reporting unanticipated problems & protocol deviations ... · reporting unanticipated problems...

Reporting Unanticipated Problems & Protocol Deviations & Violations

Presented By: Jim Outland, R.N., CCRC

September 29, 2009

1

Objectives of Presentation

• To better understand:

– Unanticipated problems

– Unanticipated problems vs. adverse events

– Criteria for reporting unanticipated problems

to Tulane IRB

– Protocol deviations, violations (major &

minor), exceptions, lapsed research

2

Confusing Because So

Many Parties Involved

PI

IRB Sponsor

Institution Regulatory

Agency

4

Confusing Because

• Often different requirements imposed by:

– FDA

– OHRP

– Funding agencies

– Tulane IRB

– Collaborating Institutions

5

Are there ways to eliminate the

confusion?

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PI Reporting Requirements to IRB:

PIs are required by Federal regulations to report

unanticipated problems to the IRB

1. That involve risks to subjects or others

2. That are unexpected & serious (e.g., protocol deviations,

exceptions, breaches of confidentiality, side effects, deaths,

serious or continuing noncompliance, or other problems).

[45 CFR 46.103(b)(4), 46.109(e), 46.103(b)(5)]

There is no PI duty to report adverse events (or serious adverse

events) to the IRB unless they are an unanticipated problem in which

case the unanticipated problem must be reported to the IRB.

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What are Unanticipated Problems?

3 Criteria

1. Unexpected AND

2. Related or Possibly

Related to Participation in

Research AND

3. Research Places Subjects

or Others at Greater Risk

of Harm Than Previously

Known or Recognized, or

Incident was “Serious”

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Unexpected

Greater

RiskRelated

Unanticipated Problem versus

Unexpected Event • An event is “unanticipated” when it is unforeseeable at

time of its occurrence.

– The word unanticipated is not a synonym for unexpected.

– A research protocol can monitor for unexpected events, but

cannot monitor for unforeseen events.

– All unanticipated events are unexpected, but not vice versa.

• An event is “unexpected” when its specificity and

severity are not accurately reflected in the Informed

Consent document, Investigators Brochure, or Package

Insert.

• Only unanticipated problems must be reported to the IRB

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Tulane IRB Unanticipated Problem

Reporting Requirements

• An unanticipated problem must be reported to Tulane‟s

IRB if:

– It occurs any time DURING or AFTER the research study, which

in the opinion of the PI:

(1) Involves harm to one or more subjects or others,

or placed one or more subjects or others at

increased risk of harm AND;

(2) Is unexpected AND;

(3) Is related to the research.

– This includes on-site and off-site event reports, injuries, side

effects, breaches of confidentiality, deaths, serious or continuing

non-compliance, or other problems

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Adverse Events (AEs) versus

Unanticipated Problems

• Not all adverse events are unanticipated

problems involving risks to subjects or

others (i.e., expected);

• Not all unanticipated problems involving

risks to subjects are adverse events (i.e.,

no increased risks)

11Michael A. Carome, M.D., OHRP

Unanticipated Problems Reporting Diagram

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Timeframe for PI to

Report Unanticipated Problems to IRB

For internal unanticipated problems, OHRP recommends*

the following reporting period:

1. Unanticipated & Serious: 1 Week (IRB Policy 5

working days)

2. Other Unanticipated: 2 Weeks (IRB Policy 10 working

days)

[45 CRF 46.103(b)(5)]

13*“Recommendations” Different from OHRP “Requirements”

OHRP Recommendations for Content of

Reports of Unanticipated Problems

1. Appropriate identifying information

2. Detailed description

3. Explanation of basis for determining event is an unanticipated problem involving risk

4. Description of any change to protocol or other corrective action

*Tulane University IRB requires additional and specific information, and

it MUST be reported on Tulane Unanticipated Problem Report Form

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Scenario 1• Facts:

– A subject is enrolled in a phase 3, randomized clinical trial evaluating the relative

safety and efficacy of vascular stent placement versus carotid endarterectomy

for the treatment of patients with severe carotid artery stenosis and recent

transient ischemic attacks. The patient is assigned to the stent placement study

group and undergoes stent placement in the right carotid artery.

– Immediately following the procedure, the patient suffers a severe ischemic stroke

resulting in complete left-sided paralysis.

– The IRB-approved protocol and informed consent document for the study

indicated that there was a 5-10% chance of stroke for both study groups. To

date, 25 subjects have been enrolled in the clinical trial, and 2 have suffered a

stroke shortly after undergoing the study intervention, including the current

subject.

– The DSMB responsible for monitoring the study concludes that the subject‟s

stroke resulted from the research intervention.

• Question:

– Is this event an unanticipated problem that is reportable to Tulane‟s IRB?

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Scenario 1 (continued)

• Answer: – This is not an unanticipated problem because the

occurrence of stroke was expected and the frequency

at which strokes were occurring in subjects enrolled

so far was at the expected level, and DOES NOT

need to be reported to IRB under DHHS Regulations

at 45 CFR 46 (sponsor may require reporting).

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Scenario 2

• Facts:

– As a result of a processing error by a pharmacy technician, a

subject enrolled in a multicenter clinical trial receives a dose of

an experimental agent that is 10-times higher than the dose

dictated by the IRB-approved protocol. While the dosing error

increased the risk of toxic manifestations of the experimental

agent, the subject experienced no detectable harm or adverse

effect after an appropriate period of careful observation.

• Question: – Is this event an unanticipated problem that is reportable to Tulane‟s

IRB?

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• Answer:– This is an unanticipated problem for the institution

where the dosing error occurred because the incident

was:

(a) unexpected;

(b) related to participation in the research; and

(c) placed subject at a greater risk of physical harm than was

previously known or recognized.

– It MUST BE REPORTED to the IRB, appropriate

institutional officials, and OHRP under DHHS

Regulations at 45 CFR 46

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What is an Adverse Event?

An adverse event is:

Any untoward or unfavorable medical occurrence in a

human subject, including any abnormal sign (e.g.,

abnormal physical exam or laboratory finding), symptom,

or disease, temporarily associated with the subject‟s

participation in the research, whether or not considered

related to the subject‟s participation in the research.

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Two Types of Multi-Center Unanticipated

Problems/Adverse Events

• Internal--occurred at Tulane or

collaborating facility

• External--incident occurred outside

Tulane or collaborating facility

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Scenario 3• Facts:

– Subjects with essential hypertension are enrolled in a phase 2, non-randomized clinical trial testing new investigational antihypertensive drug. At the time the clinical trial is initiated, there is no documented evidence of Gastroesophageal Reflux Disease (GERD) associated with the investigational drug, and the IRB-approved protocol and informed consent document do not describe GERD as a risk of the research.

– Three of the first ten subjects are noted by the investigator to have severe GERD symptoms that began within one week of starting the investigational drug and resolved a few days after the drug was discontinued.

– The investigator determines that the GERD symptoms were most likely caused by the investigational drug and warrant modification of the informed consent document to include a description of GERD as a risk of the research.

• Question: – Is this either an adverse event or unanticipated problem and, if

so, must either be reported to Tulane‟s IRB?

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• Answer:– This is an adverse event because it is:

• An untoward or unfavorable medical occurrence; and

• Likely temporarily associated with the subject‟s participation in the research

– Although not serious, this also is an unanticipated problem

because it was:

(a) unexpected in nature;

(b) possibly related to participation in the research; and

(c) suggested that the research placed subjects at a greater risk of physical

harm than was previously known or recognized.

– Adverse events never have to be reported to the IRB. They are

only reported by the PI to the sponsor [21 CFR 56.108(b)(1)]

– Unanticipated problems must be reported to the IRB

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Scenario 4

• Facts– An investigator is conducting a psychology study evaluating the

factors that affect reaction times in response to auditory stimuli. In order to perform the reaction time measurements, subjects are placed in a small, windowless soundproof booth and asked to wear headphones. The IRB-approved protocol and informed consent document describe claustrophobic reactions as one of the risks of research. The twentieth subject enrolled in the research experiences significant claustrophobia, resulting in the subject withdrawing from the research.

• Question– Is this either an adverse event or unanticipated problem and, if

so, must either be reported to Tulane‟s IRB?

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• Answer:– This is not an unanticipated problem because the occurrence of

the claustrophobic reactions – in terms of nature, severity, and

frequency – was expected. As such, the PI does not have to

report the event to the IRB

– This likely is an adverse event because it is:

• An untoward or unfavorable medical occurrence; and

• Likely temporarily associated with the subject‟s participation in the

research

– Adverse events are not reported to IRBs. It may need to be

reported to sponsor as an adverse event.

– Note: At time of continuing review, this should be reported to IRB

as a subject withdrawal from research study due to “expected”

event.

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Protocol Deviations/Violations

• The term “protocol deviation” is not defined by either the HHS

human subjects regulations [45 CFR 46] or the FDA human subjects

regulations [21 CFR 50].

• For Tulane purposes, a protocol deviation (“Protocol Deviation”) is

any change or alteration from the procedures stated in the study

protocol, consent document, recruitment process, or study materials

(e.g. questionnaires) originally IRB approved. Protocol Deviation is

a general term and may include, Protocol Exceptions, changes

made to avoid immediate harm to subjects, and Protocol Violations.

Protocol Deviations can be examples of non-compliance, either non-

serious or serious.

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Considered Major

• Major Protocol Violation:

– A protocol violation is a deviation from the IRB approved protocol

that may affect the subject's rights, safety, or well being and/or

the completeness, accuracy and reliability of the study data.

– Reportable within 5 working days of researcher becoming

aware of the event.

– If the deviation meets any of the following criteria, it is

considered a protocol violation and MUST be reported to IRB

using Tulane Protocol Deviation/Violation Report Form.

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Protocol Deviations/Violations, Major (continued)

• Examples of major protocol violations include: (list is not exhaustive)

– A research subject received the wrong treatment or incorrect dose;

– A research subject met withdrawal criteria during the study but was not

withdrawn;

– A research subject received an excluded concomitant medication;

– A research subject was enrolled but does not meet the protocol„s

eligibility criteria;

– Failure to treat research subjects per protocol procedures that

specifically relate to primary efficacy outcomes;

– Changing the protocol without prior IRB approval; or

– Inadvertent loss of samples or data.

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Protocol Deviations/ViolationsMajor (Continued)

– Failure to obtain informed consent prior to initiation of study

procedures;

– Falsifying research or medical records;

– Performing tests or procedures beyond the individual's

professional scope or privilege status (credentialing);

– Working under an expired professional license or certification;

– Failure to follow federal and/or local regulations;

– Repeated minor deviations;

– A breach of confidentiality; or

– Inadequate or improper informed consent procedure.

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Considered Minor

• Minor Protocol Deviation- A minor protocol deviation is any change,

divergence, or departure from the study design or procedures of a research

protocol that has not been approved by the IRB and which DOES NOT have

a major impact on the subject's rights, safety or well-being, or the

completeness, accuracy and reliability of the study data.

• Minor Protocol Violations are reportable events and reportable within 10

working days of researcher becoming aware of the event or at time of

continuing review if not previously reported, and MUST be reported on the

Tulane Protocol/Violation Report Form.

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Minor (Continued)

• Examples of Minor Protocol Violations include: (list is not

exhaustive)

– Use of unapproved recruitment procedures or materials (e.g., when

slightly altered);

– Inappropriate consent process documentation (e.g., dated by someone

other than the subject, missing signature of person obtaining consent,

incorrect date on consent);

– Use of expired or outdated consent document (i.e., it does not affect

the safety of the subject, integrity of the study, or subject‟s willingness to

participate in the Research);

– Study visits outside the protocol-prescribed visit window (e.g., the

subject is on vacation or is 1 week late for a visit due to illness);

– Failure of the subject to return unused study medication; or

– Enrollment numbers that exceed specifications.

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Protocol Exceptions

• A Protocol Exception is a planned protocol deviations. Unlike an

amendment, a protocol exception involves a single subject or, less

commonly, a small group of subjects and is not a permanent

revision to the research protocol.

• A protocol exception may include a lapsed study (e.g., IRB approval

expired) provided that such excepted activity involves an over-riding safety

concern or ethical issue indicates that it is in the subjects‟ best interest to

continue in the research. The PI also must:

– Submit a request to IRB to continue research interventions or interactions for

some or all subjects

– Clearly distinguish and explain what research activities from which he or she will

refrain as part of the lapse and what research activities require continuation.

– Explain the underlying reasons for which the protocol exception is requested for

which the lapse in approval occurred

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Protocol Exceptions

Reporting Requirements• IRB approval of a protocol exception must occur prior to its

implementation. If the research involves an investigational agent

(drug, device, or biologic), prior approval by the sponsor is also

required. Additionally, when the research involves an investigational

device and the changes or deviations may affect the scientific

soundness of the plan or the rights, safety, or welfare of the

subjects, FDA pre-approval is required [21 CFR 812.150 (4)].

• Planned protocol exceptions that may adversely affect the rights,

safety or welfare of subjects or the integrity of the research data

should be submitted to Tulane‟s IRB for review and approval prior

to implementation except where necessary to eliminate apparent

immediate hazards to the human subjects [(DHHS 45 CFR §

46.103(b)(4); (FDA 21 CFR § 56.108(a)(4); ICH 3.3.7].

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Protocol Deviation/Violation/Exception Decision Tree

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Recap on Reporting

Requirements--Drugs

1. PI Sponsor promptly any AE caused

by or probably caused by use[21 CFR 312.64 (b)]

2. PI IRB promptly all unanticipated

problems involving risks to subjects or

others[21 CFR 56.108 (b)(1), 312.53 (c)(1)(vii), & 312.66]

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Recap on Reporting

Requirements--Drugs (continued)

3. Sponsor PI new observations on drug,

particularly with respect to AE & safe use[21 CFR 312.55 (b)]

4. Sponsor PI in IND safety report of any

adverse experience associated with use that

is both serious and unexpected & any finding

from tests in animals that suggests significant

risk for human subjects[21 CFR 312.32 (c)(1)(i)(A)(B)]

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Recap on Reporting

Requirements--Devices

1. PI IRB & sponsor any unanticipated adverse device effect (UADE) no later than 10 working days after PI learns of effect[21 CFR 812.150 (a)(1)]

2. Sponsor must evaluate a UADE & report results of evaluation IRB & PI within 10 working days after the sponsor receives notice of the effect[21 CFR 812.46 (b), 812.150 (b)(1)]

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Remember…

• Internal reporting depends on what is required by Tulane HRPO policies andFederal regulations.

• Report unanticipated problems to Tulane IRB promptly.

• Remember to consider research non-compliance.

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References

• FDA Guidance on Adverse Event Reporting:

– “Guidance for Clinical Investigators, Sponsors, and

IRBs Adverse Event Reporting – Improving Human

Subject Protection” January 2009

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126572.pdf

• OHRP Guidance on Unanticipated Problem

Reporting:– “Guidance on Reviewing and Reporting Unanticipated

Problems Involving Risks to Subjects or Others and

Adverse Events” January 15, 2007

http://www.hhs.gov/ohrp/policy/AdvEvntGuid.pdf

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Questions?

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