European Medicines Agency Recommends Human-Based Tests After Fatal Drug Disaster

Seven out of 10 Americans take at least one prescription drug every day. Regulatory agencies, such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) work to ensure these drugs are safe for human use, from the first time they are tested in humans to market approval.

Prior to human testing, pharmaceutical companies conduct preclinical tests—primarily in animals—to help understand how the drug may interact with the human body. The utility of these tests is questionable, as the National Institutes of Health reports that more than 95 percent of potential medicines fail in humans after appearing safe in animals.

Last year, a previously healthy man died and four others experienced brain damage during a clinical trial in France. An extensive investigation concluded that the potential medicine being studied, BIA 10-2474 (BIA), caused Guillame Mollinet to die, and caused varying degrees of brain damage in the four others who were hospitalized.

As a result of this tragedy, the EMA began revising its regulatory guideline on risk mitigation for first-in-human and early clinical trials to further assist stakeholders in risk mitigation and translational issues. While the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines that include requests for animal data still apply, this guideline adds that additional approaches involving in vitro human cell systems or human-derived material may be useful for risk assessment by providing relevant information about translational differences.

The updated guideline also states that scientifically sound nonanimal tests should be used wherever possible.

A recent study supports the addition of human-focused approaches to preclinical assessment. Following up on the BIA disaster, a group of international researchers sought to find out why BIA was not safe by using activity-based protein profiling (ABPP) to screen BIA using human cells and brain tissues.

Researchers found that BIA disrupted the activity of several lipases, including an off-target enzyme that has been linked to neurological disorders, suggesting BIA may disrupt how neurons in the brain metabolize lipids. The off-target effects found using ABPP were not seen in preclinical experiments on mice, rats, monkeys and dogs. If the additional human-based test was conducted on BIA as part of preclinical screening, BIA may not have continued to animal tests and human trials.

The EMA guideline, which goes into effect in January 2018, is an important step toward improving the predictability of preclinical approaches that are meant to protect humans. In response to a tragedy, the EMA assessed and revised its practices.

The FDA should follow in its footsteps and work to revise its regulations and guidance that prioritize animal data, by clearly communicating that sufficiently evaluated human-based approaches are accepted in drug development.