There are times when a sponsor may implement a change to clinical research protocol prior to FDA approval.
For example, a subject comes close to meeting eligibility criteria; however, they meet one exclusion criterion or fall just short of meeting an inclusion criterion. Or, there is a manufacturing change in the development of a medical device. In both cases, and a myriad of others, a sponsor may issue a protocol waiver. In which scenarios is this appropriate? What are FDA requirements with regard to the use of a clinical research protocol waiver?
FDA’s Criteria For Clinical Research Protocol Changes
According to the FDA (21 CFR 812.35 (a)(3)), there are several circumstances where a sponsor may make changes to clinical research protocol without prior approval of a supplemental application.
A sponsor may apply for a protocol waiver “if they determine that these changes meet the criteria [below]…and the sponsor provides notice to FDA within five working days of making the changes.”
Any protocol changes must be:
1. Developmental changes in the device that do not constitute a significant change in design or basic principles of operation and that are made in response to information gathered during the course of an investigation.
2. Changes to clinical protocol that do not affect:
- The validity of the data or information resulting from the completion of the approved protocol, or the relationship of likely patient risk to benefit relied upon to approve the protocol
- The scientific soundness of the investigational plan
- The rights, safety, or welfare of the human subjects involved in the investigation
Does Your Change Meet the Criteria?
The determination about whether the clinical research protocol change meets this criteria must be based on credible information defined by FDA as follows,
“…the sponsor’s documentation supporting the conclusion that a change does not have a significant impact on the study design or planned statistical analysis, and that the change does not affect the rights, safety, or welfare of the subjects. Documentation shall include information such as peer-reviewed published literature, the recommendation of the clinical investigator(s), and/or data gathered during the clinical trial or marketing.” (812.35 (a)(3)(iii)(B)).
If the sponsor determines that the criteria are met, then the protocol change can be made without prior FDA approval; however, the sponsor must submit a notice of change to FDA no later than five business days after making the change.
Notifying the Site(s) of Clinical Protocol Changes
“Changes to a clinical protocol are deemed to occur when a clinical investigator is notified by the sponsor that the change should be implemented…identified as a “notice of IDE change”” (812.35 (a)(3)(iv).
Required elements must be included in the notification in order to fully explain the change to the sites.
“…the notice shall include a description of the change (cross-referenced to the appropriate sections of the original protocol); an assessment supporting the conclusion that the change does not have a significant impact on the study design or planned statistical analysis; and a summary of the information that served as the credible information supporting the sponsor’s determination that the change does not affect the rights, safety or welfare of the subjects” (812.35 (a)(3)(iv)(B)).
These required elements also serve as documentation for the appropriateness of the change in the event that the site is audited.
Along with FDA, there is another body responsible for oversight that must be considered: the Institutional Review Board (IRB).
“…sponsor must obtain…IRB approval when appropriate, prior to implementing a change to an investigational plan” (812.35 (a)(1).
FDA allows for expedited IRB reviews for minor changes in approved research. The IRB’s reportable events policy should outline the requirements for submitting clinical protocol waivers. Of note, if the protocol waiver is not submitted to the IRB prospectively it may be considered either a protocol deviation or protocol violation. If this is the case, be sure to refer to the reporting timelines based on the IRB’s definition of the modification as protocol violations often require quicker reporting than protocol deviations.
Ensuring you follow the appropriate steps when implementing a sponsor protocol waiver will help you become audit ready.
Have you ever implemented a change to your protocol prior to FDA approval? Share your experiences below!