How to Navigate the IRB Process

Todd Rice, M.D., M.Sc.Vanderbilt Institutional Review BoardChair, Health Sciences Committee #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

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)

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

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

IRB Numbers2005

• 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

(615) 322-2918

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

“I’m Just a Research Proposal…”

The long journey to becoming an “IRB Approved Study”

With apologies to Schoolhouse Rock

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

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

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

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

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

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)

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

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

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

Writing an ICD – General Tips1. Avoid exculpatory language

• “You must…” or “You have to…” or language indicating they “waive” any rights

2. Avoid the phrase “Free of Charge”• Instead, use “at no cost to you”

3. Don’t forget to fill out the header4. 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.

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

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

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

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…”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

QUESTIONS??Useful Resources:

IRBwww.mc.vanderbilt.edu/irb

Phone: 322-2918 (ask for protocol analyst or the Process Improvement

Team)

Research Support Serviceshttp://www.mc.vanderbilt.edu/root/vumc.php?site=support

Phone: 322-7343