By Ernie Hood
In April 2003, Janet Woodcock, MD, the director of the FDA’s Center for Drug Evaluation and Research, told an agency committee that the time had arrived to incorporate pharmacogenetic data in drug approvals and labels. “We need to find a way to get the information in, develop our policies, develop a regulatory framework…and help to move this field along,” she said.
Since then, the agency has made strides in implementing Woodcock’s recommendations, but some observers say it’s still falling short of fully supporting pharmacogenetics via labels.
By 2005, the FDA issued its first guidelines governing the voluntary submission of genomic data by pharmaceutical companies. “They have engaged with a number of groups, developed education programs to increase awareness about pharmacogenetics, and at one point they were working with pharmaceutical companies on pharmacogenetic data sets, trying to determine how this new data would be incorporated into the application submitted to the FDA by a drug company,” explained Susanne Haga, Ph.D., of the Duke University Center for Applied Genomics and Precision Medicine, who has published extensively on drug labeling and pharmacogenetics.
Then, by 2007-2008, the FDA had accumulated enough experience and in-house knowledge to issue a series of guidance documents specifically intended “to facilitate progress in the field of pharmacogenomics and genetics…”
“They were still learning about the validity of that data and how it could be analyzed, with the whole range of other measures that clinical trials collect data about,” Haga said. “But it’s grown to where it has become almost standard for these types of analyses to be incorporated by researchers investigating the effects of new drugs. When it reaches the point where a patient population may be excluded based on genetic data, certainly that would go into the label.”
The Table Is Set
Today, the FDA maintains a website called the Table of Pharmacogenomic Biomarkers in Drug Labeling, where all drugs with any type of pharmacogenomic information in their labels are listed. The agency now seems to have embraced its role as facilitator, as evidenced by the October 2013 publication of a landmark report, Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development.
Over the past decade, the Table has grown to include pharmacogenomic information related to 140 drugs, with new ones being added frequently as more data emerges from clinical trials and more drugs with pharmacogenetic elements are approved for marketing.
Remarkably, 28 of those drugs, fully 20 percent of the list, are psychiatric and behavioral medications, including such household names as Prozac (fluoxetine), Valium (diazepam), Paxil (paroxetine), and Abilify (aripiprazole).
Haga was not surprised by that number. “It is one of the areas at the forefront of the application of pharmacogenomics, given the challenges of identifying an effective drug for patients affected by certain mental illnesses and trying to minimize the risk of side effects or adverse responses,” she said.
Watch Those Metabolizing Enzymes
Many of the psychiatric drugs listed are selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) and are metabolized by the enzymes CYP2D6 and/or CYP2C19.
“Those enzymes are well known for genetic variations that lead to phenotypic differences,” noted Michelle Whirl-Carrillo, Ph.D., associate director of the Pharmacogenomics Knowledge Base (PharmGKB). “So it’s not surprising that response to these drugs is influenced by pharmacogenetics,” she added.
Although most of the labels on the list do relate information about so-called CYP2D6 poor metabolizers (individuals at risk of overdose as the medications build up in their systems and are not eliminated efficiently), Whirl-Carrillo said the FDA Table could do more by providing information in support of pharmacogenomic testing.
“In fact, many of the labels just suggest monitoring patients in case they are poor metabolizers, especially if they are taking another drug that is a CYP2D6 inhibitor,” she said, adding that the labels could go further. “I don’t believe that appearance on the FDA biomarker list is indicative of pharmacogenomic testing.”