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)?  

Yes. Details are provided below and can also be found on the MPA website under “Investigator - suitability and GCP”.

Under Chapter 7, Section 1 of the Medicinal Products Act (läkemedelslagen) (2015:315), a clinical trial may only be conducted on humans by a qualified medical doctor (physician licensed by the Swedish National Board of Health and Welfare) or qualified dental practitioner (dentist licensed by the Swedish National Board of Health and Welfare). The investigator shall possess sufficient competence in the area that the trial concerns.

Staff performing tasks in a clinical trial at the clinical trial site shall have the training and experience necessary to perform their respective tasks. In addition, the principal investigator, other investigators, and other staff to whom tasks in the trial have been delegated shall have documented knowledge of good clinical practice and sound knowledge of the investigational medicinal product.

The investigator is responsible for ensuring that there is access to appropriate facilities as well as competent and suitable staff for proper and safe conduct of the trial.

The principal investigator is expected to allocate trial-related tasks in a trial to delegated co-investigators and other staff, such as research nurses, in a way that does not compromise the safety of subjects or the reliability and robustness of the data generated in the trial.

If the investigator delegates some of the duties to other staff at the clinical trial site, this shall be done in writing, and it shall be clear which duties are included and who is to carry them out. A delegation shall be signed both by the person delegating and the person who receives the delegation.

A combined signature and delegation list is often used (ICH GCP 4.1.5, 8.3.24). An example of such a list is available on the Swedish Pharmaceutical Society website.

Duties may only be delegated to someone who has adequate training and experience in carrying out the tasks, and who has had relevant trial-specific training. It should be noted that qualified medical doctors or qualified dental practitioners are always responsible for medical decisions and for the provision of medical care, e.g. decisions concerning inclusion in the trial and assessment of adverse events/reactions.

The Swedish MPA normally expects the persons to whom the investigator has delegated study-related duties to be included in the delegation list. Study-related duties may mean study-specific performance and/or study-specific assessment and documentation, for example on trial-specific worksheets or in the case report form (CRF).

However, the investigator does not need to delegate duties that are carried out according to normal clinical practice, i.e. when the person who carries out the task does not need study-specific training in order to either perform the task or document/report the outcome.

The investigator also does not need to delegate duties that are regulated in an agreement between the sponsor and the performer, if the sponsor for example has an agreement with the pharmacy for the handling of medicinal products, or with a radiology department for study-specific radiology examinations.

Basic provisions for delegation in healthcare can be found in the Patient Safety Act (patientsäkerhetslagen) (2010:659) and the National Board of Health and Welfare’s regulations and general guidance SOSFS (1997:14) on the delegation of duties within healthcare and dental care.

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

It is not clear what the position is if the PI is located outside Sweden; this topic would need to be discussed in advance with the MPA.

The Swedish law indicates that a clinical trial may only be qualified on humans by a qualified medical doctor (physician licensed by the Swedish National Board of Health and Welfare) or qualified dental practitioner (dentist licensed by the Swedish National Board of Health and Welfare) and that the investigator shall possess sufficient competence in the area that the trial concerns.

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

Yes, electronic administration of ICF is permitted, including electronic signatures. Please refer to the discussion in Sections 7.7 and 7.8 of this guidebook.

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

Yes, ICF may be administered in an Audio/Visual form and this must be recorded, as required by Art. 29(1) of the EU CTR 536/2014, which reads as follows:

"Informed consent shall be written, dated, and signed by the person performing the interview referred to in point (c) of paragraph 2, and by the subject or, where the subject is not able to give informed consent, his or her legally designated representative after having been duly informed in accordance with paragraph 2. Where the subject is unable to write, consent may be given and recorded through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent document. The subject or, where the subject is not able to give informed consent, his or her legally designated representative shall be provided with a copy of the document (or the record) by which informed consent has been given. The informed consent shall be documented. Adequate time shall be given for the subject or his or her legally designated representative to consider his or her decision to participate in the clinical trial."

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 Sweden must comply with the EU GDPR (the General Data Protection Regulation) and the Swedish Data Protection Act (2018:218).

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?

The EU CTR 536/2014 does not mention OTC but instead, they are using 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 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)?

Not addressed at the national level by the MPA.

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.” 

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?

According to the Swedish “Guidance on Ethical Review of Research in Humans”, in Sweden, most research principals have established their own rules for what reasonable remuneration to research subjects is. Find out what applies within your organization.

In the ethical review, the members assess, among other things, whether the remuneration is reasonable for the time that the research subjects devote to the research through their participation. The compensation must not be too large which would attract research subjects to participate because of it. In such cases, the compensation constitutes undue influence aimed at persuading people to participate.

According to the Swedish Tax Agency, remuneration to research subjects is regarded as income from employment and is therefore taxable. Exempt are allowances for the donation of blood, breast milk, or organs, which are tax-free. Travel expenses are also tax-free. Read more on the Swedish Tax Agency's website.

Information to research subjects must state whether they are being compensated for their participation or not. It must also be stated whether the remuneration is taxable.

The MPA provides some clarification under their page “Subjects and informed consent” for clinical trials on incapacitated subjects: “No incentives or financial inducements shall be given to the subject or their representative, except for compensation of expenses and loss of income directly related to participation in the trial.”

5.9 Specific labeling requirements for clinical study product

The labeling of investigational medicinal products and auxiliary medicinal products shall be in accordance with Chapter X, Articles 66 to 67 and Annex VI, Sections A to D of the EU CTR 536/2014, and also in accordance with the Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use, Section 6.6 (Labeling).

For the labeling of radioactive medicinal products, see Article 68 of the EU CTR 536/2014.

According to the national regulations HSLF-FS 2021:109, the labeling of investigational medicinal products and auxiliary medicinal products shall be in Swedish. The investigational medicinal product may also be labeled in other languages. In certain exceptional cases, English labeling may be accepted after being justified in the application. Such an exception may, for example, apply to a hospital trial where the medicinal product is only handled in the clinic by a few people who are well acquainted with the trial.

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?

Please refer to Section 2.6 of this guidebook.

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

Please refer to Section 2.6 of this guidebook.

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 specified by MPA.

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