Checklist for clinical trials with medical devices for in vitro diagnostics

List of documents to be submitted when notifying clinical trials of medical devices for in vitro diagnostics.

The documents must be submitted as independent files. There are help documents for several of the subsections, follow the link.

01.01 Cover letter

01.02 Application form

1. The relevant forms can be found here.   

02.01 Investigators Brochure

1. The documents below under the Investigators Brochure can be submitted as part of the IB or as separate documents.

02.02 Instructions for use

1. Requirements for the document are described under 4. Requirements for the Investigators Brochure

02.03 Checklist for fulfillment of general safety performance requirements

1. The template is available from the Danish Medicines Agency
2. Requirements for the document are described under 4. Requirements for the Investigators Brochure

02.04 For devices with biological material a detailed description of the material and compliance with GSPR and risk management plan

1. Requirements for the document are described under 4. Requirements for the Investigators Brochure

03.01 Clinical trial plan

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

04.01 Participant information

04.02 Declarations of consent

05.01 Statement of compliance

1. The template is available from the Danish Medicines Agency
2. Please note, for CE marked devices, please attach the declaration of conformity (DoC) and any CE certificates.

06.01 Sponsor statement on how to comply with GDPR

07.01 Danish synopsis

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

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

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

11.01 Danish version of relevant parts of sponsorship contract
Regarding publication conditions and fees for researchers/subjects as well as researchers' access to data

12.01 Documentation for the experience, training and identity of the trial supervisors (for all trial supervisors at all Danish sites (if several documents, number them then, e.g. 12.01, 12.02, etc.) – NB! Only one supervisor per site

1. Resume
2. Authorization ID (printout from the authorization register)
3. Copy of health card, driver's license (physical card or screenshot from app) or passport. Possibly. the last 4 digits of the social security number can be crossed out

13.01 Documentation for the sponsor's identity (if several documents, numbers then, e.g. 13.01, 13.02, etc.)

1. The company's 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 about the EU designated representative's address and CVR number must be provided.

14.01 Billing Information

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

Your trial plan/protocol must include the following information:

1. The 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 within the scope of the device's CE marking. For non-CE marked equipment, it should be stated whether the purpose of the trial is to obtain CE marking.
   2. Brief literature review and bibliography
   3. If a previous trial is being repeated, justify why
5. Method
   
   1. Including design, methodology, use of control groups, and randomization
   2. The practical implementation, investigations, and scope
   3. Monitoring plan
   4. Indicate if algorithms are used in the device
   5. The start and duration of the trial
6. Statistical considerations
   
   1. Power calculation or other statistical consideration justifying the number of trial subjects
7. 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, discomfort, fear, and other risks
9. Withdrawal of new biological material or collection of biological material from an existing biobank
   

   See also Exemption from consent.

   Describe:
   1. What 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 withdrawal)

      See Guidelines on Biobanks, section 5.2:
      
      
   4. How long and what is the purpose of the storage?
      

      If the project material is sent abroad:

   5. Which country and what purpose
   6. That the General Data Protection Regulation and the Data Protection Act are complied with. For transfers to third countries, additionally state that Chapter V of the General Data Protection Regulation is complied with
   7. Which country's law protects personal data abroad, if not the General Data Protection Regulation and the Data Protection Act
      

      If there is surplus biological material after the project's completion

      See Guidelines on Biobanks, section 5.2.2:
      
      
   8. Whether destruction or full anonymization of the material occurs, or
   9. Whether the material is saved for future research, and that data protection rules continue to be complied with
      

      If extra material is also taken for future unspecified research:

   10. This is not within the committee's jurisdiction but is regulated by the General Data Protection Regulation and the Data Protection Act. However, it can be stated in the protocol that participants will be asked separately about this to subsequently document that the material in the biobank was taken in connection with the specific research project
       

       If project material is imported:

   11. Submit documentation/declaration from the company/institution that the material was taken/collected ethically in accordance with the legislation at the place of collection and legally carried out by the country
10. Information from patient records
    

    If information from the patient's 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 will be used for. A distinction must be made between information needed before trial subjects have consented to participate, e.g., in connection with identification/recruitment, and the information needed for the project after consent to participate has been given
    2. It must be stated that the information needed for the project before consent has been given by the trial subjects is forwarded to the researcher
    3. It must be stated that the consent gives the trial responsible, sponsor, and sponsor's representatives, as well as any control authority, direct access to obtain information in the patient's record, etc., including electronic records, 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, as they are obliged to perform.
11. Processing of personal data in the project
    
    1. You must state that the General Data Protection Regulation and the Data Protection Act 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 about registering the project on an internal list.
       

       Describe if personal data is sent abroad:

    2. Which country and what purpose
    3. That the General Data Protection Regulation and the Data Protection Act are complied with, including when exported to third countries, where you additionally must state that Chapter V of the General Data Protection Regulation is complied with.
    4. Which country's law protects personal data abroad, if not the General Data Protection Regulation and the Data Protection Act.
12. Economy
    
    1. Describe who has initiated the trial.
       

       If there are sponsors, describe:

    2. Name of sponsors, including the amount for each sponsor (lump sum and/or per trial subject).
    3. How the support is involved in the trial, e.g., remuneration of personnel, laboratory tests, etc.(attach budget if applicable).
    4. Whether the support is paid directly to the researcher, their department/institute, research fund, or other (for researchers in RVK Syddanmark, the account number the support is deposited into must be specified).
    5. Whether the researcher has a financial connection to the sponsor or other stakeholders in the trial.
13. Any remuneration and/or other benefits to the trial subjects
    

    See also Appendix 1: Guidelines for remuneration and other benefits to voluntary trial subjects.

    1. The amount of remuneration, including any travel reimbursement, lost earnings, and/or inconvenience compensation
    2. How much participants will be paid proportionally if they withdraw early
    3. Other benefits - economic value
    4. For trial patients, you must account for the requirements in Appendix 1 being met.
14. Recruitment of trial subjects and informed consent
    

    See also the standard Guidelines for providing oral participant information.

    Describe the recruitment and the procedure for providing oral information and obtaining consent:

    1. How the trial subjects are recruited (posting, advertisement, recruitment letter, internet, social media, or through journals)
    2. How the initial contact with the trial subject occurs
    3. The process for obtaining informed consent
       
       1. Where, when, and by whom the oral and written information is provided
       2. How it is ensured that the conversation takes place undisturbed.
       3. How the right to have a companion is ensured.
       4. What reflection time there will be between the provision of oral and written information and the acquisition of informed consent.
       5. When consent is sought.
15. Publication of results
    
    1. State where a report on the investigation of the device's performance and a summary thereof, understandable to the intended user, is made available.
16. Ethical section
    Describe:
    
    1. Why the risks, either by themselves or in relation to the benefits of the trial, are not unjustifiable and
    2. Why the therapeutic gain for the trial subjects or future patients justifies the trial.
17. Information about compensation scheme
    

    1. Whether the trial is covered by the patient compensation scheme, or if an independent insurance has been taken out.

The document must be dated and versioned, with changes updated accordingly.

The written participant information should cover the following aspects:

1. The trial's original title
2. An invitation to participate in a clinical trial
3. The purpose of the trial, its significance, and scope
4. The method and practical organization of the trial
5. The risks associated with the trial
   
   1. Including foreseeable risks, side effects, complications, discomforts, and burdens in the short and long term, such as radiation risks,
   2. Any safety measures
   3. It should be noted that unforeseen risks and burdens may be associated with the trial.
6. What the standard treatment is and whether there are other treatment options
7. Journal Information
   If the project involves the use of information from patient journals, it must be clear:
   
   1. What information is needed and the purpose thereof.
   2. That the participant's consent grants the trial responsible, sponsor, and their representative direct access to relevant health information in the journal to conduct, monitor, and control the trial.

8. Treatment of Personal Data

   1. Describe that personal data will be processed in the trial. State that the data protection law and regulation are complied with (Be aware of the obligation to inform (about the rights of the data subjects), as required by the data protection regulation, see the guidance from the Danish Data Protection Agency).
9. Extraction of Biological Material from Participants
   Also, see Guidelines on Biobanks
   Describe:
   1. The type and amount of material taken
   2. The purpose of the extraction
   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 extracted):
   4. How long the material is stored
   5. The purpose of the storage
      If the material is sent abroad, specify:
   6. Which country and for what purpose?
   7. Demonstrate compliance with the General Data Protection Regulation and the Data Protection Act. When sending to third countries, additionally specify the country and recipient, and that Chapter V of the General Data Protection Regulation and the Data Protection Act are complied with
   8. 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 excess biological material at the end of the project, specify:
   9. Whether the material is destroyed or completely anonymized, or
   10. Whether the material is saved for future research, and in such cases, the data protection rules still apply. It must be stated that new research on the biological material must be approved by the scientific ethics committee and that, as a rule, new consent must be obtained, but that the committee can dispense (see section 5.2.2. in the biobank guidance)
10. The utility of the trial
    
    1. What benefit there is for the subject, for others, and for research.
11. If the trial may be discontinued
    
    1. What can lead to the subject being removed from the trial, or the trial being completely discontinued.
12. Possible remuneration and/or other benefits to the subject
    Describe:
    
    1. The size of the remuneration, including possible transportation reimbursement, lost earnings, and/or inconvenience compensation
    2. How much will participants be paid proportionally if they withdraw early?
    3. Other benefits – economic value
    4. Taxation
13. Economy
    Describe:
    1. Who initiated the trial.
    2. Names of sponsors
    3. Who supports the trial – the amount of support for each sponsor, and how the support is incorporated into the trial
    4. Whether the trial responsible has financial ties to companies or foundations with interests in the trial
14. Contact person
    
    1. How the subject can get more information
    2. Name, address, email address, and phone number of a contact person in the trial
15. The general rights of the subject
    
    1. You must enter the information that appears on the page, Your rights as a participant in trials with in vitro diagnostic devices

The Investigator's Brochure (IB) must contain clinical and non-clinical information about the equipment intended for testing that is relevant to the trial and available at the time of application.

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

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

1. Front page with the following information

   1. Sponsor's name

   2. The medical device intended for testing

   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 only for use by the Investigator team and authorities.

3. Table of contents

4. Summary

5. Introduction

   1. A brief introduction of which equipment is included in the testing, the rationale for testing the medical device, and the expected use afterwards.

6. Description of the in vitro diagnostic medical device under testing
   

   1. Identification and description of the equipment

   2. Information on the stated purpose

   3. Risk classification and applicable classification rule according to Annex VIII

   4. The equipment's design and manufacture

   5. Reference to previous and similar generations of the equipment

7. Use of the in vitro diagnostic medical device (Instruction for use) – May be a separate document
   

   1. Manufacturer's instructions regarding installation, maintenance, maintaining hygiene standards, and usage requirements, including requirements for storage and handling,

   2. Information stated on the labeling (to the extent such information is available)

   3. Instruction manual that must be provided with the equipment when it is marketed

   4. Information on any relevant required training

8. Analytical performance of the in vitro diagnostic medical device
9. Clinical data
   

   1. Existing clinical data from relevant scientific literature that has been subjected to peer review, and available consensus statements or opinions from experts from relevant professional organizations, relating to the equipment's and/or equivalent or similar equipment's safety, performance, clinical benefits for patients, design characteristics, scientific validity, clinical performance, and stated purpose

   2. Other relevant available clinical data relating to safety, scientific validity, clinical performance, clinical benefits for patients, design characteristics, and stated purpose for equivalent equipment, including information on their similarities and differences in relation to the equipment in question

10. Summary of benefit/risk analysis
    
    1. Summary of the analysis of the relationship between benefits and risks, including information on known or predictable risks and warnings
11. For in vitro diagnostic medical equipment containing biological material (tissue, cells, substances of human, animal, or microbial origin) – May be a separate document
    

    1. Detailed information about the relevant tissue, cells, and substances

    2. Detailed information on compliance with the general requirements for safety and performance

    3. Detailed information on the specific risk management measures for this tissue, cells, and substances

12. Checklist for fulfillment of general safety performance requirements (GSPR) – May be a separate document

    1. A list indicating that the relevant general safety and performance requirements (GSPR), set out in Annex I of IVDR, 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 and performance requirements, insofar as the concerned standards and common specifications are not or only partially complied with or lacking

13. Procedures, testing, and deviations from normal clinical practice in performance investigation

    1. A detailed description of the clinical procedures and diagnostic tests used during the investigation of performance, particularly information on any deviation from normal clinical practice.

For trials involving equipment in persons lacking the capacity to act, the ethical section of the application must consider the conditions for conducting trials in such situations according to the following.

1. Research with Children

From IVDR:

Article 61[1]

Performance Study on Minors

1. A performance study on minors may only be conducted if all of the following conditions, in addition to the conditions in Article 58(5), are met:

   1. informed consent has been obtained from their legally designated representative

   2. the minors have received the information referred to in Article 59(2) from the investigator or members of the trial team who are trained in or have experience working with children, in a manner adapted to their age and mental maturity

   3. the investigator respects an explicit wish from a minor who is capable of forming an opinion and assessing the information referred to in Article 59(2), not to participate in or to withdraw at any time from the performance study

   4. no inducement or financial incentive is given to the subjects or their legally designated representatives, apart from compensation for expenses and loss of income that is directly related to participation in the performance study

   5. the performance study aims to investigate treatments for a disease condition that only occurs in minors, or the performance study is essential for minors to validate data obtained in performance studies on individuals capable of giving informed consent, or by other research methods

   6. the performance study must either directly relate to a disease condition the concerned minor is suffering from, or be such that it can only be conducted on minors

   7. there is scientific evidence to assume that participation in the performance study will provide:

      1. a direct benefit to the minor subject that outweighs the risks and burdens associated with it, or

      2. certain benefits to the population represented by the affected minor, when the performance study will only involve minimal risk and minimal burdens to the affected minor compared to the standard treatment of the condition the minor is in

   8. the minor participates in the informed consent procedure in a manner adapted to their age and mental maturity

      1. if the minor becomes legally competent to give informed consent according to national law during the performance study, their explicit informed consent must be obtained before this subject can continue their participation in the performance study.

2. Paragraph 1, point g), ii), does not affect stricter national provisions, which prohibit the conduct of these performance studies on minors when there is no scientific evidence to assume that participation in the performance study will provide the subject with a direct benefit that outweighs the risks and burdens associated with it.

[1] REGULATION (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU

2. Research with Adults Lacking Capacity to Act

From IVDR:

Article 60[1]

Performance Studies on Subjects Lacking Capacity to Act

1. Regarding subjects lacking capacity to act, who have not given or have not refused to give informed consent before they were unable to consent, the performance study may only be conducted if all of the following conditions, in addition to the conditions in Article 58(5), are met:

   1. informed consent has been obtained from their legally designated representative

   2. subjects lacking capacity to act have received the information referred to in Article 59(2) in a manner adapted to their ability to understand it

   3. the investigator respects an explicit wish from a subject capable of forming an opinion and assessing the information referred to in Article 59(2), not to participate in or to withdraw at any time from the performance study

   4. no inducement or financial incentive is given to the subjects or their legally designated representatives, apart from compensation for expenses and loss of income that is directly related to participation in the performance study

   5. the performance study is essential for subjects lacking capacity to act, and data of comparable validity cannot be obtained by performance studies on individuals capable of giving informed consent, or by other research methods

   6. the performance study directly relates to a disease condition the subject is in

   7. there is scientific evidence to assume that participation in the performance study will provide:

      1. a direct benefit to the subject lacking capacity to act, that outweighs the risks and burdens associated with it, or

      2. certain benefits to the population represented by the affected subject lacking capacity to act, when the performance study will only involve minimal risk and minimal burdens to the affected subject compared to the standard treatment of the condition the subject is in.

2. The subject should participate in the informed consent procedure as far as possible.

3. Paragraph 1, point g), ii), does not affect stricter national provisions, which prohibit the conduct of these performance studies on subjects lacking capacity to act, when there is no scientific evidence to assume that participation in the performance study will provide the subject with a direct benefit that outweighs the risks and burdens associated with it.

[1] REGULATION (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU

If the study involves extensive mapping of the genome, the following must be described. For other genome projects where there may also be a risk of significant health-related findings, the committee may also apply the same principles in the assessment, for example, in targeted investigation of a very large number of genes. The checklist for research in biological material applies concurrently with the following.

Describe:

1. Research Methods

   1. That it involves extensive mapping of the genome

   2. Which part of the genome is being examined (e.g., gene panels, exomes, whole genome, epigenome, RNA) and what types of sequences are being studied (rare and/or common variants, structural variants, etc.)
      See method list here:

   3. Which sequencing platform or high-density array is used, as well as sequencing depth.

   4. Which bioinformatics tools are used.

2. Data Storage

   1. How data is stored, including where and for how long.

3. Reporting Incidental Findings

   1. If it's a study with the risk of mutations in high-penetrance genes: That participants will receive genetic counseling prior to the research

   2. How you otherwise assess the likelihood of incidental findings. Justify this. Handling of participants' wishes regarding feedback. Both about the genes being studied and about incidental findings. Follow the Genome Guidance if incidental findings arise

   3. That an independent group of experts will be established to assess incidental findings and advise on how they can be handled

   4. If you otherwise use the method to minimize the likelihood of incidental findings, whereby focus is only on specific areas of the genome and ignoring other areas that may involve clinically relevant genes, e.g., the genes on ACMG’s list. It should be stated that the filtering out of these genes is done in such a way that data regarding the unwanted information is not generated or recorded. See the Guidance on Genomics and Research in Sensitive Bioinformatics Data and possibly use the formulations from this.

4. Potential Research Collaborations
   See Guidance on Genomics and Research in Sensitive Bioinformatics Data
   Describe

   1. The name of the collaboration partner

   2. What the collaboration entails:

      1. Laboratory analyses, including any bioinformatics analyses: Describe that a data processing agreement is entered into about this (see The Danish Data Protection Agency)

      2. If there is (also) an actual research collaboration: Describe that the external party may only research within the protocol's purpose and is aware of the 5 criteria about the duty to feedback in the Genome Guidance.

   3. Which data access is given (and is it e.g., in coded form?)

   4. Whether genome data is transferred abroad

   5. That personal data from sequencing will be processed according to the rules in the General Data Protection Regulation and the Data Protection Act, as well as according to the principles in the Health Act for relatives.

5. Participant Information in Genome Research
   You may use the optional pre-printed standard for good information in genome research.
   A standard consent declaration and a declaration for opting out of knowledge have also been developed.
   If you do not use the standard, the information should include the following:

   1. Explain that it involves extensive mapping of the participant's genetic material and explain the purpose.
      Describe:

   2. The method briefly (whole genome sequencing or exome sequencing, etc.)

   3. What knowledge you expect to gain

   4. Whether the participant benefits from the study and if so, how

   5. If it's a study with the risk of mutations in high-penetrance genes: State that participants will receive genetic counseling prior to the research

   6. If genome data is stored after the experiment: That the storage is in accordance with the General Data Protection Regulation and the Data Protection Act

   7. If you have a research collaboration with domestic or foreign partners. Then provide:

      1. The name of the collaboration partner

      2. What the collaboration entails

      3. Which data access is given (is it e.g., in coded form?)

      4. Whether genome data is transferred abroad

      5. That personal data from sequencing will be processed according to the rules in the General Data Protection Regulation and the Data Protection Act.

6. Feedback on Health Findings
   Describe:

   1. That knowledge may emerge that was not anticipated (incidental findings)

   2. That the participant will be informed in rare situations where a change in the genes is discovered that may lead to serious illness that can be prevented or treated

   3. That it may also be relevant to inform family members if the information can prevent death or serious deterioration of health

   4. That the participant can refuse to receive information about incidental findings, but in that case, the participant must contact the researcher separately (Declaration of opting out of knowledge).

   5. How the participant can get information about the result of the study.

7. Genome Research in Biological Material Without Consent

   1. There must be a detailed justification for not obtaining consent from the participants. Describe the risk of incidental findings and how these will be handled. Guidance on Genomics and Research in Sensitive Bioinformatics Data

   2. The same conditions as in Research in Biological Material with Exemption from Consent must be accounted for. See the Guidance on the Use of Biological Material in Health Science Research Projects

8. Genome Research with Children

   1. Specifically justify how either i., ii., or iii. is met:

      1. It concerns the child's clinical condition, the patient group gains a benefit, and you are validating data from research with capable individuals or other research methods. Healthy children are advised against in genome research

      2. The experiment directly benefits the child, and genome research with adults does not provide the same benefit

      3. Genome research can only be conducted with this age group, which gains significant advantages and is subjected to minimal risk.

   2. Describe whether incidental findings that only manifest in adulthood may arise.

       

When it comes to research on the deceased, a number of details included in the standard protocol would naturally be omitted, such as procedures for information and consent, etc. This guidance is supplemented with applicable legal rules to clarify the interface to the Health Act.

1. Describe if it involves research on material taken during an autopsy (Committee Law § 8, paragraph 1):
   Specify whether:
   
   1. Forensic autopsies (Health Act § 184)
      

      Specify whether:

   2. The material was taken before January 1, 2012 (no consent requirement according to the Health Act), or

   3. The material was taken after January 1, 2012 (with consent according to Health Act § 187, see the Ministry of Health's Guidance on consent for research in tissue and other biological material obtained through forensic autopsy. See Guidance on consent for research in tissue and other biological material obtained through forensic autopsy

   4. Medical autopsies (with consent according to Health Act § 187, see the Ministry of Health's Guidance on consent for medical autopsies etc. (hospital autopsies)
      NB: Statements for information and consent should not be submitted.

2. Describe that it involves research on biological material from the deceased, but not autopsy, according to Committee Law § 8, paragraph 2:

   1. The deceased's donation of the body to science according to Health Act § 188, or

   2. Other interventions according to Committee Law § 8, paragraph 2

   3. That is, minor interventions such as blood extraction, removal of skin patches, and similar interventions (but not removal of retinas, which are treated as autopsies).
      Note: Statements for information and consent must be submitted. Find consent forms here
      You can read more about research on the deceased in the committee system's Guidelines for Research on Deceased Persons.