Trial Master File

Identifying Missing Documents: Protocol and Country-Level Informed Consents

Post by
Denise Lacey
Identifying Missing Documents:  Protocol and Country-Level Informed Consents

Next up in our TMF series:  finding missing informed consents. Buckle up, because this is going to be a long ride.

Most studies produce informed consents at two levels: protocol-level models and site level versions. Some studies also have country-level versions, and some have regional versions as well. Thus, the first step to an effective QC is to ascertain at which levels ICFs are expected.

Starting at the protocol level, the next step is to review the informed consent SOP to determine which documentation is expected for each protocol-level form and which reviewers and approvers are required to sign it. Some sponsors/CROs use a single form to capture review of required elements and approval, whereas others use up to three separate forms.  Some sponsors/CROs require full approval for each version, whereas others require limited approvals after the first version unless there are substantive changes. Using this information, build a checklist to capture whether required documentation is on file for each version.

Then determine how many versions of the protocol-level model are expected in section 02.02.03. If the team has maintained a tracker, this is easily done. If not, go through the TMF section at the protocol level and capture the version and date for each document filed and hope that a clear pattern emerges. ICF versioning conventions are rarely straightforward, so you may find yourself with versions 1.0, 1.1, 1.2, and 3.1, unsure what, if anything, is missing in the interim or on the tail end. ICF versions can be identified by the associated protocol, date of internal approval, date of IRB approval, protocol version, or a combination. Interview the study team, if necessary, to determine the numbering conventions and identify missing versions. Then determine whether expected review and approval documentation is on file for each version.

Cross-check the protocol-level ICF versions against the protocol to verify that any significant protocol amendments were reflected in ICF changes.

At the country or regional level, first ascertain which countries or regions are active in the study and when they became active. Confirm whether country-level ICFs are filed at the corresponding country/regional level in the TMF or at the protocol level. For some international studies conducted in the US, the protocol-level ICFs also serve as the US country/regional ICF.

The process of determining expected review and approval documents and expected versions is similar to the protocol-level process above, but with a twist:  Translations. Depending on the countries and language patterns involved, translations may be filed at the protocol, country, or site level. The translation plan can help identify standard translation expectations, but translation needs can crop-up mid-study - for example, an Arabic speaker could enroll at a site in Italy. A country-level ICF tracker is a useful tool for cross-checks. If this doesn't exist, start the painstaking process of listing each country-level version and look for gaps in version numbers. Compare the country-level versions to protocol-level versions, keeping the activation date for each country in mind. There won't always be a one-to-one correspondence, but gaps can be identified in this way.

Build the checklist for expected versions and associated documents as for the protocol level, but list each translation as a separate document, and include translation documents such as English masters and translation certificates to the list of documents to be checked off.  Many sponsors/CROs file the English master, translation, certificate, and back-translation (if any; check the relevant SOP for requirements) as a package. If this is not your practice, identifiers on these documents should enable the reviewer to match them up.

To cross-check, for all countries with a central IRB/IEC, go to section 04.01.02, IRB/IEC Approval, and compare the ICF versions approved by the central IRB/IEC to the country-level versions on the list to determine whether any IRB/IEC-approved versions are missing from the TMF, or whether any IRB/IEC approvals of ICFs are missing.

Having fun yet?  Now, repeat the checks above for other subject-facing information:  Subject diaries (01.02.01); questionnaires (02.02.02); participation cards (02.02.05), and "other" (02.02.07).

Denise DeRenzo Lacey, RQAP-GCP, has over twenty years’ experience in clinical Quality Assurance and clinical development operations.  Her practice focuses on application of quality risk management techniques for clinical studies, including risk-based approaches to auditing, data quality and integrity, and SOP development.  She has provided consulting services to a wide range of pharmaceutical, medical device, biotech and CRO clients in the US and Europe and has held senior positions at Vertex Pharmaceuticals and Radius Health.