Managing and Reporting Unanticipated Problems Including

Adverse Events

Elizabeth L. Hohmann MDChair, and Physician Director, Partners IRBs

Sarah A. White MPHDirector, Partners QI Program

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Today’s objectives

• Unanticipated Events

– Definition

– Reporting Timeline

• What do you tell the IRB, including changes to your protocol?

• Cases/examples

– Is the event reportable?

– How and to whom should it be reported?

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What are ‘Other Events’?

• New information that occurs during the conduct of the research study.

– Adverse events

– Interim analysis, DSMB report

– Investigational Drug/Device Brochure

– New package Insert or FDA notice

– Protocol Exception

– Unanticipated Problem (UAP’s)

– Other information (not a UAP)3

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Adverse Event (AE)

vs.

Unanticipated Problem (UAP)

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• Adverse Event:

– Untoward or unfavorable medical

occurrence

– Can be physical or psychological

• Serious Adverse Event:

– Death

– Hospitalization

– Prolonged hospitalization

– Disability/permanent damage

– Congenital anomaly/birth defect

– “Other impt medical event” • Drug addiction, Seizures, Serious blood dyscrasia, Bronchospasm

necessitating ED visit or ICU admit 6

What are Unanticipated Problems?

• Something that happens in your research study that you didn’t expect

– In nature, frequency, or severity

• Is related to the research

• Places subjects or others at increased risk than was previously known

– Risk = Physical, Psychological, Economic, Legal, Social

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AE vs. UAP

http://www.hhs.gov/ohrp/policy/advevntguid.html 8

Is it related to your study drug, device, or intervention?

• Temporally related

• More likely than not

• No other reasonable explanation

• Physician believes it to be related

• Outside of expected disease progression

• “Can’t rule out” an association is probably too soft a call!

• Make a “Clinical Global Impression!”

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General examples of UAPs• Breech of confidentiality

• Serious subject complaint

• Medication or laboratory error (even if no harm)

• DSMB report or publication that indicates new risks or less benefit

• Change in FDA status (e.g. recall, warning, black box)

• Incarceration of subject

• Noncompliance with federal law (483, FDA Warning letter)

• Suspension of the research study

• Scientific misconduct

• Deviation from protocol (WITH harm, or needed to prevent harm)

• Any other problem that indicates the research places subjects at increased risk

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Is the event reportable?

• 3 questions:

– Is the event unexpected?

– Is it related/possibly related to participation in research?

– Does the event suggest that the research places subjects/others at greater risk of harm than previously known/suspected?

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Reminder: external SAEs

Why do you have to report UAPs to the IRB?

• Unexpected problems or new information may indicate that the research places subjects (or others) at increased risk of harm– Are risks still reasonable in relation to benefit?

– Are changes warranted in order to protect subjects or others

• We have a policy because the feds say we have to (45 CFR 46, 21 CFR 56)– In cases where UAP is of very serious nature: If the study is federally

funded or FDA regulated, the IRB is required to report UAPs to appropriate federal agency

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When are UAPs reported?

• Report within 5 working days/7 calendar days of investigator being notified

• Report problems that occur:

– During conduct of study

– After study completion

– After subject withdrawal/completion

• Insight: reported as an ‘other event’

Within reasonable medical timeframe

What do you need to report to the IRB?

• A detailed description of the event

• Basis for determining:

– The event was unexpected in nature, severity, or frequency

– The event was related

– The research places subjects at an increased risk

• Corrective action/Preventive measures

• What changes need to be made as a result

– Note: an amendment can be noted as “planned.”

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What might you consider changing?

• Inclusion/exclusion criteria

• Safety follow up timeframe and/or procedures

– i.e. additional clinical or lab monitoring needed?

• Information regarding new risks to previously enrolled subjects (e.g. information sheet)

• How you might inform new subjects

• Suspension of enrollment of new subjects

• Stop drug dosing in all

• Suspension of overall study

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Best practices: identifying and reporting UAPs

• Ensure staff is adequately trained

• Ensure subjects are well informed of what they are getting into

• Adequate subject follow up

• Routine monitoring

• If a UAP occurs:– Meet IRB reporting timelines, even if it means

submitting a preliminary report followed by F/U report

– Ensure documentation in subject files can be understood from a 3rd party perspective

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Cases/Examples

Actual submissions/issues brought to the Partners IRBs.

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Case 1.

• You’re writing a letter to a subject to reschedule their Echo because of a snow storm

• Neither you nor they were in that day. • They will be 2 days outside of the study visit

window.

Do NOT send this in to us as an other event!Keep a copy in your file, and record as a minor

deviation. Minor deviations reported in tabular format at CR

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Case 2.

• Subject has significant allergy to iodinated CT contrast and you wish to do an MRA with gadolinium instead. The sponsor has agreed to this.

• This is a prospective exception request. • You should get IRB and sponsor approval,

prospectively. • Renal function? MRI screen criteria? • Reporting this after the fact as a deviation is NOT

advised. • Consent needs to be considered/discussed.

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Case 3.

• You’ve lost a video with a psychotherapy visit discussing depression and sexual orientation.

• Unanticipated problem – potential risks to subject.• Notify the IRB AND the Privacy Office, ASAP.• MGH: Erika Barber JD, Privacy Office.• BWH: Privacy Office

– Katherine Li Greene or Christopher McAllister – Also: Jackie Raymond, Exec. Director of Health Info

Email: bwhcHIPAA@partners.org Call: (617) 582-5214

• We’ll ask you how you’ll avoid this going forward• NB: Privacy breaches may trigger HIPAA monetary fines

and timelines. 20

mailto:bwhcHIPAA@partners.org

Case 4.

• Patient becomes pregnant on an investigational drug with teratogenic potential.

– Uncovered on study-mandated hCG testing

– Double contraception needs clearly spelled out

• ? Unanticipated?

– Sponsor needs to know

– Action needs be planned

– Follow-up of child, if applicable?

– Resolution of situation must be made

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Case 5

• Computer algorithm error has erroneously sent patients assigned to active drug placebo on month 2 of the study!

• Clearly a UAP.

• Risks to subjects – probably not but could be

• Risks to study data – major

• How will study be “fixed”

• What will subjects be told???

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Case 6

• John Scott and John Smith are scheduled to come in on the same day for your study.

• Mr. Smith calls from New Hampshire after the visit to say he’s got a pill bottle that says John Scott! What should he do?

• Clearly a UAP.

• Risks to subjects? – potentially.

• Risks to study data – minor, he caught it for you….

• How will you prevent this from happening again?

• Analysis and corrective action plan is needed!

• Contact Pharmacy.

• Submit a hospital safety report?

Case 7

• Subject with heart failure on orthopedic study related to knee OA is hospitalized for MI and dies.

• Not related to arthrocentesis 3 mo ago!

• Insight won’t let me report but sponsor is insisting I do!

• Reportable event per protocol/sponsor!

• Explain in detail why unrelated

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Case 8.

• You receive a call from an employer who witnessed phlebotomy in the back seat of a car in “his” parking lot.

• Employee reluctantly gave your name and contact information when pressed.

• Complaint that can’t be resolved?

• This person may have contacted IRB already.

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Case 9.

• Post op ketimine study – drug bag found to be running at thrice the rate prescribed in study.

• IRB notified by hospital when Safety Report submitted by RN.

• “Near Miss” situation

• Timeliness of reporting.

• Look back/root cause analysis/fix going forward

• Hospital Safety AND the IRB need to be involved.

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Case 10.

• DVT in study of bariatric surgery.• ICF clearly describes DVT as possible risk, high

risk population.• Out pt eval and sent home with LMW heparin

• Did it prolong hospitalization? • Did it require another hospitalization?• What about ED Obs overnight? • Trackable event, but may not be SAE. • Review protocol. Ask sponsor. Your call!

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Case 11

• New catheter based valve study

• Patient has small arterial lac, but bleeds 2 units on the table – all’s well that ends well…

• Pt confesses he forgot to stop coumadin

• Yes it’s a UAP.

• Check definition of bleed/serious bleed

• Can you document that you reminded him?

• Was there any pre-procedure testing?

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Case 12.

• Dr. was away at meetings/vacation in Europe for 2 weeks. Returns, and is reviewing study files and finds apparently forged signature and date when she was out of the country.

• Needs IRB report.

• Needs scientific misconduct investigation!

• Needs report to FDA, OHRP, NIH (if applicable) if substantiated. Prelim report likely will be made.

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Case 13

• BWH is a coordinating center for study of a nutritional supplement in a neurological ds.

• East Overshoe Hospital can’t get it together and enrollment is being stopped at the site.

• Investigator reports this to the IRB, FDA, and OHRP.

Nastygram arrives from NIH – program officer left off the CC list!

TRIUMVIRATE of federal reporting is OHRP, NIH and FDA – include them all. More is better.

Direct complaints to IRB

• TNTC recruitment matters• Privacy concerns• Unprofessional behaviors• Enrolled demented persons• Unapproved documents• Parent is a scientist and….• Not aware of some key component of study• Hospital safety reports/colleagues concerns

– Trainees?

• Funder’s concerns/requirements – NIH either via program or DSMBs

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Don’t forget to send us:

• Safety pause to enrollment

• Results of planned interim analyses

• DSMB reports/findings

• Follow-up reporting on actions taken to protect a subject, if not clearly described in protocol already.

– Potassium is 6 and no plan for that

– Do what you need to do, but report after

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Thank you for attending! Questions?

Please tell us what worked and what didn’t!

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