Clinical trials - questions and answers
- Which clinical trials must be authorised by the Danish Medicines Agency?
- What is a clinical trial of a medicine?
- What is a non-interventional trial?
- What is a PASS study?
- Must PASS studies be registered in the EU?
- When are PASS studies to be authorised by the Danish Medicines Agency?
- When must I notify the Danish Medicines Agency about non-interventional PASS studies?
- What documentation must I submit to the Danish Medicines Agency for non-interventional PASS studies?
- What is a Type A trial?
- What is a tool trial?
- Must I report tool trials to the Danish Medicines Agency?
- Can I get the Danish Medicines Agency's assessment of whether a specific trial is to be approved?
- How to submit the application to the Danish Medicines Agency
- How do I provide my invoice details?
- When must I submit notifications/inform the Danish Medicines Agency?
- Which types of contraception does the Danish Medicines Agency consider safe in clinical trials?
- The power of attorney for representatives from foreign authorities who are to monitor the trial, what must it give access to and for how long?
- Does the Danish Medicines Agency accept deviations from the protocol (waivers)?
- When is a revised Investigator's Brochure a substantial amendment?
- Which amendments are substantial?
- Is a comparator an investigational medicinal product?
- What distinguishes background treatment from an investigational medicinal product?
- How often must I submit a report incl. a list of serious adverse reactions to the Danish Medicines Agency?
- What is VHP?
- What is VHP-plus?
- Which documents are to be submitted under a national VHP?
- What is a SUSAR?
- How should I submit SUSARs to the Danish Medicines Agency?
- How can I as a non-commercial sponsor report SUSARs, when I don't have access to EudraVigilance?
- Which documentation must I submit, when I import medicines from countries outside the EU?
- How is my trial registered in the EU Clinical Trials Register?
- How can I get scientific advice in connection with development of medicinal products?
- How frequently is the sponsor expected to submit safety information to the investigator for clinical trials of medicinal products in humans?
- What is required of the sponsor in relation to providing safety information to the investigator sites in the period from the Investigator's Brochure (IB) is final and until the trial is initiated at a site?
We must authorise the conduct of clinical trials of medicinal products and clinical investigations of non CE-marked devices or CE-marked devices for a new purpose. (please see www.medicaldevices.dk).
A clinical trial is defined as any trial in humans that aims to:
- Uncover or verify the clinical effects of one or more investigational products and/or
- Uncover or verify the pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal products and/or
- Test the absorption, distribution, metabolism and excretion of one or more investigational medicinal products (pharmacokinetics) and/or
- Identify adverse drug reactions from one or more investigational medicinal products
with the purpose of assessing the safety and/or effect of investigational products.
We recommend you to use our Guide to assessing if a trial falls under the definition of a clinical trial
A clinical trial application must be sent to the Danish Medicines Agency for approval.
It is a non-interventional trial when:
- The medicinal product or medicinal products in the trial are prescribed in the usual manner in accordance with the terms of the marketing authorisation
- The decision to prescribe the medicine concerned is clearly separated from the decision to include a specific patient in the trial
- The actual treatment follows normal practice and is not decided by a trial protocol
- No additional diagnostic or control procedures are carried out (in Denmark, questionnaires are not considered to be additional procedures)
- Epidemiological methods are used for the analysis of the gathered data.
Non-interventional trials are not to be notified to the Danish Medicines Agency unless it concerns certain types of non-interventional PASS studies. Please see below.
We recommend you to consult our Guide to assessing if a trial falls under the definition of a clinical trial.
For further information, please see the Commission's Questions & Answers: http://ec.europa.eu/health/files/eudralex/vol-10/ctqa_v10.pdf – see Annex: Decision tree.
- A PASS study (post-authorisation safety study) is:
a study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard or confirming the safety profile of the medicinal product. It can also be conducted with the aim of measuring the effectiveness of risk management measures.
- a study in which the medicinal product is used in compliance with the conditions of the marketing authorisation. A PASS study may be an clinical trial (interventional) or a non-interventional study.
A PASS study may be initiated by the marketing authorisation holder voluntarily, or pursuant to a condition in the marketing authorisation, and it may be conducted in one or more European countries.
For further information about PASS studies, please see this European Guideline on good pharmacovigilance practices (GVP).
Yes, PASS studies must be registered in the electronic register for post-authorisation studies known as the EU PAS Register. The study protocol must be submitted to the register before the start of data collection. The Danish Medicines Agency is not to be informed of PASS studies before they have been registered in the EU PAS Register.
For further information please see the EU PAS Register Guide
This depends on whether the PASS study is initiated voluntarily by the marketing authorisation holder or pursuant to a condition in the marketing authorisation granted by the Danish Medicines Agency or a condition in a European marketing authorisation.
- Non-interventional PASS studies which are initiated due to a condition in the marketing authorisation granted by the Danish Medicines Agency must be authorised by the Danish Medicines Agency if the study is only to take place in Denmark.
- Non-interventional PASS studies which are initiated based on a condition in a European marketing authorisation are assessed, authorised and monitored by PRAC (the Pharmacovigilance Risk Assessment Committee) – a committee under the European Medicines Agency (EMA). The Danish Medicines Agency does not authorise these studies. For more information, please see PRAC
- Non-interventional PASS studies which are initiated voluntarily by the marketing authorisation holder must not be approved by the Danish Medicines Agency.
- Interventional PASS studies must be approved by the Danish Medicines Agency.
For further information about PASS studies, please see this European guideline: Guideline on good pharmacovigilance practices (GVP)
The Danish Medicines Agency must be notified of and receive documentation for non-interventional PASS studies when:
- non-interventional PASS studies are initiated based on a condition in a marketing authorisation granted by the Danish Medicines Agency.
- non-interventional PASS studies are initiated based on a condition in a European marketing authorisation if the study takes place in Denmark. Documentation must be submitted after PRAC (Pharmacovigilance Risk Assessment Committee) has authorised the trial.
- non-interventional PASS studies are initiated voluntarily by the marketing authorisation holder, if Denmark acts as reference member state or rapporteur for the medicinal product.
For more information, please see Annex to GVP module VIII - Post-authorisation safety studies
8. What documentation must I submit to the Danish Medicines Agency for non-interventional PASS studies?
The Danish Medicines Agency must receive the following documents:
- Cover letter detailing:
- the date of registration in the EU PAS Register and registration number
- if the study is initiated voluntarily or based on a condition in a marketing authorisation
- if Denmark acts as rapporteur/reference member state in the case of voluntary non-interventional PASS studies
- if the study takes place in Denmark
- the date of authorisation by PRAC (for studies with a condition in a marketing authorisation)
- PRAC's assessment report for studies initiated on the basis of a condition in a European marketing authorisation
- trial protocol
- updated trial protocol following substantial amendments
- the finial clinical study report no later than 12 months after the trial has ended.
Further details about the information to be submitted to the Danish Medicines Agency regarding PASS studies appear from this Guideline on good pharmacovigilance practices (GVP)
A trial must satisfy the criteria below in order for it to be a Type A trial:
- The investigational medicinal products to be tested are authorised in an EU or EEA country
- The investigational medicinal products are tested in the patient population they are licensed for
- The investigational medicinal products are tested under the licensed indication, dose and route of administration
- The risk involved for the trial participants is on the same level as the risk of standard treatment
We offer an assessment time of 14 working days for Type A trials provided that the application is complete when we receive it. Further information is available here.
- The medicinal product (the tool) is not the subject of the trial and is used as a tool to induce a well-known physiological response.
- Pupil dilating eye drops used to study the physiology of the eye
- Radioactive trace elements (medicinal product) in PET scans to produce an image of, for example, oxygen use or glucose metabolism in the body
- The therapeutic, diagnostic or preventive effect or safety of the medicinal product (the tool) is NOT being verified or tested.
- NO data is gathered concerning the medicinal product’s pharmacological effects, including pharmacodynamics and/or pharmacokinetics.
A clinical trial, in which medicinal products are only used as a tool should not be notified to the Danish Medicines Agency. Read more about the legislation
No, this type of trial is not subject to a notification duty.
12. Can I get the Danish Medicines Agency's assessment of whether a specific trial is to be approved?
We recommend you to consult our Guide to assessing if a trial falls under the definition of a clinical trial
If you are still not sure if the clinical trial in question should be notified to the Danish Medicines Agency, you can send us an enquiry about the obligation to apply.
Such an enquiry must include the trial protocol and data about the product you wish to study. If the protocol is not yet completed, we can assess it based on a synopsis describing purpose, effect aims and a description of how these are to be achieved. Please send your enquiry to email@example.com.
If you are unsure whether the substance to be trialled is characterised as a medicine or not, please consult this page: How to distinguish between medicines and other products.
13. How to submit the application to the Danish Medicines Agency
Clinical trial applications can be submitted to the Danish Medicines Agency via DKMAnet, on CD-ROM or via Eudralink.
- Application via DKMAnet
Companies, including CROs (Contract Research Organisations) engaged in clinical trials of medicines in humans can apply for authorisation of clinical trials and submit notifications about ongoing trials to DKMAnet, our access-controlled extranet: Read more about Applying for clinical trial authorisations via DKMAnet.
- Application on CD-ROM or via Eudralink
Applicants who do not have access to the DKMAnet can submit their documentation digitally on a CD-ROM or via Eudralink. Eudralink is the European Medicines Agency's (EMA's) system for secure file transfer.
Read more about Clinical trial applications on CD-ROM or online via Eudralink
14. How do I provide my invoice details?
Invoice details must be stated in the cover letter (EAN no. for public institutions).
Please also see the checklist for applications: Checklist for application for authorisation of a clinical trial – Appendix 10 – click on Appendix 10.
The Danish Medicines Agency must be notified in the following cases:
- Extension of trial period relative to the date approved on the Danish authorisation.
- New trial sites/change of trial sites (including updated XML file).
- Change of principal/coordinating investigator (including updated XML file).
- Changes in CRO/applicant (incl. updated XML file if changed)
- When the trial ends in Denmark
The above changes are not to be approved by the Danish Medicines Agency.
Only substantial amendments must be submitted to the Danish Medicines Agency.
16. Which types of contraception does the Danish Medicines Agency consider safe in clinical trials?
We acknowledge the following contraceptive products as safe in connection with trials of medicinal products: Intrauterine devices or hormonal contraception (oral contraceptive pills, implants, transdermal patches, vaginal rings or long-acting injections).
It is accepted in certain cases to include subjects having a sterilised permanent partner or subjects using double barrier contraceptive methods. However, this should be explicitly justified in special circumstances arising from the study design, product characteristics and/or patient population. For the purpose of this guideline, double barrier methods of contraception means a condom combined with a diaphragm and spermicide.
For more information, please see: Guideline for applications for authorisation of clinical trials of medicinal products in humans – 5.1 Contraception
17. The power of attorney for representatives from foreign authorities who are to monitor the trial, what must it give access to and for how long?
A power of attorney is only required if inspections are to be carried out by representatives from foreign authorities that will be monitoring the trial
By signing a power of attorney, trial subjects grant access to their entire patient record for a specific number of years.
If data from the trial is expected to be used for authorisation of a medicinal product, the number of years in which access is granted to the patient's record must take into account the time expected to pass until authorisation.
Please note the following minimum requirements for the power of attorney:
It must be clearly evident from a headline or a subheading that it is a power of attorney.
The wording "I hereby authorise..." must be used. Phrases such as "I give my consent to..." or "I am informed that..." are thus not accepted.
The power of attorney must apply to the entire patient record. Access to the patient record must thus not be limited to parts or relevant sections of the record.
The purpose of the power of attorney must appear (inspection/monitoring).
It must appear that access to the patient record applies during and after the trial in a period of up to at least 5 years after the end of the trial. Both a period and a number of years must be specified.
We recommend that no reference is made to any legislation since the power of attorney is based on contract law.
Authorisation to transfer data to third countries is not to be placed in the the power of attorney as it belongs under the Danish Data Protection Agency's legislation. The information on such transfer of data can instead be inserted in the information for trial subjects..
The power of attorney may be part of the consent form, but we recommend keeping consent form and power of attorney as two separate documents.
Please also be aware that it must appear from the information for trial subjects that the Danish Medicines Agency and the sponsor have access to the entire patient record for monitoring and inspection purposes.
For more information, please see: Guideline for applications for authorisation of clinical trials of medicinal products in humans – under section 10.
No. We do not accept deviations from the protocol (waivers).
Only in cases where the risk-benefit assessment is changed.
Here you can find a more detailed description of what the Investigator's Brochure must include: Investigator's Brochure.
See our list of 'changes considered substantial': Amendments to clinical trials
You can find further information in the European Commission's Questions & Answers, question 1.3, via the following link: http://ec.europa.eu/health/files/eudralex/vol-10/ctqa_v10.pdf.
Background treatment is not considered an investigational medicinal product when the following criteria are met:
- The aim of the trial is not to gather information about the background treatment or the combination of background treatment and other investigational medicinal products in the protocol
- The protocol does not make any specific requirements for the background treatment, apart from the requirement that it must be administered to all trial subjects in combination with the investigational medicinal product including the comparator
- The protocol defines the background treatment without requiring that a specific trademark is used
- The background treatment is the standard treatment in Denmark, and it is the treatment that would be offered to the trial subjects if they chose not to participate in the trial.
23. How often must I submit a report incl. a list of serious adverse reactions to the Danish Medicines Agency?
Once a year throughout the trial period, you must submit a list of all serious suspected adverse reactions and a report on trial subject safety.
The Voluntary Harmonisation Procedure (VHP) is a procedure which makes it possible to obtain coordinated assessment of an application for a clinical trial that is to take place in several European countries.
For more information, please see: Voluntary Harmonisation Procedure (VHP) for the assessment of multinational clinical trial applications.
The VHP procedure has been extended and now includes the VHP-plus procedure, in Denmark the National Research Ethics Committee. The Danish Medicines Agency will be involved in VHP-plus only for clinical trials involving ATMPs and clinical trials involving children. Quality data (IMPD) will not be assessed by the ethics committee.
Please note that clinical trials with ATMP and children that have been assessed in the VHP must be notified to the National Research Ethics Committee for final ethics approval (and not the local REC), since it is the National Ethics Committee that is involved in the VHP procedure.
No later than three weeks after a clinical trial application has been approved via VHP, the application must be submitted to the participating national regulatory authorities for authorisation. The regulatory authorities must authorise the clinical trial within 10 days, provided the application is complete.
The application is to comprise the same elements as if it were an ordinary clinical trial application, cf. Appendix 10 of our guidelines. It is important to submit the same documentation which was authorised via VHP with the national application.
In addition to the documents submitted under VHP, the national application must include submission of the following documents:
- An email from which it appears that the application has been approved under VHP
- National EudraCT application form (PDF and XML file)
- Invoice details must be stated in the cover letter (EAN no. for public institutions)
- Label examples
- Documentation proving that the manufacturer is notified of the trial
- Patient information and power of attorney
A SUSAR is a Suspected Unexpected Serious Adverse Reaction. SUSARs must be reported to the Danish Medicines Agency immediately.
An adverse reaction is a SUSAR if the reaction:
- is serious, i.e. results in death, is life-threatening, requires hospitalisation or prolongation of hospitalisation,
- results in persistent or significant disability or incapacity, or
- causes congenital anomaly or birth defect.
- The adverse reaction must be related to the investigational medicinal product. In other words, it is suspected that there is a causal relationship between use of the medicinal product and the adverse reaction that has occurred. Both investigator and sponsor must assess the causality. The sponsor must not override the investigator's evaluation, and reports where the sponsor does not agree with the investigator must be reported.
- The adverse reaction must be unexpected, i.e. it must be an adverse reaction whose character or gravity is not consistent with the product information described in, for example, the Investigator's Brochure for an unlicensed investigational medicinal product or the summary of product characteristics for a licensed medicine.
If it is a blinded trial, the adverse reaction must be assessed before unblinding, but the data must be unblinded before they are reported to the Danish Medicines Agency.
SUSARs must be reported electronically, please see: Reporting of adverse reactions in clinical trials. The report must also be submitted to EMA via E2B as we do not forward the reports that we receive via E2B.
If you report via our e-form for non-commercial sponsors, please see here: Reporting of suspected unexpected serious adverse reactions (SUSARs) seen in clinical trials (e-form.)
29. How can I as a non-commercial sponsor report SUSARs, when I don't have access to EudraVigilance?
If you do not have access to EudraVigilance, you can report SUSARs to the Danish Medicines Agency using an e-form: Further information is available here Reporting of suspected unexpected serious adverse reactions (SUSARs) seen in clinical trials (e-form.)
The Danish Medicines Agency forwards all reported SUSARs to EudraVigilance, so that they are included in the complete European adverse reaction data for the product concerned.
Please see the form "Documentation for good manufacturing practice (GMP) and the quality of investigational products in connection with the application for the conduct of clinical trials in Denmark" as well as the form "Qualified Person declaration". Please see section 7.1 of our guideline.
The EU Clinical Trials Register is compliant with the requirements of the International Committee of Medical Journal Editors (ICMJE), which provides that clinical trials must be registered prospectively in a public clinical trial register before the editors will accept articles on the trials for publication.
The EU Clinical Trials Register retrieves data from the EudraCT application form which is submitted to the Danish Medicines Agency when a clinical trial is to be authorised. When we have registered that authorisation has both been given by the Danish Medicines Agency and the Scientific Ethical Committee System in the database, data on the trial will be published.
Follow this link to read more about the EU Clinical Trials Register.
The Danish Medicines Agency offers scientific advice. This is free.
For more information, please see: Request for advice in connection with development of medicinal products (scientific advice).
33. How frequently is the sponsor expected to submit safety information to the investigator for clinical trials of medicinal products in humans?
Pursuant to the 'Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use' (‘CT-3’), the sponsor must ensure that all relevant information regarding SUSARs is reported to the competent authorities and ethics committees as soon as possible and within seven days as regards fatal and life-threatening SUSARs and within 15 days for other SUSARs. The sponsor must also inform all investigators.
The purpose of informing the investigators is, according to CT-3, to inform the investigators about safety issues in light of reported SUSARs. The information must be concise and practical and where possible should be aggregated in a line listing of SUSARs in periods as warranted by the nature of the protocol/project and the volume of SUSARs generated. This line listing should be accompanied by a concise summary of the evolving safety profile of the product.
Furthermore, item 5.16.2 of the ICH GCP guideline provides that the sponsor should promptly notify all concerned investigators of findings that could adversely affect the safety of subjects or impact the conduct of the trial.
As a result of the above, the Danish Medicines Agency does not stipulate a maximum number of days/weeks/months within which the investigators are to be informed of specific safety information. Generally, it would be inappropriate to establish a deadline for dealing with information regardless of nature, because the degree of importance will vary from case to case.
Consequently, some information will need to be sent to the investigator immediately, other information could wait and be sent out as regular line listings in periods decided by the sponsor for the individual project/protocol. This should be decided on a case-by-case basis.
34. What is required of the sponsor in relation to providing safety information to the investigator sites in the period from the Investigator's Brochure (IB) is final and until the trial is initiated at a site?
We will expect to find relevant safety information in the investigator's Trial Master File. Typically, this will be the latest Investigator's Brochure with subsequent SUSARs which have not yet been included in an Investigator's Brochure.
The information must reach the investigator well before the trial agreement is made and must be updated on a regular basis as required by the significance of the information.
- Invoice details must be stated in the cover letter (EAN no. for public institutions)