7. Decentralized Clinical Trials

7.1 Do the country regulations allow Decentralized Clinical Trials (DCT) elements (e.g., eConsent, ePRO administration, remote investigator site, etc.)?

Yes.

7.2 Is there any specific regulation/guidance on the use of DCT elements within a clinical trial?

Yes, the MPA has a section on “Decentralized Clinical Trials” on its website, with a Q&A about DCT covering the following topics:

• Planning
• Consent Process
• Remote visits
• Safety Monitoring
• Distribution of investigational medicinal products
• Computerized Systems
• Monitoring

Additionally, within the European Union, the EMA published a “Recommendation Paper on Decentralized Elements in Clinical Trials” in Dec 2022.

7.3 What is the overall acceptability of DCT elements by the Swedish Regulatory Authorities and Ethics Committees?

Overall, DCT elements are accepted but it is important that the sponsor takes into consideration the recommendations provided by the MPA and the EMA. 

Additionally, the Swedish MPA provides regulatory advice with regard to decentralized elements in clinical trials.

7.4 Has a fully virtual trial (DCT) been conducted in the country yet? If so, please provide an example including the registration number and any link to it, whether COVID/non-COVID trials.

During 2020-2021, the Swedish MPA carried out a feasibility study and a subsequent project about decentralized clinical trials. The project's aim was to establish conditions for how clinical trials can be carried out in a decentralized manner in Sweden. Five clinical trials with decentralized elements were included as pilots in the project. Below is some information about the elements approved by the Swedish MPA and the experience that sponsors, investigators, and other study staff have shared. The pilots represent all clinical trial phases and both academic and commercial sponsors. Indications include diabetes, COVID-19, breast cancer, etc.

The decentralized elements in one or more of these trials include:

• Remote electronic consent
• Home sampling administered by the patient himself
• Remote visits within the framework of the trial
• Medical device solution to capture symptoms of possible side effects
• Distribution of investigational medicinal products
• Medical device solution to register compliance with treatment

More information on these trials can be found on the MPA website.

7.5 Are there any non-regulatory DCT initiatives in the country, such as where the investigator sites and local CROs founded an alliance?

The Swedish Association of CROs (ASCRO) is a member of EUCROF which has initiatives on DCTs.

7.6 Are there any general considerations when using DCT elements in a study?

Yes, currently those are provided under the EMA “Recommendation paper on decentralized elements in clinical trials” as well as the recommendations reflected within the MPA website.

Sponsors must make sure that the study design and the DCT elements are fit for purpose, taking into consideration the intended population and the safety profile of the study drug, and ensuring appropriate risk management is applied.

Sponsors must provide to the authorities clarity, risks and benefits of using DCT elements in a study, demonstrating how participant safety (data and physical) and well-being are guaranteed, how GCP standards will be upheld, and how compliance with data privacy requirements (GDPR) will be maintained. 

When considering a DCT/hybrid study, it must be ensured that the sponsor and investigator are able to keep oversight of trial participant safety and well-being.

Oversight: 

• Providing clear roles and responsibilities.
• Documenting which tasks are conducted: where, when, and by whom and how oversight is maintained.
• Clear communication plan between the different parties involved: sponsor, investigator, participants, and service providers.
• Trial participants informed on information flow, and how to make contact with acute safety concerns/events, device malfunctions, and other questions.
• Training of participants and study staff in the use of any electronic platforms or devices to be used within the study.

It is important to conduct a trial-specific risk-benefit assessment when proposing a decentralized clinical trial (DCT). This assessment evaluates whether the proposed elements are suitable for the participant populations involved in the trial. Regulators typically expect this assessment to ensure participant’s safety and data integrity.

The MPA reflects on the “planning” of a DCT, indicating the following:

“Planning for decentralized elements in a clinical trial requires a careful and study-specific risk-benefit assessment.

Factors to consider are for example:

• type of study
• study design
• study population
• characteristics of the investigational medicinal product
• indication

The reasons for performing decentralized elements must be based on a scientific basis and may, for example, be an increased opportunity to include a relevant study population, collection of additional relevant data, or reduced risk or burden for patients. Cost efficiency is not an acceptable reason to introduce decentralized elements.

The same requirements regarding ICH GCP, GMP, the scientific value of the study, and the safety of subjects, apply to decentralized trials as to traditional trials. Seeking advice from agencies may be appropriate before submitting an application for clinical trials with decentralized steps for approval.

The investigator's overall responsibility in the study applies, even if different procedures are carried out at locations other than the trial site itself.

DCT is considered a new approach and, therefore, sponsors are encouraged to describe these elements in more detail compared to traditional study protocols. The DCT elements planned for should be clear from the cover letter of the application. A description of the elements (what task is performed by whom and how) as well as a benefit-risk assessment of DCT elements should, as a rule, be included in the protocol (or other protocol-related document).”

7.7 Considerations/Requirements for the Use of eConsent/Remote Consent

eConsent / Remote Consent can be permitted in Sweden.

The response from the Swedish authorities on eConsent can be found under the EMA’s Appendix within the “Recommendation Paper on Decentralized Elements in Clinical Trials”.

The Recommendation Paper on Decentralized Elements in Clinical Trials states that:

“An important aspect of a clinical trial is that the potential trial participants give their voluntarily informed consent to participate. To give consent, the potential participant needs adequate information. Informed consent is not only of ethical and legal importance: good communication between the investigator and the trial participant is beneficial for mutual trust and may promote trial compliance. Therefore, when considering the appropriateness of conducting the informed consent process in a remote manner, to use digital information leaflets, and/or to use electronic methods for the signature of the informed consent form, several aspects have to be thoroughly assessed. These include the design of the clinical trial, the characteristics of the trial population, and the risks, burdens and potential benefit related to participating in the clinical trial. 

The entire procedure for obtaining informed consent, i.e. the selection, the evaluation of the eligibility, and the actual informed consent process, should be described step-by-step in the clinical trial application to ensure appropriate ethical review. The rationale for not having a physical examination as part of this procedure should be given in the protocol or other protocol-related document. The sponsor should also describe in the protocol the chosen method for obtaining informed consent. 

Regardless if only a part of or the whole informed consent process is conducted remotely, the process should still be carried out in compliance with the principles laid down in the CTR or the CTD, ICH E6, the GDPR and national legislation. 

The informed consent process should be documented in a manner that allows verification of the receipt of information by the trial participant, the discussion between the person qualified to obtain the consent and the trial participant, as well as giving of the consent.” 

The MPA provides additional clarification on the eConsent process within its website:

• Is it possible to obtain informed consent remotely?

Yes, provided that ICH GCP(R2) and other applicable regulations are complied with, it may be possible to obtain informed consent remotely. The procedure needs to be described and justified in detail in the study protocol.

• What are the requirements for a remote consent process?

The subject must always be informed and given the opportunity to ask questions as stated in ICH GCP(R2). This can be done in a digital meeting between the subject and the investigator in real-time. The parties should be able to both see and communicate with each other via audio and video, and the investigator should be able to ensure that the subject is the right person or, if necessary, check his/her identity, i.e. contact only via telephone/e-mail/chat is not considered sufficient.

That informed consent has been obtained must always be documented in the subject's medical record.

• Is it possible to electronically sign an informed consent?

Yes, it is possible, provided that the electronic system used is appropriate and validated for the purpose. For example, signatures must be possible to be verified and different versions of the consent must be stored. As usual in clinical trials, the subject signs first and then the investigator.

• How should the informed consent be saved and how should the copy be distributed to the subject?

The signed consent can be sent via, for example, a link with a password or regular mail. Note that consent should not be sent unencrypted via email.

Signed consents can be saved in paper form or in another format as long as any changes can be traced, and readability can be guaranteed throughout the archiving period. As with all clinical trials, filing consent is the responsibility of the investigator.

• Who can hold a digital consent process?

The same requirements as in a conventional clinical trial apply. Informed consent must be obtained from the investigator or delegated co-investigator who must be a licensed doctor or, where applicable, a licensed dentist. Signing of the consent cannot normally be delegated to a nurse. The nurse, on the other hand, can preferably be involved in informing the subject about the trial.

7.8 Considerations/Requirements for the Use of eSignatures

eSignatures in the eConsent are permitted in Sweden (please refer to Section 7.7 above).

BankID is one of the most common electronic signatures used in Sweden.

7.9 Considerations/Requirements for Electronic Patient Reported Outcome (ePRO)

This is not specifically addressed in the national legislation. However, Swedish CA and ECs accept the use of ePROs within clinical trials.

The EMA “Recommendation paper on decentralized elements in clinical trials” makes some remarks with regard to ePRO:

“The trial participant should be fully informed in advance on how the information transmitted via digital tools, for example electronic Patient Reported Outcomes (ePROs), will be acted upon. It should be made clear to the trial participant that the investigator may not review such data in real time, and that if the trial participant experiences any specific safety concern, they need to directly contact the investigator to report such an issue.”

ePROs considerations are also reflected within the EMA guidance on “Computerized Systems and electronic data in clinical trials.”

7.10 Considerations/Requirements for Home Health Care (HHC)- Home Nursing

Home nursing is allowed in Sweden.

The response from the Swedish authorities can be found under the EMA’s Appendix within the “Recommendation Paper on Decentralized Elements in Clinical Trials.”

EMA's summary of these recommendations can be found below: 

• Investigator to ascertain suitability for trial procedures to be conducted at the participant’s home.
• Inclusion/exclusion criteria should include provisions related to adequacy of 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. 
• 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. 

Qualification on the HHC will also depend on the type of responsibilities allocated to the individual HHC.

7.11 Considerations/Requirements for HHC - Home Lab Collection

In Sweden, it may be permitted to collect biological samples from study participants; however, the sponsor should take into consideration EMA’s “Recommendation paper on decentralized elements in clinical trials.” 

Collection of biological samples at home is permitted, as long as the procedures involved do not cause any additional risk to trial participants or to the reliability of the data, and the person performing the task is qualified and/or trained to perform the task. If biological samples are collected at home, it should be considered whether persons taking the sample are qualified and allowed by their local legislation to take the sample. In addition, adequate handling and storage conditions for the samples throughout the entire process should be assured.

There may be additional requirements at the country level, such as IATA training for handling infections and biological material.

7.12 Considerations/Requirements for Direct-to-Patient Study Product Delivery

MPA provides the following recommendations on the direct distribution of investigational medicinal products.

• Can investigational medicinal products be sent to a subject’s home?

Yes, provided that it is deemed appropriate for the trial in question based on, for example, the safety profile, route of administration, and storage requirements of the investigational medicinal product and that it is described in the clinical trial application.

The Sponsor must not know the identity of the subject. Home delivery to a subject must thus take place from the trial site or from a Swedish pharmacy with which the investigator or sponsor has established an agreement for the trial in question. It shall be clear from the agreement that it is the trial site that provides the courier with the subject’s address and contact details and that this information must not be passed on to the Sponsor. In addition, quality requirements and other requirements for the transport shall be clear from the agreement. It may also be acceptable for home care staff to collect investigational medicinal products at the trial site, which they then hand over to the subject. In case home delivery means that the subject’s identity is disclosed to an additional party, this shall be described in the written subject information.

It is the investigator who must initiate all deliveries of investigational medicinal products. Routines for the handling of investigational medicinal products shall be established, and the handling must be carefully documented and be traceable in the study documentation in the investigator’s file.

It must be ensured that the right investigational medicinal product in the right quantity is delivered to the right person. These products must not be left in the mailbox, outside the door, or similar. Deliveries must meet the requirements specified for storage of the product. It may also be appropriate for the trial site to follow up with the subject after delivery (for example by telephone) to ensure that the investigational medicinal product has been received.

7.13 Considerations/Requirements for the Use of Telemedicine

While not specifically addressed in the national legislation, telemedicine is permitted in Sweden.

Ethics Committees tend to enquire about the privacy settings of any platform used for telemedicine purposes and sometimes may request clarification if the software to be used is considered a medical device.

It is important to consider which are the study-specific assessments that are under the responsibility of the investigator (such as physical, neurological examinations, etc.) and if such assessments are related to the study endpoints. There may be instances where some assessments may be permitted to be conducted remotely, for example, where a qualified nurse is physically present with the study participant and the investigator is instructing or overseeing remotely via telemedicine. However, there may be occasions where those assessments can only be performed by a physician.

The MPA provides additional consideration on remote visits, see below:

• Can some or all visits to a clinical trial be made remotely?

Yes, provided that the Sponsor can show that there are prerequisites for collected efficacy and safety data to be of the same quality as during conventional study visits and that the safety of the participant must not be compromised. By remote visits, it is meant here, for example, different types of digital contact, visits to a location other than the trial site such as a primary healthcare provider, or visits to the subject's home.

It is important to initially clarify the roles, responsibilities, and tasks that the sponsor, investigator, and others involved (such as other healthcare personnel or providers of the system used) have in the trial.

• What are the general requirements for remote visits?

ICH GCP(R2) and other applicable regulations apply to all clinical trials.

All visits during the trial are primarily the responsibility of the investigator. The investigator's control over the trial (PI oversight) must be ensured and proven even when the trial takes place at a location other than the trial site. For example, it is important that the investigator has sufficiently close contact with the staff who perform study tasks or treatment in a study.

Anyone who performs study-specific tasks, which is not a clinical routine, needs, as with all investigational clinical trials, training in GCP and study-specific training.

The sponsor should consider whether the clinical assessments in a particular trial are suitable to be performed remotely, taking into account what type of data is collected and how the results are to be used (screening/inclusion, primary variable, incidents, etc.).

• Related information

EMA’s Q&A (GCP matters), questions 10 and 11.

7.14 Considerations/Requirements for the Use of Wearables

Not specifically addressed in the existing national legislation, but support for their use may be found in the EMA's “Recommendation paper on decentralized elements in clinical trials” which makes some remarks with regards to wearables as part of handling data. 

References to Wearables as well as Bring Your Own Device (BYOD) can also be found within the EMA guidance on “Computerized Systems and electronic data in clinical trials”.

7.15 Considerations/Requirements for Remote Monitoring

Remote monitoring is not permitted in Sweden.

The MPA indicates within its website the following:

• How are decentralized trials monitored?

The Sponsor must decide for each individual clinical trial on the scope and type of monitoring based on a risk-based approach.

Performing remote monitoring has been brought to the fore with the COVID-19 pandemic. According to the Patient Data Act, direct remote access to the patient's electronic medical record is currently not permitted in Sweden which means that on-site monitoring (at least to some extent) is required for all trials.

We suggest that sponsors wishing to conduct remote monitoring in a clinical trial discuss previously with the MPA.

7.16 Considerations/Requirements for Digital Health Technologies (such as Platforms)

The MPA indicates the following on its website:

What are the requirements for the computerized systems used for data collection/handling in a decentralized clinical trial?

It is the Sponsor's responsibility that the computerized systems used for the collection and/or handling of data in a clinical trial are, based on a risk-based approach, validated for the purpose and meet the requirements of ICH GCP(R2) 1.65 and 5.5.3 including Addendum.

Related information

• EMA's “Guideline on computerized systems and electronic data in clinical trials”
• EMA's "Notice to sponsors on validation and qualification of computerized systems used in clinical trials"
• EMA's Q&A (GCP matters), questions 8 and 9