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THERAKOS' 8-METHOXYPSORALEN/PHOTOPHERESIS NEEDS ANOTHER STUDY

Executive Summary

THERAKOS' 8-METHOXYPSORALEN/PHOTOPHERESIS NEEDS ANOTHER STUDY before the combination therapy can be considered for approval as a treatment for scleroderma, FDA's Arthritis Drugs Advisory Committee recommended at its Dec. 6 meeting. The committee felt that a second, definitive clinical study was necessary because the combination therapy of ICN's Oxsoralen (8-methoxypsoralen) and the J&J subsidiary's UVAR Photopheresis System did not show sufficient efficacy versus the active control drug D-penicillamine (Merck's Cuprimine). Committee member Gerald Aronoff, MD, Boston Pain Center, said that "it appears from the evidence that the photopheresis group was no less efficacious than what is available right now, possibly with less toxicity. However, "what has been suggested is that the study may have methodological flaws and therefore [raises] questions about whether there is clear and convincing evidence that supports" the treatment's efficacy. He advised the committee "to look at the possibility of further study." FDA Pilot Drug Evaluation Staff Director John Harter, MD, suggested that the committee establish a subcommittee to head up the project of developing a protocol. "If it looks like the company is interested in getting input from us on an additional study," Harter said, "then we will try to do it through [a] subcommittee of this committee incorporating the dermatology group and the device group so that we can help design a definitive study." Harter said he considered the study submitted by Therakos to be a pilot study. "It is a small study [and] it's not adequate for us to approve on the basis of a single study," Harter noted. Committee members also expressed concern about the design of a second clinical study. Scleroderma is a difficult disease to study in clinical trials due to the small number of patients available for studies and because D-penicillamine is the only therapy that is thought to have any effect on the disease. Scleroderma is a life-threatening disease that causes chronic hardening and shrinkage of connective tissues. The committee also felt that the combination therapy has to be shown to be truly effective to justify its cost to patients. Therakos Business Development Director George Sillup, PhD, said that the cost for one treatment session, not including physician's costs, is $1,000 -- including $500 to cover the cost of pheresis disposables. To obtain approval for the scleroderma use, FDA required a supplemental NDA for ICN's Oxsoralen and a supplemental PMA (premarket approval) application for Therakos' UVAR system. In March 1988, FDA approved the combination therapy for the treatment of cutaneous T-cell lymphoma under a supplemental NDA for 8-methoxypsoralen and a full PMA application. The submissions to FDA for the scleroderma indication contain one Phase III parallel, single-blind trial comparing a once-a-month two-day photopheresis for six months to D-penicillamine 750 mg in patients with systemic scleroderma. The study's design and results were presented by principle investigator Alain Rook, MD, associate professor of dermatology, University of Pennsylvania. Of the 40 patients randomized into the photopheresis arm, 34 received treatment, and 31 received six months of therapy. Efficacy was determined by skin severity scores (skin hardening) and percentage of skin involvement. For the skin severity scores, Rook said that "80% of the photopheresis patients had some degree of improvement that meant one point change towards improvement...19% had at least one point worsening. In contrast, slightly less than half of the D-penicillamine patients had some degree of improvement, while 40% had some degree of worsening." Curtis Wright, MD, a medical officer in the Pilot Drug Evaluation Staff, provided a review of the study results. "Looking at all the patients for the trial, both limbs together, there's clearly not a dramatic change," Wright told the committee. In his review of the study, committee consultant Michael Weisman, MD, University of California Medical Center, noted that a placebo effect appears to have occurred in past scleroderma trials. A possible explanation for the improvement seen in the Oxsoralen/UVAR study, he said, "may be what other people have called the natural history of the disease or the placebo effect in controlled trials." One study investigator noted that a group of investigators have set up a protocol for a multicenter trial that will compare low-dose and high-dose D-penicillamine in 120 scleroderma patients. The idea of adding a photopheresis arm and a sham photopheresis arm to this study was considered during the committee discussion as a possible opportunity for Therakos' next study. However, investigators involved in that study were not enthusiastic about the idea.

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