5. Investigator and Investigational Product

5.1 Does local regulation require PI/CI to be approved/registered by any health authority (e.g., RA/EC)?  

The sponsor must submit an application to the Ethics Committee competent for the clinical site, which will include details of the proposed PI/CI who is required to supervise the trial for its duration. 

If the relevant Ethics Committee approves the application, it is assumed that the PI/CI meets its criteria, unless it advises otherwise.

See Art 49 of the Clinical Trial Regulation (EU) 536/2014:

“The investigator shall be a medical doctor as defined in national law, or a person following a profession which is recognized in the Member State concerned as qualifying for an investigator because of the necessary scientific knowledge and experience in patient care”. 

“Other individuals involved in conducting a clinical trial shall be suitably qualified by education, training and experience to perform their tasks”. 

5.2 Does local regulation require any specific documents if PI/CI is based outside the country?

Not specified by national regulations.

It is not clear what the position is if the PI is located outside of the EMA, but unless EU qualified (or with a qualification recognized in the EU), they are unlikely to meet the requirements of either national legislation and/or Art 49 of the Clinical Trial Regulation (EU) 536/2014 whereby the investigator/principal investigator must meet national requirements:

“The investigator shall be a medical doctor as defined in national law, or a person following a profession which is recognized in the Member State concerned as qualifying for an investigator because of the necessary scientific knowledge and experience in patient care”. 

“Other individuals involved in conducting a clinical trial shall be suitably qualified by education, training and experience to perform their tasks”. 

5.3 Does local authority allow electronic ICF administration, including electronic signatures?

Yes, if RA and EC approval has been provided.                                               

Please refer to Sections 7.7 and 7.8 of this guidebook for more information. 

5.4 Does local regulation require ICF to be administered as audio/visual and do these need to be recorded?

No – However, the “Guidelines for collecting informed consent to participate in clinical trials” indicate, on the templates for ICFs excerpts for those participants who may not be able to sign the informed consent, the following:

“If you are not able to sign the informed consent, the consent can be provided and recorded using appropriate alternative tools, for example, audio or video recordings in the presence of at least one impartial witness.”

5.5 Is there any specific information/requirement on data capture/management (e.g., privacy regulations, etc.)?

The EMA’s final guidance of 09 March 2023 on Computerized Systems and Electronic Data in Clinical Trials includes the following:

“6.1. Data capture and location 

The primary goal of data capture is to collect all data required by the protocol. All pertinent observations should be documented in a timely manner. The location of all source data should be specified prior to the start of the trial and updated during the conduct of the trial where applicable. 

6.1.1. Transcription 

Source data collected on paper (e.g. worksheets, paper CRFs or paper diaries or questionnaires) need to be transcribed either manually or by a validated entry tool into the EDC system or database(s). In case of manual transcription, risk-based methods should be implemented to ensure the quality of the transcribed data (e.g. double data entry and/or data monitoring).

6.1.2. Transfer 

Trial data are transferred in and between systems on a regular basis. The process for file and data transfer needs to be validated and should endure that data and file integrity are assured for all transfer. 

Data that is collected from external sources and transferred in open networks should be protected from unwarranted changes and secured/encrypted in a way which precludes disclosure of confidential information. 

All transfers that are needed during the conduct of a clinical trial need to be pre-specified. 

Validation of transfer should  include appropriate challenging test sets and ensure that the process is available and functioning at clinical trial start (e.g. to enable ongoing sponsor review of diary data, lab data or adverse events by safety committees). Data transcribed or extracted and transferred from electronic sources and their associated audit trails should be continuously accessible (according to delegated roles and corresponding access rights). 

Transfer of source data and records where the original data or file is not maintained is a critical process and appropriate considerations are expected in order to prevent loss of data and metadata. 

6.1.3. Direct capture 

Direct data capture can be done by using electronic data input devices and applications such as electronic diaries, electronic questionnaires, and eCRFs for direct data entry. Where treatment-related pertinent information is captured first in a direct data capture tool such as a trial participant diary, a PRO form or a special questionnaire, a documented procedure should exist to transfer or transcribe information into the medical record, when relevant.

Direct data capture can be done by automated devices such as wearables or laboratory or other technical equipment (e.g. medical imaging, electrocardiography equipment) that are directly linked to a data acquisition tool. Such data should be accompanied by metadata concerning the device used (e.g. device version, device identifiers, firmware version, last calibration, data originator, timestamp of events). 

6.1.4. Edit checks 

Computerized systems should validate manual and automatic data inputs to ensure a predefined set of validation criteria is adhered to. Edit checks should be relevant for the protocol and developed and revised as needed. Edits checks should be validated and implementation of the individual edit checks should be controlled and documented. If edit checks are paused at any time during the trial, this should be documented and justified. Edit checks could be either run immediately at data entry or automatically during defined intervals (e.g. daily) or manually”.

Clinical trials conducted in Italy must comply with the General Data Protection Regulation (GDPR) No 2016/679 and the Italian Data Protection Code (DPC) (Legislative Decree no.101 of 10 Aug 2018) which outlines clear responsibilities for organizations processing personal data.

5.6 If a clinical study involves the study product as OTC and this is provided via pharmacy/amazon, etc., are there any specific regulations for IP management that need to be followed?

There is no such local regulation available in Italy.

The EU CTR 536/2014 does not mention OTC but instead, they are using the term of Auxiliary Medicinal Product (AMP), which is defined in Art 2 (8) as “a medicinal product used for the needs of a clinical trial as described in the protocol, but not as investigational medicinal product”.

Art 2. (10) goes further on the AMP clarification indicating: “a medicinal product authorized in accordance with Regulation (EC) No 726/2004, or in any Member State concerned in accordance with Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, which is used as an auxiliary medicinal product”.

In March 2024, the EMA updated the recommendations on “Auxiliary Medicinal Products in Clinical Trials”. These recommendations can also be found in Chapter III- Quality section under the Eudralex Volume 10. This publication provides additional clarifications, such as:

“Examples are medicinal products used as rescue medication, challenge agents, to assess end-points in the clinical trial, or background treatment. Further, the medicinal product should be related to and relevant for the design of the clinical trial, which excludes ‘concomitant medications’. As outlined in preamble 54 concomitant medications is unrelated to the clinical trial and not relevant for the design of the clinical trial”. For further definition and examples, see Annex 1 of this document."

Therefore, an authorized or marketed medicinal product (i.e.: Auxiliary Medicinal Product) used in a clinical trial will need to comply with the requirements set within the EU CTR and will be labeled accordingly.

5.7 For a marketed study product/OTC, can a participant be compensated after confirmation of the purchased study product, or upfront prior to product acquisition? Does compensation in any way impact how the study is viewed (i.e., RWE vs. Interventional Study)?

National provisions do not directly address this topic.

Art 92, Clinical Trial Regulation (EU) 536/2014, indicates that:

“Investigational medicinal products, other products and procedures, free of charge for the subject.

Without prejudice to the Member States' competence for the definition of their health policy and for the organization and delivery of health services and medical care, the costs for investigational medicinal products, auxiliary medicinal products, medical devices used for their administration and procedures specifically required by the protocol shall not be borne by the subject, unless the law of the Member State concerned provides otherwise.” 

This suggests that it is possible, to ensure that the costs are not borne by the clinical trial subject; however, subject to Member State (national) law.

5.8 Is it permitted to pay participant stipends (i.e., is it permitted to pay the patients for their participation in the clinical trial)? If so, what is the average range?

The National Coordination Center of Local Ethics Committees for Clinical Trials issued a guideline in May 2023 - “Guide to the evaluation of the territorial ethics committees of the documents referred to Art 7 of the CTR 536/2014”. Section 9 clarifies the reimbursement of expenses and compensation for trial participants:

“… According to the Regulation, therefore, it can be recognized:

i. The Compensatory Allowance, i.e. compensation for loss of earnings and reimbursement of expenses incurred for participation in the study (e.g. expenses for accommodation, food, transport, etc.), can be recognized to subjects included in the categories referred to in the articles. 31-34 of the Regulation. 

The Compensatory Allowance (i.e. reimbursement of expenses and lost earnings) can be recognized also for the companion of patients who are unable to travel alone. It is understood that the contract between the Sponsor and the Research Center (“Centre”), in addition to regulate the possibility of recognition of the Compensatory Allowance, must provide for both access criteria and the methods of disbursement and documentation of the expenses incurred.

ii. The reimbursement of expenses, which unlike the compensatory allowance does not include the possibility of reimbursing the lost earnings resulting from participation in the study, can be recognized under the conditions set out in the protocol and the contract also in further categories other than to incompetent subjects, minors and pregnant women. Expense reimbursement can be also recognized for accompanying patients who are unable to travel alone. 

It is understood that the contract between the Sponsor and the Centre, in addition to regulating the possibility of recognition of expense reimbursement, must provide both the access criteria and the delivery mode.

The material disbursement of expense reimbursements and compensatory allowances can be made instead by employees of each research center, by specialized organizations (“Supplier of services”), appointed to carry out this activity through the stipulation, in written form, of specific contracts. It must, however, ensure that the provision through the Service Provider does not cause any harm in any case prejudice to the fundamental principle that prohibits direct economic relationships between patients and sponsors and/or investigators and in general to the independence and autonomy of patients and investigators. The following are considered to constitute a minimum guarantee for this purpose:

1. an adequate verification by the Centre, prior to the signing of the contract, aimed at acquiring information on the activity and experience of the Service Provider – in particular if proposed by promoter, and on its independence.
2. the stipulation, in written form, of a contract between the Center and the Service Provider which provides, among other things:
   1. the payment of the Service Provider by the Center as consideration for the performance of specific services relating to the management of refunds, with funding to be provided by the sponsor;
   2. the declaration of the Service Provider, under its own responsibility, not to receive any other consideration, from the sponsor or from third parties for the same title;
   3. the contractual obligation, assumed directly by the Service Provider towards the Centre (with explicit and exclusive assumption of any and all liability in this regard), not to communicate, transmit or reveal personal data or other identifying elements in any way of patients and/or others entitled to the reimbursement of expenses or the compensatory allowance al profit promoter (see art. 1, paragraph 1, letter r, Legislative Decree 200/2007) of the trial;
   4. the appointment of the Service Provider as responsible for the processing of personal data by the Center so that it has direct responsibility in the event of a data breach.

The Compensatory Allowance and/or Expense Reimbursement cannot be used to compensate for the violation of the rights and safety of participants or to cause undue influence.”

Note: the “Reimbursement and Allowance for Trial Participants” declaration available within the Ethics Committees Coordination Center webpage, is required to be completed and submitted as part of Part II of the initial clinical trial application.

5.9 Specific labeling requirements for clinical study product

Yes, these are set out in Annex VI of the Clinical Trial Regulation (EU) 536/2014.

“A. Unauthorized Investigational Medicinal Products

A.1. General rules

1. The following particulars shall appear on the immediate and the outer packaging:

(a) name, address and telephone number of the main contact for information on the product, clinical trial and emergency unblinding; this may be the sponsor, contract research organization or investigator (for the purpose of this Annex this is referred to as the ’main contact’);

(b) the name of the substance and its strength or potency, and in the case of blind clinical trials the name of the substance is to appear with the name of the comparator or placebo on the packaging of both the unauthorized investigational medicinal product and the comparator or placebo;

(c) pharmaceutical form, route of administration, quantity of dosage units;

(d) the batch or code number identifying the contents and packaging operation;

(e) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere;

(f) the subject identification number and/or the treatment number and, where relevant, the visit number;

(g) the name of the investigator (if not included in (a) or (e));

(h) directions for use (reference may be made to a leaflet or other explanatory document intended for the subject or person administering the product);

(i) ’For clinical trial use only’ or similar wording;

(j) the storage conditions;

(k) period of use (expiry date or re-test date as applicable), in month and year format and in a manner that avoids any ambiguity; and

(l) ’Keep out of reach of children’, except when the product is for use in trials where the product is not taken home by subjects.

2. Symbols or pictograms may be included to clarify certain information mentioned above. Additional information, warnings or handling instructions may be displayed.

3. The address and telephone number of the main contact shall not be required to appear on the label if subjects have been given a leaflet or card which provides these details and have been instructed to keep this in their possession at all times.

A.2. Limited labelling of immediate packaging

A.2.1 Immediate and outer packaging provided together

4. When the product is provided to the subject or the person administering the medicinal product in an immediate packaging and outer packaging intended to remain together, and the outer packaging carries the particulars listed in section A.1., the following particulars shall appear on the immediate packaging (or any sealed dosing device that contains the immediate package):

(a) name of the main contact;

(b) pharmaceutical form, route of administration (may be excluded for oral solid dose forms), quantity of dosage units and, in the case of clinical trials which do not involve the blinding of the label, the name/identifier and strength/potency;

(c) batch and/or code number identifying the contents and packaging operation;

(d) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere;

(e) the subject identification number and/or the treatment number and, where relevant, the visit number; and

(f) period of use (expiry date or re-test date as applicable), in month and year format and in a manner that avoids any ambiguity.

A.2.2. Small immediate packaging

5. If the immediate packaging takes the form of blister packs or small units such as ampoules on which the particulars required in section A.1. cannot be displayed, the outer packaging provided shall bear a label with those particulars. The immediate packaging shall contain the following:

(a) name of the main contact;

(b) route of administration (may be excluded for oral solid dose forms) and, in the case of clinical trials which do not involve the blinding of the label, the name/identifier and strength/potency;

(c) batch or code number identifying the contents and packaging operation;

(d) a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere;

(e) the subject identification number/treatment number and, where relevant, the visit number; and

(f) period of use (expiry date or re-test date as applicable), in month and year format and in a manner that avoids any ambiguity.

B. Unauthorized Auxiliary Medicinal Products

6. The following particulars shall appear on the immediate and the outer packaging:

(a) name of the main contact;

(b) name of the medicinal product, followed by its strength and pharmaceutical form;

(c) statement of the active substances expressed qualitatively and quantitatively per dosage unit;

(d) batch or code number identifying the contents and packaging operation;

(e) clinical trial reference code allowing identification of the clinical trial site, investigator and subject;

(f) directions for use (reference may be made to a leaflet or other explanatory document intended for the subject or person administering the product);

(g) ’For clinical trial use only’ or similar wording;

(h) the storage conditions; and

(i) period of use (expiry date or retest date as applicable).

C. Additional Labelling For Authorized Investigational Medicinal Products

7. In accordance with Article 67(2), the following particulars shall appear on the immediate and the outer packaging:

(a) name of the main contact;

(b) clinical trial reference code allowing identification of the clinical trial site, investigator, sponsor and subject;

(c) ’For clinical trial use only’ or similar wording.

D. Replacing of Information

8. The particulars listed in sections A, B and C, other than those particulars listed in paragraph 9, may be omitted from the label of a product and made available by other means, for example by use of a centralized electronic randomization system, use of a centralized information system, provided that the safety of the subject and the reliability and robustness of data are not compromised. This shall be justified in the protocol.

9. The particulars referred to in the following points shall not be omitted from the label of a product:

(a) paragraph 1, points (b), (c), (d), (f), (j) and (k);

(b) paragraph 4, points (b), (c), (e), and (f);

(c) paragraph 5, points (b), (c), (e), and (f);

(d) paragraph 6, points (b), (d), (e), (h), and (i)."

5.10 What documents need to be submitted (including relevant fee if any), and to whom, if a permit is needed for an investigational/study product being shipped from outside the country? Are there any specific requirements for biologics?

From the research conducted, it was not possible to ascertain exactly which documents need to be submitted if an investigational or study product is being shipped into Italy.

The import-export of medicinal products is permitted within European countries only for those products of EU origin, while products imported from extra-EU countries and several categories of special products are subjected to Custom controls upon arrival at the destination port or airport.

5.11 What is the turn-around time to get an import permit?

This is not specified. AIFA coordinates and directs all aspects concerning investigational medicines, including the granting of import authorizations.

Information regarding the procedure to follow and forms to submit in order to apply for authorization of the importation of IMP is available on the AIFA website, in Italian.

5.12 Does local authority allow the destruction of clinical supplies at an off-site location (e.g. third-party vendor in or outside the country) after study completion? Are certificates of destruction required?

This is not stated in national regulations.

Within the models of clinical trial agreements between the sites and the sponsors, which are available within the Ethics Committees Coordination Center on the AIFA webpage, Section 4.6 of the “Clinical Trial Agreement for the Drug” indicates the following provisions:

“4.6. (a) (In the event of collection of the Trial Drugs by the Sponsor):
All the expired or otherwise unusable Trial Drugs or those that have not been used on conclusion of the Trial will be collected by the Sponsor (or its representative) and will subsequently be disposed of at the Sponsor’s expense.

Or

4.6. (b) (In the event of destruction of the Trial Drugs by the Entity):
All the expired or otherwise unusable Trial Drugs or those that have not been used upon conclusion of the Trial will be disposed of by the Entity, at the Sponsor’s expense. The Entity shall provide the Sponsor with certification of disposal, in accordance with current regulations. With regard to the disposal of unused Trial Drugs and the related operations, the Sponsor shall pay the Entity the amount indicated in Annex A (Paragraph “Costs and Payments” – Part 1) attached to this Agreement. The Entity will invoice the indicated amount plus VAT at the ordinary rate, with the description “Ancillary cost for the disposal of expired or unused Trial Drugs”. “