Italian Ministerial Decree 15.11.2011
Aggiornamento: 31 ago
MINISTRY OF HEALTH
DECREE 15 November 2011
Definition of minimum requirements for Contract Research organizations (CROs) for pharmaceutical clinical trials.
Article 1. Scope
Article 2. Definitions
Article. 3 General minimum requirements
Article. 4 Requirements for monitoring activities
Article. 5 Requirements for auditing activities on trials or on experimental centers
Article. 6 Requirements for statistical analysis and data management
Article. 7 Operation and notification of requirements
Article. 8 Legal representation and liability of promoters
Article. 9 Method of transmission of information
Article. 10 Entry into force
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Article 1. Scope
1. This decree establishes the minimum requirements that private organizations, referred to in art. 20, paragraph 3, of the legislative decree of 24 June 2003, n. 211 must possess, or any other body to which the trial sponsor has entrusted some or all of the clinic trial responsibilities, which are defined in the following art. 2 contract research organizations (CROs).
Article 2. Definitions
1. For the purposes of this decree the following definitions apply:
a) Contract Research Organization (CRO): a company, an institution, or a private organization or any other body with which the trial Sponsor has established a contract or another form of agreement, to entrust some or all of its responsibilities in clinical trials (protocol drafting, center and investigator selection, monitor selection and use, report processing, statistical analysis, preparation of documentation to be submitted to the regulatory authority, etc.), such as provided by the Standards of Good Clinical Practice (GCP), without prejudice to the responsibilities of the trial Sponsor itself;
b) Standards of Good Clinical Practice (GCP): the standards referred to in attachment 1 to the ministerial decree of 15 July 1997 and as per legislative decree 6 November 2007, n. 200, referred to in the introduction;
c) The Promoter of the trial (Sponsor): a company, institution or body that takes responsibility for starting, managing, and possibly financing a clinical trial. A person or entity is also considered as Sponsor of a Clinical Trial who assumes the responsibility indicated above, and acts as the investigator at the facilities referred to in art. 1, paragraph 2, letter a) of the decree of the Minister of health 17 December 2004, limited to those cases regarding non-industrial (non-profit) clinical trials;
d) Monitor: the person who evaluates the progress of the study at clinical centers, to ensure research is carried out in compliance with the protocol, the Standard Operating Procedures (SOP), the applicable regulatory provisions, Good Clinical Practice Standards (GCP) and is responsible for the monitoring activities of the trial as required by annex 1 of the ministerial decree of 15 July 1997;
e) Quality assurance (QA): is the set of planned and systematic actions prepared to ensure:
1) that the studies entrusted to the CRO are conducted and that the data is produced, documented (recorded) and communicated in compliance to GCP and applicable regulatory provisions;
2) that for all activities conducted, the CRO meets the adequate quality requirements.
f) Verification or auditing: a systematic and independent control of the activities and documents pertinent to the study to determine whether the activities relating to the study/trial center, and whether the data has been recorded, analyzed and accurately transmitted in accordance with the protocol, the Standard Operating Procedures of the CRO and the Sponsor, to Good Clinical Practice (GCP) and to applicable regulatory provisions;
g) Verifier or Auditor: the person who assumes responsibility and the relative coordination of CRO activities related to auditing;
h) Medical or scientific director: the person who assumes technical-scientific responsibility and the relative coordination of CRO activities related to medical or scientific aspects;
i) Statistician: the person who assumes scientific technical responsibility and the relative coordination of CRO activities connected with statistical aspects;
l) Expert monitor: the person in possession of the requirements referred to in the following art. 4, paragraph 1 and 2 together with the requirements set out in paragraph 5 of the same art. 4;
m) Expert auditor: the person in possession of the requirements referred to in the following art. 5, paragraph 1 and 2 together with the requirements set out in paragraph 5 of the same art. 5;
n) Trial: a clinical trial of medicinal products so as defined by letter o) paragraph 1, of article 1 of the legislative decree 6 November 2007, n. 200.
Article 3. General minimum requirements
1. In order to operate, the CRO must satisfy at least the following general requirements:
a) Organizational and structural requirements. The CRO must possess:
1) a Constituent Instrument and Articles of Association, consistent with the objective of the CRO itself;
2) a list of the activities that the CRO will carry out and perform;
3) a functional organization chart and a nominal organization chart in which a responsible person is identified for each activity of the CRO;
4) an appointed medical director or scientific director with a degree respectively in medicine or in scientific disciplines related to the issues carried out by the CRO, with documented experience of at least two years in one or more medical or scientific fields of competence of the CRO;
5) a sufficient number of qualified personnel suitable for the foreseen activities;
6) appropriately structured operational headquarters to ensure the correct performance of the CRO's activities and the secure storage of confidential documents.
b) Quality requirements. There must be:
1) presence of standard operating procedures for the activities that the structure intends to carry out;
2) presence of a quality assurance system, set up and defined according to ISO standards, or equivalent, as well as a quality manual which is implemented and maintained;
3) documented quality assurance (QA) activities;
4) presence of a QA manager, with a university degree, documented experience of at least 1 year of practical activity in the sector and at least 15 days of theoretical training in the quality assurance field in general and specific to the activities of the CRO, carried out in the last two years; the QA manager must not coincide with the auditor on the same trials as specified in the following art. 5;
5) preparation and documented implementation of an annual training program for employees and consultants;
6) all CRO activities must be compliant with GCP;
7) adequate documentation system to ensure the traceability of all CRO activities.
c) Requirements for staff updating:
1) Personnel carrying out technical-scientific and quality control activities that the CRO is willing to perform, as well as the personnel referred to in paragraph 1, letter a), point 4), must receive updated training for at least 30 hours every 12 months on issues relating to the assigned functions. Administrative, financial, human resources and services staff in general are exempt from these training updates.
Article 4. Requirements for monitoring activities
1. If the CRO carries out monitoring activities, it must be appropriately staffed with personnel in possession of at least the following requirements:
a) a degree in health/scientific disciplines related to the issues to be carried out;
b) at least 40 hours of theoretical training carried out over the 12 months prior to the start of monitoring activities in relation to the following topics:
1) methodology and legislation of clinical trials;
3) standards of Good Manufacturing Practice (GMP) with specific reference to the investigational drug;
5) quality systems and quality assurance;
6) monitoring tasks referred to in paragraph 5.18 of Annex 1 to the ministerial decree of 15 July 1997;
c) at least 20 days of monitoring activities supporting an expert monitor, carried out in the 12 months before starting independent monitoring activities. At least 50% of the activities must be carried out on-site, during visits to the experimental centers before, during and after the conclusion of an experiment; the minimum number of days of supporting monitoring activities required for personnel with documented experience in coordinating monitor activities, through specific on-site activities carried out for at least 6 months in the 12 months preceding the start of the autonomous monitoring activity, is 5 days, of which at least 3 during on-site visits to the experimental centers;
d) at least 4 months of activity in the 12 months preceding the start of the autonomous monitoring activity, in the sectors of control and/or supervision of medicinal products and/or clinical trials; in alternative, further 40 days of activity referred to in letter c) carried out in the 12 months preceding the start of the autonomous monitoring activity; alternatively, a university master's degreeor equivalent postgraduate university degree in clinical trials or regulatory science or equivalent disciplines, in the previous 36 months before starting the autonomous monitoring activities;
e) specific training on the Monitoring trial objective.
2. Whoever, on the date of entry into force of this decree, has performed the functions of monitor of the trials referred to in paragraph 5.18 of attachment 1 to the ministerial decree of 15 July 1997, and is able to document this activity, is exempted from the possession of the requisites referred to in paragraph 1, letters a), b), c) and d) e may continue to perform his/her functions.
3. The CRO must use Monitors which, in addition to the requirements referred to in paragraphs 1 and 2, who have received specific annual updates of no less than 30 hours on one or more of the following topics:
a) methodology and legislation in clinical trials;
c) GMP with specific reference to the investigational drug;
d) quality systems;
f) clinical-scientific topics relevant to the clinical trials;
g) other matters connected with the tasks to be carried out.
4. For monitoring trials or centers that use advanced technological systems, such as for example electronic data collection forms (e-CRF), it is necessary to provide evidence of having received suitable training and updates in this specific sector.
5. The Expert Monitor, as defined in art. 2, letter l), of this decree, is the person able to carry out autonomous activities of monitoring and that annually performs at least 15 days on monitoring visits.
6. For the monitor and the expert monitor, a justified interruption of activity does not result in loss of qualification. However, for the monitor only, in cases of justified interruption of more than twelve months, before the restarting autonomous monitoring activity, it is necessary to perform at least 2 monitoring visits supported by personnel with equivalent qualification for the same activities.
Article 5. Requirements for auditing activities on trials or on experimental centers
1. If the CRO carries out auditing activities on the experiments or experimental centers, it will have to be equipped with the related personnel possessing at least the following requisites:
a) possession of a degree or specialist degree, in health/scientific disciplines related to the health related matters to carry out;
b) at least 60 hours of theoretical training carried out over the twelve months prior to starting the auditing activities in relation to the following topics:
1) quality systems and quality assurance;
2) methodology and legislation of clinical trials;
4) standards of Good Manufacturing Practice (GMP) with specific reference to the investigational drug;
6) auditor duties referred to in paragraph 5.19 of the annex 1 to the ministerial decree of 15 July 1997;
c) at least 20 days of auditing activities supporting an experienced auditor, performed in the 12 months prior to starting autonomous auditor activity; this training must be carried out during on-site visits to the experimental centers for at least 50% of the total time;
d) at least 4 months of activity in the 12 months preceding the independent auditor activity start in quality assurance and/or quality control sectors or in pharmacovigilance of medicinal products or in clinical trial related topics; alternatively, an additional 40 days of activities referred to in point c) or 60 days of activity as a monitor carried out in the 12 months preceding starting autonomous auditing activities; alternatively, a post-graduate university master's degree or postgraduate school or equivalent postgraduate university degree in clinical trials or regulatory sciences o in equivalent disciplines, in the 36 months preceding the start of the autonomous auditor activity;
e) specific training on the trial being audited.
2. Whoever, on the date of entry into force of this decree, has performed the functions of trial Auditor referred to in paragraph 5.19 of attachment 1 to the ministerial decree of 15 July 1997, and is able to document this activity, is exempted from the possession of the requisites referred to in paragraph 1, letters a), b), c) and d) of this article and can continue to perform his/her functions.
3. The CRO must make use of Auditors who, in addition to the requisites referred to in paragraphs 1 and 2 of this article, receive annual specific updates of the duration of no less than 30 hours on one or more of the following subjects:
a) methodology and legislation in clinical trials;
c) GMP for the investigational drug;
d) quality systems;
f) clinical-scientific topics relevant to the clinical trial;
g) other matters connected with the tasks to be carried out.
4. For auditing of trials or centers that use advanced technological systems, such as for example electronic data collection forms (e-CRF), it is necessary to provide evidence of having received suitable training and updates in this specific sector.
5. The expert Auditor, defined by art. 2, letter m) of this decree, is the person able to carry out autonomous activities of audit and that annually carries out at least 12 audit days.
6. For the auditor and the experienced auditor, a justified interruption of activity does not result in loss of qualification. However, for the auditor only, in cases of justified interruption of more than twelve months, before the restarting autonomous auditing activities, it is necessary to perform at least 2 audit visits supported by personnel with equivalent qualification for the same activities.
7. Those who, on the date of entry into force of the ministerial decree of March 31, 2008, being in possession of the requisites provided within it, have carried out at least 1 audit visit, can continue this activity even if the degree they hold is not in health or scientific matters.
Article 6. Requirements for statistical analysis and data management
1. If the CRO carries out statistical analysis of data coming from clinical trials, it will have to be provided with a qualified statistician, in possession of at least the following requirements:
a) a degree in a statistical discipline or a discipline equivalent for the performance of their duties or a degree in one scientific discipline whose study plan includes adequate statistical training or a specialization university degree, a doctorate or a 1st or 2nd level master's degree in statistical disciplines;
b) at least two years of experience in the related field;
c) an annual update in the related field.
2. The data management activities must be carried out by qualified personnel and using suitable and validated software according to the provisions in GCP.
3. For the activities referred to in this article, the CRO must be equipped with adequate structures and IT systems to guarantee both physical and logical data security.
Article 7. Operation and notification of requirements
1. From the date of entry into force of this decree only CROs in possession of the requirements referred to in the previous articles can operate for experiments conducted on the Italian territory unless as provided in the following paragraphs.
2. Whoever, on the date of entry into force of this decree, anyone who has fulfilled the documented function of scientific director, or QA, pursuant to art. 3, can continue these functions even if not meeting the requirements provided in art. 3 of this decree.
3. Whoever, on the date of entry into force of this decree, performs the documented function of statistician referred to in art. 6, can also continue in the fulfillment of these functions if he/she is not in possession of the university qualifications required in art. 6, paragraph 1, letter a).
4. Professionals or operators who perform, within the scope of their own freelance consultancy activities which abide by a contract with the clinical trials promoter or with a CRO, must possess the same requirements provided by this decree for the fulfillment of these functions, and must operate within the quality system of such structures.
5. CROs which, on the date of entry into force of this decree, have already transmitted their requirements, are not required to submit them again and can continue to operate. CROs who, on the other hand, were formed after the ministerial decree of March 31st, 2008 came into force and have not yet provided for the registration in the National Observatory on Clinical Experimentation of Medicines (OsSC), must notify, within fifteen days from the date of entry into force of this decree, the possession of the aforementioned requirements by self-certification, drawn up in accordance with the provisions in the annexes to this decree, in order to continue to operate. The self-certification must be sent to the GCP Inspectorate and to the AIFA Research and Clinical Trials Office.
6. In the case of activation of new CROs following entry into force of this decree, the notification referred to in the above paragraph 5 must take place at least 30 days before the start of any activity.
7. The possession of the requisites referred to in this decree, notified pursuant to this article, may be subject to verification from the local regulatory authority AIFA, as part of the planned inspection activity as in art. 15 of the legislative decree of the 24th June 2003 n. 211 and from Chapters V and VI of the legislative decree n. 200 of the 6th November 2007.
8. CROs, pharmaceutical companies and promoters of clinical trials must release to employees and/or collaborators entitled to and who request it, all documentation certifying the activities carried out relating to the present decree.
Article 8. Legal representation and liability of promoters
1. Any CRO established outside Italy wishing to carry out activities in Italy must have legal representation in one of the Member States of the European Union and must meet requirements at least equivalent to those set out in this decree.
2. This Decree shall not exempt the promoters of trials who entrust CROs with part or all of their competences in the field of clinical trials from the responsibilities assigned to them by the existing rules and regulations on clinical trials.
Article 9. Method of transmission of information
1. The modalities for the transmission of information to AIFA follow the provisions of the aforementioned resolution of the 23rd December 2008 described in the introduction.
Article 10. Entry into force
1. This decree will be sent to the Court of Auditors for registration.
2. This decree replaces the ministerial decree of 31st March 2008 and enters into force on the fifteenth day following its publication in the Official Gazette of the Italian Republic.
Rome, November 15, 2011
The Minister: Fazio
Registered at the Court of Auditors on December 19, 2011 Control office on the acts of MIUR, MIBAC, Min. Health and Min. work, register no. 15, sheet no. 7
You can learn more about this important regulatory document in the Course in Italian:
The Decree is particularly implicated in INTERVENTIONAL STUDIES run on the Italian territory. If you are a foreign CRO, you cannot use freelance consultants either.
The decree does not apply to observational studies or studies with medical devices. For this reason, monitors operating for these types of studies do not have to have the specific requirements mentioned in the Ministerial Decree.
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