A Quiet International Revolution in Clinical Trial Regulation

There is a major international collaboration quietly underway to pull clinical trials firmly towards the future, featuring big hitters from across the world's major regulatory authorities and drug firms. The work is going on within ICH—the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, to give it its full and laborious title—and should result in an extensive rewrite of its 1997 guidance over the next couple of years.

The still little-known ICH is even older, making its debut in Brussels in 1990 with the engagement of top regulatory and industry figures from Europe, the USA, and Japan. Over the next decade or so it generated and promoted local adoption of a range of guidelines on safety, quality, and efficacy, as well as contributing to the creation of MedDRA (the medical dictionary for regulatory activities) and the Common Technical Document. By 2015 it had responded to the obvious need to widen its engagement, and since then has expanded its membership and adapted its institutions accordingly.

A flavor of the changes under consideration for clinical trials emerges from remarks made by Fergus Sweeney during a mid-May webinar on the process. Sweeney, who played a key role in the early days of the European Medicines Agency's work on GCP inspections, has himself matured over the years and is now head of the EMA's clinical studies and manufacturing task force, and has recently acquired a prominent public profile particularly in the context of the Covid pandemic and the related development of vaccines.

The essence of the current ICH initiative is that clinical trials are increasingly global, with wide use of data generated in other regions, and a consequent reliance on their regulators and scientists. As Sweeney put it, "We need to be responsive to the rapidly evolving ecosystem." This means working in an increasingly digital world and being prepared to adapt to it. It means responding to innovative trial designs –taking advantage of digital technology, the increase of statistical techniques and other opportunities for sourcing data that simply did not exist in the 1990s when the current guidelines were developed. The definition of essential documents may need updating since trials have moved on from a paper world with some rudimentary patient medical records and paper and paper case record form. In a more sophisticated world, it is also necessary to ensure that things are kept in the right format to actually be retrievable after a period.

"We need to progress evidence generation," Sweeney went on. "The last year has shown us how important it is to be able to move forward in a very organized high-quality way to deliver evidence on new medicines and on repurposing existing medicines," he pointed out. His view is that there needs to be a possibility of obtaining returns on the investment of taking time for good trial design. "We need to ensure that innovations in technology and design are facilitated and encouraged." There is a need for a better balance between on-site monitoring, centralized monitoring, medical monitoring, data reference systems, and new data types. In addition, it is time to ensure the involvement of all parties in better study planning—"not only the sponsors and experts, but patients who may use the medicine in the future, trial participants, the clinical trial investigators, healthcare professionals and regulators."

Above all, he suggested, "We need to set the foundation for responsible and efficient clinical trial conduct so we can deliver the results that everybody needs. We shouldn't just add more requirements to the status quo. We need to have a different approach. It's about change, and about managing that change."

Unsurprisingly, this complex exercise across borders and cultures is taking a long time—longer than anticipated. But a public consultation on the rewrite, initially scheduled for December 2021, will not now happen until December 2022. Nonetheless, the delay does not spring from any indolence: multiple working groups are hard at it in multiple video conferences around the globe, and inch by inch progress is being made towards shaping a more 21st century approach to that age-old fundamental dilemma of measuring the balance between risk and benefit.