Clinical trials - questions and answers

1. Clinical trial with a medicinal product or not?

Which clinical trials require authorisation from the Danish Medicines Agency?

 We must authorise clinical trials involving medicinal products and medical devices not CE marked for the purpose it is being tested for. (Read more about medical devices here).

2. What is a clinical trial with medicinal products?

According to Article 2 of the Clinical Trials Regulation, the definitions are as follows. Clinical trials and clinical low-intervention trials must be authorised before initiation.

1. ‘Clinical study’ means any investigation in relation to humans intended: (a) to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products; (b) to identify any adverse reactions to one or more medicinal products; or (c) to study the absorption, distribution, metabolism and excretion of one or more medicinal products; with the objective of ascertaining the safety and/or efficacy of those medicinal products.
2. ‘Clinical trial’ means a clinical study which fulfils any of the following conditions: (a) the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned; (b) the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or (c) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.
3. ‘Low-intervention clinical trial’ means a clinical trial which fulfils all of the following conditions: (a) the investigational medicinal products, excluding placebos, are authorised; (b) according to the protocol of the clinical trial, (i) the investigational medicinal products are used in accordance with the terms of the marketing authorisation; or (ii) the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on the safety and efficacy of those investigational medicinal products in any of the Member States concerned; and (c) the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to normal clinical practice in any Member State concerned;
4. ‘Non-interventional study’ means a clinical study other than a clinical trial.
   
   

3. When can a medicinal products be defined as a tool?

The medicinal products (tool) is not the subject of the investigation and is used as a tool to achieve a well-known physiological response.

Examples: Pupil-dilating eye drops are used to examine eye physiology.

Radioactively labeled tracer (medicinal product) in a PET scan to obtain an image of, for example, oxygen uptake or glucose metabolism in the body.

No therapeutic, diagnostic, or preventive effect or safety of the medicine (tool) is investigated. No data are collected regarding the pharmacological effects of the medicine, including pharmacodynamics and/or pharmacokinetics.

A clinical study where the medicinal products are used solely as tools does not need to be notified to the Danish Medicines Agency.

4. Do I need to notify trials where medicinal products are used as tools to the Danish Medicines Agency?

No, this type of trial is not subject to notification requirements.

5. Can I get an assessment of whether the Danish Medicines Agency should approve a specific clinical trial?

If you are unsure whether a clinical study or trial should be applied for and approved by the Danish Medicines Agency, you can submit an inquiry. The inquiry must include the trial protocol and information of the medicinal product to be tested (e.g. SmPC). If the protocol is not complete, we can assess it based on a synopsis, which must include the purpose, endpoints, and description of how they are achieved.

You can submit your inquiry via this link: Inquiry about clinical trial classification. If there is doubt about whether the substance to be tested is a medicine or not, you can get help here: Distinguishing between medicines and other products.

Read more about the definitions for clinical trials in the latest version of the Question and Answers document under the Eudralex Vol. 10 Clinical Trials Guidelines. 

6. What is the definition of a non-commercial clinical trial?

A non-commercial trial is defined by one that is conducted entirely or predominantly without the influence of pharmaceutical companies. It is therefore researcher-initiated and no pharmaceutical companies have influence over the trials design, initiation, and execution, as well as the registration and publication of trial results.

1. Where can I see which documents need to be submitted?

In Annex 1 of the regulation, the documents that need to be submitted are listed. The Danish Research Ethics Committees have also created a Q&A page for CTR/CTIS, where they answer a wide range of questions about submission requirements. Link: Clinical Trials with Medicinal Products under the CTR | Danish Research Ethics Committees

2. Are there guidelines for naming documents?

Documents uploaded to the CTIS portal must not contain dates and version numbers in the file name. Instead, refer to "Instruction Naming Documents".

3. How do I submit and update documents in CTIS?

3 a) Submission of documents:

Can be done either with initial application, substantial modification, or non-substantial modification. Documents are uploaded either under the sections they belong to or under the "All documents" tab. Find more information about this in The GCP Units guide to CTIS (overall guideline) on the GCP-units´ home page. From 18 June 2024 the new transparency rules are implemented in CTIS. This means that only structured data, protocol, synopsis, and patient information will be published in the future. Remember to ensure that the structured data in CTIS (Title, language, version, and date) match the actual content of the document. Version and date should not appear in the document title but only in the structured data - see the CTCG best practice guide naming of documents.

3 b) Updating documents:

When uploading new versions of existing documents, use the "Update" button (paper icon) next to the existing document.

4. What information should the trial protocol contain?

The Danish Medicines Agency has created a template for trial protocols (in English as a Word file), which describes the information that must be included in a protocol to comply with the requirements of Annex 1, section D of the regulation, as well as the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) M11 template.

5. What information should be included in the cover letter, when submitting an application?

According to Annex 1, section B of the regulation, the cover letter must contain core information about the trial such as the EU trial number, protocol code/number, title, and sponsor. The cover letter must indicate who the sponsor has delegated GCP monitoring of the trial to and confirm that the monitor understands Danish. Invoicing information can be mentioned in the cover letter or uploaded as a separate document in the "Proof of payment" section. There must be a list of all trial medicinal products and auxiliary medicines, indicating their regulatory status (marketed or not). It must be indicated in the application where the reference safety documents (RSI) for the individual trial medicines are located. If there are any special circumstances regarding the trial design, trial medicine, or population, this must also be stated in the cover letter, such as first-in-human trials, decentralized trials, trials in children, or particularly vulnerable populations, among others. For a detailed list, we refer to Annex 1, section B of the regulation, which describes the requirements for the content of the cover letter.

In case of a resubmission, the changes made should be specified.

Please see CTCG's Templates for cover letters. The latest edition can be found on CTCG's website under "Key documents list".

6. Do I still need to submit my application to the Danish Medicines Agency and the Ethics Committee system after the regulation comes into force?

The clinical trial application is processed by both the Danish Medicines Agency and the Medicinal Research Ethics Committee (VMK) when submitted to the new EU portal. Therefore, applications do not need to be submitted directly to the Danish Medicines Agency or the VMK.

7. Which documents need to be submitted in Danish?

Annex II to the EU Commission's question and answer document specifies which documents can be submitted in Danish or English for Part I. The question and answer document can be found under Set of documents applicable to clinical trials authorized under Regulation EU No 536/2014, EudraLex Volume 10 to the regulation.

8. Should the same documents be submitted multiple times?

In the future, it may create problems in the structure of the CTIS portal if the same document is uploaded in multiple sections. Instead, the current document can be uploaded in one section and a blank document with a reference can be uploaded in the other sections.

9. Should trials that only take place in Denmark (mono-national trials, including trials from non-commercial sponsors) be submitted through the EU portal?

All trials with medicinal products must be submitted through the EU portal (CTIS).

10. Should all submissions be made through the portal, e.g. annual safety reports?

All submissions during the trial's lifetime, including notifications, substantial modifications, annual safety reports, final report, and results, must be made through the portal. An exception, however, is SUSARs, which must be sent directly to the EudraVigilance database. EMA has developed guidance and organized training.

11. Is it possible to refer to quality documentation from other trials or refer to quality documentation submitted separately by the manufacturer to ensure confidentiality?

It is possible to refer directly to another trial approved under the regulation or transitioned to CTIS, where the same quality documentation has been assessed. Alternatively, a procedure has been agreed upon where the manufacturer can submit the quality documentation (IMPD-Q) separately in CTIS. Both of these scenarios are described under question 2.15 in the EU Commission's question and answer document under Set of documents applicable to clinical trials authorized under Regulation EU No 536/2014 in EudraLex Volume 10 to the regulation.

12. What should I be aware of if my trial is a gene therapy trial?

Human trials with preparations containing living, genetically modified organisms are subject to the "Act on Environmental and Genetic Technology", with focus on the law's rules on research. The rules are outlined in the executive order (no. 910 of September 11, 2008) on "genetic technology and the work environment". The executive order includes requirements for notification of the classification of premises where all or part of the trial will take place, as well as notification of projects. Notifications are made to ensure both the work environment and the external environment. The Danish Working Environment Authority then approves both premises and trials. A cooperation has been agreed between the Danish Working Environment Authority and the Danish Environmental Protection Agency on the handling of certain notifications of the classification of premises and notifications of research projects. This has led to the following practice: Notifications of the classification of premises for gene therapy and notifications of projects on the use of living, genetically modified microorganisms for gene therapy are submitted to the Danish Working Environment Authority, which then sends a copy of the notifications for consultation to the Danish Environmental Protection Agency. Trials involving gene therapy must, according to the above, be notified to the Danish Working Environment Authority. This can be done in parallel with the application to the Danish Medicines Agency. Further information on notifications can be obtained by contacting the Danish Working Environment Authority (or phone 39 15 20 00).

1 a) How do I apply in the EU portal (CTIS)?

We refer to the training program from EMA. Here, all steps are covered via video and guides. Furthermore, the GCP unit has prepared a CTIS guide, and EMA has prepared a Sponsors Handbook.

1 b) Where does the sponsor need to be registered to use the EU portal (CTIS)?

The sponsor must be registered in EMA's Organizational Management Service (OMS), further information can be found on EMA's website with information regarding training and preparation for using CTIS.

1 c) Are there requirements in Denmark for registration of a Legal Representative in the CTIS portal?

If the sponsor is residing in a country outside the EU, it is a requirement under the Act on Clinical Trials of Medicinal Products §21 that a Legal Representative residing in the EU is registered in CTIS. It is not sufficient for the "Contact point for the union" to reside in the EU.

1 d) How do I link investigational medicinal products and placebos in the CTIS portal when applying for a new clinical trial?

All medicinal products/substances used in the trial must be registered in EMA's Extended EudraVigilance Medicinal Product Dictionary (XEVMPD) before they can be linked to the trial in CTIS. However, the placebo product can also be entered directly into CTIS. For development products registered in XEVMPD, EU MP number and EU substance number must be known to link them to the trial in CTIS. Marketed products can be retrieved from CTIS using multiple search criteria.

1 e) How should I handle documents with signatures in CTIS?

If signed documents (e.g. QP declaration) are submitted, these must be uploaded in a version "not for publication" in addition to the version uploaded "for publication". Link to guidance from ACT EU here.

1 f) Where can I see the processing times for my application?

In CTIS, there is a "Timetable" under each application (for initial application and subsequent substantial modifications). This timetable is automatically generated and takes into account weekends and public holidays in the affected member states. It is also worth noting that some deadlines are dynamic, as they depend on when the assessment by the authorities is completed. You can read more about application deadlines in EMA's guidance on CTIS Evaluation Timelines.

1 g) Where can I see if my trial is approved in CTIS and which versions of the documentation are approved?

The Danish Medicines Agency does not issue approval letters for clinical trials, as all information about the trial's approval is available in CTIS. The approved versions of the trial documentation are shown in the final assessment report, in the Introduction and Conclusion sections, respectively. In addition, the sponsor can download the structural data from CTIS as a PDF file, which contains the product names and the estimated end-of-trial date. EMA's Step-by-step guide - How to search, view and download a CT and a CTA (Sponsors) shows how to download structured data (on page 4). Afterwards, you can cut out the page with the end-of-trial date from the PDF file if you do not wish to share further information.

1 h) Where can I find help regarding technical questions related to CTIS?

Dedicated CTIS helpdesk for non-commercial sponsors

The Accelerating clinical trials in the EU (ACT EU) initiative has established a dedicated helpdesk,

which employs different measures to support non-commercial sponsors in navigating the clinical trial landscape in the EU.

Currently, the helpdesk offers tailored technical assistance on CTIS functionalities and other questions by raising a ticket in the CTIS Service Desk and indicating their status as a non-commercial sponsor in the mandatory field “User affiliation”.

Non-commercial sponsor are invited to contact the Clincal Trials Unit at the Danish Medicnes Agency directly when questions arise (Send an e-mail). Further are the GCP-units also available for assistance. 

Link: CTIS Service Desk

2. Transition to the Clinical Trials Regulation

How do I transition my ongoing trial to the regulation?

For trials that need to transition to the regulation, we recommend reading more here.

3. Substantial Modifications (amendments) and notifications

3 a) Is it still possible to submit a new substantial modification when I already have a modification under review in CTIS?

For submission of Substantial Modifications in CTIS, we recommend reading more here: Substantial Modifications.

3 b) What are the requirements for notifications in the CTIS portal before, during, and after the trial?

Member states must be notified about the following in the CTIS portal:

• Start of the trial
• Start of recruitment
• End of recruitment
• End of trial (national and global)
• Expected date for publication of Summary of Results
• Third-country inspections

If safety events occur, such as Temporary halt, Urgent Safety Measures, Unexpected Events, or similar, the sponsor must notify member states in CTIS. Guidance is available in the Sponsors Handbook, section 7.1.2.

4. Transparency

How much is disclosed in the EU portal and database (CTIS)?

From 18 June 2024 the new transparency rules are implemented in CTIS. This means that only structured data, protocol, synopsis, and patient information will be published in the future. More information in Quick guide: Revised CTIS transparency rules & Historical trials: Quick guide for users (europa.eu) Re-submission

5. How do I submit a re-submission in CTIS?

Re-submission is applied for in CTIS using the "re-submission" functionality on the existing EU CT trial number. It must be stated in the cover letter that it is a re-submission. We recommend that, in all uploaded documents containing an EU CT number, the last two digits of the number be removed, as these change with each re-submission. This way, you avoid having to update this number again in case of a new re-submission. Advantageously, with re-submission, the corrections that were requested during the initial submission of the trial can be made. It is only necessary to address these changes in the cover letter and clarify where in the documentation the updates are found. In addition, updated documents must be uploaded in both a clean version and a track changes version.

For guidance on resubmission, see EMA’s FAQ, section 6.5

What requirements apply to reporting GCP deviations (serious breaches)?

According to the EU regulation, there are requirements to report serious GCP deviations (read definition on our page regarding serious breaches). Serious deviations from the protocol/regulation must be reported in the EU portal. You can find more information in module 5 under Sponsor Workspace in EMA's online training.

Requirements for Contraception in Clinical Trials

The requirements for the use of contraception in clinical trials differ from those in regular clinical practice. In clinical trials, the sponsor has an obligation to minimize the risk of exposure to a potential fetus. Therefore, there are specific requirements for pregnancy testing and the use of contraception to ensure patient safety and avoid unnecessary risk to a potential fetus.

It is essential that the trial protocol includes a detailed description and justification of how contraception requirements and pregnancy testing are handled in the specific clinical trial.

General reference should be made to the Clinical Trials Coordination Group (CTCG) guidelines, which provide detailed EU recommendations on contraception methods and pregnancy testing in clinical trials.

The guidance document from CTCG Clinical Trials Coordination Group "Recommendations related to contraception and pregnancy testing in clinical trials Version 1.2" can be found on  HMAs homepage under Key Documents list under the subsection Other Guidance and Q&A Documents. 

Requirements for Inclusion of Men in Trials

Sexually active men with a fertile female partner must use a condom at a minimum as long as it cannot be ruled out that the investigational medicinal product may pose a risk to a fetus. If the Investigator’s Brochure (IB) or the product information for an approved medicinal product describes proven embryofetal toxicity, the fertile female partner of the male trial participant should be encouraged to use effective contraception in combination with a condom.

Requirements for Inclusion of Fertile Women in Trials

It must be clearly stated in the protocol, or an addendum thereto, that fertile women are tested for pregnancy before participation (negative pregnancy test required). Fertile sexually active women must use effective contraception (highly effective methods of contraception) during participation in clinical trials until sufficient data has been collected to conduct a satisfactory analysis of the potential risks that an investigational medicinal product under development poses to a fetus and for investigational medicinal products with an identified high-risk profile (proven reproductive/genotoxicity and/or teratogenicity).

The following methods are considered effective contraception: intrauterine device (with or without hormones), hormonal contraception (pills, implants, transdermal patches, vaginal ring, or depot injection), or abstinence (only acceptable if it is consistent with the trial participant's normal lifestyle). In special cases, other contraception methods may be accepted, which requires thorough professional justification based on the trial design, the toxicity profile of the medicinal product, the impact on hormonal contraception, and/or the patient population.

If there is sufficient documentation that the medicinal product is not reproductive toxic in humans, less effective contraception methods than those previously mentioned may be sufficient. This is further described in the CTCG guideline which can be found on  HMAs homepage under Key Documents list under the subsection Other Guidance and Q&A Documents.

Contraception Requirements During and After the Trial

Fertile women and men included in trials must use contraception in accordance with the CTCG guidelines throughout the trial period and after the trial ends for a period until the systemic exposure of the investigational medicinal product has decreased to a concentration that is not relevant for human teratogenicity. This period is generally defined as five times the half-life of the medicinal product after the last dose or the time interval that may be described in the product information or Investigator’s Brochure.

The protocol must clearly include:

• A correct definition of fertile women / women of childbearing potential (WOCBP)
• Description of the toxicity profile of the investigational medicinal product (reproduction, genotoxicity, teratogenicity)
• Justification for the choice of required contraception methods based on the toxicity profile of the investigational medicinal product and a detailed list of acceptable contraception methods
• Considerations of interactions affecting hormone-based contraception
• Indication of the duration of contraception use (typically until five times the half-life of the medicinal product after the last dose)
• At a minimum, pregnancy testing at inclusion; pregnancy testing is often also required during the trial until the end of clinically relevant exposure
• Timing and frequency of additional pregnancy testing based on the toxicity profile of the investigational medicinal product
• Relevant inclusion and exclusion criteria for contraception requirements, pregnancy, and breastfeeding
• For male trial participants, consideration of the need for condom use and/or contraception requirements for the WOCBP partner

Link for the protocol tempale is found here.

Participant Information

Participant information must always reflect the protocol's contraception requirements, including which contraception forms are considered acceptable in the trial and pregnancy testing, as well as convey information about potential toxicity risks. If relevant, trial participants should be informed about the prohibition of sperm/egg donation and the duration of this prohibition. Consideration should also be given to whether there is a need for information and procedures for freeze-storage of sperm/egg for future use.

Exceptions

Sterile or non-fertile trial participants are exempt from contraception requirements. Sterility is typically defined as surgically sterilized (vasectomy/bilateral tubectomy, hysterectomy, and bilateral oophorectomy) or postmenopause defined as the absence of menstruation for at least 12 months without another cause and confirmed by measuring FSH levels.

Special Conditions

For certain individuals or specific populations, there may be conditions that argue against the use of the above methods. Examples include severely debilitated hospitalized patients or non-sexually active fertile children. The protocol must provide a robust justification for any exceptions and deviations from the CTCG guidelines, based on the necessity for the trial to be conducted.

Can one participate in multiple clinical trials simultaneously?

It is the clinical trial protocol that must determine whether inclusion in the trial can be permitted with simultaneous treatment in another clinical trial. Some protocols include a standard exclusion criterion, which excludes the inclusion of individuals who are already participating in another clinical trial. New types of trial designs, such as low-intervention cluster trials (where investigational medicinal products are authorized, such as influenza vaccination), can challenge this type of general exclusion, as the new low-intervention trial designs may include very large populations, thereby significantly limiting recruitment. Therefore, it should be considered that the exclusion criterion for participation in other trials is flexible and assessed ad hoc. It is our assessment that if a trial protocol is updated with a flexible exclusion criterion to address the above challenge, it constitutes a non-substantial change.

What should I do if I want DK to take on the role of RMS?

Submission requirements

It is our general approach that we would like to take on the task of RMS when a sponsor appoints us in CTIS. Therefore, it is not necessary to send an email in advance, as we will do our best to accommodate the request. However, there may be periods where we are forced to decline, for example, if we have many trials received in the same period.

Where can I read more about Scientific Advices?

Read more on the Danish Medicines Agency's page: Scientific advice on medicinal products

Where can I find information about Complex Clinical trials?

CTCG has collected the Recommandation and Questions and Answers on their website under Key document list.

Direct link to recommendation paper on complex clinical trials can be found here.