently developed?
A) As for the clinical trials data saved into the OsSC central database before 18th January 2008, the filling of the request of a substantial amendment e-form will cause a re-opening of the CTA form file and an empty button will be displayed besides some sections; this means that these sections were not part of the file at the time of initial entering the CTA form data and therefore should be completed when entering the amendment data, even though not referring to the amendment. This is required in order to complete the information added to the OsSC system in compliance with the decree 21st December 2007. It deals with the following sections:

medical devices form;
request of the CTA form file in xml version;
list of documents to attach (according to the on-line update in January 2008);
the form to collect information about the sites where the qualified person certificate butch release.

B) As for the clinical trials data saved into the OsSC central database since 18th January 2008, the filling of the request of a substantial amendment e-form will cause a re-opening of the CTA form file and a semi-full button will be displayed besides each single section; this means that the sponsor may enter all the sections of the file containing the information object of amendment to modify the data. For details in entering the data, it is available a Guide in the right margin of the OsSC page where the form is reported.

3.24 Should the letter of transmission of the amendment to upload in the OsSC, in attachment with the request of amendment, be signed?
If at the time of entering the amendment request data into the OsSC the letter signed is not available, this can be attached electronically even without signature, provided that the content is consistent with the paper version sent via mail.

3.25 How many copies of a substantial amendments request form and supporting documents should be submitted for approval?
The decree does not provide information about this, but by analogy with the initial CTA form, the maximum number of copies to be submitted in case of substantial amendments form ha been defined as 5 copies.

3.26 Does adding a new clinical site to the list of the participating sites in a multicenter trial - non substantial amendment - cause a change of the initial CTA form and its consequent submission to the Ethics committee?
The sponsor has to update the list of the participating sites in the OsSC database following with the usual procedure through the utility "Aggiungi centro alla sperimentazione già inviata in BD centrale" (Add a clinical site to clinical trial saved into the central database), afterwards the sponsor will simply notify the coordinating Ethics committee the amendment, attaching a copy of the CTA form modified to it.

3.27 Should scheduled and periodical updates of the Investigator's Brochure be considered as substantial amendments and therefore be submitted to the competent Authority and Ethics committee through the Appendix 9?
The periodical and scheduled updates of the Investigator's Brochure should be regarded case by case as substantial amendments according to the relevance of the elements modified and where they are likely to have a significant impact on:

the safety or integrity of the subjects;
the scientific value of the trial;
the conduct or management of the trial; or
the quality or safety of any IMP used in the trial.

As of consequence, the different procedures provide by the ministerial decree 21^st December 2007 will be followed for these amendments.

3.28 Is it mandatory to enter the data of clinical trials with medical devices?
No, only the data of clinical trials with investigational medicinal products (IMP) should be entered into OsSC. Yet, when the aim of the trial is that of investigating a medical device containing an investigational medicinal product, data transmission into the OsSC is mandatory.

3.29 Is it mandatory to enter the data of clinical trials in which medicinal products are not used?
No, as the purpose for this database is to collect clinical trial information for IMPs.

3.30 Does data of observational studies have to be entered into the OsSC?
No, data of observational studies have not to be entered into the OsSC database but in an appropriate register. This register (Register of Observational Studies – ROS), established according to a guideline issued by AIFA on 20th March 2008, is working from 16th February 2010. The above mentioned guideline is available in Italian in the section “Regulations” on the website of OsSC (https://oss-sper-clin.agenziafarmaco.it/normativa/direttive_OsSC-000099-000000.pdf). According to the Ministerial Circular n. 6, 2nd September 2002 “Attività dei comitati etici istituiti ai sensi del decreto ministeriale 18 marzo 1998” (Functions of Ethics Committees established according to the Ministerial Decree of 18th march 1998) the observational studies are those studies focusing on problems and pathologies for which drugs are prescribed according to the SmPC. Patients are not allocated according to a specific therapeutic strategy designed in the protocol but are treated according to the normal clinical practice.

3.31 Is it necessary to apply for a password in order to access to the Register of the Observational Studies (ROS)?
No, in order to access this register and enter the data of the studies the same keys (user ID and password) required to access OsSC can be used.

Please note: in the case of organisations which intend to manage observational studies in Italy, even though they are not established as sponsor/CRO (applicants) at the OsSC, new applications for user ID and passwords will be taken into consideration by AIFA. In this case, applications may not be made through the ordinary on-line procedure used to access OsSC but through an e-mail message.

4. The role of the CROs within Osservatorio (OsSC)

4.1 What a C.R.O has to do in order to act as an applicant on sponsor’s behalf within OsSC?
A C.R.O should apply for a password through the link “Nuovi utenti” (New users) in the Home Page of the website. Instructions in English are available. After a C.R.O. has obtained a password, it can be authorised by sponsors to perform all the functions of an applicant for a specific trial, through an OsSC on-line procedure. Each time a sponsor authorises a C.R.O. to enter the information of a clinical trial, the person responsible for data input receives an automatic e-mail message which notifies the authorisation.

4.2 Could the sponsor simply communicate its password to the C.R.O, in order to delegate the C.R.O. to act as an applicant?
No, this is not advisable because in this case the C.R.O. would access all the data of sponsor’s clinical trials.

4.3 What is the procedure which a sponsor has to follow to authorise a C.R.O. to act as an applicant for the clinical trial concerned?
The procedure to authorise a C.R.O. to act as an applicant is the following:

access the link “Autorizza/revoca C.R.O.” (Authorise/suspend C.R.O);
select the type of competent Authority (central one – AIFA, ISS - or local one connected with its Ethics Committee responsible for single opinion if multicentre trial);
enter clinical trial identification data: title, protocol code;
select the name of C.R.O. from the database containing the companies registered endowed with password;
specify the clinical site where the coordinating investigator works;
enter the collaborating clinical sites; in case the sponsor can leave this task to the C.R.O;
save the data into the central database (“Salva i dati in banca centrale”);
finally, the responsible C.R.O. receives an automatic e-mail message which notifies its authorisation procedure has been completed.

How to authorise a CRO

4.4. What kind of clinical trials information can be inputted by a C.R.O authorised by a sponsor to act as an applicant?
All the data which the sponsor should enter, and namely:

trial file data (CTA form, substantial amendment form);
any clinical trial application withdrawal;
trial start up data for each clinical site participating in the trial;
possible amendments data;
completion data for each clinical site participating in the trial;
completion data of the trial as a whole;
a summary/synopsis of the trial results;
references of publication of trial results, when applicable.

4.5 When a sponsor/applicant delegates its proper functions to a C.R.O., does it remain ultimate responsible for the completeness and the quality of the data submitted?
Yes, it does.

4.6 May a sponsor enter, modify or update some data through the e-query system after authorising a C.R.O. to do it?
No, after a sponsor has authorised a C.R.O. to act as an applicant, it cannot intervene in data input but only view the data or suspend the authorisation issued to the C.R.O.

5. The European Clinical Trial Database - EudraCT

5.1 What is EudraCT?
EudraCT is a database of all clinical trials with medicines commencing in the European Union from 1^st May 2004 onwards. It has been established at the European Medicines Agency in accordance with Directive 2001/20/EC. This database is confidential and accessible only to the Competent Authorities of the Members States, the EMA and the Commission.

5.2 Should the data of clinical trials carried out in Italy be entered into both the Italian database OsSC and EudraCT?
No, entering the data into OsSC is enough. From the Italian database OsSC, the data of clinical trials commenced from 1^st May 2004 are transferred into EudraCT.

5.3 What is the EudraCT number?
It is a unique number issued free on request by the EudraCT site http://eudract.ema.europa.eu/ or through the OsSC and it is for providing a unique reference for clinical trials involving at least one site of the European Union.

5.4 How to apply for a EudraCT number?
Applicants can request a EudraCT number at the site http://eudract.ema.europa.eu/ or at the OsSC website through the link “Servizi” (“Utilities”) and “Richiesta numero EudraCT” (“Apply for a EudraCT number”) in the menu. Instructions are also available in English.

How to request a EudraCT number

5.5 In case of multinational companies, should the sponsor of a clinical trial ongoing in Italy also (sponsored by the Italian branch) request two EudraCT numbers?
No, the EudraCT numbers issued by the system are unique. The sponsor should obtain only one EudraCT Number per protocol irrespective of the number of trial sites or Member States in which the trial is performed and then communicate it to the Italian branch.

5.6 Is a EudraCT Number required for an international clinical trial commenced prior to 1^st May 2004 and for which a new application will be made in Italy after 1^st May 2004?
Yes, the EudraCT Number is actually a mandatory field in the OsSC database.

5.7 Is it necessary to obtain the EudraCT number before an amendment of an international clinical trial begun in Italy before 1^st May 2004 and whose data have been already entered into the OsSC?
No, it is not necessary.

5.8 If the trial is cancelled and the issued EudraCT number is no longer required what action has to be taken?
No action is required. The EudraCT number must not be-reused. A new EudraCT number is required upon submission of a new application. An unused EudraCT number remains available on the system linked to the sponsor’s protocol number.

5.9 If more than one EudraCT number is inadvertently requested for the same trial must the requestor inform the EMA or System Administrator?
No, that is not necessary. The number that is not required should not be used.

6. Printing section

6.1 What has the applicant (sponsor, sponsor’s Italian affiliated company, C.R.O. delegated) to print of all the data entered into the OsSC database?
The applicant, after entering the data, has to print directly from the OsSC database:

the CTA form as in Appendix 5 to the decree 21^st December 2007;
the request of authorisation/opinion about possible substantial amendments as in Appendix 9 of the above mentioned decree;
the declaration of completion of the trial as in Appendix 12 of the above mentioned decree.

6.2 Who signs the forms filled and printed from the OsSC database?
The sponsor or the applicant appointed to this.

6.3 Has the CTA form to be submitted to the Ethics committee with the signature of the applicant in original?
To clarify what provided in the section 4.1.3 of the Attachment 1 of the decree of 21^st December 2007, it has been established that the applicant's signature on the CTA form must be in original on at least one of the five copies to be sent to the Ethics committee of each clinical site.

6.4 To whom must the signed forms be sent?
The initial CTA form and the substantial amendment request form for authorisation/opinion must be sent to the competent Authorities and Ethics committees concerned. The form of notification of trial conclusion instead, must be sent to the competent Authorities and Ethics committees concerned only in case of early conclusion; it must be always sent to AIFA within 90 days since the conclusion (15 days in case of early conclusion).

6.5 What kind of information entered into OsSC database has the Ethics committee (technical-scientific secretariat) to print?
The technical-scientific secretariat of the Ethics committee, after entering the data, prints directly from OsSC:

the single opinion, (Appendix 6, ministerial decree 21st December 2007) or
the acceptation/refusal of the single opinion (Appendix 8 of the above mentioned decree);
the suspension of the single opinion (Form not available in the ministerial decree 21st December 2007);
the suspension of the acceptation/refusal of the single opinion (Form not available in the ministerial decree 21st December 2007);
the opinion on possible substantial amendments submitted.

6.6 Is it possible to print the opinion of the Ethics committees according to the format provided in the ministerial decree 21st December 2007?
Yes, in detail:

the single opinion form compliant with Appendix 6 of the above mentioned decree can be printed since 18 September 2008 and the acceptation/refusal of the single opinion as well;
the opinion on the possible substantial amendments can be printed directly from OsSC as well for all the requests made through OsSC after 17^th July 2008 (to this, the date of the transmission letter should be referred to).
the function of printing the suspension of the opinion is available since 10^th December 2008.

6.7 Who should sign the opinion forms as of the Appendixes 6 and 8 of the ministerial decree 21^st December 2007?
The president of the Ethics committee or a person appointed.

6.8 Who receives a signed copy of the opinion of the Ethics committee?
The applicant; AIFA in carbon copy but only the single opinion, both positive or negative.

6.9 6.9 May the opinions (single opinion, acceptation/refusal of single opinion, opinion on substantial amendments) edited through OsSC, according to the mandatory format provided in the ministerial decree 21st December 2007, take the place of the minutes of the Ethics Committee?
Yes, if this is provided by the internal rules of the Ethics committee.

7. Questions and answers concerning the ministerial decree 31st March 2008
“Definition of the minimum requirements which Contract Research Organisations (CRO) shall satisfy in order to work within clinical trials on medicinal products.” (AIFAII/11029/P-I.9.a.b./85 – Roma, 4th February 2009).

7.1 Some activities delegated to a CRO could be performed by CROs which do not have a legal head office in the European Union: a sponsor of clinical international trials conducted in Italy could delegate CROs to perform some activities, such as the protocol drawing up or the statistical analysis of the data collected in the countries participating in the trial (Italy included). Therefore these CROs would perform the above mentioned activities in a Third Country (outside the European Union ) without a legal head office in a Member State of the European Union. Since the results of these trials could be used to support the request for a marketing authorisation in Italy, is a CRO working in a Third Country obliged to comply with the ministerial decree 31st March 2008 and to provide self-certification of the requirements according to the determination of 23rd December 2008?
The ministerial decree aims at having the sponsors of clinical trials conducted in Italy to delegate their functions only to organisations that satisfy the minimum requirements established. Therefore, the question is not whether the trial is directed towards a marketing authorisation request or whether the activities delegated by the sponsor are actually performed in Italy or abroad but whether these activities concern trials conducted in Italy. In this case, it is necessary that the CRO self- certificates and fulfills all the obligations prescribed by the decree. According to the GCP, the sponsor delegating a CRO to carry out the activities relating to the clinical trials, shall inform the foreign CRO about the regulations applicable in Italy.

7.2 Does this decree apply to the CRO working on non-interventional clinical trials as defined by the legislative decree no. 211/2003, article 2, section 1, letter c)?
No, in this case, it does not apply.

7.3 If an organisation different from the sponsor performs on sponsor’s behalf any activities correlating to tasks/functions which can be delegated to a CRO (such as clinical activities of Quality Assurance), is it obliged to self-certificate according to the ministerial decree 31st March 2008 and AIFA determination 23rd December 2008?
Yes, in this case the CRO is obliged to self-certificate.

7.4 Do the activities of external laboratory used in clinical trial (such as laboratories of analytical chemistry, clinical biochemistry, haematology, microbiology, histopathology, cytology, genetics and so on) fall within the process of self-certification in compliance with the ministerial decree 31st March 2008 and AIFA determination?
No, because this is not a function regulated by GCP as a function peculiar of the sponsor and, for this reason, it shall not comply with the prescriptions of the ministerial decree 31st March 2008.

7.5 When a CRO has the head office abroad, is it sufficient that the requirements established by the decree 31st March 2008 are satisfied at an international level?
Yes, on condition that the above mentioned requirements are used for functions performed in Italy; in this case it is sufficient that the CRO satisfies the requirements at a central level. It is important to remember that should the CRO not have an operating branch office in Italy, it is necessary that it has a legal representative in a Member State of the European Union, according to the article 8 of the above mentioned decree.

7.6 Who is obliged to follow annual refreshment courses in a CRO?
In compliance with article 3, section 1, letter c), point 1 of the decree, the whole personnel of a CRO has to follow 10 days at least of annual refreshment relating to all the activities performed within the CRO itself. In particular, the participation in internal training courses and in investigators’ meetings may be considered as a part of professional updating.

7.7 Which requirements should be satisfied by those who are going to begin the activity of monitor?
The requirements described in article 4, section 1, letters a), b), c), d) e) of the ministerial decree 31st March 2008.

7.8 Which requirements should be satisfied by an experienced monitor?
The requirements described in article 4, section 2 of the Ministerial decree 31st March 2008. The expression “experienced monitor” refers to a monitor who has performed this activity during the 30 months prior to the date of publication of the above mentioned decree and, namely, 110 days of documented activity of monitoring compliant with the section 5.18 of the Attachment 1 to the ministerial decree of 15th July 1997 (GCP). At least 50% of this activity should consist in visits in clinical sites. Therefore, a very experienced monitor who, for some reasons, has not performed at least 110 days of activity in the 30 months prior to the date of publication of this decree is obliged to comply with article 4, section 1 of the decree.

7.9 How should the personnel working in a CRO certify the satisfaction of the requirements established in the ministerial decree? Is self-certification allowed?
No, self-certification is not allowed. It is necessary to provide certificates and documents specifying dates and periods of training and work experience.

7.10 As for the new personnel engaged, which documents, within confidentiality limits, should be exhibited to certify the compliance with the requirements described in article 4, section 1, letters b), c) and d)?
The documents and certificates have to be prepared and signed by the persons responsible for curricular and work activities provided by the ministerial decree, and should contain specific references to the dates and periods of training and work experience.

7.11 Is a CRO which makes use of independent professionals (article 7, section 4) who work within the quality system of the CRO itself obliged to exhibit the requirements of these free-lance professionals in compliance with the ministerial decree 31st March 2008?
Yes, it is.

7.12 Which are the minimum requirements for protected registration (article 3, section 1, letter a), point 6)?
The minimum measures of security provided by the legislative decree n. 196/2003 (Privacy code) may be consulted in addition to the adequate measures provided in article 21 of the legislative decree 200/2007 in order to avoid the deterioration of documents.