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 investigator/principal investigator must meet national requirements – 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?

This is a matter for the EU Member State concerned (i.e., a national matter) - please see the relevant country guidebook.

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?

This is a matter for the EU Member State concerned (i.e., a national matter) - please see the relevant country guidebook.

The EMA “Recommendation paper on decentralized elements in clinical trials” includes an overview of national provisions for specific decentralized clinical trial elements to be used in clinical trials; expectations of eConsent and eSignatures are reflected within the appendix.

In March 2023, the EMA published the final Guideline on computerized systems and electronic data in clinical trials which covers electronic signatures (Section 4.8) and electronic informed consent (Section A5.3). 

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

Within the EMA “Recommendation paper on decentralized elements in clinical trials”, there are no set requirements as to how an eConsent can be administered, as long as the participant obtains adequate information.

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

The EMA published the final Guideline on “Computerized systems and electronic data in clinical trials” in March 2023, becoming effective on the 09^th of September 2023. 

The purpose of this guideline is to assist Sponsors, investigators, and other parties involved in clinical trials to comply with the requirements of the current legislation (EU CTR 536/2014, Directive 2001/20EC and Directive 2005/28/EC), as well as IHC E6 Good Clinical Practice (GCP) regarding the use of computerized systems and the collection of electronic data in clinical trials. 

EMA’s guidance sets expectations on the handling of electronic data at trial level where, for each trial, it should be identified what electronic data and records will be collected, modified, imported, exported, archived, and how they will be retrieved and transmitted. It includes expectations on the audit trail such as accessibility to investigators, monitors, auditors, and inspectors without compromising the confidentiality of participants’ identities. Please refer to section 6 of the EMA's guidance for more information on electronic data.

Clinical trials conducted in the EU/EEA must comply with the General Data Protection Regulation (EU) No 2016/679, which outlines clear responsibilities for organizations processing personal data.

5.6 Does local regulation allow Home Healthcare Professional Visits (HHCP) in decentralized and/or hybrid studies? If yes, explain if there are any specific requirements to fulfill these obligations.

Yes, the EMA provides considerations of trial-related procedures that can be conducted at home, within section 5 of the “Recommendation paper on decentralized elements in clinical trials”.

Summary of those recommendations are:

• Investigator to ascertain suitability for trial procedures to be conducted at the participant’s home.
• Inclusion/exclusion criteria should include provisions related to the adequacy of the participant’s home.
• Participant should be informed during the consent process about planned trial procedures conducted at their home.
• Trial-related procedures at home should only be done if the procedures do not cause additional risk to trial participant or reliability of the data and the person performing the task is qualified and/or trained to perform the task. 
• The sponsor and/or investigator should ensure that appropriate guidance and training are provided to the delegated person(s) to conduct the tasks at home correctly. 
• The insurance or indemnity or a guarantee or a similar arrangement foreseen by CTR or the CTD should be in place to cover any damage resulting from trial-related procedures performed at home. 
• The investigator should monitor compliance of the trial participant considering the lack of/decrease in the number of face-to-face visits/meetings between the trial participant and the investigator and/or delegated staff. 
• Trial participants should be given the opportunity to visit the investigator in person if needed/preferred and they should be able to have a direct contact line if further support to perform a trial-related task/collect data is needed. 
• There should be procedures in place for reporting and management of adverse events noticed by the trial participant or by any delegated person during home visits.
• The sponsor should provide alternatives if a trial participant is unable or not willing to use her/his/their own private device (mobile phone, tablet, etc.) to capture trial data. 

5.7 Does local regulation allow Direct-to-Patient (DTP) study product delivery (such as home delivery) in clinical trials? Are there specific requirements to fulfill (e.g., acknowledgment of/signature for the product by the patient, etc.)?

Yes, the EMA provides considerations of trial-related procedures that can be conducted at home, within section 4 of the “Recommendation paper on decentralized elements in clinical trials”. 

Some of the considerations are summarized below:

• Sponsors should conduct a risk assessment to determine if IMP can be adequately delivered and/or administered at the trial participant’s home.
• Vendors responsible for delivering the IMP should be authorized to distribute or dispense the IMP.
• The investigator remains responsible for the decision of treatment which should be documented (i.e.: Interactive Response Technology System -IRT-) prior to any delivery of the IMP to the participant’s home or suitable address.
• There are several options for delivery of the IMP to the trial participant’s home, depending on what is permitted by national requirements.
• The sponsor has overall responsibility for the process and the contracts or agreement, which should reflect the PI’s responsibilities pursuant to ICH E6.
• Arrangements for delivery of IMP to trial participants should be described in the protocol or the IMPD.
• The sponsor should ensure that the personal data of the trial participants required for the delivery of the IMP is used in accordance with the GDPR on a need-to-know basis. Access to personal data should be restricted as soon as the final delivery is completed.
• Trial participants should be made aware during the informed consent process that their details will be used for delivery purposes.
• Delivery of the IMP should be handed over to the trial participant (or representative when applicable), or the present healthcare professional involved in the trial.
• Sponsor procedures should be in place to handle the entire process.

It is important to consider that acceptability at the country level may not be the same for all Member States - please refer to the specific country guidebook for more information.

Shipping and contractual arrangements regarding IMP shipments between the sponsor and investigator site or pharmacy are covered by the “ Guideline on the responsibilities of the sponsor with regard to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing Practice”, which became effective on the 01^st Jan 2023.

5.8 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?

The EU CTR does not mention OTC but instead, they use the term 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 labeling of the medicinal product, which is used as an auxiliary medicinal product”.

In June 2017, the EMA published 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 to the design of the clinical trial, which excludes ‘concomitant medications’. As outlined in preamble 54, concomitant medications are unrelated to the clinical trial and not relevant to the design of the clinical trial. For further definitions 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.

5.9 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)?

The position on this is not entirely clear, but the purchase of the study product potentially conflicts with the provisions of Annex VI of the Clinical Trial Regulation (EU) 536/2014 which provides, at C.7, in respect of authorized investigational products, that “the following particulars shall appear on the immediate and the outer packaging:

1. Name of the main contact
2. Clinical trial reference code allowing identification of the clinical trial site, investigator, sponsor, and subject;
3. 'For clinical trial use only' or similar wording”.

In any event, investigational products should be free for participants: Art 92, Clinical Trial Regulation (EU) 536/2014:

“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”).

5.10 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?

According to Article 31(1)(d), Article 32(1)(d), and Article 33(d) of the Clinical Trials Regulation, no incentives or financial inducements, other than compensation for participation in the clinical trial, are to be given to incapacitated subjects, legal representatives, minors and pregnant and breastfeeding women. This compensation should not cover more than expenses and loss of earnings, directly related to participation in the clinical trials.

Examples of expenses directly related to the participation in the clinical trials are travel costs for the participating subject and the legally designated representative (if applicable) or (if applicable) the person accompanying the subject, costs for accommodation, or additional costs due to participation in the clinical trial collected by the subjects’ health insurance (compulsory patient contributions/own risk). The information on compensation shall be submitted in the application dossier (CTR Annex I, P(70)) and as such is subject to assessment by Member States. A small token of appreciation is not considered an incentive but needs to be explicitly allowed by the ethics committee.  

5.11  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:
   1. 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’);
   2. 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;
   3. pharmaceutical form, route of administration, quantity of dosage units;
   4. the batch or code number identifying the contents and packaging operation;
   5. a clinical trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere;
   6. the subject identification number and/or the treatment number and, where relevant, the visit number;
   7. the name of the investigator (if not included in (a) or (e));
   8. directions for use (reference may be made to a leaflet or other explanatory document intended for the subject or person administering the product);
   9. "For clinical trial use only" or similar wording;
   10. the storage conditions;
   11. 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
   12. ’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):
   1. name of the main contact;
   2. pharmaceutical form;
   3. 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;
   4. batch and/or code number identifying the contents and packaging operation;
   5. a clinical trial reference code allowing identification of the trial, site, investigator, and sponsor if not given elsewhere;
   6. the subject identification number and/or the treatment number and, where relevant, the visit number; and
   7. period of use (expiry date or re-test date as applicable), in the 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:
   1. name of the main contact;
   2. 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;
   3. batch or code number identifying the contents and packaging operation;
   4. a clinical trial reference code allowing identification of the trial, site, investigator, and sponsor if not given elsewhere;
   5. the subject identification number/treatment number and, where relevant, the visit number; and
   6. 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 outer packaging:
   1. name of the main contact;
   2. name of the medicinal product, followed by its strength and pharmaceutical form;
   3. statement of the active substances expressed qualitatively and quantitatively per dosage unit;
   4. batch or code number identifying the contents and packaging operation;
   5. clinical trial reference code allowing identification of the clinical trial site, investigator, and subject;
   6. directions for use (reference may be made to a leaflet or other explanatory document intended for the subject or person administering the product);
   7. "For clinical trial use only" or similar wording;
   8. the storage conditions; and
   9. 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:
   1. name of the main contact;
   2. clinical trial reference code allowing identification of the clinical trial site, investigator, sponsor, and subject;
   3. "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:
   1. paragraph 1, points (b), (c), (d), (f), (j) and (k);
   2. paragraph 4, points (b), (c), (e), and (f);
   3. paragraph 5, points (b), (c), (e), and (f);
   4. paragraph 6, points (b), (d), (e), (h), and (i).

5.12 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?

This is generally a matter for the EU Member State concerned (i.e., a national matter) - please see the relevant country guidebook. 

Art 61, Clinical Trial Regulation (EU) 536/2014, states the requirements for “Authorization of manufacturing and import” provides that the sponsor “shall have at its disposal, for manufacture or import, suitable and sufficient premises, technical equipment and control facilities complying with the requirements set out in this Regulation”, as well as “permanently and continuously at its disposal the services of at least one qualified person who fulfills the conditions of qualification set out in Article 49(2) and (3) of Directive 2001/83/EC (‘qualified person’)”.

Documentation required to show compliance of the IMP and AxMP with Good Manufacturing Practice (GMP) is outlined in Chapter IX and Annex 1 section F of the Clinical Trial Regulation:

• For IMPs authorized in the EU (even if not manufactured in the EU), no documentation is required.
• For IMPs that are not authorized in the EU, do not have a marketing authorization from a third country that is part of ICH, and are not manufactured in the EU, an authorization referred to in Article 61 (1) and a qualified person (QP) declaration of GMP equivalence is required. In the latter case, if a Mutual Recognition Agreement (MRA) covering also clinical trials is in place with the particular country, the latter declaration is not required if the MRA provides for GMP equivalence already.
• In all other cases, an authorization is required according to article 61 of the Clinical Trial Regulation.

In terms of investigational/study product being imported into the EU from a third country (such as the UK or the US), then it depends which EU Member State the product lands in and clears customs at.

For shipments within the EU (i.e., between the Member States), which is a largely internally borderless customs union, the expectation is that a bill of lading, certificate of conformity, etc. would be required – i.e., limited documentation.

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

This is a matter for the EU Member State concerned (i.e., a national matter) - please see the relevant country guidebook.

5.14 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 a matter for the EU Member State concerned (i.e., a national matter) - please see the relevant country guidebook.

It is expected that Member State (national) authorities would permit the destruction of clinical supplies at an off-site location as described.