FDA Arthritis advisory committee meetingguidelines for clinical evaluation of therapies for scleroderma.код для вставкиСкачать
835 GOVERNMENT AFFAIRS FDA ARTHRITIS ADVISORY COMMITTEE MEETING: GUIDELINES FOR CLINICAL EVALUATION OF THERAPIES FOR SCLERODERMA HAROLD E. PAULUS The Food and Drug Administration (FDA) Arthritis Advisory Committee held an open session on January 23, 1992 to discuss the clinical evaluation of therapies for scleroderma. Three protocols were specifically reviewed and used as vehicles to facilitate the discussion. In a randomized, parallel-group study of 80 patients with progressive diffuse scleroderma, photopheresis (after pretreatment with 8-methoxypsoralen) given on 2 consecutive days every 4 weeks was compared with D-penicillamine given daily for 6 months. The study was reviewed by the Arthritis Advisory Committee in December 1990, as the basis for its approval as a new treatment for scleroderma. A blinded observer was used to evaluate efficacy, but the patients and the treating physicians were not blinded. Thirty-one evaluable patients completed the photopheresis protocol and 25 completed the D-penicillamine protocol. There were more patients with modest improvement in the skin severity score, and fewer with worsening of the skin severity score, among the photopheresis-treated group than among the D-penicillamine-treated group, but there were no betweengroups differences in measurements of oral aperture, fist closure, visceral disease, Raynaud’s phenomenon, or findings on paired skin biopsies (at baseline and end of study). The FDA and the Arthritis Advisory Committee concluded that the study did not adequately demonstrate that the patients derived benefit with good safety from the photopheresis/8-methoxypsorHarold E. Paulus, MD: American College of Rheumatology Liaison to FDA Arthritis Advisory Committee, UCLA School of Medicine, Department of Medicine, Division of Rheumatology, lo00 Veteran Avenue, 32-47, Los Angeles, CA 90024-1670. Arthritis and Rheumatism, Vol. 35, No. 7 (July 1992) alen treatment, and that additional studies would be needed. Although the sponsors have withdrawn the New Drug Application for approval of this treatment for scleroderma, it remains available as an approved treatment for cutaneous T cell lymphoma and can be prescribed on an individual basis as a non-approved treatment of scleroderma. The Committee also discussed an investigatorinitiated prospective, randomized, double-blind comparison of treatment with standard-dose (75&1,000 mg/day) versus low-dose (125 mg every other day) D-penicillamine for 2 years, in 130 patients with diffuse scleroderma; as an entry criterion, all patients must have had sclerodermatous skin induration for <I8 months. The study is being conducted by researchers at a consortium of 17 academic rheumatology centers throughout the US,and is in the early stages of patient recruitment. (The University of California, Los Angeles is the coordinating center; a list of the other centers is available upon request.) The D-penicillamine has been supplied by Merck Sharp & Dohme (West Point, PA), and the study is partially supported by start-up grants from the United Scleroderma Foundation and The Scleroderma Foundation, by the FDA Orphan Drugs Program, and by the unreimbursed clinical research services of the investigators themselves. The goal of this study is to definitively evaluate the beneficial effect of D-penicillamine that has been cited in reports of retrospective analyses. The third protocol that was discussed is a proposed single-center pilot study, at the University of Pittsburgh, which will evaluate the effects of FK 506 (an immunosuppressive macrolide previously studied in organ transplantation patients) in 50 patients with early diffuse scleroderma, who are to be treated for 6 GOVERNMENT AFFAIRS months. In a concentration-controlled trial, patients will be randomized to equal-size groups receiving sufficient FK 506 to achieve trough plasma concentrations of either -1 ng/ml or -0.2 ng/ml. A blinded observer will record efficacy observations; the treating physician will not be blinded because of the need to adjust the dosage to achieve and maintain the desired plasma concentrations. Guidelines for the clinical evaluation of therapies for scleroderma have not been proposed in the past because of the minimal interest of potential sponsors of New Drug Applications and the perceived difficulties in studying drug treatments for this complex disease. However, since preliminary reports now suggest a number of candidate therapies for scleroderma drug trials, the development of guidelines may help to rationalize clinical trials and expedite the drug development process, by defining minimal requirements for approval and providing examples of acceptable study designs. Several features of scleroderma may be treatable, but each requires a specific study design to efficiently demonstrate benefit. For example, angiotensin-converting enzyme inhibitors have been beneficial for scleroderma hypertensive renal crisis, vasodilators may be useful for digital ulcers and Raynaud’s phenomenon, and D-penicillamine has been used for diffuse systemic sclerosis. Since 3040% of patients die within 5 years after the onset of diffuse scleroderma (many within the first 18 months), development of a treatment that is effective in early scleroderma is a high priority. The above protocols are directed toward this phase of the disease. Treatment efficacy can be assessed by enumerating deaths or hypertensive renal crises that occur during a trial, but it would be necessary to study a fairly large number of subjects prospectively for a number of years in order to demonstrate statistical significance, making these primary end points difficult for use in randomized trials. Since the severity, extent, and rate of progression of skin involvement early in the disease appear to be related to prognosis, it can be hypothesized that a treatment that reverses or prevents the progression of skin involvement in early scleroderma may also decrease organ failure and mortality. The Committee focused on the need to determine intra- and interobserver reliability and reproducibility of the methods chosen to clinically assess skin involvement, both at a single point in time and during the longitudinal observations of a clinical trial. Several methods have been used to quantitate the degree of skin involvement; they demonstrate that skin sclerosis (as measured by skin scores) increases during the first several years of diffuse scleroderma, reaches a peak, and then slowly declines as the affected skin becomes thinner, softer, and more atrophic with time. These temporal changes in skin scores during the natural history of scleroderma complicate trial design, since recorded improvement in skin score may be unrelated to treatment if the trial begins at a time when the patient’s skin score is at a peak and then continues as the score begins to improve spontaneously. This suggests that pre-randomization stratification for disease duration may be needed to improve the power of these trials. An external subcommittee has been requested to draft initial Guidelines for the Clinical Evaluation of Therapies for Scleroderma, for extensive review and revision by the Advisory Committee, appropriate American College of Rheumatology subcommittees, pharmaceutical industry representatives, and other interested parties.