OBJECTIVE:

To describe the review process for proposed modifications/changes to research currently under VCU IRB approval.

DESCRIPTION:

Investigators must report planned modifications in the conduct of research and receive IRB approval PRIOR to implementing these changes.  All principal investigators of exempt, expedited, and full board human subjects research with IRB approval receive a letter of approval which outlines the requirement to submit any changes in their research project to the IRB for prior review and approval.  Modifications that were unplanned and involved deviations from the protocol in order to minimize or eliminate a serious hazard are unanticipated problems that involve risk to subjects or others.  See WPP #VIII-7: Required Reporting of Unanticipated Problems Involving Risk or Harm to Subjects or Others.

Modifications include, but are not limited to, procedural changes to a protocol, requesting additional subjects beyond the approved number, changes in protocol or investigational drug brochure, and any changes in informed consent materials or advertisements. 

A.     Review Type:

Full Board – proposed modifications to research originally reviewed via full board review are also reviewed via full board review unless found to be minor, as defined below.

Expedited – proposed modifications to research previously approved via expedited review during the period (one year or less), for which approval has been granted may also be reviewed by expedited review (unless the change results in the research activity no longer meeting the above conditions for expedited review, in which case, the modification request will be referred for full board action).

B.     Types of Modifications:

Modifications fall into one of two categories: minor modifications or major modifications.

1.       Minor Modifications:

a)      Involve no added risk beyond minimal risk;

b)      Make no change to study design; and

c)      All added procedures fall into expedited categories (1)-(7) of procedures that can be reviewed using the expedited procedures.

2.       Major Modifications are modifications that are not minor.

C.     IRB Evaluation of Type of Modification:

It is the responsibility of the IRB to determine whether a proposed modification to currently approved research is a minor or major modification.

1.       Examples of modifications that are MINOR:

a)      Changes to a telephone number

b)      Correction of typographic and grammatical errors that do not change the meaning of the protocol

c)      Modified wording to clarify the original intent of the protocol that does not change its meaning (e.g., “Store drug at 4 degrees” to “Store drug in a refrigerator at 4 degrees C.” “WBC<2400” to “WBC<2400 (either manual or automated counting is acceptable.”)

2.       Examples of modifications that may be MAJOR:

a)      Addition of staff (Staff may not be qualified)

b)      The deletion of staff (This might be a deletion of necessary staff, thus reducing the resources available to protect participants.)

c)      Reduction in planned research participants (This might affect the knowledge expected to result.  This might result in too few participants being studied to get meaningful data.)

d)      The deletion of questions in a questionnaire. (This might affect the knowledge expected to result.)

e)      Extending the time period of the study for follow-up.  This depends on what procedures are done in follow-up. CAT scans?  Spinal taps?  Bone marrows?  If so, this would not be minimal risk.

f)       Adding a research site.  Does the site need to have special resources to protect participants?  Are new personnel involved?  This may not be minimal risk.

3.       Examples of modifications in which the first presumption should be that they are MAJOR modifications:

a)      Changing the treatment or intervention

b)      Decreasing the drug dosage

c)      Increasing the drug dosage

d)      Changing the frequency of drug administration

e)      Revising eligibility to include or exclude study participants

f)       Changing the consent to include a newly identified side effect or adverse event related to the study drug. (NOTE: These should have been reviewed by the convened IRB as unanticipated problems involving risks to participants or others.

D.     Expedited Review of Minor Modifications (to Research Previously Approved as Full Board) Notes and Process:

Federal guidelines state, “An IRB may use the expedited review procedure to review… (2) minor changes in previously approved research during the period (of one year or less) for which approval is authorized.” [45 CFR 46.110(b)(2)]

The expedited review procedure allows the IRB Chairperson and/or a qualified member of the IRB to review the modification and determine approval.  A modification cannot be disapproved by expedited review; however, the Chairperson or the IRB member may recommend that the modification be reviewed by the full IRB.  Thus, expedited procedures may be used for minor modifications described in detail above

All members of the IRB will be informed of modifications to study protocols approved by the expedited review procedures as part of the IRB agenda, agenda attachment, and minutes (as appropriate). 

When the principal investigator intends to modify a protocol, the following actions will occur:

1.       The ORSP provides a form for submission of proposed modifications on its website or upon request. 

2.       The completed form is received by the ORSP staff and is reviewed for completeness, then forwarded to the reviewer (who determines if process can be expedited).

3.       The primary reviewer (named at initial review) will conduct the expedited review.  This reviewer must be an experienced IRB member designated by the chairperson to conduct reviews using the expedited procedure.  If the original primary reviewer is not available, the VCU ORSP staff will make an assignment based upon a list of reviewers designated by the IRB chairperson (including the chairperson and vice chairperson) and by area of experience as documented to the staff.  Assignments are subject to the approval of the Chairperson or designee.  If staff detect that a reviewer may not be available or have the expertise required, they contact the chairperson to obtain a consultation recommendation.

4.       If there is any protocol-related information requiring clarification, the expedited reviewer should contact the principal investigator (or student/trainee conducting the activity) directly.

5.       Final review comments by the expedited reviewer must be documented in writing and forwarded to the IRB coordinator for processing (email documentation is strongly recommended).

6.       Upon receipt of final approval of modifications, modified consent/assent materials will receive a stamp of approval and correspondence will be sent to the investigator indicating materials approved.  The length of approval (for required continuing review) will not be changed.  This correspondence reminds investigators of their responsibilities for ongoing approval.

E.     Full Board Review of Major Modifications Notes and Process:

When the principal investigator intends to modify a protocol, the following actions will occur:

1.       The ORSP provides a form for submission of proposed modifications on its website or upon request. 

2.       The completed form is received by the ORSP staff and is reviewed for completeness, then forwarded to the reviewer.

3.       Investigators are notified in writing of the decision of the IRB and any changes required.  Final approval is not granted until all required changes have been made and submitted for review and approval. (For more information on Review of Revisions Requested by the IRB, please see XIII-6).

4.       Upon receipt of final approval of modifications, modified consent/assent materials will receive a stamp of approval and correspondence will be sent to the investigator indicating materials approved.  The length of approval (for required continuing review) will not be changed.  This correspondence reminds investigators of their responsibilities for ongoing approval.

F.     General Continuing Review Notes:

In conducting review of modifications to previously approved research, the IRB will consider whether:

1.       The IRB will consider whether verification is needed from sources other than the investigator that no material changes have occurred since previous IRB review.  Examples of when the IRB may require verification from other sources include:

a)      The investigator has a pattern of submitting the wrong version of the protocol or consent document at time of continuing review, and

b)      The investigator has a pattern of submitting reports of unanticipated problems (UPs) past the deadline for reporting UPs.

2.       The IRB will also ensure that the active research plans demonstrate that:

a)      The investigator will obtain the legally effective consent of the participant or the participant’s legally authorized representative.

b)      The circumstances of the consent process provide the prospective participant or the legally authorized representative sufficient opportunity to consider whether to participate.

c)      The circumstances of the consent process minimize the possibility of coercion or undue influence.

d)      The individuals communicating information to the participant or the legally authorized representative during the consent process will provide that information in language understandable to the participant or the representative.

e)      The information being communicated to the participant or the representative during the consent process will not include exculpatory language through which the participant or the legally authorized representative is made to waive or appear to waive any of the participant’s legal rights, or release or appear to release the investigator, the sponsor, the institution, or its agents from liability for negligence.

RESPONSIBILITY:

It is the responsibility of the principal investigator to ensure that changes in research activity are not initiated without prior IRB review and approval except when necessary to eliminate apparent immediate hazards to subjects (in which case the investigator must promptly report the modification to the IRB).

REFERENCES:

45 CFR 46.110(b)(2)