1. Senior Research Compliance Auditor
Marina Tuzova
Senior Research Compliance Auditor
September 11, 2018
Marina Tuzova
Senior Research Compliance Auditor
September 11, 2018

2. Regulatory Binder

3. Learning Objectives: Attendees will be able to:
Identify what documents are found in a regulatory binder
Organize and save all IRB and regulatory documents preferably as hard copies

4. What is a regulatory binder?
GUESS WHAT?
IT IS A BINDER!!!!
Repository for all research study-related documentation
Generally there are 2 kinds of documents:
Study-specific (regulatory binder)
Subject-specific (subject’s chart)

5. Summary introduce the concept:

6. Purpose: Required by Federal regulations and the Institutional policy
The working concept of good clinical practice
Guidance for the investigator

7. Important concepts in a changing environment
Investigator responsibilities + Regulatory Binder = Consistency/Continuity/Uniformity
Regulatory compliance and Successful study management
Important concepts in a changing environment

8. Why use the regulatory binder?
Reason 1: when developing the protocol, the binder keeps things in order:
Research plan
Consent document
IRB application/submission
Amendments
IRB communications
Data collection tools

9. Reason 2:
When you inherit a study, the binder provides a snap-shot of the study:
Protocol/research plan
Study team info
Approved documents
Reports submitted
Records of events
Data collection tools
(no searching or guessing)

10. Reason 3: Leaves and retirements
Regulatory binders can be passed to the next person

11. Reason 4:
Q: if we have iRIS, why do we need to maintain hard copies of the same documents? A:
Program can crash or become inaccessible
Program changes can occur
Does not contain study-specific documents:
DOA logs
Training logs
Monitoring logs
Enrollment logs
Drug/device accountability logs
Tracking forms
Miscellaneous documents
No access to the Protocol or other not-shared documents for the new staff

12. Binder guidance: Set it up ate the start of the study
Keep it current and up-to-date
File current documents on the top
Store in secure location (accessible for the study staff)
Customize it for the needs of your study

13. Quotation:
“If everyone is moving forward together, then success takes care of itself” ~Henry Ford

14. To make it clear one more time:
The regulatory binder serves to demonstrate that the research is being conducted according to accepted standards of research practice and applicable regulatory and institutional requirements.

15. Regulatory Binder Sections
All Studies
Study Specific
Licensure
Investigator Brochure/ Device Manual/ Package Insert
Laboratory Documentation
Drug/Device
NIH
Sponsor
DSMB
External/Local Ethical Review
Protocol
CVs for all study staff
Logs
IRB Documentation
Consent and Recruitment Materials
Data Collection Materials
Training
Data Protection

16. Essential Documents (all studies)
Section
Purpose
Considerations / Recommendations
Protocol
Describes the study aims, research design, research site(s), plus all study-related activities and procedures.
Ensure that the version number/date reflects the current, approved Research Protocol approved by the IRB.
CVs and licensures
Documents the qualifications and expertise of study staff to perform delegated tasks.
CVs and licenses
Maintain licensure for staff conducting clinical study- related procedures

17. Protocol Original Protocol and all amended versions
Requirements
Guidance
Original Protocol and all amended versions
All versions should contain a version date and/or number
Federal Regulations/Good Clinical Practice
GCP: 8.2.2; 8.3.2

18. CVs CVs for all study staff Requirements Guidance
If CVs are filed collectively for the department, write a signed and dated note-to file indicating the location
Federal Regulations/Good Clinical Practice
GCP: 4.1.1; ; 8.3.5

19. Licensure
Requirements
Guidance
Professional certification information should be included in individual CVs. The frequency with which certification must be renewed varies widely, depending on the requirements of the certifying body.
Valid licenses/certification for all professional study staff (e.g., medical or nursing license)
Current professional certification, as indicated
Federal Regulations/Good Clinical Practice
GCP: 4.1.1

20. Essential Documents (all studies)
Section
Purpose
Considerations / Recommendations
Logs
Assists with the collection of data that is required by or reported to the IRB or other regulatory authorities (e.g., Enrollment Log, Delegation of Responsibility Log, Sample collection log, Training log).
Information about log templates can be found here:
IRB Documentation
Demonstrates that the IRB has reviewed and approved the initial project and all modifications prior to the initiation of study procedures. Confirms that continuing review has been performed (as applicable) and that reportable new information has been communicated to the IRB.
Print the documents from iRIS and include the hard copies into your binder.

21. Logs Requirements Guidance
Check all that are included:
Pre-Screening Log
Enrollment Log
Staff Signature Log
Delegation of Responsibility Log
Monitoring Log*
Adverse Event Tracking Log
Protocol Deviation/Exception Tracking Log
Retained Tissue Log
Training Log
*Required for FDA-regulated protocols
Update logs in a timely manner. To ensure accuracy, logs should be updated as soon as possible after a recordable event occurs, preferable on the same day.

22. IRB documentation Requirements Guidance
A.Copies of signed and dated submissions:
Initial Application for Human Research
Continuing Review(s)
Modifications/Amendments
Reportable New Information
Adverse Events
Protocol Violations
Unanticipated Problems
B.Original Approval letters and/or notification of IRB decisions
C.Copy of investigator response to IRB notification (if applicable)
D.Approved/validated recruitment materials
E.Approved/validated additional study information distributed to participants
F.Any foreign language materials (if applicable)
G.Print out of Institution’s FWA Information from OHRP website
H.IRB Membership Roster*
I.Any additional correspondence related to the study (e.g. s)
*Required for FDA-regulated protocols
Approved/validated recruitment materials and additional study information distributed to participants should include version dates and/or numbers.
File documents in reverse chronological order.

23. Essential Documents (all studies)
Section
Purpose
Considerations / Recommendations
Informed Consent &
Recruitment Material
Documents that information given to participants supports their ability to give voluntary informed consent.
Ensure that the most recently approved consent form and recruitment documents are used in the field.
The most recently approved consent form and recruitment documents can always be accessed in iRIS.
Data Collection
Maintains original copies of all forms used to collect study data (e.g., case report forms, questionnaires, surveys).
Only blank copies of forms should be kept in the Regulatory Binder.

24. Consent Forms Federal Regulations/Good Clinical Practice
Requirements
Guidance
Original copies of all IRB approved versions (evident by the IRB approval/validation stamp) with version dates or numbers
Copies of foreign language consent materials, if applicable
Federal Regulations/Good Clinical Practice
HHS: 45 CFR 46
FDA: 21 CFR 50; 21 CFR 56
GCP: 8.2.3; 8.3.2;

25. Data collection
Requirements
Guidance
Blank set of case report forms (CRFs), data collection sheets, and/or study questionnaires
The difference between data collection sheets and case report forms is that data collection sheets typically act as source documentation. That is, during study visits, information is written directly onto the worksheets. An industry sponsor usually provides CRFs; all protocol-required information is transferred to CRFs from data collection sheets. Some studies do not use CRFs. All studies should use some type of data collection sheet.
Federal Regulations/Good Clinical Practice
FDA: 21 CFR ;
GCP: ; ; 4.9.3

26. Essential Documents (all studies)
Section
Purpose
Considerations / Recommendations
Investigator’s brochure/Device Manual/Package Insert
To provide the investigators with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures.
These documents are a part of your study application. Have to be printed as hard copies.
Laboratory documents
CLIA requires all facilities that perform even one test, including waived tests, on “materials derived from the human body for the purposes of providing information for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of, human beings” to obtain a CLIA certificate and meet CLIA regulatory requirements.
In most cases, research testing where patient-specific results are reported from the laboratory, and those results will be or could be used “for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of, human beings” are presumed to be subject to CLIA absent evidence to the contrary.

27. Investigator’s Brochure/Device Manual/Package Insert
Requirements
Guidance
Most recent version of investigator brochure or product information, e.g., package insert or sample label (for investigational drugs)
Device Manual or Report of Prior Investigations (for investigational devices)
Send updated versions to the IRB.
If the investigational product is marketed and its pharmacology is widely understood, a basic product information brochure or package insert may be an appropriate alternative.
Federal Regulations/Good Clinical Practice
FDA: 21 CFR
GCP: 8.2.1; 8.3.1

28. Laboratory Documents Requirements Guidance
Lab certification (e.g. CLIA, CAP) and updates
Lab Director’s CV
Handling Instructions (if not specified in Investigator’s Brochure, Device Manual, or Package Insert)
Normal lab/reference values and updates
Keep updated documents to exhibit the competency of all lab facilities being utilized, and to support the reliability of test results.
If lab documentation is filed separately, write a signed and dated note to file indicating the location.
Research labs typically do not have lab certifications, e.g., CLIA, CAP, and may not have “normal” lab values. If research labs are used, ensure that the lab director’s CV and research lab references values are on file.
Federal Regulations/Good Clinical Practice
GCP: ; ; ; 8.3.6; 8.3.7

29. Essential Documents (all studies)
Section
Purpose
Considerations / Recommendations
Training
Documents adequate human subjects training as well as any other study-specific training for all IRB approved study personnel.
All study staff approved by the IRB must complete CITI human subjects training requirements every 3 years.
Additional institution, department, or study-specific training requirements and time frames may vary (e.g., data security, laboratory safety, IATA).
Data Protection
Maintains documentation of data protection procedures not included in the Research Protocol, as well as specific records that may not be included.
For all documents maintained in e-records, include a signed and dated note-to-file in the Regulatory Binder detailing the location of the documentation (shared drive).

30. Training Requirements Guidance Human research training
Additional training certification of study staff, e.g., phlebotomy, vital signs, etc.)
Sponsor training (e.g. study initiation visits, use of device, GCP)
Institution specific training

31. Data Protection Recommended contents Guidance
Data Collection/Use Plan (if not in the IRB approved protocol)
Data Storage Plan (if not in the IRB approved protocol)
Data Transfer/Sharing Plan (if not in the IRB approved protocol)
Data Management Plan (if not in the IRB approved protocol)
Protection and security of research data
Risk Management, which includes data breach and response
Data Retention/Return and/or Destruction Plan
Data Use Agreements or other agreements/contracts pertaining to data sharing with external collaborators, vendors, and/or 3rd party business associates (signed and dated by all parties)
Documentation of Authorization to use protected health information for research purposes (in informed consent form or stand alone authorization)
Waiver of HIPAA Authorization (if applicable)
Investigators must follow their institution’s policies and procedures.
Federal and State Regulations
OCR: HIPAA Privacy Rule and Security Rule (as amended):
HHS: 45 CFR 160, 162 and 164 (Subparts A and C)
FDA: FDA: 21 CFR, Part 11

32. FDA Requirements Guidance
Clinical Investigator:
Copy of all versions of the Form FDA 1572 (for investigational drugs)
Copy of all versions of Investigator Agreement (for investigational devices)
Copy of all Safety Reports submitted to the FDA
Financial Disclosure:
Signed and dated copy of all Form FDA 3455 (Disclosure: Financial Interests and arrangements of Clinical Investigators)
Sponsor-Investigator:
Copy of all Form FDA 1571 submitted to the FDA (for investigational drugs only), Initial IND/IDE or Application
Amendments/Supplements to the application
Safety Reports
Annual Progress Reports
Form 3674, certification of registration to ClinicalTrials.gov (
The Form FDA 1571 should be used as the cover sheet for all correspondence sent to the FDA (sponsor-investigator)
Instructions for completing The Form FDA 1572 can be found at: (drug/device studies, mostly sponsored)
Update the 1572 each time there is a change to any of the information originally provided. Notify the Sponsor of updates.
Federal Regulations/Good Clinical Practice
FDA: 21 CFR 54; ; ; ; (b)(1); (b)(5); ; (c)
GCP: 4.11; ; ; ; ; ;

33. NIH Copy of the NIH grant application and progress reports
Requirements
Guidance
Copy of the NIH grant application and progress reports
Submit a copy of the most recent progress report as specified by your IRB.
Any additional study correspondence (e.g. s) with the NIH and Collaborators.

34. Sponsor Requirements Guidance
All correspondence to and from the sponsor (e.g. letters, meeting notes, and notes of telephone calls)
Signed Agreements, including Financial Agreements
Insurance Statement (when required)

35. DSMB Federal Regulations/Good Clinical Practice GCP: 8.3.10; 5.19.3
Requirements
Guidance
If your study has a DSMB, submit a copy of the most recent DSMB report to the IRB at the time of continuing review
Any additional correspondence (e.g. s, letters, meeting minutes) with the DSMB and its members
Copy of all documentation for data safety monitoring plan as outlined in the IRB approved protocol
Copy of all DSMB reports
Copy of all monitoring reports
Federal Regulations/Good Clinical Practice
GCP: ;

36. Single IRB and Multi-site Research
9/10/2019
Single IRB and Multi-site Research
Include all institutional determinations and reliance agreements (SmartIRB or IRB Authorization Agreement and Institutional acknowledgments) in an External/Local Ethical Review file
Regulatory documentation should reflect any reliance agreements
The Overseeing IRB’s researchers should document up to date training and activities for all study staff that fall under the reviewing IRB’s oversight.
Most reliance agreements allow for the reviewing institution to conduct an audit, for cause, of the ceding institution’s study documentation
Regulatory documentation should still be kept at each institution to at least maintain site specific information.
The protocol will determine how Participant Files should be maintained at each site.
For the study-specific guidance contact Stefanie Juell:
Stefanie Juell, MA, CIP
Associate Director, Education and Compliance

37. External IRB documentation
Requirements
Tips
External IRB documentation, including IRB submissions, IRB notifications, and significant correspondence between the IRB and investigator.
Documentation of an institution’s agreement to rely on another for IRB review, e.g., protocol-specific IRB Authorization Agreement, acknowledgement letter demonstrating cede review.
If documentation is maintained electronically, write a note-to-file indicating the location and who maintains them
If helpful, maintain links to applicable local, regional, and/or national regulation/guidance on file
To reduce the administrative burden of concurrent IRB review, consider an IRB Authorization Agreement whereby one institution relies on another for IRB review
Investigators must follow their institution’s policies and procedures. Contact your institution for additional guidance.

38. Tips for Successful Record Keeping
9/10/2019
Tips for Successful Record Keeping
Customize the Regulatory Binder to meet the specific criteria for your study
Maintain binders in a secure location (e.g., locked file cabinet)
Document and update materials in the Regulatory Binder in real time
File hard copy documents in reverse chronological order (most recent on top)

39. Tips for Successful Record Keeping
9/10/2019
Tips for Successful Record Keeping
Review documentation routinely
Using the Investigator Self-Audit tool as a guide when reviewing regulatory documentation (
Address and resolve documentation issues immediately upon discovery

40. Note-to-File A Note-to-File can reconcile many issues
9/10/2019
Note-to-File
A Note-to-File can reconcile many issues
When in doubt, write a note!
Use to explain apparent discrepancies
Use to identify location of files that are maintained outside of the Regulatory Binder Each note-to-file should include the study number, PI name, date, and the initials of the person writing the note-to-file

41. http://www. einstein. yu

42. The purpose of your regulatory binder should serve three-fold:
Summary: 1. PURPOSE
The purpose of your regulatory binder should serve three-fold:
Streamline work processes by compiling all study related documentation in one place
Allowing ease of access to most current documentation to all personnel with minimal effort
A tool for monitoring regulations and standards set by federal departments (FDA, HHS, OHRP), your sponsor (NIH), and local regulatory bodies (IRB)

43. Summary: 2. LAYOUT
Files should be customized to the demands of the study
Organization
Tabs and/or sub-tabs
Most frequently accessed documents should be in the front
Reverse chronological order
Clean copies of documents (may include marked copies as well)
IRB approval letters for each document

44. Summary: 3. Identifying Elements
Cover and Binding Label
IRB study number
Study title PI
Sponsor
Institution and location
Book number (if multiple books)
Title Page
IRB number and study title

45. Summary: 4. Administrative Documents
Regulatory File Checklist
Itemizes each element
Notates they are present in the binder
Notates dates when documents were changed
Additional comments
Memos
You may include memos in the reg. binder
Memos document missing items or changes in the organizational structure of the reg. binder

46. Summary: 5. Structure Protocol
All final IRB approved versions of the study protocol in reverse chronological order.
May include marked copies
Should include IRB approval letters (FALs)
Consent
MOST CURRENT APPROVED CONSENT SHOULD BE FIRST (recommend plastic cover)
Previous expired consents with IRB approval letter

47. Structure - cont IRB Correspondence
All informal correspondence with the IRB ( s, faxes, phone log)
Submissions/Continuing Review
Initial Submission
Study application, Protocol, Consent, study documents, FDA correspondence, etc.
NOTE: These documents are what you submit to the IRB. After approval, place an approved copy in the appropriate sections (include the IRB Outcome Letter)
Continuing review applications

48. Structure - cont Amendments Reverse chronological order
Each amendment should be sub-tabed with a title page (recommend colored paper)
Amendment number
IRB Study No. / Title
Submitter’s name or initials
Date submitted
Date approved
Documents included / summary of changes
Clean copies of submitted documents (may include marked)
Approval letter on top. Again, approval letters for consents should be filed with the consent forms.

49. Structure - cont Adverse Events Protocol Deviations
Key Study Personnel
Research study signatory log
Notates all study personnel and their dates of involvement in the project
CVs of all current key study personnel
Documentation of trainings, formal and informal (IATA, Lab safety, phlebotomy)

50. Structure - cont Case Report Form (CRF) Data management tool
Purpose is to streamline data entry process
Snapshot of all participant data (identified or de-identified) that goes into your database
Participant code number, age, gender, educational level, height, weight, BP, questionnaire scores, etc.
A blank CRF template is filed in the binder
CRF Appendix
All questionnaires or forms the participant actually completes (if any).

51. Structure - cont Laboratory Certificate of accreditation
CV of laboratory director
Copy of normal ranges or criteria for classifying samples
Banking log of samples
Advertising / Recruitment
Screening log with de-identified information
Enrollment log
Approved IRB ads or language

52. Structure - cont Standard Operating Procedures (SOP)
Detailed instructions of work flow
Someone should be able to come into your lab and run your study from the SOP
Examples of elements in an SOP
Phone script for screening, directions to the DNA Core Lab and how to bank samples, Instructions on data entry and questionnaire scoring, etc.
Ensures consistency between personnel changes
Not required, but an example of a best practice policy

53. Structure - cont Sponsor
All correspondence with the sponsor (formal and informal)
Copy of the grant
Other sponsor related documents
Misc
Catch-all tab for things you are not quite sure what to do with

54. Conclusion
Regulatory binder is a tool that should fit the demands of the study and expectations set by regulating bodies
Organized in a reversed order fashion with most recent items in the front
Should be in a central location where all approved personnel may access the documents
Updated on a regular basis

55. Resources
Einstein IRB Website Resources Montefiore-Einstein Research Compliance
Required Documentation Checklist - Regulatory Binder*
FDA.gov
HHS.gov *