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Need to Make Changes (Amendments)?

Published on Jun 15, 2022 · Last Updated 3 weeks 4 days ago
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Most studies require modifications to keep the investigative team current, to incorporate changes to the protocol, study instruments or consent form(s). Amendments to approved studies represent the single largest volume of IRB submissions. No changes may be made to the approved research plan without first submitting a request to the IRB and obtaining the IRB's approval, unless there is need to eliminate an immediate hazard facing the subject as outlined in 45 CFR 46.103(b)(4).

Amendments that are minor may be reviewed and approved by the IRB using Expedited Review procedures. IRB SOP 403: Amendments & Reports of New Findings to Approved Research defines Minor Amendment to mean A proposed change in the research related activities that does not materially affect assessment of the risks and benefits of the study and does not substantially change the specific aims, objectives or design of the study. A modification may not be considered “minor” if the changes involve the addition of a procedure that is more than minimal risk or a procedure that cannot be reviewed under Expedited Categories.... The Appendix 2 of IRB SOP 401: Expedited Review Procedures includes a list of examples of minor modifications to approved research.

Amendments can be more complicated and harder for the IRB to review than initial submissions. It takes attention to detail, on the investigator's part, to fully explain the changes that are proposed, the reasons for those changes and to ensure that all of the applicable study documents consistently incorporate the proposed changes throughout.

Frequent Reasons for Amendments to Fail to Obtain Approval During Initial Review

Amendment fail to obtain IRB approval during their initial review due to the following:

  • failure to explain the rationale for the proposed change;
  • failure to consistently implement the proposed change throughout the protocol, eIRB application, consent form, etc.;
  • failure to update the analysis plan and sample size to account for the changes in objectives, endpoints, measurements or sample size;
  • submitting the wrong documents or incorrect versions of documents to the IRB; and
  • inclusion of changes in study documents that are not discussed or listed in the cover letter or list of changes document.

Careful review of each revised document prior to submission can prevent unnecessary delays.

Unless the change is very minor, each Amendment should be accompanied by a Cover Letter that explains what is being changed and why it is being changed. The IRB provides an Amendment Cover Letter template that investigators can use to explain the changes they are proposing.

Not infrequently an amendment involves a new request for a waiver of consent, assent, HIPAA or documentation of consent. When a new waiver is requested, the IRB needs to have a complete discussion of the justification for the new waiver.

Amendments can be more complicated and harder for the IRB to review than initial submissions. It takes attention to detail, on the investigator's part, to fully explain the changes that are proposed, the reasons for those changes and to ensure that all of the applicable study documents consistently incorporate the proposed changes throughout.

Frequent Reasons for Amendments to Fail to Obtain Approval During Initial Review

Amendment fail to obtain IRB approval during their initial review due to the following:

  • failure to explain the rationale for the proposed change;
  • failure to consistently implement the proposed change throughout the protocol, eIRB application, consent form, etc.;
  • failure to update the analysis plan and sample size to account for the changes in objectives, endpoints, measurements or sample size;
  • submitting the wrong documents or incorrect versions of documents to the IRB; and
  • inclusion of changes in study documents that are not discussed or listed in the cover letter or list of changes document.

Careful review of each revised document prior to submission can prevent unnecessary delays.

Unless the change is very minor, each Amendment should be accompanied by a Cover Letter that explains what is being changed and why it is being changed. The IRB provides an Amendment Cover Letter template that investigators can use to explain the changes they are proposing.

Not infrequently an amendment involves a new request for a waiver of consent, assent, HIPAA or documentation of consent. When a new waiver is requested, the IRB needs to have a complete discussion of the justification for the new waiver.

The cover should include the following:

  • an overview of the global changes included in the amendment with the rationale (scientific or other justification) for the changes;
  • an assessment of the impact of the change to current and future subjects (changes in the risk or benefits to subjects);
  • a list of each change made to the protocol, consent form and other study documents.
    • type of change (protocol, consent form, study instruments, investigator's brochure, eIRB application);
    • justification for the change;
    • old text
    • new text

The updated documents should be attached to the eIRB application. Each updated document should include a tracked version and a clean version (all changes accepted) with updated version and version date.

When the amendment involves a new study population, new inclusion/exclusion criteria, and new analysis plans, an amendment is no longer appropriate. The investigator should develop a new protocol rather than try to amend an existing one. The IRB strongly prefers that investigators complete their approved study and open a new one rather than trying to amend a previously approved study. If uncertain, consult one of the IRB chairs and discuss the proposed changes.

A one-time amendment to a protocol is sometimes referred to as a prospective protocol deviation. Some of the protocol modifications proposed as part of a one-time amendment (prospective protocol deviation) are relatively minor - e.g., changes to study visit windows to accommodate subjects' schedules, obtaining a second blood sample after loss of a prior sample - while others are major and involve modifications to the inclusion or exclusion criteria or other study procedures.

Both the study sponsor and the IRB need to approve a one-time amendment prior to implementing the change. If the investigator anticipates that the circumstance is likely to arise again, then the protocol should be amended to add sufficient flexibility to avoid the need for additional one-time amendments.

What are the regulatory requirements for a one-time amendment (prospective deviation)?

FDA Requirements for Protocol Amendments:

21 CFR 312.30 (b)(2)(a) The sponsor has submitted the change to FDA for its review; and (b) The change has been approved by the IRB with responsibility for review and approval of the study. The sponsor may comply with these two conditions in either order.

(ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol change intended to eliminate an apparent immediate hazard to subjects may be implemented immediately provided FDA is subsequently notified by protocol amendment and the reviewing IRB is notified in accordance with 21 CFR 56.104 (c).

All changes to an IRB-approved research plan subject to 45 CFR 46 require prospective IRB review and approval. The IRB receives a wide range of propsed exceptions from the approved research that will apply to a single subject. Common examples include:

  • Change in the inclusion or exclusion criteria (most require full-board review)
  • Change in study procedures, including omission of a study procedure (most can be expedited)
  • Change in the timing of study procedures such as a change to the procedure window (most can be expedited)
  • Requests to continue the participation of a subject who has violated adherence requirements or who was enrolled incorrectly.

Minor amendments involving investigational agents subject to FDA oversight and regulations do not require approval by the FDA. However, the regulations require that the IRB approve all changes in the research activity. The only exception is the to eliminate an immediate hazard to the subject. Examples of eliminating an immediate hazard include:

  • Stopping the study drug due to hypertension, hypotension or allergic reaction
  • Altering the treatment plan to treat or mitigate an adverse drug reaction
  • Stopping PK sample collection due to lack of venous access

What steps should be taken before making a prospective protocol deviation?

The following steps should be taken:

  • Obtain the permission in writing (or email) of the study sponsor or study steering committee. If the investigator is the study sponsor (e.g. holds the IND) then a letter from a physician independent of the research should be obtained that confirms that the change will not adversely impact risk to the participant.

  • Submit the request to the IRB for approval in eIRB as a Prospective Protocol Deviation. Changes to the research that are minor (e.g., change in study visit window, change in sampling schedule for a PK study) may be approved using expedited procedures. Changes that are more significant may require approval of a convened IRB.

  • The request should include:
    • a description of the rationale for the proposed change
    • information about the subject and their medical condition
    • a listing of the proposed changes to the protocol
    • a revised consent form document (if applicable), and
    • and explanation for why the change will not adversely impact the risk-benefit assessment for the subject or prospective subject.

Important Caveats:

  • If the change is not urgent or if it will apply to more than one subject, submit a protocol amendment for the IRB to review and approve. Do not use the Prospective Protocol Deviation pathway in eIRB.

  • Recognize that if the same change is requested on more than one occasion, the IRB will request that the investigators amend the protocol.

Unplanned Protocol Deviations

Some protocol deviations are not intended and are only discovered after the fact. The timing of reporting of unplanned protocol deviations depends on the nature of the event; most may be reported as part of the progress report at the time of continuing review but some events require prompt reporting to the IRB. See the reportable events page for more information about reporting unplanned deviations.