Renewing An Approved Protocol:IRB Review Process

Columbia University Medical Center IRB

Monthly IRB-Investigator Meeting

February 15, 2005

Regulatory Requirements

IRB approval is a temporary authority that may be withdrawn at any time if warranted by the conduct of the research

DHHS [45 CFR 46.109(e)] and FDA [21 CFR 56.109(f)] regulations require the IRB to perform continuing review of applicable non-exempt research at intervals appropriate to the degree of risk but not less than once per year

Approval periods at CUMC:

• Most protocols are approved for a one year period

• Exempt protocols are “approved” for a two year period

Purpose of Continuing Review

• Verify the correctness of the decisions made during the initial review using the study results to date and other relevant new information to make this judgment

• Determine that the frequency and extent of continuing review for each study is adequate to assure the continued protection of the rights and welfare of research participants

IRB Criteria for Review

Same criteria as for initial review [45 CFR 45.111 and 21 CFR 56.111], applied differently:

• Risks to subjects are minimized…– Is it the determination of the IRB that risks are still minimized?

• Risks to subjects are reasonable in relation to anticipated benefits…– Is it the determination of the IRB that risks are still reasonable in

relation to anticipated benefits?– Have any subjects been seriously harmed?

• Selection of subjects is equitable – Has the actual selection/enrollment of subjects represent an

equitable distribution of the benefits and burdens of the research (versus the anticipated study population)?

Review Criteria (cont.)

• Informed consent will be sought – Has consent been obtained from enrolled subjects?– Is the consent process adequate or are changes required (to the

process or the form/forms) before additional subjects may be enrolled?

– Is there new information that should be, but has not yet been, conveyed to enrolled subjects so that they may make an informed choice about continuing their participation?

• Informed consent will be appropriately documented– Has consent been appropriately documented for enrolled subjects?

Review Criteria (cont.)

• When appropriate…adequate provision for monitoring the data– Has the IRB been informed of any unforeseen problems or accidents

that may have occurred?– Do reports of adverse events and monitoring bodies reflect that the

data are being adequately monitored? – Should the IRB request that progress reports be submitted at regular

intervals, more often than annually?

• When appropriate…adequate provisions to protect the privacy and confidentiality….– Have their been complaints from subjects, or reports of

unanticipated problems related to privacy and confidentiality?

• Appropriate safeguards have been included to protect vulnerable subjects

IRB Actions • Approve

• Require modifications

– defer to Chair as “pending” or

– defer to Board as “returned”

• Suspend enrollment*

• Suspend the study*

• Terminate*

*Reportable to OHRP and/or FDA, as applicable, sponsor, subjects, institution

IRB may also:

• Impose additional precautions or reassess special requirements previously imposed

– E.g., the IRB has the authority to observe or have a third party observe, the consent process as well as the research itself [45 CFR 46.109(e) and 21 CFR 56.109(f)]

How to Submit a Renewal Request for an Approved Protocol

Information/documentation required

• The IRB relies on the investigator to provide all necessary information

• OHRP and FDA regulations require that each Board member be provided with specific types of information

How-to in RASCAL• Complete the Renewal Information Page

• Review the personnel list and update, if changes to the research team are applicable (these changes must be reflected in a modification summary, see below)

• Ensure that the most recent version of the following documents are attached, as applicable to the research:– IDB and/or sponsor’s protocol– Package insert for approved drugs– Consent and assent forms (clean copies for stamping)– Recruitment material– Funding applications– Study instruments

How-to (cont.)

• Attach relevant and new material:

– Summary of AEs that have occurred and recent DSMC/DSMB reports

– Letters from sponsors or FDA

– Cover letter, if unusual or complex situations cannot be described within the RASCAL fields

Obtaining Approval Before the Expiration date

Points to consider:

• Federal regulations make no provision for any grace period extending the conduct of research beyond the expiration date of IRB approval

• It is the responsibility of each investigator to submit a timely renewal request

• As a courtesy, reminder notices are sent to investigators prior to the expiration date of the IRB approval for each protocol

• Failure to provide the appropriate type of information and level of detail required may delay re-approval of the project and result in suspension of research activities

IRB Review• Upon submission of a renewal request to the IRB, administrative

review is conducted • Some renewals may be conducted by an expedited review process • Protocols that cannot be expedited require review by the full Board• Time required for review is dependent upon the type of review and

other factors• Chair schedule• IRB meeting schedule• Completeness of submission• Other required approvals

• Recommendation: Allow 60 days for renewal of full Board protocol

Expedited Review

Once the submission is complete, it is logged in and available to the IRB Chair for review or distribution to a qualified IRB member

Categories:– The protocol was previously reviewed by expedited review, the

research presents not greater than minimal risk to subjects, and all procedures continue to fall within one or more of the expedited review categories 1-7

8(a): The protocol was previously reviewed by the convened IRB and all of the following criteria are met:

– The research is permanently closed to the enrollment of new subjects– All subjects have completed all research-related interventions– The research remains active only for long-term follow-up of subjects

Expedited Review (cont.)8(b): The protocol was previously reviewed by the convened IRB and both of the following criteria are met:

• No subjects have been enrolled to date at this site• No additional risks have been identified

8(c): The protocol was previously reviewed by the convened IRB and the remaining research activities are limited to data analysis

9: The protocol was previously approved by the convened IRB and all of the following criteria are met:

• The research is not conducted under an IND or IDE• Categories 2 through 8 do not apply• The IRB determined and documented at a convened meeting that the

research involves no greater than minimal risk• No additional risks have been identified

Full Board ReviewOnce the submission is complete, it is logged in and available to the IRB Chair to distribute to a qualified reviewer; after distribution, it may be assigned to an agenda for a meeting

Rationale: • If a protocol does not meet any of the conditions above for expedited review,

in most cases, it involves a vulnerable population and/or presents greater than minimal to participants

• These protocols should be discussed by the full Board even if there are no proposed changes to the protocol

• Progress reports may indicate that the risk/benefit ratio has changed, or new information about how subjects understand consent forms may require that the forms currently in use be modified

Special Considerations for Studies Previously Approved by WIRB

• Include all of the material that was submitted to WIRB

• Revise consent documents to reflect CUMC contact information

• Submit a clean copy of the consent document(s)

• Attach all documentation that would be needed for a new protocol:

• copies of all relevant committee approvals

• the sponsor protocol, IDB, funding documentation, IND/IDE documentation (as applicable)

• Include all material that is otherwise required for a renewal

Particular Requirements for Protocols Reviewed under an Authorization Agreement

Weill-Cornell

If CUMC is the IRB of record:

• Submit a renewal request sufficiently in advance of the expiration date to allow for regular processing and review

• The approval letter will be copied to Cornell; the CUMC consent document(s) will be stamped as approved if recruitment is ongoing

• The renewal will then have to be submitted to the Cornell IRB

If Cornell is the IRB of Record:

• Submit a renewal request in RASCAL as soon as the protocol is renewed at Cornell.

• Attach all materials that were submitted to Cornell for review, the Cornell approval letter, and the consent documents that were stamped by Cornell

Authorization Agreements (cont.)

NCI Central IRB (CIRB)

• The CIRB will review of renewals and modifications to the protocol.

• When the CIRB approval is issued, the local investigator should submit the renewal or modification request to the CUMC IRB

• The request will undergo a facilitated review; when approved, revised consent forms will be stamped with the CUMC approval stamp

When the Study Status has Changed

“Recruitment ongoing” to “closed to accrual/follow-up is ongoing” or “data analysis only”

• Submit all renewal information previously described WITHOUT consent documents, recruitment material, study instruments

• The IRB cannot approve consent documents

“Data collection not yet started” to “recruitment ongoing”

• Submit all renewal information previously described, as applicable, AND current consent documents

How to Include a Modification Request with a Renewal

The IRB requires:

• a detailed description of the change(s),

• the reasons for the change(s), and

• identification of where in the submitted materials the changes have been made

• Clean and highlighted copies of consent documents (if generated outside of RASCAL), or clear identification of what has changed (if the forms were generated using the RASCAL consent builder)

A cover letter is recommended when a modification is included with a renewal request

Lapse in Approval

• When continuing review of a research protocol does not occur prior to the end of the approval period specified by the IRB, IRB approval expires automatically

• The IRB cannot grant extensions or temporary approval

• If a lapse in approval occurs, all subject accrual must cease as of the date of suspension, and all research related procedures must stop

• If suspension of research procedures poses a health hazard to individual subjects, the IRB will consider exceptions upon receipt of written justification

Repercussions (cont.)

• Failure to maintain current IRB approval may:

– disqualify data intended for submission to the FDA, other federal agencies, and sponsors

– result in embargo of data collected during a lapse in approval

• Performance of study procedures during a lapse in approval also may result in IRB sanctions

When Continuing Review May End

• Continuing review by the IRB may cease when:– There is no need to follow-up or re-contact enrolled subjects; and/or– There is no need to verify research data obtained from subjects or private,

identifiable source documents (e.g., medical record); and/or– Analysis of subject identifiable data has concluded

• Closure of industry-sponsored research should be discussed with the sponsor or CRO before terminating the IRB approval.

• Once a study is closed, all data collection and analysis of subject identifiable data and review of source documentation must stop