Protocol Development,
Review, and Approval
Process
Elizabeth Ness, RN, MS
Nurse Consultant (Education)
Center for Cancer Research
National Cancer Institute
Planning a Clinical Trial
• Formulate the Research Question
• Develop the Study Design
• Define the Study Population
• Select the Measurement Tools/Endpoints
• Determine Sample Size and Statistical
Analysis
• Data Collection and Storage
Formulate the Research
Question
• Define Objective(s) clearly and precisely
• Objective(s) need to be tied to
measurable study endpoints
• Primary objective of the study must be
identified
• May have several secondary objectives
Characteristics of a Good
Research Question – “FINER”
1
• Feasible
• Adequate number of subjects
• Adequate technical expertise
• Affordable in time and money
• Manageable in scope
• Interesting
• Novel
• Confirms or refutes previous
findings
• Extends previous findings
• Provides new findings
• Ethical
• Relevant
• To scientific knowledge
• To clinical and health
policy
• To future research
directions
1
Hulley, S.,B., Cummings, S.R., Browner, W.S., Grady, D., Newman, T.B. (2007). Designing
Clinical Research (2nd Ed.), Philadelphia: Lippincott Williams & Wilkins.
Select the Study Design
Selection of the study design is based on:
• study question
• ethical considerations
• resources
Study Subject Selection
• Subjects who may benefit
• Subjects who may be at
greater risk
• Subject’s ability to comply
• Subject’s concurrent
conditions
• Inclusion criteria
• Exclusion criteria
Measurement
Tools/Endpoints
• Toxicity
• Response
• Survival
• QOL/Patient Reported Outcomes (PRO)
• Biological Endpoints and Surrogate Markers
• Get statistician involved early!!
• Estimate the appropriate number of
subjects for a given study design
• Test the hypothesis
• How to handle dropouts/withdrawals?
• For interventional studies:
• How large a difference between treatment
groups is medically important
• Include enough participants to get a
statistically significant results
Determine Sample Size
Determine Statistical
Analysis
• Analysis plan appropriate for objectives
and design
• How endpoints will be measured
• Statistical methods to be used
• How will common problems be
addressed
• Management of safety data
• DSMB?
Data Collection & Storage
• Identify critical data elements to be collected
• Develop case report forms
• Safe and secure mechanism for data storage
• Anticipate audits of clinical data
• Length of time for storage
• Know FDA regulations
• Know institutional policies
as appropriate
• NIH Manual Chapter 1743 “Keeping & Destroying Records
THE PROTOCOL
Clinical Research Protocol
A written, detailed action plan that:
• Provides background about the trial
• Specifies trial objectives
• Describes trial’s design and
organization
•
Ensures that trial procedures are
consistently carried out
NOTE: Each IRB or Sponsor will have their own Protocol
template.
Required Protocol Sections
(SOP #8)
• Title page*
• Précis
• Table of contents
• Background
• Study Objectives
• Study design and
methods
• Inclusion & Exclusion
criteria
• Clinical and laboratory
methods
• Collection and storage of
human specimens or data
• Statistical analysis
• Human subjects
protection
• Privacy and confidentiality
• Study
agents/interventions
• Reporting requirements
for UPS and AEs
• Data and safety
monitoring plan
• Data/record management
• Compensation
• References
• Appendices
Protocol Development at the
NIH IRP
Investigator
initiated protocol
Concept/Branch Review
(scientific, priority,
resources)
Scientific Review
(scientific, statistical,
priority)
Sponsor
(regulatory)
IRB
(ethical)
Radiation Safety
IBC/OBA
(safety)
Protocol Management
Systems at NIH
• 2 web-based information management
systems:
• Integrated Research Information System
(iRIS)
• Protocol Tracking and Management
System (PTMS)
Protocol Life Cycle
Approval
Continuing
Review
Ethics Review
Institutional Review
Board (IRB)
Study
Enrollment
Ends
Amendments:
Expedited
or Full Board Review
Additional Reports:
Unanticipated Problems
Safety Reports
Deviations
Violations
File Closed
Post-approval Process
Principal Investigator
(PI)
Concept Review &
Approval
Scientific Review
& Approval
Protocol
Generated
Pre-approval Process
Regulatory
Reviews
COI
Branch/Concept Review
• Does it fit well within the research portfolio of
the IC?
• Should it be given priority?
• Can it be accomplished with the proposed
staff and resources of the Clinical Center?
• Does the IC have appropriate funds to
support the study?
Scientific Priority
Resources
Scientific Review
• Institute or Branch Level Review
• Primary focus is science, not safety
• Are the objectives of the study scientifically
founded?
• Are the design and methods correct?
• Is this appropriate use of our resources?
• (IRB is safety not science)
• First level of review before IRB review
Regulatory Considerations:
Pre-IRB Approval
Radiation
Safety
Gene
Transfer
COI
Radiation Safety
• NIH Radiation Safety Program
• Ensure safe use of radioactive materials and all
sources of ionizing radiation throughout NIH and
NIH-occupied buildings
• Radiation Safety Officer (RSO)
• Oversight by the Radiation Safety Committee
(RSC)
• RSC and RSO report to NIH Director
Radiation Safety Committee
• Reviews protocols using ionizing radiation (x-
rays, nuclear-medicine, PET)
for research
purposes
• Approval by RSC is required before the
initiation of IRB approved clinical research
protocol
• RSC meets monthly
• Submit protocol using From NIH 88-23 (a) :
Application for Authorization to use Radiation
in Research involving Human Subjects
• http://www.ors.od.nih.gov/sr/drs/rsc/Pages/index.a
spx
Human Gene Transfer (HGT)
Trials
• Research involving recombinant or
synthetic nucleic acid molecules or DNA
or RNA derived from recombinant
synthetic nucleic acid molecules into
human subjects to:
• compensate for defective genes
• produce a potentially therapeutic
substance
• trigger the immune system to fight disease
HGT Research Oversight
Federal
• NIH IC Program
Staff
• NIH OBA
• OHRP
• FDA
Local & Non-Federal
• IBC
• IRB
• Investigators
• Sponsors
Institutional Biosafety
Committee (IBC)
• Group of experts that provides local
review, oversight, and approval of
HGT research
• Follow
NIH Guidelines for Research
Involving Recombinant DNA
Molecules
Responsibilities of an IBC…
• Examine experimental protocols that
are submitted
• Evaluate the expertise of the Principal
Investigator (PI) and staff to conduct the
work
• Evaluate the potential dangers of the
work
• Evaluate the biological containment
plan and facilities per the NIH
Guidelines
… Responsibilities of an IBC
• Determine whether additional expertise
should be consulted
• Determine whether health surveillance
of laboratory staff is necessary
• Request additional information from PI
• Approve or disapprove the protocol
NIH IBC
• Provides recommendations to NIH Director in
matters pertaining to the control of hazards
associated with the intramural use of
microbiological agents, their vectors, and
recombinant DNA
• Committee serves as an advisory body to the
Division of Occupational Health and Safety
(DOHS), Office of Research Services (ORS)
• PI-dashboard used for submissions
• http://www.ors.od.nih.gov/sr/dohs/SafetyReso
urces/committees/Pages/inst_biosafety_com
mittee.aspx
Office of Biotechnology
Activities (OBA)
• NIH office promoting science, safety
and ethics in biotechnology
• Establish and maintain the
NIH
Guidelines for Research Involving
Recombinant DNA Molecules First
published in 1976 - Evolved over time
with increase scientific understanding &
technological developments
http://oba.od.nih.gov/oba/index.html
NIH Guidelines: Appendix M
• Articulate principles for the safe and ethical
conduct of HGT research to allow research to
move forward safely and with public
acceptance
• Requirements for Information Submission to
NIH:
• Protocol
• Responses to questions about the scientific and
safety-related dimensions of the gene transfer
intervention
• Issues pertinent to the informed consent process
• Safety and Annual Reporting Requirements
• RAC Review Process
Recombinant DNA Advisory
Committee (RAC)
• Federal advisory committee composed
of national experts to provide advice
and recommendations to the NIH
Director regarding HGT research
• NOT an approval process
Summary of HGT Protocol
Review Process
• Protocol submitted to OBA
• Sent to RAC Members
• RAC Members review and recommendations
• May or may not be selected for full RAC review
• Written review sent to PI
• Written response to OBA
• Public discussion at RAC meeting
• OBA Letter
Timing of Protocol Review
• Final IBC approval cannot occur until
RAC review is completed
• IRB review and approval can occur
before or after RAC review
• FDA review and authorization of IND
application can occur at any time
Post-Enrollment Reporting
• Within 20 days of enrollment of the first participant, PI
must submit to OBA:
• Response to RAC recommendations (if applicable)
• Copy of final protocol
• Copy of final IRB-approved informed consent
• Copy of IRB approval
• Copy of IBC approval
• Subsequently, PI must submit:
• Protocol amendments
• Serious adverse event reports
• Annual reports
• Due within 60 days after the one-year anniversary date of IND
authorization and yearly until trial is completed
Conflict of Interests and
Financial Disclosures
Federal regulations and Institutional
policies require that investigators disclose
any significant financial interests that may
present an actual or potential conflict of
interest in relationship to externally
sponsored research prior to the initiation of
a protocol/study
Financial Disclosure
• FDA Financial Disclosure
by investigators – 21 CFR
54
• Form 3454: certification
• Form 3455: disclosure
• PLUS NIH requirements:
Deputy Ethics Counselor’s
(DEC) Clearance
NIH COI…
• NIH Employees: NIH Ethics Office
• Key Research Personnel: based on their role on
the protocol not just their designation on the
protocol
• All individuals involved in recruiting and enrolling human
subjects
• Obtaining informed consent
• Reviewing/reporting adverse events
• Analyzing data
• IRB members
• DSMB members
• Non-NIH Employees: PI
…NIH COI
• Clearance of NIH Investigator Personal
Financial Holdings by IC Ethics Office
• Submit for:
• New Protocol
• Continuing Review
• Amendment (Investigator Added or Product Added
or Changed)
• Assessing for conflicts or financial interests
• NIH Ethics Program
• http://ethics.od.nih.gov/
Role of the IRB
• A committee charged with the review of
human subject research
• Primary mandate is to protect and
safeguard the rights and welfare of
human subjects
• Balance rights of individual subjects with
development of knowledge to further
society as a whole
IRB Assurances &
Registration
• Agreement between the institutional official of
a research entity and the DHHS
• Purpose:
•
establish binding agreement between institution
and government that the institution agrees to
comply with the Federal Regulations for the
Protection of Human Subjects
• Registration of the IRB with DHHS
IRB Membership
• Minimum of 5 Members
• 1 member whose primary concerns are in the
scientific areas
• 1 member whose primary concerns are in
nonscientific areas
• 1 member who is not affiliated with the institution
• Various backgrounds and professional
competence to review specific research
activities
• Diverse by race, gender, and cultural
backgrounds and sensitivities to such
issues as community attitudes
…IRB Membership
• Knowledgeable and experienced if working
with vulnerable subjects
• No participation on a given project in which
they or their family have a conflict of interest
• Invited experts in an area beyond or in
addition their expertise to review a project
and provide input for the Board’s
consideration
• OHRP YouTube video
http://www.youtube.com/watch?v=GHtIbdLkSwU
NIH IRB SOP #2 Additional
Requirements
• Scientific or professional staff member not
affiliated with the IRB’s Institute
• Member with expertise in statistics or an
epidemiologist
• Member who is either a pharmacist or
pharmacologist,
and
• An ethicist or individual who has expertise
in the ethics of human subjects protection
• CC Department of Clinical Bioethics s
Membership Roster
• First and Last Name
• Earned Degrees
• Phone Number
• E-mail Address
• Term Start Date
• Term End Date
• Scientific Status
(scientist or non-
scientist)
• Affiliation Status
• Area of Specialty
• Narrative
Description of Area
of Expertise
• IRB Officers (e.g.
Chair, Vice-chair)
• Membership Status
(e.g., primary or
alternate)
• Alternate Member(s)
and who they can
alternate for
Must be current
IRB Meetings
• Regulations require a quorum
• More than half the members present at the
meeting
• Example: 22 IRB members then you need
12 people need to be present
• Check your IRB website for meetings
dates and due dates for submissions
IRB Meeting Minutes
Minutes must be in sufficient detail to show the
actions undertaken by the IRB including:
• Meeting Attendance (quorum)
• Vote on the action
• Summary of the discussion
• Controverted issues and their resolution
• Majority of the members are present
• Conflicts of interests of members and their recusal
• Determinations of the IRB including conditions
(stipulations) for approval
What Must Be Submitted
For Review?
• New protocols
• Amendments to existing protocols
• Continuing reviews
• Adverse events
• Safety/Compliance Reports
• Deviations & Violations
• DEC Clearance – COIs
• Status changes
IRB Review
Types of Review
• Full Board Review
• Expedited
• No greater than
“minimal risk”
• Chair or designee
• Exempt (HRPP
review, no IRB
review, SOP #)
Possible Outcomes
• Approve
• Approve with
Stipulations
• Defer Approval
• Table
• Disapprove
Basic IRB Review
Standards
• Research is sound and with no unnecessary risks
• Risks are reasonable in relation to anticipated
benefit
• Subject selection is equitable
• Adequate safeguards for vulnerable populations
• Informed consent document & methods acceptable
• Subject safety is maximized
• Privacy and confidentiality considered
• Regulatory issues approved
• Collaborative research addressed
• FDA regulated research meets FDA guidelines
Risk Assessment
• Risk = a calculation of the probability and
magnitude of a harm
• Minimal risk is 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 (45
CFR 46.102(h)(i)).
Benefit Assessment
• A research benefit is considered to be
something of health-related, psychosocial, or
other value to an individual research subject,
or something that will contribute to the
acquisition of generalizable knowledge.
• Money or other compensation for participation in
research is not considered to be a benefit, but
rather compensation for research-related
inconveniences.
Risk Category: Adults
• IRBs should assess one of the risk categories
for adults ≥ 18:
• Research not involving greater than minimal risk
• Research involving greater than minimal risk to
subjects
• Research involving greater than minimal risk but
presenting the prospect of direct benefit to the
individual subjects
• Research involving greater than minimal risk and
no prospect of direct benefit to individual subjects
Benefit Category: Adults
• IRBs should assess one of the
benefit categories:
- No prospect of direct benefit to individual
subjects, but likely to yield generalizable
knowledge about the subject's disorder or
condition
- No prospect of direct benefit to individual
subjects, but likely to yield generalizable
knowledge to further society’s understanding of
the disorder or condition under study
- The research involves the prospect of direct
benefit to individual subjects
Risk Analysis: Pediatrics
• 45 CFR 46.404: Research not involving greater than
minimal risk to the children
• 45 CFR 46.405: Research involving greater than
minimal risk but presenting the prospect of direct
benefit to the individual child subjects involved in the
research
• 45 CFR 46.406: Research involving greater than
minimal risk and no prospect of direct benefit to the
individual child subjects involved in the research, but
likely to yield generalizable knowledge about the
subject's disorder or condition
• 45 CFR 46.407: Research not otherwise approvable
which presents an opportunity to understand, prevent,
or alleviate a serious problem affecting the health or
welfare of children
IRB Review:
Post Initial Approval
What Needs to be
Submitted?
• Amendments
• Unanticipated Problems
• Adverse Events
• Safety/Compliance
Reports
• Deviations
• COIs
• Continuing Reviews
• Status changes
To whom should
these reports be
directed?
• IRB OHSRP OHRP
• FDA/Sponsor/OBA
• DSMB
• Institute CD
Amendments
SOP #10
Reasons
• Personnel
• Safety issues
• Protocol
• Treatment schedule
• New drug
• Dosage
• Follow up schedule
• Consent/Assent
How to Amend
• Prepare memo to IRB
chair
• State clearly what is to
change and why
• Marked*, updated
protocol
• Updated* consent/assent
• Other supporting
documents as required
(FDA, RSC, etc)
*track changes or bold & strikeout
Continuing Review(CR)
SOP #9
• Report on how the protocol is going:
• Any new developments in alternatives?
• Risks and discomforts haven’t changed?
• Benefits haven’t changed?
• Any new risks identified?
• Are the initial statistical assumptions still valid
• Have any/all amendments been incorporated into
the protocol and IC document?
• Protocols must be reviewed annually, or as
appropriate to risk - decision made by the IRB
• Suggest submission early, ~2 months to avoid a
lapse in approval
CR: What is Submitted…
• Continuing review application, includes
• Inclusion enrollment report
• Latest IRB approved protocol and
consent/assent forms
• Aggregated summary report:
• UPs
• Deviations
• All Unanticipated Adverse Device Effects (UADE)
• All Adverse Events (AEs) (including expected AEs,
except those specified in the protocol and approved
by the IRB as not reportable)
…CR: What is Submitted
• Any information in the literature, or
evolved from similar research, that
might affect the IRB’s analysis of
risk/benefit for the protocol.
• If such information is obtained before the
time of continuing review, it should be
reported to the IRB at the time that it
becomes known, and summarized at the
time of continuing review.
• A summary of any research-related
complaints from subjects.
Expedited Review
SOP #7A
• An IRB may use the expedited review
procedure to review either or both of the
following:
• Some or all of the research appearing on
the list and found by the reviewer(s) to
involve no more than minimal risk
• Minor changes in previously approved
research during the period (of one year or
less) for which approval is authorized
Examples of Common
Expedited Reviews…
• Collection of blood samples by finger stick, heel stick,
ear stick, or venipuncture
• Prospective collection of biological specimens for
research purposes by noninvasive means
• Collection of data through non invasive procedures
• Research on existing data, specimens, materials
collected for n
on-research purposes
• Surveys/questionnaires
• When IRB has determined and documented at a
convened meeting that the research involves no
greater than minimal risk and no additional risks have
been identified
…Examples of Common
Expedited Reviews
• Continuing Review when
• Research is permanently closed to the enrollment
of new subjects; (ii) all subjects have completed all
research-related interventions; and (iii) the
research remains active only for long-term follow-
up of subjects; or
• where no subjects have been enrolled and no
additional risks have been identified; where the
remaining research activities are limited to data
analysis
IRB Record Keeping
• What needs to be maintained
• Copies of all protocols
• Samples of approved consent documents
• Correspondence with investigators
• Board procedures
• IRB meeting minutes
• Records are subject to inspection by
authorized member of the department or
agency
• Records must be maintained for 3 years after
protocol terminated
MORE NIH IRP SPECIFICS
NIH’s FWA
• 1 FWA for 12 NIH IRBs
• Each with different perspectives and SOPs
• FWA#: 00005897, Expires: 2/25/2014
• Granted to:
• Michael M Gottesman, MD
Deputy Director for Intramural Research
NIH Intramural IRBs…
• National Cancer Institute (NCI)1
• National Heart Lung and Blood Institute (NHLBI)2
• National Institute of Allergy and Infectious Diseases
(NIAID)1
• National Institute of Child Health and Human Development
(NICHD) 2
• National Human Genome Research Institute (NHGRI) 2
• National Institute of Diabetes and Digestive and Kidney
Diseases and National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIDDK/NIAMS) 2
1 iRIS
2 PTMS
…NIH Intramural IRBs…
• Combined Neuroscience (CNS)
(red, white,
blue, purple panels) 2
• National Institute of Neurological Disorders and
Stroke (NINDS)
• National Institute of Mental Health (NIMH)
• National eye Institute (NEI)
• National Institute on Deafness and other
Communication Disorders (NIDCD)
• National Institute of Dental and Craniofacial Research
(NIDCR)
2 PTMS
…NIH Intramural IRBs
• National Institute of Environmental Health
Sciences (NIEHS)
in North Carolina2
• National Institute on Aging (NIA)
Medstar IRB in
Baltimore2
• National Institute on Drug Abuse (NIDA) and
National Institute Alcohol Abuse and Alcoholism
(NIAAA)
in Baltimore2
2 PTMS
NIH Resources & IRB
Related Committees
• OHSRP’s website
• https://federation.nih.gov/ohsr/nih/
• IRB Professional Administrators
Committee (IPAC)
• Human Subjects Research Advisory
Committee (HSRAC)
NIH Protocol Applications
• Protocol Resource Impact Assessment
(PRIA)
• Form 1195
• Form 1195-1
• All forms found at OPS website:
http://intranet.cc.nih.gov/ops/forms.html
CCR Resources
Protocol Support
Office
• Provides regulatory
support throughout the
protocol lifecycle to CCR
Investigators and their
research team
• nciprotocolsupportoffice
@mail.nih.gov
IRB Administrative
Office
• Provides administrative
support for the NCI IRB
• IRB Chair: J. Michael
Hamilton, M.D.
• https://ccrod.cancer.gov/c
onfluence/display/CCRC
RO/IRB+Administrative+
Office
• nciirbadmin@mail.nih.gov
PSO Goals
▪ Facilitate the writing of scientifically valid,
internally consistent protocols
▪ Decrease administrative and regulatory
stipulations
▪ Move protocols quickly through approval
process
▪ Manage INDs on behalf of PI Sponsors
▪ Allows Research Nurses more time for protocol
management (i.e. research documentation and
QA) and patient support
PSO Services Provided
▪ Regulatory coordination
▪ Protocol writing
▪ SRC/IRB submissions
▪ FDA submissions
▪ Other submissions
▪ Minutes for CCR meetings
▪ Administer Scientific Review
Office of Protocol Services
(OPS): Background
2000
Renamed Office of Protocol Services
Reporting line to the CFO
1996
Protocol Coordination Service Center formed
1994
Credentialing and Protocol Services became their own sections
1988
Protocols and Credentialing became a section within the
Medical Record Department
Protrak developed
Functions of OPS…
• Maintain intramural program data repository “Protrak”
• Contains ~1900 active protocols and ~7800 inactive protocols
• Over ~ 400 data fields
• Conduct a Quality Review of Actions/Abstract data into
Protrak
• Last step in the review process
• Review for NIHCC/policy/NLM requirements are adhered to
• Resolve discrepancies with Protocol/IRB Coordinators
• Update Protrak
• Route initial protocols to Director, CC/DDICR
• Assign protocol number
• Year approved by IRB
• Institute
• Sequential #
• Process 420 protocol actions per month
…Functions of OPS
• NIH CC Studies
• Post consent documents to NIH Clinical
Research Studies Active consent/Assent
Documents website
• ~580 consent documents sent monthly
• Maintain Short-form Consents available in
41 different languages
Services…
• Generate Cumulative Accrual
Reports
• BTRIS provides ability to validate and
generate cumulative enrollment reports
• http://btris.nih.gov
• Generate ad-hoc reports from Protrak
• Respond to Inquiries
• Notify CC Departments monthly of
new/terminated protocols
…Services…
• Update protocol websites/databases via feed
to the CC Data Warehouse:
• Clinicaltrials.gov
• NIH CC Search the Studies
• Protocol Query System
• BTRIS
• CRIS
• ATV System
• Provide guidance and consult on issues
related to the protection of human subjects
research/NIH or CC policies procedures
…Services
• Intramural Representative for Tracking
and Inclusion Compliance
• Serve on committees/workgroups related
to tracking and inclusion
• Analyze policy implementation
• Generate data reflecting participant accrual
by Ethnicity-Race-Gender annually for
Congressional reporting
Role of OPS in Complying
with FDAAA
• Serve as the Intramural Liaison for
Clinicaltrials.gov
• Register Protocols
• Serve as Administrator for Protocol
Registration System (PRS)
• Confirm “Responsible Party” with PI
• Monitor for Compliance
Protocols Posted by NIHCC
Updating Protocol
Information
• Nightly feed from Protrak
• Continuing review/Amendments
• Request of research team
• CC_Protocol_Services@cc.nih.gov
• If ownership of the protocol record has
been transferred in the PRS,
responsibility defaults to RP/designee
Protocol Life Cycle
Approval
Continuing
Review
Ethics Review
Institutional Review
Board (IRB)
Study
Enrollment
Ends/Data
Analyzed/No
specimens
remain
Amendments:
Expedited
or Full Board Review
Additional Reports:
Unanticipated Problems
Safety Reports
Deviations
Violations
File Closed
Post-approval Process
Principal Investigator
(PI)
Concept Review &
Approval
Scientific Review
& Approval
Protocol
Generated
Pre-approval Process
Regulatory
Reviews
COI
Questions
Thank you to Kim Mitchell, Director OPS, for
the use of her OPS slides.
