Expectations for eCRF sign off in Germany
On 17 February 2020 the Zentralstelle der Länder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten (ZLG) (Central office of the federal states for health protection for drugs and medical devices) issued the opinion of the Clinical Trials Expert Group (EFG 05) regarding investigator signatures for the verification of eCRF data.
2Richards assess the potential implications of this short document to help readers determine whether they should revise existing approaches to securing investigator approval of eCRFs.
Please note that this is our assessment of the potential impact to Sponsors based upon this notice. It is the responsibility of the reader to review the relevant, current regulations and guidance documents in their entirety to determine appropriate actions to be taken, if warranted.
Our Assessment
This ZLG ruling from the Clinical Trials Expert Group (EFG 05) responsible for harmonizing the country-wide monitoring of clinical trials, is a short, two-page document that could have significant impact on eCRF design, and is based on their interpretation of the following sections of ICH E6(R2):
§4.9.1 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.
§5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
§5.1.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.
It is usual practice to have a single approval by the Investigator on each Subject’s eCRF casebook. The investigator’s electronic signature is usually applied once the Subject has completed the study and all data queries have been closed.
ZLG does not accept that this approach complies with ICH E6(R2) section §4.9.1 since this signature confirming data review by the investigator is not applied contemporaneously. Furthermore, since the data are transmitted to the Sponsor on an ongoing study without investigator signature, ZLG considers the data to be “unreviewed” and acceptance of them a deficiency on the part of the Sponsor to fulfil their QC requirements per ICH §5.1.1. and §5.1.3. ZLG makes it clear that their expectation is for an investigator signature to be applied at the end of each Subject visit.
ZLG describes these deficiencies as a serious deficiency and it is likely that this will change the expectations for eCRF approval during GCP pre-approval inspections.
Potential Impact
Historically, paper-based CRFs had Investigator wet-ink signatures either on each page or minimally at the end of each Subject visit, and often an additional final sign off page to signify complete review of each casebook. This approach documented timely review of the data at each visit, providing evidence of investigator oversight recorded in the CRF.
Most eCRF systems do not capture evidence of timely review of Subject CRF data by the investigator; relying on a single sign-off prior to locking Subject data. The incorporation of electronic signatures to confirm timely review of data by the investigator is something that Sponsors should consider in the design and build of eCRFs. This is perhaps particularly relevant when on-site monitoring is restricted, and Sponsors must rely on remote (central) review of eCRF data to assess Subject safety and adherence with the Protocol.
