FDA Letter Calls on Device Sponsors to Independently Verify Third-Party Data

In response to an “alarming trend” in regulatory submissions containing unreliable data generated by third-party test labs, the U.S. Food and Drug Administration (FDA) sent a Letter to Industry reminding Sponsors of device studies and Manufacturers of devices (“device firms”) to carefully evaluate the third parties they engage to conduct performance testing and to independently verify all testing results before submitting to the FDA. 

In their communication released on February 20, 2024, entitled “Fraudulent and Unreliable Laboratory Testing Data in Premarket Submissions: FDA Reminds Medical Device Manufacturers to Scrutinize Third-Party-Generated Data”, the FDA noted “it is incumbent on device firms to take proactive steps to qualify third-party test labs and to closely scrutinize all testing data that a firm does not perform itself, especially relating to biocompatibility and other performance testing, that are included in a submission to the FDA.” They further stated, “While the FDA encourages device firms to partner with third-party labs that have been voluntarily accredited under the Accreditation Scheme for Conformity Assessment (ASCA) program, doing such does not substitute for conducting an independent assessment of all third-party data.”

This reminder from FDA comes as they have observed that “an increasing number of entities that contract with device firms to conduct testing on medical devices (“third-party test labs”) are generating testing data that are fabricated, duplicated from other device submissions, or otherwise unreliable. When such data are submitted to the FDA, the agency is unable to rely on them to grant marketing authorization and it calls into question the data integrity of the entire file.”

The move for more stringent oversight is further supported by FDA’s Bioresearch Monitoring (BIMO) program, which was established, in part, to assure the quality and integrity of data submitted to the agency in support of new product approvals and marketing applications. Through on-site inspections, data audits, and remote regulatory assessments, BIMO serves as a “cornerstone of the FDA preapproval process.”

How should sponsors and manufacturers respond?

In light of this increased scrutiny from FDA, Beaufort’s Clinical Monitoring Oversight solutions stand as a vital resource for medical device companies, providing a scope of services that aligns with the FDA’s call to action for proactive and independent assessments. Our team of experts offer clients an additional layer of vigilance through an objective review of all third-party activities and performance.. We deploy local oversight monitors to conduct thorough on-site visit evaluations and assessments, collecting actionable insights to swiftly pinpoint and rectify non-conformances, affirm data integrity, and maintain trial timelines.

Our approach to mitigating regulatory risks that could compromise trial data, participant safety, and submission viability utilizes a rigorous process that includes:

• Clinical Monitoring Oversight Plan Development
• Strategic Site and Partner Selection
• On-site Performance Evaluation
• Real-time Metrics and Analysis
• End-of-Trial Reporting and Inspection Readiness

Ultimately, our primary purpose is to help ensure the acceptability of trials for regulatory submission and instill sponsors with confidence, clarity, and consistency across all clinical endeavors.

It is important to note that the FDA’s letter specifically reminded device firms of their responsibility to ensure that all information submitted to the FDA is truthful and accurate. The Premarket Notification Truthful And Accurate Statement required by 21 CFR 807.87(l) to accompany each premarket submission reinforces this call for increased diligence.

How Beaufort can help

As the FDA intensifies efforts to confront data integrity violations through initiatives like the BIMO, Beaufort emphasizes the importance of vigilance and preemptive measures throughout the clinical trial process.

We invite you to explore our Clinical Monitoring Oversight solutions to learn more about how we can help fortify the integrity of your trial data, improve regulatory compliance, and safeguard your medical device development.

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Insights from ICH Draft Revision E6(R3), Risk-Based Approaches, and Quality Systems in GCP Compliance

The International Council on Harmonisation (ICH) E6 Good Clinical Practice (GCP) Guideline was first finalized in 1996 and described the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, sponsors, and Institutional Review Boards (IRBs). Subsequent revisions encouraged the implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, and recording and reporting, while continuing to ensure human subject protection and reliability of trial results.

On May 19, 2023, the ICH released draft revision E6(R3) with updated regulatory and quality standards for a more modernized and adaptive risk-based approach to planning, designing, conducting, recording, and reporting clinical trials. The major areas of focus in ICH E6(R3) Draft remain concise:

“Fostering a quality culture and proactively (versus retrospectively) designing quality into clinical trials and drug development planning, identifying factors critical to trial quality, and engaging stakeholders, as appropriate, using a proportionate risk-based approach.”

Beaufort is adept at advising sponsors in the application of GCP guiding principles throughout the clinical trial process

Beaufort is adept at advising sponsors in the application of GCP guiding principles throughout the clinical trial process. Our team has thoroughly reviewed E6(R3) and was asked to be a contributing author to the 2024/2025 edition of Barnett’s Good Clinical Practice: A Question and Answer Reference Guide.

Our team addressed over 70 questions related to Study Sponsors and Investigator Site Monitoring, and below are several key takeaways and important issues covered:

What are the key messages for Monitoring of Trials (Section 3.11.4) in ICH GCP E6(R3) Draft?

• Sponsor should use a risk-based approach to determine appropriate nature and extent of monitoring
• Monitoring plan development should consider objective, design, complexity, size, investigational product, safety profile, and trial endpoints
• The identified potential safety risks, risks to data quality, and any other risks impacting the reliability of trial results should guide the nature and the extent of the monitoring strategy selected.
• The monitoring plan that is developed should be focused on aspects that are critical to quality

Should sponsors have their site monitors monitor against the FDA’s GCP regulations/guidelines or the ICH GCP guideline, or both?

• FDA views ICH E6(R3) as entirely consistent with FDA GCP regulations and standards
• FDA BIMO inspections are focused on finding deviations from FDA GCP guidelines
• Some believe that adhering to ICH guidelines in addition to FDA guidelines increase FDA’s comfort level with site and sponsor performance

What is Adaptive Monitoring?

• Adaptive trial monitoring has a flexible study design, allowing for real-time adjustments to various aspects of the protocol as data is collected
• It is often utilized in situations where the optimal treatment regimen may be uncertain at the trial outset, or where there are resource allocation challenges
• Some key components are interim data analyses, reallocation of participants, dose adjustments, re-evaluation of sample size, enrollment and treatment adjustments, predefined stopping rules

Is there any guidance on how risk-based monitoring plans should be developed and what elements should be included?

• The primary principles of quality risk management as stated by the FDA in Q9(R1) Quality Risk Management Guidance for Industry (May 2023) are: (1) the evaluation of the risk to quality should be based on scientific knowledge and linking to patient protection, and (2) the intensity of the response to identified risks should be proportionate to the assigned risk level
• Prospectively identify the data and processes that are critical to trial quality, and then perform a risk-assessment to identify and understand the risks to those critical factors
• The monitoring plan should then be developed to focus on the prevention and/or mitigation of the most important and likely risks to critical data and processes
• Per ICH, the Sponsor should determine the appropriate extent and nature of monitoring based on the identified risks.  The monitoring plan should be tailored to the identified potential safety risks, the risks to data quality and/or other risks to the reliability of the trial results
• In addition to describing and justifying the monitoring strategy, activities, methodologies, and tools, the plan should put emphasis on participant safety and trial endpoints and should focus on aspects that are critical to quality

How should sponsors determine monitoring frequency for clinical studies?

• A risk-based approach to monitoring where the frequency of monitoring visits and the types of other activities to support monitoring is based on the study design and a risk assessment of the plan
• Factors to consider when determining the extent, frequency, and method of monitoring activities include: the complexity of study design, types of study endpoints, clinical complexity of the study population, geography, relative experience of the CI and of the sponsor with the CI, electronic data capture, relative safety of the investigational product, stage of the study, and the quantity of data
• Sites that enroll a large number of patients in a short period of time need to be monitored far more frequently than sites that are low, slow enrollers

FDA compliance officials increasingly are speaking about the importance of sponsors’ quality systems in clinical research, and of the shifting expectations for sponsor’s clinical trial oversight, to a quality risk management approach in trial oversight. What do they mean by this?

• FDA acknowledges that the previous model for compliance and managing the quality of trials was simply not sustainable, and recent technological advancements have created opportunities for more efficient trial management without impacting quality
• FDA’s current guidance advises sponsors to maintain trial participant protection and ensure the quality of clinical data by emphasizing oversight on the aspects of conduct and reporting that have been identified as the most critical to quality
• Prospectively identifying the data and processes that are critical to trial quality, and then perform a risk-assessment to identify and understand the risks to those critical factors
• Trial oversight will then focus on the prevention and/or mitigation of the most important and likely risks to critical data and processes

What implications does the FDA’s “fitness for use” definition and approach to high-quality data have for clinical trial monitoring, acceptable error rates, source data verification, and related issues?

• Fitness-for-use can be thought of as the suitability and appropriateness of data or materials for their intended purpose within the trial
• “High-quality data” can be thought of as data that effectively and efficiently demonstrates the clinical benefits and risks of a medical product while assuring the protection of trial participants
• There is not going to be one set standard for monitoring approaches, acceptable error rates, source data verification (SDV) strategies, and other trial design specifications
• The study protocol, patient population, investigational product and intended use are all going to impact what ‘high-quality data’ needs to look like for any given study in order to effectively support the evaluation of the safety and efficacy of the drug being studied

What kinds of alternate monitoring practices exist if a sponsor is not going to conduct 100% verification through extensive on-site visits?

• Sponsors using centralized monitoring should ensure that site processes and expectations for record keeping, data entry, and reporting are well-defined and support the ability to access trial data in a timely manner
• Remote monitoring activities that can be performed as well as or better than on-site activities include routinely reviewing the quality of submitted data, conducting statistical analyses, analyzing site performance metrics, and completing administrative and regulatory tasks
• Methods to securely and accurately validate source data include through electronic data capture (EDC) systems, electronic health records (EHRs), and remote access to site data systems
• There is evidence to suggest that centralized monitoring techniques may in some cases be even more efficient at detecting certain types of data anomalies, including fraud, fabrication of data, and other non-random data distributions.

How Beaufort can Help

As the clinical research landscape continues to evolve with ICH E6(R3) Draft, Beaufort stands as a trusted partner, bringing a wealth of GCP expertise to meet the latest industry standards. Our team is dedicated to guiding sponsors through the intricacies of risk-based monitoring, ensuring a proactive approach to quality in clinical trials. Beaufort’s provides a seamless integration of cutting-edge strategies, compliance assurance, and a commitment to unlocking the full potential of your research programs.

Contact us today to learn more.

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Did changes in your trial monitoring result in critical data gaps that can impact FDA approval?

During the COVID-19 pandemic, restrictions put in place to limit the spread of the virus made most traditional clinical trial monitoring methods logistically impossible. While thousands of trials stopped altogether, trials that continued throughout the acute phase of the pandemic did so by adjusting the method and frequency of clinical monitoring efforts. Due to the need to isolate impacted individuals and the enormous strain on the healthcare industry, there was an unprecedented shift toward remote monitoring and many novel data collection technologies and approaches were employed.

As a response to the upheaval that ongoing clinical trials were experiencing, FDA relaxed the expectations for clinical trial monitoring during the most restrictive period of the pandemic. This “Gap Period” between normally enforced monitoring activities pre- and post-pandemic saw trials shift fully to remote monitoring, decrease the scheduled frequency of monitoring visits, and sometimes even pause monitoring activities altogether. Trial data continued to be generated, but the monitoring efforts to ensure the quality and integrity of that data looked vastly different than they had before pandemic restrictions were put in place.

The Challenge for Sponsors

Despite the FDA relaxing monitoring expectations, the monitoring requirements and regulations remained the same, and once pandemic-era restrictions were lifted, sponsors largely resumed operations according to pre-pandemic standards. Upon this return to customary clinical monitoring practices, sponsors may not have necessarily addressed the integrity of their Gap Period data or any issues pertaining to participant protection that may have occurred.

Sponsors should be prepared if FDA asks during pre-approval inspections to demonstrate that any critical issues of data integrity and subject protection were not missed during the pandemic.

For trials conducted during the pandemic that are still ongoing, non-conformances during the Gap Period may not have been documented and addressed — or even discovered yet. Sponsors should be prepared if FDA asks during pre-approval inspections to demonstrate that they have ensured that any critical issues of data integrity and subject protection were not missed during the pandemic. Without having a robust response to that inquiry, sponsors are at a risk of more inspection findings during regulatory audits.

As a sponsor, how do you fill that gap?

A Targeted Approach to Ensuring Trial Integrity

With this risk to development timelines and budget, sponsors need a solution that can ensure confidence in the quality of their pandemic-era trial. Auditing each site is a cumbersome solution; it may be prohibitively costly and is not fit-for-purpose. A more effective approach to ensure audit-readiness is to perform clinical monitoring oversight visits tailored to the Gap Period.

Beaufort has a proven and flexible process that can objectively identify red flags and blind spots that can emerge during regulatory audits. We perform oversight visits to specifically address the period of time during which a trial was monitored according to more relaxed standards and provide reporting that supports trial results and reduces regulatory risks. Ensuring the integrity of Gap Period trial activities, and the quality of trial data generated during that time, allows all levels of an organization to have confidence in the validity of their trial results and their readiness to defend their trial during regulatory audits.

Contact Beaufort today for a consultation on how we can customize a solution that best suits your needs.

I’m traveling in Southeast Asia for a series of meetings with pharmaceutical companies that operate manufacturing facilities across the region and are interested in entering the US market.

Beaufort supports organizations considering this type of business expansion by providing a top-down gap assessment of their facility’s current manufacturing processes, targeting alignment with cGMP. The output of our review will identify gaps that can be corrected either through staff training and process improvement or if there is a need for greater capital / infrastructure investment. Ultimately, Beaufort’s strategic analysis details the scope and scale of business investment needed to meet the requirements for US market entry.

All GMP standards implemented worldwide require manufacturers to adhere to minimum standards throughout the entire production process. However, understanding the similarities and differences between non-cGMP and cGMP requirements is critical.  Our team is skilled at identifying and reporting on deviations across all areas, including facility design and maintenance, equipment design and validation, Quality Risk Management (QRM) systems, Quality Management Systems (QMS), process validation, SOP implementation, as well as documentation and record keeping.

Reach out to Beaufort if you are a pharmaceutical manufacturer interested in evaluating US market entry strategies and need a team of experts that can review, assess, and ensure compliance with cGMP.

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Sponsors can group information that comes out of any clinical trial testing into two main categories: 1) the data collected and, 2) all activities supporting the collection and reporting of the data. Reliance on one without the other provides sponsors with an incomplete view to adequately assess clinical trial performance and data integrity. Clinical Monitoring Oversight offers sponsors an objective onsite evaluation and assessment of a trial site’s conduct — and provides crucial information about a trial and site performance that is most often completely undetected from the data itself.

Sharing his extensive experience with Clinical Monitoring Oversight, John Wilson, Ph.D., Senior Vice President and Chief Quality Officer at Beaufort, answers questions about data blind spots, and how proper monitoring oversight bridges the gaps.

Q: Why is Clinical Monitoring Oversight so important?

A: First, let’s think of the more fundamental question “How does a sponsor know if their CRO is doing everything it should be doing to conduct a high-quality study and adequately protect the safety and rights of human subjects?” This question is increasingly asked by regulators as well as sponsor stakeholders. Clinical Monitoring Oversight provides the answer in a manner that allows the sponsor to have complete confidence in the data, and not worry about losing data or a study due to lack of oversight. In short, it’s about your ability to defend your study to a regulatory agency when it comes time for end-of-trial reporting and readiness.

Q: What information can Clinical Monitoring Oversight provide that data can’t?

A: Data may be able to tell a sponsor that something is incorrect or missing, but it will never tell them why, or what an appropriate corrective action might be. Through Clinical Monitoring Oversight, on the other hand, you can truly get to the root cause of a non-conformance.

For example, you might be able to see from a data readout that a site is averaging thirty days to respond to queries, when it should not be taking that long. However, the data doesn’t tell you the cause of the delay. From Clinical Monitoring Oversight, you can learn that the study coordinator might be overworked from managing eight different studies, or that they are simply not as fast or efficient as required to meet timelines. Those nuanced insights that data alone would never reveal allow you to accurately identify the “why” of issues — and more quickly respond with corrective action.

Q: Is it important for oversight monitors to be onsite to conduct these assessments?

A: We’ve found that one of the most critical success factors for sponsors in the management and execution of their clinical trial is to have highly qualified oversight monitors at the trial sites, engaging with principal investigators (PIs), site staff, and clinical research associates (CRAs). Through their high level of interaction with everyone involved in the trial process at the site, oversight monitors are able to quickly identify and facilitate the correction of issues, some in real time, that would never have been captured by processes such as data cleansing, exception reports, and artificial intelligence (AI). 

Q: So Clinical Monitoring Oversight also helps to assess site staff performance?

A: Absolutely. It’s integral for evaluating the work of all key site staff. Let’s stop and realize that the role of site staff in a clinical trial, whether PI, Study Coordinator, or any other role, is a difficult job with many moving parts. Other demands can reduce the time and focus required for a clinical trial – and result in underperformance or deviations from the protocol that impact the integrity of the data.

One of the most critical success factors for sponsors in the management and execution of their clinical trial is to have highly qualified oversight monitors at the trial sites.

By relying solely on data, sponsors can miss excellent performance, as well as performance that falls below expectations. A strong CRA can make a mediocre site look better, or a mediocre site can make an exemplary CRA look like they are not doing their job. Further, a CRA can do everything possible to handle a situation, but a site may simply not be performing to the standard required. We have found that it’s important to divorce site performance and CRA performance from one another, which you can’t do in a database. An objective observer, such as an oversight monitor, can more accurately evaluate a CRA’s qualification and suitability.

Q: Are there any other areas where Clinical Monitoring Oversight can provide insight?

A: Inspection readiness is another critical element that can be evaluated by an oversight monitor in a manner that won’t necessarily show up fully in database reporting. Take, for instance, the case of informed consent one of our oversight monitors recently encountered: Everything was going smoothly from all measures, and the CRA was engaged and performing at a high level. However, the oversight monitor discovered that the study population was primarily composed of people who are illiterate, and only a checkbox denoted that informed consent had been obtained. There was no documentation of this activity that would have been evident in a database. Even though the CRA was doing an excellent job in every other way, they did not have time to check every detail. However, the oversight monitor was able to pick up on this detail and elevate to the sponsor immediately. That level of oversight can be crucial when it comes time for inspection.

Q: What should a sponsor look for in hiring a company to perform Clinical Monitoring Oversight?

A: There are many factors a sponsor should consider when selecting a partner. A strategic approach will help the sponsor evaluate whether the partner has the right qualifications to match your needs and, importantly, will be equally invested in your success. Some key factors to look for are: Do they have the relevant experience, qualified staff, local resources, technology infrastructure, and operational expertise to support the outcome of your trial?

Beaufort has decades of experience providing leading health science companies with Clinical Monitoring Oversight. Our proven process helps proactively assess CRA and site performance, ensure participant safety, maintain data integrity, and demonstrate to regulatory bodies that your trial meets the highest scientific, ethical, and regulatory standards. 

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You can also watch Dr Wilson’s webinar “What Data Alone Won’t Tell You: The Rising Value of Clinical Monitoring Oversight” presented at the 2^nd Annual Clinical Oversight Conference.

Learn more about Beaufort’s Clinical Monitoring Oversight

The rising value of Clinical Monitoring Oversight

The Clinical Monitoring Oversight landscape has changed dramatically. New strategies and processes are required due to rapid technology adoption accelerated by the pandemic, as well as new regulatory guidance driving quality cultures that prioritizes proper oversight. As a sponsor, you are increasingly responsible for the integrity of all activity and data generated by your third-party vendors. The question many sponsors now face is: how do we adapt our approach to properly oversee the activities and ensure the quality of our CRO’s work? 

John R. Wilson, Jr., Ph.D., Beaufort’s SVP and Chief Quality Officer addressed these pressing issues at the 2^nd Annual Clinical Quality Oversight conference. Dr. Wilson is an industry leader in Clinical Monitoring Oversight and Beaufort was proud to sponsor this important event to share our proven approach to helping sponsors effectively protect the integrity and safety of their clinical trial.

Ensure Clinical Trial Integrity, Patient Safety and Regulatory Conformity Right from the Start

Dr. Wilson’s presentation covered the following topics: 

• The new landscape of Clinical Monitoring Oversight for sponsors 
• FDA guidance on CRO oversight and the importance of risk-based monitoring 
• Reinforcing a culture of quality through comprehensive oversight planning 
• The core elements of effective Clinical Monitoring Oversight
• Understanding the blind spots sponsors risk with a data-only approach to Clinical Monitoring Oversight 
• The impact of on-site oversight monitoring on end of trial reporting and readiness 
• The tangible benefits of comprehensive Clinical Monitoring Oversight   

Beaufort has decades of experience providing leading health science companies with Clinical Monitoring Oversight. Our proven process helps proactively assess CRA and site performance, ensure participant safety, maintain data integrity, and demonstrate to regulatory bodies that your trial meets the highest scientific, ethical, and regulatory standards. 

Learn more about Beaufort’s Clinical Monitoring Oversight

Participating in the first Vendor Day sponsored by the Avoca Quality Consortium, John R. Wilson, Jr., Ph.D., MPH presented an overview of Beaufort’s quality oversight program and the value it brings in ensuring a successful trial.

You can watch the webinar below: