Clinical trials on medicinal products for human use according to Clinical Trials Regulation (CTR)
As of January 31st, 2022, the EU regulation regarding Clinical trials of medicinal products for human use, EU No 536/2014, is imposed. In Sweden this also affects the process for biobank applications in clinical trials.
According to the EU regulation for CTR, an application for clinical trial is submitted through the web portal CTIS (Clinical Trial Information System). If a clinical trial is to be conducted in several EU countries a joint assessment is made by the involved countries.
In Sweden, a joint assessment is made by the Swedish Medical Products Agency and the Swedish Ethical Review Authority, and in cases where the trial includes human biological material, and where the Biobank Act (2023:38) applies, an assessment is also made by an RBC.
The RBC gives their opinion to the Swedish Ethical Review Authority that includes considerations regarding the subject information and the informed consent form, and to the Swedish Medical Products Agency concerning other issues.
At present, all RBCs has assignments from all regional biobanks, which means that an RBC will assess documentation relating to biological samples and submit an opinion for all applications/notifications where newly taken samples are established in a regional biobank and where existing samples are released from, remain in or be established in a regional biobank.
The opinion from the RBC is included when the request for information is sent to the sponsor. The assessment results in a national decision, made by the Swedish Medical Products Agency, available on CTIS.
For more information about how to apply according to the EU regulation, CTR, visit the Swedish Medical Products Agency’s webpage.
Application documents for clinical trials
If a clinical trial is to include human biological material, a document is to be submitted into CTIS with a description of the handling of the biological material. A useful document called “Följsamhet med regler för hantering av biologiska prov” has been created by Biobank Sweden, the Swedish Medical Products Agency and the Swedish Ethical Review Authority and can be seen as a Swedish equivalent of the English document ”Compliance with applicable rules for biological samples”. You can download the document at the webpage of the Swedish Medical Products Agency:
Följsamhet med regler för hantering av biologiska prov
Transitional rules and the transfer of active clinical trials
Transitional rules
As of January 31, 2023, it is no longer possible to apply for samples according to the old directive (2001/20/EC)/national legislation. If you already have an ethical approval – apply for access to samples with document L1.1 and/or L1.2.
For guidance, use our K2.1 form selector
Documents can be found here: Documents – biobanksverige.se
Transfer of trial to CTR “transitional trials” and subsequent update of biobank agreement
Information about transition of trial to CTR
Active clinical trials, approved according to the old directive (2001/20/EC)/national legislation, need to be transferred over into CTIS according to CTR (EU No 536/2014) before January 31, 2025, to be allowed to continue.
Please note that all information provided to subjects must be accurate as to the responsibilities of the clinical trial. The sponsor is responsible for assessing whether the documentation needs to be updated and if a substantial modification is needed.
Example of investigator-initiated clinical trials:
The same organisation represents the clinical trial towards authorizing authorities, i.e., the former research principal in previously ethical approval is the same organisation that applies as a sponsor in CTIS when transferring the trial to CTR. In this case, the existing biobank agreement does not need to be updated in connection with the transition.
Example of company-initiated clinical trials:
Before CTR was applied, a clinical trial of medicinal products could have a research principal (with a principal/national coordinating investigator) who applied for ethical approval from the Ethical Review Authority and also access to samples from the biobank/RBC. The sponsor applied for a permit for clinical trials from the Medical Products Agency. With CTR, the concept of research principal and principal/national coordinating investigator is not applicable, and sponsor is instead responsible for the entire trial. In these cases, the biobank agreement must be updated and the sponsor is stated as responsible instead of the principal/national coordinating investigator.
Update of biobank agreements after transition of trial to CTR:
The sponsor must send a request for updating the biobank agreement to: kliniskaprovningar@biobanksverige.se at the same time as the transfer of the trial to CTR has been approved. The request should contain the current EU trial number and all previously approved biobank agreements.
The responsible RBC then notifies current biobanks about the update of biobank agreements..
Important! The last day to notify RBC that the responsible organisation in biobank agreements needs to be updated in connection to the transfer of trial to CTR is June 30, 2025.
Material transfer agreements (MTAs) where signing parties have not changed, e.g. signed by the responsible biobank and sponsor, do not need to be updated.
Biobank samples are included
Biobank application
A biobank application is required for studies where newly collected samples will be established in and/or existing samples will be released from, remain in or be established in a regional biobank. The biobank application is then submitted to a RBC on the same day as Part II of the application for clinical trial is submitted into CTIS.
An RBC reviews the biobank application in parallel with the application for clinical trial and the sponsor is given the opportunity to address any considerations to the biobank application during the ongoing authorisation process, which means that the approval of the biobank application is accelerated after a decision on approval for a clinical trial.
Read more about the application process for access to biobank samples under the headline, “The process of the biobank application in clinical trials of medicinal products”.
Newly collected biobank samples
Please note that tissue samples taken at the same time as healthcare samples are usually defined as “existing healthcare care samples” even if they are newly taken in connection to the study.
In cases where newly collected biobank samples are included in the clinical trial, it needs to be clear who is to be the responsible biobank principal.
If the sponsor does not have its own biobank in Sweden and wishes to use the region’s biobank, it is recommended that the sample collection is established in one responsible biobank, even if the collection of sample takes place in several different regions. The sponsor is responsible for contacting a biobank in one of the participating regions early in the process, with a request if the biobank can be responsible for the sample collection.
If the sponsor has a registered biobank in Sweden, or if samples are to be established in another non-regional biobank, regions where biobank samples are newly collected must be notified that they should not be responsible for these biobank samples and that the samples will be established in another principal’s biobank. This is notified by completing the form T7a, signed by the concerned biobank’s biobank custodian and sent to the biobank coordinator in each concerned region in good time before the collection of samples will start.
Existing biobank samples
If the biobank application includes existing pathology/cytology samples, the local pathology laboratory should be contacted regarding the conditions in the current study and if they have any objections. Contact information can be found on Biobank Sweden’s service map under the heading “Study Coordinators Patology”. It is often an advantage that the local investigator contacts the pathology department in their region as they are familiar with the local conditions in the study.
In parallel with the application for clinical trial, a pathologist will perform a national feasibility assessment. The sponsor is given the opportunity to address any objections from the pathologist during the ongoing permit process, which means that the biobank application can be approved more quickly after a decision on permission for a clinical trial.
The feasibility assessment assesses whether:
- the required amount of material is reasonable in relation to the analyses to be carried out
- the choice of material is suitable for the analyses to be carried out
- the total amount of material does not exceed the national assessment criteria developed in collaboration with the Svensk Förening för Patologi (SvFP): From biopsies (small materials) that are archived in a healthcare sample collection, a maximum of 40μm in total is considered reasonable to distribute across all analyses, provided that the material is sufficient. From surgical material (larger material) that is archived in a healthcare sample collection, a maximum of 3–5 sections (4μm) per assay (maximum 2 sections per IHC marker/assay (one back-up section per marker)) and 30μm for DNA extraction are considered reasonable.
Please note that the amount of material in the criteria cannot be guaranteed in any way. In the case of biopsies, this amount is rarely even left in an existing block after sections have been used for care and diagnostics.
Whether the material is possible to access in the relevant regions is always assessed by the biobank concerned. The biobank application is approved by the biobank custodian after permission for a clinical trial and after approval by the relevant sample collection controller. Requested material can only be provided on the condition that sufficient material regarding type and quantity is left in the healthcare sample collection for the patient’s possible future care, diagnosis and treatment.
For more information, see assessment form TY4.
The process of the biobank application in clinical trials of medicinal products
Prior to submitting the biobank application
- Contact RBC early in the process, preferably at the planning stage, for guidance regarding the biobank application by e-mailing kliniskaprovningar@biobanksverige.se.
- A) Responsible biobank belongs to a region – Complete forms T1.1. If the application includes existing samples, form L1a and/or L1b is also to be completed.
B) Responsible biobank does not belong to a region – Newly collected samples could be established directly in the responsible biobank by the biobank custodian and according to the biobank’s own routines. No biobank application should be sent to RBC. If existing samples should be released from a region’s biobank, form L1a and/or L1b should be completed.All forms can be found at biobanksverige.se/en/documents/ under the toggle menu called “Clinical trials/performance studies”. - Send the un-signed biobank application to kliniskaprovningar@biobanksverige.se at the same time as the application for a clinical trial of medicinal product is registered into CTIS.
Assessment
- RBC validates and assesses the biobank application. If the application includes existing pathology/cytology samples a feasibility assessment is made by a pathologist.
Please note: RBC will communicate regarding the biobank application directly to the sponsor (or the person who represents the sponsor by submitting the biobank application). All communication regarding the clinical trial application shall go through CTIS.
Statement
- RBC will present the statement in form TY5 (RBC’s assessment report) and send to the sponsor by e-mail together with last date for response.
- If existing samples are to be released, RBC prepares the form for release of samples (T1.2) and sends it to the sponsor for possible correction together with the statement.
- Sponsor states the response to considerations in the form TY5 and send it back to RBC.
Final assessment
- RBC sends out final biobank application forms together with TY5 containing final assessment and instructions for approval of the biobank application.
Approval
Please note that the biobank application is approved by the biobank custodian after permission for a clinical investigation or performance study and after any endorsement by the relevant sample collection controller (if existing samples are included). If the deciding biobank region applies “wet ink” signing, the sponsor must submit all signed biobank applications to the deciding biobank(s) according to the instructions in TY5. for decision by an authorized representative of the biobank. Many biobanks instead apply digital signing, which is stated in TY5.
The following applies for assessed biobank applications:
Remaining documentation does not need to be enclosed but are sent to the appropriate biobank by the RBC.
If any modifications are made to the biobank application after the assessment, this must be stated in a separate covering letter addressed to the representative that is going to make the final decision – this may prolong the process.
Please note: the biobank agreement does not come into force until the biobank application and all appendices, if any, are signed by sponsor and approved and signed by an authorised representative of the biobank.
Request of alterations of the biobank agreement
If a request for substantial modifications of a clinical trial is made and the modification concerns a previously approved biobank agreement (e.g., modifications in study design that affect the agreement, change of sponsor, change of investigators, added sites, more samples or new sample types*), a request for alteration needs to be submitted to the RBC by e-mailing kliniskaprovningar@biobanksverige.se. If it concerns a biobank agreement established for a clinical trial before it was submitted to CTIS (established on form L1 or N1a), a copy of the earlier approved and signed agreement shall be appended to the request for alteration to facilitate and speed up the assessment.
Forms for alterations to previously approved biobank applications for clinical trials
- For ongoing biobank agreements established under the previous multicentre principle (on forms N1a, T1/T1a/T1c), form N2 shall be used for request of alterations.
- For all other ongoing agreements, form T1.3 shall be used for request of alterations.
All forms are available on the page with all documents.
*Please note, there can be other substantial modifications that concern the approved biobank application.
There can also be modifications that are non-substantial modifications for the clinical trial but that still need to be reported to the RBC, e.g., more research patients in Sweden and an extended sample collection period in Sweden.
For questions, please contact
A lot of frequently asked questions can be found on our FAQ-page.
For additional questions, you are also welcome to contact us by e-mailing:
kliniskaprovningar@biobanksverige.se