How to Write an IRB Protocol YVONNE BOYD

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 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/ct 2/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 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 v. 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 START

1. The Protocol 2. The Protocol Schema Protocol Description The Title Page Benefits from Use of the Protocol Writing the Protocol: Tips and Challenges 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: ü Names and affiliations for Sub-Investigators ü IND or IDE holder (Sponsor or Sponsor-Investigator) ü 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: 1. Healthy volunteers 2. Between the ages of 1880 Exclusion Criteria: 1. History of heart disease 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? ü § 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 (10 ml). 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 (10 ml) 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 (10 ml) 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 (10 ml) 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 (10 ml) 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 self-administered 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? ü 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 Ø Only if applicable

1. The 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/Biomedical 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/jul 01 a. 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

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