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ORIENTATION FOR NEW CLINICAL RESEARCH PERSONNEL
WEEK 2
Presented by
NC TraCS InstituteUNC Office of Clinical Trials
UNC Network for Research Professionals
Overall Agenda for OrientationWeek 1 –• Introduction to the series, NCRP and educational programs, Running a clinical
trial beginning to endWeek 2 –• UNC Institutional Review Board Processes, Conflict of InterestWeek 3 –• Good Clinical Practice and Study Documentation, Informed Consent Processes,
Research Monitor AccessWeek 4 –• Contracts and Clinical Trial Agreements, Billing Coverage Analysis, Budgeting
and Accounting of Research Funds, Preparing and Executing NIH BudgetsWeek 5 –• Study Startup and Roles of Research Personnel, Recruitment Services and CDW,
UNC Investigational Drug Services, Investigational Device Management PolicyWeek 6 –• Investigator-Initiated Study Processes, ClinicalTrials.gov and ICMJE
requirements, Investigational Drug and Device studies at UNC
INTRODUCTION TO THE UNC IRBSEPTEMBER 18, 2019
Office of Human Research Ethics Institutional Review Board• Mike Matamoros – Quality Assurance/Improvement Manager• Jeanne Lovmo – Compliance Manager • John Roberts – Compliance Manager - Reliance
Discussion TopicsIRB Process & Function
IRB Application Submission Process, Waivers
New Safety Information
Reliance Agreements
Navigating the IRB Website
Objectives• Become familiar with:
• IRB review process• IRB applications• Investigator responsibilities following IRB approval• Research-related institutional responsibilities• Understanding waivers• Reporting of New Safety Information (NSI)• Reliance agreements• The IRB website
IRB PROCESS & FUNCTION
Mike Matamoros, MS, CIP
What is an Institutional Review Board (IRB)?
• An Independent committee formally designated to review, approve and monitor research involving humans that is mandated by federal regulations.
• Protects the rights and welfare of human subjects in research activities through independent review of proposed research.
IRB Membership
• > 5 members • Most UNC IRBs have 7-10 members
• Not all members of one profession
• No all male or all female
• At least one scientist, one non-scientist
• At least unaffiliated member
• Expertise appropriate to review research
UNC IRB Office Basic Facts~ 6000 active protocols/year
~12,000 activity items/year
6 IRBs
6 IRB Chairs and 2 Vice-Chairs
2 Senior IRB Analysts & 7 IRB Analysts
5 Managers: QA/QI; 2 Compliance; Education & Training and Data & Information
3 Administrative staff
UNC IRB Committees Biomedical (A,B,C,D): Biomedical research (clinical trials, pharmacological research, etc.) B and D only—Oncology, Dentistry
Non-Biomedical (E): Behavioral and social sciences; including public health and nursing
IRB Safety Committee: Compliance and New Safety Information
The IRB as “Gate keeper”Serves as the “gate keeper”/monitor to ensure compliance with Institutional Responsibilities:
• Radiation Safety• Investigational Drug Services• Institutional Bio-safety• Ethics training • Conflict of Interest• Privacy Office• Office of University Counsel (OUC)
Definitions• Research: a systematic investigation designed to develop or contribute to generalizable knowledge
• Human subject: a (living)* individual about whom an investigator (whether professional or student) conducting research:• Obtains information or biospecimens through intervention or
interaction with the individual, and uses, studies, or analyzes the information or biospecimens; OR
• Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.
Levels of IRB ReviewN
o G
reat
er T
han
Min
imal
Ris
k
“Exempt” from continuing review
Expedited Review
Full board review
RISK
Not Human Subjects Research
2. Does research include Human Subjects?1. Is it Research?
3. Is it on the list of exempt categories?
4. Is it on the list of expedited categories?
Note: The level of review is determined by IRB, not by the investigator or by the client. The requirements for each level are given in the regulations.
NHSR Determination
• Screening questions
• Determine if (1) it is research (2) if there are human subjects. 1 = No. Project is NHSR; 1 = Yes, 2 & 3 must = No for a project to be NHSR
NHSR DeterminationDoes not meet definition of human subjects researchNot Human Subjects Research (NHSR) includes things like…
Interview for campus newspaper Review of billing data without collection of identifiers Research of leftover cadaver specimens Case studies Quality Improvement projectsScholarly and journalistic activities (per Revised Common Rule)
Public health surveillance activities. (per Revised Common Rule)
Important: Although IRB review is not required to make a NHSR determination, if you are unsure you should complete and submit an application to the IRB. An incorrect assessment could result in inability to publish results (or worse).
Exempt Research
Involves no greater than minimal risk Must be “on the list” (45 CFR 46.101(b)(1)-(8)) Determination concurrence by IRB Chair or designee IRB may choose to provide additional measures of
protection The standard requirements for informed consent (or its
waiver, alteration, or exception) apply regardless of the type of review (expedited or convened) utilized by the IRB
Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests. 21 CFR 56.102 (i)
Exempt Research Categories1. Comparison of normal educational practices in established educational settings
2. Educational tests, surveys, interviews, or observation of public behavior
3. Benign Behavioral Interventions in conjunction with the collection of information from an adult subject
4. Secondary research uses of identifiable private information or identifiable biospecimen
5. Research and demonstration projects that are conducted or supported by a Federal department or agency
6. Taste and food quality evaluation and consumer acceptance studies
7. Storage or maintenance for secondary research for which broad consent is required (not being used at UNC)
8. Secondary research for which broad consent is required (not being used at UNC)
Expedited IRB Review Involves no greater than minimal risk or… Involves a minor change in previously approved research May be carried out by IRB Chair or designee IRB may choose to provide additional measures of
protection Described in (45 CFR 46.110 and 21 CFR 56.110)—must
be “on the list” (63 FR 60364-60367, November 9, 1998) As of January 21, 2019, these studies do not require
continuing review, unless a rationale is documented by the IRB.
Expedited IRB Review1. Studies of drugs and medical devices
when no IND or IDE is needed.
2. Blood samples by finger stick, heel stick, ear stick, or venipuncture.
3. Biological specimens for research purposes by “noninvasive” means.
4. Data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves.
5. Materials (data, documents, records, or specimens) that have been collected, or will be collected solely for nonresearchpurposes. Evaluation of public benefit service programs
6. Data from voice, video, digital, or image recordings made for research purposes.
7. Research employing survey, interview, oral history, focus group, etc.
8. Continuing review where: (a) only-follow-up remains, (b) no subjects enrolled, or (c) only data analysis remains.
9. Continuing review where: (1) not conducted under an IND/IDE, (2) other expedited categories n/a, and (3) Board considers minimal risk.
Full Board Review
Human subjects research involves procedures or issues that do not qualify for exempt or expedited review
Additional pre-review may be required; dependent on department/center Protocol Review Committee (PRC) - Studies involving oncology patients Scientific Review Committee (SRC) - Investigator-initiated research
Scientific Review Process at UNC• Any new study, classified as greater than minimal
risk*, submitted for IRB review will be required to have scientific review completed and documented prior to the review.
• *Office of Clinical Trials (OCT) can give you guidance on risk level. They may consult with IRB, as needed.
Scientific Review Process at UNC• Scientific Review can be done by UNC SRC, UNC
Protocol Review Committee (PRC; Oncology only) or waived it if meets any of the options:
• The protocol was reviewed by a protocol review committee empaneled for this purpose by Federal-funding agency (e.g., NIH, CDC, DOD) or a national foundation. Please provide evidence of this in the form of a letter from the project office if it is not evident from the protocol. Study section or FDA IND/IDE review is not adequate.
• The protocol was developed by an industry sponsor (e.g., pharmaceutical, device or diagnostics trials) and involves multiple research sites.
Scientific Review Committee (SRC)• Scientific Review Process at UNC - UNC Research
• SRC resources available to help:• OCT• TraCS – Bios and Regulatory Support (for protocol development)
Criteria for IRB Approval
1. Risks minimized2. Favorable risk : benefit ratio3. Equitable selection of subjects4. Informed consent sought5. Informed consent documented6. Monitoring plan for safety7. Privacy and confidentiality protected8. Additional safeguards for vulnerable populations
45 CFR 46.111 & 21 CFR 56.111OHRE SOP 701
Section 2.3
The IRB Meeting -- Possible actions
ApprovedMinor
contingencies required for
approval
Deferred (major
changes required)
Disapproved
When You Get a Contingency Memo…• Don’t despair
• Don’t take it personally
• It is rare for an initial proposal not to raise at least one question from the IRB
• The PI should respond to each contingency by responding to the stipulation AND making the corresponding changes to the application and/or consent forms.
• If you believe that the IRB misinterpreted or did not fully understand the information you provided, or you don’t understand a stipulations; you should call the office. Ask to speak with the IRB Analyst at whose meeting your study was reviewed
When You Get a Contingency Memo:
Approved!
• Research may proceed upon receipt of written documentation of IRB approval
• Investigator has a responsibility to report to the IRB:
• Changes BEFORE they are implemented
• Protocol violations
• Protocol deviations (keep deviations log)*
• Any unexpected problems involving risks to subjects or others (including unresolved subject complaints)
Protocol ModificationsAll protocol changes must be approved by the IRB before
implementation.
All changes to documents used with subjects (consent forms, questionnaires, recruitment materials, etc.) must be approved by the IRB before use.
The IRB assesses if the modification changes the level of risk:
• Do subjects need to be made aware of the new information? Which subjects?
• If a revised consent form necessary, has it been included; is it accurate?
Continuing Review or “Renewal”
No approval is valid for longer than one year from the initial review—depending on risk level, could be a shorter review period.
Expired (lapsed) approval = no approval
Must meet same criteria for approval as at initial review
Administrative Review
This only applies to studies approved under expedited review.
Administrative review report is due annually. Will include COI and other information.
Studies not subject do NOT expire, however, failure to submit administrative review report could is considered noncompliance.
Annual COI Review
Submission will be created 45 days prior to expiration (or administrative review due) date.
IMPORTANT: We highly recommend all personnel changes be made before the 45 day COI submission is created to avoid delays.
When can I close my study?
• Renew the study as long as data analysis of identifiabledata is on-going (Don’t forget publication reviews)
• When you are completely done with all interventions, follow-up and data analysis, the study should be closed
• If IRB approval of a study expires, no new subjects may be enrolled and all ongoing research activities must stop
Administrative Closures
• In order to be able to appropriately determine which version of the “Common Rule” regulations a study is under, the OHRE will start administratively closing studies that have been expired for 90+ days unless you have been in contact with the OHRE.
NAVIGATING THE IRB WEBSITE
OHRE.UNC.EDUCall IRB Analyst with questions @ 919-966-3113
*As of September 2019 no more Biomedical/Non-Biomedical distinction. Dates and deadlines will be updated for 2020.*
IRB Resources• IRB Staff (see website for listing of staff names): http://research.unc.edu/offices/human-
research-ethics/
• Website: IRB and Office of Human Research Ethics - UNC Research
• Telephone: 919-966-3113
• Address: Bolin Creek, 720 Martin Luther King, Jr. Blvd, CB # 7097 Second Floor
• Education Programs• http://www.hhs.gov/ohrp/• https://www.youtube.com/watch?v=hsUS0k3Ie_g&list=SP5965CB14C2506914&i
ndex=8• IRB Pop up
• IRB Analyst “Office Hours” for specific or general IRB questions.• See schedule of events at https://research.unc.edu/events/category/ohre/list/
IRB APPLICATION SUBMISSION PROCESS
Call IRB Analysts with questions @ 919-966-3113
Plan Ahead!
• Your application may be one of 100’s submitted that week• Pay attention to dates and deadlines (tentative)• Complete the application as directed• Provide consents; recruitment materials; and supporting
documents• Familiarize yourself with the “IRB” SOPs• If you have questions while completing the application or
consents, please •call 919-966-3113 or •email [email protected]
On-line Submissions
• NEW APPLICATION WIZARD!
• Allows you to select the application type you want
• System builds consent forms
• Electronic Routing and Approvals
• On-line communication to and from the IRB
• Include a cover memo that explains special circumstances
The Application Proper
The online IRB Application proper consists of three primary Parts:
A: Questions Common to All Studies B: Direct InteractionC: Existing Data Records, Specimens
• Parts A and C are always present, if sometimes conditionally abbreviated.
• Part B is displayed only if theresearcher is collecting personal information through subject interaction.
• The number of constituent sections may vary, depending on: the nature of the research (e.g., whether the study uses biomedical or behavioral methodology); or the level of review requested (e.g., Exempt or NHSR).
IRBIS Orientation: Initial Application types(As reflected in the ITEM LIST)
A completed application:• The PI is prevented from
submitting until all sections/parts of the IRB application are complete (as denoted by green checkmarks).
The full IRB Application:• Consent Form templates are tailored specifically to
each application, but are not presented until all preceding sections are complete.
• An application is considered “full” even if Part B is suppressed (i.e., response to Screening Q #2 is No).
Exempt Request• Consent forms are
neither required nor presented
NHSR Request
Consent Templates• Study specific templates are generated in IRBIS.
• Sample templates are available on the OHRE website at https://research.unc.edu/human-research-ethics/consent-forms/
Routing of IRB Submissions
PI and/or Study Staff
Drafts Application
Certification by PI
(and Faculty Advisor if
Student PI)*
PI’s Home Department
(Chair or Dept Review Committee)
Administering Department
(if any)
Oncology PRC or
SRS(if relevant)
IRB
Non-IRB Issues (if any)
Principal Investigator Affirmation
Department ApproversBy approving, the Home or Administering department affirms that:
• The research is appropriate for the investigator and Department
• The investigator(s) are qualified to conduct the research
• There are adequate resources (financial, support, and facilities) available
• For units that have a local review committee for pre-IRB review, this requirement has been satisfied
• The department supports the application and its review by the IRB
• The department agrees to accept responsibility for managing data security risks in consultation with departmental or campus security personnel
Research Data SecurityGrading System
Subject IDs
Sensitive Questions
Security Level
Requirements*
--- --- I Password protectionYES --- II Level I plus secure network--- YES II Level I plus secure networkYES YES III Level II plus encryption, vulnerability
scans, security audits
* Note that schools and departments will be expected to play a more central role in ensuring security requirements are met. Investigators should consult with IT managers for their units.
IT Expert within the Approving Department (Department Responsible for the Study)
UNDERSTANDING WAIVERS AND APPLICATION HOT
SPOTS
Types of Waivers and Alterations of IC• Limited waiver of HIPAA Authorization
• Waiver of consent in its entirety
• Alteration of Consent – One or more of the required elements is eliminated or altered
• Waiver of written (signed) consent—Subject is consented but no signature required. May require providing subjects with an “information sheet”.
Limited Waiver of HIPAA Authorization• Allows for access to existing medical records for the
purpose of identifying and making initial contact with potential subjects (e.g. recruitment)
• Data collection limited to minimum necessary information to allow identification of potential subjects.
• Records must be destroyed for all subjects who decline participation. All other subjects must sign a HIPAA Authorization form.
Waiver or Alteration of Elements of ICUnder 45 CFR 46.116(d) the IRB may waive the requirement for obtaining informed consent or approve a consent procedure that leaves out or alters some or all of the elements of informed consent, provided that the IRB finds and documents that all of the following four criteria are met:
• the research involves no more than minimal risk to the subjects;
• the waiver or alteration will not adversely affect the rights and welfare of the subjects;
• the research would not be possible to conduct the study with only de-identified data
• the research could not practicably be carried out without the waiver or alteration; and,
• whenever appropriate, the subjects will be provided with additional pertinent information after participation.
ExamplesWaiver of Consent in Entirety• A “full” waiver of consent and HIPAA Authorization is
generally requested Retrospective Chart Reviews.
Waiver or Alteration of Some of the Elements of Informed Consent • In a study that includes deception, the entire purpose of
the research may not be included in the consent form. Doing so would not allow for data to be collected in way that is meaningful. Subjects are debriefed and informed about the true purpose of the research following their completion of the study.
Hot Spot!The research could not practicably be carried out without the waiver or alteration. Why is virtually impossible to conduct the research without the waiver?• Is contact information of potential subjects readily available?• Are potential subjects likely to be deceased or lost to follow up?• How many records are required to review?• What are the age of records?• What would be the additional burden to potential subjects?
Guidance document available at: https://research.unc.edu/human-research-ethics/training-and-education-resources/irb-guidance-documents/
Waiver of written (signed) consent
Federal regulations allows the IRB to waive the requirement for written consent for some or all subjects if it finds at least one of the following is true:• That the only record linking the subject and the research would be the consent document AND
the principal risk would be potential harm resulting from a breach of confidentiality.
• That the research presents no more than minimal risk of harm to subjects AND involves no procedures for which written consent is normally required outside of the research context.
• The subjects or LARs are members of a distinct cultural group or community in which signing forms is not the norm, the research presents no more than minimal risk of harm to subjects, and there is an appropriate alternative mechanism for documenting that informed consent was obtained.
The default is for subjects to sign a written document that contains all the elements of informed consent. Under limited circumstances, the requirement for a signed consent form may be waived by the IRB. For example, this might occur for phone or internet surveys, when a signed consent form is either impractical or unnecessary, or in circumstances where a signed consent form creates a risk for the subject.
New Safety Information
• Jeanne Lovmo, M.A., OHRE Compliance Manager
•For New Clinical Research PersonnelSeptember 18, 2019
Learning Objectives
• Identify what information is reportable as New Safety Information (NSI)
• Identify the time frame for reporting NSI
• Complete NSI submissions in IRBIS
• Describe the IRB’s NSI review process
Regulatory Overview
HHS and FDA regulations require that institutions establish and follow written procedures for: • Ensuring prompt reporting to the IRB of changes in the
research • Ensuring prompt reporting to the IRB, appropriate institutional
officials, the department or agency head, the HHS Office for Human Research Protections (OHRP), and the Food and Drug Administration (FDA) of: Any unanticipated problems involving risks to subjects or
others (UPIRSO)Any Serious or Continuing NoncomplianceAny suspension or termination of IRB approval
• 45 CFR 46.103(a) and (b)(5), 21 CFR 56.108(b)
Definitions
•HHS and FDA do not provide definitions for Noncompliance, Serious Noncompliance, or Continuing Noncompliance but the scope of reportable noncompliance is described as:Noncompliance “…with this policy/these regulations
(Common Rule/FDA) or the requirements or determinations of the IRB”
•UPIRSO is not defined in the regulations but is defined in guidance by both OHRP and FDA. UNC uses OHRP definition of UPIRSO.
UNC’s UPIRSO Definition
Any incident, experience, or outcome that is unexpected in nature, severity, or frequency; and is related or possibly related to a participant’s
participation in the research; and is serious OR suggests that the research places
participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
UPIRSO Terminology
Unexpected: The nature, severity or frequency of the event is not consistent with the procedures/risks that are described in the IRB
approved application and protocol-related documents; and
the characteristics of the participant population being studied.
• Possibly related: Reasonable possibility that the adverse event, incident, experience or outcome may have been associated with the procedures involved in the research.
UPIRSO Terminology
•Serious:1. Death 2. Life-threatening3. Hospitalization4. Persistent or significant disability5. Congenital abnormality/birth defect6. Important medical event that may jeopardize the
participant and may require intervention to prevent outcomes 1-5
UNC’s Noncompliance Definitions
Noncompliance: Intentional or unintentional failure to follow applicable federal regulations, the requirements or determinations of the IRB, the IRB approved study protocol, or University policies.
Continuing Noncompliance: Any “Noncompliance” that occurs after implementation of an IRB approved CAPA plan that is due to the failure of the investigator and/or research team to comply with that CAPA plan OR repeated instances of noncompliance within one study or across multiple studies that has a high likelihood of resulting in Serious Noncompliance.
Serious Noncompliance: “Noncompliance” that adversely and significantly affects the rights or welfare of participants.
New Safety Information (NSI)
Information that may represent an Unanticipated Problem Involving Risk to Subjects or Others (UPIRSO), Serious Noncompliance, or Continuing Noncompliance and requires prompt reporting is reportable as New Safety Information.
New Safety Information is reportable promptly within 7 calendar days of the investigator becoming aware of the information.
Adverse Events (AEs)
Any untoward or unfavorable medical occurrence in a human subject, temporally associated with the subject’s participation in the research.
Only a small subset of Adverse Events Constitute NSI
Internal Adverse Events
Internal Adverse Events are AEs experienced by subjects or others at sites for which UNC IRB is the IRB of record
Internal AEs are reportable as NSI if they meet the criteria for UPIRSO:
1. Unexpected2. Related or possibly related3. Serious OR suggest increased risk
External Adverse Events
External Adverse Events are AEs experienced by subjects or others at sites for which UNC is not the IRB when UNC is participating in the multi-site researchExternal are reportable as NSI if they meet the criteria for
UPIRSO:1. Unexpected2. Related or possibly related3. Serious OR suggest increased riskAnd4. Changes to the study or notification of
participants or others are warranted.
Noncompliance •Any intentional or unintentional failure to follow applicable federal, state and local laws and/or institutional policies governing human subjects protections, or the requirements or determinations of the IRB, including the requirements of the approved investigational plan that
1.increases the risk of harm to participants; 2.adversely affects the safety, rights, or welfare of participants; 3.adversely affects the integrity of the research; and/or4.continues after initial discovery.
•Noncompliance that is not 1,2,3 and/or 4 is not reportable as NSI and should be documented with a CAPA by the investigator in the research record.
Examples of Noncompliance
Conducting human subjects research without an IRB-approved protocol or exemptionStarting research prior to IRB approval, or conducting research during a lapse in approvalFailure to obtain informed consent or provide a participant with new information that may affect the participant’s willingness to continue in the studyInitiating changes to the protocol without IRB approval, including using unapproved materials
Examples of Noncompliance Dosing or other errors in the prescription,
dispensing or administration of investigational product
Failing to perform safety assessment; follow data safety monitoring plan
Repeated instances of the same mistake on a specific protocol or across multiple protocols, after the initial events were discovered, reported, and a corrective action plan implemented
Pervasive noncompliance with the approved protocol that adversely affects the validity and integrity of the study data
Other NSI
Data Safety Monitoring report (e.g., DSMB, DMC, etc.) with any recommendations other than “Continue as is”Findings from other studies, including findings from
animal or in-vitro, or other finding(s) that indicate (1) there are increased risks to subjects, or (2) a reduction in direct benefit Unanticipated adverse device effect (e.g., action of a
device used as part of the research that increases risks or resulted in harm to subjects)Changes made to the research to eliminate an immediate
hazard to a subject without IRB approvalUnexpected pregnancy on a study that could expose a
fetus to harm
Other NSI
Failure to protect participant confidentiality or privacySubject or third-party complaint, other than complaints
regarding minor administrative issues such as a brief delay in compensation, or allegation of noncompliance Change in PI’s ability to conduct or supervise the study
due to actions taken by Federal, State, University or Hospital authorities (e.g., suspension or restriction of license)Institution-, investigator-, or sponsor-initiated hold or early
closure as a result of safety concerns
Other NSI
Audit, inspection, or inquiry by a federal agencyAny negative actions by a government oversight office,
including, but not limited to, FDA Warning Letters, FDA 483 Inspection Reports with action indicated, FDA restrictions on investigators, and any corresponding compliance actions taken under non-US authorities related to human research protectionsFinding by other auditing entity internal to the institution
indicating that subjects were placed at increased risk of harm or that the subjects' rights or welfare were adversely affected
NSI - UNC is Ceding Review
• Events that involve UNC participants or research for which the IRB of record have made a regulatory determination of Unanticipated Problem Involving Risk to Subjects or
Others (UPIRSO)Serious Noncompliance (SNC)Continuing Noncompliance (CNC)Suspension Termination
• HIPAA violations that affect UNC participants
Case Studies
Three participants are reporting symptoms of GERD 6 after 5 weeks of study treatment. The participants do not have previous
history of GERD and the participants’ GERD symptoms improved a few days after the drug was discontinued.Endoscopic examination reveals ulceration
in two participants. The Investigator Brochure (IB) and consent
document do not describe GERD or esophageal ulcers as risks of the study agent
Case Studies
• Information about participants was emailed to individual that is not associated with the study or UNC. The email was sent to an external server and was not encrypted per UNC policies. The email contained: Case 1: The participants’ first and last name, DOB,
lab results of Hepatitis B Surface Antigen. Case 2: A spreadsheet with participants’ first and
last name, DOB and test scores on the Rey Visual Memory test.Case 3: A list of DOBs of participants.
Case Studies
• A complete CBC is needed to monitor participant safety during a trial is missed for a participant participating in a phase 3 trial examining the safety and efficacy of a new chemotherapy regimen.
• As a result, grade 3 neutropenia is not detected until the next study visit. The protocol stipulates a reduction in dosage if > grade 3 neutropenia occurs. The CBC was left of the study visit checklist by accident.
NSI Reporting in IRBIS
NSI Report
• Event description:Timeline: Date of
event/discovery, visit #, treatment cycle/dayAffected participants (study
ID) or othersAffected studiesSalient detailsRoot causeStudy status
*Submit one NSI report per event per study*
•Corrective and Preventative Action (CAPA) plan: Taken and/or
planned corrective and preventative actions that address the root cause
Flow of NSI Review
Triage Imminent Serious Risk to ChairTriage NSI to SWAG
Resolve non-NSI
Imminent Serious Risk = Interim
Suspension
Fact-findingCAPA reviewRefer
UPIRSO, CNC, SNC,
Suspension to IRB
CAPA ReviewUPIRSO,
CNC, SNC, Suspension, Termination Determinatio
ns
PI, Chair, IO, Federal Agencies Notificatio
n of Outcomes
OHRE Safety
Compliance Team
IRBSafety
Welfare Analysis Group
CHAIR
OHRE Safety
Compliance Team
Safety/Compliance Team
•Office of Human Research Ethics919-966-3113/[email protected]
•Jeanne Lovmo, Safety/Compliance Manager [email protected]
•Cassie Myers, Director of [email protected]
•TBA, Safety/Compliance Analyst
IRB Reliance Agreements
• Formal document that provides a mechanism for an institution engaged in research to delegate IRB review to an independent IRB or an IRB of another institution, oraccept primary review responsibilities regarding the research on behalf other institutions or individuals.
• Used when research is conducted at multiple sites, when a participating research entity does not have its own IRB, or when the research requires specialized IRB expertise.
• Expected benefits include reduction in duplication and variation, decrease in activation time, and foster collaboration between sites.
Adapted from: http://www.niaid.nih.gov/LabsAndResources/resources/toolkit/Pages/faq.aspx
OHRP Federalwide Assurance (FWA)
Documents an institution’s commitment to comply with federal regulations governing human subjects research.
• Covers all research supported or conducted research involving human subjects
• **Requires written formal agreement of compliance from all non-affiliated investigators
Requirements in UNC’s FWA (#4801) The institution bears full responsibility for ensuring that all
human subject research is conducted in accordance with Federal regulations.
The IRB must review and approve or disapprove research involving human subjects according to guidelines set forth in 45 CFR 46.
The investigators acknowledge and accept their responsibility for protecting the rights and welfare of human subjects and for complying with the FWA.
NOTE: Without an FWA, Federally Funded research can not be conducted at an institution. An FWA can be cancelled by the Office for the Protection of Human Subjects (OHRP)!
4 Types of AgreementsIAA: IRB authorization agreements (e.g., UNC relies on Duke IRB,
Wake Forest relies on UNC IRB; can be executed between institutions when both have an FWA)
IIA: Independent Investigator Agreements (e.g., Bob Smith relies on UNC IRB; typically consultants, subcontractors, former students; UNC IRB extends our FWA to a small non-profit that does not have an FWA)
Central or Commerical IRB Agreements: IAAs (e.g., UNC relies on WIRB, UNC relies on the NCI CIRB; at UNC, ‘central IRB’ typically refers to a commercial IRB or NCI CIRB)
Broad Agreements: IAAs (e.g. the joint NCSU/UNC biomedical engineering dept, EPA relies on UNC IRB for all HSR reviews)
UNCs most common agreements when providing regulatory oversight
• UNC’s IRB Authorization Agreement (IAA) template may be used when both parties have a Federal Wide Assurance (FWA).
• Smart IRB Authorization Agreement may be used when both parties have an FWA and are Smart IRB Participating Institutions.
• UNC Individual Investigator Agreement (IIA Institutional) is used when the external group or organization does NOT have a Federal Wide Assurance (FWA)
• UNC Individual Investigator Agreement (IIA Individual) is used when an Independent Investigator will be covered by the UNC IRB.
Templates provided for review of terms on OHRE Reliance webpage: https://research.unc.edu/human-research-ethics/reliance/
Independent Investigators
• When a collaborator outside of UNC-CH is not acting as an employee of another group or organization with respect to their involvement in the research, they may be considered an Independent Investigator. Typically independent investigators are volunteers, recent graduates or former staff who are no longer affiliated with UNC, or independent consultants contracted to work on the research. In order to be considered an independent investigator, this person is required to complete an ‘Independent Investigator Confirmation Form’
Multi-Site Study InformationAn Independent Investigator Confirmation Form is required for all individuals lacking a primary appointment at another institution, when UNC IRB will be providing oversight.
The form includes the following statement:I confirm that my collaboration on the above referenced research project is independent of any other organization or institution as I am: (a) not otherwise an employee or agent of an assured (i.e., FWA holding) institution*, and (b) not acting as an employee of any organization or institution with respect to my involvement in the research being conducted by UNC, and (c) not using the collaboration for scholarly advancement (e.g., promotion, tenure) at an organization or institution.
Multi-Site Study Information cont.This table is from the reliance guidance document and indicates who is covered by UNC IRB, and allowed to serve as Principal Investigator
UNC Affiliation
Covered by UNC IRB?If ‘No’, a reliance agreement is required.
Allowed to serve as PI?
Adjunct Faculty who hold primary appointments at other institutions or organizations. Please note that some UNC faculty also hold adjunct appointments in another UNC department in addition to their primary appointment.
No No
Visiting Scholars (hold primary appointments at other academic or research institutions) No No
Emeritus Faculty (Retirees) NoNo, but may continue to serve as PI on studies that are in data analysis only
Faculty, other (Professor, Associate Professor, Assistant Professor, Instructor, Lecturer, Teaching Professor, Clinical Professor, Research Professor)
Yes Yes
Retirees No No
EHRA Non Faculty, including Post-Doctoral Fellows YesYes, but Post-Doctoral Fellows are required to have a faculty advisor
SHRA Employees Yes NoSHRA Temporary Employees Yes No Vendors/contractors No NoVolunteers No NoInterns (who are not UNC Students) No NoUNC Students (Graduate and Undergraduate Students, Interns) Yes Yes, faculty advisor must be identified
Fogarty Global Health Fellows (UNC Institute for Global Health & Infectious Diseases) Yes
Yes, faculty advisor must be identified. A faculty advisor is not required on a reliance application.
Process for Requesting a Reliance Agreement: IRBIS application
Requesting a reliance agreement cont.When electing to cede review to an external IRB, after selecting “Rely On” you will be prompted to select the external IRB type:
Multi-Site Study Information cont.Both pathways (accept review for others, or cede review) require additional information to be provided. May include:
• FWA# of other institution,• description of the role of collaborators, • full legal name of collaborating institutions, • signatory official (or designee) contact information for
collaborating institution, • is collaborating institution AAHRPP accredited, Y/N?
*Contact the collaborating institutions IRB to obtain the most accurate information for the collaborating institution
Relying on Commerical IRBs• Multicenter, industry-sponsored study, already approved and where the
Sponsor/CRO has identified a commercial IRB as the IRB of record for the study.
• Use of a commercial IRB is expected for industry sponsored multisite clinicial trials
• You may choose to work with some and not with others or for some kind of studies but not others (e.g., Phase II-IV but not Phase I studies)
• Revised policy allows for the use of commercial IRBs: WIRB-Copernicus Group (e.g. New England IRB, Aspire)Advarra (acquired Chesapeake/Schulman/Quorum)Sterling IRB
Broad AgreementsExecuted to provide IRB coverage for multiple protocols, when the collaborator and reviewing IRB have special arrangements, typically to accommodate substantial collaborations.
• Joint NCSU & UNC Biomedical Engineering Department –the broad agreement with NCSU covers most of the research protocols conducted by this department, most staff have dual appointments
• Environmental Protection Agency (EPA) – UNC IRB is the IRB of record for the EPAs HSR, has broad agreement to cover EPA research conducted at EPA facilities on campus, as well as other EPA/UNC collaborations.
NIH Single IRB Review MandateEffective January 25, 2018
For applications with due dates on or after January 25, 2018, and contract solicitations published on or after January 25, 2018, NIH expects that all sites participating in multi-site studies, which involve non-exempt human subjects research funded by the NIH, will use a single Institutional Review Board (sIRB) to conduct the ethical review required for the protection of human subjects.This policy applies to the domestic sites of NIH-funded multi-site studies where each site will conduct the same protocol involving non-exempt human subjects research. It does not apply to career development, research training or fellowship awards. Implementation of the NIH sIRB policy is expected to reduce unnecessary administrative burdens and systemic inefficiencies while maintaining appropriate human subjects protections.Applicants will be expected to include a plan for the use of a sIRB in the grant applications and contract proposals they submit to the NIH (for due dates on or after January 25, 2018).
NIH Single IRB Review Mandatehttps://smartirb.org/• Currently ~625 Participating Institutions, all 64 CTSA hubs• Smart IRB: a platform designed to ease common
challenges associated with initiating multisite research and to provide a roadmap for institutions to implement the NIH Single IRB Review policy
• Smart IRB Agreement: a standardized reliance agreement, does not require negotiating of agreement terms, may be cited for multisite collaborative arrangements sponsored by any funding type
• Reviewing IRB = IRB of Record = Lead IRB = sIRB• Relying Institution = participating site ceding review
NIH Single IRB Review MandateNOTES:
• Investigators who intend to cede review to another institution (sIRB, commerical IRB, etc) still require an application in IRBIS. UNC IRB will conduct a review of UNC personnel (ethics trainings & COI disclosures) since participating sites will follow their own institutional policies regarding ethics trainings and conflicts of interest (COI).
• Local context will be provided by the UNC IRB pertaining to ancillary reviews (radiation safety, biosafety, etc) and any relevant institutional policies or concerns regarding specific research protocols at the time of review, including customization of the consent form to be used at UNC.
• UNC Researchers should always use the separate standalone HIPAA authorization, and not a combined consent & HIPAA
IRB Contacts for Reliance Agreements:http://research.unc.edu/human-research-ethics/reliance/OHRE main line 919-966-3113
For questions about commercial IRBs:
[email protected] orSara Phelan [email protected]
For questions about all other reliance agreements:
[email protected] orJohn Roberts [email protected]
CONFLICT OF INTERESTJoy Bryde, MSWConflict of Interest OfficerConflict of Interest [email protected]
Who is Covered by the Policy on Individual Conflicts of Interest (COI) and Commitment?
Eight sections for Conflict of Interest, including Research
UNC Chapel Hill
What is a Individual COI?Conflict of interest is a situation in which financial or other personal considerations:
• may compromise, • may involve the potential for compromising, or • may have the appearance of compromising
an employee’s (covered individual’s) objectivity in meeting University duties or responsibilities, including research activities.
UNC Board of Governors Policy Manual
Visualizing Individual COI at UNC
• Actual Conflict of Interest• Potential Conflict of Interest• Appearance of a Conflict of Interest
Institutional (aka University) Duties
External or Personal Interests
What is a Individual COI ?(continued)The bias that such conflicts may impart can affect many University duties, including:• decisions about personnel, • the purchase of equipment and other supplies,• the collection, analysis and interpretation of data, • the sharing of research results, • the choice of research protocols, • the use of statistical methods, • and the mentoring and judgment of student work.
Why the Conflict of Interest (COI) Process?
Comply with: • UNC Board of Governors’ Policies and Regulations• North Carolina State Statutes and Regulations• Federal requirements (funding, human subjects) • DHHS 42 CFR Part 50, 45 CFR Part 94 effective 08/24/ 2012• NSF Grant and Administrative Guidelines January 2013
Mantra: Disclose and Manage
Terms to know• COI: Conflict of Interest• FCOI: Financial Conflict of Interest means a Financial Interest that could directly and significantly affect the design, conduct, or reporting of research.
• Disclosure: to submit to the University the details of any interests, financial or personal, that might be a potential conflict of interest
• Disclosure: to share details of a conflict of interest with subjects, a research team or in presentations or publications as necessary
COI SnapshotFCOIs
COIs
COI Disclosure
Research COI Training
Steps of the Research COI Process?Research COI Training coi-training.unc.edu – Valid four years
Event-based Disclosure• Created from two areas
• Sponsored Research (aka Ramses)• IRB Protocols (aka IRBIS)
• Submission• Evaluation and Review• Initiate Management Plan if needed• Report to Sponsor if applicable• Send out COI Finalization Letter to submitter, copy to PI if needed
Submit Event Specific Disclosure Annually OR on Change of Circumstances
Research COI Disclosures
Not trigger COI disclosures:Graduate Research Assistant, Other Key Participant, Project Manager, Technical Staff, Undergraduate Student, Administrative Contact, Administrative Asst
Not trigger COI disclosures:Research Assistant, Regulatory Associate, Other (Read Only Access)
IRB (IRBIS)Principal Investigator
UNC Faculty Member in any role
Co-investigator
Faculty Advisor
Project Manager or Study Coordinator
OSR (RAMSeS)Lead Principal Investigator
Principal Investigator
Investigator
Faculty Advisor
Fellow or Fellow NIH
Postdoctoral Research Associate
Clinical Research Coordinator
Other Key Participant (UNC Faculty)
Independent Consultant Investigator
Who Completes the Disclosure?• Each person is responsible for submitting their own form –
this means that the faculty MUST complete their own COI form.
• It a violation of multiple policies for an individual to login using another’s ONYEN and PW to complete the form.
Policies Governing this Process (minimum):• UNC CH ITS Password Policy and Standards for General
Users• UNC CH Individual COI Policy• UNC CH Research Code of Conduct and Standards• UNC System Policy on Individual Conflicts of Interest and
Commitment
Why is a Disclosure Required for Each Study and Reviewed for a “Known” Conflict ?• Federal regulation • University Policy• Each study is different even if the “conflict” appears to be
the same• Different drugs• Different protocol• Different people
• For human subjects’ research, informed consent text must be context specific
What Happens Next?No conflicts indicated • System filters immediately• IRBIS/Ramses automatically updated
Potential conflicts indicated • Initial Evaluation at COI Office, usually further information is
needed• Next Step
• Expedited Review with Committee Chair(s) (Existing Management plans or <$10K) OR
• Full Committee (New conflict, >10K)
NOTE: Five Standing COI Committees – Medicine, Public Health, Dentistry, Pharmacy and College of Arts & Sciences. Some committees meet 1x per month; others every 2-3 months.
What are Financial Interests?
Tangible• Personal Income - real or potential value
• Equity/Stock/Options (mutual funds excluded)
• Royalties/licensing fees/copyrights• Indirect – family member• Gifts (for self or others)
What are Non-Financial Interests?
• Board membership• Executive position• Scientific or technical advisor
• Trustee• Volunteer position
• (such as fundraising)
Management PrinciplesPrinciples• Transparency• Honoring the Student/
Trainee Experience• Protection of the
credibility of the individual doing the work
Human Studies: Specific Points of Concern Review and/or Manage• Study Design• Obtaining Informed Consent
• Referring Patients• Influence
• Adverse Event decisions• Research specific decisions versus clinical care• Access to research information• Data Analysis involvement
Management ToolsTools• Management Plans
• Public Disclosure• Independent Review of Data• Change in Roles• Change in Activities
• Monitoring Committee• Alternative Options for Trainees
• Alternative Administrative Routing
NOTE: Significant financial interests presumed not allowable in human subjects research, particularly for a principal investigator. “Rebuttable” but like anything with human subjects research, higher standard.
How Can I Check the Review Status?
Federal Anti-Kickback Statute Purpose: To protect patients and federal health care programs from fraud and abuse
Summary: Prohibits the solicitation, receipt, offer or payment of remuneration “in return for” or “to induce” the referral of program related business, arranging for, or recommending, the purchase, lease, or ordering of any item or service reimbursed by a federal healthcare program
Penalties• Civil: Fines up to $50,000; Exclusion from federal health care
programs • Criminal: Felony; Up to five years in prison; Fines up to
$25,000
Anti-Kickback: Clinical Trial Risks & Solutions
Risks
Direct payments to investigators
Incentives for investigators ( exotic meeting locations)
Unbudgeted payments
Financial COI
Study biases (site selection, prescribing)
Excess funds
Study merit
Potential Solutions
Institutional financial management
Institutional contracting
Institutional financial management
Published and enforced COI policies
IRB and training
Published Policy on Excess Fund Disposition
Internal review and approval
UNC-CH CONFLICT OF INTEREST POLICY IS STRICTER THAN FDA
• Stricter definition of significant financial interest• Project-by-project disclosure of financial and other conflicts of interest
• Any changes to financial and other interests must be reported within 30 days.
• University rules regarding compensation from Sponsors
UNC Policy regarding Compensation from Sponsors
• University employees may not accept gifts, payments, or in-kind support (including but not limited to financial payments, gift certificates, books, conference attendance and payment of travel expenses) • as inducements for performance in a University project • except as expressly included in budgeted project costs
in a contract between the University and the project sponsor.
Pages 6-7
UNC Health System & UNC School of Medicine -- The Search for Balance
• Belief in Benefits of Industry Engagement • Positively influence the development of products and services to
benefit patients and society• Opportunities to develop collaborations
• Activities Prohibited under Vendor Relations Policy Due to Perceived Influence:• Ghostwriting• Speakers’ Bureaus • Any personal gifts• Meals/hospitality
COI in the News
And the latest COI in the News….
Foreign Influence ??Through a variety of mechanisms, the U.S. government has raised concerns about “foreign threats” to the integrity of research at national academic and research institutions. • Also being referred to as National
Security
3 Main Areas of Concern1. Diversion of intellectual property to foreign
entities (govt, schools, other)2. Disclosing confidential grant application
information by NIH peer reviewers to third parties, which may or may not include foreign entities
3. Failure of researchers to disclose research resources and support provided by other organizations, including foreign entities
Some Sample Means• Conduct computer intrusions
via email or in person• Copy laptop data along with
presentation• Through possible COI
activities – relationships with foreign entities or international activities
• Conferences = collect sensitive research
• Talent Programs• Teaching
FOR US GOVT “Intellectual property” also includes pre-publication data and sensitive information.
Websites & EmailActivities, Interests and Relationships: air.unc.edu All COI disclosures, External Activities for Pay
COI Training: coi-training.unc.edu
Conflict of Interest Program: research.unc.edu/offices/coi
Compliance Line - contact anonymouslywww.unc.Ethicspoint.com or call 866-294-8688
General Email for questions: [email protected], [email protected]
Contact InformationJoy M. Bryde, MSWConflict of Interest OfficerMailing Address: Conflict of Interest Program
UNC-CH CB 9103Physical Address: Bynum Hall, Suite 301D
222 E. Cameron Ave. E-mail: [email protected] Phone: (919) 843-9953
