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Guideline for applications for authorisation of clinical trials of medicinal products in humans

Updated 29 July 2014

Contents

1. LEGISLATION ON CLINICAL TRIALS OF MEDICINAL PRODUCTS 2. FEES 3. APPLICATION4. CONTENTS OF THE APPLICATION5. TRIAL PROTOCOL6. GOOD CLINICAL PRACTICE (GCP) 7. DOCUMENTATION8. LABELLING 9. DISPENSING/SALE 10. INFORMATION PATIENTS/TRIAL SUBJECTS11. TRIAL INITIATION AND CONDUCT12. ADVERSE REACTIONS/ADVERSE EVENTS13. REPORT 14. ADDITIONAL GUIDELINES

Appendices

Appendix 1: Danish Medicines Act no. 1180 of 12 December 2005 (Lov om lægemidler nr. 1180 af 12. december 2005).
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 3: Danish executive order no. 744 of 29 June 2006 on good clinical practice in clinical trials of medicinal products in humans (Danish title: Bekendtgørelse nr. 744 af 29. juni 2006 om god klinisk praksis i forbindelse med kliniske forsøg med lægemidler på mennesker).Appendix 4: Executive Order on fees for application for authorisation of clinical trials Appendix 5: Application form for authorisation of clinical trials in humansAppendix 6: Notification of Amendment formAppendix 7: Declaration of the end of trial formAppendix 8: List of guidelinesAppendix 9: Form for reporting suspected unexpected serious adverse reactions occurring in clinical trials (CIOMS). Appendix 10: Checklist for requests for the authorisation of clinical trialsAppendix 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

Authorisation to conduct clinical trials of medicinal products

Pursuant to section 88 of the Danish Medicines Act (Appendix 1), an application must be submitted to the Danish Health and Medicines Authority, formerly the Danish Medicines Agency, for authorisation to conduct clinical trials with medicinal products.

Clinical trials with medicinal products must only be conducted when the Danish Health and Medicines Authority has given its authorisation. Furthermore, trials of medicinal products in humans must be conducted in accordance with the Good Clinical Practice quality standards, see chapter 6.

The obligation to apply for an authorisation under the Danish Medicines Act comprises all prospective trials in the clinical assessment of medicinal products (phases I-IV, including pilot studies).

The Danish Health and Medicines Authority refers to the ICH definition of clinical trials of medicinal products, appearing from the guideline: ICH Topic E 8 General Considerations for Clinical Trial (ICH-E8), in which the individual phases are described.

The obligation to apply also extends to radiopharmaceuticals, herbal medicinal products as well as strong vitamin and mineral preparations (please see the 'Guidelines for marketing authorisation for vitamin and mineral products' under Vitamins and mineral preparations.

The obligation to apply includes clinical trials carried out at one or more sites, whether in one or more Member States.

Definition of a clinical trial of medicinal products

According to the Danish executive order on clinical trials of medicinal products in humans (see Appendix 2), a clinical trial means: Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal products and/or to identify any adverse reactions to one or more investigational medicinal products and/or to study the absorption, distribution, metabolism and excretion of one or more investigational medicinal products with the object of ascertaining their safety and/or efficacy.

Definition of a medicinal product

The Danish Medicines Act defines a medicinal product as any product that

  1. is presented as a suitable medicinal product for the treatment or prevention of diseases in humans or animals;
  2. may be used in or administered to humans or animals to recover, change or affect physiological functions by having a pharmacological, immunological and metabolic effect, or to make a medical diagnosis.

The Danish Medicines Act also regulates contraceptives.

Non-interventional studies

According to the Danish Medicines Act, the obligation to apply for authorisation does not apply to non-interventional studies, which are defined in the executive order as:

A study in which the medicinal product or medicinal products are prescribed pursuant to clinical practice and in accordance with the terms of the marketing authorisation. The prescription of the medicine is clearly separated from the decision to include the patient in the study.

The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol, but falls within current practice. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data.

Trials in which medicinal products are used as a tool

Some trials have the sole objective of studying the physiological mechanisms of the body, and in which the medicinal product is used as a tool to induce a physiological response. In this type of trial, the medicinal product is administered solely to induce a known and well-documented pharmacological response, which is necessary to study the body's physiology.

One such trial could involve pupil dilating eye drops used to study the physiology of the eye, or the use of antidiuretic hormone to evaluate kidney function, or the use of radioactive trace elements (medicinal product) in PET scans to produce an image of, for example, oxygen use or glucose metabolism in the body.

In trials, in which the medicinal product is used as a tool, the decisive factor is that the trial's objective is NOT to study the therapeutic, preventive or diagnostic effects and safety of the medicinal product or to obtain new knowledge about the medicinal product's pharmacological effects.

Trials in which the medicinal product is used as a tool are not subject to the obligation to apply laid down in the Danish Medicines Act. In cases where a medicinal product is only intended to be used as a tool and no marketing authorisation has been issued, or the medicinal product is not marketed, it is required that a compassionate use permit be obtained from the Danish Health and Medicines Authority before any study is initiated, cf. section 29 of the Danish Medicines Act.

Please also consult our Guide to assessing if a trial falls under the definition of a clinical trial, for guidance on whether or not a trial is defined as a clinical trial of medicinal products. For further information concerning a possible obligation to apply, please call +45 4488 9595, or write to: kf@dkma.dk

2. Fees

For more specific information about fees, please see the page Fees for clinical trials here at the Danish Health and Medicines Authority's website.

We charge fees for the authorisation of new applications for clinical trials as well as for notification of substantial protocol amendments of authorised trial protocols, which are to be authorised by the Danish Health and Medicines Authority. The fee must be paid no later than one month after receipt of the invoice.

It is up to the individual applicant to determine who should be the payee, whether this be the company/doctor (sponsor/investigator).

The form containing the invoice details must be submitted together with applications for new trials or notifications of protocol amendments. See the form in the factbox to the right. However, companies that submit applications for new clinical trials or amendments to an authorised clinical via our DKMAnet extranet need not use the e-form for notification of invoice details as this is integrated in the application form on DKMAnet.

When submitting protocol amendments for trial protocols not yet authorised, no additional fees are to be paid to the Danish Health and Medicines Authority. However, if material is submitted in the course of our processing of the application, it may, depending on the nature of the amendment, delay our reply to the application.

A fee must only be paid for substantial protocol amendments that must be authorised by the Danish Health and Medicines Authority, and if several amendments are submitted together, only one fee is to be paid. Please see our page on Amendments of clinical trials for further information on the types of protocol amendments for which a fee is charged.

The executive order on application fees for the authorisation of clinical trials stipulates that the fee applies to all trials comprised by section 88 of the Danish Medicines Act, and the Danish Health and Medicines Authority does not hold the statutory authority to grant any exemptions.

3. Application

In the following, we describe how to apply to the Danish Health and Medicines Authority for authorisation to conduct a clinical trial. Please also see chapter 4 below for information about which appendixes to submit with the application. We also refer to the guidelines for application for authorisation of a clinical trial, notification of substantial amendments and declaration of the end of the trial (CT1), which are available on the Commission's website:

Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1): http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2010:082:0001:0019:EN:PDF

Who can apply for authorisation?

The sponsor is the applicant. Pursuant to the Danish Medicines Act, the sponsor is the person, company or institution which undertakes the responsibility for the initiation, management and possibly the financing of a clinical trial. The sponsor may delegate the task of applying for authorisation for a clinical trial. In such cases, a document that confirms this relation must be submitted.

The sponsor or the sponsor's legal representative must have a permanent address in an EU/EEA country, cf. the Danish Medicines Act, section 88(7) (Appendix 1).

Obtaining a EudraCT number

Before applying to the Danish Health and Medicines Authority, the applicant must order a EudraCT number. The EudraCT number is an identification number for the clinical trial, which applies throughout the EU. This number can be ordered via https://eudract.ema.europa.eu/eudract-web/index.faces. See the 'Create' button on the top bar, and select EudraCT Number.

Submission of application to the Danish Health and Medicines Authority

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 the Danish Health and Medicines Authority via DKMAnet, our access-controlled extranet. Applicants who do not have access to DKMAnet can send documentation electronically on CD-ROM or online via Eudralink. For more information, please see:

Application form (EudraCT form) and documentation

You can find the application form at https://eudract.ema.europa.eu/eudract-web/index.faces. See the 'Create' button on the top bar, and select Clinical Trial and EEA (if the trial is to be conducted in the EU).

The application form must be filled in and edited via the EudraCT website. Guidance on how to fill in the form appears when you move the cursor over the relevant text.

The applicant must download the form on his/her own computer as an XML file (Full data must be selected, see user manual). The reason you need to do this is because the EudraCT website does not store any data, but merely serves as an editing tool. The XML file is to be submitted electronically to the Danish Health and Medicines Authority on CD-ROM, via Eudralink or via DKMAnet. It is advised to save the form on the applicant's own computer to avoid data being lost.

The application form must also be printed out and signed by the sponsor/applicant. The signed version of the application form must be scanned and sent to the Danish Health and Medicines Authority.

The information listed in this guideline must be enclosed in the application and submitted in a single copy (please see point 4). Please also see Appendix 10, which is a checklist, which outlines the documents to be submitted with the application.

In pursuance of section 88 of the Danish Medicines Act, a clinical trial of medicinal products must not be initiated until the Danish Health and Medicines Authority has authorised the trial. The intention is to ensure that no trials are initiated which the Danish Health and Medicines Authority cannot accept for reasons pertaining to either ethics or patient safety.

As a consequence of this, the Danish Health and Medicines Authority requires detailed documentation on the risk/benefit ratio in order to make qualified assessments. This applies to all trials and is particularly important for trials involving healthy volunteers, or for trials employing major invasive procedures, e.g. extra catheterisation in arteries and/or central veins.

When describing the ethical considerations in relation to the clinical trial, it is thus not sufficient merely to claim adherence to the current Helsinki declaration! If a separate section on ethical considerations is prepared for the scientific ethical committee system, this can be submitted with advantage.
According to the Danish Medicines Act section 88(4), the sponsor may amend the application once, in order to allow for a reasoned objection from the Danish Health and Medicines Authority. If the application is not amended according to the objection, the application will be rejected. It is therefore recommended not to submit the application until the final protocol and all appendices are available.

Assessment times

The Danish Health and Medicines Authority has 60 calendar days to handle a duly completed application. The Danish Health and Medicines Authority aims to give grounds for non-acceptance or grant authorisation within 30 working days. Please note that the time limit is not suspended when the Danish Health and Medicines Authority gives grounds for non-acceptance. It is therefore in the best interests of all parties that the sponsor's reply to grounds for non-acceptance is submitted to theDanish Health and Medicines Authority as quickly as possible.

When processing applications for trials with medicinal products for gene therapy and somatic cell therapy as well as medicinal products containing genetically modified organisms, the 60-day deadline is extended by 30 calendar days. For these medicinal products, the deadline of 90 days may be extended by a further 90 days in cases where public boards or the like are consulted.

Please note that there is no time limit for the Danish Health and Medicines Authority's decision in applications involving medicines for xenogenic cell therapy.

Notification to manufacturer

The sponsor must inform the manufacturer of the medicinal product or the manufacturer's representative of the application at the same time as the application is submitted to the Danish Health and Medicines Authority, cf. section 88 of the Danish Medicines Act.

This allows the manufacturer to raise objections to the person responsible for the trial prior to its initiation. This information should account for the use of the medicinal product in such a manner that the manufacturer/the manufacturer's representative gain a clear understanding of how the medicinal product will be employed in the trial. A copy of the information sent to the manufacturer must be enclosed with the clinical trial application.

3.1 Application for a multi-centre trial

For trials concerning more than one site in Denmark, one full application must be submitted by the sponsor. All the additional participating trial sites must be listed on the application form (Appendix 5).

If the coordinating investigator or any other person responsible for the trial leaves the trial site, the Danish Health and Medicines Authority must be informed as to whom is to replace them, and the sponsor must submit an amendment of the EudraCT application form and related XML file to the Danish Health and Medicines Authority. The form (see Appendix 6) can be downloaded as a Word file from http://eudract.ema.europa.eu/document.html. Pharmaceutical companies can use our DKMAnet extranet to submit this notification. For more information, please see: Clinical trial applications via DKMAnet

4. Contents of the application

Please see Appendix 10. Here you can find a table of contents of the application. We recommend that this table of contents is followed as an aid for both the applicant and the Danish Health and Medicines Authority, which will be able to go through the validation and check-in of the application more quickly. If any points of the table of contents are not relevant, please indicate this on the application.

Please also see the guidelines for application for authorisation of clinical trials, amendments and declaration of the end of the trials (CT 1), along with the guidelines for the EudraCT Database (CT 5). These guidelines are available at the following websites: The Commission's website http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev10.htm.

The application must include (only one copy of each appendix):

  • a covering letter, e.g. on specific conditions which should be known to the Danish Health and Medicines Authority along with a list of appendices (possibly with a reference to the above-mentioned table of contents, Appendix 10)
  • application form, filled in electronically and downloaded onto a floppy disk/CD-ROM
  • the trial protocol, cf. section 5
  • the written patient information/ power of attorney cf. section 10

And also

  • documentation on the medicinal products (including placebo) if this is not already in the hands of the Danish Health and Medicines Authority, such as the Investigator's Brochure (section 7) and the Investigational Medicinal Product Dossier (cf. CT 1)
  • a copy of the letter of notification sent to the manufacturer pursuant to the Danish Medicines Act section 88, cf. section 3
  • a copy of the approval from a scientific ethical committee, if available
  • information on the person, who monitors the clinical trial according to GCP.

The scientific processing of the application will not be initiated until the application is complete. On receipt at the Danish Health and Medicines Authority, the application will be checked-in within a few days and if any shortcomings are found, the missing material will be requested.

The Danish Health and Medicines Authority's evaluation of an application may take place at the same time as its evaluation in the scientific ethical committee system.

For the sake of the evaluation, it is important that the contents of the protocols, which form the basis for the evaluation in the two systems, are comparable. The Danish Health and Medicines Authority will accept both English-language and Danish-language protocols, but only one protocol is to be submitted. It is up to the sponsor/applicant to decide which of the two languages they wish to use.

4.1 Scientific Ethical Committee

According to the Act on a Scientific Ethical Committee System and the Processing of Biomedical Research Projects, a Biomedical Research Project must be authorised by a regional scientific ethical committee. This also applies to projects covered by the Danish Medicines Act.

In applications for trials with medicinal products in humans, the Danish Health and Medicines Authority must make its decision known to the scientific ethical committee concerned, cf. the Danish Medicines Act section 88(6).

Further information on applications to the scientific ethical committee system can be obtained by contacting the Danish National Committee on Biomedical Research Ethics, www.dnvk.dk, (tel. +45 7226 9370, dnvk@dnvk.dk).

4.2. Danish Data Protection Agency

According to the Danish Act on Processing of Personal Data, medicinal product trials must also be notified to the Danish Data Protection Agency. This may take place at the same time as the application to the Danish Health and Medicines Authority. However, please be aware that several areas of the private sector are exempt from this notification duty. More information in Danish can be find via this link: http://www.datatilsynet.dk/nyheder/seneste-nyheder/artikel/nye-fritagelser-fra-anmeldelsespligten-i-den-private-sektor/

For further information on such notification, please contact the Danish Data Protection Agency (www.datatilsynet.dk or tel. +45 3319 3200, 9:00 to 14:00).

4.3. Danish Working Environment Authority (trial on gene therapy)

Patient trials with products containing living, genetically modified organisms are subject to the Danish Environment and Gene Technology Act, more specifically this Act's rules on research. The rules are contained in the Danish Ministry of Labour's Executive Order (No. 910 of 11 September 2008) on "gene technology and working environment".

One of the things this Executive Order covers is the requirement for notification of the classification of premises, at which all or part of the trial is to take place, as well as notification of projects. The purpose of the notifications is to safeguard both the working environment and the external environment. The Danish Working Environment Authority will then grant authorisation of both the premises and the trial.

A cooperative agreement has been entered into by the Danish Working Environment Authority and the Danish Environmental Protection Agency on the evaluation of certain notifications of the classification of premises and notification of research projects. This has led to the following practice:

Notifications on the classification of premises for gene therapy and notification of projects concerning the use of living, genetically modified microorganisms for gene therapy are to be submitted to the Danish Working Environment Authority, which will then send a copy of notifications for consultation to the Danish Environmental Protection Agency.

Medicinal product trials with gene therapy must be notified to the Danish Working Environment Authority, cf. above. This may take place at the same time as the application to the Danish Health and Medicines Authority.

For further details concerning notification, please contact the Danish Working Environment Authority (http://www.arbejdstilsynet.dk/ or tel. +45 3915 2000).

5. Trial protocol

Please see the "Bekendtgørelse om god klinisk praksis i forbindlese med kliniske forsøg med lægemidler på mennesker, no 744 of 29 June 2006 (appendix 3). Generally, a trial protocol should comprise the points listed below. Some of the information may appear from separate appendices if local circumstances so require. Other parts of the points below may be described, for example, in the Investigator's Brochure.

A trial protocol must contain the following information, etc.:

1. General information

a. Protocol title, date and code (if applicable). All appendices and amendments must be numbered and dated.

b. Name and address of the sponsor and any Contract Research Organisation (CRO) (e.g. conducting monitoring)

c. Name and title of the person/persons authorised to sign the protocol and the protocol amendments on behalf of the sponsor.

d. Name, title, address and telephone number of the sponsor's medical/dental advisors for the trial.

e. Name and title of the investigator responsible for the trial and the address and telephone number of the relevant trial centre(s). In the case of multi-site trial please state the name and title of the investigator responsible for the trial at all centres, the coordinating investigator and the addresses and telephone numbers of all trial centres.

f. Names and addresses of laboratories and other hospital departments, technical departments and/or institutions involved in the trial.

g. A declaration stating that the trial will be carried out in accordance with the protocol and current statutory requirements/legislation.

h. A description of the time schedule, including dates for the start of the trial, the trial period and completion.

2. Background information

a. Product name(s) and 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

f. References to literature and data that are relevant and form the basis for the trial.

3. A detailed description of the purpose of the trial with references to relevant literature.

4. Trial plan and trial design

a. Clear indication of the primary and any secondary endpoints of the trial.

b. A description of the type/design of the trial (e.g. double blind, placebo controlled, parallel group comparative) – ideally illustrated by a flow chart

c. A description of arrangements for the reduction or elimination of bias, including: - randomisation; a description of the randomisation method – including procedures and practical arrangements -blinding; a description of the blinding (single blind, double blind, double dummy etc.) and practical procedures for safeguarding the blinding

d. A description of the trial treatment, dose, posology, frequency, packaging and labelling of the study medicine including any placebo and reference products (see instructions in section 7 for further information on requirements for documentation for the products used and section 8 for labelling requirements)

e. A description of the expected duration of the individual trial subject's participation in the trial and an indication of the trial periods (e.g. run-in, wash-out and follow-up) and the duration of these

f. A description of the rules for stopping the trial or interrupting treatment of individual subjects and/or parts of the trial

g. Procedures for accounting for the trial medicine, including placebo and reference products

h. Information on where the randomisation code is stored and procedures in case the code is breached

i. An indication of the data considered to be source data and which is recorded directly on the Case Report Forms (CRFs) – e.g. data not previously written down or electronically registered.

5. Selection of trial subjects and criteria for inclusion in and exclusion from the trial

a. A description of the inclusion criteria.

b. A description of the exclusion criteria

c. A description of criteria and procedures for leaving the trial (i.e. withdrawal of the study medicine/cessation of participation in the trial), stating:

-when and how the trial subjects are to discontinue the study medicine/leave the trial

-which data is to be collected from trial subjects from whom the study medicine is to be withdrawn or from trial subjects who have left the trial, as well as when such data should be collected -to what extent and how trial subjects leaving the trial are to be replaced by new subjects -follow-up procedures for trial subjects who have stopped using the study medicine/left the trial – NB! including drop-outs.

6. Treatment of trial subjects

a. A description of the treatment, including product name(s) of all products, dose, posology, frequency and treatment period(s), including follow-up periods.

b. Rules for concomitant treatment/medication before and/or during the trial (including "rescue medicine")

c. Arrangements for promoting and controlling close adherence to the treatment (compliance monitoring)

d. Statement of any subsequent treatment for the trial subjects when they leave/terminate the trial.

7. Evaluation of effect

a. Specification and justification of the effect parameters

b. Methods for time points for measurement, registration and analysis of efficacy parameters.

8. Safety evaluation

a. Specification and justification of safety parameters

b. Methods and times for measuring, recording and analysing the safety parameters

c. Procedures for registration and reporting of adverse events/adverse reactions (see section 12 concerning events/adverse reactions), including how long these records should continue after the trial subject has stopped using the study medicine. Also, procedures on how these individual reports are to be forwarded on completion of the trial – Final report

d. Arrangements for avoiding and treating complications

e. Statement of how and how long the trial subject should be monitored in case of adverse events/adverse reactions.

9. Statistics

a. Description of the statistical methods employed – including time(s) for scheduled interim analyses.

b. Justification of the scheduled number of patients – including considerations/calculations of the size of the trial and its clinical relevance.(In multi-centre trials, the number of trial subjects planned to be included per trial must also be indicated)

c. The significance level to be applied

d. Criteria for termination of the trial

e. Procedures for dealing with missing data, unused data and false data. False data may be e.g. interpolated data, and it is not necessarily false

f. Procedures for reporting deviations from the original statistical plan

g. Statement of the trial subjects, whose data will be included in the statistical analysis (e.g. all randomised subjects, all subjects receiving medication, all eligible subjects and all subjects who can be evaluated).

10. Direct access to source data/documents, including the investigator's authorisation to direct access to source data/documents (including patient files) in connection with monitoring, auditing and/or inspection by an scientific ethics committee, the Danish Health and Medicines Authority or by health authorities in other countries.

11. Quality control and quality assurance, including confirmation that ordinary procedures for quality control and assurance are complied with, cf. sections 3 and 4 of the Danish executive order on GCP (Appendix 3) / Confirmation that standard procedures for quality control and quality assurance will be complied with, cf. ICH GCP guidelines (see Glossary sections 1.46 and 1.47).

12. Ethical questions

a. Specific ethical considerations in relation to the trial

b. Description of how the trial subjects (patients, healthy volunteers, patients for whom the treatment of their illness is not the aim of the trial) are to be informed and how their consent will be obtained. Possible reasons for not obtaining informed consent from the trial subjects themselves.

13. Handling and archiving data. Guidelines for handling, processing and archiving all of the collected data for each trial subject participating in the trial, plus other data relevant to the trial.

14. Financing and insurance. Specification of the financing and insurance status of the trial.

15. Guidelines for publication:

a. Description of where the results are intended to be published/announced - Please see the current guidelines for researchers and scientific ethical committees.

16. Summary and appendices. The trial protocol must contain a summary and relevant appendices (e.g. instructions for personnel, description of special methods of approach).

17. Literature references. A list of the literature referred to in the protocol must be attached.

5.1. Contraception

Where relevant, it must be clearly stated in the protocol, or in an amendment to this that it is ensured that fertile women are not pregnant when included in the trial (negative pregnancy test at the inclusion) and that safe contraception is used.

The Danish Health and Medicines Authority considers the following contraceptive methods to be safe in connection with clinical trials: intrauterine devices, hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release). 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.

Fertile women included in a trial must thus use contraceptive methods in line with the above throughout the entire trial period and after the last dose of trial medication for a period of at least 5 times the plasma half-life of the investigational product.

Sterilised or infertile subjects are exempt from the requirement to use contraception. In order to be considered sterilised or infertile, subjects must generally have undergone surgical sterilisation (vasectomy/bilateral tubectomy, hysterectomy and bilateral ovariectomy) or be postmenopausal defined as 12 months or more with no menses prior to enrolment.

For some individuals or special populations, there may be arguments against using the above-mentioned methods. Examples include seriously ill, hospitalised patients or fertile children who are not sexually active. The investigator has the responsibility of determining whether any such populations exist. The reasons for a deviation, if any, must be recorded (in, for example, the CRF) and shall not be submitted to the Danish Health and Medicines Authority, but must be stored for documentation in connection with any future inspection.

5.2. Non-compliance to the register

A procedure for preauthorisations of non-compliance from the register (waivers) is in general not accepted by the Danish Health and Medicines Authority.

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 http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:02001L0020-20090807:EN:NOT.
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: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002874.pdf.

6.1. Inspections

Under the Danish Medicines Act section 90, subsections 1, 2 and 3, the Danish Health and Medicines Authority 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 at the Commission's website. http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm

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.

If the Danish Health and Medicines Authority 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 Health and Medicines Authority may order complete reports or any other supplementary information.

7.1 Manufacturers

Please see the guidelines for application for clinical trials, notification of amendments and declaration of the end of trial. http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm

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. The directives are available at: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/index.htm. 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

Please see the guidelines for application for clinical trials, notification of amendments and declaration of the end of trial. http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm

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 Health and Medicines Authority, it is sufficient to refer to it and, if possible, with an indication of the Danish Health and Medicines Authority'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.

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

  1. EU Directive 2001/83/EC – Community code relating to medicinal products for human use
  2. 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)
  3. EU Directive 2004/9/EC – on the inspection and verification of good laboratory practice (codified version)
  4. 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
  5. 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. Link: http://ec.europa.eu/health/files/eudralex/vol-4/2009_06_annex13.pdf.
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 Health and Medicines Authority.

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 Health and Medicines Authority 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 Health and Medicines Authority may in special circumstances make an exemption ad regards the supply of investigational medicinal products free or charge if:

  1. the purpose of the trial cannot be fulfilled, however, provided that the investigational medicinal products are supplied free of charge
  2. 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 Health and Medicines Authority 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 Health and Medicines Authority 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 Health and Medicines Authority'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 Health and Medicines Authority 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 personal details may be disclosed to the Danish Health and Medicines Authority as part the authority'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 Health and Medicines Authority and must be submitted together with the application for authorisation of a clinical trial of medicines. Pursuant to the Danish act on scientific processing of health scientific research projects, which entered into force on 1 January 2012, 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 and monitor's 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 Health and Medicines Authority 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 Health and Medicines Authority has granted an authorisation and the Scientific Ethical Committee System has approved the trial. Only when the authorisation from the Danish Health and Medicines Authority 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 Health and Medicines Authority 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 Health and Medicines Authority'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 Health and Medicines Authority for permission before the sponsor implements amendments to the trial protocol when the amendments could have an impact on:

  1. the safety of the trial subjects,
  2. the interpretation of the scientific documentation which the trial is based on,
  3. the completion or management of the trial,
  4. 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 Health and Medicines Authority'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 Health and Medicines Authority 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 Health and Medicines Authority 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: http://laegemiddelstyrelsen.dk/~/media/6F1F7A3BA197409B94E8B1040879173D.ashx, which links to relevant documents. The form must be filled in, printed, signed and submitted to the Danish Health and Medicines Authority with documentation enclosed.

The completed form must be signed by the sponsor/applicant.

Notifications to the Danish Health and Medicines Authority

The Danish Health and Medicines Authority 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 Health and Medicines Authority.

12. Adverse reactions/Adverse events

The sponsor must inform the Danish Health and Medicines Authority 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 Health and Medicines Authority:

Sponsor's obligations

Under section 89(2)(i) of the Danish Medicines Act, the sponsor must immediately inform the Danish Health and Medicines Authority 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 Health and Medicines Authority 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 Health and Medicines Authority 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 Health and Medicines Authority 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 Health and Medicines Authority 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 material

Furthermore, the documentation must include which reference materials are 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 and an Investigator's Brochure for non-marketed products.

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 material throughout the entire trial.

If the reference material 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 Health and Medicines Authority 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 Health and Medicines Authority.

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 Health and Medicines Authority'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 Health and Medicines Authority by commercial sponsors should be reported via the EudraVigilance Gateway.

The ID concerning SUSARs of the Danish Health and Medicines Authority (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).

Until all commercial sponsors are registered in the EudraVigilance system, the Danish Health and Medicines Authority 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.

DKMAnet

Pharmaceutical companies can use our DKMAnet extranet to submit annual safety reports using the service for safety surveillance of authorised clinical trial. For more information, please see: Applying for clinical trial authorisations via DKMAnet.

13. Report

No more than 90 days after completion of trial, the sponsor must inform the Danish Health and Medicines Authority that the trial has been completed (use Declaration of the end of a Clinical Trial) and as soon as possible and at the latest before one year after thereafter, the sponsor must submit the trial results to the Danish Health and Medicines Authority, cf. the Danish Medicines Act section 89(2), no. 4. In summarised form, this must comprise information about the number of patients treated, doses used, duration of medication and results obtained, as well as any adverse events and adverse reactions observed pursuant to the protocol. If it is a multinational trial the Danish Health and Medicines Authority must be informed when the trial is completed in Denmark. When the trial is finished globally we ask that the before mentioned declaration is used.

The Danish Health and Medicines Authority will, if deemed necessary, request the complete report.

As regards studies in children based on a paediatric investigation plan, the trial results must be submitted within six months.

A paediatric investigation plan must be prepared at the time of filing a marketing authorisation for a new medicinal product, a new indication (including paediatric indications), a new pharmaceutical form or a new route of administration for an already approved product, as provided by Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004.

DKMAnet

Pharmaceutical companies can use our DKMAnet extranet to notify us when a trial has ended (use the service for safety surveillance of authorised clinical trial) and to submit the clinical study report and associated publications (use the service for notification about authorised clinical trial). For more information, please see: Clinical trial applications via DKMAnet.

14. Additional guidelines

Several EU guidelines exist on clinical trials in general as well as specific guidelines for certain therapeutic groups.

More information on these 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-Publikationer
Herstedvang 12
DK-2620 Albertslund

It is possible to find guidelines on the internet starting from 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 this programme is not installed on your computer, you can download it via the following address: http://www.adobe.com/


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

CIOMS form

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

General Considerations for Clinical Trials