Stanford University Office of the Dean of Research
Human Research Protection Program (HRPP)
DOMAIN II: RESEARCH COMPLIANCE OFFICE, INCLUDING IRBs
Chapter 8: Documentation of IRB Activities
The IRBs maintain documentation of their activities. (AAHRPP Standard II-3) Their records include IRB protocol files, minutes for convened IRB meetings, and other documentation.
The Research Compliance Office (RCO) maintains a complete set of materials relevant to the review of each research study, for all research proposals that are reviewed. (AAHRPP Element II.3.A)
Content of Protocol File
Each individual protocol file contains some or all of the following materials, as relevant to the review and applicable to the specific research study:
1. The New Protocol Application Forms Regular Medical and Non-medical Research (Documents F.1.a. and F.1.b.), the Protocol for Human Subjects Investigation Using Biological Agents or Recombinant DNA Vectors (Document F.1.c.), or the Exempt Protocol Application Forms for medical and non-medical research (Documents F.1.e. and F.1.f.). The New Protocol Application Forms include the complete research or investigational plan and are designed to address all relevant regulatory requirements. IRB staff use the Protocol Checklist (Document D.2.f.iii.) to assure that all relevant topics are covered. The RCO application forms are updated as needed. Since the application forms are updated as regulations change, older versions of the forms should not be used if there is a newer version available. The Exempt Protocol Application Forms are shorter and are designed to elicit the answers needed to ascertain exemption from full IRB review.
2. The IRB-approved informed consent document(s) The most current approved consent form(s) is identified with the date at which the consent(s) was approved on the first page or in the header of the consent form. The approval and expiration dates are also found on the last page of the consent form. Previously approved consent forms or consent forms which are not approved are also maintained in the protocol files, with a red line across the first page of the document (red-lined documents) to indicate that changes have been made which render the form out-dated. Sample consent templates are DHHS-compliant with 45 CFR Part 46 and 21 CFR Parts 50 and 56. When there is a sample DHHS consent form, this document will also be included in the protocol file. (Documents F.3.e.-i. and F.3.l.-o.).
3. The IRB-approved Assent form(s). Children less than 18 years of age must assent to studies when the IRBs judge the children to be capable of assenting. If children between the ages of 7 and 17 are participating in a study, the protocol includes one or more assent forms with a signature line for the child to sign his/her name if, in the opinion of the IRB, a signature of the child is appropriate. Assent forms must be age-appropriate.
4. Scientific evaluations of the proposed research. Scientific review of research studies as described in Chapter 1.5 is performed by different units at STANFORD and are part of the protocol file when provided by the Protocol Director (PD). Some groups which perform scientific review include the Scientific Review Committee of the Comprehensive Cancer Research Center (Document C.5.d.iii.), the General Clinical Research Center (GCRC) (Document C.3.a.iv.), the VAPAHCS Research and Development Committee (Document B.5.n.), and Department Chairs and Division Chiefs when studies are not part of an externally sponsored project. Scientific reviews are done either prior to or concurrently with IRB review.
5. Sponsor Materials. For drug studies, the Investigator’s Brochure and Sponsor’s Protocol, including current amended editions of these documents and all previous versions are filed in the protocol files.
For devices, a report of prior investigations and Sponsor’s Protocol are filed.
6. Application for federal grant support with description of the proposal as submitted for funding. All federal grant proposals are filed in the protocol files. If the federal funding is subcontracted through another institution, the sub-contract with that institution which describes Stanford’s role in the research is documented in the protocol file.
7. Advertisements, phone screening scripts and non-medical oral scripts, flyers, website or other subject recruitment materials.
8. Questionnaires, surveys, interview scripts, diaries or other documents used in the course of the study.
9. Participant informational sheets, brochures and sponsor newsletters.
10. Revision Applications for protocol amendments or modifications for medical and non-medical review. (Documents F.1.g.-i.).
11. Continuing review progress reports and related information, including annual Renewal Notices (Document F.2.a.), Renewal Questions (Documents F.2.b. and F.2.c.), and Continuing Review Checklist for IRB Staff and Members (Document F.5.l.).
12. Reports of unanticipated problems involving risks to subjects or others or reports of injuries to participants through the IRB Report Forms. (Documents F.2.f. and F.2.g.). The Report Form is also used as a cover document to items 12 through 17 as noted below.
13. Reports of unexpected adverse events occurring at STANFORD (or involving employees or agents of STANFORD) and reported to any regulatory agency.
15. Reports of protocol violations or deviations from the approved research plan.
16. Reports of external adverse events received from investigators through sponsors or cooperative groups.
17. Allegations of non-compliance and their review.
18. Data and Safety Monitoring Board (DSMB) reports.
19. Conflict of Interest documents when conflict of interest is applicable. These documents include a copy of the IRB Conflict of Interest email (Document D.2.c.ii.C.) sent to the PD along with the IRB Conflict of Interest Checklist (Document D.2.c.ii.B.). The Conflict of Interest Review Program Action Report Form to the IRB (Document D.2.c.ii.D.) is also included in the protocol file when received from the Conflict of Interest Committee.
20. Memoranda containing comments and questions from the IRB reviewers and administrative staff to the research investigators, and responses to comments from the research investigators to the IRB members and administrative staff. Comments and responses may also be in the form of faxed or emailed materials. (Documents D.2.f.xi. for Comments and Responses Sample (eProtocol), D.2.f.xii. for Comments and Responses Sample (paper), and F.5.f. for Comment Codes.)
21. Results of any internal quality control and monitoring activities, including routine informed consent audits forms (Document D.3.f.iv.) and protocol audit forms (D.3.f.iii.).
22. Results of any external monitoring activities, including reviews provided to the investigator by sponsors, cooperative groups, or federal agencies.
23. All IRB correspondence to or from its members and investigators.
24. All other IRB correspondence related to the research.
25. Documentation of the type of review as noted on the Review Sheets (Document F.5.a.) for all events. Type of review is also documented on the Agenda List (Electronic Section E.1.) of the IRB meeting materials.
26. Documentation of all IRB reviews including initial and continuing IRB review, reports or revisions to the protocol, as found on the Review Sheet (Document F.5.a.). This information is also documented on the Agenda List (Electronic Section E.1.) of the IRB meeting.
27. Documentation of all actions including approvals (Documents F.5.e.i.-v.), disapprovals (Document F.5.h), waivers or alterations of consents and HIPAA authorizations (as documented in the New Protocol Application Forms, the Revision Application, Renewal Questions Form and Comment Codes, expirations (Document D.3.b.vi.B.), determinations of unanticipated problems and of serious or continuing non-compliance, and suspensions or terminations.
28. Documentation of protocol closeout if any, including Final Report forms for regular protocols (Document F.2.i.). Final Report Forms are not required for Expedited protocols or non-medical protocols.
29. Statements of significant new findings identified during the research that could relate to the willingness of the subject to continue to participate elicited during continuing review or revision of the protocol and as added to the consent form.
30. Verification from sources other than the investigator that no material changes are made in the research (e.g., Cooperative Studies, or other collaborative research monitoring reports) are added to the protocol file when provided.
31. Expiration notice (Document D.3.b.vi.B.) for protocols that do not complete the continuing review process, or do not complete the renewal process before the scheduled expiration date.
32. IRB approvals from collaborating institutions, if collaborating institutions are involved in the study, are requested and included in the research file. IRB approval notices are requested from collaborating institutions when STANFORD is the coordinating center for a multi-site study, or when data is being received at STANFORD. If the study is a multi-site study, with STANFORD as one of several participants, no other IRB approval is gathered or included from other participating sites.
33. Various checklists completed as part of the review of the protocol including the Protocol Checklist (Document D.2.f.iii.), Presenter Checklist with accompanying Special Worksheets for Children, Pregnant Women and Fetuses, Neonates and VA Studies (Document F.5.b.i.-iv.), Informed Consent Checklist (Document F.3.a.), Intake Checklist(Document D.3.a.ii.), Exemption Eligibility Checklist (Document D.2.f.i.), Expedited Eligibility Checklist (Document D.2.f.ii.), Protocol Audit Checklist (Document D.3.f.iii.), Informed Consent Audit Checklist (Document D.3.f.iv.), and Continuing Review Checklist for IRB Staff and Members (Document F.5.l.).
Organization of Records for a Protocol File
1. Each medical protocol file is organized to allow a reconstruction of a complete history of all IRB actions related to the review and approval of the protocol.
a. Each protocol file is labeled with the name of the PD, the name of the research study and the protocol identification number. If the file consists of multiple file folders, the files are numbered in sequential order, with the most recent information in the latest files. For ease of retrieval, files are color-coded with colored dots which correspond to the color of the specific IRB (Document D.3.b.iii.J.). VAPAHCS protocols are color coded with a light blue dot in addition to the IRB color.
b. Files which are too large for a single file folder are put into numbered file folders, with the oldest Master event packets in File 1, newer event packets in File 2, and so on. The last file folder contains the most recent Master event packet(s) and the back-up packet.
c. The Protocol Master File
i. The protocol “Master” file is divided into “event” packets. Each event packet represents an episode of IRB review and action. Each protocol file begins with a “New” event packet when the protocol is first reviewed and approved. Additional event packets are added throughout the history of the protocol as applicable to the specific protocol file. Event packets might consist of continuing review (renewals), reports of unanticipated problems or revisions to the protocol or consent forms, and final reports or combinations of these types of review.
ii. When “actions” are combined, there is a prescribed order to the event. If a revision is combined with a report, the event is labeled a revision. If a revision or report is combined with a renewal, the event is labeled a renewal. Reports might also be combined with a New event or Final Report event, in which case the New or Final Report event takes precedence.
iii. Each event packet in the file is marked by a red “IRB APPROVED” date-stamp, the date corresponding to the date at which the action was taken and the event was approved. The stamp is placed in the lower right-hand corner of the application. (An older version of the “date stamp” is represented by the date of the convened meeting inked in red pen in the same position.) Documents within the approved packet are approved unless they are “red-lined” (marked with a diagonal red line across the face of the document) which indicates a non-approved document, or a document which is no longer current and may not be used.
iv. The history of the protocol can be reconstructed by reviewing the event packets in chronological order, from most recent to oldest.
v. The order of the documents in each master packet is detailed in Documents D.3.c.i.-v.
d. The Back-up File
i. Each protocol file also contains a condensed form of the Master file event packets in the form of a “back-up” packet. The back-up packet is a tool for the use of the IRB reviewer, and contains the application forms, and all other pertinent information regarding approved modifications and amendments to the protocol, to allow the reviewer access to the history of the protocol at the time of review.
ii. At a minimum, the back-up packet contains a copy of the New Protocol Application Form, any forms related to past revision and renewal events such as sponsor protocol and investigator brochures, any questionnaires, phone scripts, advertisements for recruitment, report forms for unanticipated problems occurring at this institution, comments to the investigator and responses of the investigator to the IRB reviewer, and any checklists, laminated sheets or presenter guidelines.
iii. The back-up file does not contain out-dated consent forms because the reviewer’s packet currently under review would contain the most recent consent form. Only the most recent copies of the sponsor protocols or investigator’s brochures are included in the back-up packet.
iv. The back-up packet is sent to the reviewer each time a new event is reviewed, and each new event becomes part of the back-up packet for the following event. Each “event” within the back-up packet is indicated by the date of the approval marked in pencil on the lower right hand corner of the application.
v. The order of the documents in the back-up packet is detailed in the Document D.3.c.v.
vi. If the back-up file becomes too large to include in a single file, a separate back-up file is created and marked as a back-up file only. When this occurs, the back-up files are also numbered sequentially, from the earliest to the latest. When the back-up file becomes prohibitively large to send the complete back-up to the reviewer, the last several events and a copy of the initial protocol are sent. The reviewer is informed that the back-up is incomplete, and that he/she should request any information needed to complete the review.
2. The non-medical protocol file is organized somewhat differently than the medical protocol file. Since most of the non-medical studies are completed within the IRB approved year and do not require continuing review, the non-medical protocol file does not routinely contain a back-up file or a stamped approval date. The most recent approval letter is always placed on the top of the event packet. If a non-medical study requires renewal, a back-up file is created. The event packet is arranged in a different order than that required for medical studies, with the approval letter on top, followed by the protocol application, informed consent form(s), consent form checklist, comments and responses, faculty sponsor letter or email, and a signed review sheet.
Protocol Tracking System
The RCO ensures the maintenance of a reliable, electronic research protocol tracking and database system. (See document D.3.b.iii.B. for database screenshots.) The database contains a search function which allows routine identification of a study by protocol number, IRB number, month of review, protocol name or key words contained in the title, internal funding number, type of protocol, name of Protocol Director (PD), names of co-investigators or any combination of the above categories. The database includes the following information:
1. Title of the Research Study
2. Names of Principal Investigator (PI)/PD and co-investigators where appropriate
3. Name of VAPAHCS investigator if applicable
4. Contact information for PD and for his/her administrative contact
5. Brief summary of the purpose of the research study
6. Location where the study will take place
7. Identification of any vulnerable subjects
8. Identification of special concerns, for example, use of DNA, gene transfer, stem cells, radiation, oncology, use of blood or biohazard materials
9. Funding source(s) (if any)
10. Date of initial approval (once a protocol is approved)
11. Date of most recent approval of reports or revisions
12. Date of most recent continuing review and approval
13. Date of protocol expiration
14. Type of review (expedited (including paragraph citation), convened review (regular) or exempt (including paragraph citation))
15. Current status (under review, approved, withdrawn, closed, expired)
16. Investigational drug name and IND number
17. Investigational device and IDE number
18. Device risk level: significant or non-significant
19. Number of subjects enrolled at time of last continuing review.
20. Problems or complications identified upon continuing review.
21. Children Findings by section number (§46.404, §46.405, §46.406, §46.407)
22. Other findings, e.g. Waiver or Alteration of Consent
23. HIPAA instruments, e.g. HIPAA Authorization, Waivers of HIPAA Authorization and Certification of De-identification.
The eProtocol system contains the entire protocol application, all consent forms, and all attached documents, as well as the information in the database tracking system as listed above.
Documentation of Regular Protocol Reviews
Regular protocol IRB review procedures are described in Chapter 7. Documentation for regular initial and continuing review and approval includes the primary reviewers’ questions and comments (Document D.2.f.xii.) in the research application file, and the IRB presentation, discussion, deliberation, and determinations required by the regulations. Protocol specific findings supporting those determinations are documented in the minutes (Electronic Section E.1.) for each study’s initial and continuing review, along with the length of approval, and vote in the minutes of the convened IRB meeting in which the research project is formally reviewed. The following documents are found in the protocol file:
· The New Protocol Application Regular Medical or Nonmedical (Documents F.1.a.-b.), or the Protocol for Human Subjects Investigation Using Biological Agents for Recombinant DNA Vectors, and the Renewal Questions Medical or Nonmedical (Documents F.2.b.-c.), and Continuing Review Checklist for IRB Staff and Members (Document F.5.l.), when applicable.
· Informed Consent checklist completed by the IRB manager and reviewed for completeness and correctness by the reviewer(s). This document is also part of the “blues” (IRB glossary, Document D.3.a.vii.) placed before each voting member of the IRB at the convened meeting.
· Staff and IRB member reviewers' questions and comments to the research investigator in the research application file. The questions and comments may take the form of email or faxed correspondence.
· Research investigator’s responses to the reviewer’s questions and comments. The responses usually take the form of email or faxed correspondence. Revised consent forms or other documents often accompany the investigator responses and are considered part of the investigator response.
· Review sheets (Document F.5.a.) which contain the reviewer(s) initialed and dated recommendation for approval. The review sheets are sent out with each review packet. The presenting reviewer’s review sheet is highlighted in pink (type of review, reviewer’s name and number of review cycle), and the second (non-presenting) reviewer’s sheet is highlighted in yellow (type of review, reviewer’s name and number of review cycle). In addition there is a master review sheet which notes type of review, all reviewers, with the appropriate reviewer name highlighted in pink or yellow. This review sheet stays in the protocol research file. On the master sheet, if the reviewer recommends the study for approval, a red “+” (plus) sign is entered next to his/her name. If the reviewer has comments and does not recommend the study for approval, a red “-“ (minus) sign is entered in the space next to the reviewer’s name.
The reviewers’ packets might be sent out several times with additional or revised information and documents, until the reviewer sees fit to recommend approval of the protocol. A protocol is maintained on a list of protocols to go to a convened meeting for review, presentation, discussion and voting when all reviewers have recommended the study for approval and the final marks are entered as “+” next to the name of each reviewer on the master review sheet.
· Approval letter (Document F.5.e.) for each approved event. It is possible to have more than one approval letter per protocol event, as a separate approval letter is created for each separate organization or “funder” which funds the study. The approval letter also specifies the expiration date for the specific protocol and the need for continuing review if the protocol is to continue past the expiration date.
· Documentation of regular review is found in the Meeting Agenda, Agenda List, Minutes List and Minutes of the convened meeting (see Electronic section E.1. for copies of all these documents for all IRBs for May, June, and July, 2005). These documents are discussed under the chapter subheading of IRB Minutes in Chapter 8.3.
· Documentation of the level of risk of the proposed research is addressed in the New Protocol Application Forms in Section 8(b), along with the reason for the level chosen and planned protections to be put in place to reduce the level of risk. Documentation of the level of risk (minimal) is also addressed in the Expedited and Exempt Eligibility Checklists (Documents D.2.f.i. and ii.) completed when each expedited and exempt protocol is new.
Documentation of Expedited Protocol Reviews
Expedited IRB review procedures are described in Chapter 7. Documentation for Expedited initial and continuing review and approval includes the reviewer(s)’s questions and comments in the research application file, the specific permissible category as recorded on the Expedited Eligibility Checklist (Document D.2.f.ii.), the protocol-specific circumstances that justify using the determined category for expedited procedures, determinations required by the regulations along with the protocol-specific findings justifying those determinations and the reviewer(s)’s recommendation for approval. The following documents are found in the protocol file:
· The New Protocol Application Regular [or Expedited] Medical or Nonmedical (Documents F.1.a.-b.), or the Renewal Questions Medical or Nonmedical (Documents F.2.b.-c.), and Continuing Review Checklist for IRB Staff and Members (Document F.5.l.), when applicable.
· Expedited Eligibility Checklist completed by the IRB manager and reviewed for completeness and correctness by the IRB reviewer. Documentation of the level of risk of the proposed research is addressed in the Expedited Eligibility Checklist and in Section 8(b) of the New Protocol Application Forms, along with the reason for the level chosen and planned protections to be put in place to reduce the level of risk.
· Informed Consent checklist completed by the IRB manager and reviewed for completeness and correctness by the reviewer(s), if applicable.
· Staff and Reviewers' questions and comments to the research investigator in the research application file. The questions and comments may take the form of email or faxed correspondence.
· Research investigator’s responses (Documents D.2.f.xi. and D.2.f.xii.) to the reviewer’s questions and comments. The responses usually take the form of email, faxed or electronic correspondence.
· Review sheets which contain the reviewer(s) initialed and dated approval. The review sheets are sent out with each review packet. The reviewer’s review sheet is highlighted in yellow. In addition there is a master review sheet which notes the appropriate reviewer name highlighted in yellow. The master review sheet stays in the protocol research file. On the master sheet, if the reviewer recommends the study for approval, a red “+” (plus) sign is entered next to his/her name. If the reviewer does not recommend the study for approval, a red “-“ (minus) sign is entered in the space next to the reviewer’s name.
The reviewer’s packets might be sent out several times with additional or revised information and documents, until the reviewer sees fit to recommend the protocol for approval. A protocol is not approved until the reviewer has recommended the study for approval and a mark is entered as “+” next to the name of the reviewer on the master review sheet.
· Approval letter for each approved event. It is possible to have more than one approval letter per protocol event, as a separate letter is created for each separate organization or “funder” which funds the study. The approval letter also specifies the expiration date for the specific protocol and the need for continuing review if the protocol is to continue past the expiration date.
· Any findings required by DHHS and FDA regulations are documented by the inclusion of the appropriate laminated sheets in the reviewer’s packet (for example, the light blue laminated sheet regarding children findings from the FDA and the orange laminated sheet from OHRP, the gray laminated sheet regarding waivers of HIPAA Authorization (including a definition of PHI and a list of 18 HIPAA identifiers, the pink laminated sheet regarding research involving pregnant women, fetuses or neonates, and the blue Waiver or Alteration of Consent requirements and so on. Protocol-specific findings for making these determinations are required.
· Documentation of review is also found in the Meeting Agenda, Agenda List and Minutes List (See Electronic Section E.1 for copies of these documents for all IRBs for May, June, and July, 2005). These documents are discussed under the chapter subheading of IRB Minutes in Chapter 8.3.
The Expedited 8 review category is assigned to regular protocols undergoing continuing review as a result of responses to the following questions found on the Renewal Questions forms (Document F.2.b. and F.2.c.) and on the Expedited Eligibility Checklist (Document D.2.f.ii.).
Documentation for Expedited 8 review includes the following documents:
· The Renewal Notice (Document F.2.a.) form indicating that the research investigator wishes to renew the protocol
· The Renewal Questions form (Document F.2.b. and F.2.c.) answered in the manner described above
· A current consent form
· Reviewer’s questions and comments, as described above (Document D.2.f.xii. and D.2.f.xi.)
· Research investigators responses (Document D.2.f.xi. and D.2.f.xii.) to comments, as described above
· Review Sheets (Document F.5.a.) as described above
· Approval letter (Document F.5.e.)
· Expedited Eligibility Checklist (Document D.2.f.ii.)
· Documentation of review is also found in the Agenda List of the convened meeting for informational purposes (See electronic section E. for copies of the Agenda List for all IRBs for May, June and July, 2005).
Documentation of Research Exempt from Full IRB Review
Procedures for determining if research is exempt from full IRB review are described in Chapter 7. Documentation of verified exemptions consists of a voting reviewer’s written concurrence in the research application file and the specific category of exemption determined by the reviewer. The exempt protocol file contains the following documents:
· An Exempt Protocol Application for medical or non-medical studies (Document F.1.e. or F.1.f.)
· An Exemption Eligibility Checklist (Document D.2.f.i.) citing the protocol-specific regulation under which the protocol is considered exempt (The Exemption Eligibility Checklist is completed by IRB staff and is reviewed by the IRB member reviewer for correctness and concurrence.)
· Staff and Reviewer’s questions and comments, as described above (These comments often take the form of email correspondence.)
· Research investigators responses to comments, as described above (These responses often take the form of email correspondence.)
· A review sheet bearing the reviewer’s initialed concurrence that the exemption is warranted
· A Notice of Exempt Review (Document F.5.e.v.)
· Exempt protocols are noted in the Agenda list for the convened meeting for informational purposes (See Electronic Section E.1. for copies of the Agenda List for all IRBs for May, June, and July, 2005).
Exceptions from IRB Approval Requirements for Emergency Use of FDA Test Article
The emergency use of an investigational drug, device, or biologic under FDA regulations at 21 CFR 56.104(c) is described in Chapter 5. Documentation of the emergency use by a physician and of the satisfaction or lack of satisfaction of each condition for such use listed in Chapter 5 is required from the investigator.
Materials that must be submitted to the IRB within 5 working days by the physician include:
1. The first three pages of the New Protocol Application Form (Document F.1.d.) up to and including the Department Chair signature
2. Consent form, if applicable
3. PD Certification (Document F.2.e.i.)
4. Certification by Independent Physician (Document F.2.e.ii.)
5. Certification by IRB (Document F.2.e.iii.).
The IRB Chair (of one of the medical IRBs) or a designated physician member will review the PD’s Certification and other materials submitted. The Chair or member will verify that the conditions of 21 CFR 56.103(c) have been met, including the requirements for informed consent unless the conditions of 21 CFR 50.23(a)-(b) have been met, and document that through completion of the IRB Certification, which is placed in the IRB files. The emergency use is also entered on an Agenda List (See Electronic Section E.1. for copies of the Agenda List for all IRBs for May, June, and July, 2005.) that is circulated to all IRB members before the next meeting and again at the convened meeting for informational purposes. This record is used to monitor the emergency use of a specific test article to one time per organization. The investigator is required to submit an IRB protocol application for additional uses. This emergency use is recorded as “medical treatment” and not “research” in the IRB records.
Exceptions from Informed Consent Requirement in an Emergency Use of FDA Test Article
In the absence of informed consent in an emergency requiring the use of an investigational drug, device, or biologic under FDA regulations at 21 CFR 50.23, as described in Chapter 5, the following documentation is required and placed in the protocol file:
· Items 1-5 as listed above for Emergency Use of a Test Article
· Documentation of the absence of informed consent in an emergency by an investigator and of the satisfaction or lack of satisfaction of each of the following conditions:
a. The human subject is confronted by a life-threatening situation necessitating the use of the test article
b. Informed consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from the subject
c. Time is not sufficient to obtain consent from the subject’s legal representative
d. There is available no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject.
· The IRB Chair or designated IRB member will assess whether or not the above conditions have been met and document their findings through completion of an IRB Certification which is placed in the IRB files. The RCO will maintain this documentation in the IRB records.
Documentation of Other Special Circumstances
As described in Chapters 1.3, 5 and 7, other laws require IRB review of certain activities even when a human subject may not be a participant and the activity may not be research. This includes FDA regulations relating to humanitarian use devices (Document F.4.v.) and California law relating to stem cell research (Document C.5.e.iv.). For these endeavors, a New Protocol Application Form is required. Documentation of such activities by the involved physician and of the satisfaction or lack of satisfaction of each condition for such activity listed in Chapters 5 and 7 is required from the physician. The IRB Chair or designated IRB member will verify that the conditions have been met, document that through completion of a review sheet, and place the review sheet in the IRB files. The RCO will maintain this documentation in the IRB records.
The RCO retains required records for a period of time sufficient to meet federal, state, and local regulations, sponsor requirements, and organizational policies and procedures. (AAHRPP Element II.3.B.) In accordance with the Common Rule and FDA regulations, IRB records are retained for at least three years after the completion of the research with which they are associated. In accordance with federal HIPAA privacy regulations, IRB records pertaining to HIPAA (which contain PHI) are retained for at least six years after the completion of the research with which they are associated. When different periods of time are mandated, it is STANFORD policy to retain records for the greatest amount of mandated time. Thus, at the present time, no record is discarded prior to the six year period required by HIPAA. This policy applies to all research studies, whether or not subjects were enrolled. Sponsored grants and contracts may require additional periods for record retention.
For University policy for record retention, see the following web address at http://www.stanford.edu/dept/DoR/rph/2-10.html (Document A.3.h. (RPH 2.10.)).
If a study is cancelled without participant enrollment, the IRB maintains the protocol file for at least 3 full years after cancellation, although these studies are not handled separately from other research files, and in actuality can be held for a full six years after closure.
Records of VAPAHCS research are maintained for a minimum of five years after the completion of the study in accordance with the VAPAHCS Records Control Schedule (RCS 10-1). In actuality, the VAPAHCS records are also maintained for 6 years in order to comply with the longest mandated time.
Other documents, such as Agenda and Agenda Lists and Minutes and Minutes List for the current IRB year are maintained in the office of the IRB Manager. (See Electronic Section E.1. for copies of the Agenda List for all IRBs for May, June, and July, 2005.) After the current year, these documents are sent to an external vendor for long-term storage.
General correspondence from investigators and other documents that do not correspond to a particular research protocol are maintained indefinitely in the office of the Sr. IRB Manager.
Maintenance of and Access to IRB Records
Individual IRB Protocol files are maintained by the IRB managers and IRB associates. Operational guidelines for this maintenance are included in Documents D.3.c.i., D.3.c.ii., D.3.c.iii., and D.3.c.iv. Following each convened meeting, the file is re-ordered to add master event packets and additional information to the back-up packet, before the file is returned to the general departmental files.
All IRB records at the RCO are kept secure in closed filing cabinets in locked buildings with regular security patrols and alarms. When a protocol is completely closed out, a “protocol events” list (Document D.3.b.iii.B.) is used to verify the presence of all relevant documents. Then the materials are sent to an external vendor for long-term storage. Subsequent access to those materials can be obtained within 48 hours, or sooner, if necessary.
Access to IRB records is routinely provided to the Vice Provost and Dean of Research and Graduate Policy (Dean of Research), the Associate Dean of Research, IRB Chairs, IRB members, IRB staff, authorized VAPAHCS representatives (e.g., R&D Committee representatives) to carry out HRPP operations. Research investigators are provided reasonable access to files related to their own research.
All other STANFORD access to IRB records is limited to those who have legitimate work need for them, such as the Research Management Group (Document C.4.g.), Office of Technological Licensing (Document C.4.d.), Office of Sponsored Research (Document C.4.b.), or Internal Audit (Document C.3.c.). In addition, the RCO may allow access to IRB records by outside entities (e.g., monitors of sponsors of clinical trials) and agencies (e.g., regulatory agencies). The RCO will consider the IRB confidentiality policy and use its discretion and the reason for the request to determine whether to grant access. (The IRB confidentiality policy is found in the online Research Policy Handbook at http://www.stanford.edu/dept/DoR/rph/1-5.html) as well as in Document A.3.c.).
The IRBs document pertinent discussions and decisions on research studies and activities. (AAHRPP Element II.3.C) The minutes of the IRB meetings (See Electronic Section E.1. for copies of the Minutes for all IRBs for May, June, and July, 2005) are compiled by the Senior IRB Manager and the relevant IRB Manager, based on notes taken at the convened meeting. The following specific information is recorded in the meeting minutes:
· Attendance
· Voting results
· Actions taken by the IRB
· Summaries of discussions which reflect substantive decision making
· Specific findings regarding children, pregnant women, prisoners, waivers or alterations of consent and assent, waivers of HIPAA authorization, with protocol-specific justification for these findings
· Summaries of discussions of controverted issues and their resolution.
A complete set of minutes includes the following documents, which are stored in each IRB Manager’s office by meeting date:
· Minutes of Meeting (See Electronic Section E.1. for copies of the Minutes for all IRBs for May, June, and July, 2005) which record the proceedings of the convened meeting, voting results, actions taken, findings made, discussion of controverted issues and substantive decision making
· Minutes List, (See Electronic Section E.1. for copies of the Minutes Lists for all IRBs for May, June, and July, 2005) which lists all protocols which are approved at the convened meeting.
In addition, the following supporting documents are stored with the minutes:
· Meeting Agenda (See Electronic Section E.1. for copies of the Meeting Agenda for all IRBs for May, June, and July, 2005) which lists the items for the convened meeting, including protocols which are presented as part of the “early agenda”
· Agenda List, (See Electronic Section E.1. for copies of the Agenda List for all IRBs for May, June and July, 2005) which lists all protocols which are proposed for approval at the convened meeting. Expedited protocols for approval are listed for informational purposes and studies found to be Exempt from further IRB review are listed for informational purposes. The agenda list also indicates the name of the IRB member responsible for reviewing and presenting (when applicable) the protocol to the IRB.
· IRB Members’ Conflict of Interest Declaration (Document D.3.b.vi.F.) handed out at the beginning of each convened meeting and signed by members.
Attendance
· The first pages of the Minutes of Meeting record a list of voting members present. This list includes the names of members present at any time during the meeting, including those who arrive late or depart early. In each vote the names of voting members, included in the list of members present, who are not present for a specific vote are recorded as absent for that vote. If a member is present by audio (telephone) teleconference, a special note is made of that fact.
· The minutes note that all members whether present in person or by audio (telephone) teleconference receive all pertinent information prior to the meeting and are able to actively and equally participate in all discussions.
· Names of IRB members present but not voting are included, for example, ex-officio members or alternate members attending for informational purposes.
· Names of alternates attending in lieu of specified (named) absent members, as designated on the official IRB membership roster, are included. Alternates not attending are also listed.
· Names of others present, if any, are included. These may include guests, investigators invited to address the IRB, or investigators requesting to address the IRB, and consultants.
· Names of staff present are included.
· A special note is made of non-scientific members attending the meeting.
Quorum and Voting Results
The results of each vote are recorded in a manner that shows whether a quorum was present for the vote including:
· Total Number Voting ( ); Number for ( ); Number opposed ( ); and Number abstaining ( ), If a member abstains from voting, the member’s name is listed for that protocol.
· If a member leaves the room due to a conflicting interest the following statement is included in the minutes: Dr. John Doe left the room due to a conflicting interest, was not counted as part of the quorum, and was recorded as recused. If a member leaves the room due to any other reason the following statement is included in the minutes: Dr. John Doe left the room and was not counted as part of the quorum.
· The arrival and departure time of any member arriving after the start of the meeting or leaving before the adjournment is recorded at the beginning of the minutes. One of the following statements is added to each protocol discussed and voted on at the meeting if the vote total increases or decreases: Dr. John Doe left the meeting early and did not vote on this protocol or Dr. John Doe arrived late and did not vote on this protocol.
· The IRB member representing the San Mateo County Clinics votes only on ACTG protocols that involve the San Mateo County Clinics. His arrival and departure times are included at the beginning of the minutes with a statement that he votes only on ACTG protocols that involve the San Mateo Clinics. A statement regarding his participation is added to each protocol on which he votes.
Protocol Presentation
The reviewer’s presentation of the protocol to the full IRB convened meeting consists of the name of the study and the PD, a brief summary of the purpose and procedures of the study. It also includes an assessment of the accuracy of the consent form in representing the study, the appropriateness of using vulnerable participants, findings necessary for approval and an assessment of the risks relative to the anticipated benefits. If controverted issues are identified, these are presented as part of the protocol presentation.
Actions of the IRB
All actions of the IRB will be taken by majority vote on a motion, where a majority is defined as more than half of the membership present at the meeting. Minutes will record the actions of the IRB by recording the motion for each vote of the IRB.
Summaries of Substantive Decision Making
Any substantive decision making, including all sides presented on any controverted issues, and any actions taken by the IRB will be summarized for at least the following actions:
· A written summary of the discussion of controverted issues and their resolution
· Justification of any deletion or substantive modification of information concerning risks or alternative procedures contained in the sample informed consent document
· Approval of a protocol, including the justification for any changes, any conditions and criteria for that type of protocol described in Chapter 7, and identification of research that warrants review more often than annually
· For initial and continuing review, the approval period, including if the approval period is one year
· Disapproval of a protocol and the basis for disapproving the research
· Names of IRB members who absented themselves from the meeting under the conflict of interest policy
· Determination of the level of risk of the research study
· Decisions that are part of continuing review, including modifications or amendments to a protocol or informed consent form
· Additional protections for participants who are likely to be more vulnerable (e.g., to coercion or undue influence), such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons
· Action based on unanticipated problems involving risks to subjects or others, adverse event reports, or reports from sponsors, cooperative groups, or DSMBs (See Chapter 3.10)
· Determinations of non-compliance, particularly any serious or continuing non-compliance (See Chapter 3.9)
· Determinations of suspensions or terminations of research (See Chapter 9.3)
· Decisions on special situations not involving human participants or research that are listed in Chapters 1.3, 5 and 7, including emergency use of an FDA test article, humanitarian use devices, and California law relating to stem cell research
· Approval of research contingent on specific minor conditions by the chair or designee, which are documented in the minutes as an addendum to approved minutes (for example, “Note: Verbatim language was added to the consent form per the IRB’s request.”).
For each protocol undergoing initial or continuing review or modification, the minutes will record:
· Separate deliberations, actions and voting
· The basis for requiring changes in research
· A justification of any deletion or substantive modification of information concerning risks or alternative procedures contained in the sample informed consent document that was approved by the IRB
· A determination of which protocols require continuing review more often than annually, as appropriate to the degree of risk
· Decision making about controverted issues.
Specific Findings
Protocol-specific findings as required in Chapter 7 and a summary of the substantive decision-making, including all presented sides on any controverted issues, and any action taken by the IRB on those findings will be documented for regular new and continuing review of research involving the following:
· Waiver or alteration of informed consent [45 CFR §46.116(c)] and [45 CFR §46.116(d)] (Document D.5.b.)
· Waiver of informed consent documentation [45 CFR 46.117(c)] and [21 CFR § 56.109(c)]
· Research involving pregnant women, human fetuses and neonates [45 CFR §46.204], [45 CFR §46.205], [45 CFR §46.206], and [45 CFR §46.207] (Document D.5.g.)
· Research involving prisoners as participants [45 CFR §46.305] and [45 CFR §46.306 (Document D.5.i.)
· Research involving adults unable to consent in VAPAHCS research. (Document F.5.b.iv.)
· Research involving children as participants [45 CFR §46.404], [45 CFR §46.405], [45 CFR §46.406], [45 CFR §46.407], [45 CFR §46.408] and {FDA 21 CFR §50.51}, {FDA 21 CFR §50.52}, {FDA 21 CFR §50.53}, {FDA 21 CFR §50.54}, and {FDA 21 CFR §50.55} (Documents D.5.a. and D.5.h.)
a. Additionally, the IRB considers whether the permission of one parent/guardian or both parents/guardians are required. (See guidance Parental Permission.)
b. The IRB requires the investigator to explain how assent is to be solicited or obtained, unless waived.
· Research involving children who are wards of the state [45 CFR §46.406], [45 CFR §46.407] and {FDA 21 CFR §50.53}, {FDA 21 CFR §50.54} and [45 CFR §46.409(a)] and {FDA 21 CFR §50.56(a)}
· Research involving transplantation of fetal tissue [42 USC §498A(b)(1)and (2)] (Document F.4.w.)
· Waiver of HIPAA Authorization or Limited Waiver of HIPAA Authorization (Document D.5.c.)
· Significant and Non-significant risk device determinations and the rationale for the determinations [21 CFR 812.2(b)], [21 CFR 812.150(b)(9)], and FDA Information Sheet entitled “Significant and Non-significant Risk Medical Device Studies (Document D.5.f.).
Color-coded laminated sheets (Documents D.5.a.-j.) which contain the applicable regulations are available at every convened meeting for every voting IRB member, every ex-officio member and every staff member present as well as being part of the research protocol review packet for every reviewer.
The above protocol specific findings are also made in the case of new or continuing review of expedited research protocols. Documentation is found in the protocol file itself. The PD is asked to provide justification for the findings, and the IRB member reviewer then either concurs or not with the researcher’s justifications. If he does not concur, comments or questions are sent to the researcher until a satisfactory response is received. The laminated sheets also remain part of the review packet.
Access to IRB Minutes
Minutes are written and available to the VA R&D Committee for review within three weeks of the meeting date.
The body of the minutes may not be altered by anyone except the members, including a higher authority, after approval by the members, except for the addition of notes regarding resolved contingencies for that meeting.
Minutes of a meeting are circulated to IRB members before the next convened meeting for review. A call for corrections or comments is made at the convened meeting. If none are made, a motion to approve the minutes is made, and voted on. After approval, the IRB Manager places a copy of the IRB meeting minutes in the IRB files located in each IRB Manager’s office.
When IRB Chairs prepare annual reports to the President through the Office of the Dean of Research (summarizing the nature and volume of the IRBs’ activities), these minutes are made available to the President. Access to copies of IRB meeting minutes are made available to the VAPAHCS Research and Development Committee.
In addition, the IRB will consider requests for access to IRB minutes to others within STANFORD (e.g., Stanford University Internal Audit) and to outside agencies (e.g., regulatory agencies). The IRB will consider the IRB confidentiality policy (Document A.3.c.) and use its discretion and the reason for the request to determine whether to grant access.
Other Documentation
The RCO maintains the following other types of documentation associated with convened meetings:
· Meeting Agenda – the Meeting Agenda is prepared by the IRB Manager in conjunction with the Senior IRB Manager and the IRB Chair. The agenda lists the plan for the convened meeting.
· Agenda List – the Agenda List is prepared by the IRB Manager in conjunction with the Senior IRB Manager and the IRB Chair. The Agenda List lists all items reviewed by the IRB members for the month.
· Minutes List – the Minutes List is prepared by the IRB Manager after the conclusion of the convened meeting, and lists all protocols approved and reports accepted at the convened meeting. The Minutes List includes protocols approved with contingencies, but it does not include tabled, moved or withdrawn protocols.
IRB Membership Rosters
The RCO maintains current IRB membership rosters (Document A.1.h.). The RCO Director shall insure that any changes in IRB membership are reported promptly to the Office of Human Research Protection (OHRP) as an amendment to STANFORD Federalwide Assurances (FWA) (Document A.1.a.-e.).
See Chapter 6.5 for a complete description of the IRB membership roster.
Education and Training Records
See Chapter 4 for a summary of education and training records maintained by the IRB. These records include an ongoing record of continuing education and fulfillment of the human research protection training requirement for investigators and staff.
The IRB also maintains a resume for each IRB member. These files are maintained by the IRB Education Specialist.
The RCO maintains a resume for each IRB staff member. These files are maintained by the RCO Associate Director.
All Other Correspondence
The RCO ensures that accurate records are maintained of all correspondence to or from the IRBs that is not related to a research protocol.
For example, IRB files include copies of all correspondence between the IRB and PD that are not related to a particular protocol file and therefore cannot be filed in a protocol file. They are kept in the office of the Senior IRB Manager and are filed by the name of the PD.
In addition all correspondence between the IRB and the VAPAHCS Research and Development Committee is maintained indefinitely. This correspondence is kept in the office of the Senior IRB Manager.