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What does the IRB really
want? Elizabeth L. Hohmann MD
Chair and Director, Partner’s IRBs
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Today’s Topics
• Describe review process for context.
• Discuss protocol sections and provide explicit practical advice for your submissions.
• Frequently encountered problems and how to avoid them.
• Consent forms/writing (tiny)
• Miscellaneous topics
• Responding to IRB Reviews
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Who’s on the IRBs?
• Now have SEVEN panels at MGH/BWH.
• Physicians, Scientists, RNs, Lay members, Clergy, Statistician, Ethicists, Pharmacist, Genetic Counselor, Lawyer, HMS…. And a Psychiatrist!
• Reviewers are confidential, they may contact you if they wish. (If they do that is a good thing – answer their questions).
• Most meet twice monthly
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Really:
• Primary and Secondary reviewer
system, similar to NIH study section.
• Surgeons are not assigned psychiatry....
• Majority vote carries
• Discussion by full Committee.
• Committee decides upon action and
review interval (maximum: one year).
• If you don’t have it in print….
• Every file stands alone
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Panel Staff
• Scientific Chair (MD, PhD, RN/PhD)
• Administrative Chair (Science/profess.
training or lots of IRB experience).
– Some are CIPs= certified IRB professional!
• You may communicate with any of
these people directly; JUST ASK.
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CR panels
• Regulations require a substantive annual review by a Committee at least annually.
• “Reality check” on the study to date.
• What’s new in your project and literature?
• Not usually same group that did initial go!
• Think about what you would want to know if you were not highly familiar.
• Make it easy for the reviewers……
• Be aware problems may trigger an audit!
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Actions of the committee
• Approval (miracles happen!).
• Requires modifications (requests for alterations, usually with specific directions)
• Deferred (not enough information to assess risk benefits, any substantive clarifications or questions; “open-ended questions”….).
• Disapproval (major scientific or ethical problems. Maybe you should talk to someone….).
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The Full Review Protocol.
• We are a scientific and ethical review.
• Scientifically invalid research, or research not able to answer the questions posed or add something valuable to medical science is not ethical – it’s a waste of time/resources
• “Science Lite” is poorly received (by your peers, not IRB administrators).
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Full Protocol
• Data
sheets/ancillary
• Background
• Specific Aims
• Subject selection
• Subject enrollment
• Study procedures
• Biostatistics
• Risks and
Discomforts
• Potential Benefits
• References
• Tools/Attachments
• Ethical / Regulatory
Considerations
• Site specific details
• Qualifications and
Responsibilities
1. Big Problem #1: An
appropriately qualified individual
did not spend enough time on the
preparation of the protocol.
2. Big Problem #2: We can’t tell
what’s planned or we don’t have
enough data to assess risks and
benefits (e.g. no previous animal
or clinical data provided).
3. Big Problem #3: 100 Little
Ones!
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Deferral safety issues
• Possible over-sedation/drug interaction
• Inadequate safety monitoring procedure
• No objective drop criteria/safety stops
• Animal studies inadequate
• Invasive techniques not justified
• Concerns re withdrawal of current Rx
• Not necessary to use humans - rare
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General pointers-1
• An NIH grant is not a protocol – Please don’t cut-and-paste it into the protocol
documents!
• Aim for up to date generalist physician
• The protocol summary is a key document – Most members will only read this document
and the consent form.
– Key for continuing review.
– Highlights and summarizes your study.
– Sets the “tone” for your review!
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GP’s 2 – Protocol Summary
• Intended for college ed. audience and should not be highly technical. But also not like a consent form (9th grade).
• Spend some time on it. Avoid extensive use of acronyms please!
• Don’t make it a duplicate of detailed protocol! Must be CONSISTENT with that.
• Should include site specific details.
• No references needed – put in detailed protocol.
• Please don’t use the word “YOU” in the protocol summary, it puts reviewers off.
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General Pointers-3
• Think ahead: Ancillaries: Nursing, Radiation, Pharmacy, RDRC, Biosafety, Biomed Engineering.
• Contact these groups directly – they can help you and want to! Get to know them.
• Consider a picture = 1000 words. Really.
• Include a cover letter if you want.
• Ask an experienced colleague, current or past IRB member in your division to help or review = Priceless!
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Specific Aims
• Be clear and concise, with some detail
for the expert if relevant.
• Don’t be too optimistic or nonspecific.
• Identify secondary, exploratory goals,
“while I’m there” goals as such.
• Aims drive results reporting on CT.gov
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Background -1
• Clarify clinical problem briefly
• Summarize current data and therapy
• Justify populations, e.g.
– Children, end-stage pts vs. early stage
• Rationalize study design: equipoise.
• Don’t provide outdated or unlinked refs.
• Summary of YOUR previous protocols or work in the field may be v. helpful!
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Subject Recruitment -1
• How are you identifying the subjects?
– Med records search, EW log, clinic log, referrals to you, advertisements, registries, databases, support groups, families?
– Postings, letter to MDs or pt, website, “scripts” need advance approval
– READ the advertising policy.
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Subject Recruitment-2
• Who initiates contact with subject, and where and when?
– If based upon confidential medical info, should be with a person with a reason to know that info.
– Industry protocols provide NADA here
– ? Rationale for chosen approach?
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Subject Recruitment-3 • No “cold calls!”
• “Permission” of PMD alone is not adequate - they must participate in the process.
• Outpt. contact by letter, co-signed by primary or specialist physician known to the subject and a researcher (PI).
• PMD cover note on research letter; see web
• You may call after letter sent, if no “opt out”
• Opt out (std) vs. Opt in (S, D, P, A)
• Scripts for non-physicians. Checklist?
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Subject Recruitment-4
• Contact in person in the course of care -OK
– Responsible attending MD must be aware
– Medically appropriate time and place.
– A caregiver should introduce you!
– Where??
• Genetic counselor’s office : YES.
• Cardiac stepdown unit: MAYBE.
• Open chemotherapy suite: NO.
• Wheeling into OR: NO, NO, NO!
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Subject Recruitment-5
• “Coercion” or undue influence
• Most prominent when you are fulfilling 2
roles: physician /researcher.
• Prominent when last ditch or no std care.
• We will ask you to address this issue!
• Colleagues, extra time to consider, patient
advocate, PMD involvement, consent
process : timing and details.
EPIC? E-mail?
• EPIC
– Overstated
– Automated real time searches are possible
– Contact Holly Barr-Vermilya
• E-mails
– Current: Send Secure or Patient Gateway!
– Unsecured email with PHI is problematic!
– More coming on this.
• Facebook/Online
– Posts only, no interaction
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Inclusion/Exclusion Criteria
• Be EXPLICIT, in bullet format.
• Every full review study needs this.
• Many IRB safety changes made here.
• Think ahead: WBC 4.0? AST 60?
– “Clinically significant hepatic disease.”
– Must labs all be WNL?
– “MD discretion” – the good old days
– Never the case for FDA regulated.
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Inclusion/Exclusion
• Don’t exclude non-English speakers
• We strongly encourage inclusion of all ages, languages and ethnic groups in the research mission of the hospitals!
• Sometimes tools, activities or safety precludes.
• This is implementing principles of autonomy, beneficence and justice
• Physio study with risk, no benefit – caution!
• See updated policies, FAQ on short form/translation at the IRB website – Guidance
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Exclusion:
Pregnancy/WOCBP?
• Many reasons to exclude pregnant, rare to exclude WOCBP.
• CAUTIOUS presumption of inclusion.
• Know the category of drugs: A, B, C, X
• Specify pregnancy testing plan
• You have to talk with women about this
• Contraception: specify what (std. Lang)!
• 2 methods for toxic /teratogenic/no data
Pregnancy testing
• 1 or 3 T MRI: questioning only OK
• Injected radioactivity: stat serum hCG
• Regular x-rays: questioning and urine
hCG testing.
• See QI pages for documentation
templates
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Procedures - 1
• Lay out chronologically and completely.
• Don’t presume too much prior knowledge!
• Consider appendices or SOPs for your “standard” research procedures
Write once, attach often!
• Clarify your and others’ experience and keep track of safety/complications.
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Procedures -2
• NB: Reference routine clinical events.
• OBJECTIVE “Bail outs,” stopping rules. – When is a person withdrawn for safety?
– Esp. w/ placebo control where Rx exists • Again “MD Discretion alone” usu. not good enough.
• Interaction with clinical prescribers or other caregivers?
• Toxicity management?
• WHAT HAPPENS when study is over?
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Procedures - 3
• How does research data make its way
to subjects, if at all?
– “Healthy volunteers” with problem found?
– Research data returned?
– Burden of knowledge?
– Special issues related to genetics, families
– Are outside HCP’s in the loop?
– Formal written permission for data release
– Be guided by good medical practice!
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Procedures - 4
Think AHEAD:
• Future contact of subjects?
• “Can we keep your name on an interest list for other asthma research studies?”
• Future use of specimens for related work – with your group, not the universe
• Sharing of specimens with others?
• Commercial applications?
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Statistics
• A description of variables and data
• How will you analyze the data?
• A clear justification of sample size.
– How do you know you can answer
the research question posed?
– Formal SS calculation or OTHER!
• My theory of statistical relativity……….
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Quality Assurance and
Monitoring • Monitoring to ensure that data appropriately
collected, accurate, and that study protocol IS FOLLOWED.
• Usually done by an Industry Monitor.
• Sometime NIH sends monitors – You can’t monitor you own work!
• QI team can help you: – Set up your files
– Provide documents, logs, forms
– Show you what monitoring is
– Advise you how to do it within your team
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How is risk minimized?
• We need to “find and document” that you and we did this.
– “AE reporting to the IRB” does not accomplish or equal “minimizing risk!
– Aspects of study design and screening, exclusion of some subjects, stopping rules, objective criteria for removing subjects for safety, having an independent DSMB or medical monitor DO help minimize risk.
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AE and SAE reporting • Standard definitions – see website
– Hospitalized/Prolonged, Death, Disability, Ca etc
• YOUR PROTOCOL can define “SAE.”
• Stopping rule or safety pause rule? - One stroke? One MI? More than 3% w/ neutropenia?
• Include a chart defining mild/mod/severe lab results for safety labs
• Clarify to whom reports go – NIH, DSMB, COMS, (in addition to the IRB of course). We want to see DSMB charters and membership.
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Data/Safety Monitoring Plan
• Every study needs a plan for this!
• Not a “one size fits all”
• Possible approaches:
– PI and IRB
– Independent medical monitor
– Formal DSMB (high risk or phase III MCT); not
really needed for simple low risk studies like med
records or much health services delivery
research.
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Ethical and Regulatory
Considerations
• Provide us with some insight into your
thought processes. Often missing!
• Why you think don’t need an IND/FDA
• Why this study design is ethical
– placebos, risks to normals, blinding
• Why large risks are worth taking
• Why you think any risk is worth taking
Justification advised
• Special populations
– Children, Fetus, Incapacitated
• Time pressure/timing
• Deception
– ?Authorized deception
• Withholding standard care
– Rationale, duration, safety
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Consent: intro
• It’s a legal document reflecting an important, ongoing process.
• Do not delegate this process lightly.
• Process s/b in your protocol – follow it!
• If you have a big problem, people will be reading your consent form with a microscope.
• You may not write/edit/amend by hand
• Needs a current footer from the IRB or it’s NOT an approved consent form!
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Consent: Who asks for it?
• You may obtain consent for activities commensurate with your typical clinical practice in medicine.
– B.A. Study coordinator (study screen).
– RN (GTT, xrays, lab work).
– RN-P (DM- initiation and education for FDA approved drugs for that purpose).
– Licensed MD - investigational drugs, devices = practice of medicine
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Consent - Who gives it
• Competent adults with capacity to do so
– If capacity to consent or “competency” at issue, then
an evaluation for this need be done.
– The evaluation should be specified in protocol.
– Consider formal scale– e.g. MMSE, Clinical
Dementia Rating Scale.
– See our website on this – Informed Consent of
Research Subjects.
– All minors require parent/guardian consent, child
must assent to participate themselves.
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Surrogate consent
• When an adult individual cannot consent on their own to participate – NOT the same as what’s allowed for care!
– Must be requested, and approved by IRB.
– What is the nature of subject’s incapacity?
– Medical care or physiological study?
– Risks and benefits?
– What happens if/when capacity regained?
– Legal matters……..
• See the complicated document on this at the IRB Website if you’re venturing into this.
• Emergency waiver – COMPLEX
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Consent forms
• Give it your best shot in simple language
• Writing level is 8-9th grade/no medical smarts
• Ask a lay person to review!
• OK response: All changes accepted except…
• You’re executing the form. You should be
comfortable with it (Germs vs. Bacteria) and
know it backwards and forwards………
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Risks to not Forget • Risk of opportunity lost?
• Risk of withdrawal of current meds
• Delay in treatment, either related to screening, run in period or placebo.
• Non-medical risks of genetics = loss of confidentiality, insurance, job is possible
• Discomforts (not the same as risks): – Be realistic and honest
• Prolongation of a procedure/anesthesia time? (give minutes, with context)
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Responding to IRB queries
• You’ve gotten this far: don’t blow it now!
• Consider the source and motivation.
• You may argue your point. Please do so politely, convincingly, with data, not indignation, insult or offense.
• Respond completely!
• Everything you should’ve learned in kindergarten……
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Responding to IRB queries - 2
• We want to hear from you as the PI
and a local, experienced clinician, not
from some desk jockey at Drugs R Us!
• Do not make changes not requested:
but feel free to enclose a separate
amendment with your response.
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If I can’t find your
answers easily,
it will ROT on my desk.
Self contained, complete response
document: an FDA/industry
standard you need to learn.
Q1: Why is a brain biopsy needed?
A1: We have justified this in the
protocol.
In my e-“activity list!”
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Responding to IRB queries - 4
• Q1: Why is a brain biopsy needed?
• A1: A brain biopsy is essential because… This text is added verbatim to the protocol on page 54 (Section 3.2) of the revised detailed protocol and protocol summary (p. 4). The consent is revised on p. 3, under procedures to include … “The risks section of the consent form has been revised on page 5 to state … Highlighted and clean copies are enclosed.
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Tracked change documents!
• “Marked vs Clean”; “Tracked vs Final”
• Show both eliminated AND added
elements:
• RED Strike-through for deletions
• for additions.
• IRB consensus for fastest on screen review!
• If you don’t, you risk return to add this.
Yellow highlighting
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Responding to IRB queries - 3
• If we misunderstood, you did not make it clear, so please restate and clarify, politely.
• If we aren’t smart enough to understand your project, you should join the Committee! Come on down!
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Perplexed?
• Ask to speak to the associate chair or
scientific chair of the meeting,
• Ask him or her to address a specific
question by email.
• Ask for guidance on what part of the
website might be helpful.
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Happy researching!
Many of your questions can be answered by
looking at this website. Some things are
intentionally not written in stone, and may be
open to interpretation or negotiation!
‘APPLY” section of the NAVIGATOR
