Good documentation practice in clinical trials

Expectations for clinical trial documentation

We frequently observe deviations in documentation during GCP inspections. As a consequence, we are specifying our expectations regarding the documentation generated in connection with clinical trials below.

Regulation (EU) No 536/2014 (the Regulation) and the ICH GCP guidelines define the documents that must be available in the Trial Master File (TMF) for a clinical trial. Moreover, the ICH GCP guidelines include a description of additional expectations for documentation.

Good documentation is an important part of a quality management system and essential for our control of whether a clinical trial has been planned, completed, registered, analysed and reported in accordance with good clinical practice.

The sponsor and the investigator keep a Trial Master File (TMF) for the clinical trial. The clinical trial master file must, at all times, contain the essential documents relating to the clinical trial which allow verification of the conduct of a clinical trial and the quality of the data generated, taking into account all characteristics of the clinical trial, including in particular whether the clinical trial is a low-intervention clinical trial.

The clinical trial master file kept by the investigator (Investigator Site File (ISF)) and that kept by the sponsor may have a different content if this is justified by the different nature of the responsibilities of the investigator and the sponsor.

The master file must be readily available, and directly accessible upon request, to the Danish Medicines Agency.   

Traceability

Preparation and distribution of essential documents

Essential documents, forms and other documentation are prepared, checked and distributed with traceability in accordance with the approved trial protocol and other documents relevant to the trial. Thus, it must be documented to whom the material has been distributed and when.

One of the reasons for this is that on GCP inspections, we have found laminated 'pocket forms' that had been prepared for the investigator's staff. The staff often use these documents with, for example, inclusion and exclusion criteria.

So it is important that they reflect the current approved protocol and not a previous version. Once documents, forms or other documentation have been changed and approved, it should be ensu

red that previous versions are not used.

Registration and change of data

The inspectors generally expect both sponsors and investigators to make sure that documentation related to the trial is recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification. This is a basic principle of the ICH GCP guidelines.

Registration of data should be performed and completed immediately following the collection of data.

Deleting data without traceability should not be possible.

Changes made to documents and registered data that are not obvious must be explained. On GCP inspections, we frequently find that changes have been made but not explained even though it is not obvious to, for instance, inspectors, auditors, monitors or new staff on the site, why the changes were made. This is frequently the case in connection with drug accountability forms and forms for the evaluation of adverse events and/or adverse drug reactions, etc.

Dating and signature

Essential documents, forms and other documentation must be dated and signed.

On GCP inspections, we regularly observe that CVs, job descriptions and other staff records are not signed and/or dated. We emphasise the importance of the person concerned acknowledging that the document has been prepared, signed and dated by him/herself.

Questionnaires and worksheets are examples of other documents that are often not signed and dated. Since both documents often contain source data, it is important that we can see who has collected/filled in data and when.

Sometimes we also find that the principal investigator has not signed the patient identification list. We consider this to be a key document of the clinical trial and expect the principal investigator to sign it no later than at the end of the trial (and preferably sign completed pages) to indicate that this is the complete list of the trial participants involved.

In general, documents must be approved, signed and dated by the relevant/authorised persons.

Initials and/or signatures added to documents must be accompanied by a date. On inspections, we often find examples of deviation in the form of dates added in advance. 

Electronic documents

In terms of electronic documents and data, please refer to the EU GCP inspectors' guidelines on computerised systems and electronic data in clinical trials. Link?

Written instructions

Instructions that are additional to the instructions described in the protocol must as a main rule be written down. In the everyday clinical practice, oral agreements/instructions are sometimes followed.

However, the requirements for documentation relating to clinical trials are more stringent. For example, it is expected that written instructions are available describing when and in what situations a doctor must be called in, for instance in cases where inspection visits are carried out by a nurse.

Controls

The sponsor or the investigator is expected to implement adequate controls to ensure the above-mentioned, for example by way of monitoring, audit, spot checks etc., and that the control is documented.

Renewed consent in clinical trials

The Danish Medical Research Ethics Committees (MREC) have published 'Questions and answers' regarding expectations for obtaining re-consent and providing information to trial participants. Furthermore, expectations relating to re-consent are described in the ICH GCP guidelines.

The Danish Medicines Agency's GCP inspectors often observe written participant information being updated during the conduct of a trial. The changes do not always seem to affect the trial participants' decision to participate in the trial. Prior to possibly inconveniencing the trial participants and the investigator sites by obtaining re-consent, it should therefore be ensured that the Ethics Committee's requirements for importance are met. In this context, it should also be clear whether the changes require re-consent from trial participants who are already part of the trial, or only from new trial participants. Moreover, the process (including timeframe) for obtaining re-consent is expected to be included in the submission to the Medical Research Ethics Committees (MREC).

Change log:

July 3, 2025 - minor changes according to Regulation (EU) 536/2024