Unanticipated Problems Unanticipated Problems Involving Risk to Involving Risk to

Subjects or Others Subjects or Others (UPIRSO)(UPIRSO)

Roy R. Estrada, PhD, PA-C, CIPRoy R. Estrada, PhD, PA-C, CIP

Associate Director IRBAssociate Director IRB

UTHSCSAUTHSCSA

The UTHSCSA Institutional The UTHSCSA Institutional Review Board (IRB) applies an Review Board (IRB) applies an Adverse Events reporting Adverse Events reporting process based on federal process based on federal guidanceguidance

The scope of what must be The scope of what must be reported promptly to the IRB is reported promptly to the IRB is narrow and definednarrow and defined

What?What?

Scenario #1Scenario #1

Ph II, clinical trial testing a new investigational Ph II, clinical trial testing a new investigational antihypertensive drug, at UTHSCSAantihypertensive drug, at UTHSCSA

Determined by the IRB as greater than minimal risk Determined by the IRB as greater than minimal risk No documented evidence of GERD associated with No documented evidence of GERD associated with

the drugthe drug 3 of 10 subjects had severe GERD that began 3 of 10 subjects had severe GERD that began

within one week of starting drugwithin one week of starting drug Internal or External?Internal or External? Related or Unrelated?Related or Unrelated? Anticipated or Unanticipated?Anticipated or Unanticipated? Report to IRB? If yes, what time frame?Report to IRB? If yes, what time frame?

Categories of Categories of ReportingReporting

Prompt reporting: Promptly report all adverse

events and unanticipated problems that might meet the definition of “Unanticipated Problems Involving Risks to Subjects or Others”

Non-Prompt Reporting: Not meet definition of UPIRSO Summarize Non-UPIRSO /

UPIRSO in next progress report.

Categories of EventsCategories of Events

Adverse EventsAdverse Events involve involve “physical or psychological harm” “physical or psychological harm”

Non-Adverse EventNon-Adverse Event does not does not involve physical or psychological involve physical or psychological harmharm

UNANTICIPATEDUNANTICIPATED e.g., not in the consent e.g., not in the consent form, Sponsor Brochure, or labeling; not form, Sponsor Brochure, or labeling; not expected as part of subject’s disease or expected as part of subject’s disease or conditioncondition

RELATEDRELATED e.g., (or possibly related) a result e.g., (or possibly related) a result of the research interaction/ identifiable of the research interaction/ identifiable data collectiondata collection

GREATER RISKGREATER RISK to subjects or others e.g., to subjects or others e.g., harm (including physical, psychological, harm (including physical, psychological, economic, or social harm)economic, or social harm)

SERIOUSSERIOUS e.g., severe/life threatening/fatal e.g., severe/life threatening/fatal

Categories of UPIRSO Categories of UPIRSO CriteriaCriteria

UNANTICIPATEDUNANTICIPATED in Nature, in Nature, Severity or FrequencySeverity or Frequency

RELATEDRELATED ReasonablyReasonably Sure Sure

GREATER RISKGREATER RISK Greater Risk of Greater Risk of harm than was previously known harm than was previously known or recognizedor recognized

SERIOUSSERIOUS relates to adverse events relates to adverse events

Categories of UPIRSO Categories of UPIRSO CriteriaCriteria

Scenario #1Scenario #1

Ph II, clinical trial testing a new investigational Ph II, clinical trial testing a new investigational antihypertensive drug, at UTHSCSAantihypertensive drug, at UTHSCSA

Determined by the IRB as greater than minimal risk Determined by the IRB as greater than minimal risk No documented evidence of GERD associated with No documented evidence of GERD associated with

the drugthe drug 3 of 10 subjects had severe GERD that began 3 of 10 subjects had severe GERD that began

within one week of starting drugwithin one week of starting drug Anticipated or Unanticipated?Anticipated or Unanticipated? Related or Unrelated? Related or Unrelated? Serious? If not, Greater Risk?Serious? If not, Greater Risk? Internal or External?Internal or External? Report to IRB? If yes, what time frame?Report to IRB? If yes, what time frame?

Scenario #1Scenario #1Is a UPIRSOIs a UPIRSO

Internal: Unanticipated and RelatedInternal: Unanticipated and Related Not Serious Not Serious Greater risk than previously knownGreater risk than previously known

Prompt report Prompt report Submit changes, submit UPIRSO Submit changes, submit UPIRSO

report to IRB within 7 daysreport to IRB within 7 days

Relatedness - Old WayRelatedness - Old Way

Scenario #2Scenario #2 International study -multiple countries-multiple sitesInternational study -multiple countries-multiple sites UTHSCSA is IRB for local PI and VA PIUTHSCSA is IRB for local PI and VA PI Methods: interviewing 2000 mothers (mothers and Methods: interviewing 2000 mothers (mothers and

babies are subjects) regarding breastfeeding babies are subjects) regarding breastfeeding (records)(records)

IRB determined to be minimal riskIRB determined to be minimal risk Known risks of breach of confidentiality Known risks of breach of confidentiality VA study coordinator reports that 6 babies VA study coordinator reports that 6 babies

(subjects) died of malnutrition(subjects) died of malnutrition Anticipated or Unanticipated?Anticipated or Unanticipated? Related or Unrelated? Related or Unrelated? Serious? If not, Greater Risk?Serious? If not, Greater Risk? Internal or External?Internal or External? Report to IRB? If yes, what time frame?Report to IRB? If yes, what time frame?

UTHSCSA UPIRSO Guidance Regarding Probability of Relatedness

100%

Possibility(How Convinced you are of Relatedness

0% Relatedness

UTHSCSA UPIRSO Guidance Regarding Probability of Relatedness

100% 100% sure

Possibility

(How Convinced you are of Relatedness

0%

Relatedness Could not even guess

UTHSCSA UPIRSO Guidance Regarding Probability of Relatedness

100% 100% sure

Possibility

(How Convinced you are of Relatedness

0% Not Definitely Related, Relatedness related,

but could not but could not even guess even guess

>50

%?

co

nvi

nce

dR

easo

nab

ly

sure

UTHSCSA UPIRSO Guidance Regarding Probability of Relatedness

100% 100% sure

it is not related Possibility

(How Convinced you are of Relatedness

0% Not Definitely Related, Relatedness related,

but could not but could not even guess even guess

>50

%?

co

nvi

nce

dR

easo

nab

le

sure Not Reasonably sure of relatedness

Do not report until more information

UTHSCSA UPIRSO Guidance Regarding Probability of Relatedness

100%

Possibility(How Convinced you are of Relatedness

0% Not Definitely Related, Relatedness related,

but could not but could not even guess even guess

>50

%?

co

nvi

nce

dR

easo

nab

le

sure Not Reasonably sure of relatedness

Do not report until more information

100% sure definitely related it is not related Not Related at least partially related to participation in research

100% 100% sure it is

>50

%?

co

nvi

nce

dR

easo

nab

le

sure

UTHSCSA UPIRSO Guidance Regarding Probability of Relatedness

100% 100% sure it is100% sure definitely related it is not related Not Related at least partially related to participation in research

Possibility(How Convinced you are of Relatedness

Not Reasonably sure of relatednessDo not report until more information

0% Not Definitely Related, Relatedness related,

but could not but could not even guess even guess

Scenario #2Scenario #2 International study -multiple countries-multiple sitesInternational study -multiple countries-multiple sites UTHSCSA is IRB for local PI and VA PIUTHSCSA is IRB for local PI and VA PI Methods: interviewing 2000 mothers (mothers and Methods: interviewing 2000 mothers (mothers and

babies are subjects) regarding breastfeeding babies are subjects) regarding breastfeeding (records)(records)

IRB determined to be minimal riskIRB determined to be minimal risk Known risks of breach of confidentiality Known risks of breach of confidentiality VA study coordinator reports that 6 babies VA study coordinator reports that 6 babies

(subjects) died of malnutrition(subjects) died of malnutrition Anticipated or Unanticipated?Anticipated or Unanticipated? Related or Unrelated? Related or Unrelated? Serious? If not, Greater Risk?Serious? If not, Greater Risk? Internal or External?Internal or External? Report to IRB? If yes, what time frame?Report to IRB? If yes, what time frame?

Scenario #2Scenario #2Is not a UPIRSOIs not a UPIRSO

Internal: Unanticipated and Serious Internal: Unanticipated and Serious but Unrelatedbut Unrelated

Prompt Reporting not required. Prompt Reporting not required. Follow other reporting Follow other reporting

requirements listed in protocol requirements listed in protocol (e.g., sponsored studies) as well(e.g., sponsored studies) as well

Scenario #3Scenario #3 Multi-center NCI studyMulti-center NCI study UTHSCSA one of 80 sitesUTHSCSA one of 80 sites IRB determined - greater than minimal risk - DSMPIRB determined - greater than minimal risk - DSMP Procedures include bone marrow transplant, Procedures include bone marrow transplant,

chemotherapy, blood drawing, transfusionschemotherapy, blood drawing, transfusions Risks listed in protocol documentationRisks listed in protocol documentation Subject dies in Detroit site from Subject dies in Detroit site from

complications of the chemo, UTHSCSA PI complications of the chemo, UTHSCSA PI receives IND safety reportreceives IND safety report

Anticipated or Unanticipated?Anticipated or Unanticipated? Related or Unrelated? Related or Unrelated? Serious? If not, Greater Risk?Serious? If not, Greater Risk? Internal or External?Internal or External? Report to IRB? If yes, what time frame?Report to IRB? If yes, what time frame?

UNANTICIPATEDUNANTICIPATED AND AND RELATEDRELATED (possibly(possibly RELATED) events/problems that represent a RELATED) events/problems that represent a GREATER RISK to subjects or others GREATER RISK to subjects or others

GenerallyGenerally will warrant consideration of will warrant consideration of substantive changessubstantive changes

UNANTICIPATEDUNANTICIPATED and and RELATEDRELATED (possibly RELATED)(possibly RELATED) and and SERIOUSSERIOUS adverse adverse events should also be considered to be events should also be considered to be represent GREATER RISK. represent GREATER RISK.

AlwaysAlways will warrant consideration of will warrant consideration of substantive changessubstantive changes

UPIRSOUPIRSO

Examples of corrective Examples of corrective actions or substantive actions or substantive

changeschanges Changes to eliminate apparent immediate Changes to eliminate apparent immediate

hazards to subjects (before or after IRB approval);hazards to subjects (before or after IRB approval); Modification of inclusion or exclusion criteria to Modification of inclusion or exclusion criteria to

mitigate the newly identified risks;mitigate the newly identified risks; Implementation of additional procedures for Implementation of additional procedures for

monitoring subjects; monitoring subjects; Suspension of enrollment;Suspension of enrollment; Suspension of research procedures;Suspension of research procedures; Modification of informed consent documents to Modification of informed consent documents to

include a description of newly recognized risks; include a description of newly recognized risks; Notification of previously enrolled subjects about Notification of previously enrolled subjects about

newly recognized risksnewly recognized risks

Scenario #3Scenario #3 Multi-center NCI studyMulti-center NCI study UTHSCSA one of 80 sitesUTHSCSA one of 80 sites IRB determined - greater than minimal risk - DSMPIRB determined - greater than minimal risk - DSMP Procedures include bone marrow transplant, Procedures include bone marrow transplant,

chemotherapy, blood drawing, transfusionschemotherapy, blood drawing, transfusions Risks listed in protocol documentationRisks listed in protocol documentation Subject dies in Detroit site from Subject dies in Detroit site from

complications of the chemo, UTHSCSA PI complications of the chemo, UTHSCSA PI receives IND safety reportreceives IND safety report

Anticipated or Unanticipated?Anticipated or Unanticipated? Related or Unrelated? Related or Unrelated? Serious? If not, Greater Risk?Serious? If not, Greater Risk? Internal or External?Internal or External? Report to IRB? If yes, what time frame?Report to IRB? If yes, what time frame?

Scenario #3Scenario #3Is not a UPIRSOIs not a UPIRSO

External: Related, and Serious, External: Related, and Serious, and some argue and some argue Unanticipated Unanticipated vs. Anticipatedvs. Anticipated

If confusing If confusing Substantive change required?Substantive change required?

Anticipated Anticipated

ANTICIPATEDANTICIPATED in the consent form, in the consent form, Sponsor Brochure, or labeling; expected Sponsor Brochure, or labeling; expected as part of subject’s disease or conditionas part of subject’s disease or condition

Can’t Determine if RELATEDCan’t Determine if RELATED Not Not ReasonablyReasonably sure sure

Represents a RISKRepresents a RISK But maybe not a But maybe not a Greater Risk of harm than was previously Greater Risk of harm than was previously known or recognizedknown or recognized

Clarify at each levelClarify at each level

Scenario #4Scenario #4

UTHSCSA Ph II cancer trial on biologic made UTHSCSA Ph II cancer trial on biologic made from human serafrom human sera

After 4 subjects enrolled audit revealed After 4 subjects enrolled audit revealed administered product was obtained from administered product was obtained from improperly screened donors (HIV,Hep-B risk)improperly screened donors (HIV,Hep-B risk)

IRB determined it is greater than minimal IRB determined it is greater than minimal riskrisk

Known risks: extensiveKnown risks: extensive No subject experienced any harmNo subject experienced any harm Anticipated or Unanticipated?Anticipated or Unanticipated? Related or Unrelated? Related or Unrelated? Serious? If not, Greater Risk?Serious? If not, Greater Risk? Internal or External?Internal or External? Report to IRB? If yes, what time frame?Report to IRB? If yes, what time frame?

UNANTICIPATEDUNANTICIPATED AND AND RELATEDRELATED (possibly(possibly RELATED) events/problems that represent a RELATED) events/problems that represent a GREATER RISK to subjects or others GREATER RISK to subjects or others

Only events that involve physical / Only events that involve physical / psychological harm (AKA adverse events) can psychological harm (AKA adverse events) can be be SERIOUSSERIOUS

UNANTICIPATEDUNANTICIPATED and RELATED (possibly and RELATED (possibly RELATED) and SERIOUS adverse events should RELATED) and SERIOUS adverse events should also be considered to be represent GREATER also be considered to be represent GREATER RISK). RISK).

UPIRSOUPIRSO

Scenario #4Scenario #4

UTHSCSA Ph II cancer trial on biologic made UTHSCSA Ph II cancer trial on biologic made from human serafrom human sera

After 4 subjects enrolled audit revealed After 4 subjects enrolled audit revealed administered product was obtained from administered product was obtained from improperly screened donors (HIV,Hep-B risk)improperly screened donors (HIV,Hep-B risk)

IRB determined it is greater than minimal IRB determined it is greater than minimal riskrisk

Known risks: extensiveKnown risks: extensive No subject experienced any harmNo subject experienced any harm Anticipated or Unanticipated?Anticipated or Unanticipated? Related or Unrelated? Related or Unrelated? Serious? If not, Greater Risk?Serious? If not, Greater Risk? Internal or External?Internal or External? Report to IRB? If yes, what time Report to IRB? If yes, what time

frame?frame?

Scenario #4Scenario #4Is a UPIRSOIs a UPIRSO

External: Unanticipated and External: Unanticipated and Related, although would not Related, although would not call it “Serious” as no harm call it “Serious” as no harm occurred.occurred.

Greater riskGreater risk Report to IRB promptly Report to IRB promptly

Report all internal (Report all internal (locallocal), ), unanticipated, related, unanticipated, related, life life threateningthreatening or or fatalfatal events within events within 48 48 hours hours (Submit “Fatal toxicities” only if (Submit “Fatal toxicities” only if NCI)NCI)

Report Report all othersall others within within 7 working7 working daysdays if local if local ((internalinternal) or ) or 14 working days off site 14 working days off site (external or follow-up reports)(external or follow-up reports)

How Promptly?How Promptly?

InternalInternal Events or problems experienced by Events or problems experienced by

subjects enrolled by investigators subjects enrolled by investigators approved by the UTHSCSA IRB to approved by the UTHSCSA IRB to perform research at their respective perform research at their respective institutions.institutions.

ExternalExternal Events or problems experienced by Events or problems experienced by

subjects enrolled by investigators subjects enrolled by investigators approved by IRB’s other than UTHSCSAapproved by IRB’s other than UTHSCSA

How Promptly?How Promptly?

Protocol Violations come in two flavors:Protocol Violations come in two flavors: ExceptionsExceptions are sought prior to are sought prior to

implementation implementation (Yes it deviates from the (Yes it deviates from the protocol but it is approved to do so by the IRB protocol but it is approved to do so by the IRB beforehand.)beforehand.) Exceptions are not part of the UPIRSO process Exceptions are not part of the UPIRSO process

and are requested using an and are requested using an amendment formamendment form For example a request for an exception to the For example a request for an exception to the

inclusion criteria for a single potential subjectinclusion criteria for a single potential subject DeviationsDeviations are reported after they occur are reported after they occur

Deviations are a measure of complianceDeviations are a measure of compliance Deviations may also represent a Deviations may also represent a UPIRSOUPIRSO

What about Deviations?What about Deviations?

Possible UPIRSO: AE or Non-AE UPIRSO ReportPossible UPIRSO: AE or Non-AE UPIRSO Report The report that replaces the forms used for The report that replaces the forms used for

Prompt Reporting: Adverse Event and IND Safety Prompt Reporting: Adverse Event and IND Safety Report formsReport forms

Non-Prompt ReportingNon-Prompt Reporting To report Adverse Events or IND Safety Reports To report Adverse Events or IND Safety Reports

that do not meet criteria for prompt reporting; that do not meet criteria for prompt reporting; Report in Progress Report.Report in Progress Report.

UTHSCSA Event Tracking Log - OptionalUTHSCSA Event Tracking Log - Optional Assists you in summarizing on your next Assists you in summarizing on your next

progress report: all non-prompt, non-UPIRSO progress report: all non-prompt, non-UPIRSO and UPIRSO in relation to your entire studyand UPIRSO in relation to your entire study

Forms Forms cancan be found on our website be found on our website http://research.uthscsa.edu/irbhttp://research.uthscsa.edu/irb

How?How?

Any Unanticipated Any Unanticipated Problem, Adverse Event, Problem, Adverse Event, or Deviation submitted is or Deviation submitted is considered a considered a possible possible UPIRSOUPIRSO and will be and will be reviewed by an IRB Chair reviewed by an IRB Chair or designated reviewer. or designated reviewer.

How will reports be How will reports be processed?processed?

If Promptly Reported:If Promptly Reported: Possible UPIRSO Report will be Possible UPIRSO Report will be

reviewed by expedited or full IRB reviewed by expedited or full IRB review as appropriate. review as appropriate.

PI must act on requirements of PI must act on requirements of involved institutions and requests for involved institutions and requests for more information to resolve the more information to resolve the issue.issue.

PI must submit follow-up PI must submit follow-up reports/report of resolution.reports/report of resolution.

Discovery processDiscovery process

OIRB must report, PI must act:OIRB must report, PI must act: ASAP report to involved institutions ASAP report to involved institutions

Institutions will distribute internallyInstitutions will distribute internally

PI must gather requirements and act PI must gather requirements and act

PI must submit a follow-up reportPI must submit a follow-up report

““Is the action plan fully initiated and Is the action plan fully initiated and can we call the issue resolved”can we call the issue resolved”

Determined to be a Determined to be a UPIRSOUPIRSO

IRB may act/IRB must report to OHRP:IRB may act/IRB must report to OHRP:

Failing to meet deadlines may be Failing to meet deadlines may be considered noncomplianceconsidered noncompliance

IRB can suspend enrollment, suspend IRB can suspend enrollment, suspend procedures or terminate a studyprocedures or terminate a study

Suspensions, terminations and serious Suspensions, terminations and serious or continuing noncompliance are or continuing noncompliance are reported to OHRPreported to OHRP

Final report to OHRP Final report to OHRP ((±± FDA) FDA)

UPIRSO ResolutionUPIRSO Resolution

If Prompt Reporting is not If Prompt Reporting is not required:required:The report will be returned to The report will be returned to

the PIthe PI with instructions to with instructions to summarize in their next summarize in their next progress reportprogress report

If sponsor If sponsor requiredrequired prompt prompt reporting send them a copy of reporting send them a copy of UTHSCSA policy letter.UTHSCSA policy letter.

How will reports be How will reports be processed?processed?

Scenario #5Scenario #5

UTHSCSA study of HIV patientsUTHSCSA study of HIV patients Procedures include interviews, (e.g., illicit Procedures include interviews, (e.g., illicit

drugs)drugs) Known risk of loss of confidentiality but data is Known risk of loss of confidentiality but data is

in password protected computer without in password protected computer without encryptionencryption

Event = computer with data is stolenEvent = computer with data is stolen Anticipated or Unanticipated?Anticipated or Unanticipated? Related or Unrelated? Related or Unrelated? Serious? If not, Greater Risk?Serious? If not, Greater Risk? Internal or External?Internal or External? Report to IRB? If yes, what time frame?Report to IRB? If yes, what time frame?

If an amendment is required:If an amendment is required: Submit ASAP. Submit ASAP. May qualify for expedite approval.May qualify for expedite approval.

Especially if not really a UPIRSOEspecially if not really a UPIRSO Substantive change Substantive change

Amendment associated with UPIRSO Amendment associated with UPIRSO will go to full IRBwill go to full IRB

PI must include thorough description of PI must include thorough description of event and any immediate actions event and any immediate actions taken.taken.

What if a change is What if a change is needed?needed?

Scenario #5Scenario #5

UTHSCSA study of HIV patientsUTHSCSA study of HIV patients Procedures include interviews, (e.g., illicit Procedures include interviews, (e.g., illicit

drugs)drugs) Known risk of loss of confidentiality but data is Known risk of loss of confidentiality but data is

in password protected computer without in password protected computer without encryptionencryption

Event = computer with data is stolenEvent = computer with data is stolen Anticipated or Unanticipated?Anticipated or Unanticipated? Related or Unrelated? Related or Unrelated? Serious? If not, Greater Risk?Serious? If not, Greater Risk? Internal or External?Internal or External? Report to IRB? If yes, what time frame?Report to IRB? If yes, what time frame?

Scenario #5Scenario #5Is a UPIRSOIs a UPIRSO

Internal: Unanticipated and Internal: Unanticipated and Related and represents greater Related and represents greater risk due to confidentiality of datarisk due to confidentiality of data

Changes required? Changes required? Amend protocol to add improved Amend protocol to add improved

security of data security of data Letter sent to those whose data Letter sent to those whose data

was compromised. was compromised. Submit UPIRSO report to IRB Submit UPIRSO report to IRB

within 7 dayswithin 7 days

Yes, with UPIRSO reportsYes, with UPIRSO reportsNo, (e.g., IND Safety Reports) No, (e.g., IND Safety Reports)

with progress reportswith progress reports

What about What about accompanying accompanying

documentation documentation ??

Examples of corrective Examples of corrective actions or substantive actions or substantive

changeschanges Changes to eliminate apparent immediate Changes to eliminate apparent immediate

hazards to subjects (before or after IRB approval);hazards to subjects (before or after IRB approval); Modification of inclusion or exclusion criteria to Modification of inclusion or exclusion criteria to

mitigate the newly identified risks;mitigate the newly identified risks; Implementation of additional procedures for Implementation of additional procedures for

monitoring subjects; monitoring subjects; Suspension of enrollment;Suspension of enrollment; Suspension of research procedures;Suspension of research procedures; Modification of informed consent documents to Modification of informed consent documents to

include a description of newly recognized risks; include a description of newly recognized risks; Notification of previously enrolled subjects about Notification of previously enrolled subjects about

newly recognized risksnewly recognized risks

QUESTIONS?QUESTIONS?

Roy R. Estrada, PhD, PA-C, CIPRoy R. Estrada, PhD, PA-C, CIPAssociate Director, IRBAssociate Director, IRB

UTHSCSAUTHSCSA(210) 567-3083(210) 567-3083

Fax (210) 567-2360Fax (210) 567-2360estradar3@uthscsa.eduestradar3@uthscsa.edu

UDEUDE

Unanticipated is different than FDA’s Unanticipated is different than FDA’s Definition of Definition of Unexpected drug Unexpected drug experienceexperience which only includes which only includes protocol documentationprotocol documentation

This is not necessarily a problem if This is not necessarily a problem if you simply identify that you need to you simply identify that you need to report to the sponsor the unexpected report to the sponsor the unexpected adverse drug experience and not adverse drug experience and not report to the IRB since it is not a report to the IRB since it is not a UPIRSO as it is not unanticipated by UPIRSO as it is not unanticipated by the condition of the subject. the condition of the subject.

UADEUADE

For device studies, investigators are For device studies, investigators are required to submit a required to submit a reportreport of a UADE of a UADE to to the sponsorthe sponsor and the reviewing IRBand the reviewing IRB as soon as soon as possible, but in no event later than as possible, but in no event later than 10 10 working daysworking days after the investigator first after the investigator first learns of the event (§ 812.150(a)(l)).learns of the event (§ 812.150(a)(l)).

SponsorsSponsors must immediately conduct an must immediately conduct an evaluation of a UADEevaluation of a UADE, and must , and must reportreport the the results of the evaluation results of the evaluation to FDAto FDA, all , all reviewing reviewing IRBsIRBs, and participating , and participating investigatorsinvestigators within within 1010 working days after working days after the sponsor first receives notice of the the sponsor first receives notice of the effect (812.46(b), 812.150(b)(l)).effect (812.46(b), 812.150(b)(l)).

UADEUADE

So for devices you may find So for devices you may find yourselves forwarding yourselves forwarding UADE’s to the UADE’s to the IRB but not as a UPIRSOIRB but not as a UPIRSO and then and then later after investigation by the later after investigation by the sponsor forwarding the results of the sponsor forwarding the results of the sponsors investigation as a UPIRSO if sponsors investigation as a UPIRSO if they discover that it is not as you they discover that it is not as you suspected caused by the underlying suspected caused by the underlying condition but actually an effect of the condition but actually an effect of the device not previously known device not previously known