ORIENTATION FOR NEW CLINICAL RESEARCH PERSONNEL

MODULE 1

Presented by

NC TraCS InstituteUNC Office of Clinical Trials

UNC Network for Research Professionals

Overall Agenda for Orientation• Module 1:

Introduction to Orientation, Training / Education, and IRB• Module 2:

Study Start-up and Roles of Research Personnel, Documentation and GCP, Informed Consent

• Module 3: Contracting, ClinicalTrials.gov, IDS / Device Policy, Recruitment

• Module 4: COI, Preparing & Executing NIH Grant Budgets, Budgeting & Accounting, and Billing Coverage Analysis

• Module 5: Essential Documents, From CDA to Study Close Out

Overall Objectives• Discuss options available for training/education of research personnel• Review human subject research protection and the IRB• Define appropriate responsibilities for study team members• Describe steps for successful implementation of a study • Describe appropriate management of study documentation • Define Good Clinical Practices (GCP)• Review the informed consent process, including HIPAA• Discuss compliance, essential documents & UNC drug/device policies• Review basic elements of contract negotiation and grant management• Understand policies on disseminating research via ClinicalTrials.gov• Review process for preparing a billing coverage analysis• Describe steps for managing budgets and accounting of funds• Describe steps for preparing and executing NIH grant budgets• Describe good recruitment practices and support available at UNC• Understand policies and implications of conflict of interest• Describe how to implement a clinical trial from CDA to study closure

Confidentiality Disclosure

Agreement (CDA) Sent to Site

Sponsor Sends Site Information

Questionnaire/Protocol Synopsis

Site Provides Sponsor

with Information

Sponsor Accepts

Site

CDA Submitted to Office of Clinical Trials

(OCT) via CRMS (Clinical Trials

Management System)

OCT negotiates terms and

executes CDA with sponsor

Sponsor Sends Protocol; Budget;

Clinical Trial Agreement (CTA);

and draft ICF

Feasibility Assessment

Review Protocol for Uncommon

procedures or requirements

Complete Billing Coverage Analysis in

CRMS

IDS SubmissionCTRC ApplicationHospital Services

Complete CTA

Submission via CTRMS

CTA/Budget/ICF

Finalized

Negotiate Final

Budget With

Sponsor

IRB Submission

Receipt of IRB Approval Documents

including ICF

Local IRB or Central

Conflict of Interest eForms

Completed

CTA/ICF checked for Consistency

eIPF completed in Ramses

Account Number Assigned

Conflict of Interest eForm

completed

Study Information is pushed to EPIC

via CRMS

Billing Calendar

Built in Epic

CTA Executed

CTA Executed

Prepare for/Enroll Subjects

Enrollment Complete

Site Initiation

Visit

Study Closure

Speaker Office/Department Phone number Email

Marie Rape NC TraCS 919-966-6844 Marie_rape@med.unc.edu

Laura Tuttle Family Practice 919-966-2881 laura_tuttle@med.unc.edu

Mike Matamoros OHRE / IRB 919-966-3113 matamoro@email.unc.edu

Erika Hanami NRP 984-974-3669 erika_hanami@med.unc.edu

Valorie Buchholz OCT / QA 919-445-9355 buchholz@unc.edu

Terry Hartman Radiology 919-966-4997 terry_hartman@med.unc.edu

Christine Nelson OCT 919-843-0832 chrisnel@email.unc.edu

Trey Fraune OIC - Contracts 919-843-3198 Trey_Fraune@unc.edu

Monica Coudurier OCT / CT.gov 919-843-2333 m_coudurier@unc.edu

Andrea Eiring OCT / BCA 919-843-2698 aneiring@email.unc.edu

Jill Cunnup Budgeting 919-966-0134 Jillyan_cunnup@med.unc.edu

Joy Bryde COI office 919-843-5328 jbryde@email.unc.edu

Carol Breland Recruitment 919-966-6274 brelandc@email.unc.edu

Sue Pope Invest. Drug 919-966-2371 Spope@unch.unc.edu

Sandy Barnhart Ophthalmology 919 843-0076 Sandy_barnhart@med.unc.edu

Amanda Wood IND/IDE Support 919-843-9445 Amanda_wood@med.unc.edu

Knowing the Resources AvailableTopic Unit/Office Website Telephone

Clinical Research Management System CRMS https://irbis.research.unc.edu/crms/ 919-843-1629

Clinical research support NC TraCS Institute http://tracs.unc.edu/ 919-966-6022

Clinical Research Unit CTRC http://tracs.unc.edu/index.php/services/ctrc 919-843-1070

Clinical Trials, QI Program, CT.gov Office of Clinical Trials http://research.unc.edu/offices/clinical-trials/ 919-843-2698

COI & Research Compliance Research Compliance Program http://research.unc.edu/offices/research-compliance-program/index.htm 919-843-9953

Conflict of Interest Training COI Office https://apps.research.unc.edu/coi-training/ 919-843-9953

Contracting for Clinical Trials, BCA, DUAs Office of Industry Contracting http://research.unc.edu/offices/oic/ (919) 962-3630

Data and Safety Monitoring Boards TraCS DSMB http://tracs.unc.edu/index.php/services/regulatory/data-and-safety-monitoring-board 919-966-6844

Hazardous Material Shipping, Safety Training Environmental Health and Safety http://ehs.unc.edu/workplace-safety/ 919-962-5507

HIPAA Policies, Training HIPAA online Training http://www.med.unc.edu/security/hipaa n/a

Human subjects Office of Human Research Ethics (OHRE) http://research.unc.edu/offices/human-research-ethics/ 919-966-3113

Human subjects, GCP, and RCR training CITI on-line program https://www.citiprogram.org/ n/a

IND/IDE Guidance TraCS IND/IDE Program http://tracs.unc.edu/index.php/services/regulatory/ind-and-ide-application-support 919-843-9445

Investigational Drugs Investigational Drug Service (IDS) http://pharmacy.intranet.unchealthcare.org/services/investdrugs 919-843-9919

Laboratory Assays for research UNC Core Labs http://www.med.unc.edu/corefacilities n/a

Learning Exchange Research Compliance Learning Community http://researchcompliance.web.unc.edu/about-learning-exchange/ n/a

Additional Resources• See new website at

http://researchcompliance.web.unc.edu/about-learning-exchange/

• Also, see the University Standard on Research Code of Conduct at http://policies.unc.edu/policies/university-standard-research-conduct/

Who should attend Orientation?• Personnel involved in clinical research

• Study coordinator• Social / Clinical research assistant• Research nurse• Research associate• Regulatory personnel• Investigators

• Involved in any type of clinical research• Clinical trials• Investigator initiated research• Federal grants• Social / behavioral research

Training, Training, TrainingWell educated study personnel are key to conducting quality research!

• Knowledge of research best practices, good clinical practices, regulatory requirements

• Keeping abreast of current rules, policies, requirements is key to conducting quality research.

• You need to take responsibility for staying informed and educated

Recommended / Required Trainings • CITI Good Clinical Practice (GCP) Training, www.citiprogram.org

• required if working with clinical trials (including NIH trials)• CITI Ethics Online Course (IRB modules), www.citiprogram.org

• required if involved in human subject research• Epic / BCA training (Research Admin 100) – via Hospital LMS system

STUDY COORDINATOR EDUCATIONJuanita Cuffee, MPHPediatrics – Hematology/OncologyChair, NRP

Why Coordinator Education?

Responsibility of the investigator to ensure that any individual to whom a task is delegated is qualified by education, training and experience (and state licensure where relevant) to perform the delegated task.

Documentation of training is essential for meeting the guidelines put forth by regulatory agencies for the conduct of Human Subject Research.

Study Coordinator EducationDocumentation of coordinator education may be part of the investigator/ department/division/center processes. This may include (dependent on type of research being conducted):

• Completion of Human Research Ethics Training• Completion of Good Clinical Practices Training• CV and/or state licensure• Job Skill Training (such as conducting an EKG)• Training plan per your specific job title• Documentation of Training for each protocol

(training logs)• Informed consent training

Example: Training & Education Checklist

Example Matrix of Training

Study Coordinator EducationOHRP – Office of Human Research Protection

Responsibilities of UNC• Before any human subjects research can be conducted, the

institution must provide the department or agency a written Assurance that it will comply with the requirements of the Policy

www.hhs.gov/orhp/• The HHS regulations are intended to implement the basic ethical

principals governing the conduct of human subject research

General ResponsibilitiesAll parties involved, institution, investigator, and IRB must actively engage in ensuring human subject protection and this is only achieved through proper training/education of all research professionals

The purpose of the UNC-NRP is to promote excellence in the conduct of clinical, social, behavioral, and

translational research through education, professional development and mentoring

NRP Educational Programs• Monthly educational seminars• Phlebotomy training• Peer-to-Peer support for new coordinators• Certification study groups - ACRP & SoCRA• Listserv for all individuals involved in human

subjects research (unc.crc listserv)• Informational emails directed specifically to research

professionals• “Did You Know” emails• Educational opportunities• Contact Juanita Cuffee to join

Current Projects• Updating NRP website• Hands on education seminars• Improving communication with the UNC research

community• Involving UNC research community in workgroups• Including more social/behavioral research topics• Planning 2018-19 monthly educational seminars

NRP is here for you! Please let us know what you need to do your

job better!

Final Points…• Please make continuing education a priority• Ensure that the training is documented• Saves time from creating unnecessary errors or having to re-do work

• Things change (i.e.: job duties, policies, procedures)• Elevates the quality of your research• Increased knowledge and skills makes you indispensable to your department

• Wisdom is knowledge applied; must apply what we know.

Who to Contact• To join the list serv, contact Juanita Cuffee at

Juanita_cuffee@med.unc.edu

• To serve as a volunteer, contact the NRP chair

• Information regarding committees and upcoming events can be found on our web site

www.uncnrp.org

INTRODUCTION TO THE UNC IRBMARCH 7, 2018

Office of Human Research Ethics Institutional Review Board• Mike Matamoros – Quality Assurance/Improvement Manager• Carter Church – Senior IRB Analyst• 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)?

• A committee mandated by federal regulations.

• Protects the rights and welfare of human subjects in research activities through independent review of proposed research.

• Independent committee formally designated to review, approve and monitor research involving humans

UNC IRB Mission Statement

The University of North Carolina at Chapel Hill is committed to expanding and disseminating knowledge for the benefit of the people of North Carolina and the world. An important part of that commitment to knowledge is research of the highest quality on all aspects of the health and behavior of people, and such research is only possible through the participation of humans as research subjects. Human subjects are partners and participants in research and a precious resource to the university. At UNC-Chapel Hill, human subjects research is a privilege, but not a right.

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

1 Senior IRB Analysts & 7 IRB Analysts

5 Managers: QA/QI; 2 Compliance; Education & Training and Data & Information

4 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 conducting research obtains:• Data through intervention or interaction with the individual,

OR • Identifiable private information

* HIPAA (Health Insurance Portability & Accountability Act of 1996) Change

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 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 projects

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).

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

Exempt Research

Involves no greater than minimal risk Must be “on the list” (45 CFR 46.101(b)(1)-(6)) 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 (may change in 2018)

1. Normal educational practices in established educational settings

2. Educational tests, surveys, interviews, or observation of public behavior -unless identified & sensitive**

3. Research on elected or appointed public officials or candidates for public office

4. Research using existingdata, if publicly available or recorded without identifiers

5. Evaluation of public benefit service programs

6. Taste and food quality evaluation and consumer acceptance studies

* Exception for prisoners ** Exception for children

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)

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• As of September 2016, 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 (summarize at continuing review)

• 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”(may change in 2018)

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

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

NAVIGATING THE IRB WEBSITE

OHRE.UNC.EDUCall IRB Analyst with questions @ 919-966-3113

New SOPs in effect as of June 1, 2017

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=SP5965C

B14C2506914&index=8

New Safety Information

Jeanne Lovmo, M.A., OHRE Compliance Manager

For New Study CoordinatorsMarch 7, 2017

Learning Objectives What is “New Safety Information”

(NSI)? What is the time frame for

reporting NSI? What to include in your NSI

report? What happens to the NSI report

once it has been submitted?

New Safety Information (NSI) Information previously

unknown to the IRB that suggests increased risk to participants or others.

Risk is defined as the probability of physical, psychological, social, or economic harm occurring as a result of participation in a research study.

Increased risk denotes potential as well as actual harm

INCREASED RISK

New Safety Information

Adverse Events

New findings

Deviations

Noncompliance

Other

Adverse Events (AEs) Any untoward or unfavorable

medical occurrence in a human subject, temporally associated with the subject’s participation in the research

Encompass both physical and psychological harms

Only a small subset of Adverse Events Constitute NSI

AEs in Single-Center TrialAdverse Events in single site research is reportable as NSI if:

1. unexpected, and2. related or possibly related, and3. serious OR suggest increased risk

AEs in Multi-Center TrialAdverse Events of subjects enrolled at UNC or enrolled by another site for which UNC is the IRB of record = NSI if:

1. Unexpected*, and 2. related or possibly related*, and3. serious OR suggest increased risk

Adverse Events of other subjects in the trial = NSI if the report include: a clear explanation of why the adverse event meets 1, 2

and 3, and a description of any proposed protocol changes or other

corrective actions

Unexpectedness?*The nature, severity, or frequency of the event is not consistent with either: the known or foreseeable risk of events associated with

procedures involved in the research as described in the protocol-related documents or other relevant sources;

OR the expected natural progression of any underlying

disease, disorder, or condition of the participant(s) and the participant’s predisposing risk factor

* As determined by central monitoring entity (e.g., the research sponsor, a coordinating or statistical center, or a DSMB/DMC)

Examples of UnexpectednessParticipant without a history of liver disease Unexpected nature: Participant suffers liver

injury but the protocol-related documents and other relevant sources did not indicate that the study treatment was associated with adverse effects on liver;

Unexpected in severity: Participant experiences acute liver failure but the protocol-related documents and other relevant sources identified transient, asymptomatic elevations in liver enzymes as an effect of the study treatment

Relatedness?* Is there is a “reasonable

possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research (i.e., drug exposure).”

Requires evaluation of available evidence

* As determined by central monitoring entity (e.g., the research sponsor, a coordinating or statistical center, or a DSMB/DMC)

Examples of Relatedness A single occurrence of an event that is uncommon

and known to be strongly associated with drug exposure (e.g., hepatic injury, Stevens-Johnson Syndrome)

One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture)

AEs - Increased Risk?

Is it serious?Step 1

Did the research place subjects or others at a greater risk of physical or psychological harm than was previously known or recognized? Step 2

Serious 1. Death

2. Life-threatening

3. Hospitalization

4. Persistent or significant disability

5. Congenital abnormality/birth defect

6. Other important medical events that may require intervention to prevent outcomes 1-5.

Example of AE that is Unexpected, Related and Increased RiskPhase 2, non-randomized clinical trial testing a new investigational antihypertensive drug in patients with hypertension. Unexpected in nature: No documented evidence of

gastroesophageal reflux disease (GERD) associated with the investigational product (IP); IRB-approved document do not describe GERD as a risk of the research.

Possibly related: Three of the first ten subjects are noted by the investigator to have severe GERD symptoms that began within one week of starting the IP and resolved a few days after the drug was discontinued.

Increased risk: Although not serious, the AE suggested that the research placed the participant at increased risk of harm (although no actual harm resulted).

New “Findings”New “finding” that indicates (1) there is increased risks to participants, or (2) participants are less likely to receive any direct benefits from the research.

Interim analysis DSMB/DMC report Findings from other studies Findings from animal testing Findings from in-vitro testing

Noncompliance Intentional or unintentional

failure to follow applicable federal regulations and the requirements or determinations of the IRB or University policies

= NSI when that failure adversely affects the rights or welfare of participants.

Examples of Noncompliance Conducting research without IRB approval or

exemption or during a lapse in approval

Failing to obtain informed consent or to re-consent w/ new serious risk

Using unapproved recruitment materials

Failing to follow the IRB approved data security requirements

Over-enrolling in a study that is greater than minimal risk

Protocol Deviations

Increased Risk

Eliminate Hazard

Immediate w/o IRB

approval

Examples of Deviations Failure to obtain protocol required safety labs (i.e.

LFTs) Infusing chemotherapy at a higher rate than the

protocol dictates Enrolling participants who are not eligible per

protocol when participation may place them at increased risk of harm

Administering a double dose of chemotherapy

“Other” Breach or potential breach of confidentiality or privacy Subject complaint

Rights, welfare, or safety adversely affected, or Cannot be resolved by the investigator

Incarceration of subject in study not approved to include prisoners

Audit, inspection, or written report by a federal agency (FDA 483)

State board action (e.g., suspension of professional license)

What is Reportable When UNC is Ceding Review? Events that involve UNC subjects 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

See SOP 1401 and 1402 for definitions

When to Report?

*Calendar days

What to include in your NSI report?

WHEN Relevant Dates Visit number, treatment

cycle/day WHO

Participants (no PHI, study id is ok)

Others WHAT

What happened? Provide rationale for increased

risk. Include mitigating factors.

WHY – Why did it occur? Results of the Root Cause Analysis (RCA) as applicable.

HOW – Corrective And Preventative Actions Taken and/or planned Additional information

needed to complete CAPA

Flow of NSI at the IRB

Receipt of NSI in IRBIS

Review by Compliance

Manager

Imminent serious harm to participant

= suspension by Chair

Review by SWAG –refer subset to

Safety Committee

Review by the Safety Committee –

Regulatory Determinations

Notification of PI, Chair, IO, federal

agencies as applicable

SWAG versus IRB Safety CommitteeSafety Welfare Analysis Group

This is NOT an IRB – at least 3 members who have experience with research, including an MD

Evaluates all New Safety Information

Requests additional information Works Corrective and

Preventative Actions (CAPA) Plans

Refers information to Safety Committee

IRB Safety Committee

A duly constituted IRB in accordance with federal regulations

Makes determinations of UPIRSO, SNC, CNC, Suspension, Termination

Develops and approves CAPAs Makes recommendations to IO

Contact InformationOffice of Human Research Ethics 919-966-3113/irb_questions@unc.edu

Kim Brownley, IRB Safety Committee Chair kim_brownley@med.unc.edu

Jeanne Lovmo, Compliance Manager lovmo@unc.edu

Shahila Sriskanda, IRB Analyst shahila@email.unc.edu

IRB APPLICATION SUBMISSION PROCESS

& HOT SPOTS

Call IRB Analysts with questions @ 919-966-3113

Research Equation

Funding + IRB Approval = Study

Grant Submission

IRB submission should be prepared with same care as grant submission.

If done, will have fewer/no stips or delays in approval.

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 irb_questions@unc.edu

On-line Submissions

• Smart form approach

• Single form builds on itself: NHSR – Exemption – Full application

• System builds consent forms

• Electronic Routing and Approvals

• On-line communication to and from the IRB

• Include a cover memo that explains special circumstances

Question #1: Is this RESEARCH?Does your project involve a systematicinvestigation, including research development, testing and evaluation, which is designed to develop or contribute to generalizable knowledge?

N N N N Y Y Y Y

Questions #2&3 determine if there are HUMAN SUBJECTSWill you be obtaining information about a living individual through direct intervention or interaction with that individual? This wouldinclude any contact with people usingquestionnaires/surveys, interviews, focus groups, observations, treatment interventions, etc. PLEASENOTE: Merely obtaining information FROM an individual does not mean you should answer 'Yes,' unless the information is also ABOUT them.

N Y N Y N Y N Y

Will you be obtaining information about a living individual through use of identifiable private information about that individual? This would include data, records or biological specimens that are currently existing or will be collected in the future for purposes other than this proposed research (e.g., medical records, ongoing collection of specimens for atissue repository).

N N Y Y N N Y Y

Application sections A9+C+ NHSR

A9+C+ NHSR

A9+C+ NHSR

A9+C+ NHSR

A9+C NHSR

A+B+C+ D

A+C+D3only

A+B+C+D

Additional questions (Multisite, CTRC, PRC) No No No No No Yes Yes YesOutcome NHSR NHSR NHSR NHSR NHSR Full App Full App Full App

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 TemplatesUniversity of North Carolina at Chapel Hill Consent to Participate in a Research Study Adult Participants [If using more than one adult form, identify adult group.] DELETE THIS AND ALL OTHER INSTRUCTIONS IN ITALICS AND YELLOW HIGHLIGHTS. ADDITIONALLY, YOU SHOULD DELETE ANY INFORMATION REQUESTED THAT DOES NOT APPLY TO THIS STUDY. The consent form must be written in 2nd person (e.g., You are being asked to take part in a research study about…). Also the page numbering already inserted in the footer must be maintained to show what each page is out of the total number of consent form pages (e.g., 2 of 4). Consent Form Version Date: ______________ IRB Study # 13-1567 Title of Study: Annotated application Principal Investigator: Carter Church Principal Investigator Department: Office of Human Research Ethics Principal Investigator Phone number: (919) 966-3113 Principal Investigator Email Address: carter.church@unc.edu Co-Investigators: Faculty Advisor: Faculty Advisor Contact Information: Funding Source and/or Sponsor: Yale University

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.

Basic Elements of Consent1. A statement that the study involves research an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental2. A description of any reasonably foreseeable risks or discomforts to the subject3. A description of any benefits to the subject or to others 4. A disclosure of appropriate alternative procedures or courses of treatment 5. A statement describing the extent, if any, to which confidentiality of records identifying the subject must be maintained6. For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs 7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research‐related injury to the subject8. A statement that participation is voluntary

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 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.

Provide explanation supporting request for waiver of IC or elements of IC

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?

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 either:

• 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.

OR

• 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 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.

Provide explanation supporting request for waiver of written documentation

IRB RELIANCE AGREEMENTS

John Robertsjtr@unc.eduPh) 919-966-2748

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 a trial is conducted at multiple sites, when a participating research entity does not have its own IRB, or when a trial 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 done. 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 IRB Agreements (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 (e.g. the joint NCSU/UNC biomedical engineering dept, EPA relies on UNC IRB for all HSR reviews)

Process for Requesting a Reliance Agreement

Guidance documents are located on the OHRE website here: http://research.unc.edu/human-research-ethics/reliance/

All requests for reliance agreements are submitted through IRBIS. General Information > 4. Screening Questions > question #6:

Multi-Site Study Information cont.

Multi-Site Study Information cont.

Multi-Site Study Information cont.An 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:

• I confirm that my collaboration on the above referenced research project is independent of another institution as I am NOT:

• (a) exercising authority or responsibility on behalf of a group or organization,

• (b) performing activities designated by a group or organization, or • (c) using the collaboration for scholarly advancement (e.g., promotion,

tenure) at a group or organization.

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

Multi-Site Study Information cont.If the intent is to rely on another IRB for review (cede review):

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 Central IRBs• Multicenter, industry-sponsored study, already approved and where the

Sponsor/CRO has identified a given central IRB as the IRB of record for the study.

• Use of a central IRB is optional

• 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 6 central IRBs: WIRB QuorumCopernicus ChesapeakeSterling Schulman

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 285 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 Mandate• UNC is actively piloting a number of multisite research

projects through a new review process to address sIRBreviews.

• Updates to the IRBIS application and review process are expected over the next few months to accommodate sIRBreviews.

• Note: Investigators who intend to cede review to another institution (sIRB, central IRB, etc) still require an application in IRBIS. UNC will maintain review of UNC personnel (ethics trainings & COI disclosures) as participating sites will usually follow their own institutional policies regarding ethics trainings and conflicts of interest (COI)

IRB Contacts for Reliance Agreements:http://research.unc.edu/human-research-ethics/reliance/OHRE main line 919-966-3113

For questions about Central (commercial) IRBs:

central_IRB@unc.eduCeleste Cantrell or Hsin-Lei Yao

For questions about all other reliance agreements:

IRBReliance@unc.edu orJohn Roberts jtr@unc.edu