Regulators and scientists with the U.S. Food & Drug Administration (FDA) carefully consider the risk for liver injury associated with a drug or biologic throughout its life cycle, both before a drug is approved and after it is put out into the population.
“Over time we build a more refined picture of a drug, the patient population treated, and the risk effects,” said Mark I. Avigan, MD, Associate Director for Critical Path Initiatives at the Office of Surveillance and Epidemiology at the FDA. “The assessment of risk for drug-induced liver injury (DILI) is something that develops over the whole life cycle of a drug and we use different data streams to characterize this risk at different points in the life cycle of the product.”
During Monday’s Hyman J. Zimmerman Hepatotoxicity State-of-the-Art Lecture, Dr. Avigan will discuss not only the evaluation of liver toxicity during different phases of a drug life cycle, but also some of the challenges associated with analyzing drug-related risk for serious liver toxicity.
The issue of DILI is always an evolving story, Dr. Avigan said, because there are always new therapeutic areas in need of evaluation. For example, one new area is the use of certain immunotherapies – immune checkpoint inhibitors – for the treatment of a variety of cancers. These inhibitors have the ability to augment immunity to kill cancers cells, but many also cause autoimmunity.
“One of the target organs for autoimmunity is the liver,” Dr. Avigan said.
During his presentation, Dr. Avigan will address drug-induced liver toxicity with messages geared toward practitioners, academia, drug developers and industry consultants.
For practitioners, the main message will be to realize that there is a wide variety of reasons why or how liver injuries occur, not only the mechanisms but how they present.
“Risk for serious life-threatening hepatotoxicity for most of the drugs we are concerned about is idiosyncratic,” Dr. Avigan said. “This means that these adverse liver injury events still only occur in a small percentage of all the individuals who are treated with the particular offending agent.”
Although rare, as more and more new therapies are approved, practitioners must pay attention to new modalities that have different signatures than they are used to seeing. Practitioners also play an important role in reporting liver injury to the FDA. Clinicians must report cases that they see at bedside, Dr. Avigan said, because the information is vital.
In the arena of drug development, one of the topics that Dr. Avigan will address is assessing signals of liver injury in clinical trials.
“We don’t often see liver failure or very serious liver injuries with life-threatening reactions because those are rare,” Dr. Avigan said. “We see something in between. Injuries that will go away or reverse.” Investigators must question not only what occurred in the study population, but what the results will mean in the larger population, he added.