Advancing Safeguards for Innovative Clinical Research

Applied Clinical Trials Online

As the field of clinical research undergoes rapid evolution, so too must the methodologies employed to safeguard patient participants. Whereas the focus of recent decades was predominantly on developing novel cardiovascular treatments for heart disease, contemporary research increasingly targets innovative therapies for conditions such as Alzheimer’s disease, cancer, and rare disorders. Personalized medicine and digital therapeutics are emerging as adjuncts to traditional pharmacological treatments, and recently, there has been a surge of interest in the use of psychedelics for managing mental health conditions, including depression and post-traumatic stress disorder.

However, these advancements bring about increased complexity and risk, necessitating that all stakeholders implement strategies to mitigate these challenges, thereby preserving the integrity of the research and ensuring participant safety.

A pivotal resource that clinical trial sponsors have increasingly turned to is independent data monitoring committees (IDMCs), even when not explicitly required by the FDA. Over the past thirty years, as clinical trials have grown in complexity, the utilization of IDMCs has expanded to include ongoing reviews of unblinded trial data. For instance, the use of data monitoring committees (DMCs) in high-impact journal trials was reported at 21% in 1990, a figure which rose to 35% in industry-sponsored trials by 2010 and continues to increase.While the exact percentage can vary by region and type of trial, it’s generally estimated that around 50-60% of clinical trials currently use DMCs.

The digital transformation of healthcare has led to an explosion of data, and artificial intelligence (AI) offers enhanced capabilities for decision-making across diverse data sources by improving data acquisition, processing, and interpretation. Current trends in AI, including generative and multimodal AI, quantum technologies, federated learning, and computer vision, are rapidly expanding the analytical toolbox. AI and machine learning provide unprecedented insights into clinical data, with real-time adaptation posing challenges to traditional regulatory assessments, inspections, and audits. In this context, DMCs play a crucial role in facilitating continuous data review.

DMCs are now employed across a broader spectrum of studies, including:

• Multiregional clinical trials
• Early-phase trials for severe conditions
• Trials for rare diseases
• Trials involving vulnerable populations, such as neonates, the elderly, and individuals at risk of self-harm

A notable instance highlighting the importance of independent DMC oversight is the case of Lykos Therapeutics’ ecstasy-based therapy trial in California. In June, the FDA rejected the application for approval and has initiated an investigation, following reports that the Lykos studies failed to identify serious adverse effects, including suicidal ideation.

Furthermore, DMCs are now overseeing entire clinical development programs rather than just individual trials. They review aggregate data for safety reporting and assist in implementing adaptive trial designs. While DMCs can recommend whether to continue, modify, or terminate a trial, the final decision rests with the sponsor.

In April, the FDA released new draft guidance acknowledging the increased role of DMCs and offering recommendations for their operational scope and practices. This represents the first substantial update since 2006 and suggests that DMC charters should be more comprehensive and detailed.

Crucially, the new guidance underscores the necessity for DMCs to maintain true independence, with recommendations for strengthening conflict-of-interest policies. Despite the apparent need for impartiality, challenges persist in ensuring that DMC reviews remain unbiased.

The ambiguities of contract research organizations

While the growing reliance on DMC reviews is promising, it is essential that these reviews are genuinely independent. Sponsors must implement safeguards within their DMC agreements to minimize potential biases and prevent the premature disclosure of unblinded interim results.

Sponsors should establish written procedures as part of the DMC charter to ensure confidentiality of interim data. The FDA also recommends that confidentiality provisions be included in written agreements between sponsors and DMC members.

Despite these guidelines, many sponsors opt to fully outsource DMC reviews to contract research organizations (CROs), which inherently have a financial stake in the trial outcomes. The FDA’s draft guidance clearly states that maintaining DMC independence from both sponsors, organizers, and trial investigators is critical to:

• Preventing sponsor interests from influencing the DMC
• Enhancing DMC objectivity and reducing bias, thereby increasing the validity of trial conclusions
• Allowing sponsors to make unbiased trial modifications
• Protecting the trial from conflicts of interest

Sponsors outsourcing DMC oversight to their CRO may not adhere to these principles due to the financial relationship between the entities, potentially leading to detrimental outcomes.

An independent DMC offers an unbiased assessment of critical trial data, providing sponsors with crucial insights into trial conduct, product safety, and key performance indicators. When such evaluations are conducted by parties with vested interests, the results may be perceived as biased, undermining the trial’s integrity.

Advanced technologies, such as Advarra’s Safety Oversight Activation and Reporting (SOAR) system, represent vital tools for maintaining data integrity. SOAR ensures that all DMC members operate within a secure, HIPAA-compliant environment, minimizing risks associated with data sharing and access.

Could an independent DMC have prevented the issues faced by the Lykos Therapeutics trial? While many factors influenced the trial’s outcome, the role of an independent DMC in ensuring rigorous, unbiased evaluation cannot be overstated. Employing ongoing, impartial data reviews could have identified issues sooner, facilitated adaptive trial designs, and potentially offered innovative solutions for managing mental health disorders.