By Alessandra Baffa and MaryAnn Badala, Halloran Consulting Group
As emphasized in Part 1 of this series, sponsors are responsible for the protection of human subjects and the quality and integrity of their data when it comes to the conduct of clinical investigations for investigational drugs and devices. From a high level, this responsibility presents as a daunting task for a commonly difficult problem to mitigate and diagnose. However, there is a way to break down key elements of oversight in a holistic way to ensure that sponsors are using the best approach with regard to scientific misconduct and fraud: robust site evaluation and selection, a comprehensive monitoring and risk management process, in-depth data reviews, and proactive reporting.
Robust Site Evaluation And Selection Criteria
Site evaluation is the foundational element for ensuring a site is able to conduct studies compliantly. The site feasibility process provides the sponsor with a distinct overview of how sites can operate, considering the requirements of your study and protocol. A robust site feasibility process should minimally consider the number of active studies per principal investigator, study coordinator, research program coordinators, data coordinators, and other site staff. This may even include interviewing staff, including monitors and investigators, during site initiation visits (SIVs). Site staff interviews present an opportunity for sponsors to assess a site team’s overall understanding of fraud and misconduct and set sponsor expectations for compliant operations. Sponsor representatives may participate during these interviews, in which they can tailor interview questions that probe for how a monitor should handle suspected misconduct or identification of systemic data irregularities. Selected monitors should actively identify systemic data irregularities across patients at the given site. Furthermore, a thorough evaluation of study-specific equipment and facilities will help sponsors understand capabilities and organizational design of a site and whether a particular study is suitable for day-to-day study conduct.
In addition to an operational evaluation, sponsors must perform their due diligence, whether taking on a new site or engaging a contract research organization (CRO). At minimum, sponsor review should involve a thorough check of publicly available data, including verification of the FDA Debarment List, site warning letters, site follow-up communications, and any outcomes of FDA inspections. While debarment checks, for example, may be performed by a CRO, sponsors should be made aware of any outcomes of checks [FDA Compliance Program (CP) 7348.810 Sponsors and CROs].
CROs should also be assessed with the same level of scrutiny. On one hand, CRO processes and compliance programs and histories should be reviewed in accordance with current regulatory requirements, and supplementary trainings can be provided from the sponsor side. However, the sponsor can gain more acute awareness of unsatisfactory practices by investigating previous inspection data, analyzing the company’s financial well-being (including any recent mergers or acquisitions), and looking for any previous or current litigation issues.
Comprehensive Monitoring & Risk Management Process
To start off, monitoring processes (monitoring standard operating procedures [SOPs] and plans) should be clear and concise. Robust sponsor oversight plans should be in place and include the evaluation of monitors, review of monitoring reports, and metrics. Periodic site checks, designed with adequate frequencies, should be included in monitoring plans. These processes should not only specify direct access to original records but also outline issue management and follow-up activities. This can be facilitated by establishing and maintaining clear communication plans and ongoing meetings between applicable parties.
These efforts expand a sponsor’s ability to better understand what is occurring at the site level and ensure that any problems that may arise are addressed appropriately. As a starting point, robust monitoring incorporates and ensures the proper training of site staff. While this may mitigate misconduct rooted in ignorant practices, it may not necessarily prevent someone with the intent of committing outright fraud. However, it is integral to ensuring foundational awareness and must include GCP compliance and protocol/investigational plan training. However, training does not — and should not — stop there. Providing training on scientific misconduct, good documentation practices, and data integrity presents important opportunities to build broader awareness for study site staff. If these study activities are outsourced to a CRO, ensuring that its processes adequately prepare staff and provide accessible mechanisms for reporting non-compliance to sponsors is equally important. Sponsors should continue to actively engage CRO personnel and outline guidelines for communications to foster continued compliance and oversight.
Lastly, if it is anticipated that remote monitoring and risk-based monitoring will be used during the conduct of the study, an assessment of its robustness is key. Utilizing a study-specific risk assessment categorization tool (RACT) and/or risk register as part of a risk management process allows sponsors to define risks and parameters for data outliers. Once established, sponsors and CRO representatives should actively work with one another to identify key areas of risk and data outliers and incorporate these elements into their monitoring activities.
In-Depth Data Reviews
Structuring feasible and comprehensive data review is essential and, as we’ve seen recently, increasingly important for sponsor oversight. Processes for data review should first delineate the roles and responsibilities and include appropriate stakeholders who will be reviewing data. In this way, data is carefully examined by those within the relevant area of expertise. These reviews should include, but are certainly not limited to, medical monitors/clinical research scientists assessing data from a medical/clinical perspective, or data managers reviewing data consistency and trends, for example.
Why are we looking at data reviews so carefully? From a study perspective, medical, biostatistical, data management, and safety teams should be continuously scrutinizing patient profiles, case histories, and other data outcomes. Particularly concerning patterns can take the form of repeated data error trends, inability to reconcile data collected with safety reporting, and other data inconsistencies. This can even include highly “attractive” data that is free of discrepancies normally encountered (for example, no evidence of serious adverse events [SAEs] for complex hematology and oncology trials). How, then, do we tackle data review? Data reviews should be designed and established in a risk-based manner. For example, data review can be driven by status of subject enrollment, SAE trends, or number of protocol deviations.
Sponsors should incorporate periodic quality assurance data audits conducted by independent auditors into audit plans. Quality issues and site metrics should be leveraged to determine which sites to audit. These activities provide sponsors with clearer data insights and the opportunity to respond to potential suspicious activity in a timely manner.
While sponsors can make strides in developing processes to mitigate scientific misconduct and fraud, reporting any suspected behavior demands equal importance. Sponsors should not only design and implement procedures for prompt notification, evaluation, and reporting of misconduct but also conduct comprehensive and routine training to accompany these systems.
The FDA can be informed of potential misconduct and escalate issues appropriately (to the DOJ, for example) and there are also resources for sponsors to self-report through the U.S. Office of Research Integrity (ORI). Sponsors are also expected to report to international health authorities such as the EMA or MHRA, as appropriate. For example, if misconduct is identified at a U.S. site in which the U.K. is participating, the MHRA would need to be informed appropriately. As a sponsor, it is critical that any study conduct issues regarding potential scientific misconduct or fraud are evaluated and reported, if applicable.
“Reliable clinical trial data is a foundation for FDA drug approval. Falsifying that data leaves consumers at risk of taking drugs that are neither safe nor effective,” said Assistant Commissioner Catherine A. Hermsen for the FDA Office of Criminal Investigations (OCI). “We will continue to investigate and bring to justice those who endanger the public health when they engage in conduct that might subvert the FDA approval process.”
As is evident, a sponsor’s role in overseeing the conduct of a study and ensuring patient safety and data integrity continues to be a critical issue for regulated clinical trials. Actively engaging sites performing robust site criteria and evaluation, designing, and executing comprehensive monitoring and risk management processes, carrying out in-depth data reviews, and engaging in proactive reporting are essential for sponsors to place their best foot forward. Most importantly, continuing to ask about the next best step in proactive sponsor oversight will aid in fostering a sustained compliance strategy.
About The Authors:
MaryAnn Badala is a quality assurance professional and principal consultant at Halloran Consulting Group. She has more than 15 years of experience in the biotechnology and pharmaceutical industry. Her career has focused on clinical quality assurance process improvement initiatives, good clinical practice (GCP) audits/investigations, and inspection readiness activities.
Alessandra Baffa is a GxP quality consultant at Halloran Consulting Group. She is actively engaged in biotechnology and pharmaceutical operations across multiple therapeutic areas and stages of development. She currently leads and supports various client engagements implementing quality management systems and eTMF systems, coordinating audit activities and gap analyses, managing SOP development projects, and enhancing inspection readiness activities.