Center for Clinical and Translational Science

Since the inception of the Clinical Research Support Office’s program of post-approval auditing and monitoring of study conduct, one of the core goals of the program has been to minimize the number of protocol deviations and violations. Any departure from the specific Institutional Review Board (IRB)-approved written procedures in a research protocol, is a protocol deviation. Some deviations are beyond the control of the research team (such as a participant failing to appear for a scheduled visit), but many common deviations can be prevented by designing and writing a protocol that accomplishes the scientific aims, while not imposing unnecessary rigidity or collecting unnecessary data.

This article will review the definition of protocol deviations and violations, and the procedures for documenting and reporting deviations and violations. It will also explore strategies in protocol design that minimize these types of errors.

Distinguishing Between a Protocol Deviation and Violation

All departures from the approved written protocol procedures are deviations; deviations that meet additional criteria are defined as ‘violations.’

A protocol deviation occurs when the activities during a study differ from the IRB-approved protocol, but there is no additional risk or consequence for the subject. An example of a protocol deviation is a missed visit due to the specified date of the visit (e.g., day 20) falling on a holiday when the outpatient/research center is closed.

A protocol violation is defined as a departure from the IRB-approved protocol that results in one or more of the following:
• Reduces the quality or completeness of the data.
• Involves protocol procedures different from those described in the informed consent form.
• Impacts a subject’s safety, rights, or welfare.

Some examples of protocol violations include enrolling subjects who do not meet inclusion/exclusion criteria, conducting tests not described in the protocol, missing tests that are described in the protocol, and conducting an inadequate informed consent process.

Reporting and Documenting Deviations and Violations

The reporting requirements for reporting deviations and violations are set by the IRB, and must be followed for all research studies conducted at Rockefeller. Deviations must be reported to the IRB annually at the time of continuing review. Protocol violations must be reported to the IRB in writing within 5 working days of detecting the event.

The IRB requires all deviations and violations to be reported through the iRIS electronic submission system. For access to iRIS, to obtain a User ID, password, or training, please contact Ross Gillman at rossg@mail.rockefeller.edu.

Consequences of Protocol Deviations and Violations

The IRB evaluates all deviations and violations for their frequency and severity, the circumstances of their occurrence, and their potential impact on participant safety and scientific integrity. It is expected that research teams will evaluate each deviation or violation with an eye toward improving process and avoiding repeated errors. Numerous or repeated deviations may result in the IRB requesting a for-cause audit, additional training, and/or more frequent oversight. Repeated violations may prompt a formal review by the IRB and may be cause for suspension of the research protocol.

Avoiding Protocol Deviations and Violations

The Center for Clinical and Translational Science (CCTS) Navigation process is designed to insure that the written protocol has input from all of the relevant departments so as to avoid errors that will lead to deviations and violations, such as inadvertently scheduling appointments when the facilities are closed. Such reviews provide an opportunity for professionals familiar with protocol implementation to make sure the study requirements are realistic. A common source of deviations uncovered in audits is the omission of procedures or collections described in the protocol. Such omissions are often due to logistical or practical obstacles. Investigators can minimize deviations by ensuring that study requirements are realistic from the staff and participant perspectives. For example, a protocol may specify that nutritional supplements be given at noon every day under observation, when in fact participants are often out on pass at lunchtime. As written, this protocol plan would lead to deviations due to missed pills and missed observations if the participants were out on pass. If the supplements could be given at breakfast without compromising the science, the potential for deviations could be easily avoided. Since missed visits are another source of avoidable deviations, it is important to insure that each visit is absolutely required to conduct the study.

Another common cause of deviations is the creation of a new protocol by cutting and pasting from other protocols. During this process, investigators may include lab data from the prior study that are irrelevant to the current protocol. If these unnecessary labs are then not collected, deviations occur. Careful review of the intended data should insure that the protocol contains only data collection relevant to the current scientific question.

When consistent with the science of the study, protocol visits should have ‘windows’ to allow for flexibility in clinic scheduling. A ‘window’ is a range of days within which the data collection is still valid. For example, in a pharmacokinetic study, the scientific rationale may require that a subject come to clinic on a specific day, hence the window would be very narrow: “Visit 3 on Day 3”. In contrast, in another study completion of a survey anytime within a given week would allow for this schedule: “Visit 6, on Day 31 ± 4 days.” Building in visit windows also helps to avoid deviations due to scheduling conflicts.

In summary, protocol deviations and violations occur when the IRB-approved protocol is not adhered to. Most, but not all, deviations and violations can be avoided. Deviations and violations must be reported to the IRB. Careful adherence to protocol procedures is one key in avoiding deviations. Deviations and violations can further be avoided by care in writing or amending protocols to accurately reflect the research plan, building flexibility into timelines when appropriate, avoiding extraneous tests or visits, and consulting with research support resources to make sure research plans are realistic.

If you would like a Navigation meeting, please contact Donna Brassil at dbrassil@rockefeller.edu or ext 7886 to discuss your protocol.