2. General Questions

2.1 Name of Regulatory Authority

Swedish Medical Products Agency/Lakemedelsverket (“MPA”)

2.2 Name of Ethics Committee

Swedish Ethical Review Authority/Etikprövningsmyndigheten (“ERA”)

2.3 Clinical Trial Application Language

In Sweden, the CT application may be written in Swedish or English.

Note that a synopsis of the trial protocol must be submitted in Swedish. The synopsis shall be understandable to a layperson and should not exceed two A4 pages in length.

In Sweden, labeling documents for investigational medicinal products and auxiliary medicinal products, as well as the application dossier for Part II (national part) shall be submitted in Swedish. Where the information on biological samples referred to in point 17(s) of Annex I to the CTR is submitted in a separate document, that information shall be written in Swedish.

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

Yes. Simultaneous submission of applications for clinical trials may be made to MPA and Swedish EC via the CTIS portal. In some cases, approval by the Regional Biobank Centre or a biobank is also required.

2.5 Can regulatory authority and EC submission be done in parallel?

Yes, a single application submission for Part I (intended for the ANSM review) and Part II (intended for the EC review) can be submitted in parallel through the EMA CTIS portal.

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

Yes. Both manufacturing and importing from third countries require a Manufacturing and Import Authorization (MIA). Release within the EU/EEA must be performed by a qualified person (QP).

Verification documents in a clinical trial application

All manufacturing steps of a medicinal product, including packaging and labeling, should be performed under Good Manufacturing Practice (GMP). The following documents should be used to verify compliance with EU GMP.

Manufacture in Sweden

A copy of a valid MIA/GMP certificate or a reference to the authorization number (“diarienummer”).

Manufacture in other EU/EEA countries

A copy of a valid MIA or GMP certificate and, if relevant, a translation to English or Swedish.

Manufacture in a third country where the EU has a Mutual recognition agreement (MRA)

A QP declaration and a copy of a valid MIA or GMP certificate from the issuing authority in the country in question. The importing and QP certification site within the EU should also have an MIA.

Manufacture in a third country without an MRA

A QP declaration. The importing and QP certification sites within the EU should have an MIA.

QP declaration

The importer’s qualified person declares that the drug product manufacturing steps performed outside the EU/EEA are performed in line with EU GMP or comparable standards. The declaration should include the basis for the QP’s assessment, generally an audit or an inspection by a relevant EU-based (or MRA country) authority.

A template is available in EudraLex Volume 10, Clinical Trials Guidelines, Chapter III. 

Manufacturing of active substances for IMP

For chemically manufactured substances, compliance with EU GMP part II is recommended, but not required. Verification of GMP need not be submitted with the clinical trial application.

For biotechnologically manufactured substances, compliance with EU GMP part II is generally required. GMP verification as described above should be submitted.

Importing from non-EEA countries

Importing from a third country may be done by MIA holders, not by pharmacies. After QP certification, wholesalers/depots and pharmacies may distribute the IMP within the EU/EEA.

Swedish regulation

Swedish provisions for manufacturers and importers are available in Swedish on the MPA website. Refer to:

• The Medical Products Agency’s regulations (LVFS 2004:6) on good manufacturing practices for pharmaceuticals
• The Medical Products Agency’s regulations and general guidelines (LVFS 2004:7) regarding permits for the manufacture and import of pharmaceuticals

2.7 Biological Specimen Export Requirements

The Swedish Biobanks in Medical Care Act was replaced by a new Swedish Biobank Act (effective July 1st, 2023) which applies to identifiable samples collected and stored in a biobank or when used for research purposes.

The Biobank Act exempts the following:

• Samples intended to be destroyed within nine months of sampling and are destroyed immediately after analysis. Both conditions must be met. 
• Samples that are anonymized.
• Samples for transfusion, transplantation, insemination, or fertilization outside the body. 
• Samples used in situations covered by privacy protections in other laws. 
• Samples to be included in medicinal products or medical devices. These are rather to be considered as material.

If the clinical trial involves the collection of human biological samples, the sponsor is recommended to submit a biobank application (note that this document is the Swedish equivalent to the English document “Compliance with applicable rules for biological samples” and has been created by the Swedish Ethics Review Authority) to the EC in parallel with the application in CTIS. During the review of Part II, the EC will submit a statement to the Swedish Ethical Review Authority regarding information to research subjects and consent. The need for supplementation in terms of biobanks can be addressed during the authorization process.

Biobank Sweden has published detailed guidance on how to request a Biobank:

• Infographic: Access to biobank samples for clinical trials and performance studies
• Biobank Sweden: Biobank samples in clinical trials/performance studies

Sponsors are required to set a Biobank in Sweden (even for those instances when samples are going to be shipped abroad). If the Sponsor does not have a biobank, they could enquire with the Swedish sites participating in the study and agree if one of them could be used. The sample collection must then be established in the biobank using the form T1.1. If existing samples (tissue) are included, the form L1a will also be required.

For transferring biological samples outside Sweden, an agreement between the biobank and the recipient has been made using the form L2a2.

Shipping biological samples

Requirements will depend on the classification of the biological samples. In Sweden, the classification of infectious substances is based on the WHO document guidance on regulations for the transport of infectious substances.

Classification of biological samples is as follows:

• Category A: those are substances that when transported in a way that may cause permanent disability or life-threatening or fatal illness in otherwise healthy people exposed to.
• Category B: those are infectious substances that do not meet the criteria under category A, and be assigned the UN 3373 Biological category.
• Excluded: Those are samples taken from humans, in which there is a minimal probability that pathogens are present, those should be sent as an “exempt medical sample”. Exempted medical samples are not covered by the regulations for the transport of dangerous goods if they are packaged and labeled according to the regulations indicated on page 17 of the “Guidance for correct packing” (Packa Provet rätt from the Folkhälsomyndigheten).

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?

Yes, studies of GMOs are permitted subject to the applicable rules.

The Swedish Medical Products Agency (Swedish MPA) and the Swedish Work Environment Authority cooperate regarding the regulation of clinical trials of medicinal products containing or consisting of genetically modified organisms (GMOs) or genetically modified microorganisms (GMMs). This also includes clinical trials on animals covered by the Medical Products Agency's regulations.

Deliberate release of GMO and contained use of GMM

The Swedish MPA is the supervisory authority for the so-called deliberate release of medicinal products containing or consisting of GMOs, while the Swedish Work Environment Authority is the supervisory authority for the so-called contained use of GMMs. In Sweden, clinical trials with GMOs are assessed as deliberate release, but within the framework of the trial, there are parts that can be judged to constitute contained use of GMMs:

Deliberate release of GMOs into the environment refers to the stage from when the patient has been administered the investigational medicinal product. Thus, the Swedish MPA has supervisory responsibility from the time point at which the GMO‍-‍containing medicinal product has been administered to the patient.

Other aspects of the clinical trial such as manufacturing, transport (indoors), storage (e.g. at the hospital pharmacy), administration, and waste management regarding investigational medicinal products that contain or consist of GMM are counted as contained use and regulated by the Swedish Work Environment Authority’s statutes. The Swedish Work Environment Authority always also has the supervisory responsibility for work environment issues in these contexts.

2.9 Is in-country sponsor presence/representation required?

Only if the sponsor is not established in the EU, in which case, the Sponsor needs to establish a legal representative within the EU.

See Art 74, Clinical Trial Regulation (EU) 536/2014:  

“1. Where the sponsor of a clinical trial is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication to that legal representative shall be deemed to be a communication to the sponsor.

2. Member States may choose not to apply paragraph 1 as regards clinical trials to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.

3. As regards clinical trials to be conducted in more than one Member State, all those Member States may choose not to apply paragraph 1 provided that they ensure that the sponsor establishes at least a contact person in the Union in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.”

Pursuant to Chapter 4, Section 3 of the Medicinal Products Ordinance (2015:458) (Läkemedelsförordningen), the Swedish Medical Products Agency (MPA) may decide that the sponsor does not need to appoint a legal representative, but instead at least one contact person who shall receive all communications provided for within the framework of CTR. According to Article 74(2) of the CTR, this contact person shall be in Sweden if Sweden is the only EU Member State in which the clinical trial is to be conducted. If the clinical trial is to be conducted in more than one Member State, this contact person shall be within the EU, as pursuant to Article 74(3).

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country? 

Yes, a local investigator is required.

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.

See also the MPA page for clinical trials where extensive information is available.

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator? 

No, under the EU Clinical Trial Regulation 536/2014, there is no role for a Chief or Coordinating Investigator, only for a Principal Investigator and Investigator.

The definitions within the EU Clinical Trials Regulation 536/2014 referred to above, are as follows:

Art. 2 (2) (15): “Investigator” means an individual responsible for the conduct of a clinical trial at a clinical trial site.

Art. 2 (2) (16): “Principal Investigator” means an investigator who is the responsible leader of a team of investigators who conduct a clinical trial at a clinical trial site.

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled? 

Yes, a written contract is required between the sponsor and the CRO, delegating authority. The contract does not need to be notarized and/or apostilled, so far as we are aware, at an EMA level, now that applications are made electronically.

Article 71, Clinical Trial Regulation (EU) 536/2014, provides clarification on the sponsor's role:

“Sponsor

A clinical trial may have one or several sponsors.

Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution, or an organization. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial. The investigator and the sponsor may be the same person.”

2.13 Is there a requirement to register clinical trials on a local registry or database?

Yes, on the EU database of clinical trials.

From the 31^st Jan 2023, all initial clinical trial applications in the EU/EEA must be submitted through the Clinical Trials Information System (CTIS). The status and results of all trials submitted under the CTIS will be available to the public.

EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trials Regulations 536/2014 are publicly accessible through CTIS. 

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

The clinical trial master file must be retained for 25 years after the end of a clinical trial, whilst retention of medical files of clinical trial subjects is as per national law.

The format is unspecified, the requirements being that it be complete and legible – see Art 58, Clinical Trial Regulation (EU) 536/2014: 

“Archiving of the clinical trial master file

Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national law.

The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities.

Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article.

The sponsor shall appoint individuals within its organization to be responsible for archives. Access to archives shall be restricted to those individuals.

The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph.

Any alteration to the content of the clinical trial master file shall be traceable.”

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

Relevant provisions on periodic safety reporting are a part of the EU CTR 536/2014.

Articles 41 & 42, EU CTR 536/2014, relate to this.

Art 41 CTR: “Reporting of adverse events and serious adverse events by the investigator to the sponsor

1. The investigator shall record and document adverse events or laboratory abnormalities identified in the protocol as critical to the safety evaluation and report them to the sponsor in accordance with the reporting requirements and within the periods specified in the protocol.

2. The investigator shall record and document all adverse events, unless the protocol provides differently. The investigator shall report to the sponsor all serious adverse events occurring to subjects treated by him or her in the clinical trial, unless the protocol provides differently.

The investigator shall report serious adverse events to the sponsor without undue delay but not later than within 24 hours of obtaining knowledge of the events, unless, for certain serious adverse events, the protocol provides that no immediate reporting is required. Where relevant, the investigator shall send a follow-up report to the sponsor to allow the sponsor to assess whether the serious adverse event has an impact on the benefit-risk balance of the clinical trial...”

Art 42 CTR: “Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency

1. The sponsor of a clinical trial performed in at least one Member State shall report electronically and without delay to the database referred to in Article 40(1) all relevant information about the following suspected unexpected serious adverse reactions:

(a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred at a clinical trial site in the Union or in a third country;

(b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:

(i) by that sponsor, or

(ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product or information to a future potential marketing authorization holder on safety matters shall not be considered a joint development; and

(c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after the end of the clinical trial.

2. The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency shall take account of the seriousness of the reaction and shall be as follows:

(a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction;

(b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not later than 15 days after the sponsor became aware of the reaction;

(c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or non-life threatening but which turns out to be fatal or life-threatening, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening….”.

The MPA has more information available on Safety Reporting within their webpage “Safety Reporting”.

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

A safety report is required annually.

Article 43, Clinical Trial Regulation (EU) 536/2014:

“1. Regarding investigational medicinal products other than placebo, the sponsor shall submit annually through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational medicinal product used in a clinical trial for which it is the sponsor.

2. In the case of a clinical trial involving the use of more than one investigational medicinal product, the sponsor may, if provided for in the protocol, submit a single safety report on all investigational medicinal products used in that clinical trial.

3. The annual report referred to in paragraph 1 shall only contain aggregate and anonymized data.

4. The obligation referred to in paragraph 1 starts with the first authorization of a clinical trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor with the investigational medicinal product…”.

There are also other reporting/notification requirements, that will be required to be performed within the CTIS, those are:

2.17 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol? 

Yes, notification is required within seven days of becoming aware of the breach (see details below).

Notification of a Serious Breach allows the sponsor to inform about a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial. These notifications must be made without undue delay but no later than 7 days from the date on which the sponsor became aware of the breach (article 52 of the CT Regulation). 

For more information, refer to the following EMA guidance on notification of serious breaches: 

1. Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol 
2. Appendix III b – Information to be submitted with a notification of a serious breach

2.18 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

Yes. According to the Patient Injury Act (1996:799), healthcare providers are obliged to have insurance that covers damages in healthcare. The regions have their insurance, Patient Insurance, with the Regions Mutual Insurance Company (LÖF). This insurance also covers damages that may occur in connection with research on people who are patients in health care.

Läkemedelsförsäkringen AB provides compensation for damages that occur as a result of the use of drugs or placebos. The insurance applies to medicines from companies and organizations that have taken out insurance with Läkemedelsförsäkringen. It also covers damages that have occurred in connection with research.

The Swedish Clinical Studies Sweden (Kliniska Studier Sverige) provides useful templates for clinical trials according to the EU Regulation 536/2014, and one of them is a template for the certificate of insurance coverage.