Our Clinical Research 101 series takes an in-depth look at key steps and tips for navigating the clinical research process. The sixteenth installment in our Clinical Research 101 series is by Leslie Love, Senior Project Manager at CHÉOS. The following is a brief discussion of protocol deviations, how to avoid them, and what to do when they occur.
Ms. Love is a certified clinical research professional with over 25 years of experience in a variety of research settings. Her primary role is to provide project management support to CHÉOS and Canadian HIV Trials Network-supported investigators, as well as develop research training materials and programs. Ms. Love is one of many project managers who work for CHÉOS. The Centre’s project managers are experts in the regulatory, policy, budgeting, and implementation requirements for clinical research studies, and can be contacted for consultation by completing our Service Request Form.
Clinical Research 101 Series
What are protocol deviations?
Protocol deviations are instances where researchers or support staff conduct some part of a research project in a way that is different from how it was described in the study protocol. This could be as minor as an out-of-window follow up visit, and as large or significant as enrolling a participant who did not meet the inclusion/exclusion criteria. (Note: if the out-of-window visit is delayed when there are safety concerns, then it may not be minor.) Regardless of their perceived severity, importance, or consequence, all protocol deviations must be correctly documented.
Section 4.5 of the International Council for Harmonization Good Clinical Practice Guidelines (ICH GCP)* specifically states that study investigators must comply with the protocol, and “should not implement any deviation from or changes of, the protocol without agreement by the sponsor and prior review and documented approval from the IRB/IEC of an amendment”.
The exception to this is when the change(s) are implemented to eliminate an immediate hazard to the study participant. In other words, for any clinical research study, you must always follow the protocol, unless doing so would cause harm to the study participant. For example, if a participant experiences a serious reaction that could be related to the product being studied, then the research team should stop the dosing of that product.
* As a reminder, Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, and that clinical trial data are credible.
What is to be done if a deviation occurs?
If you are unable to follow the protocol for any reason, this is a protocol deviation. A protocol deviation must be documented, and explained, and in most cases submitted to the Research Ethics Board (REB), study sponsor, and if required, to the regulatory authorities.
There are several ‘types’ of protocol deviations that can and have occurred during a study, although these definitions are not specifically described in GCP. Check with your local REB or the study sponsor as to how each of these should be handled. The REBs at UBC require that “all protocol deviations that: 1) expose subjects to potential increased risk; 2) compromise the integrity of the entire study; 3) are repetitive in nature; 4) alter subject eligibility, or 5) affect the privacy of the subject” be reported to them.
The following are a few types of protocol deviations:
A departure from the protocol to protect the life or well-being of a study participant. Generally, the sponsor and REB should be notified as soon as possible after the situation occurs.
Generally, these should be approved before the change is implemented. An example would be enrolment of study participants outside the inclusion/exclusion criteria. Ideally, sponsor and REB approval would be obtained in advance.
These deviations generally do not affect the “scientific validity of the research, or the rights, safety or welfare of participants”. An example would be a missed question on a quality of life assessment form. These types of deviations should be reported to the REB and study sponsor on a pre-defined regular basis.
How do you prevent deviations?
- Ensure each study team member is well trained on the protocol
- If any test, or task or wording is confusing, ask questions! It is important to foster an environment in which staff and researchers are comfortable coming forward with questions or concerns.
- Keep manuals or schedules of assessments handy, or develop ‘cheat sheets’ of any detailed procedures that can be available for quick access.
- Ensure the study participants are clear on what is required of them and that they understand the study.
Clinical research staff should do their utmost to avoid deviating from the study protocol, but protocol deviations are often inevitable in the “real world”. This is not an excuse to allow deviations to happen, but if they do, ensure you document each deviation as it occurs and report them to the study sponsor or REB as defined in the protocol, or per local REB requirements. If the same deviation occurs on a regular basis, a corrective and preventative action plan (CAPA) may need to be developed, or an amendment to the protocol may be in order.
References and Resources:
- ICH GCP 4 (Investigator)
- Guidance Note for Submitting Protocol Deviations to the REB (UBC Clinical Research Ethics Board, PHCRI)
- Office of Human Subjects Research: Institutional Review Board (Johns Hopkins University)
If you have any questions on the details about how to avoid and manage protocol deviations, please contact firstname.lastname@example.org and we can assist you.