Stakeholders seek clarity, use of international standards in FDA protocol deviations guidance

Industry groups are asking the US Food and Drug Administration (FDA) for more clarity about a proposed uniform system for classifying protocol deviations in clinical studies. They say clarification is needed to avoid duplicative work and want the agency to reference more international standards that industries already follow.

In January, FDA published a draft guidance proposing a uniform system for classifying protocol deviations in clinical studies to help sponsors, clinical investigators, and institutional review boards (IRBs) report deviations for drugs, biological products, and medical devices. The guidance clarifies the agency's expectations for sponsors and clinical investigators' different responsibilities when identifying, mitigating, and reporting clinical trial protocol deviations and was open to public comment until 28 February. (RELATED: FDA proposes uniform system for classifying protocol deviations, Regulatory Focus 9 January 2025)

The Association of Clinical Research Organizations (ACRO) commented on the guidance, expressing concern that its language may impose too much responsibility on investigators for defining and reporting deviations. The group said the agency's proposal would significantly change how deviation identification, reporting, and tracking are conducted.

"Individual investigators typically lack a comprehensive view of the deviation data and trends which play a significant part in assessing classification of important vs. non-important deviations," said ACRO. "ACRO members are concerned that industry may interpret this draft guidance as suggesting the implementation of new technologies or expanded use of technologies such as a protocol deviations section added to [electronic data capture (EDC)] systems for investigators to formally report protocol deviations."

"While this is the practice in some cases today (a small number of trials use EDC or other site-facing systems to document and track deviations), most sponsors and CROs track and manage protocol deviations in a [clinical trial management system (CTMS)] that does not have a direct reporting interface for sites," the group added.

ACRO said that if much of the reporting burden shifts to investigators instead, it may require more effort from the CRO and sponsors to clean, query, and maintain effective and efficient reporting. It argued that this would also duplicate efforts and create confusion at the site level.

"ACRO members do agree that sites should be informed of what have been defined as important deviations and that if an investigator realizes that an eligibility, endpoint or safety-related mistake was made, they should contact their sponsor or designee as soon as possible for instructions on how to proceed, including decisions around a patient’s ability to continue in the study or other steps to minimize risk to the patient or trial integrity," said the group.

Since the guidance also applies to institutional review boards (IRBs), clinical investigators, and sponsors, the drug lobby group PhRMA urged the FDA to change its title to state that it also applies to IRBs and investigators. The group also said the guidance does not align with relevant International Council for Harmonisation (ICH) guidelines and asked the agency to ensure it is aligned ICH guidelines and to consider whether the guidance is necessary.

"Specifically, we ask that FDA align the recommendations in this draft guidance with additional relevant ICH guidelines, namely E6 (R3) Guideline for Good Clinical Practice (GCP), to clarify Sponsor and Investigator roles and responsibilities related to defining, identifying, documenting, and reporting protocol deviations, as well as for conducting appropriate training and preventing protocol deviation reoccurrence," said the group.

PhRMA agreed with FDA's recommendation that sponsors use Quality by Design (QbD) principles when designing and conducting clinical trials to prevent and mitigate protocol deviations while reducing burdens. The group said the agency should align the guidance language with relevant ICH guidelines such as ICH E6 and ICH E8.

"PhRMA is concerned the draft guidance suggests that 'all' protocol deviations need to be reported when FDA has in ICH guidance recommends reporting 'important' protocol deviations," said PhRMA. "FDA should revise the guidance to conform that it recommends the reporting of 'all important' or 'important' protocol deviations rather than 'all' deviations."

"This revision would be consistent with direction provided to sponsors regarding reporting in other realms, such as the 2012 guidance on [investigational new drug (IND)] safety reporting requirements that served to reduce instances where Sponsors provided uninformative safety reports to FDA," the group added.

The medtech lobby group, AdvaMed, also asked FDA to include references to several international standards, including ISO 14155 and ICH E6(R3). Furthermore, it asked FDA to allow the use of derived deviations when reporting protocol deviations. The group said including derived deviations will improve deviation reporting and minimize duplicate data entry and reconciliation.

AdvaMed also asked FDA to define key terms at the beginning of the guidance and include consistent terminology throughout the document. The group asked the agency to clarify whether the guidance applies to all medical device investigations.

"The document appears to use the terms 'protocol' and 'investigational plan' interchangeably," said AdvaMed. "[We] suggest defining key terms at the beginning of the document and using consistent terminology throughout the document, ensuring the terminology remains relevant and applicable to devices."

AdvaMed asked for clarification on what the agency means by data quality and when data quality would be considered an important protocol deviation. It also said the guidance should clarify the difference between deviations from protocol requirements and state that not all potential good clinical practice (GCP) violations are protocol deviations.

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Stakeholders seek clarity, use of international standards in FDA protocol deviations guidance

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