Checklist for applications for clinical trials with medical devices

List of documents to be submitted when reporting clinical trials of medical devices.

The documents must be submitted as independent files. There are help documents for several of the sub-items, follow the link:

01.01 Cover letter

01.02 Application form

1. The relevant forms can be found here.

02.01 Investigators Brochure

02.02 Instruction for use

02.03 Checklist for fulfilment of general safety performance requirements

1. Template can be found at the Danish Medicines Agency

03.01 Clinical trial plan

1. An international trial plan must be supplemented with Danish special requirements in an appendix if the international protocol does not comply with Danish law. The supplement should refer to the original project title and have a date and version number.

04.01 Participant information

04.02 Consent forms

05.01 Copy of conformity assessment if the equipment is not CE-marked

1. Template can be found at the Danish Medicines Agency

06.01 Sponsor's statement on how to comply with GDPR

07.01 Danish synopsis

08.01 Questionnaires (possibly in a combined file) (if several documents, number afterwards, e.g. 08.01, 08.02 etc.)

09.01 Recruitment material
For example, advertisements, postings, recruitment letters, text on sundhed.dk or social media

10.01 Documentation for insurance if the Patient Compensation Association does not cover
See Guidelines on Insurance and Compensation.

11.01 Danish version of relevant parts of the sponsor contract
About publishing conditions and fees for researcher/test subjects as well as researcher's access to data

12.01 Documentation for CE-marking

13.01 Documentation of the trial responsible's experience, education and identity (for all trial responsible at all Danish sites (if several documents, number afterwards, e.g. 13.01, 13.02 etc.) – NB! Only one responsible per site

1. CV
2. Authorisation-id (printout from authorisation register)
3. Copy of health card, driver's license (physical card or screenshot from app) or passport. Possibly the last 4 digits of social security number can be crossed out

14.01 Documentation for sponsor's identity (if several documents, number afterwards, e.g. 14.01, 14.02 etc.)

1. Company address and CVR no.
2. Contact person
3. If the sponsor is located outside the EU (with the exception of Norway, Iceland, Lichtenstein and Turkey), information must be provided on the EU-appointed representative's address and CVR no.

15.01 Billing information

1. Link to form
2. The billing form must be signed and attached to the application at the same time as the application is submitted

Your protocol must include the following information:

1. Original Title of the Trial
2. Description and Classification of the Device
3. Information about the Manufacturer, or the EU-authorized Representative and Importers
4. Purpose
   1. Rationale and Objective of the Trial, including whether the trial is conducted within the framework of the device’s CE marking. For devices that are not CE-marked, indicate whether the purpose of the trial is to obtain CE marking.
   2. Brief Literature Review and Reference List
   3. If a previous trial is being repeated, justify why.
5. Method
   1. This includes design, methodology, as well as the use of a control group and randomization.
   2. The practical implementation, investigations, and scope.
   3. Indicate if algorithms are used in the device.
   4. Start and Duration of the Trial
6. Endpoints
   1. Describe and justify the trial’s endpoints.
7. Statistical Considerations
   1. Power calculation or other statistical considerations justifying the number of participants.
   2. Describe and justify the trial’s effect size (or any margin for non-inferiority).
   3. Describe how the data will be analyzed (e.g., intention-to-treat, per protocol, etc.).
8. Participants
   1. Inclusion Criteria
   2. Exclusion Criteria
9. Risks, Side Effects, and Disadvantages (Short and Long Term)
   1. This includes safety measures to minimize pain, discomfort, fear, and other risks.
10. Monitoring Plan
    The monitoring plan must align with the trial's risks and any deviations from usual clinical practice, both in scope and character.
    Describe:
    1. Who is responsible for monitoring the trial
    2. The qualifications of the monitor
    3. The activities performed for monitoring purposes
       Relevant factors could include:
       • Data Quality (e.g., correct transfer of data from source documents)
       • Consent Process (e.g., approved version of participant information, correct translations)
       • Handling of the Device (e.g., adherence to the Investigators Brochure, proper labeling of the device)
       • Adverse Events (e.g., proper and timely reporting)
11. Laboratory Samples (e.g., sample storage, use of labels) Statistical Analysis (e.g., identification of missing data, large variations between centers) Collection of New Biological Material or Use of Existing Biobank Samples
    Describe:
    1. What and how much material
    2. The purpose
    3. Whether the material will be destroyed after analysis.
       If the material is stored in a research biobank (i.e., for more than 5-7 days):
       See the Biobank Guidelines, Section 5.2:
    4. The duration and purpose of storage?
       If project material is sent abroad:
    5. Which country and for what purpose
    6. How the General Data Protection Regulation (GDPR) and data protection laws are complied with. For transfer to third countries, additionally explain how Chapter V of the GDPR is adhered to.
       If there is surplus biological material after the project concludes, See Biobank Guidelines, Section 5.2.2:
    7. Whether the material will be destroyed or anonymized, or
    8. Whether it will be stored for future research, and that data protection rules will continue to be followed.
       If extra material is collected for future unspecified research:
    9. This is outside the committee's authority but is regulated by GDPR and data protection laws. However, it can be stated in the protocol that participants will be separately asked for consent to document that the material in the biobank was collected for the specific research project.
       If project material is imported:
    10. Submit documentation/declaration from the institution/company stating that the material was collected in an ethically responsible manner, in accordance with the laws at the collection site and legally performed by the country.
12. Patient Record Information
    If patient record information is to be used in the project, the following should be described:
    1. What information is required and for what purpose. Clearly differentiate between information required before the participant’s consent is obtained (e.g., for identification/recruitment) and the information used after consent has been granted.
    2. Clearly state that the information used before consent is obtained will be passed to the researcher.
    3. Clearly state that consent grants the trial supervisor, sponsor, sponsor's representatives, and any regulatory authorities direct access to obtain information from the participant's medical records, including electronic records, to view health-related data necessary for conducting the research project, as well as for oversight activities such as self-monitoring, quality control, and monitoring.
13. Processing of Personal Data in the Project
    1. You must state that the General Data Protection Regulation (GDPR) and data protection laws are being followed. Note that it is the sponsor's or trial supervisor’s responsibility to ensure compliance with data protection rules in the handling of personal data in the project. There may be requirements in the region or at the university to register the project in an internal registry.Describe if personal data is sent abroad:
    2. Which country and for what purpose
    3. How the GDPR (including Chapter V) is followed when transferring data to third countries.
14. Finances
    1. Describe who initiated the trial.
       If there are sponsors, describe:
       Names of sponsors, including the amount for each sponsor (fixed sum and/or per participant)
    2. How the support is used in the trial (e.g., staff compensation, laboratory tests, etc.) (attach budget if necessary)
    3. Whether the support is paid directly to the researcher, their department/institute, research fund, or another entity (for researchers at RVK Syddanmark, provide the account number where the support is deposited)
    4. Whether the researcher has financial ties to the sponsor or other stakeholders in the trial.
15. Any compensation or other benefits for participants:
    See also Appendix 1: Guidelines for Compensation and Other Services for Voluntary Participants.
    1. Compensation amount, including transport reimbursement, lost wages, and/or inconvenience allowance
    2. How much participants will be reimbursed proportionally if they withdraw early
    3. Other benefits – economic value
    4. For trial patients, justify that the requirements in Appendix 1 are met.
16. Recruitment of Participants and Informed Consent
    See also the standard Guidelines for Oral Participant Information.
    Describe recruitment and the procedure for providing oral information and obtaining consent:
    1. How participants are recruited (e.g., via posters, advertisements, recruitment letters, internet, social media, or medical records)
    2. How the initial contact with the participant occurs
    3. The process for obtaining informed consent
       1. Where, when, and by whom oral and written information is provided
       2. How it is ensured that the conversation occurs in private
       3. How the right to have an assistant is ensured in practice
       4. The waiting period between providing oral and written information and obtaining informed consent
       5. When consent is to be obtained
17. Publication of Results
    1. Describe where the results will be made publicly available after the trial.
18. Ethical Considerations
    Describe:
    1. Why the risks, either in isolation or in relation to the benefits of the trial, are justifiable, and
    2. Why the therapeutic benefit for participants or future patients justifies the trial.
19. Compensation Scheme Information
    1. Whether the trial is covered by the patient compensation scheme, or if an independent insurance policy has been taken out.

You must submit a Danish summary of the protocol, i.e., a synopsis, which should be an accurate and comprehensive description that can be understood by individuals without a healthcare background. It should be written in general, easily understandable Danish, with clinical terms explained or reworded. Note: Only information included in the other project materials (e.g., the trial plan or participant information) should appear in the Danish summary.

1. The Original Title of the Clinical Trial Plan
2. Name of the Trial Supervisor/Sponsor and Trial Site
3. Purpose of the Trial
4. Method, Design, and Investigation Procedures of the Trial, including information about any research biobank
5. Participants, including inclusion and exclusion criteria
6. Side Effects, Risks, and Disadvantages
7. Financial Aspects
8. Recruitment of Participants
   The same requirements as for protocol item 12
9. Publication of the Trial Results
10. Ethical Consideration Statement

The date and version number must be added to the document and each time changes are made.

The written participant information must describe the following:

1. Original title of the test
2. Request to participate in a clinical trial
3. Purpose, significance and scope of the test
4. Method and practical organisation of the test
5. Risks, disadvantages and stresses of the test
   1. The foreseeable risks, side effects, complications, disadvantages and strains in the short or long term – including radiation risks – and their expected frequency
   2. Possible safety measures
   3. It must be stated that there may be unforeseen risks and strains associated with the testing.
6. What is the standard treatment and are there other options for treatment?
7. If information from the patient record is to be used for the project, it must state:
   1. What information is to be used and its purpose
   2. That the subject's consent gives the investigator, sponsor and his/her representative direct access to relevant health information in the medical record in order to conduct, monitor and control the study
8. Processing of personal data
   1. Describe that personal data will be processed in the trial. Please state that the Data Protection Act and the General Data Protection Regulation are complied with. (Please note the duty of disclosure (about the rights of data subjects) that applies under the General Data Protection Regulation, see the Danish Data Protection Agency's guidance on this)
9. Extraction of biological material from test subjectsSee also Guidelines on the use of biological material in health science research projects. Describe:
   1. Which material and how much material is taken out
   2. What the purpose of the set-aside is
   3. Whether the material is destroyed after analysis
   4. Or whether the material is stored in a research biobank (i.e. storage beyond 57 days after it has been extracted):
   5. How long the material is stored
   6. What the purpose of the storage isIf the material is sent abroad, state:
      1. Which country and for what purpose?
   7. That the General Data Protection Regulation and the Data Protection Act are complied with. In the case of transfers to third countries, please provide additional information on how Chapter V of the General Data Protection Regulation is complied withIf there is any surplus biological material at the end of the project, please state:
   8. Whether the material is destroyed or completely anonymized, or
   9. Whether the material will be stored for future research, and if so, that the data protection rules will continue to apply. It must be stated that new research on the biological material must be approved by the research ethics committee and that, as a general rule, new consent must be obtained, but that the committee can grant exemptions (see section 5.2.2 of the biobank guidelines)
10. Usefulness of the test
    1. What potential benefit there is for the test subject, for others and for the research.
11. If the test has to be interrupted
    1. What can lead to the subject being taken out of the trial or the trial being completely discontinued.
12. Any remuneration and/or other benefits to the trial subjectDescribe:
    1. The amount of the remuneration, including any transport allowance, lost earnings and/or inconvenience allowance
    2. How much will the participants be paid proportionately if they withdraw early?
    3. Other goods – economic value
    4. Taxation
13. EconomyDescribe:
    1. Who initiated the testing?
    2. Names of donors
    3. Who is supporting the trial – the amount for each donor, and how the support is included in the trial
    4. Whether the person responsible for the trial has financial ties to companies or foundations with an interest in the trial
14. Contact person
    1. How interested parties can get more information
    2. Name, address, email address and telephone number of a contact person in the test
15. Publication of results
    1. Describe where participants can subsequently find information about the results of the experiment in an accessible format
16. General rights of the subject
    1. You must enter (or attach) the information that appears here.

The investigator's brochure (IB) shall contain clinical and non-clinical information on the device intended for testing in question that is relevant to the trial and which is available at the time of application.

The purpose of the IB is to provide the investigator and other persons involved in the trial with guidance and a clear understanding of the possible risks and side effects of the trial, as well as what specific tests, observations and safety measures are necessary during the conduct of the trial.

The IB must be clearly identifiable and in particular contain the following information:

1. Front page with the following information
   1. Sponsor's Name
   2. Medical devices intended for testing
   3. Version number
   4. The release date of the IB
   5. Reference to the version that the current IB replaces
2. Statement
   1. If the sponsor wants the Investigator to treat the IB as a confidential document only for use by the Investigator team and authorities.
3. Table of contents
4. Summary
5. Introduction
   1. A brief introduction of which device is included in the trial, the rationale for the testing of the medical device and the expected use afterwards.
6. Description of the medical device under investigation
   1. Identification and description of the device: including information on the declared purpose, risk class and applicable classification according to Annex VIII of the Medical Device Regulation (MDR), the design and manufacture of the device, and reference to previous and similar generations of the device.
   2. The manufacturer's instructions for installation, maintenance, maintenance of hygiene standards and use, including requirements for storage and handling, and the extent to which such information is available, information to be included on the label, and instructions for use to be supplied with the equipment when it is placed on the market. In addition, information on any relevant required training for handling the equipment.
   3. For devices incorporating a medicinal product, including a human blood or plasma derivative, or devices manufactured using non-viable tissues or cells of human or animal origin or of derivatives thereof, detailed information on the medicinal product or on the tissues, cells or derivatives thereof, and on compliance with the relevant general safety and performance requirements and specific risk management measures in relation to the substance or tissues; cells or their derivatives, as well as evidence of the added value of the incorporation of such constituents in relation to the clinical benefits and/or safety of the device.
   4. A list indicating that the relevant general safety and performance requirements set out in Annex I, including the standards and common specifications used, have been fully or partially complied with, as well as a description of the solutions used to meet the relevant general safety and performance requirements, insofar as those standards and common specifications have not been or have only been partially complied with or are missing.
7. Non-clinical studies
   1. Preclinical evaluation on the basis of relevant preclinical testing and study data, in particular regarding design calculations, in vitro tests, ex vivo tests, animal tests, mechanical or electrical tests, reliability tests, sterilisation validation, software verification and validation, performance testing, biocompatibility evaluation and biological safety, if applicable
8. Clinical trials
   1. Existing clinical data from:
      1. relevant available scientific literature describing the safety, performance, clinical benefit to patients, design characteristics and stated purpose of the device and/or similar or similar device;
      2. other relevant available clinical data describing the safety, performance, clinical benefits to patients, design characteristics and stated purpose of similar or similar devices from the same manufacturer, including how long it has been on the market, and a review of performance, clinical benefit and safety issues and any corrective actions;
9. Summary of data and guidance for the investigator
   1. Summary of the analysis of the benefit/risk balance, including information on known or foreseeable risks, possible side effects, contraindications and warnings.
   2. A detailed description of the clinical procedures and diagnostic tests used during the clinical trial, in particular information on any deviation from normal clinical practice.

1. Research with children
   The test plan is supplemented with the following:
   1. Scientifically justify why it is necessary to conduct the experiment on children.
   2. Specifically justify that the trial has a reasonable potential for direct gain to the participant that outweighs any risks or burdens associated with the trial
   3. Describe the age of the children and justify the choice of age group concretely, as older children should be included rather than smaller children
   4. Describe any measures that can minimize pain, fear or discomfort in relation to the child's development
   5. The procedures for information and consent must be supplemented by the following:
      1. Indicate that consent will be obtained from both parents in the case of joint custody. See also the declarations of consent
      2. What prerequisites the informing healthcare professional has, i.e. knowledge of the area and pedagogical prerequisites for informing the age group
      3. How the information to the child will be adapted to the child's ability to understand the experiment, its age and maturity (from 5 years and up, written information must be provided)
      4. That independent consent will be obtained from the young person when the young person reaches the age of majority, in the case of young test subjects who reach the age of majority in the trial
   6. In particular, in less intrusive attempts, where permission has been sought for the young person to give consent independently, you must:
      1. explain that it is a 15-17-year-old who is not exposed to intervention or other forms of stress, e.g. swab experiments, and
      2. state that the holder of custody receives the same information as the young person and is involved in the decision on the trial.
2. Research with adults incapacitated (incompetent)
   See also Guidelines on informed and proxy consent in health science research projects, section 3. The test plan is supplemented with the following:
   1. Explain why the subjects are incapable of acting (unable to take care of their own affairs)
   2. Scientifically justify why it is necessary to conduct the trial with disqualified participants.
   3. Specifically justify that the trial has a reasonable potential for direct gain to the participant that outweighs any risks or burdens associated with the trial
   4. The procedures for information and consent shall be supplemented by information on:
      1. That proxy consent will be obtained from the next of kin and the trial guardian. See also the declarations of consent
      2. What prerequisites the informing healthcare professional has for involving the trial subject
      3. That the information provided to the subject is adapted to the subject's ability to understand the trial
      4. That written participant information has been prepared for the deputy
      5. How the trial guardian is appointed – he or she must use his or her professional knowledge to assess whether the trial subject in question can participate in a trial of this nature. See section 3.4 of the Guidance on informed and proxy consent.
      6. That an independent consent will be obtained from the trial subject if he/she regains his/her impartiality in the trial. This only applies to experiments that have a character where impartiality can be regained.

3. Research with pregnant or breastfeeding womenThe test plan is supplemented with the following:
   1. Scientifically justify why it is necessary to conduct the trial with pregnant or breastfeeding women
   2. Specifically justify that the trial has a reasonable potential for direct gain to either the participant, embryo, fetus or child, outweighing any risks or burdens associated with the trial
   3. Explain if breastfeeding women are included in the trial that special consideration is given to the child's welfare
4. Research in emergency situationsThe test plan is supplemented with the following:
   1. Scientifically justify why it is necessary to carry out the experiment in an emergency situation.
   2. Specifically justify that the trial contains a reasonable potential for direct gain to the participant, which can provide a measurable health benefit.
   3. Explain that the trial involves only minimal risks and burdens compared to standard treatment.
   4. Procedures for consent and information are supplemented with the following:
      1. Explain that the subject is unable to receive information and give consent in advance due to sudden illness or life-threatening condition.
      2. Explain that consent will be obtained without undue delay from the subject (if possible) or his/her legally appointed representative.
      3. Explain that consent is obtained from the subject without undue delay as soon as possible.
      4. Explain that it is not possible to provide information in advance and obtain prior proxy consent from the subject's legally appointed representative.
      5. Explain that the trial coordinator is not aware that participants in the trial have previously asked not to participate.
      6. Describe how the trial guardian is appointed – he or she must use his or her professional knowledge to assess whether the trial subject in question can participate in a trial of this nature. See section 3.4 of the Guidance on informed and proxy consent.

If it is a comprehensive mapping of the genome, the following must be described. For other genome projects, where there may also be a risk of significant health findings, the committee will also be able to apply the same principles in the assessment, e.g. in the case of targeted examination of a very large number of genes. The checklist for research in biological material applies in parallel with the below.

Describe:

1. Examination methods
   1. That it is a matter of comprehensive mapping of the genome
   2. Which part of the genome (e.g. gene panels, exomers, whole genome, epigenome, RNA) and what type of sequences are being studied (rare and/or frequent variants, structural variants, etc.)See the list of methods here:
   3. Which sequencing platform or high-density array is used, as well as sequencing depth.
   4. Which bioinformatics tools are used.
2. Data Retention
   1. How data is stored, including where and for how long.
3. Reporting of random findings
   1. If it is a study with a risk of mutation in high-penetrant genes: That the subjects will receive genetic counselling prior to the research
   2. How you assess the probability of random findings. Justify this. Handling of the subjects' requests for feedback. Both about the genes that are being studied and about random findings. The genome guide must be followed if random findings occur
   3. That a group of independent experts will be set up to assess incidental findings and advise on how to deal with them
   4. If you also use this method to minimize the likelihood of random findings, then focus only on specific areas of the genome and disregard other areas that may deal with clinically relevant genes, e.g. the genes on the ACMG's list. In such a case, it must be stated that the filtering of these nuisances is done in such a way that no data is generated or registered regarding the unwanted information. See the Genome Guide and use the wording from this guide.
4. Possible research collaborations
   See The Genome Guide.
   Describe:
   1. Name of the business partner
   2. What the collaboration is about:
      1. laboratory analyses, including bioinformatic analyses, if any: Describe that a data processing agreement is entered into in this regard (see the Danish Data Protection Agency)
      2. If there is (possibly supplementary) research collaboration: Describe that the external party may only conduct research within the purpose of the protocol and is aware of the 5 criteria regarding the duty to provide feedback in the Genome Guide.
   3. What data is given access to (and is it in coded form, for example?)
   4. Whether genomic data is transferred abroad
   5. That the personal data from the sequencing is processed in accordance with the rules of the General Data Protection Regulation and the Data Protection Act as well as in accordance with the principles of the Health Act for relatives.
5. Participant information in genomics 
   A standard declaration of consent and a declaration of opt-out of knowledge have been prepared. If you do not use the standard, the information should include the following:a. Explain that this is a comprehensive mapping of the subject's genetic material and explain the purpose. Describe:
   1. The method in short (whole genome examination or exome sequencing etc.)
   2. What knowledge you expect to gain
   3. Whether the subject will benefit from the study and if so, what
   4. If it is a study with a risk of mutations in high-penetrant genes: State that the test subjects receive genetic counselling prior to the research
   5. If genome data is stored after the experiment: That the storage takes place in accordance with the General Data Protection Regulation and the Data Protection Act
   6. If you have a research collaboration with domestic or foreign collaborators. Please state:
      1. Name of the business partner
      2. What the collaboration is about
      3. What data is given access to (e.g. is it in coded form?)
      4. Whether genomic data is transferred abroad
      5. That the personal data from the sequencing is processed in accordance with the rules of the General Data Protection Regulation and the Data Protection Act.

6. Feedback on health findings
   Describe:
   1. That knowledge can emerge that was not foreseen (random findings)
   2. That the subject will be informed in the rare situations where a genetic variation is detected that may cause serious disease that can be prevented or treated
   3. That it may also be appropriate to inform family members if the information can prevent death or serious deterioration of health
   4. That the trial subject can request not to receive information about random findings, but that the trial subject must contact the researcher separately (Declaration on opt-out of knowledge).
   5. How the subject can get information about the outcome of the study.
7. Genomic research in biological material without consent
   1. There must be a detailed reason for not obtaining consent from the test subjects. Describe the risk of getting random findings and how these will be handled. SeeThe Genome Guide.
   2. The same conditions must be explained as in Research on biological material with exemption from consent. See also. here.
8. Genomics with children
   1. Explain specifically how either i., ii. or iii. is fulfilled:
      1. It is about the child's clinical condition, the patient group gets a benefit, and you test data from research with competent or other experimental methods. Healthy children are discouraged from genomics
      2. The experiment directly benefits the child, and genomics with adults does not provide the same benefit
      3. Genomics can only be carried out with this age group, which benefits very much and is exposed to minimal risk.
   2. Describe whether random findings may occur that only become apparent in adulthood

When it comes to research on the deceased, a number of information included in the standard protocol will naturally have to be omitted, e.g. procedures for information and consent and the like. This guide has been supplemented with current legal rules to clarify the interface with the Danish Health Act.

1. Describe whether it is research on material taken by autopsy (section 8(1) of the Committee Act):
   1. Forensic autopsies (section 184 of the Health Act)Specify whether:
   2. The material was extracted before 1 January 2012 (no requirement for consent under the Danish Health Act), or
   3. The material was extracted after 1 January 2012 (with consent pursuant to section 187 of the Danish Health Act, see the Ministry of Health's Guidelines on consent to research in tissues and other biological material taken by forensic autopsy. See Guidelines on consent for research on tissue and other biological material taken at a forensic autopsy.
   4. Medical autopsies (with consent pursuant to section 187 of the Danish Health Act, see the Ministry of Health's Guidelines on consent to medical autopsies, etc. (hospital autopsies).NB: Declarations for information and consent do not need to be submitted.
2. Describe that it is research on biological material from the deceased, but not an autopsy, cf. section 8(2) of the Committee Act:
   1. The deceased's donation of the body to science pursuant to section 188 of the Health Act, or
   2. Other interventions pursuant to section 8(2) of the Committee Act
   3. That is, minor procedures such as blood draws, removal of skin areas and equivalent procedures (except removal of retinas that are treated as autopsies).NB: Declarations for information and consent must be submitted. Find declarations of consent here. You can read more about research on the deceased in the committee system's Guidance on research on the decease.