Guideline for applications for authorisation of clinical trials of medicinal products in humans
NOTE – It is no longer possible to apply for at clinical trials authorization under the Directive 2001/20/EC.
For information regarding clinical trials applied under the new Clinical Trials Regulation (EU) No 536/2014, please see the Danish Medicines Agency page for the Regulation and relevant guidance in EudraLex Vol 10 for the Regulation.
Please note that this guidance is only applicable for clinical trials applied for under EU directive 2001/20/EC and the subsequent submissions of Substantial Amendments, Annual Safety Report and Results.
Contents
1. LEGISLATION ON CLINICAL TRIALS OF MEDICINAL PRODUCTS
4. CONTENTS OF THE APPLICATION
6. GOOD CLINICAL PRACTICE (GCP)
10. INFORMATION PATIENTS/TRIAL SUBJECTS
11. TRIAL INITIATION AND CONDUCT
12. ADVERSE REACTIONS/ADVERSE EVENTS
Appendices
Appendix 2: Executive order no 295 of 26 April 2004 on clinical trials of medicinal products in human as amended by executive order no. 903 of 18 August 2006
Appendix 4: Executive Order on fees for application for authorisation of clinical trials
Appendix 5: Application form for authorisation of clinical trials in humans
Appendix 6: Notification of Amendment form
Appendix 7: Declaration of the end of trial form
Appendix 8: Comprehensive overview of guidelines
Appendix 10: Checklist for applications for the authorisation of clinical trials
Appendix 11: Overview of adverse reaction reporting (appendix deleted).
Appendix 12: Description of phases for clinical trials of medicinal products
1. Legislation on clinical trials of medicinal products
Permission to conduct clinical trials with medicinal products
Pursuant to section 88 of the Danish Medicines Act (Appendix 1), an application must be submitted to the Danish Medicines Agency, for authorisation to conduct clinical trials with medicinal products.
Clinical trials with medicinal products may only be initiated once the Danish Medicines Agency has granted permission. Furthermore, trials of medicinal products in humans must be conducted in accordance with the Good Clinical Practice quality standards, see chapter 6.
The requirement to comply with the Medicines Act encompasses all forthcoming trials in the clinical medication evaluation (phases I-IV, encompassing pilot trials). The Danish Medicines Agency adheres to the ICH definition of clinical medication trials, as outlined in the ICH guideline E8: General Considerations for clinical trials (ICH-E8 guideline). For a more comprehensive description of the individual phases, refer to appendix 12. The obligation to comply also extends to radioactive medications, herbal remedies, and potent vitamin and mineral formulations (refer to Guidance on Marketing Authorization for Vitamin and Mineral Preparations - Vitamin and Mineral Preparations). The obligation to apply includes clinical trials conducted at one or more trial sites, in one or more countries.
Definition of a clinical trial of medicinal products
A clinical trial with medicinal products is, according to the Legal notice for clinical trials (see appendix 2), defined as: Any trial on humans, aimed at uncovering or verifying the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal products and/or identifying adverse reactions to one or more investigational medicinal products and/or investigating the absorption, distribution, metabolism, and excretion of one or more investigational medicinal products for the purpose of assessing safety and/or efficacy.
Definition of a medicinal product
Medicinal products are defined in § 2 of the Medicines Act as any product that
- is presented as a suitable medicinal product for the treatment or prevention of diseases in humans or animals;
- can be used in or administered to humans or animals to restore, alter or influence physiological functions by exerting a pharmacological, immunological and metabolic effect, or to provide a medical diagnosis.
Furthermore, the Medicines Act covers contraceptives.
Non-interventional studies
According to the Medicines Act, the obligation to apply does not apply to non-interventional trials, defined in the announcement as follows:
A study wherein medications are prescribed following clinical norms and in alignment with the conditions specified in the marketing authorization. The decision to prescribe the medication is distinctly separate from the decision to enroll the patient in the study. The treatment itself does not adhere to a trial protocol but rather follows standard medical practice. No additional diagnostic or control procedures are undertaken, and epidemiological methods are utilized to analyze the gathered data.
Trials utilising medications as tools
There exist trials primarily aimed at investigating the body's physiology, where a medication is employed as a tool to elicit a physiological response. In such trials, the medication is administered solely to induce a known and well-documented pharmacological response essential for studying the body's physiology. Examples include trials using pupil-dilating eye drops to study ocular physiology, or employing antidiuretic hormone to evaluate kidney function, or utilizing a radioactively labeled tracer (medication) in a PET scan to visualize aspects such as oxygen uptake or glucose metabolism in the body.
In trials where medications are used as tools, it is crucial to note that the trial's purpose is NOT to explore the therapeutic, preventive, or diagnostic effects and safety of the medication or to acquire new insights into the medication's pharmacological effects.
Trials where medications are used as tools are not bound by the obligation to adhere outlined in the Medicines Act. If a medication is intended solely for use as a tool, and no marketing authorization has been granted or the medication is not commercially available, such usage necessitates prior approval from the Danish Medicines Agency in accordance with § 29 of the Medicines Act.
The document Guide to Assessing Whether a Trial Is Defined as a Medication Trial provides guidance for determining whether a trial falls under the category of a medication trial. Queries regarding the obligation to adhere can be addressed via phone (at phone number 44 88 9123) or in writing to: [Send an email].
2. Fees
For fees, please refer to the page on Fees for Clinical Trials here on the Danish Medicines Agency's website.
We charge a fee for the approval of new applications for clinical trials and for the notification of substantial protocol amendments to approved trial protocols, which must be approved by the Danish Medicines Agency. The fee must be paid no later than one month after receipt of the invoice.
It is up to the applicant to decide who pays; company/doctor (sponsor/investigator). Please indicate in the cover letter to whom the invoice should be sent, as well as any comments to be included on the invoice. If the sponsor is from a public institution, we kindly ask for the EAN number to be included in the cover letter.
When submitting protocol amendments to trial protocols not yet approved, no additional fees need to be paid to the Danish Medicines Agency. However, if the material is sent while the processing is ongoing, this may, depending on the nature of the amendment, delay our response to the application.
Only substantial protocol amendments that require approval by the Danish Medicines Agency incur a fee, and if multiple amendments are notified at once, only one fee needs to be paid. See our page on Changes to Clinical Trials for further information on which protocol amendments are subject to fees.
According to the Announcement on fees for applications for approval of clinical trials, the fee applies to all trials covered by § 88 of the Medicines Act, and the Danish Medicines Agency has no legal basis for dispensing from this.
3. Application
4. Contents of the application
5. Trial protocol
6. Good Clinical Practice (GCP)
Clinical trials with medicinal products in humans must be conducted in accordance with good clinical practice (GCP) cf. the Danish Medicines Act section 88(2).
Also view Executive order on good clinical practice on medicinal products - humans (no. 744 of 29 June 2006, appendix 3, sections 3-6).
Here it is evident, that there must be a monitoring and audit of the trials. The executive order's section 2 defines monitoring as: The monitoring of a clinical trial's progress and assurance that it is conducted, recorded and reported in compliance with the trial protocol, the sponsor's written procedures, good clinical practice (GCP) and any other applicable law.
The provisions of the Danish Medicines Act that regulate clinical trials have been changed (most recently on 12 December 2005), implying that there is a now a statutory basis for implementing parts of the European Parliament's and the Council of Europe's Directive 2001/20/EC of 4 April 2001 on the approximation of the Member State's acts and administrative provisions on application of good clinical practice in trials of medicinal products for human use. The points which concern clinical trials in Act no. 382 enter into force on 1 May 2004. The Directive aims at harmonising legislation on clinical trials of medicinal products in humans within the EU.
The Directive introduces the requirement that all phases of clinical medicinal product trials in humans must proceed according to GCP, which is an internationally recognised ethical and scientific quality standard. Thus, GCP comprises both the ethical and scientific aspects associated with clinical trials. Compliance with GCP standards for the protection of trial subjects' rights, safety and welfare helps to ensure that it is ethically justifiable to let humans participate in medicinal product trials. At the same time, there is a requirement that the trial should be planned, conducted and reported in accordance with GCP, in order to ensure scientifically acceptable implementation. Study data must be well-documented and correct as to ensure reliable trial results, which can be used as documentation for the authorisation of a medicinal product and how it should be used in treatment of patients.
Standards have also been introduced in other areas within development and handling of medicinal products. This development, which e.g. involves a toxicological assessment of a medicinal product's constituents prior to any clinical trial, is encompassed by the Good Laboratory Practice (GLP) protocol. Likewise, there are standards for Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) respectively.
GCP imposes demands on the parties of the trial (the sponsor and the investigator), the ethical committees and the competent authorities.
A basic element of the GCP standard is that the sponsor, before an authorised trial is initiated, must construct a documented quality assurance system with standard operation procedures (SOPs) for the different phases of the trial and for data handling. During the trial, the sponsor must, as an element of quality control, ensure compliance with the established procedures and the competent authority may choose to carry out an inspection of the trial centre or other relevant centres. Once a trial is completed, quality control also encompasses analysis of data. All trial activities, control visits etc. must be documented by means of written reports.
The Directive (2001/20/EC) is available at EUR-Lex.
Pursuant to Directive 2001/83/EC, the information and documentation accompanying an application for marketing authorisation must be presented in accordance with a range of detailed rules. With regard to the execution of trials, all phases of the clinical development, including studies of bioavailability and bioequivalence, must be planned, conducted and reported in accordance with Good Clinical Practice. In a press release, the Committee for Proprietary Medicinal Products (CPMP) (now the Committee for Human Medicinal Products - CHMP), the EU "registration board", has stressed that in handling marketing authorisation applications, emphasis will be placed on whether trials are carried out and reported according to the CHMP's Note for guidance entitled Good Clinical Practice for Trials on Medicinal Products in the European Community III/3976/88-EN. In January 1997, this was replaced by the International Conference of Harmonisation (ICH) guidelines concerning GCP, entitled Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95). The guidance is available at European Medicines Agency.
6.1. Inspections
Under the Danish Medicines Act section 90, subsections 1, 2 and 3, the Danish Medicines Agency is entitled to inspect any trial it has authorised.
An inspection of a clinical trial normally comprises inspections on the premises of both the sponsor and the investigator to establish whether the trial is carried out in accordance with national legislation, the GCP guidelines, the trial protocol and the sponsor's quality assurance system, as well as to establish whether the data is correct and reliable.
7. Documentation
Applicants that have access to EudraVigilance must register the Investigational Medicinal Product (IMP) in the Medicinal Product Dictionary (MPD). Naturally, this only applies if the IMP is not already registered.
Non-commercial sponsors are not expected to have access to EudraVigilance.
For products for which a marketing authorisation is already issued or is being applied for, as well as for products for which documentation was submitted in connection with a previous application, reference to the previously submitted material is usually sufficient.
For other products, documentation on the chemical, pharmaceutical, animal pharmacological, toxicological and human pharmacological properties must be attached along with information on existing clinical experience.
The documentation must be submitted as a summary – in the form of an Investigational Medicinal Product Dossier (IMPD), (please see the guidelines for application for clinical trials, notification of amendments and declaration of the end of trial) and must be initiated with a summary of the contents. The guidelines can be found in EudraLex Volume 10 at Commission's website.
Where relevant, the Investigator's Brochure may be referred to for information regarding toxicological, animal pharmacological and human pharmacological properties as well as existing clinical experience. The Investigator's Brochure should follow the format set out in the ICH-guidelines for Good Clinical Practice (E6).
If the Danish Medicines Agency has previously assessed the documentation, and amendments of e.g. the Investigator's Brochure are subsequently submitted, any changes must be clearly indicated. The case handling process will not start unless there is such a document. Information on changes to versions not submitted must likewise be indicated clearly. Revised versions should only be submitted for assessment if the changes are significant to ongoing trials or if it occurs in connection with an application for new trials. If necessary, the Danish Medicines Agency may order complete reports or any other supplementary information.
7.1 Manufacturers
Please also see the Danish executive order on GMP (available in the factbox to the right: 'Bekendtgørelse nr. 264 af 4. april 1997 om god fremstillingspraksis (GMP) og god distributionspraksis (GDP) for lægemidler'), Directive 2001/20/EC, article 13 and GMP Directive 2003/94/EC. For Directive 2001/20/EC, click 'Volume 1'; for the GMP Directive, click 'Volume 4'.
In the case of direct import to Danish companies from third countries (non EU/EEA countries), please see the Danish GMP executive order referred to above as well as our frequently asked questions about GMP, which you can find at www.dkma.dk under Companies > Authorisation of companies > FAQs on GMP. Please also 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 also see point 9.
7.2. Pharmaceutical chemical documentation
For medicinal products on the market which, for trial technical (e.g. blinding) or other reasons, have the form, appearance or composition changed, information on the complete qualitative and quantitative composition must be submitted together with considerations on bioequivalence with enclosed results of relevant in vitro tests (for compressed medicinal products, e.g. in the form of dissolution tests) for both the marketed and the amended formulation.
If this information has previously been submitted to the Danish Medicines Agency, it is sufficient to refer to it and, if possible, with an indication of the Danish Medicines Agency's record number and/or EudraCT number.
7.3. GLP in clinical trials
In accordance with EU Directives 1,2,3,4,5, applicants are reminded that all pivotal non-clinical studies (i.e. those studies identified in ICH guidelines as needing to be carried out in accordance with the principles of good laboratory practice) conducted to support submissions for Marketing Authorisation Applications (MAA) and Clinical Trial Applications (CTA) must be conducted in, or inspected by, a country that has implemented the OECD Mutual Acceptance of Data (MAD) system. Studies conducted at a facility located in a non-MAD adherent country may be accepted if the facility has been subject to a full monitoring inspection conducted in the last three years by a monitoring authority from a country which is a signatory to the MAD agreement. However, if the study is considered to be pivotal to the application, there is a possibility that a study audit will be required by some regulatory receiving authorities at the time of a MAA.
Read more in 'Question and Answer document on Good Laboratory Practice
As applications for CTAs do not include individual study reports, Sponsors should include a statement confirming the OECD GLP status, either within the Investigator's Brochure (IB) or within the covering letter.
References
- EU Directive 2001/83/EC – Community code relating to medicinal products for human use
- EU Directive 2004/10/EC – on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances (codified version)
- EU Directive 2004/9/EC – on the inspection and verification of good laboratory practice (codified version)
- EU Directive 87/18/EEC – on the Harmonisation of Laws, Regulations and Administrative Provisions Relating to the Application of the Principles of Good Laboratory Practice and the Verification of their Applications for Tests on Chemical Substances
- EU Directive 88/320/EEC – on the Inspection and verification of Good Laboratory Practice
8. Labelling
Labelling must comply with the requirements of the current Annex 13 to the GMP directive.
Labelling must be in Danish, yet for products which are exclusively administered by hospital personnel English, language marking may be accepted. However, Danish-language instructions must be available to the personnel.
9. Dispensing/sale
Pursuant to the explanatory notes to the Danish Medicines Act, No. 1180 of 12 December 2005, products may be dispensed or sold for use in clinical trials authorised by the Danish Medicines Agency.
When the authorisation is granted, dispensing/sale may take place to:
- the doctor or dentist responsible for the trial
- pharmacies or hospital pharmacies with the intent to distribute to the person responsible for the trial.
Import and export (from third countries) as well as manufacture of medicinal products for clinical trials may only be undertaken by companies authorised pursuant to section 39 of the Danish Medicines Act. The authorisation must include manufacture of medicinal products for clinical trials. The import and export of such products thus require no further authorisation. Please also 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" for import or manufacturing activities in a third country as well as the form "Qualified Person declaration".
The investigational medicinal products must not be dispensed to the investigator until the Danish Medicines Agency has authorised the trial. Distribution to a pharmacy may take place prior to trial approval, but the pharmacy must not dispense any of the medicinal products concerned to the investigator before the trial is approved. For further information, please see Directive 2003/94/EC, the GMP protocol and Annex 13.
Pursuant to section 13 of the Danish GCP executive order (appendix 3 https://www.retsinformation.dk/Forms/R0710.aspx?id=152402), trial subjects must receive investigational medicinal products free of charge, including any devices used for their administration.
The sponsor supplies the investigational medicinal products and any devices used for their administration. The sponsor must supply, but must not necessarily pay for the investigational medicinal products. In trials conducted at hospitals where the patient already receives the product as part of the hospital treatment, the sponsor can make an agreement with the hospital, deciding that the hospital pays the expenses for the investigational medicinal product in connection with the trial.
The Danish Medicines Agency may in special circumstances make an exemption ad regards the supply of investigational medicinal products free or charge if:
- the purpose of the trial cannot be fulfilled, however, provided that the investigational medicinal products are supplied free of charge
- the investigational medicinal product is used to treat an indication in the summary of product characteristics, and the trial subject is treated with the product regardless of participating in the trial and the trial subject pays for the product himself.
The dispensing of euphoriant substances/preparations for use in clinical trials is only allowed when the Danish Medicines Agency has issued an authorisation for this purpose, cf. section 4(5) of the Ministry of Health's Executive Order on Euphoriants.
Likewise, companies' receipt and storage of euphoriant substances requires that the Danish Medicines Agency has granted its permission, cf. the above executive order.
Clinical trials with euphoriant substances require special attention to the subject's ability to drive a motor vehicle. These matters may have great influence on the practical ability to recruit subjects for the clinical trial, and it is therefore important to read the following material thoroughly:
The Danish Medicines Agency's guidelines for the assessment of the health requirements to drivers of motor vehicles (in Danish only)
The sponsor is responsible for assessing whether ingestion of the euphoriant substance, in the intended doses, prevents the subject from driving a motor vehicle. This assessment must be clearly stated in a section in the protocol as well as in the patient information.
10. Information for patients/trial subjects
When the Danish Medicines Agency inspects and monitors clinical trials, it can gain access to information about the trial subjects' health and personal circumstances without specific consent or authorisation from the trial subject or his or her relatives or guardian, cf. section 90(2)-(5) of the Danish Medicines Act.
Therefore, when informed consent is obtained from a trial subject who is to participate in a clinical trial, the responsible investigator must inform the trial subject that the Danish Medicines Agency has direct access to personal details from patient records etc., including electronic records as part the agency's control activities.
However, a power of attorney must be obtained if an inspection is to be carried out by representatives from foreign authorities that will be monitoring the trial.
The power of attorney empowering representatives from foreign authorities to access the health information of trial subjects should clearly appear exactly as a power of attorney, and it should be precisely formulated to avoid any doubt with regard to what it covers. The power of attorney should therefore be a separate document addressing the access to the trial subjects' health information and the purpose of such access.
It must appear who is granting the power of attorney, to whom it is granted and what it is granted for during which period.
The power of attorney which grants representatives from foreign authorities access to health information must be approved by the Danish Medicines Agency and must be submitted together with the application for authorisation of a clinical trial of medicines. Following the entry into force of the amended Danish act on scientific processing of health scientific research projects and section 89(3) of the Danish Medicines Act on 1 July 2016, the power of attorney is no longer to cover the sponsor and the monitor, as the consent to the trial also covers the sponsor's, the monitor's and the investigator’s direct access to the trial subjects' health information.
The assessment of the patient information and consent is carried out by the Scientific Ethical Committee System.
11. Trial initiation and conduct
In connection with parallel case handling by the Danish Medicines Agency and the Scientific Ethical Committee System, there may be cases where both systems produce grounds for non-acceptance to closely related problems.
This must be regarded as the cost necessary to avoid the delay, which a successive evaluation between the two systems would otherwise entail.
11.1 Authorisation
The trial may be initiated when both the Danish Medicines Agency has granted an authorisation and the Scientific Ethical Committee System has approved the trial. Only when the authorisation from the Danish Medicines Agency is available, can the medicinal products for the trial can be dispensed to the party or parties responsible for the trial.
11.2. Amendments
Subsequent amendments/additions to the protocol and changes hereto must be sent in the same version to both the Danish Medicines Agency and the regional research ethics committee before implementation. Amendments to the protocol should be submitted in the same language as the protocol assessed during application. A fee must be paid, see section 2.
It follows from section 10(1) of the Danish executive order no. 744 of 29 June 2006 on good clinical practice in clinical trials of medicinal products in humans (the GCP order) that a trial protocol must contain the information, etc. appearing from Schedule 1 of the executive order. This information could be gathered in one document, cf. section 10(2). It is therefore not required that all the information of the trial protocol be gathered in one document.
It appears from Schedule 1 of the GCP order that a trial protocol must include the following information, among other things:
"Background information on the investigational medicinal products, including:
- a) Product name(s) and a description of the active substance(s),
- b) A summary of relevant results from non-clinical and clinical trials,
- c) A summary of known and potential risks and possible benefits for the trial subjects,
- d) A description and justification of the dose, method and frequency of administration and treatment periods,
- e) A description of the study population, and
- f) References to literature and data that are relevant and form the basis for the trial."
In the Danish Medicines Agency's view the information about investigational medicinal products, including information about the products' quality, previous trials and toxicological studies, which for example is gathered in the Investigator's Brochure or the Investigational Medicinal Product Dossier (IMPD), is to be considered as forming part of the trial protocol.
It follows from section 4(1) of the Danish executive order no. 295 of 26 April 2004 on clinical trials that the sponsor must apply to the Danish Medicines Agency for permission before the sponsor implements amendments to the trial protocol when the amendments could have an impact on:
- the safety of the trial subjects,
- the interpretation of the scientific documentation which the trial is based on,
- the completion or management of the trial,
- the quality or safety of the investigational medicinal products used in the trial,
or if the concerned amendments are otherwise considered as substantial.
In the Danish Medicines Agency's view, section 4(1) of the executive order also covers (substantial) amendments in relation to the information about the investigational medicinal products in the Investigator's Brochure or an IMPD. Consequently, the sponsor must also apply to the Danish Medicines Agency for permission before the sponsor implements substantial amendments in relation to the background information about the investigational medicinal products in the Investigator's Brochure or IMPD.
You can find further information about this in our announcement Amendments to clinical trials.
For further information, please see the guidelines for applications for clinical trials, amendments and the declaration of the end of trials, http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm, which contributes with examples of substantial amendments that requires an authorisation from the Danish Medicines Agency before the changes may be implemented.
These guidelines also contain a form for applying for authorisation for amendments. The form can be downloaded as a Word file from the following link: /~/media/6F1F7A3BA197409B94E8B1040879173D.ashx, which links to relevant documents. The form must be filled in, printed, signed and submitted to the Danish Medicines Agency with documentation enclosed.
The completed form must be signed by the sponsor/applicant.
Notifications to the Danish Medicines Agency
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).
- Change of CRO/applicant.
- When the trial ends in Denmark
These changes do not require the approval of the Danish Medicines Agency.
12. Adverse reactions/Adverse events
The sponsor must inform the Danish Medicines Agency immediately if suspected unexpected serious adverse reactions (SUSARs) occur during the trial, cf. the Danish Medicines Act section 89(2)(i).
The definitions are as follows, cf. the Executive Order on clinical trials:
- Adverse event: any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment
- Adverse reaction: All untoward and unintended responses to an investigational medicinal product related to any dose administered.
- Unexpected adverse reaction: an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g. Investigator's Brochure for an unauthorised investigational product or summary of product characteristics for an authorised product).
- Serious event or serious adverse reaction: any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect.
Please see the guideline on the subject:
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).
This guideline is available at the Commission's website under "Volume 10".
12.1. Adverse reactions and adverse events occurring in trials in Denmark
The trial protocol must state which adverse reactions and adverse events the investigator must report to the sponsor and when the reporting is to take place after the adverse reaction/adverse event is ascertained.
It must also be stated how long the trial subjects are followed after they have stopped using the trial medication with regard to registering any late-occurring adverse reactions/adverse events.
The following must be reported to the Danish Medicines Agency:
Sponsor's obligations
Under section 89(2)(i) of the Danish Medicines Act, the sponsor must immediately inform the Danish Medicines Agency if any suspected unexpected and serious adverse reactions occur during the trial.
The sponsor must ensure that all relevant information about suspected unexpected serious adverse reactions (SUSAR), which are fatal or life-threatening, is recorded and reported to the Danish Medicines Agency as soon as possible, and no later than 7 days after the sponsor is informed of such a suspected adverse reaction.
No later than 8 days after the reporting, must the sponsor inform the Danish Medicines Agency of relevant follow-up information on the sponsor's and the investigator's follow-up action to the reporting.
Any other suspected unexpected serious adverse reactions must be reported to the Danish Medicines Agency no later than 15 days from the time when the sponsor is informed about them.
All reports must be accompanied by comments on possible consequences for the trial.
Regarding blinded trials, please refer to section 7.11.1 (115-117) of the guideline on adverse reactions (CT 3).
However, for trials in high morbidity or high mortality disease, where efficacy end-points could also be SUSARs or when mortality or another 'serious' outcome (that may potentially be reported as a SUSAR) is the efficacy end-point in a clinical trial, the integrity of the clinical trial may be compromised if the blind is systematically broken.
Under these and similar circumstances, the sponsor should reach agreement in the authorisation process as to which serious events would be treated as disease-related and not subject to systematic unblinding and expedited reporting.
At the end of the trial, all adverse reactions and events must be reported to the Danish Medicines Agency in the final report.
Investigator's obligations
Furthermore, the investigator has the following obligations, cf. the Executive Order on clinical trials: The investigator must immediately report all serious incidents to the sponsor with the exception of serious incidents that according to the trial protocol or Investigator's Brochure are incidents which do not require to be reported immediately.
Reporting must be followed-up by a detailed report in writing, and in both the immediate report and the subsequent report, the investigator must identify the trial subjects with a personal code number.
Moreover, the investigator must report to the sponsor any incidents and/or irregular analysis results that according to the trial protocol are critical to the trial subjects' safety.
Reporting must be done in compliance with the rules and deadlines stated in the protocol. When reporting deaths, the investigator must submit all the additional information the sponsor may request.
Reference Safety Information
Furthermore, the documentation must include which Reference Safety Information (RSI) is intended to be used when assessing whether a suspected adverse reaction (SAR) is unexpected/expected and thereby may be a SUSAR.
We recommend a specified summary of product characteristics for marketed products (section 4.8 of the summary of product characteristics) and an Investigator's Brochure for non-marketed products (specific section and/or table). The Clinical Trials Facilitation Group (CTFG) has described the requirements related to the Reference Safety Information in a questions and answers document.
If a trial of a marketed medicinal product is to be carried out in several countries, the sponsor must choose which summary of product characteristics must be used as Reference Safety Information throughout the entire trial.
If the Reference Safety Information is changed, it must be submitted as a substantial change, unless it is submitted together with the annual report (ASR/DSUR).
12.2. Serious adverse reactions and serious adverse events occurring in trials abroad
SUSARs occurring in other EU/EEA countries must be reported to the Danish Medicines Agency if the trials have the same protocol (EudraCT-number) as in Denmark. This only concerns trials applied for after 1 May 2004. SUSARs from non-EU/EEA countries should not be reported to the Danish Medicines Agency.
Please also see the guidance on reporting of adverse reactions arising from clinical trials (CT 3).
12.3. Reporting and reporting forms
Sponsor/sponsor-investigator has a duty to report any suspected adverse reactions or unexpected adverse reactions from medicinal products.
In order for an adverse drug reaction to meet the requirement for reporting, the adverse reaction must be serious, i.e. result in death, be life-threatening, require hospitalisation or prolongation of hospitalisation, result in significant or persistent disability or incapacity, or consist of a congenital anomaly or birth defect.
Moreover, the adverse reaction must be related to the investigational medicinal product. In other words, it is suspected that there is a causal relationship between the use of the medicinal product and the adverse reaction that has occurred.
Both investigator and sponsor (or sponsor-investigator) must assess the causality.
The sponsor must not override the investigator's evaluation, so reports must be submitted even though the sponsor does not agree with the investigator.
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 (e.g. the Investigator's Brochure for an unlicensed investigational medicinal product or the summary of product characteristics for a licensed medicine).
If the serious adverse reaction is not indicated in the product information, it is considered to be unexpected.
If it is a blinded trial, the adverse reaction must be assessed before unblinding. From blinded trials, all SUSARs must subsequently be unblinded before they are reported to the authorities.
Follow-up reports are only to be submitted if relevant. The decision as to which information is relevant should be based on a medical and scientific evaluation.
Only SUSARs from the investigational medicinal product(s) must be reported
Only reports concerning suspected unexpected serious adverse reactions (SUSARs) related to the investigational medicinal products of clinical trials which fall under directive 2001/20/EC must be reported by the sponsor to the EudraVigilance Clinical Trial Module (EVCTM).
Adverse reactions from clinical trials conducted in compliance with directive 2001/20/EC which are suspected only to be related to non-investigational medicinal products (or another medical product not covered by the clinical trial) and where there is no interaction with the investigational medicinal products are to be considered as spontaneous reports and must therefore be reported to the EudraVigilance Post-Authorisation Module (EVPM).
Reporting
SUSARs occurring in Danish trials and clinical trials with the same protocol (same EudraCT number) in other countries should be reported electronically to the SUSAR database (EudraVigilance Clinical Trial Module, E2B).
Since non-commercial sponsors are not expected to have access to the SUSAR database, reporting from this type of sponsor can be done by filling in and submitting the Danish Medicines Agency's e-form for reporting of non-commercial sponsors of suspected unexpected serious adverse reactions (SUSARs) seen in clinical trials.
We encourage companies to report electronically as mentioned above, as data is then transferred automatically to the database.
SUSARs reported to the Danish Medicines Agency by commercial sponsors should be reported via the EudraVigilance Gateway.
The ID concerning SUSARs of the Danish Medicines Agency (previously the Danish Medicines Agency) is DKMAEUDRA. The form is of the same format as ICH E2B M2.
However, there will be an interim arrangement until all commercial sponsors have been registered in the SUSAR database. Further details are available at: http://eudravigilance.ema.europa.eu/human/index02.asp.
In order to report electronically, it is necessary to be able to report to EudraVigilance, be registered in the system and to have tested with EMA (http://eudravigilance.ema.europa.eu/human/index.asp).
EVWeb users can be registered for E2B submission without prior testing. However, you have to let us know in advance so that we can configure your ID in our system. Otherwise, we cannot receive the reports in our system. Please contact Send an email with name, address and sender ID.
Gateway users need to test E2B exchange before we can receive cases. For further information, please see Procedure for testing exchange of E2B files.
Until all commercial sponsors are registered in the EudraVigilance system, the Danish Medicines Agency will accept SUSARs reported via the e-form.
12.4. Annual Safety Report and list of suspected serious adverse reactions
Once a year throughout the duration of the clinical trial, the sponsor must provide a list of all suspected serious adverse reactions which have occurred during the trial period and a report on the trial subjects' safety. The list and the report must be submitted to the competent authorities in the Member States on whose territory the clinical trial is carried out.
Please see the guidance on reporting of adverse reactions arising from clinical trials (CT 3), section 8.
In future, the annual report and list of serious suspected adverse reactions can be replaced by the Development Safety Update Report (DSUR, ICH E2F). You can read more about DSUR here: http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html .
A DSUR is prepared per investigational medicinal product, and it may therefore cover more than one trial. Please specify the EudraCT numbers for the trials conducted in Denmark in the DSUR cover letter.
How to submit the annual safety report
Sponsors and CROs (Contract Research Organisations) engaged in clinical trials of medicines in humans can submit annual safety reports via Eudralink or email directly to our clinical trial inbox. For more information, please see:
13. Report
After the trial has ended, the sponsor must notify the Danish Medicines Agency no later than 90 days after the end of the trial using the clinical trial completion form. If it is a multinational trial, the Danish Medicines Agency must be notified when the trial ends in Denmark. When the trial ends globally, the aforementioned clinical trial completion form should be used.
As soon as possible and no later than 1 year thereafter, the trial results must be entered into EudraCT. The data will then be published on www.clinicaltrialsregister.eu. This replaces the requirement to submit the trial results to us. You can see more here on how to enter the results into EudraCT. If you enter data into EudraCT on behalf of the sponsor, it is required that you attach an authorization letter during the process. This is only approved using EMA's template: 'Clinical Trial assignment request PDF form', which can be found at the following link (and accompanying guide): https://eudract.ema.europa.eu/result.html. Since the data will be publicly available, there will no longer be a requirement to submit a publication to us in the future. However, note that since Phase I trials are not published on www.clinicaltrialsregister.eu (except for pediatric trials), publications must still be submitted to us for Phase I trials. Further information can be found here under 'Result related documentation'. The Danish Medicines Agency may, if deemed necessary, request the full report.
Special for pediatrics
Trials For pediatric trials where a pediatric research program has been prepared, the trial results must be entered into EudraCT within six months. A pediatric research program must be prepared when applying for marketing authorization for a new medicinal product, a new indication (including a pediatric one), a new pharmaceutical form, or a new route of administration for an existing medicinal product. This is in accordance with Regulation (EC) No. 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for pediatric use and amending Regulation (EEC) No. 1768/92, Directive 2001/83 and Regulation (EC) No. 726/2004, which entered into force on 26 January 2007.
14. Additional guidelines
There are a number of EU guidelines on clinical trials in general and specific guidelines for some therapeutic groups. Further information can be found in The Rules governing Medicinal Products in the European Community vol. 3: Guidelines - medicinal products for human use, which can be purchased from: J. H. Schultz Information A/S EU-Publications Herstedvang 12 2620 Albertslund It is possible to find guidelines on the internet based on the following address: http://ec.europa.eu/health/documents/eudralex/vol-3/index_en.htm. These guidelines can be downloaded using Adobe Acrobat Reader. If you do not have the program in question, it can be downloaded at the following address: http://www.adobe.com/
15.Change log
Updated 03 November 2022:
Updated links in section 5.1 to CTCG recommendations related to contraception and pregnancy testing on clinical trials to version 1.1, implemented on 21 September 2020.
Appendices
Appendix 1: Extract from the Danish Medicines Act (no. 1180) as amended on 12 December 2005 Appendix 2: Executive Order on clinical trials of medicinal products on humans (no. 295, amended on 26 April 2004 and changes to executive order no. 903 on 18 August 2006) Appendix 3: Executive Order on God Clinical Practice on Clinical Trials - human, no 744, amendet on 29 June 2006. Appendix 4: Executive Order on fees for application for authorisation of clinical trials Appendix 5: Application form for authorisation of clinical trials on humans Appendix 6: Notification of Amendment Form Appendix 7: Declaration of the end of trial formAppendix 8: List of guidelines Appendix 9: Form for reporting suspected unexpected serious adverse reactions occurring in clinical trials (CIOMS). Appendix 10 Checklist for application for authorisation of a clinical trial Appendix 11: Overview of adverse reaction reporting (appendix deleted)
Appendix 1
The Danish Medicines Act as amended on 12 December 2005
Appendix 2
Executive Order on clinical trials of medicinal products on humans
Appendix 3
Executive Order on good clinical practice in clinical trials of human medicines (in Danish)
Appendix 4
Executive Order on fees for application for authorisation of clinical trials
Appendix 5
Go to: http://eudract.ema.europa.eu/document.html and click on: "Clinical trials application form".
REQUEST FOR AUTHORISATION OF A CLINICAL TRIAL ON A MEDICINAL PRODUCT FOR HUMAN USE TO THE COMPETENT AUTHORITIES AND FOR THE OPINION OF THE ETHICS COMMITTEES IN THE COMMUNITY
The form must be filled out via the Internet. Read the guideline above in section 3 where there is a link to guideline and form.
Appendix 6
Go to: http://eudract.ema.europa.eu/document.html and click on: "Notification of Amendment".
REQUEST FOR AUTHORISATION OF A SUBSTANTIAL AMENDMENT TO A CLINICAL TRIAL ON A MEDICINAL PRODUCT FOR HUMAN USE TO THE COMPETENT AUTHORITIES AND FOR OPINION OF THE ETHICS COMMITTEES IN THE COMMUNITY.
The form must be downloaded from the Internet. You can also read the guideline above in section 11.2.
Appendix 7
Go to: http://eudract.ema.europa.eu/document.html and click on: "Declaraton of the end of a clinical trial".
The form must be downloaded from the Internet. You can also read the guideline above in section 11.2.
Appendix 8
List of guidelines
Overview of the guidelines can be found on EU-Commissions Eudralex Volume 10, Clinical trials: http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm
CT 1: Application for authorisation of clinical trials, amendments and end of trial.
Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial, as required by Article 9 (8) of Directive 2001/20/EC revision 1.
CT 3: Reporting adverse reactions
Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use, as required by Article 18 of Directive 2001/20/EC revision 1.
CT 4: The SUSAR database
Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance – Clinical Trial Module), as required by Article 11, Article 17 and Article 18 of Directive 2001/20/EC revision 1.
CT 5: The EudraCT database
Detailed guidance on the European clinical trials database (EUDRACT Database), as required by Article 11 and Article 17 of Directive 2001/20/EC,
CT 5.1 Amendment describing the Development of EudraCT-Lot 1 for 1 May 2004 and CT 5.2 EudraCT core dataset.
These guidelines can also be found at:
http://eudract.ema.europa.eu//document.html under Guidance Documents.
Appendix 9
Form for reporting suspected unexpected serious adverse reactions occurring in clinical trials
Appendix 10
Checklist for application for authorisation of a clinical trial
Appendix 11 - Overview of adverse reaction reporting (appendix deleted)
Appendix 12
Description of phases for clinical trials of medicinal products