Regulatory Focus™ > News Articles > US Regulators Invite Industry, Public to Recommend Revisions to Liver Toxicity Guidance

US Regulators Invite Industry, Public to Recommend Revisions to Liver Toxicity Guidance

Posted 25 January 2013 | By Alexander Gaffney, RAC

A meeting proposed by US regulators would 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. The end goal of the process, they said, is to revisit an earlier guidance on liver toxicities in the hope of either updating or revising it.


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.

Points of Discussion

That guidance was principally developed between 2006 and 2009, and FDA now says it wishes to revisit the guidance and obtain additional stakeholder input, potentially laying the groundwork for a revision of the guidance. An agenda for the meeting indicates that several hours will be spent discussing how to update or revise the 2009 guidance and evaluating proposals.

The meeting will be held on 20-21 March 2013. C-Path's website indicates the mini-conference will focus on a huge number of questions divided into four different topic areas.

The first area will focus on defining what "normal" liver tests look like, and seek to resolve questions regarding the values of serum enzyme activities and whether these tests should be considered relative to the patient's individual baseline. These values would also potentially inform clinical trial cutoff values-stopping rules-for when new drugs exhibit unacceptable toxicities, and whether these values might be relative to pre-existing liver damage.

The second area seeks to evaluate knowledge already gleaned from other organs, including hepatorenal syndrome (kidney) and hepatic encephalopathy (brain).

The conference will also assess the use of "new and useful biomarkers and predictors," as well as the safety of patients enrolled in trials who may already have liver injuries, such as those suffering from hepatitis C. "How can we reconcile inherent conflicts between safety and getting approvals?" the agenda asks.

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