The source of NMEs (new molecular entities) for use in 505(b)(2) drug development programs is vast. A major benefit of an NME is the 5 year data exclusivity.
Sciele Pharma recently (4/9/09) obtained 505(b)(2) approval for a 5% benzyl alcohol lotion for the treatment of head lice in patients 6 months of age and older. Benzyl alcohol is a pediculicide in this formulation (meaning it kills the lice but not the eggs and thus needs to be used after the eggs hatch as well). Benzyl alcohol is widely used – the FDA estimated that 1,649 cosmetic products contain this ingredient. Yet, since benzyl alcohol had never been approved as an active ingredient, FDA classified it as an NME.
Let’s look at what Sciele submitted for approval.
For nonclinical pharmacology/toxicology, Sciele relied on the literature for repeat dose and genetic toxicology plus in-vitro studies demonstrating mechanism of action. Sciele referenced data from the National Toxicology program.
For clinical pharmacology/biopharmaceutics, Sciele initially conducted a pk study which generally showed very little systemic exposure, yet a few samples had very high levels. These high levels were a safety concern to the Agency. Sciele believed the high results to be due to the NaCl/0.9% benzyl alcohol catheter rinse. FDA wanted proof, so Sciele conducted a second study with a benzyl alcohol-free catheter flush and the maximim plasma concentration was 44-fold lower than observed in the first study.
For efficacy, Sciele conducted 2 essentially identical phase 3 trials, comparing the test product against the vehicle in a total enrollment of 615 subjects. The studies were designed to each have about 120 subjects on treatment.
For safety, Sciele relied on its database of eight studies: the 2 phase 3 studies, 3 phase 2 studies, 2 phase 1 studies and a special safety study. At issue for safety was the potential for causing infant gasping syndrome which had been linked to benzyl alcohol. Sciele did an extensive publication review of benzyl alcohol safety and obtained a review from the investigator who originally determined the cause of the gasping syndrome. The FDA agreed with the conclusions reached from this search, that even though many products used in babies contain lower amounts of benzyl alcohol, in actual use these products result in higher exposures which have been determined to be safe.
This development program is typical for programs that seek to take a known molecule and obtain a new indication.