Clinical trial safety reporting procedures have always been a challenge for sites, taking a disproportionate amount of time and money, but three factors are making the task even more difficult and lengthy for today’s sites: sponsors that over-report, lack of global harmonization of reporting rules and the pressures of a global pandemic that require rapid response.

Safety reporting is one of the largest hidden costs in drug development. And staying on top of dozens of countries’ rules is a daunting task, but it is essential to streamlining the reporting process and alleviating the burden on sites.

Part of the problem lies with sponsors that pepper sites with unnecessary reports of safety issues with little or no evidence of causality or relevance to the site, leaving trial staff to investigate and determine if they need to report the issues to their IRBs. Without causality, “most sponsors will take the most conservative approach and call it related,” says Leslie Williams of Pharmacovigilance Consulting. “That’s usually outlined in the protocol.”

“Many companies still distribute all safety reports to all sites and ethics committees due to a literal interpretation of [good clinical practice rules],” a practice that Steven Beales, senior vice president for WCG Clinical’s scientific and regulatory division, refers to as “brute force distribution.”

Beales says one of the largest reporting costs he has ever seen for a single clinical trial was $7.8 million for a four-year trial. “These costs are often hidden in other budget line items, so we don’t know what the real cost is,” he said. “As an industry, we have not fully tackled this.”

Sixty-one percent of sites are spending more than 80 hours of staff time per month processing safety reports; time that is taken away from patients, Beales notes. And there is money to be saved, too. Safety reports, on average, cost about $26 each to produce and the average budgeted cost per report is $45, so reducing the amount of safety reporting can free up funds to be used elsewhere.

A principal investigator (PI) involved in more than one trial can expect to receive an average of 170 reports per quarter, Beales said, and 80 percent of individual sites receive more than 20 reports per month. As a result, he estimates 20 percent of more than 2,000 sites WCG has worked with end up refusing to act on some sponsor reports.

For example, the FDA says that 86 percent of sponsor reports of suspected, unexpected, serious adverse reactions (SUSARs) in a recent oncology trial did not meet the criteria for reporting to the agency.

“You may be thinking ‘we don’t have 170 SUSARs a quarter for any of our studies,’” Beales told attendees at a recent WCG webinar. “But it is the cross-reporting where every SUSAR needs to be reported to every other study on that compound that causes these numbers to rise. We’ve worked with several companies that have seen a five-fold increase in safety report distribution over the past three years, for whom a single successful compound now has more safety distribution than almost the rest of their compounds combined.”

Kendra Hayden, WCG’s director for product strategy and governance, added that safety reporting was an even more urgent matter because of the pandemic. She said a recent search of the website ClinicalTrials.gov revealed there are currently about 1,300 interventional clinical trials that are open to recruitment and collectively looking to enroll more than 628,000 patients.

“That’s a lot of patients in a lot of studies,” Hayden said. “What this actually means is that there is extra weight and urgency on making sure that we’ve really got our processes, policies and systems really working together so we can deliver on this information. There is an urgency of finding out and getting those insights into how to better manage a global pandemic.”

And the multinational nature of today’s trials makes it difficult to know how and what to report in different countries. The timing of reporting requirements is especially difficult to reconcile.

Generally, sites must report serious adverse events to a sponsor within 24 hours, while sponsors must deliver SUSARs to regulatory authorities, IRBs or investigators within either seven or 15 days, according to severity. But Beales said 36 percent of countries have reduced their 15-day reporting requirements. “If you’re sending out your 15-day safety reports to every country, you’re not doing it correctly,” he said. He added that 62 percent of countries have no seven-day reporting requirements. “For each of these scenarios, we see how much we’re over-distributing by not following countries’ laws,” he said.

A number of high-profile sponsors have banded together to help create databases of all the safety reporting requirements globally, Beales noted, some of which use artificial intelligence (AI) to provide sponsors with reporting guidance.

AI is key to this approach, Beales said. “A rules-based approach,” he said, “will always perform better than a probabilistic one. We use machine learning when we’re not smart enough to work out the rules ourselves and need to derive them from big data.”

Beales said he advises drug safety professionals to review safety report distribution costs in their contracts. “You will be stunned at the inconsistency,” he said. “In some studies, the costs are per site, sometime per safety letter, sometimes there’s a flat fee. Study teams may understand how much you would pay to recruit a patient, but they really do not understand how much safety distribution should cost for a particular trial. Even on the same compound with the same provider, we see a dramatic variation between studies.”

Beales also recommends that sites consider centralizing safety reporting within their organization to help eliminate overspending. “Safety reporting is a compound-level activity and it best belongs in drug safety operations,” he said. “It is not a study-level activity, and study-level distribution just results in over-distribution when sites are working on multiple studies with that same compound.”