Regulatory Focus™ > News Articles > Regulators, Industry Prepare to Dig into Liver Toxicity Concerns in Bid to Improve Safety

Regulators, Industry Prepare to Dig into Liver Toxicity Concerns in Bid to Improve Safety

Posted 07 February 2014 | By Alexander Gaffney, RAC

A meeting proposed by US regulators would again seek to bring together the US Food and Drug Administration (FDA), pharmaceutical trade industry group PhRMA, the regulatory science-focused Critical Path Institute and public stakeholders to discuss best practices for detecting and assessing the likelihood that pharmaceutical products cause liver damage in patients.


Liver toxicity, sometimes referred to as hepatotoxicity, is a serious but relatively common adverse event, particularly when certain pharmaceutical products are taken at higher doses or extended periods of time. Even some commonly used over-the-counter (OTC) products, such as acetaminophen, can cause liver toxicity if taken incorrectly.

The problem lies in the function of the liver, which acts to process and clear toxicities from the body. Over time, the organ can become overloaded or damaged by chemicals, some of which can cause injury in smaller amounts.

FDA regulators have identified the problem as a serious one, noting that drug-induced liver injuries (DILI) were the "most frequent cause of safety-related marketing withdrawals for the past 50 years," and have been a critical factor in limiting the indications-or preventing the approval-of many other drug products.

A 2009 guidance from FDA, Drug-Induced Liver Injury: Premarketing Clinical Evaluation, recommended that sponsors of trials and applications conduct periodic tests of serum enzyme activities and bilirubin concentration to estimate the severity of liver injuries to patients, and adopt "stopping rules" for interrupting treatments.

Convening Regulators and Industry

In March 2013, FDA convened a related meeting to revisit that guidance in the hope of either updating or revising it.

That meeting was specifically focused on determining baselines for normal and abnormal liver toxicities, as well as recommended actions based on different scenarios, such as stopping rules for clinical trials if a drug exhibits unacceptable toxicities.

Now the same group is planning a follow-up meeting with the same general purpose but a different focus, this time looking at the reasons some patients experience DILIs and others don't.

The meeting, Serious DILI: Who Gets it? Who Doesn't? Why? was announced in a Federal Register announcement on 7 February 2014.

"Serious drug-induced liver injury (SDILI) is a major problem for drug development and clinical care," explains a meeting notice for the event. "We need a new understanding to identify especially susceptible patients, and a path forward to solve hepatotoxicity problems that affect pharmaceutical industry protocols, government regulatory bodies, academic consultants, and physicians who use drugs to provide patient care in the US and worldwide."

While the meeting is still short on details, a posted agenda contains such questions as:

  • Can we really predict SDILI? Or just detect? What progress has been made?
  • What may explain the different ways people respond?
  • What new and useful biomarkers (and predictors) are out there?
  • What else is new in DILI research?
  • Should trial subjects reflect patients to be treated?

The meeting will take place on 19-20 March 2014 in Hyattsville, MD.


Federal Register

Meeting Page

Regulatory Focus newsletters

All the biggest regulatory news and happenings.