Orientation to Clinical Research at USC
Randolph Hall
Growing Clinical Research at USC
Expand
access
to
novel
and
promising
therapies,
and
build
reputation
as
center
for
innovative
and
effective
patient
‐
centered
care.
Expedite
execution
of
clinical
trial
agreements,
and
create
master
agreements
with
major
sponsors.
Improve
research
IT,
with
clinical
trial
management
system,
clinical
data
warehouse,
supplementing
TARA
Aims of Training
Overview
of
processes
for
planning
and
executing
research
for
human
subjects
in
the
clinical
setting,
at
USC.
Introductory
level
understanding
of
all
aspects
of
clinical
trials
Course
is
for:
New
clinical
investigator
Research
coordinators
All
others
who
participate
in
executing
a
clinical
Contributors
Clinical
and
Translational
Science
Institute
and
its
Clinical
Trials
Unit
Cancer
Investigators
Support
Office
Office
for
the
Protection
of
Research
Subjects
Office
of
Compliance
Clinical
Trials
Office
Certificate of Completion
Awarded
after
attendance
in
entirety
at
both
sessions
Demonstration
that
you
have
received
training
on
basic
processes
for
clinical
research
at
USC.
Not
based
on
examination.
If
you
are
unable
to
attend
both
sessions,
we’ll
have
a
record
of
the
one
you
attended.
You
may
complete
the
certificate
during
next
course
offering
in
the
spring
(date
to
be
determined).
Certification
of
completion
not
currently
required,
but
may
be
Other Training at USC (http://oprs.usc.edu/education/)
Human
subjects
protection
training
Good
Clinical
Practice
HIPAA
Training
Responsible
Conduct
of
Research
Conflict
of
Interest
Follow-up Training and Certification Outside USC
Association
of
Clinical
Research
Professionals:
Professional
development
program,
in
‐
person
and
online
Certified
Research
Associate,
Certified
Research
Coordinator,
PI
Certification,
CTI
Certificate
Society
of
Clinical
Research
Associates
Professional
development
programs,
in
‐
person
and
online
Certified
Clinical
Research
Associate
MAGI
(Model
Agreements
and
Guidelines
International)
Clinical
Research
Contract
Professional
Future Offerings at USC
Clinical
Trials
at
USC
Orientation:
Offered
Again
in
Spring,
Date
TBD
(thereafter,
likely
once
per
year)
Clinical
Trials
Administration:
Offered
First
Time
DAY 1
WEDNESDAY, SEPTEMBER 18, 2013
TIME TOPIC INSTRUCTOR
8:00 am – 8:10 am Introduction Randolph Hall 8:10 am – 8:30 am Clinical Research at USC: An Overview Silvia da Costa 8:30 am – 9:45 am Contracting, Financial Management Soheil Jadali
and Budgeting
9:45 am – 10:15 am BREAK
10:15 am – 10:45 am Compliance: Considerations Related Dan Shapiro
to Clinical Trials
10:45 am – 12:00 pm IRB and Human Subjects Protection Susan Rose
DAY 2 WEDNESDAY, SEPTEMBER 25, 2013
TIME TOPIC INSTRUCTOR
8:00 am – 9:00 am Planning Research Anthony El‐Khoueiry 9:00 am – 9:30 am Coordination of Ancillary Services Anthony El‐Khoueiry
9:30 am – 10:00 am BREAK
10:00 am – 12:00 pm Coordinating a Study Anthony El‐Khoueiry
Orientation to Clinical Research
at USC
Silvia da Costa, PhD
Director, Faculty Research Relations Office of Research
Supplementary Material - Handout
CLINICAL TRIAL ORIENTATION: SUPPLEMENTAL MATERIALS
Supplemental materials to the Clinical Trials Orientation will be posted at the USC Office of Research website
(https://research.usc.edu/orientation‐to‐clinical‐research‐at‐usc/). Documents will include:
UNIVERSITY ENTITIES & RESOURCES
University Offices & Entities Ancillary Committees
Other Entities & Resources
CONTRACTING, FINANCIAL MANAGEMENT AND BUDGETING
Types of Funding
Budget Preparation
Proposal Routing and Approval Negotiation of Terms …
Clinical Research Orientation
Review & approval of language related
to injury,
compensation & informed consent
Office of Research
Please don’t forget
to fill out the attendance card
and drop it off as you leave.
USC Clinical Trials Office (CTO)
Answers to CTO’s who, what, when, and how
questions
Soheil Jadali
Your Clinical Trials Office (CTO)
Started its work on July 01, 2013
Director
Sr. Contract Managers
Clinical Trial Financial Administrator (MCA Analyst)
Budget Specialists
Three main operational components:
i.
Contract Review, Negotiation, and Execution
ii. Medical Coverage Analysis
iii. Budget Development and Negotiation
Transition from Pre-award to Post-award – Billing and
Accounting Services
Coordinating efforts with other units and departments involved in
clinical trial management, including hospital billing and
Clinical Trial Initiation In True 2.0
PI/Research Coordinator responds to all questions and provides mandatory documents (i.e. study protocol, proposed Clinical Trial
Agreement if provided, and sponsors first proposed budget) for CTO’s review (please refer to True 2.0 training slides).
CTO will review the submission to confirm that all required
documents and information have been provided (different documents depending on the type of submission – i.e. CTA, CDA, or
non-industry MCA request).
Once this is confirmed, submission is accepted and assigned to appropriate person (depending on the type of Submission). For
example, in the case of a CTA, assignments are made to the Contract Manager and the Financial Administrator responsible to conduct the Medicare Coverage Analysis.
Contract Review, Negotiation, and Execution
The Contract Manager reviews the proposed agreement.
Revised version of the agreement (redlined) is sent back to the sponsor for their review and comments.
The goals is to move our processes in a way that by the time there is a mutually acceptable version of the agreement terms, the other components of our
processes i.e. Medicare Coverage Analysis and budget development and negotiation are either done or close to be completed.
Contract terms, MCA, budget, IRB consistency checklist + IRB approval = Study activation
Medical Coverage Analysis
Financial Administrator conducts the Medicare Coverage Analysis (MCA) to identify and distinguish cost categories (i.e. S, I, and O).
Final MCA document facilitates the generation of Research Order Form that in turn allows proper identification of procedures and the source of their funding for billing purposes.
Once the MCA is completed, the Financial Administrator assigns the study to CTO Budget Specialists responsible for PI’s
department/therapeutic unit for budget development and negotiation in accordance with the MCA.
Budget Development and Negotiation
The Budget Specialist works with the PI and RC to develop USC’s response to sponsor’s initial proposed budget.
USC’s first budget is sent to sponsor; budget negotiation begins.
Arriving at a mutually acceptable budget and payment terms with sponsor completes the third component of CTO’s activities.
Transition from Pre-award to Post-award –
Billing and Accounting Services
Study Activated – KC budget summary is sent to DCG KC administrator.
Final Agreement and budget information is entered in IRIS.
Final documents (executed Agreement, final MCA, and budget are sent to True.
Compliance Considerations Related
To Clinical Trials
Daniel Shapiro
Office of Compliance -- Overview
Our charge is to:
Help USC faculty and staff understand and comply with the rules
applicable to their work.
Prevent and detect violations of laws or university policy.
Office of Compliance -- Overview
To accomplish our charge, the Office of Compliance:
Performs periodic risk assessments
Assists in the development of policies and procedures
Provides training and education
Conducts periodic assessments, monitoring, and auditing
Investigates allegations of non-compliance and recommends
corrective action when appropriate.
The Office of Compliance also oversees USC’s
Help and Hotline,
(213) 740-2500. You can call this number to obtain guidance or
report suspected violations of law confidentially.
The HIPAA Privacy Rule
All USC employees, including researchers and research
coordinators, have a legal obligation under the Health
Insurance and Portability Act (“HIPAA”) to safeguard and
keep confidential health information they access in the course
of performing research.
The HIPAA Privacy Rule: Legal Requirements
Generally, a written HIPAA Authorization must be obtained when
conducting a research study using a subject’s Protected Health Information, or PHI.
In limited circumstances, a HIPAA Authorization is not required, but only in instances where an authorization is not practicable to obtain (i.e.
retrospective chart review where contacting former patients is impracticable/impossible. Waivers require IRB review/approval!
A partial waiver may also be appropriate if access to PHI is only required to prepare a research protocol, and not to conduct the research itself.
USC’s template HIPAA Authorization and other HIPAA forms may be found on the USC policies page at:
http://policies.usc.edu/p2admOpBus/hipaa.html
Any modifications to these forms require Office of Compliance review and approval.
The HIPAA Privacy Rule: How to Comply
Obtain HIPAA training
Ensure use of most current version of the informed
consent and HIPAA Authorization forms as approved by
the IRB.
Verify that a research authorization has been signed by
each research participant.
If there is no research authorization, determine whether
IRB has issued a waiver – if not,
an authorization is
required.
Remember, a signed informed consent without a signed
Conflict of Interest in Research
USC encourages its faculty, staff, and students to
participate in meaningful professional relationships with
industrial and other private partners.
However, some of these relationships can create, or
appear to create, conflicts of interest.
Conflicts of interest do
not
imply any wrongdoing, but
they must be disclosed promptly so that they can be
reviewed and managed by the university in partnership
with researchers and research staff.
Conflict of Interest in Research
Several USC policies address conflicts of interest:
Conflict of Interest in Research policy: covers outside relationships by individual researchers related to research.
Institutional Conflict of Interest in Research policy: covers research-related conflicts created by USC’s financial interests.
Relationships with Industry policy: covers physician’s outside relationships with the pharmaceutical or medical device industry.
Conflict of Interest in Professional and Business Practices policy: Covers general business and personal conflicts maintained by any USC employee (i.e., familial hires, USC business relationships with
companies in which the USC employee maintains an ownership or consulting role).
Conflict of Interest in Research
With regard to individual research-related conflicts, the
following types of outside activity must be disclosed:
Payments for service (e.g., consulting, payments for service on
a board or advisory committee) in excess of $5,000 per year.
Private equity interests (e.g., stocks, stock options not publicly
traded), regardless of value
Public equity interests of $5,000, except when held in an
investment vehicle like a mutual fund.
Management roles (e.g., director, officer, or similar position of
significant decision-making authority)
Conflict of Interest in Research
How must conflicts be disclosed?
First, the conflict must be noted at the proposal submission
stage.
Second, the conflict must also be noted in
i-Star.
Third, a complete conflict disclosure must be submitted
through “diSClose”, (
https://disclose.usc.edu
), USC’s electronic
system designed to allow for researchers to disclose potential
conflicts related to their research.
Your user name and password for diSClose are the same as
your USC NetID and password.
For assistance on how to use diSClose or make a disclosure,
contact the Office of Compliance.
Conflict of Interest in Research
What happens after a disclosure is made?
The disclosure automatically is automatically routed to the
Office of Compliance.
The Office of Compliance performs an initial assessment, and
if a conflict is present, presents the disclosure to USC’s Conflict
of Interest Review Committee (CIRC) at a monthly meeting.
The CIRC reviews the disclosure and formulates a
recommendation to the VP of Research on how to manage the
conflict if appropriate.
The VP of Research makes the final decision, which is
communicated to the person with the conflict and the IRB.
Conflict of Interest in Research
How do I follow USC’s policies on conflicts of interest?
If you are a
researcher
:
Complete on-line conflict of interest training.
(
https://www.citiprogram.org/
)
Keep up to date records of all your outside relationships.
Disclose any potential conflict promptly by noting it at
proposal submission and in
i-Star
, and make a complete
disclosure in diSClose.
Cooperate in the Office of Compliance’s assessment.
Follow any management plan put in place to manage conflicts.
Seek guidance from the Office of Compliance if you are not
certain whether a particular relationship creates a conflict.
Conflict of Interest in Research
If you are a
research coordinator
:
Complete on-line conflict of interest training.
(
https://www.citiprogram.org/
)
Encourage investigators to promptly disclose outside
relationships related to research in diSClose.
Ask the investigator to complete the portion of the i-Star
submission addressing conflicts of interest.
Help ensure management plans are followed (e.g. when a
management plan requires that informed consent be obtained by
someone other than the conflicted investigator).
If you have any financial interests that may create a conflict on
a study, inform the investigator with whom you work.
Confidentiality Agreements and Clauses
Researchers may need to receive confidential or
proprietary information from a sponsor/third
party, including:
Protocols, investigator’s brochure and written
instructions
Information that is not published
Oral disclosures of confidential information
Confidentiality Agreements and Clauses
Many times, this information is provided through
via a confidential data agreement (CDA) or
non-disclosure agreement (NDA). These agreements
may be found within:
A clinical trial agreement (CTA)
Technology license
Data sharing agreement
Confidentiality Agreements and Clauses
CDA’s/NDAS:
Will define the information that is to be protected
May be one-way, or unilateral – for example, the sponsor
may want to provide a researcher with information so the
researcher can determine whether he/she wants to
participate in the research Technology license
May also be two-way, or mutual – for example, both
parties agree to exchange information and keep it
confidential
At USC, CTO reviews and signs CDA/NDA agreements
Confidentiality Agreements and Clauses
Other confidential information related to clinical
trials:
Sponsor-provided Protected Health Information
(PHI)
Certificates of Confidentiality – NIH issued
document to protect identifiable research information
in sensitive areas of research (e.g., sexual attitudes or
preferences, information related to the use of illegal
drugs, genetic information.
Certificates of
Confidentiality Agreements and Clauses
Roles/responsibilities of research coordinators
and researchers:
Review the
Guide to Confidentiality
Determine whether confidential/proprietary
information is to be provided
Become familiar with all restrictions
Work together to ensure necessary protections are
in place
Do not share confidential information outside USC,
or inside USC to those not involved in the research
Clinical Trials at USC
Protecting Human
Research Subjects
Susan L. Rose
Executive Director
So What is a Clinical Trial?
A study involving an unapproved FDA regulated test
article and one or more human subjects and/or the
results are intended to be submitted later to the FDA
as part of an application for a research or marketing
permit.
USC Human Subjects Protection Program
The USC Human Subjects Protection Program
(HSPP) Consists of the Office for the Protection
of Research Subjects (OPRS) and the four USC
Institutional Review Boards (IRB).
President
Chief USC Executive
Provost
For all academic and
research programs
Vice President for
Research (VPR)
Research advancement
Clinical Trials Office
Negotiates and manages
industry contracts
Office for the Protection of Research
Subjects (OPRS)
Policies, education, re‐
accreditation, oversight
Health Sciences IRB
(HSIRB)
Reviews biomedical research
University Park IRB
(HSIRB)
Reviews socio‐behavioral
research
Sr. Vice President
Administration
Legal counsel, institutional
compliance Office of Compliance (OOC) Regulatory issues
Human Subjects
Protection Program
Organizational Chart
Office for the Protection of Research Subjects
(OPRS)…
Directs the USC Human Subjects Protection Program
(HSPP) (including UPC/ HSC IRB)
Designs/distributes widely requested educational materials
Ensures compliance with state and federal regulations
governing research
Develops and maintains policies uniform with research ethics,
best practices, and federal regulations
Maintains national prominence for USC, leads national
Human Subjects Research Defined
Research:
A systematic investigation, including research
development, testing and evaluation, designed to develop
or contribute to generalizable knowledge
Human Subject:
Living individual(s) about whom an investigator (whether
professional or student) conducting research obtains (1) data
through intervention or interaction with the individual or (2)
identifiable private information. (OHRP)
An individual who is or becomes a participant in research, either
as a recipient of a test article or as a control. A subject may be a
healthy human or a patient (FDA)
Human Subjects Research
Regulatory Authorities
• Federal office overseeing institutions with Federalwide
Assurance to comply with the Common Rule (45 CFR 46) • Issues guidance on informed consent, conflict of interest,
federal reporting requirements, and other topics
• Federal office overseeing institutions with Federalwide
Assurance to comply with the Common Rule (45 CFR 46) • Issues guidance on informed consent, conflict of interest,
federal reporting requirements, and other topics
OHRP
• Regulates clinical research on drugs, devices, and biologics • Conducts audits and issues guidance for IRB, investigators,
and industry
• Regulates clinical research on drugs, devices, and biologics • Conducts audits and issues guidance for IRB, investigators,
and industry
FDA
• Contains statutes governing human experimentation, AIDS
research, research with prisoners, and embryonic research
among others
• Contains statutes governing human experimentation, AIDS
research, research with prisoners, and embryonic research
among others
California State
Law
• Address all aspects of review, conduct, and oversight of
human subjects research at USC
• Address all aspects of review, conduct, and oversight of
human subjects research at USC
USC Institutional
Policies and
OHRP
Office for Human Research Protections (OHRP)
oversees system to protect the rights, welfare, and
well-being of subjects involved in research, ensures research is
carried out in accordance with regulations
45 CFR part
46
.
Provides direction in human subjects research through
guidelines, interpretation of regulations, and monitoring
compliance.
Regulations/Policies
Federal Regulations for the Protection of Human Subjects
Informed Consent Requirements
Informed Consent Requirements in Emergency Research
FDA
Responsible for assuring the safety, efficacy, and security of
human and veterinary drugs, biological products, medical
devices, our nation’s food supply, cosmetics, and products that
emit radiation.”
Research studies involving human subjects must comply with
federal regulations (21 CFR 50). FDA regulations pertaining to
human subjects research include:
Protection of Human Subjects (21CFR§50)
Financial Disclosure by Clinical Investigators (21CFR§54)
Institutional Review Boards (21CFR§56)
Investigational New Drug (21CFR§312)
Biological Products (21CFR§600)
Health Insurance Portability and
Accountability Act (HIPAA)/Privacy Rule
HIPAA, known as the Privacy Rule, was designed to
protect the privacy of health information. HIPAA
protections are in addition to existing state laws.
California laws provide extra protection to patients and
include civil and criminal penalties for non-compliance.
Protected Health Information (PHI)
Identifies or could identify an individual with respect to health
records
Is created or received by a healthcare provider, health plan, or
healthcare clearinghouse
USC Submission Process for Clinical
Investigation/Trials
Research Coordinator/P.I. obtains iStar account
Takes required training
Complete and submit application incl. Informed Consent
Obtains departmental review
IRB/Ancillary Committees Review
PI/RC address contingencies
Submit amendments, continuing review, adverse events
Study Closeout
Human Subjects Protection
Program: USC Required Training
• PI and key personnel conducting Human Subjects
research
Human Subjects Protection Human Subjects Protection
• PI and key personnel conducting clinical research
Good Clinical Practice
(GCP)
Good Clinical Practice
(GCP)
• PI and key personnel who have access to private
identifiable health information (e.g. health records)
Health Insurance
Portability and
Accountability Act (HIPAA) Health Insurance
Portability and
Accountability Act (HIPAA)
• Recipients of certain NSF, NIH, PHS awards.
• Recommended for all involved in research
Responsible Conduct of
Research (RCR) Responsible Conduct of
Research (RCR)
• Investigators receiving HHS funding
Conflict of Interest (COI)
Conflict of Interest (COI)
Summary of iStar Application
iStar is the IRB application system used to…
Create and submit IRB applications
Correspond with the IRB, respond to requests, and
receive approval notices
Submit annual/ or semi-annual applications for
review as required
Report protocol deviations, subject complaints and
Departmental Review
Required for all research submitted to
the Health Sciences IRB
In iStar, Dept chair attests to:
Scientific merit and feasibility of the
study
Availability of needed resources to
conduct the study
Ancillary Committees
Oversight bodies (separate from IRB) involved in review
and approval of research.
Conflict of Interest Review Committee (CIRC):
Evaluates and
manages conflicts in research
Data Safety Monitoring Board (DSMB):
Reviews Data Safety
Monitoring Plans, safety , and scientific progress
Radiation Safety Committee:
Evaluates safety of research with
radioactive materials and radiation-producing equipment
Pathology Department (LAC+USC):
Receives requests for
specimens, confirms that appropriate consent and authorization
has been obtained for each specimen
Cancer Center Clinical Investigations Committee (CIC):
peer
review body to evaluate feasibility, scientific merit and adequate
resources for studies at Norris Cancer Center .
IRB Review and Approval
An IRB (Institutional Review
Board) reviews research involving
human subjects
Three IRB at HSC (biomed)
One IRB at UPC (soc-behavoiral)
An IRB reviews:
Risks and benefits to subjects Vulnerable status of subjects Privacy and confidentiality Conflict of interest
Informed consent content and process Scientific merit
HIPAA requirements (IRB fulfills
Levels of IRB Review
•More than “minimal risk” to subjects •Not covered under other review categories
• Example: interventions involving physical or emotional discomfort or sensitive data
Full
Board
• Not greater than minimal risk
• Fits one of the 9 Expedited Review Categories* • Examples Collection of biospecimens by
noninvasive means
Expedited
• Less than “minimal risk” • Fits one of the 6 Exempt
Categories*
• Example: Chart review studies
Exempt
Minimal Risk
Minimal risk
means that the probability and
magnitude of harm or discomfort is not greater than
what is encountered in daily life or routine physical or
psychological examinations.
“Risk”
reflects the ratio of risks to benefits that a
subject will encounter by choosing to participate in a
research activity
Balancing Risk/ Benefit Ratio
Benefit:
A valued or
desired outcome; an
advantage.
Risk:
The probability of
harm or injury (physical,
psychological, social, or
economic) occurring as a
result of participation in
a research study.
Subjects should be made
aware when research
offers no direct benefit.
Risk should always be
minimized.
Notify the IRB
whenever risks change in
a study
Informed Consent Requirements
The informed consent process must:
Explain benefits/risks/procedures posed to subjects
Distinguish between research and standard medical
care
Answer questions from subjects
Minimize possibility of coercion/undue influence
Provide subjects with adequate time to consider
participation
Be presented in language understandable to the
subject
Allow subjects to refuse or discontinue participation at
any time
Respect subject’s physical, emotional and psychological
Informed Consent
Informed consent (IC) is process used to enroll a subject to a
study. Method and documentation of consent varies according
to level of review and nature of the research.
Informed Consent Template -
http://oprs.usc.edu/hsirb/hsirb-forms/
Parental Permission – authorization from a parent or guardian for a minor
Child/Youth Assent – authorization from subjects who are minors,
parental permission must also be obtained
Short form – authorization form for subjects who do not read English
Waiver of documentation /element – permitted when documentation
(IC) linking the subject to the study would pose a risk to the subject
Information/Fact Sheet –provides study information to subjects when a
Vulnerable Populations
Vulnerability is situational and individual
Pregnant Women/Fetuses*
Comatose patients
Prisoners*
Cognitively impaired
Children*
Employees/Students
Homeless
*Federal categories of vulnerability
Vulnerability implies a power differential
Privacy and Confidentiality
PRIVACY
Subject
allows extent,
timing, and circumstances of
sharing personal
information/data with
others.
Subject
expects information
given in a relationship of
trust not to be divulged to
others without permission.
CONFIDENTIALITY
Refers to
data
/specimens
and how identifiers/privacy
are maintained.
Methods include
data
inscription, password
protection, locked storage,
and coding samples and
data.
Responsibilities After IRB Approval
Amendments:
changes to IRB approved research must
be approved by the IRB before being implemented
Reportable Events:
subject complaints, unanticipated
problems, adverse events, or protocol violations must
be reported
Continuing Review:
periodic review of an IRB
approved protocol (at least annually)
Study Closeout:
Process by which a study is ended and
Terms to Know
Significant New Information/Findings (SNIF):
Information developed during the course of research
that may affect subjects’ willingness to continue
participating
Data Safety Monitoring Plan
s
/Board
: independent
evaluation of study data to assure safety and reporting
of adverse events
