Roche should take three years to replace the current formulation of Accutane (isotretinoin) with a once-daily version, FDA Dermatologic & Ophthalmic Drugs Advisory Committee voting consultant Lloyd King, MD/PhD, said during the panel's Sept. 19 meeting.

Roche submitted an NDA for a once-daily formulation of the severe recalcitrant nodular acne treatment in October 1999 and submitted a proposed new brand name for the formulation in July.

The committee voted 14-1 that there might be safety consequences with the simultaneous marketing of two isotretinoin products because of the potential impression that the once-daily formulation would be less teratogenic than Accutane.

The panel voted earlier that additional risk management was necessary to monitor patients for Accutane-associated psychiatric disorders and recommended a mandatory pregnancy prevention program (¹ Also see "Pregnancy Test Should Be Required For Accutane Rx, FDA Cmte. Urges" - Pink Sheet, 25 September, 2000.).

Following approval of the new formulation, Vanderbilt University professor King maintained, it will take three years to study the economics of introducing the product and the possibility of phasing out Accutane.

Three years "would give Roche and FDA time to deal with the issues" of whether generics will be major competitors and "if they are going to come up with the same safety profile," he added.

Roche Chief Medical Officer Russell Ellison, MD, explained that at the outset, the products "must both be on the market. We will see how it works in that first year of conversion." Ellison indicated that, following approval, the company will conduct a three-year study of relapse with the new formulation.

The new formulation of isotretinoin would be differentiated from Accutane by dosing regimen, packaging and appearance. Current twice-daily capsules are available in 10 mg, 20 mg and 40 mg doses. The new formulation is a once-daily contrasting color capsule in 7.5 mg, 15 mg and 22.5 mg doses.

Committee members agreed that the once-daily version would be more convenient for patients, while other advantages were not as clear. "There would be more consistency in bioavailability," voting consultant Elizabeth Abel, MD, remarked, but "as far as questions of efficacy, I'm not convinced what the new formulation has to offer."

A safety and efficacy comparison trial between the two formulations indicated that "isotretinoin exposure in the Accutane arm was significantly higher than in the new formulation arm," FDA Division of Dermatologic Drug Products Medical Reviewer Kathryn O'Connell, MD/PhD, stated. The trial suggested that the labeled dosage of Accutane is not the minimum effective dosage (² Also see "Roche Accutane Recommended Dosing May Be Too High, FDA Says" - Pink Sheet, 18 September, 2000.).

The committee voted 10-5 that further dose-ranging studies for isotretinoin are not needed.

Roche Medical Science & Safety Director John McLane, PhD, argued that additional dose ranging studies with isotretinoin were unnecessary because, even "if you take the new formulation twice per day, you know you will still be in a range that has already been studied."

Committee guest Laurence Greenhill, MD, N.Y. State Psychiatric Institute, however, suggested that dose-ranging studies could address whether "higher dosage levels [are] associated within a period of follow-up with any psychiatric symptoms."

Some panel members expressed concern regarding whether the safety restrictions on Accutane would apply to generics. Generic versions of Accutane could enter the market during Roche's transition to the new formulation. Accutane's patent expires in August 2001.

FDA Center for Drug Evaluation & Research Director Janet Woodcock, MD, responded that, in the past, "if the innovator has various voluntary restrictions on them...we have successfully mandated that any generic copies would have to have equivalent programs."

King maintained that the introduction of the new formulation and generics, plus the uncertainty of physician monitoring would make tracking Accutane's psychiatric side effects difficult. "Given the new formulations," he said, "I'm not sure how you're going to figure out the psychiatric side effects when half the population is missing and you have two or three combinations. I think we're going to be back here in three years debating this once again."

Accutane Once-Daily Version Should Have Three-Year Phase-In - FDA Cmte.

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