16.2 Case Report Forms and eCRF Completion

Case Report Forms and eCRF Completion

While source documents serve as the primary medical and legal record for a clinical trial subject, the Case Report Form (CRF) is the tool used to transmit that data to the trial sponsor. ICH GCP defines a CRF as a printed, optical, or electronic document designed to record all of the protocol-required information to be reported to the sponsor on each trial subject.

In modern clinical trials, Electronic Case Report Forms (eCRFs) have almost entirely replaced paper CRFs. However, the fundamental principles of CRF completion remain the same regardless of the medium. The CRC is typically the primary person responsible for transcribing data from the source documents into the eCRF.

Purpose of the Case Report Form

The CRF serves several critical functions:

1. Standardization: It ensures that data is collected consistently across all participating sites, subjects, and visits.
2. Data Management: It structures the data in a format that can be easily entered into a clinical database, cleaned, and statistically analyzed.
3. Protocol Compliance: It reflects the requirements of the protocol. If the protocol requires a hemoglobin test at Visit 2, the Visit 2 CRF will have a field for the hemoglobin result.

Source Data Verification (SDV)

A fundamental tenet of Good Clinical Practice is that data entered into a CRF must be supported by source documentation. When a Clinical Research Associate (CRA) visits a site, a significant portion of their time is spent performing Source Data Verification (SDV).

• The CRA compares the data in the eCRF line-by-line against the original source documents (medical charts, lab reports, ECGs).
• Any discrepancies between the source and the CRF are flagged for correction. If the eCRF says the subject's weight is 75 kg, but the source document says 78 kg, the CRC must update the eCRF to match the source (assuming the source is the accurate original record).

CRF Completion Guidelines (CCGs)

Sponsors provide CRF Completion Guidelines (CCGs) (sometimes called eCRF Completion Instructions) to sites. This document is a "dictionary" or instruction manual on how to fill out specific fields in the eCRF.

• Standardizing Formats: The CCG will dictate whether dates should be entered as DD-MMM-YYYY or MM/DD/YYYY.
• Handling Unknowns: The CCG will provide instructions on what to do when data is missing. For example, if a subject knows they had surgery in 2015 but cannot remember the month or day, the CCG might instruct the CRC to enter "UK-UK-2015" (Unknown-Unknown-2015).
• CRCs should reference the CCGs frequently, as guessing how to enter data leads to queries and delays in database lock.

Best Practices for eCRF Completion

1. Timeliness

ICH GCP requires that CRFs be completed in a timely manner. Data should be entered into the eCRF as soon as possible after a subject visit. Many sponsors require data entry within 3 to 5 business days. Rapid data entry allows the sponsor to monitor subject safety (e.g., spotting a trend of severe adverse events) and enables CRAs to perform remote monitoring before an on-site visit.

2. Handling Missing Data and Protocol Deviations

Blank fields in an eCRF are a major red flag for data managers. If a protocol-required procedure was not performed (e.g., the subject refused a blood draw, or the site's ECG machine was broken), the eCRF must still account for it.

• Usually, the eCRF will have a checkbox for "Not Done" (ND).
• The CRC must select "Not Done," and the EDC system will typically prompt for a reason (e.g., "Subject Refused," "Equipment Failure").
• Missing a protocol-required procedure is a protocol deviation. The CRC must not only document this in the eCRF but also record it in the site's protocol deviation log and report it to the IRB as required by local policy.

3. Avoiding Direct Data Entry (Unless Specified)

Unless explicitly stated in the protocol or site procedures that an eCRF screen is the source document (eSource), CRCs must never enter data directly into the eCRF while evaluating the subject. The data must first be captured in the source document (e.g., the clinic chart) and then transcribed to the eCRF.

Data Queries and Resolution

When data in the eCRF is missing, inconsistent, or outside expected ranges, a query is generated. Queries can be auto-generated by the Electronic Data Capture (EDC) system (e.g., if a CRC enters a pregnancy test result for a male subject) or manually generated by a CRA, Data Manager, or Medical Monitor.

• Query Resolution: The CRC is responsible for reviewing and answering queries promptly.
• If a query points out a discrepancy, the CRC must check the source document.
• If the eCRF is wrong, the CRC corrects the eCRF and responds to the query (e.g., "Updated to match source").
• If the eCRF is correct and matches the source, but the value is highly abnormal, the CRC responds confirming the data (e.g., "Value confirmed accurate per source document").
• CRCs must never change the source document simply to satisfy a query in the eCRF. The source is the ultimate truth.

Investigator Sign-Off

Under ICH GCP, the Principal Investigator (PI) retains ultimate responsibility for the accuracy and completeness of the data reported to the sponsor.

• In paper CRFs, the PI physically signs the pages.
• In eCRFs, the PI uses a secure electronic signature (typically a combination of a username, password, and sometimes a PIN) to sign off on the data.
• The PI signature usually occurs at the end of a subject's participation (at the completion of the subject's casebook) or periodically as defined by the sponsor. The PI must review the data before signing, confirming that they endorse the clinical data being submitted.