As part of AMRC’s role to advocate for multisite clinical research corporations (MCRC), we responded to the FDA’s consultation: Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices; Guidance for Industry – Draft Guidance.

A copy of AMRC’s response can be found on the FDA website and below:

Dear Sir or Madam,

Re: Request for Comments Docket No. FDA-2023-D-5016 for “Protocol Deviations for Clinical Investigations of Drugs, Biological Products, and Devices.”

The Association of Multisite Research Corporations (AMRC) appreciates the opportunity to comment on this important guidance.

Launched in 2025, (AMRC) is a trade association aiming to advance the adoption of multisite clinical research corporations (MCRCs) to enhance efficiency, improve patient safety, and uphold data integrity in clinical trials.

Representing 14 founding organizations who employ over 7,000 people, with a global footprint of almost 400 research sites and nearly 1,000 Principal Investigators (PIs), AMRC has the scale to establish industry best-practices and help drive meaningful improvements in the clinical trials ecosystem.

AMRC is generally in agreement with what is proposed in this guidance. We believe the guidance is needed because the burden is frequently on sites to determine if a deviation affects data integrity. We support the concept underlying the guidance that the protocol should pre-specify which types of protocol deviations will be considered important. We are also in agreement that protocols should be written in such a way to allow for flexibility when possible as a control to prevent deviations.

Our specific comments follow:

• On page 8 lines 264-265 the guidance states “…if the sponsor determines that reclassification is warranted, they should then notify the investigator of the reclassification.” We would suggest the guidance include the requirement of the sponsor to notify the investigator of the reclassification “in writing by means of a protocol clarification letter or protocol amendment”. The supporting rational for this recommendation is due to the high degree of variability between CRA’s/sponsor/CRO representatives and individual interpretations. Sites have been asked to follow verbal instructions by sponsor/CRO representatives in the past and per our members’ standard processes, they follow written procedures per protocol. Providing standardized, written, IRB approved notification from the sponsor to investigators will be key in the reclassification process of “important” protocol deviations to decrease variability and provision of supportive evidence in case of inspection.
• Page 9 says “If there are recurrent protocol deviations that are similar in nature, the sponsor or clinical investigator should conduct a root-cause analysis to determine what actions may be appropriate to address: the noted non-compliance and prevent recurrence of the same of similar deviations.” Some sponsors may get overzealous with this; we would suggest an internal threshold for what is deemed too many that also triggers site RCA investigations. We would like to see additional guidance to the IRB on reporting timelines for important protocol deviations as each IRB is different and can range from ten business days to report to five calendar days.
• We would also note that central IRBs will likely need to update their IRB Handbooks to align reportable deviation references to the “important deviations per protocol” as stated in this guidance so there is not conflicting language between study protocols and IRB Handbooks.
• Although listed in a footnote, we recommend drawing clearer attention to the guidance being pertinent to not just the protocol, but also all study procedures and plans, e.g. laboratory procedures, pharmacy manual, IP prep instructions, study-specific training, etc. Any such deviations have the potential to impact participant safety and/or data quality, not just those specifically linked to the protocol. It is worth considering a broader term than “protocol deviations”, e.g. “Study Non-adherence”, to reinforce this point, and to also move away from legacy language with specific connotations.
• We appreciate the included flexibility for pre-planned deviations should be used sparingly but can be appropriate in certain situations. Our member’s experience is that IRB and sponsor procedures typically do not accommodate or allow for pre-approved deviations. It may be beneficial to include some examples of appropriate usage.  
• We appreciate the inclusion of example important and non-important deviations. As part of the guidance, we’d like to see the recommendation for the sponsor to specify minimally accepted important deviations in the protocol or a documented study plan to avoid deliberation during the study conduct. This documentation should be in place prior to the start of screening and only amended formally, e.g. protocol amendment, study-wide clarification memo.
• We agree that failure to obtain informed consent should be an important deviation and recommend further clarification that this be specific to the initial consent and amended consents that materially change the risk of participation or performance / prolongation of invasive procedures. Failure to obtain updated consent for minor and/or administrative amendments should not be classed as “important.” 
• While we fully recognize the importancet to protect personally identifiable and personal health information, such a disclosure is not a protocol deviation (unless stated in the protocol). We recommend this be excluded from the guidance, or minimally, that protection of participants identifiable PPHI be classified as non-important. Such an event would not routinely risk patient safety or data integrity and is also unlikely to be described in a protocol or other official study document.

We would also ask the FDA to consider the following changes:

• Consider adding dual enrollment (i.e. multiple studies at once) as important, with specific protocol-defined timeframes.
• In place of “Conducting certain assessments remotely when possible”, we recommend “Allowing flexibility that assessments may be conducted remotely when possible.”
• For the avoidance of confusion, the guidance should state specifically which party has responsibility to classify as important / non-important. We recommend that is the sponsor, consistent with the protocol and/or study-specific deviation plan. IRBs may also want the ability to influence this. The guidance as drafted is ambiguous on this matter.
• We recommend that the guidance stipulate that there can only be a deviation against something if it is documented. 

Once again, AMRC appreciates the opportunity to comment on this important guidance.

Sincerely,

Jim Kremidas
Executive Director
AMRC