Tardive Dyskinesia Drug Approval Illustrates Efficient Trial Design

A well-executed development program based on efficient trial design led to rapid FDA approval of valbenazine (Ingrezza) for the iatrogenic movement disorder tardive dyskinesia (TD) in April 2017.

This observation was made by a team at the FDA’s Center for Drug Evaluation and Research (CDER) in a recently published case study. The team, led by Michael Davis, MD, PhD (pictured), also included Mitchell Mathis, MD, director of the Division of Psychiatry Products at CDER.

Tardive dyskinesia, a troublesome condition that had no accepted therapy, was first described in the 1950s after the introduction of first-generation or typical antipsychotic agents such as chlorpromazine (Thorazine) and haloperidol (Haldol).

The condition, characterized by persistent, abnormal, involuntary movements such as lip smacking and pursing, was eventually recognized as an adverse side effect of long-term use of typical antipsychotics.

It was also found to result from extended use of second-generation or atypical antipsychotic, such as olanzapine (Zyprexa) and risperidone (Risperdal) — although at a lower annual incidence (3.1%) than that of typical agents (8.5%).

Tardive dyskinesia can be “disabling and can further stigmatize patients with mental illness,” Mathis said. He noted this makes valbenazine’s approval such an important advance for inflicted patients.

According to Mathis and colleagues, the FDA designated valbenazine as a breakthrough therapy in October 2014, based on an understanding of its mechanism of action (inhibition of the dopamine transporter vesicular monoamine transporter 2) and its potential to fill an unmet medical need. This designation cleared the way for the FDA to do a rolling review, which enables the drug’s sponsor to submit portions of a new drug application (NDA) for FDA review as they are completed.

The FDA then slated valbenazine’s NDA for priority review based on the drug’s potential to offer an important treatment breakthrough. This designation advanced the NDA’s completion goals by 2 months, compared with those for standard NDAs and led to valbenazine’s approval only 8 months after submission of its NDA.

Remote monitoring of patient response to the drug also helped to ensure valbenazine’s speedy approval. In the 2 key studies showing valbenazine’s efficacy for TD, the primary end-point —change in Abnormal Involuntary Movement Scale score from baseline after 6 weeks of therapy — was assessed by centrally located neurologists specializing in movement disorders.

These raters scored TD severity by reviewing videotapes of remotely monitored patients. And to minimize expectancy bias, the raters were blinded to patients’ identities, treatment, and visit number.

This severity scoring procedure was also used to determine that the 80-mg dose of valbenazine was more effective than the 40-mg dose and that, in most patients, symptoms recurred a month after treatment ended. Dose comparison, blinded rating of remotely monitored patients, and a trial design incorporating crossover from placebo to active treatment all helped to support valbenazine’s efficacy for TD.

Valbenazine’s safety review, done by Brian Miller, MD, MBA, MPH, of the University of North Carolina (UNC) Kenan-Flagler School of Business in Chapel Hill, North Carolina, was also notable in several respects. The safety review pooled controlled trials with different randomization ratios by using a mixed-effects logistic-regression model to detect abnormalities in lab test results.

Researchers also developed a prospective observational database of multiple studies and categorized patients’ exposure by dose and time, then used this database to calculate the incidence density of adverse events. These procedures helped the investigators determine that valbenazine was associated with somnolence and lengthening of the QT interval, but not with exacerbation of depression or thoughts of suicide.

Thus, according to the FDA-UNC team, the valbenazine case study teaches several important lessons in how to ensure that drug development leads to timely FDA approval. Another key lesson is that “creativity and partnership in both development and review can effectively overcome long-standing clinical challenges.”

The case study, “Efficient trial design — FDA approval of valbenazine for tardive dyskinesia,” appeared online in the New England Journal of Medicine last month.