Amendments and Reporting

Unanticipated Problems to the IRB

Josephine O’Driscoll-Davis

Assistant Director, Partners Human Research Continuing Review

November 9, 2017

Overview

During this session we will discuss:

• Amendments (Proposed Changes)

- Identifying what fields need completion in

the Amendment Applications

- What documents need updating based on

the proposed changes

- How to recognize what changes prompt full

board review

Overview

• Unanticipated Problems and Adverse Events

- Identify an Unanticipated Problem (UAPs)

and an Adverse Event (AEs)

- Identify the timeline for reporting UAPs and

AEs to the IRB

Amendments

Regulatory RequirementEach IRB shall follow written procedures for ensuring prompt reporting to the IRB of proposed changes in a research activity; and for ensuring that such changes in approved research, during the period for which IRB approval has already been given, may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject.

45 CFR 46.103(4)(iii) and 21 CFR 56.108(a)(3)(4)

AmendmentsProposed changes to approved research during the period of approval can be reviewed by:

• expedited review (review by one of the IRB

chairpersons not necessarily a shorter

timeline for review)

OR

• full board review (review by a quorum of the

members of the IRB at a convened meeting)

Minor Changes

Regulatory Requirement

The IRB may use the expedited review procedure to review… minor changes in previously approved research during the period of (1 year or less) for which approval is

authorized.

Reviewer Considerations

Does the proposed change:

1. Significantly alter the risk to benefit assessment the IRB relied upon to approve the protocol

2. Significantly affect the safety of subjects

3. Involve the addition of invasive procedures

4. Involve the addition of procedures, interactions or interventions that add significant medical, social or psychological risks

Reviewer Considerations

5. Involve the addition of a vulnerable

population in research not otherwise

eligible for expedited review (minimal risk)

6. Significantly alter the scientific question or

the scientific quality of the study

7. Are there any significant new findings that

might relate to the subject’s willingness to

continue participation in the research?

Minor Changes

If the answer to ALL of the preceding

questions is NO, the proposed change is

considered minor and may be reviewed

and approved by an IRB Chairperson

using the expedited review procedure.

Changes that are not Minor

If the answer to ANY of the preceding

questions is YES, the proposed change

is not MINOR and the amendment is

scheduled for review by the IRB at a

convened meeting.

Important Reminder

DO NOT submit proposed changes to the Protocol Summary, Detailed Protocol or Consent Form until previously submitted pending amendments to these documents have been approved.

Note: Does not apply to study staff amendments unless you are trying to attach Disclosure Form. If attaching Disclosure Forms is necessary, email the forms to your Linda Pacheco instead of attaching.

Amendment Application

Not completing the Amendment Application

correctly when submitting Amendments results

in missing data from the HRC database. Below

are some examples:

➢ When making changes like switching from one online tool to another, say Survey Monkey to RedCap, please check off the "questionnaire" field, which gives you access to the Instrument/Questionnaire form

Amendment Application

➢ Please check the "drug" box for when changes are made to anything about the study drug/administration/dose etc. Failure to do this, will result in the amendment NOT being sent automatically to research pharmacy.

➢ If making changes to the study enrollment numbers, be sure to check "study population" which provides access to the study population form, this is where the planned enrollment numbers are updated.

➢ Adding an updated version of the protocol, be sure to check “protocol” so that you can add the new version date. If this is not updated, our database and approval letter will contain the date of the prior version.

Amendment Application➢ Changing or adding Study Population: Text often

differs between the Amendment and what is listed in the NEW and/or revised Consent Form(s). Please match the subject population title in the subject line of the Consent Form(s) with what is reflected in the amendment under study population. This field is limited in the amendment application, but the text reflected in both the subject population line of the Consent Form(s) should equal what is listed in the Amendment Form for the portion displayed.

➢ When adding recruitment/advertising materials, please check the list and select the appropriate advertising instead of listing as “Other”.

➢ Funding Amendment: When adding a new funding source, please check if primary or secondary funding. This should also be reflected under proposed changes and including in the Protocol Summary.

AMENDMENTS AT CONTINUING

REVIEW

• Check the box on the Continuing Review Application to alert PHRC staff that missing documents required for Continuing Review are included with the Amendment submission.

• If Amendment submitted with Continuing Review is adding or revising drug/device or radiation procedures the following forms and ancillary reviews are required:

– Radiation form:

– Drug form:

– Device form:

AMENDMENTS AT CONTINUING

REVIEW

• Complete Amendment Application in Insight. Attach any documents revised by the Amendment to the Amendment submission only

• Check the box on the Amendment Application indicating that the Amendment should be considered with the Continuing Review

VERSIONING REVISED

DOCUMENTS

• Versioning: When making changes to any already submitted/approved documents please make sure to upload both marked and clean versions under the same attachment line: click on the Version History icon to the right of the attachment line, that will allow you to add new versions, click the "Add new version" option, and upload the marked copy first and the clean copy last.

• When you are done, save/close the window and you should be able to see the clean copy of any document you versioned.

VERSIONING REVISED

DOCUMENTS

• By uploading the clean version last, it will render in the ‘view full application’ pdf for printing and saving for your records.

• These steps should be followed with any documents (CF, PS, DP etc.) being changed. You should not add new rows for already existing documents; new rows are only for brand new documents.

• If you have any questions with regards to versioning, please call or email your protocol administrator.

Unanticipated Problems and

Other Reporting

• Adverse Events

• Deviations

• DSMB/DMC and Other Reports

• Protocol Exceptions

Unanticipated Problems

Regulatory Requirement

Each IRB shall follow written procedures for

ensuring prompt reporting to the IRB,

appropriate institutional officials, and the

department or agency head [FDA] of any

unanticipated problems involving risks to

human subjects or others.

45 CFR 46.103(b)(5)(i) and 21 CFR

56.108(b)(1)

UAP Definition

An unanticipated problem involving risks to

subjects or others means any incident,

experience, information, outcome, or other

problem that:

✓ is unexpected;

✓ is related to the research; and

✓ indicates that the research places

subjects or others at an increased risk

of harm (physical, psychological,

economic, legal, or social) than

previously known or recognized.

Why UAP Reporting is Required

• Research involves unknowns

• Research doesn’t always go according to plan

When this happens, the IRB must:

• Reassess the risks and potential benefits because the information about risks the IRB relied upon to approve the research initially has changed

• Consider whether research participants should be informed of the new information because it might affect their willingness to participate/continue in the research

Reporting Time Frame

Current policy (revised in Nov 2010):

Report all UAPs within 5 working days

of the date the investigator first

becomes aware of the problem

Reportable Problems

Report the following unanticipated problems:

• adverse events that are unexpected and

related (or possibly related) to the research

• unanticipated adverse device effects

• any event that requires prompt reporting

according to the research protocol or

investigational plan or the sponsor

Reportable Problems

• breach of confidentiality

For example,

a laptop containing individually identifiable

study information is lost or stolen;

an email is sent to all study participants that

includes the names of all of the participants

in the address line (To: … ).

Reportable Problems• medication, procedural, or laboratory error

regardless of whether subjects experienced any harm

For example, errors in drug administration or dosing, surgical or other procedure, or testing of samples or test results.

• deviation from the approved research protocol or plan that placed subjects or others at increased risk of harm regardless of whether there was actual harm to subjects or others

Reportable Problems

• Change in FDA labeling (e.g., black box

warning), withdrawal from market,

manufacturer alert from the sponsor, or recall

of an FDA-approved drug, device, or biologic

used in the research

For example, an investigator is informed by the

manufacturer of the study drug that during an

internal quality assurance check the lot of drug

shipped to him/her was found to be contaminated

with a potentially harmful product.

Reportable Problems• Interim analysis, safety monitoring report,

publication in a peer-reviewed journal, or

other findings that indicates that there are

new or increased risks to subjects or others

or that subjects are less likely to receive any

direct benefits from the research

• Complaint by/on behalf of a research subject

that indicates that the rights, welfare, or

safety of the subject have been adversely

affected or that cannot be resolved by the

investigator.

Reportable Problems• Noncompliance with applicable regulations or

requirements or determinations of the IRB

identified by the research team or others

(e.g., FDA Form 483 or Warning Letter) that

indicates that the rights, welfare, or safety of

subjects have been adversely affected.

• Suspension or termination of the research, in

whole or in part, based on information that

indicates that the research places subjects at

increased risk of harm (e.g., FDA clinical

hold)

Reportable Problems

• Incarceration of research subject during

participation in a research study that was not

approved for involvement of prisoners

• Suspension or disqualification of an

investigator by FDA, sponsor, or others

• Scientific misconduct

Reportable Problems

• any other problem that indicates the research

places subjects or others at an increased risk

of harm or otherwise adversely affects the

rights, welfare or safety or subjects or others

Reporting UAP

1. Create Other Event form in Insight/eIRB

2. Select Unanticipated Problem

3. Select the type of UAP from the list

4. Complete Form• Provide brief description of the problem

• Provide assessment of impact on the risks and potential benefits

• Indicate whether any changes are needed to the protocol and/or consent form

• Indicate whether currently enrolled subjects should be informed of this event

Reporting UAP – Major Deviation

1. Create Other Events form in Insight/eIRB

2. Select Unanticipated Problem

3. Select Deviation from the list

4. Complete Form• Provide subject ID (if applicable)

• Provide date of deviation and date deviation discovered

• Briefly describe deviation

• Describe corrective action and preventive measures

Note: Minor deviations are reported at

continuing review

Reporting UAP – Adverse Events

1. Create Other Event form in Insight/eIRB

2. Select Adverse Event (internal)

3. Complete Form

• Provide information about the subject

• Provide date of event and date notified of event

• Provide information on concomitant medications and medical problems

• Provide information on study intervention and dates of intervention

• Provide assessment of the event (unexpected, related or possibly related, serious)

• Address whether changes are needed to the protocol and/or consent form

• Address whether currently enrolled subjects should be informed of the event

SAFETY REPORTSThe PHRC does not accept sponsor IND/IDE safety reports describing adverse events that have occurred at other sites unless the report is of an incident that is:

– Serious;

– Unexpected or unanticipated;

– Related to the drug/device; and

– Suggests that subjects are at an increased risk of harm and as such warrants changes in the research, consent process, or informing subjects

DSMB/DMC and Other

Reports (not UAP)

1. Create Other Event form in Insight/eIRB

2. Select DSMB/DMC or Other, as

appropriate

3. Complete Form

• Briefly summarize the report / describe the

event

• Indicate whether any changes are needed to

the protocol and/or consent form

• Indicate whether currently enrolled subjects

should be informed of this event

Protocol Exceptions

Protocol Exception means any temporary protocol deviation that is approved by the IRB prior to its initiation, e.g., enrollment of a subject who does not meet eligibility criteria.

PI must submit request for protocol exception for prospective IRB approval.

Note: Protocol exceptions without IRB approval are considered protocol deviations. (Not considered UAP as long as prospective IRB approval is requested/granted)

Submitting Protocol Exceptions

(not UAP)

1. Create Other Event form in Insight/eIRB

2. Select Protocol Exception

3. Complete Form

• Provide subject ID and initials

• Describe the exception

• Provide assessment of impact of exception on risks and potential benefits

• Describe what subject will be told about exception

Summary

Report any unanticipated problems (or new information) that indicates that the research places subjects or others at an increased risk of harm (physical, psychological, economic, legal, or social) than previously known or recognized at the time of IRB review.

Report unanticipated problems (or new information) within 5 working / 7 calendar days.