Med Check

Regulatory Briefs

• Alkermes Inc. announced in September that the U.S. Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee voted 12-1 that Vivitrol (naltrexone for extended-release injectable suspension) should be approved for the treatment of opioid dependence. Though not binding, the advisory committee's recommendation will be considered in the FDA review of the supplemental new drug application submitted by Alkermes.

“The advisory committee meeting outcome underscores the strength of the clinical data for Vivitrol and the need for new treatment options,” said Richard Pops, chief executive officer of Alkermes, in a statement. “We believe that, if approved, Vivitrol would offer a new path to recovery as the first nonaddictive, once-monthly medication for patients with opioid dependence.”

• In September, the FDA issued a safety labeling change for Risperdal (risperidone) tablets, Risperdal oral solution, and Risperdal M-Tab oral disintegrating tablets. The labeling change is an added warning that priapism has been reported during postmarket surveillance of the medications. Adverse reactions, based on postmarketing experience, now include priapism, hypothermia, sleep apnea syndrome, urinary retention, diabetes mellitus, and hypoglycemia.

The FDA also issued a labeling change for Risperdal Consta (risperidone) long-acting injection to indicate that adverse reactions observed during premarket evaluation of the drug include abdominal pain, upper respiratory tract infection, presence of glucose in urine, initial insomnia, delayed ejaculation, and pruritus. Adverse reactions observed in postmarketing experience include urinary retention, diabetes mellitus, and hypoglycemia.

Details of the labeling changes are posted at <www.fda.gov/Safety/MedWatch/SafetyInformation/ucm225299.htm>.

• In September the FDA accepted for review a new drug application for the Aricept Patch (donepezil transdermal system) for treatment of Alzheimer's disease. The application was submitted to the FDA by Eisai Inc. on June 30.

Industry Briefs

• The FDA announced in September that Forest Pharmaceuticals Inc. entered into a plea agreement in which the company accepted responsibility for criminal actions including distribution of an unapproved new drug, distribution of a misbranded drug, and obstruction of an FDA inspection. Forest has agreed to pay more than $300 million, including $164 million in criminal penalties. The plea agreement is the culmination of a multiyear investigation conducted by the FDA's Office of Criminal Investigations in cooperation with its law-enforcement partners and the U.S. Attorney's Office for the District of Massachusetts, according to the FDA.

Charges against Forest are primarily for its marketing and distribution of Levothroid (levothyroxine sodium tablets) for treatment of hypothyroidism in the 1990s. At the time, the drug was considered a “new drug” within the meaning of the Federal Food Drug and Cosmetic Act, and manufacturers were required to obtain approved applications from the FDA by August 2000. Forest Pharmaceuticals did not obtain drug approval and ignored a subsequent warning letter to stop manufacture and distribution of the drug, according to the FDA.

But the company also is charged with distribution of a misbranded drug because of the company's off-label promotion of Celexa (citalopram) for pediatric use when it was approved only for use in adults. Celexa is a selective serotonin reuptake inhibitor for the treatment of adult depression.

Research Briefs

• Vanda Pharmaceuticals Inc. announced in September that it has initiated a phase 3 clinical trial to evaluate tasimelteon in patients with non-24-hour sleep-wake disorder, a condition experienced primarily by totally blind individuals that results in abnormal night sleep patterns and chronic daytime sleepiness. Tasimelteon binds to high-affinity melatonin receptors located in the brain that are believed to regulate circadian rhythms, or sleep/wake cycles.

The study is designed to investigate the efficacy and safety of 20 mg of tasimelteon versus placebo in totally blind individuals with the disorder, with a target enrollment of 160 individuals. It includes a six-month treatment period and an optional open-label extension. The primary endpoint of the study is improvement in total sleep time during the night.

• Forest Laboratories Inc. and Gedeon Richter announced in September the preliminary results from an eight-week phase 2 clinical trial of the antipsychotic agent cariprazine for the treatment of bipolar depression.

A total of 233 patients were randomized to enter one of two active (low dose or high dose) treatment arms or receive a placebo. The primary endpoint was the Montgomery-Asberg Depression Rating Scale (MADRS) score. Although the overall difference observed between the drugtreated and placebo-treated groups was not statistically significant, over the course of the trial there was evidence of a clinically relevant treatment effect in the high-dose arm of the study compared with placebo. Approximately 9 percent of patients discontinued the study early due to adverse events in the high-dose study arm compared with 3 percent in the placebo arm. The companies are considering conducting an additional phase 2 dose-response trial examining a wider range of doses.

• The top 10 of the world's 50 largest pharmaceutical companies have lower estimated clinical-trial approval success rates than do smaller firms in that group, according to a study by the Tufts Center for the Study of Drug Development (CSDD). But the largest firms also tended to terminate trials earlier in clinical testing, the study found. Failing early lets drug developers redirect resources into other projects and avoid more costly later-stage failures.

“While the very largest firms had lower approval success rates, they did make the decision to terminate earlier in the development process, which can help improve productivity of their new product pipelines,” said Tufts CSDD Director of Economic Analysis Joseph DiMasi, who conducted the study. “The ultimate objective is to have higher success rates for drugs that are taken into clinical testing and earlier terminations of those that likely won't survive late clinical testing or regulatory review or be successful in the marketplace.”

The study was based on 1,734 compounds that entered clinical testing from 1993 to 2004 for the top 50 companies that had 2006 revenues of more than $1 billion.

The study was reported in the September/OctoberTufts CSDD Impact Reportand is available by subscription at <http://csdd.tufts.edu/reports/description/impact_reports>.