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ОглавлениеBefore Initiation
A Case Report Form (CRF) is a printed or electronic document that is created and used in clinical trial research to capture standardised clinical data from each patient separately and to transfer it to Data Management.
see 17
Data Management
The structure of the CRF is comparable with a questionnaire that contains all of the protocol-designated information (also including (serious) adverse events) and which is in compliance with regulatory requirements, recorded by the sponsor-investigator on every study visit. In addition, CRFs ensure an accurate documentation as well as high quality of data and are defined as one of the essential documents of the Trial Master File(TMF).
see 15
Trial Master File, Updating and Archiving
Regulatory Reference
! ICH GCP Guideline, Chapters 1.11, 8.2.2, 8.2.7
! Society for Clinical Data Management: Good Clinical Data Management Practices 2009
Responsibilities
Prior to the development of the final CRF, the following steps should be followed, so that possible inconsistencies and handling errors can be avoided from the outset.
Accuracy of the Study Protocol
First of all, the sponsor-investigator and the persons involved in the draft of the study protocol must confirm its completeness and elaborateness, such that the required content of the finalized protocol can be transferred into CRF sheets.
Frequently, it is recommended to begin with the creation of the CRF at the same time as developing the protocol.
CRF-Structure
The CRF must be in accordance with the protocol and should reflect it precisely, so this document has to consist of particular forms or entry areas to be modified:
see 19
Pharmacovigilance
CRF Design and Extension
The CRF design should be implemented in an attractive, clear and unambiguous form, otherwise, extensions and misinterpretations might cause data faults on the basis of confusion.
It is required that every CRF sheet implies explicit queries, clear instructions, prompts and controlling fields (that allow the efficient and complete coding of data for processing and analysis) in combination with text fields for the sponsor-investigator’s entries.
If your CRF is in a paper-based form, optionally every sheet (except pure-tip sheets) should be printed on non-carbon paper (NCR paper) with corresponding page numbers, so that copies of the original sheets can remain in chronological order with the study site and are not lost completely in case of loss or missing CRF sheets.
Advice - Hints and Tips
• Bear in mind the CRF needs to be finalized (with version control and approval from each study site) and be a useable form before the sponsor-investigator starts enrolling patients into the clinical trial.
• Ensure that on the CRF, personal data is not identifiable; use screening numbers and randomization numbers (i.e. in a randomized study) instead of real names.
• Remember: do not make use of your printed sample CRF until you have checked the conformity, contents and completeness with the protocol.
• Usually, paper-based CRFs should be stored in an environment with regulated access authority.
• If you want to enter data electronically (eCRF/Remote Data Capture (RDC)) with the assistance of online data capture software instead of paper CRFs, please validate your electronic system correctly in the presence of an IT specialist; likewise, take universal precautions such as password protection and firewall security.
Forms and Templates
Several freely available examples illustrate how a CRF could be meaningfully designed; the level of detail reflects the protocol and can be clearly followed.
Adverse Events Form
Prior and Concomitant Med
Protocol Deviations Core Form
Serious Adverse Events Form
Study Completion
Visit Checklist
Inclusion Exclusion Core Form
Demographics Form • Medical History
Medical History Conventional
Vital Signs
Physical Exam
(all documents from http://www.nia.nih.gov/ResearchInformation/CTtoolbox/forms.htm#admin; accessed January 19, 2011)
During Study
After the CRF is compiled, approved and finalized as the latest version, it can be used to collect clinical data during the course of the clinical trial - commencing with the enrolment of the first patient - according to the protocol and in compliance with regulatory requirements.
Only the sponsor-investigator and authorized staff (authorization should be documented) are allowed to perform written entries into the provided (text) fields on the CRF sheets.
Regulatory Reference
! ICH GCP Guideline, Chapters 2.10, 4.9.1-4.9.3, 6.4.9, 8.3.2, 8.3.14-8.3.15
! Society for Clinical Data Management: Good Clinical Data Management Practices 2009
Responsibilities
Accuracy and Completeness of Medical Documentation
Ensure that all recordings in the CRF or in the required reports (e.g. with the appearance of SAEs) are:
• Devoid of patient name (i.e. anonymous)
• Exact (for accurate reporting, interpretation and verification)
• Current
• Complete
• Consistent
• Legible (also on the NCR paper, if available)
• Written in the same language as the CRF was designed, using a permanent ball-point pen
Either the study nurse or the sponsor-investigator may complete the CRF. CRF completion should be done as soon as possible with regard to the date when data were obtained (i.e. the study subject’s visit at the clinic). If the study nurse completes the CRF, this task must have been already properly delegated on the delegation of authority list provided by the sponsor-investigator.
The sponsor-investigator is still responsible for confirming the correctness and completeness of the data in the CRF through her/his signature. This confirmation cannot be delegated.
Even if tests or examinations could not be performed due to a patient’s poor compliance, those failed visits have to be registered accurately on the provided sheets and all the appropriate (text) fields should be crossed out, so that it is absolutely impossible to add any entries later.
Corrections and Changes
The sponsor-investigator should take care if any corrections, additions or changes to the CRF must be done in accordance with ICH GCP.
• Changes to the CRF: any changes made to the initial entry must be traceable and properly dated and initialled. A justification may be included whenever it is appropriate: it is not always required.
• Corrections may not cover the original entry (please cross out each wrong listing with a straight line and correct it, as previously mentioned).
see 23
Monitoring
Delivery of CRFs to Monitoring
Within the scope of long ongoing clinical trials in particular, it is recommended to transfer individual sheets or whole recorded CRFs at defined intervals to Monitoring to prevent the loss of CRF data; likewise, this ensures a prompt and continuous data capture by Data Management.
Advice - Hints and Tips
• Ensure that all authorized staff receives instructions about the correct entry and handling of CRFs to prevent loss or inaccurate documentation.
• Bear in mind that superficial or inaccurate completion of the CRF ultimately leads to data faults, which are time-consuming to be corrected afterward.
• Make sure that all essential signatures (also needed in case of changes or corrections) required in the CRF exist and are given by authorized staff.
• Data reported on the CRF that are derived from the protocol and source documents should also be consistent with those documents (any changes to the protocol also have to be reflected in the CRF and vice versa).
• Serious Adverse Events Reports (with the study’s EudraCT number) must be completed explicitly and reported immediately to the relevant pharmaceutical company (i.e. study IMP manufacturer).
see 8
EudraCT
see 19
Pharmacovigilance
After Study
Finally, when the study ends or is terminated, all the clinical information on each patient required by the protocol should be reported accurately on the CRFs without any exceptions.
Regulatory Reference
! ICH GCP Guideline, Chapters 5.18.4, 8.2-8.3
! Society for Clinical Data Management: Good Clinical Data Management Practices 2009
Responsibilities
Transferring of Remaining CRF Sheets
The sponsor-investigator must ensure that after completion of the clinical trial, all outstanding CRFs are transferred to Monitoring.
Correcting of Non-Conforming CRF Entries
The sponsor-investigator has to be informed by Monitoring about any illegible, omitted, incorrect (e.g. protocol deviation) or inconsistent CRF entries, likewise, in the context of query management.
see 23
Monitoring
see 17
Data Management
Those corrections must be made by the sponsor-investigator or by an authorized staff member directly on the CRF (and NCR paper), including all corrections, deletions and additions, which have to be:
• dated
• explained (if not self-evident)
• signed
by the responsible corrector and endorsed by the sponsor-investigator.
Destruction of Unused CRFs
With the decision of the sponsor-investigator, unused CRFs should be destroyed.
Archiving of CRFs
CRFs and all appropriate forms should remain at the study site to be archived for a definite period.
see 15
Trial Master File, Updating and Archiving
Advice - Hints and Tips
• Make sure that no CRFs/individual CRF sheets are withheld from Monitoring.
• Bear in mind that the often used adhesive post-it® notes are not conforming to ICH GCP.
• Ensure that all corrections and changes made on the CRFs are dated and signed (using a ball-point pen) by an authorized corrector, and endorsed by the sponsor-investigator.
• Ensure that all CRFs remain at your study site and are properly archived according to ICH GCP.
