Writing an Investigator Initiated Protocol: From Proposal to IRB-Ready

1. Erin Sandene RN, BSN Pediatric Research Office Writing an Investigator Initiated Protocol:From Proposal to IRB-Ready

2. What is a Protocol? ICH Guidelines: �A document that describes the objectives, design, methodology, statistical considerations and organization of a trial�-- E6, Section 1.44

3. Protocol vs. IRB A protocol is the scientific document (the plan) for a course of medical treatment or procedure. The IRB application will require explanation of the protocol and can serve as a guideline for protocol development.

4. Writing a Protocol- Getting Started Two Things I Learned the Hard Way Writing a protocol is a team effort! This takes time, with many drafts!

5. What�s gonna work?Teamwork!!-The Wonder Pets Recommended co-authors or reviewers: Statistician(s) Data manager Clinicians or epidemiologist Study coordinator or implementation expert Anyone else providing care to the study population

6. Protocol versus Grant Protocol: the plan for a course of medical treatment or scientific experiment Purpose: Describes a single study in detail Focus: Organized around specific objectives Feasibility: Specifics of enrolling, implementation, details Reviewed by: Scientists, Sponsor, IRBs Tone: Informative; focused on details

7. Protocol versus Grant Grant proposal : Purpose: Obtain funding Focus: Describes Aims, methods, hypotheses Feasibility: Costs, staffing, equipment Review by: Scientific review committee, funders Tone: Persuasive

8. The Scientific Question Clear idea of the primary research question being asked Objective(s): Specific Measurable Relevant Feasible Ethical Everything in protocol relates back to research question

9. Background/Rationale ?Review findings of other research ?Rationale�why your study needs to be done ? Describe possible unique relationships with a specific population ?Known or potential risks and benefits? (as obtained from literature review and Primary Investigator) ?If using intervention, describe in full detail

10. Sources for Background/Rationale Primary Investigator PUBMED (www.pubmed.com) DynaMed (www.ebscohost.com) Emedicine (emedicine.medscape.com) First Consult (www.mdconsult.com) Various research journals (http://www.unmc.edu/library/)

11. Study Objectives What are the specific scientific objectives (aims) of the research? Clearly state primary and secondary objectives�the fewer the better!!! Primary Example: Safety, Efficacy

12. Study Objectives Typically include �action� word, such as assess, measure, compare, etc. Example � Quantification of research nurse coordinators expressing signs and symptoms of anxiety on Day 1 of work versus Day 90.�

13. Study Objectives Method by which objective is met, outcome measures Example: �We will determine the amount of research nurse coordinators expressing anxiety symptoms via subjective reporting, objective assessment, and by utilizing the �anxiety assessment survey.�

14. Design Type of study, e.g., observational, randomized Specific outcomes/endpoints to be measured and methods of data collection How many participants, in which groups Time to complete enrollment Describe study groups/arms Expected duration of trial periods including follow-up

15. Study Population Define Population from which study participants will be drawn-focus on defense of why this population was selected Estimate number of participants Describe recruitment strategies- remember HIPPA, does your investigator have ethical/professional access to subjects? Age, gender and ethnicity

16. Study Population Example � 57 male and female research nurse coordinators with no prior psychiatric history.�

17. Study Population Special Considerations: Children Children should not be excluded from participating in research unless there are sound scientific, ethical or other reasons not to include them.

18. Study Population Special considerations: Pregnant Women Pregnant women and fetuses are defined by federal regulations as populations requiring additional protections.

19. Study Populationhttp://www.hhs.gov/ohrp/humansubjects/guidance Special Considerations: Prisoners Prisoners are defined by federal regulations as populations requiring additional protections.

20. Study Population Inclusion Criteria Inclusion Criteria Describe characteristics and conditions necessary for eligible persons to be included. Include willingness to provide consent!

21. Study Population Exclusion Criteria Exclusion criteria Describe characteristics that would disqualify otherwise eligible participants. Include exclusionary concomitant medications.

22. Study Procedures/Evaluations Obtain consent Any tests needed prior to signing consent? Medical history, physical exam, specimen collection Interview/questionnaire Counseling procedures Medications/treatments permitted and not permitted -ICH E6, Section 6.6

23. Study Procedures/Evaluations Screening: what happens to participant at first contact, including consent Enrollment: baseline assessment, randomization procedures, etc. Follow-up Visits: plan for retention What and how data are collected at each visit

24. Special considerations Genetic Testing Blood/Tissue Banking

25. Study Procedures/Evaluations Laboratory Evaluations Include specific test components and estimated volume and type of specimens needed for each test Specify laboratory methods List special assays or procedures required (e.g., immunology assays, sputum specimens, photographs) Instructions for specimen preparation, handling, storage, and shipment

26. Data Management Describe source documents Refer to DMID Source Documentation Standards Indicate schedule for data reports, and final study reports Describe how documents/data maintained Statement about who will have access Specify length of time for retention of study records

27. Safety Assessment Define potential risks Describe types of AEs that may occur, including lab values Procedures to follow if AE occurs Describe methods used to track AEs Report pregnancies ICH E6, Section 6.8

28. Safety Assessment Data and Safety Monitoring Focus on how subject safety will be assessed on an ongoing basis throughout the study. This includes specific procedures to be used to prevent or minimize potential risks and discomforts associated with study interventions and procedures. What are the specific stopping rules for research?

29. Benefits/Risks of Research To The Subject To Society Risks physical psychological sociological economic legal

30. Risk/Benefit analysis Minimal Risk (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) Greater than minimal risk but less than significant risk Significant Risk

31. Alternatives to Study Participation This section should include a reasonably detailed description of the alternatives, including therapeutic alternatives, which could be of benefit to the subject should they elect not to participate in the protocol. In some cases the alternative to participation in the research is not participating. Would any of the interventions in the study be available to the subject if they did not elect to participate in the study? Note: For example, reasons why a therapeutic intervention performed as a part of the study might not be available off-study would include (1) the intervention involves use of an unapproved drug, device or biologic, or (2) the intervention represents a significant deviation from the standard of care at UNMC and The Nebraska Medical Center and therefore should not be performed outside of a research context. -UNMC Biomedical Research Application

32. Statistical Analysis Meet with a statistician prior to even beginning protocol development!!!!!! College of Biostatistics 559-4112 Many times, your statistician can recommend study design and develop this section of your protocol. Include the process in which anticipated analysis problems will be handled Include timing of interim analysis

33. Informed Consent This is the single most important aspect of research!!! Pfizer sued for improper consent in medical experiments in Nigeria. http://biotech.law.lsu.edu/cases/research/Abdullahi_v_Pfizer.htm Brief - Misrepresentations about a physician's qualifications void informed consent - Duttry v. Patterson, 741 A.2d 199 (Pa.Super., 1999) - on appeal http://biotech.law.lsu.edu/cases/consent/Duttry_v_Patterson_brief.htm Lack of informed consent in pediatric heart patient in Delaware http://www.theheart.org/article/218117.do

34. Informed Consent Refer to ICH E6, Section 4.8 Describe process of obtaining consent Special attention for minors, different languages, and low literacy Identify if more than one consent used, i.e., for screening, for enrollment, for specimen storage Must be approved by IRB(s) prior to use

35. Resources http://www.unmc.edu/dept/irb/ UNMC IRB www.ich.org ICH guidelines http://www.fda.gov/oc/gcp/default.htm GCP http://www3.niaid.nih.gov/research/resources/DMIDClinRsrch/ DMID guidelines

36. Questions Please feel free to contact us at anytime!!! Erin Sandene esandene@unmc.edu 559-3480 Machelle Zink mazink@unmc.edu