Clinical trials - questions and answers

1. Clinical trial with a medicinal product or not?

Which clinical trials require approval from the Danish Medicines Agency?

 We must give permission for 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 have permission 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 in a trial?

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 trial where medicinal products are used solely as tools does not need to be notified to the Danish Medicines Agency. Read more about this legislation.

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 trial should be applied 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.

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 on page 12 in The GCP Units guide to CTIS (overall guideline). 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.

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.

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.

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