In January of 2016, a Phase I drug trial in France, conducted by the French contract research organization Biotrial, left one volunteer dead and five others hospitalized: four with permanent neurological damage. The drug, named BIA 10-2474, is under development, by the Portugal-based pharmaceutical company Bial, for pain relief. This is a therapeutic area where non-addictive drugs are in great need. BIA 10-2474 differs from other medications in this class as it is an inhibitor of fatty acid amide hydrolase (FAAH). This is in contrast to oxycodone (which works on opioid receptors) or naproxen (inhibitor of cyclooxygenase enzymes). How and why this catastrophe happened has been a focus of significant speculation in the medical and scientific communities. But crucial details, such as in vitro and animal studies, are lacking. At the time of the incident, PubMed listed no publications of any type from Bial on this class of drugs.
Following the Biotrial incident, the EMA updated its guidelines on first-in-human (FIH) clinical trials. Following its review of FIH trials in late May, EMA released a draft concept paper for public consultation through 30 September 2016. EMA states the concept paper will be a foundation for a draft revision to its current guidelines, which it expects to release in late 2016. According to EMA, FIH trials have changed considerably since the last guidance was published in 2007, and current trials often involve more elements, such as multiple ascending doses (MAD), food interactions, and several subject groups. The EMA says it plans to extend its FIH trial guidance to cover issues such as early phase clinical trial design, integration of non-clinical pharmacology and toxicology data, definition of stopping criteria, and the rolling review of emerging human data during the study.
Most testing for the US drug industry’s late-stage human trials is now done at sites outside the country where results often can be obtained cheaper, faster, and with less red tape. A study by Glickman et al (N Engl J Med. 2009 Feb 19;360(8):816-23) reviewed over 300 published Phase 3 trials and found that almost a third of those led by US pharmaceutical companies were being conducted entirely outside the country. The researchers found, at the same time, that the number of FDA-regulated investigators running trials abroad increased by 15% each year, while the number of US-based investigators declined 5.5% annually.
The bureaucracy associated with gaining FDA approval has been in the headlines numerous times over the years. The FDA process was recently questioned following meningitis outbreaks at Princeton University and the University of California, Santa Barbara in 2015. These outbreaks were unique because the meningitis vaccines required by schools didn’t protect against the particular meningitis strain that was determined to be the cause of the outbreak. However, a vaccine for the serogroup B strain, named Bexsero, was approved in 2012 by the European Medicines Agency (EMA) for use in the EU. The vaccine had also been previously approved for use in Australia and Canada. Within nine months, FDA permitted students on affected campuses to use the vaccine. FDA has not yet approved a design for Novartis’ Phase III trials. Completion of these trials, in addition to the submission of a new drug application to FDA, will take years to complete and cost millions of dollars.
Why doesn’t FDA just approve a product already approved for use in the EU? Do the EMA and FDA have significantly different approval standards? It has been suggested that competition between regulatory authorities could cause a “race to the bottom” as agencies cut regulations to be competitive and draw the most applications.
FDA is in the process of collecting and reviewing safety information pertinent to FAAH inhibitors under investigation in the US. In the meantime, additional FAAH inhibitors are also under development, including Janssen/Johnson & Johnson’s JNJ-42165279 for social anxiety disorder and Pfizer’s PF-04457845 for osteoarthritis pain. Therefore, updates to the regulations are timely and necessary. And, sponsors must carefully weigh the benefits (both to the sponsor and the study subject) of performing FIH trials in the EU, US or elsewhere.
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