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FDA Arthritis advisory committee meetingguidelines for clinical evaluation of therapies for scleroderma.

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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
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 Although the sponsors have withdrawn the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
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
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.
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clinical, meetingguidelines, evaluation, therapie, advisory, arthritis, fda, committee, scleroderma
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