Scope of application 

The adoption in the Republic of San Marino of the Guidelines for Good Clinical Practice of Medicines and Good Clinical Laboratory Practice and the related methods of verification and dissemination of their knowledge are established.

Definitions

1. «Good clinical practice, Good Clinical Practice (GCP) or good clinical practice standards»: a set of internationally recognised ethical and scientific quality requirements that must be observed in the design, conduct, recording, reporting of the results of clinical trials involving human participants, as well as in order to ensure the reliability and verifiability of the results obtained;
2. «Good Clinical Laboratory Practice, Good Clinical Laboratory Practice (GCLP) or good clinical laboratory practice standards»: good clinical laboratory practice applies the principles established under Good Laboratory Practice (GLP) for the generation of data used in regulatory submissions relevant to the analysis of samples from a clinical trial. At the same time, it ensures that the objectives of the GCP principles are achieved. This ensures the reliability and integrity of the data generated by the analysis laboratories;
3. «CERS – Ethics Committee for Scientific Research»: an independent body, composed of healthcare and non-healthcare personnel, which is responsible for ensuring the protection of the rights and well-being of trial subjects and for providing public assurance of such protection, for example by expressing an opinion on the trial protocol, on the suitability of the trial investigators, on the adequacy of the facilities and on the methods and documents that will be used to inform the subjects and obtain their informed consent; which carries out the tasks referred to in Law 29 January 2010 n.34 and the Regulation adopted with Delegated Decree 17 January 2011 n.2;
4. «CRO – Contract Research Organization»: a company, an institution, or a private organization or any other body with which the promoter of the trial or other structure has stipulated a contract or has stipulated another form of agreement, to entrust to the same a part or all of its competences in the field of clinical trials (drafting of the protocol, selection of centers and investigators, selection and use of the monitor, preparation of reports, statistical analysis, preparation of documentation to be submitted to the regulatory authority, preparation of the quality system, etc.), as provided for by the Good Clinical Practice (GCP) Standards, without prejudice to the responsibilities of the promoter of the trial itself connected with the trial same;
5. «ICH – International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use»: is a project that brings together the authorities responsible for the regulation of drugs from different countries, including those of the EU, Japan and the USA and experts from the pharmaceutical industry to discuss the technical and scientific aspects of the registration of pharmaceutical products;
6. «Inspections»: carrying out on behalf of the Health Authority or regulatory authorities of other States an official inspection of documents, facilities, records, quality assurance systems and any other resources that the aforementioned authorities deem relevant for the purposes of verifying compliance with this law, the rules of good clinical practice and other rules in force in the field of clinical trials of medicinal products. The inspection may take place at the trial centre, at the facilities of the trial sponsor or at the contract research organisation facilities, or in other places deemed appropriate by the authority that orders them;
7. «Inspector/GCP Inspector»: a person with specific qualifications and experience responsible for conducting inspections to verify the conformity of the Trial Centres and trials with the rules of Good Clinical Practice and the rules in force in the field of trial;
8. «Sponsor»: a company, institution or body that takes responsibility for initiating, managing and, where appropriate, financing a clinical trial;
9. «Investigator»: a medical doctor or dentist qualified for the purposes of trials, responsible for carrying out the clinical trial in a given centre;
10. «Clinical trial»: any study on human beings aimed at discovering or verifying the clinical, pharmacological or other pharmacodynamic effects of one or more investigational medicinal products, or at identifying any adverse reactions to one or more investigational medicinal products, or at studying their absorption, distribution, metabolism and excretion, with the aim of ascertaining their safety or efficacy, as well as other elements of a scientific and non-scientific nature, carried out in a single centre or in multiple centres, in the Republic of San Marino or even in other countries.

Adoption of Good Clinical Practice Guidelines

Clinical trials of medicinal products conducted in the territory of the Republic of San Marino must comply with the “Guidelines for Good Clinical Practice in the Conduct of Clinical Trials of Medicinal Products”, adopted in the integrated version of 10 November 2016 by the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and defined in the original text as “ICH – Harmonised Guideline Integrated Addendum to ICH E6(R1): Guideline For Good Clinical Practice E6(R2)” (hereinafter GCP), reported in Annex 1 in the original English text and in the Italian text.
Good clinical practice is a set of internationally recognized requirements regarding quality in the ethical and scientific fields, which must be observed for the purposes of designing, conducting, recording and communicating the results of clinical trials involving human beings. Compliance with good practice guarantees the protection of the rights, safety and well-being of subjects and ensures the credibility and verifiability of the data concerning the clinical trial itself.
All phases of the clinical trial, including bioavailability and bioequivalence studies must be designed, conducted and their results reported in accordance with GCP.
The results of trials conducted in breach of the rules of good clinical practice (GCP R2) are not taken into account for authorization purposes. 

Inspections and Audits

In order to verify the compliance of trials with good clinical practice, inspections may be carried out in one of the following situations:

1. before, during or after the conduct of clinical trials;
2. in the context of the verification of applications for marketing authorization;
3. in the context of the verifications following marketing authorizations.

The inspections are provided for by an inspection program prepared by the inspector responsible for inspection activities and approved by the Health Authority, taking into account any requests from the CERS and the health authorities. They may also be requested by the European Medicines Agency or by EU countries or other countries, with particular regard to trials relating to applications for marketing authorization, also as provided for in a memorandum of understanding with the European Commission that the Government is delegated to adopt, with a specific delegated decree.
The  inspections  are  conducted  in  the  places  affected  by  a  clinical  trial  and,  in particular, the center or centers where the trial is carried out, the analysis laboratories used during the trial and/or the premises of the trial promoter, as well as the structures involved in any phase of activity connected to the trials.
The inspections, by the required personnel, are carried out in compliance with the inspection guidelines, developed within the scope of the European Union, also in support of mutual recognition of findingsinspections in the same EU area, in accordance with what is to be provided for in the memorandum of understanding to be stipulated.
At the end of the inspection, a report is drawn up; the contents of the report must be communicated to the CERS, the promoter of the trial, the principal investigator, the Management of the healthcare facility concerned and the heads of the operational units concerned, safeguarding the confidential aspects. This report, on a reciprocal basis, may be made available to other States where the same multi-centre trial is being carried out and to the European Agency for the Evaluation of Medicinal Products (EMA), upon motivated request and within the scope of what is to be provided for in the memorandum of understanding to be signed.
Following the report, the Health Authority shall establish any requirements to be followed to make the trial compliant with the rules of good clinical practice, indicated in the report itself.
In order to verify the conformity of the conduct of the trial being inspected with the principles of good clinical practice of GCP, the inspectors may avail themselves of specific opinions from the Sammarinese Bioethics Committee which, if necessary, has the right to consult external experts.
Within the scope of the memorandum, the Inspectorates of the EU countries, if they intend to carry out inspections on trials conducted in the Republic of San Marino, must,  from  to  time,  in advance  notify it  with  specific  motivation  to the Health Authority, at least one month before the scheduled inspection date; to this end, the promoter of the clinical trial that receives the inspection notice is required to communicate this procedure to the relevant inspectorate that intends to conduct the inspection.
In cases where a non-EU country intends to conduct an inspection on a trial performed in the Republic of San Marino, it must request authorization, justifying the request, from the Health Authority. To this end, the promoter of the clinical trial that receives the inspection notice is required to communicate this procedure to the relevant inspectorate that intends to conduct the inspection. Furthermore, the aforementioned promoter must provide the Health Authority with timely information relating to the aforementioned inspection.
The inspection documents, with particular regard to the situation relating to compliance with GCP and the related consequent measures, are kept for 25 years in a specific section of the CERS archive. 

Working group for training and support on GCP

In order to optimize the execution of the trials in compliance with GCP, through the Working Group:

1. training events on GCP are organized for experimenters operating in the Republic of San Marino, which concern in particular ethical, regulatory, technical and scientific aspects of the trials;
2. support is provided to the CERS and to the experimenters of the Republic of San Marino who also act as non-profit promoters of trials, for the purposes of preparing the correct technical documentation necessary in accordance with the GCP for the execution of the trials as well as for the purposes of compliance with the requirements necessary for the suitability of the centers and for the tasks of Promoter.

Suspension of the trial following infringements of GCP

If the outcome of the inspections:

1. it follows that there are objective reasons to believe that the conditions of the application for authorization provided for by the GCP and the regulations in force have ceased to exist, the CERS revokes the previously issued favorable opinion on the trial, giving notice of this to the Investigator, the Sponsor of the trial and the General Director of the Hospital where the trial is being carried out, who, each for their part of competence, have the obligation to prohibit the trial;
2. information emerges that may raise doubts regarding the scientific conduct or management of the safety of the clinical trial, or the related ethical aspects, required by the GCP, the CERS may suspend the previously issued favorable opinion or revoke it by givingnotification to the Investigator, the Sponsor of the trial and the General Director of the Hospital where the trial is being carried out, who, each for their part of competence, have the obligation to suspend or prohibit the trial. Before adopting its decisions, the CERS, in agreement with the Inspectors, requests the evaluations of the promoter of the trial or the investigator, except in the case of immediate danger; such evaluations are expressed within one week; after this period, the CERS autonomously adopts its own decisions, communicating them to the Health Authority;
3. objective reasons emerge to believe that the promoter of the trial or the investigator or anyone else involved in the trial no longer complies with the obligations prescribed to them by the GCP and the regulations in force, the Health Authority shall immediately inform them, showing them the action plan prepared by the inspectors, which the recipients are required to implement to remedy such circumstances.
   
   The inspectors shall immediately inform the CERS of the above.
   The Health Authority, where provided for by the memorandum, shall immediately inform the competent authorities of the other States involved in the trial. same trial and the European Agency for the Evaluation of Medicinal Products (EMA) of the suspension or prohibition decision and the related reasons.

Personnel for inspection activities and Working Group for training and support for investigators on GCP

The inspections on GCP referred to in Article 4 are conducted, in the first application of this law, by external consultants in possession of the requirements, who also have the task of preparing suitable procedures for carrying out the inspections, and of carrying out the other activities listed, with particular reference to the establishment of a quality assurance system adequately designed to ensure that the inspection procedures are observed and monitored constant.
Inspections are conducted with no less than two inspectors. When necessary for particular technical-scientific specificities, inspectors may avail themselves of the support of experts in the sectors being inspected in conducting inspections, according to procedures to be defined within the quality system.
The designated inspectors,  must safeguard the confidentiality of information  when they access confidential data in carrying out inspections relating to good clinical practice.
For the purposes of the activities, a Working Group is established within the Technical-Scientific Secretariat of the CERS which, in the first application of this law, is made up of consultants in possession of the requirements for carrying out the tasks and subsequent delegated update decrees.
The professionals authorised to carry out the inspections referred to in the previous paragraphs 1, 2 and 3 are registered in a special list kept at the Health Authority which takes care of maintaining and updating it based on the documentation requested from the Inspector. 

Fees and expenses for inspections

Specific ad hoc fees are provided for the performance of inspections, differentiated by type of inspection, and reimbursement of expenses required for conducting individual inspections conducted pursuant to this law, both before and after the release of marketing authorizations. The fees and reimbursement of expenses are borne, as appropriate, by the inspected pharmaceutical companies, those requesting marketing authorization, the promoters of the trial, the contract research organizations (CRO), the subjects holding marketing authorization at the time of the inspection, and the owners of the data at the time of the inspection. The fees referred to in this paragraph are established as indicated.
In cases where several of the subjects referred to in paragraph 1 are involved in different capacities in the inspected trials or in the use or possession of the related results, the reimbursements for the expenses for the inspections are to be attributed, pro rata, to each of the subjects involved, it being understood that each interested subject is required to pay the fee in full.
Failure to pay the fees and reimbursements referred to in this article within 15 days of receiving the relevant request, without prejudice to the other measures that the Health Authority may use to recover the sums,rmina:

1. in cases where the defaulter is a pharmaceutical company or the Sponsor of the trial, the interruption by the Authority and the CERS of the procedures for the release of the authorizations relating to the same company or the same promoter;
2. in cases where the defaulter is a CRO, the suspension of the exercise of the functions of the same CRO in the Republic of San Marino.

The interruption of the procedures for the release of the authorizations referred to in paragraph 3, letter a), as well as the suspension of the exercise of functions, will be revoked upon receipt by the Health Authority of the amounts due. 

Sanctions

Unless the act constitutes a crime, anyone who carries out clinical trials of medicinal products in breach of the principles of good clinical practice referred to in paragraph 2 of the GCP is subject to an administrative pecuniary sanction ranging from €15,000.00 (fifteen thousand/00) to €90,000.00 (ninety thousand/00).
Unless the act constitutes a crime and except as provided for by other applicable laws, anyone who produces, prepares or presents data non-compliant with reality, inherent to clinical trials of medicinal products, referred to in this law, such as to be able to affect the evaluation of what was presented, shall be suspended for a period of time from six months to two years, in relation to the role performed, from the exercise of the functions of production, preparation or presentation of data inherent to medicinal product trials, as well as from the activity of experimenter and applicant for authorisations based on medicinal product trials and from the activity of promoter of trials or his delegate. The subjects referred to in the previous period are also subject to an administrative fine ranging from €25,000.00 (twenty-five thousand/00) to €150,000.00 (one hundred and fifty thousand/00).
Anyone who does not comply with the provisions of Article 4, paragraph 6, is subject to an administrative fine ranging from €5,000.00 (five thousand/00) to €30,000.00 (thirty thousand/00).
The administrative fines referred to in this article are imposed by the Health Authority following notification by the inspectors of the infringements detected and following an investigation by the Health Authority. 

Implementation of Good Clinical Laboratory Practice

The guidelines for Good Clinical Laboratory Practice adopted by the World Health Organization are implemented by delegated decree and subsequent updates. 

Definition of the minimum requirements for healthcare facilities that perform clinical trials of medicinal products

The minimum requirements for healthcare facilities that perform clinical trials of medicinal products are defined by delegated decree and subsequent updates.