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?
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.
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.
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.