Warning Letter Breakdown: Clinical Investigator Doesn't Adhere to Clinical Study Plan
Warning Letter Breakdown: Clinical Investigator Doesn't Adhere to Clinical Study Plan
The FDA warned a clinical investigator for failing to follow an investigational plan for testing a drug to treat depression. The inspection was conducted under the agency’s BIMO program.
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The FDA recently issued a warning to a clinical investigator for not following a clinical investigational plan for testing a drug to treat depression. The inspection was conducted under the agency's Bioresearch Monitoring Program (BIMO).
The clinical study plan stated that the safety assessments had to be completed by a blinded assessor. However, the investigator was not blinded. The blinded assessor was responsible for administering efficacy assessments, including the Montgomery-Asberg Depression Rating Scale (MADRS) assessments, which were required to be completed during all study visits from Visit 2 until Visit 8 or early termination.
The warning letter states that the investigator conducted a total of 16 MADRS assessments for all three subjects enrolled at his site, despite being a designated blinded rater. He was not blinded to certain safety assessments, which included vital sign measurements such as blood pressure, heart rate, and body temperature.
Below is a quick breakdown, some lessons, and recommendations for avoiding these issues.
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Non-adherence to the investigational plan
“You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60]."
The primary deficiency cited is the failure to conduct the investigation according to the investigational plan, particularly regarding blinding procedures. The plan required that the clinician-administered assessments related to study-defined efficacy endpoints be completed by a rater who was blinded to safety assessments.
The clinical investigator, however, conducted these assessments without being blinded to certain safety assessments.
Compromised blinding procedures
"The blinded assessor was responsible for administering protocol required efficacy assessments... You failed to adhere to this requirement."
The investigator cited, designated as a blinded rater, was found to have access to and evaluated safety assessments (like vital signs and clinical laboratory reports) for subjects, which should have been restricted according to the protocol.
This access potentially compromised the blinding and introduced bias into the study.
Involvement in unblinded activities
"For example, for Subject (b)(6), you evaluated safety assessments such as vital-sign measurements, including blood pressure, heart rate, and body temperature."
The investigator was also involved in both blinded and unblinded activities. For instance, he assessed vital signs and performed physical examinations for subjects while also conducting MADRS assessments as a blinded rater. This dual role conflicted with the requirements of the protocol.
Protocol deviation in conducting assessments
"You stated that when you realized that the assessments should be conducted by a rater blinded to the safety assessments, you subsequently filed a protocol deviation and did not conduct any additional MADRS assessments."
It was noted that the investigator realized at some point that the MADRS assessments should have been conducted by a rater blinded to safety assessments. Despite this realization, a protocol deviation occurred when he conducted a total of 16 MADRS assessments for all three subjects enrolled at the site.
Inadequate corrective action plan
"Your response is inadequate because you did not include sufficient details about your corrective action plan."
The FDA found the corrective actions proposed by the site, in response to the Form FDA 483, to be inadequate. While the site acknowledged the issue and outlined some corrective and preventive actions, these actions lacked sufficient details, particularly regarding the implementation of practices to ensure compliance with study protocols in the future.
Concerns about data reliability and integrity
"Your administration of at least five of the seven required MADRS assessments for each enrolled subject as an unblinded assessor, as well as your failure to ensure that protocol-required blinding procedures were followed, raises significant concerns about the reliability and integrity of the data collected at your site."
The FDA expressed significant concerns about the reliability and integrity of the data collected at the site, given the failure to ensure protocol-required blinding procedures. This puts into question the validity of the study results, especially the efficacy assessments of the investigational drug.
Responsibility of the clinical investigator
"We emphasize that as the clinical investigator, it is your responsibility to ensure that the study is conducted in accordance with the investigational plan and to ensure the integrity of the study data."
The letter emphasizes their responsibility as a clinical investigator to ensure that the study is conducted in accordance with the investigational plan and FDA regulations. The need for establishing procedures to prevent similar violations in ongoing or future studies was also highlighted.
A few important lessons
Several specific lessons can be drawn regarding the conduct of clinical investigations:
Strictly adhere to study protocols. This one should be obvious: make sure that all aspects of the clinical trial are conducted exactly as outlined in the study protocol. If a study protocol specifies that certain assessments must be conducted by a blinded investigator, follow it. In a drug trial, if efficacy assessments are to be blinded, the investigator conducting these assessments should not have access to data that could reveal the patient's treatment group, such as medication dosage or side effects observed.
Clarify and segregate roles thoughtfully. Clearly define and segregate roles within the clinical trial team. Individuals involved in blinded assessments should not participate in unblinded activities that could compromise the blinding process. One team might handle patient recruitment and consent, while another team, unaware of each patient's treatment, conducts the efficacy assessments.
Revisit your training program (GCP and protocols). A comprehensive training program should be in place for all staff involved in clinical trials. Training should cover not only general Good Clinical Practice (CGP) but also the specifics of the study protocol. For a trial involving a new cardiovascular drug, this could include training on how to measure and interpret heart rate and blood pressure accurately, as well as how to record data correctly to maintain the trial's integrity.
Maintain open and effective communication with the study sponsor and regulatory bodies. Document all communications, especially concerning protocol deviations, corrective actions, and compliance issues.
Developing detailed corrective action plans. Your response to any identified issues is crucial. The FDA found the corrective actions proposed in response to the Form FDA 483 to be inadequate. While the site acknowledged the issue and outlined some corrective and preventive actions, these actions lacked sufficient details, particularly regarding the implementation of practices to ensure compliance with study protocols in the future. This emphasizes the importance of not only identifying and acknowledging errors but also developing and clearly articulating a comprehensive plan to rectify these issues and prevent future occurrences. After identifying a protocol breach, such as unblinded assessors conducting blinded assessments, a corrective action plan could involve retraining staff on blinding procedures, conducting re-assessments where possible, and implementing additional checks to prevent future breaches. Read our CAPA guide for more best practices.
Conduct regular audits and monitor to ensure continuous adherence to the protocol and regulatory requirements. This helps in early identification and correction of any deviations. When conducting clinical trials on investigational medicinal products or devices, you are required to show the planning, study conduct, performance, monitoring, auditing, analysis, and reporting all meet the ethical and scientific standards for GCP. Implement periodic internal audits to review compliance with the study protocol. This could involve randomly checking trial data entries against source documents or observing how assessments are conducted to ensure they align with the protocol. Whether you follow a traditional approach to monitoring or are transitioning to a Risk-Based Monitoring (RBM) system, our quality professionals tailor their auditing plans to accommodate your particular needs. Learn more about our GCP and trial-related auditing services.
Take measures to ensure the integrity and reliability of trial data. This includes following the protocol strictly and addressing any issues that might compromise data quality. The FDA expressed significant concerns about the reliability and integrity of the data collected at the clinical site, given the failure to ensure protocol-required blinding procedures. Use secure, validated data management systems that track changes to data entries. This could help in a scenario where a data entry error is made, allowing the original, correct data to be restored.
A few key questions for self-assessment
Have we conducted a line-by-line review of the study protocol against our actual practices to ensure complete alignment?
Are there any aspects of the protocol where compliance is particularly challenging, and if so, what measures have we put in place to address these challenges?
Do we have a clear, documented process that outlines the specific roles and responsibilities of each team member involved in the clinical trial?
How do we ensure that individuals involved in blinded assessments are not exposed to unblinding information?
What specific training modules have been provided to staff members involved in the clinical trial, and how frequently is this training updated?
Have we tested our staff’s understanding and application of the training content in real-world scenarios?
Do we have a documented communication plan that specifies how and when information should be shared with regulatory bodies, sponsors, and other stakeholders?
How are protocol deviations, adverse events, or any other significant trial-related events documented and reported?
When a protocol deviation or non-compliance issue is identified, what is our standard procedure for developing and implementing a corrective action plan?
How do we monitor the effectiveness of these corrective actions over time?
What is our schedule for conducting internal audits, and do these audits comprehensively cover all aspects of the clinical trial?
How are findings from audits acted upon, and who is responsible for ensuring that corrective measures are implemented?
Do we have a system in place for reporting trial updates and issues transparently and promptly to all relevant parties, including regulatory authorities?
What mechanisms do we have in place to ensure the accuracy and integrity of our trial data?
How do we track and manage data amendments or corrections?
Talk to us about clinical auditing/remediation support if you're unsure of — or unsatisfied with — your answers to any of these questions. You can always book time with us directly here.
Further reading
Also, if you haven’t considered clinical operations staff augmentation as a better alternative to, or complement of, a traditional CRO, read our free white paper that introduces the model and how we’re helping clinical-stage companies overcome a number of challenges: A Modern Guide to Clinical Operations Resourcing.
A few other related resources:
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