How to Navigate the IRB Process

1. How to Navigate the IRB Process Todd Rice, M.D., M.Sc. Vanderbilt Institutional Review Board Chair, Health Sciences Committee #2

2. Outline • Overview of the IRB • Type of Research / Reviews • Behavioral vs. Health Sciences • Non-human subject and non-research • Exempt vs. Expedited vs. Full-Committee Reviews • Vulnerable Populations • The journey of a research proposal

3. Institutional Review Boards • In response to many research and ethical controversies, Congress passed the National Research Act of 1974 • Established the modern IRBs • Established the federal regulations and policies for IRB oversight of human subjects research (45 CFR 46) • Established the “National Commission for Protection of Human Subjects of Biomedical and Behavioral Research” (OHRP)

4. Institutional Review Boards • Overseen by Office of Human Research Protection (OHRP) which is a division of the Health and Human Services (DHHS) • OHRP is separate from the Food and Drug Administration (FDA) • Mission of the IRB: Ensure the protection and welfare of human subjects • Each Committee composed of: • Physicians • Non-physician Scientists • Community Members

5. IRB Oversight • Non-human Subjects Research • Human subjects research • Clinical Investigation • Diagnostic or Therapeutic Procedures • Novel interventions or treatment modalities • Data Repositories • Humanitarian Use Devices • Emergency Use of investigational drugs or devices • Case Studies • Internet Research • Pilot Studies

6. 2005 Total submissions: 7004 New Studies: 1252 Non-human / non-research: 102 Exempt: 408 Expedited: 306 Standard: 345 Misc: 91 2004 Total submissions: 6172 New Studies: 1104 Non-human / non-research: 34 Exempt: 326 Expedited: 276 Standard: 348 Misc: 120 IRB Numbers

7. (615) 322-2918

8. Investigator Training • Complete training in human subjects research • CITI program • NIH program- not a substitute for CITI • Continuing education (training) annually • IRB “News You Can Use” sessions • CITI modules

9. “I’m Just a Research Proposal…” The long journey to becoming an “IRB Approved Study” With apologies to Schoolhouse Rock

10. Types of IRB Determinations • Not Research • Research = systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge 45 CFR 46.102(d) • Quality Assurance Projects • Non-human Subjects • Human subject = a living individual about whom an investigator obtains either data through an intervention or interaction with the individual or identifiable private information 45 CFR 46.102(f) • De-identified specimens from repository • Tenncare database research

11. Types of IRB Determinations • Exempt – 6 categories • Educational tests, surveys, interviews, observations • Collection or study of existing data (retrospective) • Expedited – must be no more than minimal risk • Does not need full committee review • Categories: • Prospective, non-invasive collection of biological specimens (saliva, urine) • Blood draws – 550 ml / 8 wks; ≤ 2 draws / wk or 50 cc (3 cc/kg) • Collection of data through non-invasive procedures (MRI, EEG) • Research involving materials collected for non-research purposes • Data from voice, video, digital or image recordings • Standard (i.e. Full-committee) – greater than minimal risk • Pharmaceutical studies • Device studies • Intervention studies

12. Components of Research Proposal • Protocol • IRB Application • Informed Consent Form(s) • Vulnerable Population Form(s) • HIPAA Authorization Form • ± HSRC Form • ± Conflict of Interest Declaration Form • ± Investigator’s Brochure

14. Research Protocol • Every research proposal should have a protocol • Templates are available on IRB website • The protocol should be followed rigidly • Don’t view it as a “guide” that you can be flexible with • Build flexibility into the protocol

15. IRB Application • The form should be typewritten (not handwritten) • Use the available online instructions • Don’t forget to fill in the header • Students, Residents, and Fellows can be PI of the study, but must have a faculty advisor

16. IRB Application: Pitfalls • If it meets an expedited criteria, request expedited review (#5) • If the study is associated with another study, list the associated study (#5) • Are you functioning as a coordinating center for the study? (#6)

17. IRB Application: Pitfalls • Additional VU Committee Approvals (#7) • HSRC –if any radiation for research • GCRC –if using GCRC facilities • SRC –any study involving cancer patients • Biosafety Committee –if study involves gene transfer or uses live virus • These can be pending when the original application is submitted

18. IRB Application: Pitfalls • Purpose and Background – put in lay terms for committee (#9,10) • Number to be consented vs. number to participate beyond screening (#11) • Don’t target gender, race, etc. unless justification (principle of justice) (#12) • If population is high risk for incarceration, consider applying for prisoner approval

19. IRB Application: Pitfalls • Does person obtaining consent have relationship with participants? (#19c) • Therapeutic misconception • Consider another person obtain consent • Put all research procedures and who will pay for them in table for q23. • Every study needs Data and Safety Monitoring Plan • No such thing as “no risk” study • Monitoring may be as simple as PI will monitor the study for AEs and submit to IRB

20. Writing an ICD – General Tips • Avoid exculpatory language • “You must…” or “You have to…” or language indicating they “waive” any rights • Avoid the phrase “Free of Charge” • Instead, use “at no cost to you” • Don’t forget to fill out the header • Keep length to as short as possible • Longer consents = less comprehension 1-3 1Grossman SA, et al. J Clin Oncol. 1994;12:2221-5. 2Sharp SM. Am J Clin Onc. 2004;27:570-5. 3Joseph RR. Cancer. 1994:74(suppl):2692-3.

21. Informed Consent Documents • Use the VU IRB template • Covers all the required elements • Write the ICD in the second person • “You are being asked to…”, “side effects you may feel…”, “your child…” • Identify procedures that are investigational vs. standard of care

22. Informed Consent Documents • Don’t re-invent the wheel – use IRB approved template language if possible • Adverse Event language • Allergic reaction language • Conscious Sedation language • MRI language • Genetic rider • Pregnancy language • Chemotherapy language • High risk disease language • Lidocaine language http://www.mc.vanderbilt.edu/irb/IRBForms.htm

23. Informed Consent Documents • “Keep it simple stupid” • Language must be written at or below 8th grade level • Use short words – 2 syllables or less • Use short sentences with bullets • Use lay terms, or at least put in parentheses (www.medterms.com) • Smog readability tool:www.cdc.gov/od/ads/smog.htm • Fleisch Kincaid Readability in MS Word • Tools – Options – Spelling/Grammar –check show readability statistics

24. Writing an ICD – Item # 4:Risks, Discomforts, Inconveniences • Separate into sections by medicine or procedure (risks of blood draw, etc.) • Reporting of side effect frequencies is determined locally • Common > 10 % • Uncommon 1-10 % • Rare < 1% - only need to list serious / life-threat • Also note any AEs that may be serious or life-threatening * • If don’t know, tell the participant what you do know – “one person has died…”

25. Writing an ICD – Item # 4:Risks, Discomforts, Inconveniences • Use lay terms, or at least put in parentheses (www.medterms.com) • Do not need to include treatments for side effects, unless they are routinely given (i.e. anti-emetics, etc.) • Requirement for including risks of standard of care (SOC) procedures will vary • If being consented for SOC procedure separately, state so in study ICD

26. Writing an ICD – Item #3Costs to You for taking part • Tell participants if they will have added cost • “You or your insurance will be billed for standard of care procedures” • “The sponsor is paying for … or ___ will be given to you at no extra cost” • Use Vanderbilt template language for insurance may not cover costs associated with research

27. Writing an ICD – Payment in Cases of Injury (#6) • Explain if any compensation or medical treatment is available for injury • Who will pay • What treatment will be covered • Only immediate and necessary • No additional monies for loss of wages • Use adverse event / immediate necessary care template language • Varies with contract language for industry-supported studies – submit contract

28. Writing an ICD – Items #7a & 7bBenefits to Participants or Others • Make them aware if no personal benefit • Avoid “your taking part will benefit others” • “instead, the results of this study, will help..” • Put “but no promises can be made” at the end of any possible benefits

29. Writing an ICD – Item #9“Payments” for Participation • The FDA and OHRP state these should be “re-imbursements” for time and inconvenience • Must be “reasonable” for procedures in the study and not coercive • They should be pro-rated over the course of the study • Do not have to be exactly equal. Can “reimburse” more for finishing the whole study • Payment is NOT a benefit of taking part in the study • If total payment > $600, put template language about being taxable and reported to IRS

30. Vulnerable Populations • Children • Need child assent & parental consent form • Cat 1 = minimal risk; Cat 2 = > min risk, benefit • Cat 3 = “slightly > min risk”, no benefit; • Cat 4 = > min risk and no possibility for benefit • Pregnant Females • Prisoners – if not approved, must withdrawal * • Cognitively Impaired (Decisionally impaired) • Unimpaired population cannot be substituted • Surrogate consent • Need for ombudsman

31. After Initial Submission… • Within 1-3 weeks, will get PA pre-review • respond to all requests / questions • After response to pre-review, will go to full-committee within 1-2 weeks • Deferred, Approved pending, or Approved • Respond to all concerns • FINAL APPROVAL with STAMPED CONSENT FORMS

32. After Obtaining Approval • Continuing review must occur at least annually • Amendments must be submitted for any changes to the application, protocol, study personnel, or informed consent • Protocol Violations should be submitted as adverse events • Serious Adverse Events (unexpected, serious, related) need to be submitted when they occur • Other Adverse Events submitted as summary at time of continuing review

33. Continuing Review • Continuing review form • Notices sent out 8 weeks in advance • Submit early to allow time to resolve any questions or issues • Cover letter with summary of study procedures • If not re-approved by expiration date, study will expire for lapse

34. Continuing Review • On Continuing review form, include # of patients consented, enrolled, withdrawn • Submit summary of AEs • Report any problems or unexpected events • Submit DSMB or other safety reports • Problems recruiting • May get asked for explanation if no enrollment

35. Amendments • Amendment form • Submit whenever something changes • If minor, may be handled in expedited fashion if no change to ICF • Provide detailed summary of changes • Form also used for submission of reports • DSMB, Safety committees

36. Adverse Events • Adverse Event form • Submit serious, unexpected, and related AEs in “timely fashion” • If outside Vanderbilt, only need to submit in real time if changes required to consent form • Protocol violations submitted as AEs • If medwatch report submitted to FDA, attach report in lieu of answering questions 4-10

37. Adverse Events • Must choose one of the following: • Currently described as risk in ICD • Not described as risk and no need for revision to ICD because … • Give reason for investigator belief that it doesn’t need to be in ICD (i.e. not related, etc.) • Not described as risk but revision to ICD needed

38. Finishing Up an Approved Study • If no longer enrolling, won’t get stamped consent form (Unless new risks to communicate to pts) • Still receiving research interventions (i.e. study blood draws, study procedures) • Only long-term follow-up (i.e. all procedures std of care) • Only data analysis (no interaction with patients) • Close study – provide summary report

39. QUESTIONS?? Useful Resources: IRB www.mc.vanderbilt.edu/irb Phone: 322-2918 (ask for protocol analyst or the Process Improvement Team) Research Support Services http://www.mc.vanderbilt.edu/root/vumc.php?site=support Phone: 322-7343