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 should contain the following information:

1. Original title of the trial
2. Description and classification of the equipment
3. Information about the manufacturer, or the EU authorized representative and importers
4. Purpose
   1. Rationale and purpose of the trial, including whether the trial is within the framework of the device's CE marking. For non-CE marked equipment, it should be indicated whether the purpose of the trial is to obtain CE marking.
   2. Short literature review and bibliography
   3. If a previous trial is being repeated, justify why
5. Method
   1. Including design, methodology and use of control group and randomization
   2. The practical implementation, investigations and scope
   3. Monitoring plan
   4. Indicate if algorithms are used in the equipment
   5. Start and duration of the trial
6. Statistical considerations
   1. Power calculation or other statistical consideration that justifies the number of test subjects
7. The trial subjects
   1. Inclusion criteria
   2. Exclusion criteria
8. Risks, side effects and disadvantages in the short and long term
   1. Including safety measures that minimize pain, inconvenience, fear and other risks
9. Extraction of new biological material or collection of biological material from already existing biobank

See also Exemption from consent.

Describe:

1. Which and how much material
2. What purpose
3. Whether the material is destroyed after analysis
   
   If the material is stored in a research biobank (i.e. beyond 5-7 days from extraction)
   
   See the Biobank Guide, section 5.2:
   
   
4. How long and what is the purpose of the storage?
   
   If project material is sent abroad:
   
   
5. Which country and with what purpose
6. That the data protection regulation and data protection law are complied with. When transferring to third countries, additionally disclose that Chapter V of the data protection regulation is complied with
7. Which country's law protects the personal data abroad, if it is not the data protection regulation and data protection law
   
   If there is surplus biological material after the project's completion
   
   See the Biobank Guide, section 5.2.2:
   
   
8. Whether there is destruction or full anonymization of the material, or
9. Whether the material is stored for future research, and that data protection rules continue to be complied with
   
   If additional material is also taken for future unspecified research:
   
   
10. This is not the committee's jurisdiction, but is regulated by the data protection regulation and data protection law. However, it can be indicated in the protocol that participants will be asked separately about this in order to subsequently be able to document that the material in the biobank has been extracted in connection with the specific research project
    
    If project material is imported:
    
    
11. Submit documentation/declaration from company/institution that the material has been extracted/collected in an ethically responsible manner in accordance with the legislation at the collection site and legally exported from the country

1. Information from patient records
   
   If information from the patient record is to be used for the project, the following must be described:
   
   
   1. It must be stated which information is needed and what the information is to be used for. A distinction must be made between information that is to be used before the trial subjects have given consent to participate, e.g. in connection with identification/recruitment, and the information that is to be used for the project after consent to participate has been given
   2. It must be stated that the information to be used in the project before consent is given by the trial subjects is passed on to the researcher
   3. It must be stated that the consent gives the trial responsible, sponsor and sponsor's representatives and any control authority direct access to obtain information in the patient's medical record etc., including electronic medical record, in order to see information about the trial subject's health conditions, which are necessary as part of the implementation of the research project and for control purposes, including self-control, quality control and monitoring, which they are obliged to carry out.
2. Processing of personal data in the project
   1. You must state that the data protection regulation and data protection law are complied with. Note that it is the responsibility of the sponsor or trial responsible to ensure that data protection rules are complied with in connection with the processing of personal data in the project. There may be requirements in the region or at the university for registration of the project on an internal list.
      
      Describe if personal data is sent abroad:
      
      
   2. Which country and what purpose
   3. That the data protection regulation and data protection law are complied with, including when exporting to third countries, where you additionally must state that Chapter V of the data protection regulation is complied with
   4. Which country's law protects the personal data abroad, if it is not the data protection regulation and data protection law
3. Economy
   1. Describe who initiated the trial.
      
      If there are sponsors, describe:
      
      
   2. Name of sponsors, including amount for each sponsor (fixed sum and/or per trial subject).
   3. How the support is included in the trial, e.g. remuneration of staff, laboratory examinations or similar (possibly attach budget).
   4. Whether the support is paid directly to the researcher, their department/institute, research fund or other (for researchers in RVK Southern Denmark, the account number the support amount is included on must be stated).
   5. Whether the researcher has financial ties to the sponsor or other stakeholders in the trial.
4. Possible remuneration and/or other benefits for the trial subjects
   
   See Appendix 1: Guidelines for remuneration and other services to voluntary trial subjects.
   1. The size of the remuneration, including any transport compensation, loss of earnings and/or inconvenience allowance
   2. How much will participants be paid proportionately if they withdraw early
   3. Other benefits - economic value
   4. For trial patients, you must account for the requirements in Appendix 1 being met.
5. Recruitment of trial subjects and informed consent
   
   See also the standard Guidelines for giving oral participant information.
   
   Describe the recruitment as well as the procedure for oral information and receipt of consent:
   1. How the trial subjects are recruited (posting, advertisement, recruitment letter, internet, social media or via records)
   2. How the first contact to the trial subject is made
   3. The course of obtaining informed consent
      1. Where, when and by whom the oral and written information is given
      2. How it is ensured that the conversation takes place undisturbed.
      3. How the right to a companion is ensured.
      4. What reflection time there will be between giving oral and written information and obtaining informed consent.
      5. When consent is sought.
6. Publication of results
   1. Indication of where a report on the examination of the device's performance and a summary thereof, which is understandable for the intended user, is made available.
7. Scientific ethical section
   Describe:
   1. Why risks, either in themselves or in relation to the benefits of the trial, are indefensible and
   2. Why the therapeutic benefit for trial subjects or future patients justifies the trial.
8. Information about compensation scheme
   1. Whether the trial is covered by patient compensation, or whether an independent insurance has been taken out.

You must submit a Danish summary of the protocol, i.e. a synopsis, which must be a truthful and covering description, which can be understood by people without medical education. It must be generally understandable Danish, where clinical technical terms are explained or rewritten.

1. The original title of the clinical trial plan
2. The name of the trial responsible/sponsor and trial site
3. Purpose of the trial
4. The trial's method, design and investigation procedures, including information about any research biobank
5. Trial subjects, including inclusion and exclusion criteria
6. Side effects, risks and disadvantages
7. Economic conditions
8. Recruitment of trial subjects
9. Same requirements as for protocol point 12
10. Publication of the trial's results
11. Scientific ethical statement

The date and version number must be applied to the document, and every time changes are made.

The written participant information should describe the following:

1. The original title of the trial
2. Inquiry to participate in a clinical trial
3. The purpose of the trial, its significance and scope
4. Method and practical organization of the trial
5. The risks of the trial
   1. What risks, side effects, complications, disadvantages and burdens in the short or long term can be anticipated - including radiation risks
   2. Possible safety measures
   3. It should be stated that there may be unforeseen risks and burdens associated with the trial.
6. What is the standard treatment, and are there are other treatment options?
7. Journal information
   If information from the patient journal is to be used for the project, it must be stated:
   1. Which information is needed and for what purpose
   2. That the trial subject's consent gives the trial responsible, sponsor and his representative direct access to relevant health information in the journal in order to be able to carry out, monitor and control the trial
8. Processing of personal data
   1. Describe that in the trial personal data will be processed. State that the Data Protection Act and the General Data Protection Regulation are complied with (Be aware of the duty to provide information (about the rights of the data subjects), which applies according to the General Data Protection Regulation, see the Data Inspectorate's guide on this)
9. Extraction of biological material from trial subjects
   See the Guide on the use of biological material in health science research projects
   Describe:
   1. Which material and how much material is taken
   2. What the purpose of the extraction is
   3. Whether the material is destroyed after analysis
      Or if the material is stored in a research biobank (i.e. storage beyond 5-7 days after it has been taken):
   4. How long the material is stored
   5. What the purpose of the storage is If the material is sent abroad, state:
   6. Which country and for what purpose?
   7. Explain that the General Data Protection Regulation and the Data Protection Act are complied with.
   8. When exporting to third countries, additionally state which country and recipient, and that Chapter V of the General Data Protection Regulation and the Data Protection Act are complied with
   9. Describe which country's legislation protects personal data abroad if it is not the General Data Protection Regulation and the Data Protection Act that apply If there is possibly surplus biological material at the end of the project, state:
   10. Whether the material is destroyed or completely anonymized, or
   11. Whether the material is stored for future research, and that the data protection rules in this case continue to apply. It must be stated that new research in the biological material must be approved by a scientific ethical committee and that as a starting point, a new consent must be obtained, but the committee can dispense (see section 5.2.2. in Guidelines on Biobanks)
10. The benefit of the trial
    1. What the benefit is for the trial subject, for others and for research.
11. If the trial may be terminated What can lead to the trial subject being taken out of the trial, or the trial being completely terminated.
12. Possible remuneration and/or other benefits for the trial subject
    Describe:
    1. The size of the remuneration, including any transport reimbursement, lost earnings and/or inconvenience allowance
    2. How much will participants be paid proportionally if they withdraw early?
    3. Other benefits - economic value Taxation
13. Economy
    Describe:
    1. Who initiated the trial.
    2. Names of supporters
    3. Who supports the trial - the size of the amount for each supporter, and how the support is included in the trial
    4. Whether the trial responsible has financial ties to companies or funds with interests in the trial
14. Contact person
    1. How the trial subject can get more information
    2. Name, address, email address and phone number of a contact person in the trial
15. The trial subject's general rights
    1. You must include the information that appears on the page,  Your rights as a research participant in trials with medical equipment

The Investigator's Brochure (IB) must contain clinical and non-clinical information about the medical device under test that is relevant to the trial and is available at the time of application.

The purpose of the IB is to provide guidance and a clear understanding to the investigator and other individuals involved in the trial about the possible risks and side effects of the trial, as well as the specific tests, observations, and safety precautions that are necessary during the execution of the trial.

The IB should be clearly identifiable and particularly contain the following information:

1. Cover page with the following information
   1. Sponsor's name
   2. The medical device under test
   3. Version number
   4. Release date of the IB
   5. Reference to the version that the current IB replaces
2. Confidentiality statement
   1. If the sponsor wishes the investigator to treat the IB as a confidential document for use only by the investigator team and authorities.
3. Table of Contents
4. Summary
5. Introduction
   1. A brief introduction to the device included in the trial, the rationale for the trial of the medical device, and the expected use afterwards.
6. Description of the medical device under trial
   1. Identification and description of the device: including information on the stated purpose, risk class, and current 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. Manufacturer's instructions on installation, maintenance, maintaining hygiene standards, and use, including requirements for storage and handling, and to what extent such information is available, information that must be stated on the label, and user instructions that must be provided with the device when it is placed on the market. Also, information about any relevant required training for handling the device.
   3. For devices incorporating a drug, including a human blood or plasma derivative, or devices manufactured using non-viable tissues or cells of human or animal origin or their derivatives, detailed information on the drug or on the tissues, cells or derivatives thereof, and on compliance with the relevant general safety performance requirements and special risk management measures related to the substance or tissues, cells or derivatives thereof, as well as documentation for the added value of incorporating such components in connection with the clinical benefits and/or safety of the device.
   4. A list indicating that the relevant general safety performance requirements set out in Annex I, including the applied standards and common specifications, are fully or partially complied with, and a description of the solutions used to meet the relevant general safety performance requirements, insofar as these standards and common specifications have not been or have only partially been met or are missing.
7. Non-clinical studies
   1. Preclinical evaluation based on relevant preclinical testing and experimental data, especially regarding design calculations, in vitro tests, ex vivo tests, animal experiments, mechanical or electrical tests, reliability tests, validation of sterilization, software verification and validation, performance tests, evaluation of biocompatibility and biological safety, if relevant
8. Clinical studies
   1. Existing clinical data from:
      1. relevant existing scientific literature, which describes the safety, performance, clinical benefits for patients, design characteristics, and declared purpose of the device and/or similar or similar equipment
      2. other relevant available clinical data, describing safety, performance, clinical benefits for patients, design characteristics, and declared purpose for similar or similar equipment from the same manufacturer, including how long it has been on the market, and a review of performance, clinical benefits and safety issues and any corrective actions
9. Summary of data and guidance for the investigator
   1. Summary of the analysis of the relationship between benefits and risks, including information about known or predictable risks, any side effects, contraindications, and warnings.
   2. A detailed description of the clinical procedures and diagnostic tests that are used during the clinical trial, particularly information about any deviation from normal clinical practice.

1. Research with children
   The trial plan should be supplemented with the following:

   1. Justify scientifically why it is necessary to conduct the trial with children.

   2. Justify concretely that the trial offers a reasonable potential for direct benefit to the participant that outweighs any risks or burdens associated with the trial.

   3. Describe the children's age and justify the choice of age group concretely, since older children should be included rather than younger ones.

   4. Describe any measures that can minimize pain, fear, or inconvenience in relation to the child's development.

   5. The procedures for information and consent should be supplemented with the following:

      1. Indicate that consent will be obtained from both parents in case of joint parental authority. Also see the consent declarations.

      2. The prerequisites of the informing health professional, i.e., knowledge of the area and pedagogical prerequisites for informing the age group.

      3. The information to the child should be adapted to the child's ability to understand the trial, its age, and maturity (but not children under four years).

      4. That an independent consent will be obtained from the young person when the young person becomes of age, if there are young trial participants who become of age in the trial.

   6. Especially for less invasive trials, where permission has been sought for the young person to give independent consent, you should:

      1. justify that it is a 15-17-year-old who is not subjected to intervention or other form of burden in general, e.g., swab trials, and

      2. indicate that the holder of parental authority is given the same information as the young person and is involved in considering the trial.

2. Research with adults without the capacity to act (incompetent)
   See also Guidelines on Informed and Substitute Consent in Health Science Research Projects section 1.1
   The trial plan should be supplemented with the following:

   1. Explain why the trial participants lack the capacity to act (are unable to take care of their own affairs).

   2. Justify scientifically why it is necessary to conduct the trial with incompetent participants.

   3. Justify concretely that the trial offers a reasonable potential for direct benefit to the participant that outweighs any risks or burdens associated with the trial.

   4. The procedures for information and consent should be supplemented with information on:

      1. That surrogate consent will be obtained from the nearest relative and the trial guardian. See also the consent declarations.

      2. The prerequisites of the informing health professional for involving the trial participant.

      3. That the information to the trial participant is adapted to the trial participant's ability to understand the trial.

      4. That written participant information has been prepared for the surrogate.

      5. How the trial guardian is appointed - this person should, with their professional knowledge, assess whether the trial participant in question can participate in a trial of this nature. See section 3.4 in Guidelines on Informed and Substitute Consent in Health Science Research Projects

      6. That an independent consent will be obtained from the trial participant if they regain their competence in the trial. This only applies to trials of a nature where competence can be regained.

3. Research with pregnant or nursing women
   The trial plan should be supplemented with the following:

   1. Justify scientifically why it is necessary to conduct the trial with pregnant or nursing women.

   2. Justify concretely that the trial offers a reasonable potential for direct benefit to either the participant, embryo, fetus, or child that outweighs any risks or burdens associated with the trial.

   3. Explain that if nursing women are included in the trial, special consideration is given to the welfare of the child.

4. Research in acute situations
   The trial plan should be supplemented with the following:

   1. Justify scientifically why it is necessary to conduct the trial in an acute situation.

   2. Justify concretely that the trial offers a reasonable potential for direct benefit to the participant that can provide a measurable health benefit.

   3. Explain that the trial only involves minimal risks and burdens compared to standard treatment.

   4. Procedures for consent and information are supplemented with the following:

      1. Explain that the trial participant, due to sudden illness or life-threatening condition, is not able to receive information and give consent in advance.

      2. Explain that consent will be obtained without undue delay from the trial participant (if possible) or their legally designated representative.

      3. Explain that consent will be obtained without undue delay from the trial participant as soon as it is possible.

      4. Explain that it is not possible in advance to provide information and obtain prior surrogate consent from the trial participant's legally designated representative.

      5. Explain that the trial responsible is not aware that participants in the trial have previously declined to participate.

      6. Describe how the trial guardian is appointed - this person should, with their professional knowledge, assess whether the trial participant in question can participate in a trial of this nature. See section 3.4 in Guidelines on Informed and Substitute Consent in Health Science Research Projects

If it is extensive mapping of the genetic material, the following must be described. In the case of other genome projects, where there may also be a risk of significant health-related findings, the committee will also be able to apply the same principles in the assessment, for example in the case of targeted examination of a very large number of genes. The checklist for research in biological material applies concurrently with the one below.

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 is supplemented with applicable legal regulations to clarify the interface with the Health Act.

1. Describe whether it is research into material taken at autopsy (Section 8, subsection 1 of the Committees Act):
   1. Forensic autopsies (Section 184 of the Health Act)
      State whether:
   2. The material was taken before 1 January 2012 (no requirement for consent according to the Health Act), or
   3. The material was taken after 1 January 2012 (with consent pursuant to Section 187 of the Health Act, see the Ministry of Health's Guidance on consent for research into tissue and other biological material taken during forensic autopsy. See Guidance on consent for research on tissue and other biological material that taken by forensic autopsy
   4. Medical autopsies (with consent according to § 187 of the Health Act, see the Ministry of Health's Guidance on consent to medical autopsies etc. (hospital autopsies)
      NB: Declarations for information and consent must not be submitted.
2. Describe that this is research on biological material from the deceased, but not an autopsy, cf. section 8, subsection of the committee act. 2:
   1. Donation of the deceased's body to science according to Section 188 of the Health Act, or
   2. Other interventions according to Section 8, subsection of the Committee Act. 2
   3. That is minor procedures such as taking blood, removing parts of the skin and similar procedures (but not removing retinas, which is treated as an autopsy).
      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 Guidelines for Research on Deceased Persons