7 key annotated CRF regulatory submission requirements you should know

2. Format the aCRF as a searchable PDF that meets FDA PDF specifications

Because the aCRF is a PDF document, it must meet the FDA’s PDF specifications:

• acceptable versions (1.4-1.7, PDF/A-1, PDF/A-2)
• text must be searchable
• fonts should be standard
• no password protections
• functioning hyperlinks/bookmarks

Using an appropriately formatted PDF helps ensure you’re providing readable text for reviewers.

3. Map each CRF item to the corresponding variable(s), including variable names and coding

Guidance requires that for each CRF item included in a dataset, the variable name and coding should be annotated on the aCRF. It also states that when data is recorded on the CRF but not submitted, those fields should be annotated with “NOT SUBMITTED”, with an explanation in the reviewer’s guide. 

For example, the CRF page for “Adverse Events” might have each checkbox annotated, e.g., AEDECOD = “HEADACHE”, AESEV = “MILD”, etc. In fields where a site asks a question, but the result isn’t transcribed into SDTM, the annotation should read NOT SUBMITTED, and the Study Data Reviewer’s Guide (SDRG) should include the rationale e.g. “Field used for internal site monitoring only”. 

This level of traceability ensures clean linkage between source CRF and SDTM dataset, reducing review queries. 

4. Use appropriate bookmarking and table of contents (TOC) structure for reviewer navigation

Industry practice (e.g., CDISC Metadata Submission Guidelines – MSG v 2.0) and FDA CRF annotation standards recommend that the aCRF include a table of contents including hyperlinks/bookmarked pages. Annotated CRFs included in the eCTD (Electronic Common Technical Document) should be bookmarked via dual bookmarking: (1) bookmarks by chronology and (2) bookmarks by CRF topics or forms.

For example, your aCRF could begin with a TOC listing: Visit 1 (Screening) → Demographics CRF, Visit 2 (Baseline) → Vital Signs CRF, … then a second bookmark structure listing: Form: Demographics, Form: Vital Signs, etc. Clicking each bookmark should open the correct page. 

This way, reviewers can easily navigate and verify annotation-to-variable links without flipping through hundreds of pages manually.

5. Annotate domain/page level correctly – include domain codes, color-coding if multiple domains on a page

According to CDISC guidance, if more than one domain exists on a CRF page, each domain annotation and its variables should be color-coded; each domain should show its 2-letter code (e.g., DM, AE) and domain name. Also, you submission should not include blank pages. Supplemental qualifier domain names do not need to be annotated. Annotations for collected data which will not be in the SDTM data (e.g., prompt questions) should be annotated as “[NOT SUBMITTED]”.

For example, the CRF page that records both concomitant medications (CM domain) and adverse events (AE domain) has a light-blue background section annotated “CM (Concomitant Medications)” with CMTRT = … etc., and a light-green section annotated “AE (Adverse Events)” with AEDECOD = … etc. 

Color-coding and verifying that no blank pages exist helps prevent reviewer confusion and improves clarity.  

In the MSG 2.0, there are several stipulations on formatting, including font, font size, etc. You should refer to the guidelines to understand and implement these.

6. Include forms/treatment-assignment pages (when applicable) and capture non-submitted data properly

The FDA CRF annotation standards state that the aCRF should include treatment assignment forms (if relevant) and all CRF items collected, even if they are not submitted into SDTM. For those, annotate “NOT SUBMITTED” and provide the reason in the SDRG. 

For example, in a blinded oncology trial, the randomization/treatment-assignment form (TA) should be included in the aCRF, annotated for the TA domain variables (TAARM = “DrugA”, etc). A site-log field captured by the eCRF for monitoring only (not analyzed) should be flagged with NOT SUBMITTED and documented in the SDRG as used for internal site compliance only. 

Ensuring full coverage of CRF pages (including those not mapped into SDTM) ensures traceability and completeness. 

7. Ensure traceability via metadata standards (CDISC MSG/SDTM) and quality-control/validation

The FDA expects the aCRF to integrate with the metadata definitions (e.g., define.xml) and follow CDISC’s Metadata Submission Guidelines (MSG) for SDTM. Sponsors should validate that the annotation on the aCRF matches the define.xml mapping and that all variables are traceable. 

For example, you should compare the aCRF annotations with the define.xml, highlighting unmatched variables or annotations missing. This quality-check report can be used in the final CRF-annotation sign-off prior to submission. 

Demonstrating full metadata traceability reduces risk of rejection and supports efficient review. 

Summary and next steps

If you’re working with annotated CRFs (aCRFs), adhering to these seven key regulatory requirements will help ensure your documentation is submission-ready, traceable, and compliant: 

1. Submit at the right time with correct file name 
2. Format as searchable PDF meeting specifications
3. Map each CRF item to variable names and coding
4. Provide TOC and dual bookmarks for navigation
5. Annotate pages properly including domain codes and color-coding
6. Include all forms and handle “NOT SUBMITTED” items properly
7. Leverage metadata standards and validate traceability