Animal Study Submissions: What FDA’s CVM Cites Most and How to Design Your Next Study Around It

Every animal drug submission to FDA’s Center for Veterinary Medicine (CVM) contains documentation produced by people doing field work. Consider this scenario: A field team scores 300 to 500 animals on vaccination day. Days later, someone writes the supporting record from paper notes. Weeks after the study phase ends, a note to file appears, documenting that the protocol was followed.

The supporting record exists, what’s missing is the contemporaneous documentation that would let a reviewer verify it.

Regulators rarely publish the specific findings their reviewers cite, and almost never critique their own review processes in public. CVM has taken the unusual step of doing both. The pattern just described and other common issues appear on a published list of recurring issues observed in paper-based animal study submissions, one of two such lists the agency has made public. The other list provides the same information for studies conducted using Electronic Data Capture (EDC) systems. CVM has also stated, in the same source, that its own standard data review process is difficult to work with. [1]

Together, these published materials give sponsors useful direction: insights into what the regulator cites and what process it finds difficult. This article walks you through both lists, the agency’s own description of its review process, and what sponsors can do with that information when designing their next study.

The lists of issues, and the agency’s description of its own review process, come from a presentation CVM’s Quality Assurance Study Reviewer (QASR) team delivered at the 2023 Society of Quality Assurance Annual Meeting. [1] The QASR program has examined every animal drug submission containing study data since 2015. The recurring findings the team publishes are not isolated issues but typical outcomes of the workflows used for animal studies.

Sponsors running animal studies need to make infrastructure decisions long before the submission, often for operational reasons. Those decisions shape what CVM eventually receives, and they have regulatory consequences years down the line. The published findings describe what those consequences look like in practice.

In the next section we will take a closer look at the findings the CVM published regarding paper-based studies.

What Does CVM Cite in Paper-Based Animal Studies?

The paper-based list describes what CVM’s reviewers see when sponsors capture animal study data on paper, in spreadsheets, or in any combination of the two. The full list, in CVM’s verbatim language: [1]

• The final study report (FSR) does not fully and accurately reflect the raw data.
• Notes to file (NTF) written weeks to months after the relevant study phase ended to document protocol compliance, without supporting contemporaneous documentation.
• Study personnel who do not fully understand or execute their responsibilities.
• Apparent lack of training (e.g., GLP, GCP, protocol, etc.).
• Documentation, notification, and investigation of adverse events (AEs).
• Clinical observations not performed in compliance with the protocol.
• The amended FSR or amended contributing scientist reports do not clearly identify which part(s) of the FSR were changed and why.
• The quality assurance unit (QAU) inspection of the FSR not present on the QA statement.
• The QAU not conducting protocol-required inspections.
• QA inspection reports not reported to the SD [Study Director] and Test Facility Management (TFM) in a timely manner.
• Monitors participating in the study conduct of GCP studies.

The list breaks into two categories: some issues are direct ALCOA failures, i.e., problems with the properties of the records themselves. Others are GLP (Good Laboratory Practice) and GCP (Good Clinical Practice) compliance failures that produce ALCOA failures down the line. ALCOA is the FDA-recognized framework for data integrity in regulated studies, requiring records to be Attributable, Legible, Contemporaneous, Original, and Accurate.

The two findings at the top of the list pertain to the documentation workflow directly; both are ALCOA failures.

The first finding is that the final study report does not fully and accurately reflect the raw data. This is both an “Original” failure (the chain between observation and reported result cannot be reconstructed from the documentation) and an “Accurate” failure (the report and the raw data do not agree).

The second finding is a “Contemporaneous” failure: CVM cites cases where sponsors wrote notes to file weeks or months after the study phase ended, without contemporaneous documentation to support them.

The table below maps each finding to ALCOA where it applies, and shows which findings have no direct ALCOA dimension.

Table 1. CVM findings in paper-based animal studies, mapped to ALCOA scenarios where they apply.

Finding per CVM	Category	ALCOA Scenario
Final study report does not fully and accurately reflect the raw data	Direct ALCOA	Original, Accurate
Notes to file (NTF) written weeks to months after the relevant study phase ended to document protocol compliance, without supporting contemporaneous documentation.	Direct ALCOA	Contemporaneous
Documentation, notification, and investigation of adverse events (AEs).	Direct ALCOA	Contemporaneous and/or Accurate, depending on whether AE records were made late or made inaccurately
The amended FSR or amended contributing scientist reports do not clearly identify which part(s) of the FSR were changed and why.	Direct ALCOA	Original (the amended record does not preserve a clear record of what was originally there)
The quality assurance unit (QAU) inspection of the FSR not present on the QA statement.	GLP, possible ALCOA downstream	If the inspection occurred but is unrecorded in the QA statement, the statement itself fails Attributable and Original
QA inspection reports not reported to the study director and test facility management in a timely manner.	GLP, possible ALCOA downstream	If the reports were written late rather than only delivered late, it is a Contemporaneous failure on the inspection record
Study personnel not fully understanding or executing their responsibilities.	GLP/GCP, likely ALCOA downstream	Untrained personnel liable to produce records with Attributable, Accurate, or Contemporaneous failures
Apparent lack of training (e.g., GLP, GCP, protocol, etc.).	GLP/GCP, common ALCOA downstream	Training gaps produce Attributable, Contemporaneous, and Accurate failures in record
Clinical observations not performed in compliance with the protocol.	GLP/GCP, conditional ALCOA downstream	If protocol deviations are not documented, the records become Accurate and Original failures
Monitors participating in the study conduct of GCP studies.	GCP, weak ALCOA dimension	If records conflate the monitor’s oversight role with conduct activities, Attributable suffers
The QAU not conducting protocol-required inspections.	GLP, no direct ALCOA	The activity did not occur; there is no record property for ALCOA to govern

Of the 11 findings on CVM’s published list, four describe direct ALCOA failures and most of the remaining findings either produce ALCOA failures downstream or are tied to the quality system that surrounds the records. The findings describe what happens when study data is captured, transcribed, and reconciled by hand, and when the quality system around the study is not strong enough to catch the resulting problems before they reach the submission. Structured data capture removes the records-construction cluster of issues at the source. The training, QA, and protocol-adherence cluster recurs regardless how the data is recorded.

What Does CVM Cite in EDC-Based Animal Studies?

CVM publishes a parallel “Top 10” list for animal studies that use EDC systems. The full list, in CVM’s verbatim language: [1]

• Unexplained time discrepancies observed when comparing the audit trail date and time stamps to the protocol and other study documentation.
• EDC system limitations are not described in the submission.
• Lack of a description of quality control procedures used if data was transcribed into the EDC system.
• The ReadMe file does not include a description of the contents of the audit trail file including the variable names, label, or description, and any other information necessary for review.
• Entry errors and discrepancies indicating a lack of training on use of the EDC system.
• No statement that the EDC system is validated.
• The validation statement for the EDC system does not address if the EDC system was validated by the sponsor for their use of the system for the relevant study.
• User roles do not include descriptions of what information each role can access to maintain masking.
• Electronic Case Report Forms do not document if a recorder was used separate from the observer.
• Study personnel using other study personnel accounts.

The two lists describe different problems.

Sponsors running paper-and-spreadsheet workflows do try to address them through procedural controls: SOPs requiring contemporaneous recording, training to reinforce the requirement, dated initials and signatures, source data verification by monitors. These help but do not fully close the gap. CVM’s published findings are evidence that the problems persist in practice across enough submissions to be cited as recurring.

The reason is structural: paper-workflow problems are continuous execution problems that have to be avoided by every person on the study, every day, under field conditions. Issues like the absence of an audit trail or the gap between observation and recording are the consequences of using a workflow whose records are constructed by humans rather than produced automatically as a byproduct of data capture. Adding more procedures to prevent the gap also adds more steps where a gap can reappear.

However, most of the EDC findings are different in kind. They are sponsor implementation choices that can be corrected once and stay corrected. These are configurations the sponsor controls; once fixed, they stay fixed.

What Has CVM Built in Response? The EDC Remote Access Pilot Program

To address one of the recurring problems its reviewers face, the fragmented review process for non-pilot submissions, CVM has built and operates an EDC Remote Access Pilot Program. The program gives CVM reviewers read-only remote access to a sponsor’s EDC system, in lieu of receiving copies of electronically captured raw data. [2] What makes the program worth attention is not the program mechanics. It is what CVM has said about why the program exists and how the experience compares with the agency’s standard data review process.

Outside the pilot, study data reaches the agency as XML or XPT files submitted through eSubmitter, which CVM then converts to Excel documents for review. [1] CVM identifies several consequences:

• Submissions require README files.
• Reviewers utilize multiple Excel sheets to evaluate the full clinical picture.
• Many different Excel files are needed to develop the full clinical picture of an animal’s case while on study.
• Developing a “day by day” clinical picture of the medical record of an animal is difficult.
• The process amounts to “reviewing ‘paper’ data ‘electronically.'”

For CVM reviewers, even data submitted via EDCs currently arrives fragmented, forcing them to reconstruct individual animal cases manually. This has to happen across spreadsheets, with audit trails delivered as separate XML attachments before the review can start.

In contrast, CVM has published two perspectives on what the pilot experience looks like. The QASR team reported that feedback has been “consistently positive,” with raw data accessible in human-readable format, audit trails reviewable directly in the EDC system rather than as separate XML files, and data organized in a logical, easily navigable manner. The scientific reviewer’s perspective focused on the clinical picture: easier review, ability to see each animal’s full case in one place, and an experience the reviewer described as a “one stop shop” compared to data spread across numerous spreadsheets. [1]

The pilot is a different presentation, not a different standard. CVM is not lowering its bar for participants.

Where Does Prelude Fit?

CVM’s only public count of the pilot is four submissions, reported as of March 2023 and not updated since. [1] Prelude has supported six. One is publicly documented: VetDC’s TANOVEA.

Prelude states that it was a strategic partner in the TANOVEA pivotal trial, and that the EDC Remote Access Pilot Program gave CVM real-time access to the study database during review. [3] FDA’s Freedom of Information Summary records full approval on July 15, 2021 for the treatment of lymphoma in dogs, following conditional approval in December 2016. [4] FDA’s approval announcement described Tanovea as the first conditionally approved new animal drug for dogs to achieve full approval under the agency’s Minor Use and Minor Species (MUMS) program. [5]

What Does This Mean for Sponsors?

The pilot is one specific case of what CVM has published. For sponsors the broader question is what to do with the published material more generally. Three actions follow from that material.

1. Use CVM’s published findings list as a design input for the next study

CVM’s QASR findings name the specific issues reviewers cite most often. Sponsors planning a new study can build the protocol, the data capture approach, and the QA plan to avoid those issues. Sponsors who want a check against their existing workflow can run the same comparison against a recent submission to see which findings their current workflow produces.

2. Weigh paper-versus-EDC trade-offs for the next study with CVM’s published expectations in view

Sponsors planning a new study choose between paper-and-spreadsheet workflows and EDC-based data capture. Both involve real cost. EDC adoption requires system selection, validation, training, and operational changes; paper workflows require continuous QA effort to address the failure modes CVM publishes. CVM’s material adds concrete information about what each approach produces in review, which gives sponsors a basis for the choice.

3. For upcoming submissions consider the EDC Remote Access Pilot

Each of these comes down to one question: if a CVM reviewer pulled up your recent submissions today, what would they see: reconstructed static spreadsheets, or audit-traceable structured data?

The findings, CVM’s account of its own review process, and the pilot results point in the same direction: structured data is the foundation of a defensible animal study submission. A study designed against the record CVM has published is built on the standard it has said it applies.

Where to Look Next

Everything in this article comes from public sources, linked throughout. For a plain-language walkthrough of how CVM Remote Access works in practice, and the source material behind it, see Prelude’s CVM Remote Access resource page.

FAQs

Get the Weekly Briefing for Animal Health R&D Leaders

Prelude has powered animal health research for over 20 years. We work with 8 of the top 10 animal health pharma companies and all three top pet nutrition brands, across clinical, preclinical, post-market, and feed and nutrition studies.

Subscribe to Animal Health Weekly for the patterns, decisions, and regulatory shifts shaping how animal health evidence is generated and defended. Short, specific, actionable reading for people who lead R&D in this field.

Related Resources

• Prelude Partner VetDC Gains Full FDA Approval for TANOVEA
• Making the Switch: From Paper to EDC
• Prelude EDC Modules for Animal Health
• How to Review Data in an EDC

Sources

• [1] Lazo A, Davis D, Desilva J, Smith E, Rhodes L, Cottrell E. QASR Hot Topics. FDA Center for Veterinary Medicine, Office of New Animal Drug Evaluation (ONADE). Society of Quality Assurance Annual Meeting, March 2023.
• [2] FDA Center for Veterinary Medicine. CVM’s EDC Remote Access Pilot Program Information.
• [3] Prelude. Prelude Partner VetDC Gains Full FDA Approval for TANOVEA After CVM Remote Access Pilot Program.
• [4] FDA Center for Veterinary Medicine. Freedom of Information Summary, NADA 141-545, TANOVEA (rabacfosadine for injection). Date of approval July 15, 2021.
• [5] FDA. FDA Grants First Full Approval for Treatment of Lymphoma in Dogs. July 15, 2021. (FDA news release, distributed via PRNewswire.)
• [6] Rogers et al. Peer-reviewed analysis of FDA BIMO/GLP warning letters, FY2007 to 2018. PubMed Central PMC7993007.
• [7] FDA Center for Veterinary Medicine. Data Quality Webinar Q&A Document (revised 2021), Question 11.