The world is full of tradeoffs\u2014it\u2019s the way progress is made while proportionately managing risk.<\/p>\n
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 The new Food and Drug Administration (FDA)\u2019s Decentralized Clinical Trial Draft Guidance<\/a> issued May 1st<\/sup> has started to outline guidelines for increased oversight and planning while simultaneously supporting broader DCT adoption.<\/p>\n 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\u2019s current thinking on informed consent, review board oversight, packaging and shipping of investigational medicines, and factors to consider in a safety monitoring plan.<\/p>\n But, in many areas, the Draft Guidance is still vague, such as on the question of responsibility for principal investigator (PI) oversight when trial activities occur outside of the PI\u2019s direct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\u2014a 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\u2014akin to the guidance for ongoing trials that came out during the pandemic.<\/p>\n 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\u2019s leverage technological advances, but let\u2019s also think carefully through each discrete step, such as how we track safety events when using a sensor device in a fully decentralized trial.<\/p>\n Similar to the Chinese philosophical concept of yin-yang, the FDA\u2019s additional demands are both a positive step forward, and if it goes too far, a step backward\u2014an 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\u2014and cause DCTs to grind to a halt, which would be a disservice to all.<\/p>\n 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<\/a> 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<\/em> the antibiotic versus risk of death without<\/em> has very different consequences.<\/p>\n Therein lies the rub: how do we strike the right balance between complexity and simplicity\u2014safety and innovation\u2014in an ever-changing, organic world?<\/p>\n By applying quality-by-design principles, sponsors can create a fit-for-purpose protocol that considers each trial\u2019s current unique characteristics\u2014i.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 \u201cjust right\u201d\u2014no more, no less\u2014so innovation continues.<\/p>\n 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\u2014and, thereby validating\u2014the 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\u2014no longer trying to convince the industry to use technology, but rather, demonstrating how <\/em>to use it while holding to critical patient safety and data quality clinical trial fundamentals. Soon, we won\u2019t say \u201cdecentralized\u201d or \u201chybrid\u201d or \u201cdigital\u201d clinical trials. We will simply say \u201cclinical trials,\u201d recognizing that digital components will be baked into each trial innately.<\/p>\nYin-Yang: Opposite but Connected Forces<\/h3>\n
A Fit-for-Purpose Trial Protocol<\/h3>\n