When submitting the NDA (new drug application) or BLA (biological license application) to FDA, as part of the CTD (common technical document) or eCTD module 5 (Clinical Study Report), individual subject's case report forms (CRFs) need to be submitted for some patients. For each individual subject, there will be multiple pages of case report forms. The term 'CRF case book' may be used to refer to all CRF pages for an individual subject. Individual subject's case report forms are those with patient data (versus the blank CRFs when we discuss the CDISC and SDTM define documents).
For Which Subjects, Will Their Case Report Forms Need to be Submitted?
According to US 21 CFR 314.50 (Content and Format of an Application), individual subject's CRFs are needed for subjects who died or who did not complete the study due to an AE.
(b) The applicant shall, under section 505(i) of the act, update periodically its pending application with new safety information learned about the drug that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling and, if applicable, any Medication Guide required under part 208 of this chapter. These ‘‘safety update reports’’ are required to include the same kinds of information (from clinical studies, animal studies, and other sources) and are required to be submitted in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition, the reports are required to include the case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event (unless this requirement is waived). The applicant shall submit these reports (1) 4 months after the initial submission; (2) in a resubmission following receipt of a complete response letter; and (3) at other times as requested by FDA. Prior to the submission of the first such report, applicants are encouraged to consult with FDA regarding further details on its form and content.
According to FDA’s internal “Reviewer Guidance Conducting a Clinical Safety Review of a New Product Application and Preparing a Report on the Review”, the individual subject's CRFs for patients with SAEs will also be needed for safety review.
Before beginning the safety review, the reviewer should identify and assemble (or locate electronically) all available materials for the review. These materials include:
- The applicant’s Integrated Summary/Analysis of Safety (ISS)
- Adverse event tables in the NDA/BLA submission7
- Case report forms (CRFs) for patients who experienced serious adverse events or who dropped out of a study because of an adverse event.
The reviewer should request these CRFs if the applicant does not include them in the submission (although they are required under 21 CFR 314.50). If the number of cases is very large (e.g., for dropouts) and many of the events are similar, it may be reasonable to request only a sample of CRFs.8 Note that, in some cases, dropouts attributed to other reasons will upon review be associated with an adverse event.
To be on the safe side and avoid the additional requests from FDA, individual subject's CRFs should be provided for all subjects who:
- Died during the study
- Discontinued from the study due to an AE
- Had SAE during the study
How Should the Individual Subject’s CRFs be Prepared for Submission?
FDA guidance “Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications” has some specific requirements for individual subject’s CRFs. In old days, we had to send individual subject’s case report forms to a specialty company for scanning and bookmarking – manual bookmarking was a tedious task. Nowadays, the popular EDC systems can generate individual subject’s case report form for submission.
3. Case report formsYou should provide an individual subject’s complete CRF as a single PDF file. If a paper CRF was used in the clinical trial, the electronic CRF should be a scanned image of the paper CRF including all original entries with all modifications, addenda, corrections, comments, annotations, and any extemporaneous additions. If electronic data capture was used in the clinical trial, you should submit a PDF-generated form or other PDF representation of the information (e.g., subject profile). You should use the subject’s unique identifier as the title of the document and the file name. These names are used to assist reviewers in finding the CRF for an individual subject. Each CRF must have bookmarks as part of the comprehensive table of contents required under 21CFR314.50(b). We recommend bookmarks for each CRF domain and study visit to help the reviewer navigate the CRFs. For addenda and corrections, making a hypertext link from the amended item to the corrected page or addendum is a useful way to avoid confusion. Bookmarks for these items should be displayed at the bottom of the hierarchy.
Furthermore, PDF files for individual subject’s CRFs should follow the requirements specified in FDA guidance “Providing Regulatory Submissions in Electronic Format — General Considerations”. For example, there are requirements for page size and margin, font size, embedded fonts, ……
Is the Requirement for submitting Individual Subject’s CRFs for all FDA Submissions?
No. The requirements above are only applicable to FDA CDER and CBER divisions. CDRH for device division does not have a requirement. As a matter of fact, the above mentioned FDA guidance is only for CDER and CBER divisions, does not include CDRH.
FDA guidance “Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications” (again sponsored by CDER and CBER, but not CDRH) specified that the following submissions should follow the eCTD specifications including the individual subject’s CRFs.
- Certain investigational new drug applications (INDs)
- New drug applications (NDAs)
- Abbreviated new drug applications (ANDAs)
- Certain biologics license applications (BLAs)