The world is full of tradeoffs—it’s the way progress is made while proportionately managing risk.
When it comes to decentralized clinical trials (DCTs), arguably the most transformative innovation clinical research has seen in decades, the same is true. The new Food and Drug Administration (FDA)’s Decentralized Clinical Trial Draft Guidance issued May 1st has started to outline guidelines for increased oversight and planning while simultaneously supporting broader DCT adoption.
The guidance document is short at 19 pages, and by design not prescriptive. It covers DCT design, remote clinical trial visits and other activities, the use of digital health technologies as enablers of studies, the roles and responsibilities of sponsors and investigators, and how investigational medicine should be administered. It also lays out the agency’s current thinking on informed consent, review board oversight, packaging and shipping of investigational medicines, and factors to consider in a safety monitoring plan.
But, in many areas, the Draft Guidance is still vague, such as on the question of responsibility for principal investigator (PI) oversight when trial activities occur outside of the PI’s direct supervision and data is collected away from the site (i.e., home health visits). Further, the industry will need clarity beyond what the FDA has described regarding the completion of Form 1572 for hybrid and fully decentralized study designs (the FDA now encourages a central address where audits can take place even when some trial staff are in various locations). Also, it would be helpful for the FDA to provide guidance in a living Q&A format—a working document for sponsors who want to know about the new content and structure for the DCT-relevant content the FDA will be requiring in investigational new drug (IND) submissions going forward—akin to the guidance for ongoing trials that came out during the pandemic.
Yin-Yang: Opposite but Connected Forces
Ultimately, clinical study protocols will become longer and more detailed with the additional expectations of the FDA for clarification and documentation of planning and coordination of various stakeholders in a DCT. The FDA is essentially saying, let’s leverage technological advances, but let’s also think carefully through each discrete step, such as how we track safety events when using a sensor device in a fully decentralized trial.
Similar to the Chinese philosophical concept of yin-yang, the FDA’s additional demands are both a positive step forward, and if it goes too far, a step backward—an opposite, but connected force. Excess documentation and complex mappings can hamper rapid adoption of a better clinical trial model. Study protocols that balloon into 10-page documents can overburden organization unnecessarily—and cause DCTs to grind to a halt, which would be a disservice to all.
Here is a real-life example. A potent class of antibiotics, known as aminoglycosides, can cause hearing loss so medical schools taught students to only use these products as a last resort. As a result, they were rarely prescribed throughout the 1990s and 2000s. However, the risk profile changed recently as the World Health Organization (WHO) revealed high levels of antimicrobial resistance is causing life-threatening bloodstream infections and increasing treatment resistance for several common bacterial infections. Now, the risk factor for aminoglycosides is suddenly different as the choice between risk of deafness with the antibiotic versus risk of death without has very different consequences.
Therein lies the rub: how do we strike the right balance between complexity and simplicity—safety and innovation—in an ever-changing, organic world?
A Fit-for-Purpose Trial Protocol
By applying quality-by-design principles, sponsors can create a fit-for-purpose protocol that considers each trial’s current unique characteristics—i.e., the patient population, product being studied, therapeutic area, and trial phase. As an example, a Phase 4 trial for a drug with a known safety profile may not need as complex a protocol (and subsequent documentation) compared with a Phase 2 trial with an elderly patient population. Quality-by-design principles result in protocol designs that focus on the safety issues that matter most in proportion to the real-world risk, and align with both. The result is “just right”—no more, no less—so innovation continues.
The FDA has made a purposeful choice to write in broad strokes, stopping short of detailing ways to execute DCTs. Even so, the agency is driving adoption by acknowledging—and, thereby validating—the global shift towards an expanded model. Essentially, the FDA is broadening the definition of clinical trials to normalize the use of modern technologies in clinical trials—no longer trying to convince the industry to use technology, but rather, demonstrating how to use it while holding to critical patient safety and data quality clinical trial fundamentals. Soon, we won’t say “decentralized” or “hybrid” or “digital” clinical trials. We will simply say “clinical trials,” recognizing that digital components will be baked into each trial innately.
This is a global revolution, too. In December 2022, the European Medicines Agency (EMA) published its Recommendation Paper on Decentralized Elements in Clinical Trials, replacing its emergency pandemic guidance with a more robust framework. The paper emphasizes the protection of study participants, data integrity, and clear definition of roles and responsibilities for study sponsors, investigators, and other stakeholders. Like the FDA, the EMA supports the increased use of technology in clinical studies, so long as the fundamental principles of good study conduct remain intact. Additional health authorities around the world will follow suit as major markets make tech-enabled trials the de facto standard for quality, cost efficiency, and patient experience.
Beyond geography, the new guidance is unique in that it includes all potential investigational medical product centers—Center for Drug Evaluation and Research (CDER), Center for Devices and Radiological Health (CDRH), Center for Biologics Evaluation and Research (CBER), and Oncology Center of Excellence (OCE)—which means all investigational medical products, such as drugs, biologics, and medical devices, are incorporated. This opens new doors for all market sectors. For instance, device manufacturers benefit from a potentially more efficient way to conduct follow-up studies and post-market clinical follow-up (PMCF) as required in the EU. DCTs enable streamlined methods to capture valuable data about the quality-of-life impact of their innovations over longer timelines and in a way that is nearly burdenless to patients.
Fundamentally, the FDA isn’t issuing anything new in its latest Draft Guidance on DCTs. But, the FDA has infused credibility into technology-enabled trials, crystallized some of the operational rules (though, there is much more work to be done), and legitimized the DCT space. It still may take some work to discern the right balance of thoughtful planning and excessive documentation, but what was once thought to be a temporary remedy to get the industry through the COVID-19 pandemic, is here to stay. A clinical trial is now just a clinical trial—not decentralized or hybrid or any other characterization.
