Along with the FDA and the Clinical Trials Transformation Initiative (CTTI), the European Medicines Agency (EMA) is advocating for risk-based monitoring of trials, while at the same time saying current GCP rules render quality management in trials too costly and need to be reworked.

These comments were delivered in a reflection paper suggesting that academics, pharma companies and CROs consider new ways to ensure quality in trials as ICH GCP Section 5.1—which details what’s required of quality systems—is no longer relevant. The EMA also called out Article 2 of GCP Directive 2005/28/EC, which outlines required monitoring procedures, saying the regulation no longer fits.

“The ICH GCP was finalized in 1996 when clinical research was largely paper based, but the available technology and the approach to the conduct of clinical trials has evolved considerably,” the paper’s authors wrote, echoing the FDA’s recent assertion in its draft guidance as to why it’s now appropriate to consider centralized monitoring of trials.

Scrutinizing the definition of the word “quality” and what it means in the industry is a good place to start, the EMA wrote. “Simply advocating the ‘highest level’ of quality has little meaning in itself... the cost associated with incremental improvements in quality becomes ever higher as perfection is approached and becomes disproportionate to any additional benefit achieved.”

Liz Wool, president and CEO of QD-Quality and Training Solutions and a member of the board of trustees of the Association of Clinical Research Professionals (ACRP), said she worries that while risk-based monitoring as a concept sounds great—in theory, sponsors can send monitors to sites less frequently, saving money—many may not try it out of fear.

“I believe it’s needed, but people are going to be concerned that their particular decisions on how to do a risk-based approach, when inspected, will not be acceptable to the regulators,” said Wool.

The larger the sponsor, the larger its risk, she added, and perhaps the less likely it will be to try a new approach for fear it won’t actually be enough, should something go wrong during the course of a study.

In the meantime, while there’s still time to comment on the FDA’s new draft guidance and the EMA’s reflection paper on the risk-based monitoring approach, Wool suggests sponsors and CROs do so to get their concerns heard and their specific questions answered about how it would work. This will help put minds at ease as regulators try to reshape the way trials are monitored, she said.

The same goes for the EMA’s assertion that quality systems need to change, she said. “Sponsors need clarity on what do ‘quality’ and ‘quality systems’ mean,” Wool said, pointing out that in its reflection paper the EMA does not detail important topics such as issue escalation and management review. Without guidance in these areas, companies may shy away from any new approaches for fear trying something new could result in a bad audit.

The reflection paper offers some handy questions for a sponsor to ponder as it begins to adopt the EMA’s ideas about quality management, said Wool, but the paper’s guidance is by no means comprehensive.

“If I’m a company that doesn’t know anything about quality systems, I may look at this and say, ‘I’ll just do that,’ but that’s not enough,” said Wool. “What they say in the paper isn’t what your whole quality system is or should be, but rather they’re providing you some targeted areas to evaluate for risk.”

To do that, the EMA discusses quality tolerance limits, a concept common in drug manufacturing but new to clinical trials. Explained Wool, it means that for every functional area there must be a quality standard that has to be met.

“We do this all the time for manufacturing,” said Wool. “If, say, PH is out of range, we can’t release a product. The same is coming into play for GCP, and EMA is trying to help us translate this into some practice methods for the people who execute trials every day.”

Suz Redfearn