Good documentation practice in clinical trials

Expectations to clinical trial documentation

Based on deviations found during GCP inspections, we would like to specify our expectations regarding the documentation generated in connection with clinical trials.

The Danish GCP executive order and the ICH GCP guidelines define the documents that must be available in the Trial Master File for a clinical trial.

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

The Danish GCP executive order

According to the Danish GCP executive order, the sponsor is responsible for the conduct and quality of a clinical trial of medicines in humans and the sponsor must ensure that the trial is planned and conducted in accordance with good clinical practice and that data is registered and reported according to procedures that assure the quality of every aspect of the trial.

It is also stated that the investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports and that a description of where source data can be found is available.

In addition, any changes of registered data must be visible and be dated and signed by the person who made the changes. If the reason for the changes is not obvious, an explanation must be given.

In connection with the preparation of documents, forms or other documentation for use in the trial, the investigator should ensure that a version number is added to each document.

The investigator's approval of the material should be documented, and it should also be documented to whom the material has been distributed and when.

Traceability

Preparation and distribution of documents

It is a requirement that 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 condition is that on GCP inspections we have found laminated ’pocket forms’ that had been prepared for the investigator's staff. The staff often uses these documents with e.g. 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 ensured that previous versions are not used.

Registration and change of data

In general, both the sponsor and the investigator are expected to make sure that all 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 in connection with generating the relevant data.

It should not be possible to delete data.

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 other people, e.g. inspectors, auditors, monitors or new staff on the site, why the changes were made. For example, this is 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

Documents, forms and other documentation must be dated and signed.

We regularly observe on GCP inspections that CVs, job descriptions and other staff records are not signed and/or dated. The person concerned should acknowledge that the document has been prepared by him/herself and is valid at the time when it was signed.

Questionnaires and worksheets are examples of other documents that are often not signed and dated. Because 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 that the principal investigator signs it no later than at the end of the trial (and preferably signs completed pages) to indicate that this is the complete list of the involved trial subjects.

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 dates that have been added in advance, which is not acceptable. 

Electronic documents

Regarding electronic documents and data, please see the reflection paper of the EU GCP inspectors in this field (link to EMA).

Written instructions

Instructions followed in clinical trials 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, e.g. in cases where inspection visits are carried out by a nurse.

Controls

Moreover, it is expected that the sponsor or the investigator implements controls to ensure the above-mentioned, e.g. by way of monitoring, audit, spot checks etc., and that the control is documented.