Fujisawa Tacrolimus Ointment NDA For Atopic Dermatitis Accepted By FDA

Fujisawa's tacrolimus NDA for the treatment of atopic dermatitis was accepted for filing by FDA Nov. 12, two months after its September submission.

The tacrolimus ointment NDA is based on Phase III trials in over 1,000 patients at more than 40 sites. One-third of the patients were under the age of 15. The broad category of hand dermatitis is preferred over stratifying categories, FDA committee says.

The ointment is expected to be launched in Japan later this year under the name Protopic. Fujisawa's Grand Island, N.Y. facility is producing the product.

Tacrolimus ointment would be the first treatment specifically for atopic dermatitis, or eczema, in over 40 years, Fujisawa said.

A Nov. 4 discussion by FDA's Dermatologic & Ophthalmic Drugs Advisory Committee of hand dermatitis trial design issues had no effect on the NDA, Fujisawa said, as the company and FDA were in agreement on study design and endpoints. Fujisawa's NDA does not appear to specify body sites; the company noted that in clinical trials one-fifth of patients had atopic dermatitis involving more than 75% of their bodies.

The committee said that Phase III trials should study the broad category of hand dermatitis rather than stratifying the indication by irritant contact, allergic contact, and atopic dermatitis. Defining the different categories is difficult and inconsistent, the committee said.

"This is usually a multi-factorial disease and so it is going to be very difficult to get a pure irritant group vs. a pure atopic group," committee guest Donald Belsito, MD, Kansas University Medical Center, said. "I think lumping is a fair approach."

"You are going to get [a] different diagnosis from different people," Belsito continued. He recommended exclusion of bacterial and fungal infections, urticaria (including latex allergy), psoriasis and other diseases that may involve the hand, and suggested food handlers be examined for protein contact dermatitis.

Separating psoriasis from hand eczema can be difficult, committee consultant John DiGiovanna, MD, National Institute of Arthritis & Musculoskeletal & Skin Diseases, noted. Belsito said the exclusion of psoriasis would depend on the particular drug being studied, but cautioned "the mechanism for psoriasis may be very different."

Belsito also warned against restricting the definition of hand dermatitis to palmer involvement, which would rule out exogenous causes of hand dermatitis.

The committee favored "lumping" all hand dermatitis in protocols and subsequently using subgroup analysis.

As many as 1,000 patients would be necessary to perform subgroup analyses, committee consultant Philip Lavin, PhD, Boston Biostatistics Research Foundation, said.

Subgroup analysis should not be used for primary approval, committee member Robert Stern, MD, Beth Israel Deaconness Medical Center, said. The key factor, he suggested, should be "was there a significant effect and then if it meets that overall test for all patients eligible after proper exclusions."

Erythema, scaling and Fischer's were suggested as criteria to evaluate degree of severity, as well as the more subjective findings of burning and pruritis.

Photographs might "minimize some of the intersite and intrasite variability," committee chair Lynn Drake, MD, University of Oklahoma Health Sciences Center, suggested.

Noting the difficulty of matching subjects, Drake questioned whether using one hand of the patient to test the active and the other hand as the control would be appropriate. FDA Division of Dermatologic & Dental Drug Products Director Jonathan Wilkin, MD, said designs using "natural pairing" would not produce adequate safety results because drug exposure would be less than in normal practice.

The committee hesitated to establish strict protocol requirements and acknowledged "creative study design" would be necessary depending on the mechanism and target of the product.

"Some of the specific aspects are driven by the pharmacology of the agent and I think we recognize that," FDA's Wilkin said. "There are Phase II studies where one could find which subset the response would be best in and exactly how long one should treat," he added, "so a good Phase II program armed with the kind of advice the committee has given today I think will prepare us for good end of Phase II meetings and excellent plans for Phase III."