Regulatory requirements

20 December 2011

The Danish Medicines Agency has issued an Executive Order* on the applications for the authorisation for clinical investigations of medical devices on human subjects, Executive Order No. 292 of 19 March 2010.
*Executive Order is the legal instrument for national regulations in Denmark.

This document explains the specific regulatory requirements for clinical investigations of medical devices. Applicants are required to follow this information when wishing to perform an investigation in a centre in Denmark.

Pursuant to the Ministry of Interior and Health’s Act no 1046 of 17 December 2002 for medical devices, the Ministry of Health and Prevention’s Executive Order No. 1263 of 15 December 2008 for medical devices and the Ministry of Health and Preention’s Executive Order No. 1264 of 15 December 2008 for active, implantable medical devices the Danish Medicines Agency has issued an executive order on the applications for the authorisation for clinical investigation of medical devices on human subjects.

Scope

This executive order stipulates the regulatory requirements for the applications for the authorisation for the conduct of clinical investigation and for the authorisation for amendments to the clinical investigation of:

  1. non CE-marked devices,
  2. CE-marked devices, if the objective of the investigation of the device is for an intended use for which the device is not CE-marked, and
  3. in vitro diagnostic devices, if the device is intended to come in direct or indirect contact with the human body.

Application for the authorisation for clinical investigations of medical devices

An application for the authorisation for the conduct of a clinical investigation of medical devices on human subjects shall be submitted by the sponsor or the duly authorised representative to the Danish Medicines Agency using the Agency’s application form, together with the following accompanying documentation:

Covering letter with a list of appended documents and possible special considerations, which the agency shall be aware of,

  1. Clinical Investigation Plan,
  2. Investigator’s Brochure,
  3. The subject information sheet,
  4. Authorisation sheet, allowing the Danish Medicines Agency, the regional Scientific Ethical Committee, monitor and foreign health authorities, if appropriate, access the subject’s journal,
  5. Statement certifying that the device in question complies with the Essential Requirements, apart from those aspects covered by the investigation, and that with regard to these aspects, every precaution has been taken to protect the health and safety of the subject.
  6. Manufacturer's and, if relevant, representative's, name and contact details
  7. A description of the specified intended use of the CE-marked device a copy of the device’s Declaration of Conformity as well as certificate(s) from the Notified Body, if relevant,
  8. Copy of the Scientific Ethical Committee opinion(s), if available,
  9. Picture of the device or a specimen, if appropriate.

Clinical Investigation Plan

The clinical investigation plan shall provide the following information:

a) General information

  1. Full title, date and the sponsor's reference number. The reference number and date/version shall appear on all pages, including attachment and amendments.
  2. Declaration that the clinical investigation will be conducted in accordance with the clinical investigation plan and applicable regulatory requirements.
  3. Name and address of the sponsor, and if applicable, the Contract Research Organisation (CRO),
  4. Name and title of the person(s) duly authorised by the sponsor to sign the clinical investigation plan and any subsequent amendments.
  5. Full name, title, address and telephone number of the sponsor’s advisors (e.g., medical/dental advisor) with respect to the investigation.
  6. Name and title (academic qualifications) of the principal investigator as well as address and telephone number of the Institution involved. In a multi-centre clinical investigation the Name and title (academic qualifications) address, telephone number of the coordinating clinical investigator’s as well as the principal investigator at each centre and the centres involved.
  7. Name and address of laboratories and other hospital departments, technical departments and/or institutions involved in the investigation.
  8. Confirmation that the sponsor, the coordinating investigator, if applicable, and the principal investigator at each centre has accepted and signed the clinical investigation plan.
  9. Description of the duration of the clinical investigation, including start and finish dates.
  10. Summary of the clinical investigation plan, preferably illustrated by a flow chart.

b) Identification and description of the device under investigation

  1. Name of the manufacturer of the device, device identification name, model and/or type number, including software version and accessories. If the model and/or type number is not available upon completing the clinical investigation plan, a description of how traceability will be ensured during and after the investigation shall be provided.
  2. The manufacturer’s intended purpose of the device, including the clinical indications and contraindications as well as the intended population groups for which the device is intended.
  3. Brief description of the device under investigation and other devices designed to be used in combination with it.
  4. Identification of any features of design that are different from similar previously marketed products, if relevant.
  5. Details of any new or previously untested features of the device, including functions and principles of operation.
  6. Description of materials of the device, specifying which will come in direct or indirect contact with the tissue or body fluids.
  7. Identification of substances utilised in the device or the manufacturing of the device e.g.,
    • medicinal product,
    • animal tissue,
    • stable derivatives of human blood or plasma,
    • other biologically active substances, or
    • pthalates and other substances classified as substances which are carcinogenic, mutagenic or toxic to reproduction
    with a description of the substance’s purpose, the justification for use of the substance, and experience with the use of these substances as well as measures applied to comply with the medical devices directives’ requirements for these substances.
  8. Instructions for installation and correct use of the device, including requirements for storage and handling.
  9. A summary of necessary training and experience needed for the use of the device under investigation.
  10. A description of necessary medical and/or surgical procedures involved in the use of the device.
  11. Summary of known and potential risks and possible benefits for the subject.
  12. Result of the risk analysis and risk assessment, including a description of the balance of anticipated clinical benefit against the risks associated with the use of the device itself and the procedures involved in its use. The possible interactions with concurrent medical interventions shall be listed.
  13. Information on the method of sterilisation, if applicable.
  14. Description of the packaging used for sterilisation of the device, if applicable

c) Objectives of the clinical investigation

  1. the purpose of the investigation (e.g. primary and secondary).
  2. the population group for which the device is intended.
  3. the claims and intended performance of the device that are to be verified.
  4. the risks and foreseeable adverse device effects that are to be assessed.
  5. the specific hypotheses to be accepted or rejected by the data collected in the clinical investigation.

d) Design/method of the clinical investigation

  1. The primary and secondary end-points, with the rationale for their selection.
  2. The variables to be measured with the rationale for selecting these to demonstrate the achievement of end points.
  3. The methods and timing for assessing, recording and analysing variables.
  4. Description of the equipment used to assess the variables investigated and arrangements made for monitoring of maintenance and calibration.
  5. Specification of which data is considered as source data, and will be registered directly in the Case Report Form (CRF).
  6. A description of the type of investigation to be performed (e.g. single-blinded, double-blinded, open).
  7. A description of arrangements for the reduction or elimination of bias, including:
    - randomisation; a description of the randomisation method – including procedures and practical arrangements
    -blinding; a description of the blinding (single blind, double blind, double dummy, etc.) and practical procedures for safeguarding the blinding.
  8. The number of subjects required to be included in the clinical investigation together with the estimated time needed to include this number, and the total number of devices to be used, with a justification for these figures. In multi-centre investigations, the minimum number of subjects to be included for each centre shall be specified and justified. Where it may affect the validity of the study results, considerations shall be made on the minimum and maximum number of subjects to be included in each centre.
  9. A description of the procedures, the subject undergoes in the investigation, and a list of other devices equipment or medicines that shall be used with the device or in the follow up period.
  10. The period of the use of the device or its control and its follow-up period in a particular subject within the investigation and the justification for this.
  11. The anticipated duration of subject participation in the investigation.
  12. The follow-up period in a particular subject within the investigation and the justification for this.
  13. Description of rules and procedures for the termination or suspension of treatment for individual subjects in the investigation and/or parts of the investigation.
  14. Description of the procedure for accountability with the devices under investigation.
  15. Information concerning where the randomisation code will be stored, including rules and procedures for using the code, if relevant.
  16. Description of precautionary measures for deviations from the plan.
  17. Description of precautionary measures for changes to the plan.

e) Selection of subjects and inclusion and exclusion criteria

  1. The inclusion criteria for subject selection (e.g., age, sex).
  2. The exclusion criteria for subject selection.
  3. The point of enrolment.
  4. Specification of completion of the investigation.
  5. A description of criteria and procedures for discontinuing the investigation, stating;
    - when and how the subjects are to discontinue participation in the investigation
    - which data is to be collected from subjects discontinuing the investigation, as well as when such data should be collected
    - to what extent and subjects discontinuing the investigation are to be replaced by new subjects
    - follow-up procedures for subjects who have discontinued the investigation.

f) Statistical considerations

  1. Justification for the hypotheses and its statistical design.
  2. The reasons for the choice of sample size, including the level of significance to be used, the power of the investigation and expected drop-out rates, together with the justification for these aspects.
  3. Justification of the scheduled number of patients – including considerations/calculations of the size of the trial and its clinical relevance. In multi-centre investigations, the number of subjects planned to include at each centre should also be indicated.
  4. Pass/fail criteria to be applied to the results of the investigation.
  5. Provision for an interim analysis, if applicable, and the criteria for the termination of the investigation on statistical grounds.
  6. Description of the statistical methods employed – including time(s) for scheduled interim analyses.
  7. The level of significance to be applied.
  8. Criteria for completion of the investigation.
  9. Procedures for dealing with missing data, unused data and false data.
  10. Procedures for reporting deviations from the original statistical plan.
  11. Statement regarding use of data of particular subjects - whose data will be included in the statistical analysis (e.g. all randomised subjects, all subjects receiving medication, all eligible subjects and all subjects who can be evaluated).

g) System for the management of adverse events

  1. Contact details for reporting of serious incidents or near-incidents (i.e., adverse events).
  2. The procedures for recording and investigating adverse events during the investigation.
  3. The procedure for reporting adverse events, including specification of responsibility for reporting, to whom to report and the timing for reporting.
  4. Details of foreseeable adverse events, their likely incidents and the methods to be used for their management.
  5. The follow-up required for each subject in the case of adverse events.

h) Early termination or suspension of the investigation

  1. The criteria, arrangements and procedures for early termination or suspension of the investigation and procedures.
  2. If the clinical investigation involves blinding techniques, the criteria for access to and using the code shall be stated.
  3. The follow-up procedures required for subjects.

i) Ethical considerations

  1. Specific ethical considerations in relation to the investigation.
  2. Description of how the subjects (patients, healthy volunteers, patients for whom the treatment of their illness is not the aim of the trial) are to be informed and how their consent will be obtained. Possible reasons for not obtaining informed consent from the subjects themselves.

j) Quality control and quality assurance

  1. Describe the procedures for management, treatment and archiving of all collected data for each subject as well as other relevant investigation data.
  2. Description of procedures for quality control and quality assessment, including extent of source data verification and monitoring.
  3. Procedures for database management, treatment of data, source data verification and other aspects of quality assurance.

k) Direct access to source data/documents

Statement that the investigator agrees to allow direct access to source data/documents, including patient journals, during monitoring, auditing and/or inspection by an ethics committee, the Danish Medicines Agency or any other countries’ health authorities, respectively.

l) Financing and Insurance

Financial and insurance arrangements provided.

m) Publication policy

State whether the results of the investigation will be submitted for publication in a scientific journal.

The above information may be included in other accompanying documentation. If the information is not included in the clinical investigation plan reference to the relevant documentation must be provided in the plan.

If any of the requested information is considered inapplicable for the particular investigation, it must be clearly stated and justified.

Investigator’s Brochure

The Investigator’s Brochure shall contain:

a) A summary of the literature and an evaluation supporting the rationale for the intended use of the device and the design of the clinical investigation.
b) A general description of the device and its components.
c) A description of the mechanism of action of the device.
d) Labelling and Instructions for Use, including possible risks, contra-indications and warnings.
e) A description of the intended clinical performance.
f) A description of the materials used in the device.
g) A summary and evaluation of the in vitro, ex vivo and in vivo data, relevant to the device, including pre-clinical data such as biological studies, non-clinical laboratory studies and animal studies.
h) A summary of relevant previous clinical experience with the device and with other devices with similar features, including details of how long the device has been on the marketplace and an overview of safety and/or performance related complaints.
i) Results of the risk analysis and risk assessment.
j) A list of International standards, complied with in full or in part, including details regarding the extent to which the devices are in compliance.

Application for the authorisation to make amendments to the clinical investigation

The application for the authorisation to amend the investigation shall be submitted on the Danish Medicines Agency’s application form for amendments with the following information:

  1. The Danish Medicines Agency's journal number, reference number and date of the latest accepted clinical investigation plan.
  2. A clear statement of the changes incurred.
  3. Considerations as to whether the changes may influence the final result of the investigation.
  4. Statement on the number of subjects included and the influence on the final results.

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