Inspection of clinical trials (GCP inspection)
Danish Medicines Agency’s procedures for clinical trial inspections
Clinical trials of medicines in Denmark are supervised by the Danish Medicines Agency. The Danish Medicines Agency receives reports of serious non-compliance pursuant to the GCP executive order (no 695 of 12 June 2013) regarding clinical trials carried out under EU directive 2001/20/EC or corresponding reports of serious breaches for clinical trials conducted under regulation (EU) no 536/2014.
This page will include references to the following documents:
- Regulation (EU) no 536/2014
- Directive 2001/20/EC
- Danish GCP executive order (not available in English)
- Danish Medicines Act (not available English)
Trial Master File (TMF)
Most often, the Trial Master File (TMF) will serve as the basis for the inspections performed by the Danish Medicines Agency. The TMF has two parts, one for the investigator and one for the sponsor.
TMF requirements for clinical trials conducted under directive 2001/20/EC
Pursuant to sections 17 and 18 of the Danish GCP executive order, the sponsor and the investigator must keep a TMF covering relevant documentation and relevant material, etc. pursuant to schedule 2 of the executive order. This is to make it possible to reconstruct the clinical trial and assess the quality of the data being obtained, including whether the sponsor and the investigator have complied with the principles and guidelines for good clinical practice (GCP).
The documents, etc. must be recorded, stored and handled so as to enable verification of all steps in the clinical trial and ensure the confidentiality of information about the trial subjects.
The sponsor and investigator must ensure that the TMF is stored for at least five years after the end of a clinical trial.
For further details, please see sections 17 and 18 of the Danish GCP executive order and the page Storage and filing of essential documents (Trial Master File) in connection with clinical trials here on the website.
TMF requirements for clinical trials conducted under regulation (EU) no 536/2014.
In order to be able to demonstrate compliance with the protocol and with this regulation, the sponsor and the investigator must keep a TMF, containing relevant documentation to allow effective supervision (monitoring by the sponsor and inspection by EU/EEA member states). The TMF for the clinical trial must be archived appropriately to allow for supervision after the clinical trial has ended.
Unless other EU law requires archiving for a longer period, the sponsor and the investigator must archive the trial’s TMF for at least 25 years after the end of the clinical trial. However, the medical files of trial subjects must be archived in accordance with national law.
Please see article 58 of the regulation for further details.
Inspections by the Danish Medicines Agency
Clinical trials are primarily inspected to ensure compliance with the guidelines for good clinical practice (GCP). GCP is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. GCP compliance is to ensure that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trial are reliable.
The Danish Medicines Agency has statutory authority to inspect any company etc. that carries out or has carried out clinical trials of medicinal products in Denmark (cf. section 90(2) of the Danish Medicines Act, no 1180 of 12 December 2005).
The Danish Medicines Agency inspects clinical trials both in Denmark and abroad. This includes inspections coordinated by the European Medicines Agency (EMA).
When the Danish Medicines Agency conducts inspections on behalf of the EMA, it follows the Good clinical practice (GCP) inspection procedures published by the EMA.
When the Danish Medicines Agency conducts national inspections, it follows its own procedures. These procedures describe how trials are selected for inspection, the notice, conduct and reporting of inspections and the follow-up on observed deviations.
The main difference between national inspections and inspections conducted on behalf of the EMA is that EMA inspections are conducted as part of the application process for a marketing authorisation. This is usually not the case for national inspections. The deadlines for these two types of inspections are also different.
Selection for inspection
The Danish Medicines Agency selects clinical trials for inspection based on a risk assessment. This risk assessment considers a series of different risks, e.g. risks inherent in the trial design, the risk of the investigational medicinal product itself, the knowledge of the sponsor, contractors and trial site, including previous inspection outcomes, etc.
Inspections could be routine inspections or triggered inspections caused by, for example, reported serious deviations, breaches, received or missing safety reports or other reports, and/or information received from others (e.g. other EU authorities or whistleblowers).
A request for an inspection could also come from an authority in another EU/EEA member state or be submitted by the EMA on behalf of its committee responsible for human medicines (CHMP). In this case, the Danish Medicines Agency would usually conduct the inspection together with inspectors from other EU/EEA member states.
All clinical trials are regulated by the same legislation, and the Danish Medicines Agency does not distinguish between investigator-initiated/academic clinical trials or company-initiated trials.
Notice of inspections
The Danish Medicines Agency will usually give 2 to 6 weeks’ notice of a planned inspection, but inspections could also happen unannounced or at very short notice depending on the cause and scope of the inspection. Notice of inspections is given in writing to the sponsor and sometimes will be agreed in advance with the trial site/investigator.
The letter of notification will detail the time and place of the inspection, planned areas for inspection and will include a preliminary inspection plan. The letter of notification includes a list of documentation and data that the Danish Medicines Agency is to receive or given access to prior to the inspection. Rooms and facilities needed will also be detailed.
Who do we inspect?
The Danish Medicines Agency inspects single trials and performs system inspections covering multiple trials and in which the inspection could have a particular focus, e.g. monitoring, handling of adverse reaction reporting, or the like.
Those inspected could be anyone performing trial activities, e.g. investigator, sponsor, contractor, manufacturer, hospital pharmacy, laboratory or a supplier of computerised systems.
Inspections may be carried out before, during or after the conduct of a trial, including as part of the review of an application for a marketing authorisation or as part of the follow-up on a granted marketing authorisation.
Standard inspection course
An inspection usually takes place over three to five days, but sometimes not as long, e.g. in the case of first-in-human trials, which are usually completed before trial-start; and sometimes longer, e.g. in the case of inspections of major companies or trials or system inspections.
Normally, at least two inspectors will be present during the inspection, one is the lead inspector. Inspectors undergoing training will usually also participate. They may come from other EU authorities. Experts may also be asked to assist during an inspection if needed. They will be accompanied by an inspector and may also ask questions and access documents and data and provide input for inspection reports.
During an inspection, the inspectors will verify by carrying out spot checks that the trial is conducted in compliance with the granted authorisation, the approved trial protocol, governing law (depending on whether the trial is conducted under the directive or the regulation) and good clinical practice (GCP).
An inspection usually starts with an opening meeting. Here the purpose and legal basis of the inspection are presented, and the parties are introduced. During this meeting, the inspectors will also describe the methods, procedures and references for the inspection.
Inspections will usually comprise interviews, a review of rooms and facilities, and a review of data and documentation either on paper or electronic formats.
The usual areas covered during an inspection are: a) Organisation and staff, b) Quality control, c) Agreements/contracts, d) Trial documents, e) Rooms and equipment, f) Regulatory approvals, g) Investigational medicinal products, h) Randomisation/unblinding, i) Monitoring, j) Handling of adverse reactions, events, etc., k) Recording and reporting of data, l) Recruitment and treatment of trial subjects, m) Data handling, n) Archiving, TMF
The inspection is completed by a closing meeting at which the inspectors go through their observations. These observations are preliminary and serve as the basis for the inspection report. Observations do not necessarily translate to deviations in the inspection report but may appear as comments in the report.
In exceptional circumstances, the inspection may be conducted in whole or in part via video conferencing or similar.
Once the Danish Medicines Agency has completed a GCP inspection, it prepares an inspection report for the inspected parties and the entity responsible for the clinical trial (sponsor) or the sponsor’s representative.
GCP inspection reports will be prepared as one single report per inspection for the inspected parties.
The content of the report depends on the inspected site and the cause and scope of the inspection. It will detail the time and place of the inspection and participants. The report describes observations and summarises deviations from appliable law, guidelines, trial protocols and own procedures.
Inspections are carried out as spot checks within one or more areas of the trial.
Conditions, procedures or processes not specifically addressed or mentioned in the report cannot be considered as the Danish Medicines Agency’s indirect authorisation or approval.
The deviations in inspection reports are classified as ’critical’, ’major’ or ’minor’ pursuant to the classification used in inspections performed for the EMA.
Deviations will be classified based on the specific circumstances during the individual inspection and will be evaluated relative to the risk the deviations pose to the safety and integrity of the trial subjects and the quality of the data. This means that apparently identical deviations may be classified differently from inspection to inspection. The immediate assessment of the gravity of the deviations is reflected in the report’s conclusion and any subsequent correspondence given in additional clarifications.
Inspection reports are subjected to quality control before publication by the Danish Medicines Agency.
The Danish Medicines Agency enters the inspection findings in the European Clinical Trials Database: in EudraCT for trials conducted under directive 2001/20/EC; in the Clinical Trials Information System (CTIS) for trials conducted under regulation (EU) no 536/2014.
Inspection reports for trials conducted under the regulation will be uploaded to the sponsor via CTIS. A version of this report without personal data and company-sensitive data will also be made publicly available after the inspection process has finished.
The inspected party or parties will be requested to submit a plan for corrective action and preventive action (CAPA) regarding deviations classified as major or critical, including information about the likely cause of the deviation and timelines for implementation of these CAPAs. This plan should normally be submitted within 4 to 6 weeks, but it depends on the gravity of the deviations. The deadline for submission of the plan will be communicated with the inspection report.
The inspectors then review the plan and assess if it can be accepted. If the plan is accepted, the inspection is closed, and follow-up can be verified at a future inspection. If the inspectors do not accept the plan, communication will continue until an acceptable plan is reached.
The Danish Medicines Agency can impose sanctions, e.g. in the form of fines, if a sponsor or investigator has not sufficiently complied with the applicable law, e.g. the Danish Medicines Act.
Serious deviations and serious breaches
Clinical trials conducted under directive 2001/20/EC
For trials conducted under directive 2001/20/EC: Section 5(1)(viii) of the Danish GCP executive order provides that the sponsor, in the case of deviations from good clinical practice (ICH E6), must ensure that steps are taken to ensure the quality of the trial and that in the case of serious or repeated deviations the Danish Medicines Agency is notified immediately.
For examples of serious deviations, please also see the page Notification of serious or repeated non-compliance with good clinical practice in clinical trials.
Clinical trials conducted under regulation (EU) no 536/2014
For trials conducted under regulation (EU) no 536/2014: The sponsor must notify the member states concerned about a serious breach of this regulation or of the version of the protocol applicable at the time of the breach. Notification must be made via the EU portal without undue delay but not later than seven days of becoming aware of that breach. A serious breach means a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial.
Please also see the ‘Guideline for the notification of serious breaches of Regulation (EU) no 536/2014 or the clinical trial protocol’ (EMA/698382/2021).
Danish Medicines Agency’s handling of serious deviations and serious breaches
If the Danish Medicines Agency receives information about serious deviations and serious breaches, it will assess if further actions are required. For example, the Danish Medicines Agency may decide that a GCP inspection is necessary or may, pursuant to section 90(8) of the Danish Medicines Act, require that the sponsor or the investigator change the trial or stops it temporarily, or it may prohibit the trial. Pursuant to section 90(9), the agency must in deciding to stop or prohibit a trial of medicinal products for humans immediately notify its decision and the grounds for it to the scientific ethical committee concerned, the EMA, the European Commission and the national authorities responsible for medicinal products in the other EU/EEA countries. For trials conducted under the regulation, this notification will be submitted via the common European portal CTIS.
For further information, please see the above-mentioned references.
Questions and answers on clinical trials
Questions and answers on clinical trials, including inspections.