Transcript 2.0 Rationale and Specific Aims: Example

How to Write an
IRB Protocol
YVONNE BOYD, MS, CIP
PROCESS IMPROVEMENT TEAM
VANDERBILT HUMAN RESEARCH PROTECTION PROGRAM
Financial Disclosure
This speaker has no financial interests
or relationships to disclose.
1.The Protocol
Protocol
Description
Benefits from Use
of the Protocol
Writing the
Protocol: Tips
and Challenges
2. The Protocol
Schema
3. IRB Review
of the Protocol
The Title Page
Criteria for
Review: 45 CFR
46.111
Section:
Descriptions
IRB Reviewer
Comment Form
Section: Tips
Section:
Examples
The Office of Human
Research Protections:
An Investigation
The Protocol defined
A protocol as the written description of a study has
sometimes been referred to as a researcher’s
blueprint.
This written description typically includes
background information, objectives, eligibility
criteria, statistical plans, research procedures and
references.
1. U.S. National Institutes of Health. Glossary of Common Site Terms. 2014. Retrieved from
http://clinicaltrials.gov/ct2/about-studies/glossary#I
2. US Department of Health and Human Services. Prepare a Protocol for the Study. 2011. Retrieved from
https://www.nichd.nih.gov/health/clinicalresearch/clinical-researchers/steps/Pages/prepareprotocol.aspx
The Protocol: Key Point
All protocols, exposes participants to some
degree of risk even if that risk is minimal.
Less
than
Minimal
Risk
Minimal Risk
Greater
than
Minimal
Risk
Benefits from Use of the Protocol
1. “It guides study investigators to conduct the study according
to standardized criteria and it allows replication in subsequent
studies.” Rosenthal, J, Schafer, Mattias, B et al, 2014
2. “It provides detailed information on all aspects of the
planning and conduct of a research project and is the main
document for evaluation of the planned research (e.g. by an
independent ethics committee [IEC] and regulatory
authorities).” Rosenthal, J, Schafer, Mattias, B et al, 2014
3. Rosenthal, R., Schafer, Mattias, B, et al. How to write a surgical clinical research protocol:
literature review and practical guide. The American Journal of Surgery 2014; 207: 299-312.
To Do List when Creating a Protocol

Identify a research question or questions

Conduct a literature search relevant to the research question

Locate collaborators, if necessary

Decide upon a study design and statistical plan

Determine if the study will be experimental or observational

Identify any investigational agents/devices

Review applicable research regulations and IRB
policies/procedures

Consider funding options

Use available internal resources
4. Hanson, BP. Designing, conducting and reporting clinical research. A step by step approach. Injury International Journal of the
Care of the Injured 2006; 37: 583-594.
Randomized Control Trial
Experimental Studies
Quasi-Randomized Control Trial
Retrospective
Cohort
Study
Designs
Prospective
Observational Studies
Case
Control
Case Series
Case
Studies
Study Design Types to
Consider when Writing a
Protocol
4. Hanson, BP. Designing, conducting and reporting clinical research. A step by step approach. Injury International Journal of the
Care of the Injured 2006; 37: 583-594.
Potential Challenges When Writing a Protocol:

Ensuring that all scenarios are addressed

Creating an effective road map to guide anyone who
may become involved with the trial

Staying within the parameters of the Protocol
 Do
only what you say you are going to do, nothing more
and nothing less.

Making sure the study is scientifically sound and has
sufficient statistical power to differences when they
exist
The Protocol: Key Points
The Protocol should be written in a manner that
will allow for duplication.
If the Protocol is poorly written, no subsequent
data analysis may be able to salvage the trial
results.
The written Protocol should support the results of
the trial.
COMPLETED
PROTOCOL
PROTOCOL
START
1.The Protocol
Protocol
Description
Benefits from Use
of the Protocol
Writing the
Protocol: Tips
and Challenges
2. The Protocol
Schema
The Title Page
Sections:
Descriptions
Section: Tips
Section:
Examples
3. IRB Review
of the Protocol
Criteria for
Review: 45 CFR
46.111
IRB Reviewer
Comment Form
The Office of Human
Research Protections:
An Investigation
What to Include on the Protocol Title Page

The Full Protocol Title

The Principal Investigator’s Name and Address

Sponsor or Funding Agency Details (if applicable)

Protocol Version Date

Protocol Version Number

Optional Title Page Elements:

Names and affiliations for Sub-Investigators

IND or IDE holder (Sponsor or Sponsor-Investigator)

IND Number
International Study Funding Agency
SPONSOR NAME
555 ISFA Drive
AND ADDRESS
Anywhere, NJ 07902
PROTOCOL TITLE
The Effects of Tagalong Peanut Butter Girl Scout Cookies: A Randomized Trial
PI NAME Janice Doe, M.D., Department of Medicine
AND
Vanderbilt University, 504 Oxford House, 4315
ADDRESS
James Jones, M.D., Department of Medicine,
Vanderbilt University
SUB-INVESTIGATOR
Version 2
April 23, 2013 PROTOCOL VERSION NUMBER
AND VERSION DATE
NAME AND ADDRESS
Sample Study Schema/Plan
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
11.0
12.0
Background
Rationale and Specific Aims
Animal Studies and Previous Human Studies
Inclusion/Exclusion Criteria
Enrollment/Randomization
Study Procedures
Risks of Investigational Agents/Devices (side effects)
Reporting of Adverse Events or Unanticipated Problems involving Risk
to Participants or Others
Study Withdrawal/Discontinuation
Statistical Considerations
Privacy/Confidentiality Issues
Follow-up and Record Retention
Appendices
1.0 Background: Tips




Provide a historical, research based account of the topic
Explain why the research is important.
Include any pertinent pre-clinical, pilot, and preliminary
and/or unpublished data to support the conduct of the
proposed study.
Provide any applicable information about the disease or
condition:
How many people are affected?
Is the condition chronic or acute?
1.0 Background: Example
Over the past 8 decades, the number of boxes of cookies
being sold by girl scouts has steadily increased. Although
studies have been conducted by the Girl Scouts of America
regarding what may motivate young girls to lead a healthier
lifestyle (Schoenberg, 2006), research has not been
conducted on the potential benefits or risks associated with
the consumption of the cookies to determine its impact on
the health of the American population. This study will
examine how consuming the Tagalong peanut butter cookie
affects glucose and cholesterol levels.
2.0 Rationale and Specific Aims: Tips

State the hypothesis and scientific justification for
conducting the study or why something which is widely
accepted needs to be challenged (new information or
findings).

Be sure to justify the target population, endpoints, and
explain why particular techniques will be used for endpoint
assessment, measurement of drugs, drug effects, etc.

Clearly differentiate the specific aims in order of
importance.
2.0 Rationale and Specific Aims: Example
Each year, thousands of boxes of girl scout cookies
are sold and consumed. However, the ramifications
of subjecting the human body to sudden increases in
sugar and fat has yet to be explored. The effect on
heart disease, hyperglycemia, and weight gain needs
to be examined to determine if warning labels need
to be added to the product packaging and to
determine how long it will take for serum and
cholesterol levels to return to baseline.
2.0 Rationale and Specific Aims: Example
1. To characterize the relationship between
consumption of girl scout cookies and health risks;
2. To monitor changes in glucose and cholesterol
levels after consuming the study agent for a
period of up to 30 days; and
3. To determine how long it will take for glucose and
cholesterol levels to return to baseline.
3.0 Animal Studies and Previous Human
Studies: Tips

Include language detailing other human or animal
research on the topic.

Provide any references that are relevant to the design and
conduct of the study.
4.0 Inclusion/Exclusion Criteria: Terminology
INCLUSION CRITERIA
The criteria or standards, set
out before a study or review
which are used to determine
whether a person can
participate in a research
study.
EXCLUSION CRITERIA
The criteria or standards, set
out before a study or review
which are used to determine
which individuals are not
suitable to participate in a
study.
5. Agency for Healthcare Research and Quality. Explore Your Treatment Options: Glossary.
Retrieved from http://effectivehealthcare.ahrq.gov/index.cfm/options/glossary/?keywords=glossary
4.0 Inclusion/Exclusion Criteria: Tips and Example
Inclusion/Exclusion Criteria Tips:

Utilize bullets or numbers for each criterion to aid identification

Explain any procedures that will be used to determine eligibility

Note any special assessments that will be conducted (e.g., depression or
suicidal ideation screenings)
Inclusion Criteria:
Exclusion Criteria:
1. Healthy volunteers
1. History of heart disease
2. Between the ages of
18-80
2. Uncontrolled diabetes
3. Peanut or chocolate allergy
4. Inability or unwillingness to
give informed consent
5.0 Enrollment and Randomization: Terminology
ENROLLMENT
BLINDING
The number of participants in a clinical study.
A way of making sure that the people involved in
a research study — participants, clinicians, or
researchers — do not know which participants
are assigned to each study group.
RANDOMIZATION
A method of assigning participants in clinical
trials into two or more groups randomly (by
chance).
One group receives the treatment or drug being
researched, and one group receives either no
treatment, a placebo (inactive substance), or
another drug.
Participants are assigned to a group by various
methods.
Blinding is used to make sure that knowing the
type of treatment does not affect a participant's
response to the treatment, a health care
provider's behavior, or assessment of the
treatment effects.
Agency for Healthcare Research and Quality. Explore
Your Treatment Options: Glossary. Retrieved from
http://effectivehealthcare.ahrq.gov/index.cfm/options/
glossary/?keywords=glossary
5.0 Enrollment/Randomization Tips

State how participants will be identified and recruited for the trial.

Describe the procedure for consenting participants.

Detail whether or not potential participants have a relationship with
the PI?


If so, explain the measures the PI will use to remain impartial
when presenting the study?
Include the number of participants that will be consented along
with number of participants expected to complete the trial?
5.0 Enrollment/Randomization Tips






Provide a description of any vulnerable populations that will be
enrolled.
Include the duration of the study.
If the study involves blinding, then explain all aspects of the
blinding plan.
If the study involves use of a placebo, then describe its use.
If the study involves randomization, then include the details.
State the ratio for randomization (1:1- 2:1).
5.0 Enrollment/Randomization: Example

Participants will be selected from the…

After expressing interest in the study, the coordinator will provide an
overview of the study and obtain consent prior to initiating any research
related procedures.

Approximately xx participants will be consented with xx being expected to
complete the study.

Participants will be randomized to receive either the active study agent or
the placebo (1:1 ratio).

Study agents will be provided by Girl Scouts of America and will be stored
and dispensed through the Investigational Drug Service.
6.0 Study Procedures: Tips
Depending on the nature of the study, include language answering the following
questions:

Will patients be withdrawn from current medications or other treatments?

Is there a run-in period?

Will participants have a baseline assessment for the status of the disease being
studied?

Are overnight stays involved?

Who will administer the study drug?

What dose of the study drug will be use and how long will participants take the study
drug?

What will occur at each visit (labs, assessments, other tests). Consider including a chart
or table.

What measures will be used to minimize risk and monitor participant safety?
6.0 Study Procedures: Example
Participants will be asked to come to the clinic, and upon arrival
will have their blood drawn (10ml). Once the blood draw is
complete, the participant will be asked to consume the study
agent. After a 30 minute rest period, a second blood draw
(10ml) will be performed. The participant will be asked to
consume a second study agent and will return to the waiting
area. After another 25 minute rest period the participant will be
asked to consume the final study agent and the blood draw
(10ml) will be repeated. Patients will be monitored for signs or
symptoms of an allergic reaction, for an additional 60 minutes
after the blood draw, prior to being released.
6.0 Study Procedures: Example






Subjects will be discharged with a 30 day supply of the study agent and will
be asked to consume 6 study agents per day.
Weekly phone calls will be made to monitor for adherence and safety.
A follow-up visit with a blood draw (10ml) will be conducted at the clinic
between days 28-32. Participants will return any unused study agents at
that time.
Three additional follow-up visits will be conducted at approximately 60, 90,
and 120 days. Participants will be asked to provide a blood sample (10ml)
at each visit to monitor glucose and cholesterol levels.
Participants will not be withdrawn from any current meds. The study agents
will be administered by the study staff while at the study center and selfadministered at home.
Participants will be monitored for safety and compliance through weekly
phone calls, which will be made by the study staff and will follow an
approved script.
7.0 Risks: Tips
State all adverse events observed in other previous
animal or human studies or any laboratory
observations.
 Rank according to common, uncommon and lifethreatening/severe.
 Explain if unknown risks are possible.

7.0 Risks: Example
Most common side effects:
 Weight gain
 Blood draw risks
Less common side effects:
 The active study agent contains peanut products. The risks
associated with peanut allergies can range from a mild rash to
an anaphylactic reaction.
Unknown risks:
Because this treatment is investigational, meaning non-FDA
approved, there may be risks that we do not know about at this
time.
8.0 Reporting of Adverse Events or Unanticipated
Problems: Tips

What types of events will be reported?

Be clear and specific, definitions may be helpful.
Describe the Data Safety Monitoring Plan in detail.
 Is there a Data Safety Monitoring Board? If so, who
are the members and how often will they meet?
 Provide reporting procedures to the Sponsor, IRB, or
federal agencies (e.g. the FDA).

8.0 Reporting of Adverse Events or Unanticipated
Problems: Example

While the data and safety monitoring plan does not
include a formal data and safety monitoring board
(DSMB), the PI will be responsible for monitoring each
participant during the study and for 60 minutes after the
final ingestion of the study agent. Participants will be
contacted on a weekly basis while receiving the study
agents to monitor for adherence and adverse events.

All anaphylactic reactions will be promptly reported to the
IRB, per the IRB policy for adverse event reporting.
9.0 Study Withdrawal/Discontinuation: Tips



Explain the procedures for withdrawing a
participant.
Detail what types of circumstances will lead to
stopping the study.
State the circumstances under which the PI would
withdraw a participant (unacceptable adverse
events, non-compliance, etc.).
9.0 Study Withdrawal/Discontinuation: Examples

Participants may withdraw from the study at any
time. The study agent should not be stopped
abruptly, but should be tapered instead.

The PI will withdraw any participant who
experiences an unacceptable adverse event or is
non-compliant.
10.0 Statistical Considerations: Tips

Provide evidence the study has adequate power to detect a
difference between the two groups or to answer the question(s)
being asked.

If the study could have multiple outcomes, has a power
analysis been conducted for each outcome?

Will an interim analysis be conducted to determine any
difference between the study groups?

Will predetermined rules be established for stopping the study
due to futility?
10.0 Statistical Considerations: Tips
Consider using REDCap.
 REDCap features include options for:


Scheduling

Survey building

Export of data to Microsoft Excel, PDF, SIS, Stata, R, or
SPSS for analysis

Auto-validation, calculated fields, file uploading,
branching/skip logic and survey stop actions (advanced
features)
10.0 Statistical Considerations: Example



All participants who are randomized will be included
in the data analyses.
Demographic data will be summarized with
standard deviation, mean, median, maximum and
minimum.
The primary endpoint is change from the baseline of
blood glucose and cholesterol levels at 30, 60, 90
minutes after ingestion of the test agent.
11.0 Privacy/Confidentiality: Tips
Include language answering the following questions:

How will the privacy and confidentiality of participants be
protected?

Will data be coded, stored in a password protected
computer?

Who has access to the code?

Is information being shared with other investigators or
institutions?
11.0 Privacy/Confidentiality: Example
All study related materials will be maintained in a
locked file cabinet or stored in a password protected,
encrypted electronic database. Only the PI and
study coordinator will have access to the cabinet key
or password. Information will not be shared with other
investigators or institutions.
12.0 Follow-up and Record Retention: Tips

How long will patients be monitored or possibly screened
for signs of disease?

If there is evidence of disease, what procedures will be
followed?

How long will records be maintained after study
completion?
Must be a minimum of 3 years
 Beyond 3 years, requirements for record retention vary with the
type of research conducted and provisions of the Investigator’s
funding source.

12.0 Follow-up and Record Retention:
Example

Participants will receive weekly follow-up phone calls and
will return to the clinic for 4 follow-up visits. At each
contact, participants will be asked if they have
experienced any adverse events.

All study related documents will be retained by the
Investigator for a minimum of 6 years. At this time, all
records will be destroyed in accordance with HIPAA and
institutional policies and procedures.
Miscellaneous Sections

References

Appendices

Blinding/Un-blinding Procedures
 Only if applicable
1.The Protocol
Protocol
Description
Benefits from Use
of the Protocol
Writing the
Protocol: Tips
and Challenges
2. The Protocol
Schema
3. IRB Review
of the Protocol
The Title Page
Criteria for
Review: 45 CFR
46.111
Sections:
Descriptions
IRB Reviewer
Comment Form
Section: Tips
Section:
Examples
The Office of Human
Research Protections:
An Investigation
The Vanderbilt IRB
requires submission
of a Protocol for
consistency in the
review of Health
Science/Biomedic
al research.
The Protocol also
serves as the
reference point for
review of a Health
Science/Biomedical
IRB Application.
Tip: The Protocol and all applicable study documents,
including the IRB Application, should align.
Criteria for IRB Approval: 45 CFR 46.111








Risks to subjects are minimized
Risks are reasonable in relation to anticipated benefits
Selection of subjects is equitable
Informed consent is obtained when required
Informed consent is appropriately documented
Data and safety monitoring is adequate
Privacy and confidentiality are protected
Additional safeguards are in place for vulnerable populations
Note: The above criteria are used by the IRB during reviews.
The Office of Human Research Protections: An
Investigation

Ellen Roche, a 24 year old healthy volunteer, died as a
result of her participation in a research study at John
Hopkins.

As a result, the Office of Human Research Protections
(OHRP) conducted an investigation.

The OHRP noted “the investigators and the IRB” failed to
obtain published literature about the known association
between hexamethonium and lung toxicity.”
6. Department of Health & Human Services. RE: Human Subjects Protections Under Multiple Project Assurance (MPA) M-1011 .
Retrieved from http://www.hhs.gov/ohrp/detrm_letrs/jul01a.pdf.
7. Savulescu, M Spriggs. The hexamethonium asthma study and the death of a normal volunteer in research. Journal of Medical
Ethics 2002; 28: 3-4
QUESTIONS?
CONTACT INFORMATION
VANDERBILT HUMAN RESEARCH PROTECTION
PROGRAM 615-322-2918
YVONNE BOYD
[email protected]
615-322-2549