Food and Drug Administration
Center for Drug Evaluation
and Research
NDA: 20-905,
ARAVAÔ, (leflunomide), Aventis Pharmaceuticals,
Inc.
The "Guidance for Industry Clinical Development
Programs for Drugs, Devices, and Biological Products for the Treatment of Rheumatoid Arthritis (RA)"”
released in February 1999, includes the recommendations for the claim
“Prevention of Disability”. As noted in
this guidance, “Studies should be two to five years in duration” to support
this claim. Recent studies attempting to
assess efficacy and durability based on placebo-controlled or add-on-therapy
studies have identified limitations for proper conduct and interpretation of
these studies, because of high withdrawal rates. Therefore, FDA is considering a revision of
this claim.
The Health Assessment Questionnaire (HAQ) has been evaluated in a variety of clinical trials and settings over the years, particularly for physical function in activities of daily living. It is recognized in the RA guidance document as an adequately validated measure for use as the primary outcome measure in trials of physical function in rheumatoid arthritis.
1. In light of the available
literature on the HAQ instrument:
a) ,Does the term “physical
function” or “disability” better capture the clinically relevant information
ascertained in this instrument?.
b) Are the
more recent derivatives such as the Modified Health Assessment Questionnaire
(MHAQ) and the Multidimensional Heath Assessment Questionnaire (MDHAQ)
appropriate and validated endpoints and substitutes for the HAQ in this regard?
For this meeting, Tthe
committee has been provided revieweddata
presentedevaluating
regarding
the effects of leflunomide on physical function from clinical
studies including data at 12 and 24 months timepoints. The effects of patient withdrawals on Last
Observation Carried Forward (LOCF) landmark analyses of an
Intent to Treat (ITT) population at these timepoints has been
discussed. The current guidance notes
that “studies should be 2-5 years in duration”.
Advisory committee deliberations in 1998 concluded that the controlled
data at one year demonstrated improvement in physical function. Similar
one-year controlled data, along with durability of response during the second
year in those patients who responded at one year, have been used to support
approval of one therapy for improvement in physical function (infliximab).
2. For the domain of disability
or physical function, what duration of a superiority study (placebo or active
comparator) is needed to robustly identify an improvement?.
3. What type
of data are needed to assess durability of effect beyond an initial
superiority study period?: Examples might include:
a) maintenance of effect size
compared to baseline seen during initial superiority study period in ITT
b) maintenance of effect size
compared to baseline superiority study period only in responders during initial
treatment period
c) maintenance of effect size
compared to end of superiority study period
(ITT or responders).
4. Are the data on leflunomide presented by the sponsor adequately robust
(effect size and robustness of database) to support labeling for “improvement
in physical function”?
In the context of the strengths and weaknesses of
available evidence presented in the briefing documents and here today,
including that from controlled clinical trials, open label studies,
post-marketing spontaneous reports, etc., and conclusions that you are able to
draw regarding an association between leflunomide and
serious hepatotoxicity, please address the following
questions:
1. Considering the universe of
available disease modifying therapies therapies, is
the benefit-to-risk
profile for leflunomide acceptable for current indications:?
a) reduce signs and symptoms of
rheumatoid arthritis
b) retard structural damage as
evidenced by x-ray erosions and joint space narrowing
2.1..