Preparing the Study-Specific Documentation

For a study to be credible in the eyes of the authorities, investigators must be able to show that the study is in compliance with good clinical practice guidelines.  This means documenting every study-related action.  Therefore, documentation is essential to clinical research.  

There are two types of documentation. Study-specific documentation includes information about the study as a whole or the study as it is performed at a certain site, such as regulatory files. You should be able to recreate the study from the study-specific documentation. Subject-specific documentation includes information about the subject’s participation in the study, such as signed informed consent forms. This documentation should tell the story of the subject’s participation through the study. 

This page provides basic guidance and resources to assist teams with anticipating and maintaining appropriate study-specific documentation.

Duke Approach and Tools

“Essential documents are those documents which individually and collectively permit evaluation of the conduct of the trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements” (ICH Guideline E6).

There are many ways to organize essential documents, and there is no gold standard for how to do this. For example, the ICH GCP E6 guideline recommends that the documents be grouped according to the stage of the trial, i.e. documents relevant to the trial before it commences, documents relevant to the trial during the conduct of the trial, and those documents relevant to the trial after completion or termination of the trial. The most important thing is that the documentation is organized and that all of the necessary documents are present.

Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator or institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial. These documents are also the ones which are usually audited by the independent audits and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected.

 

Regulatory Binder

Before any study begins, a study team member collects the regulation-required documentation and sponsor-required documentation. Most researchers keep the collection of study-related documentation or essential documents together and call this the regulatory binder or regulatory file. Regulatory files used to be kept in a 3-ring binder; however, depending on the type of study, they can now be kept electronically. For example, in a retrospective review study, the regulatory documentation is kept in the eIRB system. Therefore, while the documents are collected and maintained, a separate physical binder is not necessary.  Exempt studies are not part of Clinical Research Unit oversight and are not required to maintain regulatory binders.  The regulatory information included in the IRB’s determination process (and located in eIRB) is sufficient documentation for these studies.

The Research Practice Managers in the Clinical Research Units have created a Regulatory Binder Checklistthat indicates the documents expected for each type of study conducted at Duke.  This checklist has been vetted and approved through the Office of Audit, Risk and Compliance.  This checklist does not apply to exempt studies. 

There are 4 documents required for all types of studies. They are:

  • Protocol
  • IRB Approval Notices - Upon IRB approval, the DUHS IRB issues an approval notice. Include all versions of approval notices in the regulatory files; including those for amendments, continuing renewals, and safety reports.
  • IRB Amendments or Approvals
  • Training

With the exception of retrospective chart review studies, the following documentation is expected in the regulatory files:

  • Subject Enrollment Log
  • IRB Safety Reports
  • Approved Informed Consent Form
  • Signature and Delegation of Authority Log
  • CV and Licenses for Investigators - Duke provides a curriculum vitae template for use with clinical research. 
  • Correspondence - Include all internal and external correspondence. Include any pertinent correspondence with the IRB, study sponsors, or monitors. Correspondence can include letters, faxes, e-mails, or telephone calls.
  • Registration in ClinicalTrials.gov - If your study qualifies, include documentation of registration on the ClinicalTrials.gov site in your regulatory files. Contact the Duke Office of Clinical Research for assistance with registration.
Additional Documentation

Depending on the type of study being conducted and how the study is designed, additional documents may be required. For intervention or registry studies that require informed consent, as well as drug (IND) or device (IDE) studies, you will need to include the hospital lab certificates. For IND or IDE studies, you also need to include the investigator’s brochure, financial disclosure forms, FDA Form 1572, study drug or device inventory documentation, and IND or IDE documents.

Depending on the type of study and lab procedures used, the study may need to collect laboratory certification documentation. For example, the Clinical Laboratory Improvement Amendments of 1988 requires CLIA certification for all laboratories that examine materials derived from the human body for the purpose of providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of human beings.

In sponsored drug trials, the sponsor provides the Investigator’s Brochure. It is a document that describes the known information about the investigational product. It is intended to give the investigator the information necessary to conduct the clinical trial. In sponsored device trials, an Instructions for Use document should be provided.

Financial disclosure documentation is required for Investigators who conduct IND or IDE clinical studies to prevent potential financial conflicts of interest which could lead to bias in clinical studies. The investigator can complete form FDA 3455 or 3453 depending on what is disclosed.  

The FDA Form 1572 is an agreement that the investigator will comply with FDA regulations. Include a copy of the FDA Form 1572 in the regulatory binder for each investigator in an IND study. 

For an IND or IDE study, the regulatory binder will include a copy of the IND or IDE form. 

Though not specifically listed on the Duke Regulatory Binder Checklist, Standard Operating Procedures (SOPs) should be included with study-specific documentation. SOPs may be study-specific, department-specific, or CRU-specific. SOPs define how study activities are performed to provide for consistency and reproducibility of study procedures and results. 

 

Additional Information About Specific Documents
Subject Enrollment Log

The Subject Enrollment Log documents, tracks, and follows the progress and status of each potential subject through the study process.  The log offers a snapshot of the study progress of all enrolled subjects, as well as documents the reasons for screen failures or early subject withdrawals or termination.  All participants who consent to a research study at a Duke Medicine site will be associated to that study in the Maestro Care electronic health record system. Research participants who consent to a research study at Duke who are not from a Duke Medicine site will be managed outside of Maestro Care.

The researcher may use a spreadsheet or other form to track the information required (number of participants, race, and ethnicity) or the researcher may use the Enrollment Log Template in REDCap software to capture the information electronically. The REDCap log is secure, backed-up regularly and the data can be exported for reporting. If you are interested in a copy of the template:

  1. Go to https://redcap.dtmi.duke.edu/redcap/surveys/?s=oR63f5
  2. Select Copy of Existing project
  3. Enter the name of your project in this format: Enrollment Log - Pro000#####
  4. Complete the rest of the information on the form and submit the form.

If you have questions and need to understand how to use the tool, please contact redcap-docr@duke.edu, or visit us in Hock 9047 at 11:00am on Tuesdays, when we have open REDCap office hours. A tip sheet provides additional instructions.

 

Signature and Delegation of Authority (or Responsibility) Log

It is common practice for investigators to delegate certain study-related tasks to employees, colleagues, or other third parties (individuals or entities not under the direct supervision of the investigator). However, the Principal Investigator is ultimately responsible for the conduct of the study. When tasks are delegated by an investigator, the investigator is responsible for providing adequate supervision of those to whom tasks are delegated. Include the Signature and Delegation of Responsibility Log which lists the study personnel and tasks delegated to them by the Principal Investigator. You can get a copy of the Signature and Delegation of Responsibility Log in the forms section of this page. This log should include a line for the Principal Investigator indicating his/her responsibilities along with a full signature and initials. Update the log as personnel and responsibilities change during the course of the study.

 

Investigational Product Inventory

The investigator needs to keep and maintain proper auditable records on handling, storage and use of investigational product at site. The documentation of the investigational product inventory is kept in the regulatory binder. These documents may include shipping and delivery receipts, inventory logs, temperature charts, drug dispensation records, or reconciliation records. At Duke, the investigational product may be handled by the Investigational Chemotherapy Service, Infectious Diseases Research Pharmacy, or the Investigational Drug Service. In this case, the investigator will work with the drug service provider to maintain the documentation and reference its location in the regulatory binder.

 

Form FDA 1572

Best practice recommends that at least a Primary CRC should be listed in Section #6 of the 1572 form for each study in order to follow Duke policy and the FDA guidance on the form. The FDA guidance states that research coordinators "should usually" be listed in Section #6 of the 1572 form.

 

Study-Specific Standard Operating Procedures

Each study should maintain the standard operating procedures (SOPs) specific to their study.

For studies that use the Duke ClinCard, each department using the card must establish, approve, and implement an SOP which defines the roles and responsibilities in the Duke ClinCard system within their unit.  An SOP template is available to aid in creating the procedure.

 

How to Keep the Documents

The regulatory documents or study-specific documentation can be audited by a sponsor, internal auditor, external auditor, or the FDA at any time. Therefore, maintain the documents so that they are audit ready at any time.

Keep a file or binder for each study in a secure location.  Create sections of the binder using tabs. File the documents under each tab in reverse chronological order so that the most recently dated item is at the front of the section. Do not discard or remove any documents that have been updated. Just add the updated version to the binder. Create a table of contents for each binder. Create multiple binders when a given binder or file is full.

A sponsor may provide materials and directions for maintaining the regulatory file for a sponsored study. Keep originals at the site and provide copies to the sponsor. 

Some documents, such as the investigator’s CV, is required for the regulatory document binder for all studies. To simplify the paperwork, you can maintain a separate CV binder or file that you can keep centrally. Then, in the study regulatory binder, reference the CV binder or file and indicate where the document can be found in a Memo-to-the-File.

Many documents can now be kept electronically. The FDA no longer requires paper documentation; however, they may request that you print off certain documents.

You can maintain documents electronically rather than having a paper version in the regulatory binder or file, but the documents should be organized in a similar way. Again, you must reference the electronic location of the document in a Memo-to-the-File.  The electronic documentation must be accessible to all parties that may require access to the data. For example, correspondence stored electronically in an individual study team member’s email account would not be acceptable, because others on the team would not have access.

 

What Should NOT Be Included in the Study Binder

You don’t want an auditor to view any information from another study. Therefore, ensure that your study documentation only includes information about that study. You don’t want to include any budget or contract information in the regulatory documentation. Keep this information in a separate file or location. Do not include any previous audit reports in the regulatory documentation. If the study is audited, you don’t want to provide clues to any potential issues.

 

Creating a Memo-to-the-File (aka Note-to-the-File)

When a document is located apart from the regulatory binder or file, you want to reference its location using a Memo-to-the-File. In addition, use a Memo-to-the-File to clarify missing or inaccurate data or procedures. Include the protocol number, title, date of the memo, and signature of the person completing the memo. Indicate the document that is not located where expected, where to find the document, and how to access it, if necessary. In general, the tone of the memo should be forward-looking and not seek to explain an error discovered in the conduct of a clinical research study.

 

Making Corrections to Documentation

To make a correction to documentation, make a single line through the error, write the new content; then, initial and date the correction. Provide an explanation if necessary. Do not obliterate an incorrect entry, use correction fluid, or erase an entry to study documentation. The person who created the original entry or another authorized person should make the correction. Do not alter past-dated notes, chart notes or progress notes by writing alongside or adding to prior entries.  Rather, create a new chart or progress note with the correct information.  Sign or initial and date a late entry in the present time.

Duke Policies and Guidance

Hematocrit Reference Ranges at Duke University Health System (8-8-2016)

Policy Statement Regarding Corrective Actions Declared by the DUSOM Conflict of Interest Committee (IRB, 7-25-2014)

Permissible Research-Related Activities Prior to IRB and Institutional Approvals (IRB, 3-14-2014)

Responsibilities of an Investigator Who Is Also a Sponsor (IRB, 6-8-2011)

You can find additional policies and guidance on the Duke University School of Medicine Institutional Review Board webpage.

 

Some pages and documents are located behind the Duke firewall and require a username and password to access. If you are a Duke employee or affiliate and are unable to access the information, please contact DOCR.Help@dm.duke.edu for assistance.

Training and Job Aids

Duke Reference Data - This ORA-sponsored website provides information such as Duke University tax ID status and Federalwide Assurance Number to assist with the preparation and management of sponsored research applications and awards.

Study Documentation: Regulations and Best Practices (DOCR) - This course outlines the required components of study documentation for all clinical research, defines standard documentation terminology, and applies knowledge of documentation best practices to everyday scenarios faced by study teams.

Partner Resources

The Office of Audit, Risk and Compliance (OARC) provides all institutional ethics and compliance services. OARC handles ethics and compliance monitoring, clinical trials quality assurance and compliance review services.

Frequently Asked Questions

Question: Should a Research Coordinator be listed in Section #6 on the 1572?

Answer: According to the Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs regarding the Statement of Investigator (Form FDA 1572), listing the Research Coordinator depends on the contribution that the individual makes to the study. However, it goes on to read: Generally, a research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572.

Question: Should Co-investigators be listed on the 1572 in Section #1?  Is it acceptable to have more than one investigator at a single site?

Answer: It is acceptable to have more than one investigator at a single site, however, as commonly used, the term co-investigator indicates an individual fully responsible for fulfilling all of the obligations of an investigator as described in 21 CFR 312.60.  If this is the case, each co-investigator must sign a separate 1572.

Question: Does the CV or other statement of qualifications need to be updated during a clinical study

Answer: No.

Question: Are CVs required to be signed and dated?

Answer: No. However, it is best practice to have them signed and dated.

Question: If an investigator sees study subjects at more than one site, should the investigator list all sites on the 1572.

Answer: Yes.

Question: Should research nurses, other nurses, residents, fellows, office staff, or other hospital staff be listed in Section #6?

Answer: Hospital staff, including nurses, residents, or fellows and office staff who provide ancillary or intermittent care but who do not make a direct and significant contribution to the clinical data, do not need to be listed individually.  Additionally, specific names of rotational staff who might perform specified protocol procedures or collect clinical data do not have to be listed in Section #6, rather, the names of rotational individuals and the procedures they are expected to perform should be included in the clinical study records.

Question: Should pharmacists or research coordinators be listed in Section #6?

Answer: This is a matter of judgment dependent upon the contribution the individual makes to the study.  If the individual makes a direct and significant contribution to the data for a particular study, then they would be listed in Section #6.  According to these criteria, Research Coordinators should usually be listed in Section #6.

Question: Is a statement of qualifications required for subinvestigators?

Answer: No.

Question: Do individuals who are listed in Section #6 on the 1572 have to submit information about their financial interests?

Answer: Yes.  A person listed as an investigator or subinvestigator who is directly involved in the treatment or evaluation of research subjects must submit financial disclosure information to the sponsor.  For the purposes of financial disclosure, the term investigator also includes the spouse and each dependent child of the investigator and subinvestigator.

 

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