The Investigator site file (ISF) is a crucial component of clinical research. Keeping an effective and compliant ISF is the best way for a clinical trial site to guarantee the effective and compliant development of clinical research procedures.
What is an investigator site file?
An Investigator Site File (ISF) is a collection of documents required for the development of clinical trials. An ISF contains essential documents that guarantee to the investigator and the clinical trial site that they are following the regulatory requirements outlined by the ICH and GCP guidelines.
The documentation found in an ISF permits the evaluation of the conduct of the trial as well as the assessment of the quality of all produced data. These documents play a key role in the outcome of clinical research. The ISF is colloquially referred to as the “binder” in many clinical trial sites.
What is the difference between a trial master file and an investigator site file?
A trial master file (TMF) represents the entire story of a study and is held by a sponsor. In contrast, ISF is held by the sites and represents the story of the study of the particular site that holds it. A TMF requires the inclusion of an ISF for every site participating in the study to be complete.
The management of TMF and ISF documentation can be considerably simplified by implementing electronic versions of the documents. Known as eTMF and eISF respectively, these facilitate the exchange of information between the sponsor and the sites.
What is the purpose of the investigator site file?
An ISF consists of clinical trial documents that permit the evaluation of the quality of research, the conduct of the trial, and compliance with regulatory standards.
However, electronic investigator site files (eISF) can also serve a second purpose. The different parties involved in the research process, such as the sponsor, the CRO, and multiple sites, can use an eISF as a streamlined channel of communication and collaboration. An eISF offers remote monitoring capabilities, allowing monitors to access files and complete inspection tasks without having to leave the comfort of their offices.
Benefits of electronic document management in Pharma
Who is responsible for the investigator site file?
The individual responsible for ensuring the integrity of an ISF is the principal investigator (PI). The PI must be involved with the ISF prior to the start of the study. Likewise, they must update the file whenever relevant and applicable documentation is produced.
A PI is also responsible for making sure the study is conducted in accordance with applicable regulations, the investigational plan, and the signed investigator statement. The ISF keeps the documentation that helps the PI certify that all reporting requirements are met.
What goes into an investigator site file?
The information found within an investigator site file is meant to preserve all data related to a study. ISF data must contain information about a study before, during, and after its completion.
Before a clinical trial
The following documentation should be present in an ISF before the official start of a clinical trial:
- Investigator’s brochure (IB): This document delineates scientific information about the investigational product.
- Study protocol: Current protocol information must be included alongside any amendments and historical protocols.
- Informed consent documentation: This is the information given to trial subjects (the patients). Relevant documentation includes consent forms together with any other piece of written information that supports the provision of consent. Any relevant advertisement material for recruitment is also necessary.
- Financial and insurance clinical trial agreements
- Signed agreements: All agreements between the involved parties must be included. These include agreements between an investigator and a sponsor, CRO, and other authorities.
- IRB review and approval
- Regulatory authority approval of protocol
- Curriculum Vitae: The documentation must delineate qualifications and eligibility to conduct the trial, including the resumes and certifications of all research personnel.
- Normal values along with ranges of the tests (if applicable)
- Instructions for investigational product
- Instructions for trial-related materials handling
- Shipping records for trial-related materials
- Decoding procedures of blinded trials
- Pre-trial monitoring report: Documents that ascertain the suitability of the site to conduct the trial. This includes data that certifies that procedures have been reviewed by the trial staff.
During a clinical trial
Many clinical trial documents are bound to change as research develops. Likewise, the availability of new information entails the addition of supplementary documentation.
The following information should be added:
- Updates to the investigator’s brochure
- Revisions to trial-related documents: This includes the protocol and informed consent forms.
- IRB review
- Approval of amendments and revisions: Both from IRB and regulatory authorities.
- Curriculum Vitae of new personnel
- Revisions to normal values and ranges of the tests
- Additional shipping records for trial-related materials
- Relevant communications: Including letters, meeting notes, and notes from phone calls.
- Source documents: This is documentation related to the existence of patients and verifies the integrity of collected data.
- Case report forms (CRF): These must be completed, signed, and dated. Any corrections thereof are also to be included.
- Serious adverse events reports
- Sponsor’s notification of safety information
- Reports to IRB: Interim or annual reports must be included.
- Subject screening log
- Subject ID code list
- Subject enrollment list
- Investigational products accountability: This certifies that the drug has been used according to protocol.
- Signature sheet
- Record of retained samples
After a clinical trial
The completion of a clinical trial will produce an additional amount of documentation. The following final documentation must be added:
- Final investigational products accountability
- Documentation of investigational product destruction: All unused drug products meant for the completion of the clinical trial must be documented if it is destroyed at the study site.
- Completed subject ID code list
- Final report: These documents validate the completion of a clinical trial.
- Clinical study report: This document delineates the results and interpretation of the clinical trial.
What documents are required for investigator files?
Every essential document produced during the development of a clinical trial must be included in the ISF within 5 business days of availability. This includes any relevant correspondence. Documentation must be readily available for monitoring, sponsor audits, and regulatory inspections.
Essential documents
Key documentation that should go into an ISF includes:
- The trial protocol
- Participant information sheet and consent forms
- The investigator brochure
- Regulatory documents
- Applications and approvals
- Delegation logs
- Safety reports
- Correspondence between the appointed site staff and the sponsor
Pharmacy folder
If applicable, a pharmacy folder should also be added to an ISF. Pharmacy files are kept at the site pharmacy. The delegated pharmacist is responsible for the maintenance of pharmacy files.
Pharmacy files contain the following information:
- A list of the recruited participants
- Investigational product shipping details
- Receipts
- Accountability documents
- An up-to-date trial protocol
- The investigator’s brochure
Other documentation
Any information related to adverse events (AE), adverse reactions (AR), and their variations should also be included in an ISF. In case the ISF is kept as a physical set of documents, certain information must be included on the cover and spine of the folder that comprises it.
The following information should be found in a paper ISF folder:
- A human research ethics committee (HRECS) reference number
- HRECS local project number
- The name of the Principal Investigator
- The name of the study
Whenever a document is removed from an ISF, a note explaining the reason behind the removal must be included. Information about where the document was moved to is also required.
The clinical document management process can be substantially streamlined by an eISF. This solution implements digital technology to organize and enhance clinical trial files. The eISF is the preferred choice of auditors and regulatory bodies.
How long must the investigator site file be retained?
Regulatory bodies have distinct requirements for retaining research data. For instance, all research records are to be kept for a minimum of three years after the research is completed to comply with the International Review Board (IRB) regulations. Researchers should keep documentation for the longest time applicable.
Applicable regulations are as follows:
- FDA: Any records of research that involve drugs, devices, or biologics must be kept for 2 years after the approval of the marketing application.
- OHRP: Records must be kept for 3 years after the completion of the research.
- HIPAA: Records must be kept for 6 years after the authorization is signed by subjects.
- VA: Present records of any research must be kept indefinitely.
- Sponsor requirements: These are stipulated in the contract.
- UF patent requirements: Research data must be kept for the life of the patent.
eISF for clinical trials
Agatha Remote ISF is the best solution for those interested in improving the quality and speed of clinical document management. Virtual clinical trial information provided by the Agatha eISF offers many benefits over its analog counterparts.
Thanks to Agatha, remote site monitoring is made quick and easy. The software minimizes the costs and efforts related to monitoring clinical sites. Standardized report forms and other clinical research documents guarantee that all files are ready for inspection from the moment they are created. Users can share binder contents in real-time with anyone who needs them, thereby improving how clinical operations are performed.