Guidance for Industry
Systemic Lupus Erythematosus —
Developing Drugs for Treatment
This
draft guidance, when finalized, will represent the Food and Drug
Administration’s (FDA’s) current thinking on this topic. It
does not create or confer any rights for or on any person and
does not operate to bind FDA or the public. You can use an
alternative approach if the approach satisfies the requirements
of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance. If you cannot
identify the appropriate FDA staff, call the appropriate number
listed on the title page of this guidance.
I.
Introduction
This document is intended to provide guidance
to industry on developing drugs for the treatment of systemic
lupus erythematosus (SLE). The following topics are covered:
·
Outcomes and measurements of lupus disease activity,
including the use of disease activity indices, flares, and
organ-specific outcomes
·
Indications that the Agency may be willing to
approve for new drug therapies for lupus
·
General trial design issues, the use of surrogate
endpoints in relation to lupus, and the overall risk-benefit
assessment that needs to be addressed for any new therapy of lupus
·
Issues related to lupus and pharmacokinetics
FDA’s guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
Systemic lupus erythematosus is a chronic
disease characterized by protean manifestations often
demonstrating a waxing and waning course. Whereas in the past a
diagnosis of SLE often implied a decreased life span due to
internal organ system involvement or to toxic effects of therapy,
recent improvements in care have dramatically enhanced the
survival of SLE patients with the most severe and life-threatening
manifestations. Unfortunately, current treatments for SLE remain
inadequate as many patients have incompletely controlled disease,
progression to end-stage organ involvement continues, and current
therapies carry potential risks of debilitating side effects.
Therefore, it is important to clearly describe acceptable study
endpoints to establish efficacy to facilitate the development of
novel therapeutic agents which have the potential to be more
effective and/or less toxic.
Although many patients with SLE exhibit
symptoms that involve the skin and joints, other symptoms of SLE
vary widely among patients. No single biological mechanism
explains the varied manifestations of disease. Disease activity
scores allow a comparison of disease severity in SLE patients
whose disease affects different organ systems. Several such
indices reliably measure disease activity in SLE patients in
varied settings. Some of these indices mirror the assessment of
experienced clinicians and are sensitive to changes in disease
activity. One of the scoring systems, the British Isles Lupus
Assessment Group (BILAG), scores patients based on the need for
alterations or intensification of therapy. Thus, these indices
can be used as endpoints to establish efficacy.
It is uncertain whether the SLE disease
activity indices will clearly delineate important clinical
responses to therapy in all situations. Some treatments may
target a biologic mechanism which selectively underpins only
certain lupus manifestations, or only those related to a single
organ system. In these situations, an organ-specific measure of
disease activity may be a preferable outcome measure. This
guidance addresses claims of improvement in overall activity of
SLE, as well as claims of improvement in organ-specific
manifestations of SLE such as lupus nephritis. It is important
that any therapy that claims to improve disease in one organ
system not worsen disease elsewhere. In addition to the primary
outcome measure selected for a given trial in SLE, every trial
should also assess other aspects of the disease process, as this
information may be informative about the overall risk-benefit
assessment (see Section VII, Risk-Benefit Assessment).
This guidance document first provides a
general discussion of outcomes and measurements of lupus disease
activity including the use of disease activity indices, flares,
and organ-specific outcomes. The document then presents the
claims that the Agency may be willing to approve for new drug
therapies for lupus. Following this, the document presents
general trial design issues, discusses the use of surrogate
endpoints in relation to lupus, the overall risk-benefit
assessment that needs to be addressed for any new therapy of
lupus, and, finally, briefly presents some issues related to lupus
and pharmacokinetics.
The clinical measurement of disease activity
in SLE involves an assessment of the characteristic signs and
symptoms of disease and the results of laboratory parameters.
Academic and clinical investigators have identified those measures
they believe are important for evaluation in clinical trials.
These parameters include a measure of disease activity, a measure
of disease-induced damage, a measure of therapy-induced damage, a
measure of response as determined by the patient (i.e., a
patient global response), and a measure of health-related
quality of life (HRQL).
Although patterns of stable, increasing, or
decreasing disease activity form the basis for initiating or
adjusting treatment in SLE, the specific manifestations that
characterize the level of disease activity vary considerably from
patient to patient and at different points in time. Indices of
disease activity have been developed that correlate with
assessments of panels of expert clinicians. These indices score
disease manifestations using predefined criteria based on the
presence or absence of different aspects of the disease or, in the
case of the BILAG, on the clinician’s assessment of the need to
change therapy. In clinical studies, these indices have been
shown to be valid based on the concordance of scores with expert
opinion, acceptable interobserver variability among trained
evaluators, correlation between individual patients’ scores on
different indices, and correlation between increases in scores and
clinical decisions to increase therapy. The SLE Disease Activity
Index (SLEDAI and SELENA-SLEDAI), the BILAG, the SLE Activity
Measure (SLAM), and the European Consensus Lupus Activity Measure
(ECLAM) have been shown in cohort studies to be sensitive to
change in disease activity (Strand 1999) and can be used in
clinical trials. It is important that analyses of disease
activity measures be defined prospectively, and they can include
comparisons of change in disease activity scores or in disease
activity. We recommend prespecifying in the protocol statistical
approaches regarding, for example, dropouts or missing data.
There has been considerable interest in the
development of a responder index to measure response to therapy on
an individual basis. Some proposed definitions of a responder
specify a minimum improvement in a measure of disease activity
with no worsening in other aspects of lupus. A responder index
would allow a clinical trial to determine directly what proportion
of patients had a clinically meaningful improvement from therapy.
It is important that such a responder index be assessed for
reliability, face validity, content validity, and sensitivity to
change to be fully validated. Full validation would also include
a demonstration of the ability to discriminate treatment with a
known active agent compared to an inactive control in a clinical
trial. Exploring the use of responder indices in prospective
studies will help determine the utility of these measures in
clinical trials. At present, there are no generally accepted and
validated responder indices in lupus.
The clinical course of SLE is generally
characterized by periods of relatively stable disease followed by
flares of disease activity. Studies that measure disease activity
at fixed time points may miss flares in between study
assessments. In one study, rates of flare were measured at an
average of 0.6 flares per year (Petri 1991). A flare
should reflect an episode of increased disease activity and should
correlate with a need for increase in or change in treatment on
clinical grounds. Criteria for major flare might include
initiation of high dose glucocorticoid therapy, a change in dose
of immunosuppressive therapy, hospitalization, or death. The
frequency of flares may be affected by gender, menopausal status,
treatment, and other patient characteristics. We recommend
prospectively defining flare.
Patients suffering from lupus experience
irreversible damage to internal organ systems. Accumulation of
damage occurs over a period of years. Therapy-induced organ
damage may also occur. An index of organ damage was proposed and
validated as the Systemic Lupus Erythematosus International
Collaborating Clinics/American College of Rheumatology (SLICC/ACR)
Damage Index. Validation studies show that high scores on the
SLICC/ACR Damage Index are predictive of increased mortality, and
damage in the renal and pulmonary components are associated with
poor outcomes (Stoll 1996). The prognostic information derived
from SLICC/ACR Damage Index scores suggests they may be useful as
stratification variables for clinical trials. The SLICC/ACR
Damage Index measures only changes that have been present for at
least six months; therefore, only longer-term clinical trials
could demonstrate reduction in the rate of progression of damage
using this measure. Some of the components of the SLICC/ACR
Damage Index are measures of toxicity related to current treatment
modalities. Use of the SLICC/ACR Damage Index as outcome measures
in clinical trials could be complicated if a new therapy were
associated with toxicities not measured by the Damage Index, or if
the use of organ damaging concomitant treatments were not balanced
between the groups. The SLICC/ACR Damage Index can be used as an
endpoint, but we recommend discussing this with the appropriate
reviewing division before beginning trials.
Organ-specific measures of disease provide
another approach to assessing disease activity in lupus. To
measure organ-specific disease activity in a clinical trial, a
responder analysis could be applied by measuring if subjects
demonstrate improvement in the involved organ system using
prespecified criteria, such as components of validated disease
activity indices if these components can be shown to reflect
disease activity. Examples of issues related to studies of renal
and skin involvement are provided below. We recommend
investigators propose outcome measures for specific organs
studied.
Lupus nephritis is the most commonly studied
organ-specific manifestation of lupus. The presence of diffuse
proliferative (WHO class IV) and severe focal proliferative (WHO
class III) glomerulonephritis in patients with SLE who have
measures of inflammatory activity and damage is associated with
increased long-term risk of progression to end-stage renal disease
and mortality. Patients with severe lupus nephritis are often
treated with high doses of immunosuppressive agents, including
cyclophosphamide, and high doses of corticosteroids. These
regimens are based on studies that suggest a decrease in the
long-term risk of progression to end-stage renal disease. The
outcome of lupus nephritis has improved markedly in recent years
with 5-year survival rates of 90 percent or greater and 10-year
survival rates of more than 80 percent reported (Urowitz 1999).
However, there remains a need for additional regimens as current
treatments can be highly toxic and not effective in all subjects.
After a diagnosis of lupus nephritis is
established, disease activity is assessed clinically by
examination of the urinary sediment and by measures of renal
function. A variety of outcome measures have been used in
clinical trials of lupus nephritis to assess organ-specific
disease activity. Mortality is an important outcome measure, but
low mortality rates and long observation times make it a
relatively insensitive measure in clinical trials. Measures of
renal function can be used as outcome measures, including
progression to end-stage renal disease (ESRD), sustained doubling
of serum creatinine, creatinine clearance, and iothalamate
clearance, for full approval. Other measures may also be suitable
and can be employed in therapeutic studies if sufficient data to
support the proposed measure are available. The use of the
doubling of serum creatinine is the best-validated of these
measures as it has been shown to reliably predict long-term renal
outcomes; however, it is insensitive to smaller changes that
represent earlier signs of damage that are nonetheless clinically
important. Changes in the urine protein/creatinine ratio may
serve as an indicator of the need for further assessment with a
24-hour urine collection for quantitation of the extent of
proteinuria and impairment in renal function as measured by
creatinine clearance. We recommend investigators design trials to
minimize confounding variables (Boumpas 1998) as these can
complicate interpretation of renal function measures, including
serum creatinine and creatinine clearance.
Changes in urinalysis can provide important
information for the assessment of renal inflammation in lupus
nephritis. The presence of cellular casts and hematuria, when
measured accurately, is considered a sensitive indicator of the
level of activity of lupus nephritis. However, central
laboratories may be unreliable in assessing the presence of casts
as they can break up during transport. There is no consensus on
the appropriate evaluation of urine sediment. Local or central
laboratories could be used if the chosen method is shown to be
accurate and reproducible.
Major flares of lupus nephritis, as assessed
by urinary sediment, proteinuria and renal function, have been
used as outcome measures in clinical trials. Patients who
experience nephritic flares characterized by nephritic sediment
and an increase in serum creatinine or decrease in glomerular
filtration rate (GFR) may be at increased risk of developing a
persistent doubling of serum creatinine. Renal remission in
response to therapy has been defined as a return to normal levels
of an elevated creatinine and proteinuria and normalization of
nephritic sediment. Patients who fail to normalize an elevated
serum creatinine in response to therapy may have an increased risk
of progression to renal failure (Levey 1992). Assessment of
proteinuria is particularly important in patients with membranous
glomerulonephritis; however, this is a less common form of lupus
nephritis. Increases in proteinuria in patients with other forms
of glomerulonephritis may not translate into unfavorable long-term
outcomes, and, therefore, measures of proteinuria are not adequate
to address clinical outcomes.
Skin is one of the organs most involved in
SLE. The most common of the skin manifestations include discoid
lupus, malar rash, subacute cutaneous lupus, and alopecia.
Photosensitivity and oral ulcers are additional common
manifestations. A variety of outcome measures can be used in
clinical trials to assess the efficacy of new therapies on skin
disease including erythema, induration, scaling, and physician and
patient global assessment. In addition, outcomes such as involved
surface area changes and skin biopsies can be considered.
Investigators can propose additional or alternative outcome
measures depending on the type of skin disease studied. It is
also important to differentiate irreversible damage from active
disease, as it would not be amenable to therapy.
The Agency recommends that HRQL measures be
studied in all trials of SLE. Instruments that assess health
status and HRQL may measure aspects of SLE and its impact on
patients that are not fully assessed by other outcome measures.
It is important that trials showing improvement in a specific
organ or in disease activity demonstrate no or minimal worsening
in measures of HRQL. Patients with active SLE may have increased
disability as assessed by the Health Assessment Questionnaire (HAQ)
or Modified Health Assessment Questionnaire (MHAQ).
Health-related quality of life has been assessed in lupus patients
using a number of generic instruments including the HAQ, MHAQ,
Arthritis Impact Measurement Scale (AIMS), the Medical Outcomes
Survey Short Form-20 (SF-20), and Short Form-36 (SF-36).
Differences compared to controls have been observed in several
domains and subdomains. Some instruments do not adequately assess
fatigue, an important symptom for many lupus patients. Specific
instruments have been studied for assessment of fatigue (e.g., the
Krupp Fatigue Severity Scale (KFSS)). As with any instrument,
HRQL instruments used in clinical trials of SLE should undergo
validation regarding content validity (inclusion of all relevant
domains), construct validity, sensitivity to change, and other
criteria. The use of these outcomes is critical to understanding
both the efficacy of an agent as well as its potential adverse
events. Even if the measure does not improve with a specific
therapy, it should not worsen. Improvement in HRQL alone would
not result in approval at this time.
Serologic markers play an important role in
the assessment of disease activity in SLE, including assessment of
anti-double-stranded DNA, complement levels, and others.
Serologic markers are critical for understanding the pathogenesis
of disease. Serologic markers have an imperfect correlation with
disease activity and cannot substitute for a direct assessment of
clinical benefit. We recommend studying serologic marker data in
clinical trials. These data, in conjunction with clinical
measures, may play a role in assessing clinical outcomes and
identifying potential clinical benefit from new therapies.
Serologies can serve as supportive evidence of efficacy at this
time (see Section VI, Surrogate Markers as Endpoints).
We may be willing to approve the following
claims for SLE if supported by substantial evidence: (1)
reduction in disease activity; (2) treatment of lupus involving a
specifically identified organ (e.g., lupus nephritis); (3)
complete clinical response/remission; and (4) reduction in flares.
This claim is intended to reflect clinical
benefit associated with reductions in the signs and symptoms of
SLE disease activity. SLE is a disease of long duration, with a
waxing and waning course; therefore, this claim would ordinarily
be established by trials of at least 1 year in duration. For
products that may elicit the formation of antibodies, it is
important that the clinical trials assess whether antibodies are
formed and if they adversely affect efficacy and safety. We
recommend using methods that assess the activity of disease over
the duration of the study in conjunction with methods that measure
disease activity at the beginning and end. As part of any trials
in support of this claim, we also recommend studying measures of
damage and HRQL, as well as determining a patient global
assessment. A validated disease activity index (DAI) is an
acceptable outcome measure to demonstrate a reduction in signs and
symptoms of SLE.
In a randomized clinical trial, the SELENA-SLEDAI,
the SLAM, the BILAG, the ECLAM, or other established index could
be used to measure disease activity. To represent a clinical
benefit, the change in DAI should be both statistically
significant and clinically meaningful and prospectively defined.
Since the BILAG evaluates patients based on the need for
additional treatment, the clinical interpretation of a change in
score is apparent. A success in a 1-year trial could be defined
as a greater reduction in the BILAG score at 1 year along with
supportive evidence of reduction in monthly measurements of the
BILAG score compared to controls (see also Section V.B.1, Disease
Activity Trials, for a discussion of landmark versus area under
the curve (AUC) analyses). For other indices, deciding whether
changes in score are clinically meaningful may be more
complicated. If a disease activity measure other than the BILAG
is chosen, confirmation of a positive result with two different
DAIs would be important to confirm the findings.
In general, appropriate outcome measures in
organ-specific trials are defined by the specific organ under
study. For each organ studied, these include: (1) stabilization
(no worsening of disease activity in the designated organ); (2)
partial response; (3) complete response but still receiving
medications; (4) complete remission (no ongoing treatments); (5)
flares (time to flare and/or number of flares); and (6) ability to
taper concomitant corticosteroids by clinically significant
amounts. If corticosteroid dose is chosen as the endpoint, we
recommend addressing the use of flexible dosing versus forced
tapering. We also recommend addressing in the analysis plan the
potential need for rescue medication.
For products being proposed for use in the
manner of a specified short course of treatment leading to
induction of a sustained remission, studies of 3-6 months duration
may be acceptable with longer term follow-up for safety and
durability of response. For products being proposed for chronic
use, studies as short as 1 year may be considered.
We recommend that trials to demonstrate
effectiveness in the treatment of a specific organ also include
measures of overall disease activity, damage, and HRQL. Ideally
these measures should improve in a clinically meaningful fashion.
Claims using the organ-specific approach may
be either for the treatment of each organ studied (e.g., lupus
nephritis) or for the treatment of lupus, depending on the number
of patients and the type of organ impairment studied. To obtain
approval for such a claim, you should show that there would be no
worsening in terms of a patient global assessment as well as
health-related quality of life.
Trials intended to study clinical benefit for
specific organ systems could enroll subjects with disease
affecting a single organ system (e.g., lupus nephritis). Patients
enrolled in studies evaluating multiple organ systems can be
stratified according to the specific organ system involved for
randomization and analysis. It is important that the definition
of a response be prospectively specified for each organ system
under study. Trials of patients with disease activity affecting
specific organ systems can define success as an increase in the
proportion of responders among patients receiving study drug
compared to controls.
Trials designed to assess efficacy of a
product for the treatment of lupus nephritis should demonstrate an
improved outcome for patients with biopsy-proved severe
glomerulonephritis (WHO grades III or IV), or membranous
glomerulonephritis. Short-term benefits may not reliably predict
long-term outcomes; therefore, trials of lupus nephritis should be
at least 1 year in duration. The following outcome measures could
establish efficacy in lupus nephritis:
1)
Incidence of mortality and progression to end-stage renal
disease. Mortality and ESRD (when clearly defined
prospectively) are objective, reliably determined, and the
endpoints of ultimate importance. However, studies using these as
the endpoint will generally require longer duration and larger
sample size than may be needed when other endpoints are used.
2)
Sustained doubling in serum creatinine or other measure that
has been validated including approximations of GFR such as
iothalamate clearance or creatinine clearance studies.
Doubling of serum creatinine has been shown to be associated with
progression to ESRD. Thus, a decrease in the proportion of
subjects meeting this endpoint in the treatment group compared to
controls can be interpreted as demonstrating a patient benefit.
Lesser degrees of change or changes in other measures may be
considered but should be further justified. Similarly a
significant change in GFR which has clinical importance may be
considered. We recommend that sponsors provide data to
demonstrate that these changes or other proposed measures are
associated with a true clinical benefit (e.g., a significant
reduction in the rate of progression to ESRD).
A success in a trial
utilizing this outcome measure would be defined as a decrease in
the proportion of subjects whose serum creatinine attains a level
double that of the baseline value and remains doubled for at least
six months. Alternatively, a success in a trial could be defined
as a reduction in the proportion of subjects experiencing a
sustained fall in GFR of 50 percent or more.
3)
An unvalidated surrogate marker for lupus nephritis reasonably
likely to predict clinical benefit. FDA regulations for
accelerated approval of new therapeutic agents (21 CFR 314,
subpart H and 21 CFR 601, subpart E) provide an additional
framework for FDA approval of drugs intended to treat serious or
life-threatening diseases. One approach is to base approval on
the effect on a surrogate marker, provided that specific criteria
are met, and there is a commitment to verify the actual clinical
benefit of the agent in studies completed after approval.
Demonstration of marked and sustained improvement in renal
function and renal inflammation in a seriously affected population
of patients with lupus glomerulonephritis may qualify for
consideration under these regulations. Data showing that the
measure of improvement is associated with improved patient
outcomes can contribute to supporting the conclusion that the
surrogate is reasonably likely to predict clinical
benefit. Sponsors are urged to consult with the relevant FDA
staff before embarking on a clinical program based on these
regulations.
Use of the
accelerated approval pathway for a product for lupus nephritis,
for example, would necessitate the timely completion of studies of
long-term clinical outcomes postmarketing. The verification of
clinical benefit can be a difficult task. It is important that
the necessary studies be a clearly described part of the clinical
development program at the time the studies of the surrogate
endpoint are undertaken.
4)
Induction of renal remission. Active lupus nephritis is
associated with evidence of renal inflammation, including cellular
casts, proteinuria, and decreases in renal function.
Organ-threatening WHO class III and IV lupus nephritis is
frequently treated with cyclophosphamide and high doses of
corticosteroids, agents that are associated with significant
toxicity. A treatment that induces a sustained remission in lupus
nephritis would confer a clinical benefit. Clinical studies of
lupus nephritis use varied definitions of renal remission, but
generally specify decreases in hematuria and cellular casts,
decreases in proteinuria, and stabilization or improvement in
renal function. A clinical trial intended to demonstrate
induction of renal remission would specify a definition of renal
remission that includes all relevant parameters. We recommend
providing evidence supporting an association with improved
clinical outcome (e.g., decreased likelihood of developing
end-stage renal disease or need for dialysis) to defend the
selected definition of renal remission. Because of concerns that
patients with an inactive urinary sediment may nonetheless
progress to renal failure, we recommend that studies using renal
remission as an outcome measure include follow-up renal biopsies
in at least a subset of patients.
Patients with renal
remission may be expected to experience a clinical benefit to the
extent that they are: (a) spared treatment with potentially toxic
agents; and/or (b) spared from ultimate progression to end-stage
renal disease. We encourage sponsors proposing to use attainment
of renal remission to demonstrate efficacy of a product for lupus
nephritis to discuss their clinical development plans with the
responsible reviewing division at the Agency. Proposals for
clinical trials using renal remission as an endpoint should: (a)
provide a clear definition for renal remission, and data
supporting the choice of that definition; (b) provide evidence
that attaining a renal remission would be expected to translate
into a clinical benefit to the patient; and (c) assess the
durability of the renal remissions.
5)
Resolution of nephrotic syndrome. Patients with lupus
nephritis may have high grade proteinuria with nephrotic syndrome.
A clinical trial intended to demonstrate resolution of nephrotic
syndrome would enroll patients with high grade proteinuria (e.g.,
³4 gm/d) and assess the
proportion of patients who attain a prespecified, substantial
reduction in proteinuria (e.g., to less than 500 mg per 24
hours). The trial should also collect data on the associated
features of nephrotic syndrome (i.e., hypoalbuminemia, generalized
edema, and hyperlipidemia) to assess whether changes in these
parameters mirror improvements in proteinuria. We encourage
sponsors proposing to use resolution of nephrotic syndrome to
demonstrate efficacy of a product for lupus nephritis to discuss
their clinical development plans with the responsible review
division at the Agency.
A complete clinical response/remission claim
would be approved for products that demonstrate the ability to
induce a clinical response, characterized by the complete absence
of disease activity at all sites for at least 6 consecutive
months. This response is termed complete clinical response
if the subjects continue to receive lupus-directed therapies.
Remission occurs if subjects were receiving no ongoing therapy for
their SLE. A trial in support of the claim of complete
clinical response should be at least 12 months in duration and
demonstrate an increase in the proportion of subjects in whom a
disease activity measure achieves zero.
Reductions in the rate of flares of SLE or
time to flare are considered to be clinically important outcomes.
An increase in the frequency and severity of flares of lupus
nephritis is correlated with worse outcomes. Thus, a reduction in
the rate of flares of organ-specific disease (e.g., lupus
nephritis) is also considered clinically important. If
time-to-flare is evaluated as the efficacy endpoint, the study
should be of sufficient duration to evaluate whether the flares
are suppressed or only delayed in occurrence. Thus, a comparison
of flare rate or incidence of flare-free at an appropriate time
point will be a critical secondary endpoint. An established
measure of flare may be considered in clinical trials studying
flare as a primary outcome to demonstrate a decreased frequency
of, or decreased severity of, flares. We recommend providing
evidence that the chosen definition of flare accurately measures
clinical flares. Proposals for clinical trials using renal flare
as an endpoint should: (1) provide a clear and accepted
definition for renal flare, and data supporting the choice of that
definition; (2) provide evidence that reducing renal flare
incidence by that definition of renal flare would be expected to
translate into a clinical benefit to the patient; and (3) assess
the durability of the renal benefit. A success in a clinical
trial could be defined as an increase in the time-to-flare or as a
decrease in the number or severity of flares over the course of a
1-year trial.
Careful consideration should be given to
choosing endpoints that will accurately assess the clinical
benefits of the product when designing a trial for SLE. The
clinical trial can focus on one aspect of disease (e.g., lupus
nephritis) over other important aspects. However, it is important
to collect information about other aspects of disease to ensure an
adequate assessment of the overall risk-benefit ratio. Clinical
trials in SLE generally are expected to collect information about
disease activity at all sites, irreversible damage due to SLE and
its treatment, and valid HRQL measures. Serologic studies may
also provide important information about the mechanism of action
of the product under investigation.
Phase 2 trials are used to better define dose
and exposure-related activity and toxicity of products under
development. We recommend evaluating the safety of concurrent use
of a new product with commonly used concomitant therapies,
although at this stage studies will not be powered to adequately
assess safety endpoints. Outcome measures under consideration for
trials of SLE may not have been tested in large-scale randomized
trials. Some outcome measures may prove less sensitive than
expected. Unexpected confounding variables may complicate the
interpretation of trials using these endpoints. Consequently,
experience with these outcome measures in phase 2 trials can
enable careful consideration to aid selecting valid, interpretable
clinical outcome measures for the phase 3 trials.
For the following discussion of efficacy
trials in SLE, it is assumed that trials will be parallel arm,
randomized controlled studies with a placebo or active control.
Whereas in some trials the study drug will be evaluated as
monotherapy, in many cases the study drug will be added to the
standard therapy the patient was previously receiving (add-on
trial). One of the advantages to an add-on trial of this type is
that it allows the evaluation of pharmacokinetic and
pharmacodynamic interactions with commonly used products in SLE.
Alternative trial designs such as randomized withdrawal or
replacement trials may also be considered. Investigators should
discuss these alternative designs with the appropriate reviewing
division before embarking on these studies.
For a clinical trial studying a reduction in
disease activity, we recommend that the patient population to be
enrolled reflect the patients who would reasonably be considered
for this treatment should it be shown effective. It is important
that the studied population be one that can be generalized to an
appropriate population for recommended use, and not made
artificially narrow. If existing data (e.g., from phase 2
studies) suggest that only a specific limited population is
plausibly expected to benefit from the therapy, then the inclusion
and exclusion criteria can limit enrollment to patients with a
restricted range of disease activity. If the effects of treatment
are expected to differ substantially in patients with severely
active disease as compared to moderately or mildly active disease,
then it may be desirable to stratify the randomization.
Furthermore, in DAI trials, investigators may wish to stratify by
organ to ensure balance between the two groups for at least one
major organ system involved. In general, the indication statement
in the package insert ultimately will reflect the patient
population studied.
Clinical trials should be of sufficient
length to assess the durability of benefits of therapy given the
chronic nature of SLE and its waxing and waning course. Trials of
1-year duration are usually necessary (but see Section V.D.5.,
Trial Duration). One approach is to measure the effect on disease
activity by comparing between groups the change in scores on a
disease activity index between the outset and the end of the
trial. Another approach is to use an AUC analysis based on
disease activity assessments at regular intervals throughout the
trial. An AUC analysis may more comprehensively measure disease
activity during the study than at a single time point. However,
AUC differences need to be interpreted carefully. Trials that
collect outcome data at multiple times during a trial can show the
time course of treatment effects as well as intercurrent disease
activity and thus better define the importance of the effect.
Several confounding factors could complicate the interpretation of
a trial that only examines baseline and study-end scores. First,
many SLE patients have frequent low scores on disease activity
indices, but experience intermittent flares of disease. A study
examining only study-end scores may be insensitive to the benefit
of a new product which decreases the frequency and severity of
disease flares but has only a small effect on background disease
activity. Another confounding factor is the likelihood that
subjects who flare during the trial will be treated with
additional medications (e.g., corticosteroids), potentially
reducing their disease activity scores for reasons unrelated to
the study drug (see also Section V.D.1., Concomitant Medications).
In a clinical trial intended to show an
improvement in a DAI, it is important to ensure that the outcome
measure accurately assesses disease activity in the treated
patients. Some disease activity indices give points for a new
disease manifestation and no points for a stable manifestation.
Thus, a disease manifestation that is present at screening that is
stable during the study could contribute points to the baseline
score but no points to subsequent scores leading to an artifactual
reduction in the overall disease activity score. We recommend the
protocol include definitions of disease manifestations, and levels
of disease severity be clearly specified. The interpretation of
score changes may be confounded if organ system dysfunction due to
a disease or condition other than SLE is present, or organ
dysfunction due to the treatment occurs. It is important that the
study protocol specify procedures to ensure that the scoring of
the DAI specifically reflects SLE-related organ dysfunction.
Clearly, there are situations when changes in scores may not
accurately reflect changes in disease activity. These limitations
do not preclude the use of these disease activity indices in
clinical trials, but the investigator should be aware they exist.
In addition, careful training of investigators is essential to
ensure uniform scoring. If there is a lack of reproducibility of
these measures from clinician to clinician, it may seriously
impair the interpretability of the trial results.
We recommend analyzing the results of
clinical trials to verify that an improvement in a disease
activity score represents a clinical benefit to the patient and to
assess the generalizability of the results. It is important that
patient outcomes be analyzed to determine that the improvement in
disease activity is not accompanied by worsening in other disease
manifestations. Overall, assessment of irreversible organ damage
defined as histologic or functional changes and/or measures of
HRQL should not significantly worsen. To explore the
generalizability of the benefits seen, we recommend subset
analyses be carried out regarding the extent of benefit for
disease affecting specific organ systems.
Another method to measure a decrease in
disease activity is to assess the incidence of disease flares
during the course of a clinical trial. This type of trial might
use measures of mild/moderate and severe SLE flares as the primary
outcome measure. As not all SLE patients experience flares in a
given time frame, the size and duration of the trial should be
adequate to capture a sufficient number of flares in the treatment
and control groups to demonstrate a decrease in the treatment
arm. Collection of complete information on concomitant
medications is essential to ensure that a difference in the number
of SLE flares is attributable to the study drug. We recommend
careful consideration be given to determining the appropriate
regimen for the control arm of a trial in SLE. No subject should
be denied recognized effective treatment for aspects of the
disease which may lead to irreversible harm. A design consistent
with this principle randomizes subjects to the addition of placebo
or study drug to a generally acceptable standard of care regimen.
This seeks to demonstrate that disease activity is decreased in
the treated subjects. A study could also randomize subjects to
the receipt of a known active agent or the study drug, then assess
if there is a larger decrease in disease activity in subjects
receiving the new product. It may be appropriate to include early
escape provisions for subjects who worsen during the study to
ensure that no subject is denied potentially effective therapy.
Measurement of renal disease in SLE in
clinical trials requires knowledge of the histologic description
delineating the extent of inflammation or scarring, because the
outcome and clinical features vary markedly among the various WHO
categories of lupus nephritis. A variety of endpoints can be used
to demonstrate efficacy in lupus nephritis, including progression
to end-stage renal disease, progression to a specified level of
loss of renal function as assessed by serum creatinine or
creatinine clearance, induction of renal remission, reduction in
renal flares, and resolution of nephrotic syndrome. A discussion
of the use of these endpoints in clinical trials is provided in
Sections III.C. and IV.B. and D.
Responder measures for each organ system
studied can be proposed and based on organ-specific measures from
a DAI. If an organ-specific outcome is studied, we recommend a
comprehensive DAI be included as a secondary outcome. A responder
measure has the advantage of addressing the particular disease
manifestations of most concern for an individual patient. This
approach recruits a more homogeneous population of patients
compared to the DAI approach, although it is recognized that
patients will often have more than one organ system involved.
Powering such a study may be problematic if study enrollment is
restricted to patients with one specific organ system involved.
Patient populations with disease affecting more than one organ can
be studied using an organ-specific approach if the organ system or
systems that have been most problematic for each enrolled subject
are identified. Trials can study a single organ or they might
study disease in more than one organ, with stratification by each
patient’s primary organ of involvement, allowing evaluation of
effects on several specific organs within a single trial.
Stratification by extent of organ damage at baseline may be
advantageous to ensure balance of pre-existing organ damage
between treatment groups. We recommend that clinically important
outcomes be defined for each organ system, and composite endpoints
can be considered. In disease activity trials, we recommend
measuring multiple time points, which can improve efficiency of
the trial.
A successful trial may demonstrate a
statistically significant number of clinical remissions in the
treated group versus the control group. Trends for improvement in
each organ system can then be examined. However, the
interpretation of a clinical trial using the specified organ
approach could be problematic if worsening in other manifestations
of lupus counterbalanced improvement in the organ system
measured. If changes in treatment regimens are made, such as an
increase in immunosuppressive agents, the results in the
designated organ would be confounded.
Studies to demonstrate the improved safety
profile of a new drug compared to standard therapy may also be
considered. We recommend these trials also be of adequate
duration to establish efficacy. If comparable efficacy is
expected, rather than superior efficacy, then a noninferiority
design to evaluate efficacy will be necessary. Rigorous
noninferiority demonstrations are necessary, but can be difficult
to achieve. It is recommended that sponsors proposing such
studies identify the known effect size for the comparator and
define a noninferiority margin that preserves a sufficient
percentage of the effect size to demonstrate efficacy with the new
product. These choices must be based on careful and comprehensive
review of the data available regarding the comparator agent. It
is also important for these studies to be powered to demonstrate
that the new product is noninferior and to adequately assess the
claim of an improved safety profile. It is appropriate for
steroid sparing agents to demonstrate not only that reduction in
steroid use is statistically significant, but also that these
reductions translate into an improved safety profile. Ensuring
that a trial has sufficient power to demonstrate improved safety
may be problematic in lupus, although studying a collection of
important adverse events may help in this regard. Other trial
designs may be considered but it is recommended that these be
discussed with the appropriate reviewing division before
initiation.
We recommend careful consideration of the use
of concomitant medications during trials. This includes defining
allowable medications at baseline and allowable changes in
medications during the trial. It is important that investigators
consider restricting baseline glucocorticoid use (stable dose or
limit the range of doses) to reduce the variability of dosing that
may introduce bias and make interpretation of results more
difficult because of significant variation and imbalances of
initial doses. If glucocorticoid dose changes are allowed during
the trial, it is important that these changes be carefully
discussed in the protocol before the trial begins. We also
recommend considering the use of rescue medication and whether
patients requiring rescue medication be withdrawn from continued
administration of randomized study agent. It is important to
recognize that subtle changes in concomitant medications, whether
steroids, immunosuppressive agents, or other therapies, can
influence outcomes. It is important for the protocol to provide
consideration for standardization to the use of concomitant
medications including ACE inhibitors and antihypertensive agents,
levels of blood pressure, and control of diabetes (especially for
studies of lupus nephritis).
Blinding is intended to minimize the
potential biases resulting in differences in management of
patients or assessment of patient status. Therefore, it is
important that every effort be made to ensure that trials are
adequately blinded. This can require, among other things,
identification of third parties to assess efficacy, to administer
drugs, or to make patient management decisions.
No patient enrolling in a clinical trial
should be denied standard therapy if that may lead to irreversible
harm. To avoid denying patients standard of care, clinical trials
of new therapies can use add-on study designs, or head-to-head
comparisons with an alternative standard of care. Corticosteroids
with or without cyclophosphamide plus placebo compared to
corticosteroids with or without cyclophosphamide plus new drug is
an example of an add-on design that assesses efficacy of a new
product as compared to placebo in the context of background
corticosteroids or corticosteroids plus cyclophosphamide.
To the extent that cyclophosphamide may be
effective, demonstration of an effect of a new drug may be
difficult in trials in which cyclophosphamide is considered part
of the standard of care regimen, especially if the mechanisms of
action of cyclophosphamide and the new therapy are similar. It
may be difficult to identify toxicity of the new drug in the
context of the use of multiple immunosuppressive agents. We
recommend that sponsors consider these issues when designing
trials.
Extension trials are used to demonstrate
maintenance of efficacy observed in a short-term evaluation, and
long-term safety. We recommend that sponsors consider whether
comparators are warranted in these studies, and whether these
extension studies be blinded or open label. Although it may be
difficult to perform a blinded extension study, advantages to this
include obtaining more robust efficacy and safety data. The more
robust nature of the data can be important to weighing the
strength of the evidence in making risk-benefit comparisons, and
achieving claims in approved labeling.
In general trials should be 12 months in
duration although trials of shorter periods can be considered,
depending on the organs and outcomes studied. Short-term trials
may not provide adequate demonstration of efficacy, safety, and
durability of response. However, it may be difficult to perform
long-term studies secondary to flares, changing medications,
dropouts, and changes in medical practice.
Surrogate or early markers of disease
activity can be considered for assessment of efficacy in lupus
trials. Such markers can be particularly useful in phase 2
studies, prior to definitive demonstrations of efficacy. If
surrogate endpoints are being considered for the demonstration of
efficacy to support a marketing application, we recommend they be
thoroughly discussed with the FDA reviewing division and be
validated for the treatment under study. Approval may be based on
a validated surrogate endpoint. If the surrogate is not
validated, but appears to be reasonably likely to predict a
clinical benefit, accelerated approval may be considered under 21
CFR 314, subpart H or 21 CFR 601, subpart E. In this case,
approval would be contingent upon a phase 4 study to verify the
clinical benefit.
Supporting the proposition that the surrogate
is reasonably likely to predict clinical benefit is essential to
this approach. An effect on the surrogate should be demonstrated
in adequate and well-controlled clinical trials. Trends toward
clinical improvement observed in the trials that establish an
effect on the surrogate marker can serve to strengthen an
assessment of the surrogate as being reasonably likely to predict
clinical benefit. The totality of the available data will be
examined during the review process in considering a product for
accelerated approval. The ability of the surrogate endpoint to
predict clinical outcomes will be weighed against the risks
associated with treatment.
Potential surrogate markers can be laboratory
evaluations involving physiological indicators or pathological
changes identified in the organ under study. For example, a
sustained doubling of serum creatinine is a valid surrogate marker
for the clinically important outcomes of ESRD, and the need for
dialysis or renal transplantation. Changes in creatinine
clearance or iothalamate clearance can also be considered as
potential surrogates for ESRD. Significant changes as assessed by
repeat renal biopsies also have potential to serve as a surrogate
endpoint. A significant improvement in hematuria and proteinuria
in conjunction with a substantial change in the level of
anti-double-stranded DNA antibodies can be proposed for
consideration as the basis for approval. Other composite
surrogates can also be considered. Other markers might include
assessment of B- and T-cell subsets, autoantibody subsets, immune
complexes which are specifically defined, presence or absence of
procoagulants, complement or its products. It is possible that
proof of concept studies can be useful to support subsequent
designs leading to consideration of approval. For example,
sponsors can consider measuring the effects of a study drug
against the effect of true placebo on T- and/or B-cell profiles in
short-term trials to determine a measure of potential efficacy,
possible dose, and treatment duration for subsequent study in
pivotal trials for approval. However, to be suitable as a basis
for accelerated approval, it would be appropriate to have strong
evidence that the proposed surrogate is reasonably likely to
predict clinical benefit. We recommend sponsors be cautious
about selecting a surrogate endpoint intended to support
accelerated approval until there is confidence regarding its
predictive value.
Approval of a therapy for SLE is predicated
on evidence from adequate and well-controlled studies
demonstrating efficacy and safety that support a conclusion of an
acceptable risk-benefit. Assessment of risks and benefits
requires an appraisal of the impact of the product on all aspects
of the disease process, including disease activity, irreversible
damage due to SLE and its treatment, and quality of life (Strand
1999). It is important that the size of the safety database at
approval be consistent with the recommendations made by the
International Conference on Harmonisation (ICH guideline E1A).
Particular attention should be paid to the assessment of known
toxicities, or to pharmacologic effects that might be suspected to
imply delayed toxicities. It is important to consider these
toxicities in formulating the clinical development program and
this may influence the size of the necessary safety database. The
recommended size of the safety database may be lower for orphan
indications, as it may be impossible or impractical to study a
large number of subjects. Although SLE is not an orphan
indication, there may be subsets of patients with specific
manifestations of SLE who represent an orphan population
indication. Sponsors may wish to discuss these issues with the
appropriate FDA staff early in the development of a new
treatment. Finally, if there is concern about rare but serious
adverse events (e.g., from the mechanism of action or experience
with similar agents), a phase 4 commitment may be needed to gather
additional safety information.
For many products there have been few
pharmacokinetic studies done in a prospective manner in the lupus
population. The bulk of the pharmacokinetic experience in these
subjects has been anecdotal in nature. However, pharmacokinetic
data may serve an important role in designing the clinical
development program. For example, determining the dosing interval
of a drug in individuals with lupus may be a challenge because of
the multisystem nature of the disease. It is important that
patient enrollment in pharmacokinetic studies reflect the
population for which the drug is intended. As women represent the
primary population afflicted with lupus, we recommend that
enrollment in pharmacokinetic studies incorporate a preponderance
of women. Due to the multisymptom and body system nature of
lupus, it is important that subjects enrolled in pharmacokinetic
trials for lupus have organ system involvement to assess the need
for organ-specific recommendations.
A characteristic feature of lupus is the
associated change in the kidney, both structurally and
functionally. These kidney changes make it difficult to determine
whether the standard renal transplant model is adequate for the
assessment of declining renal function in the lupus patient. It
is recommended that separate pharmacokinetic trials be considered
in lupus patients with varying degrees of proteinuria to assess
the impact on drug disposition and binding (e.g., those with
proteinuria greater than 4 grams/24 hours, greater than 1 gram/24
hours, or greater than 500 mg/24 hours).
We recommend conducting drug interaction
trials with those agents commonly used in the treatment of lupus.
It is important to assess the potential for interactions with
hormonal contraceptives. These assessments can include either in
vitro or in vivo methodologies or a combination. The reader is
directed to the published FDA guidances on in vivo and in vitro
drug interaction studies (see References).
Boumpas, DT and JE Balow, 1998, Outcome
Criteria for Lupus Nephritis Trials: A Critical Overview, Lupus,
7:622-629.
Food and Drug Administration, 1997, Drug
Metabolism/Drug Interaction Studies in the Drug Development
Process: Studies In Vitro, April 1997.
_____, 1999, In Vivo Drug Metabolism/Drug
Interaction Studies — Study Design, Data Analysis, and
Recommendations for Dosing and Labeling, November 1999.
Levey, AS, SP Lan, HL Corwin, BS Kasinath, et
al., 1992, Progression and Remission of Renal Disease in the Lupus
Nephritis Collaborative Study: Results of Treatment with
Prednisone and Short-Term Oral Cyclophosphamide, Ann. Int. Med.,
116:114-123.
Petri, M, M Genovese, E Engle, and M
Hochberg, 1991, Definition, Incidence, and Clinical Description of
Flare in SLE. A Prospective Cohort Study, Arth. Rheum.,
34:937-44.
Strand, V, D Gladman, D Isenberg, M Petri, J
Smolen, and P Tugwell, 1999, Outcome Measures to Be Used in
Clinical Trials in Systemic Lupus Erythematosus, J Rheumatol,
Feb;26(2):490-7.
Stoll, T, B Seifert, and DA Isenberg, 1996,
SLICC/ACR Damage Index Is Valid, and Renal and Pulmonary Organ
Scores Are Predictors of Severe Outcome in Patients with SLE, Br.
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SELENA Safety of Estrogen in Lupus
Erythematosus National Assessment Trial
SLEDAI Systemic Lupus Erythematosus
Disease Activity Index
SLICC/ACR Systemic Lupus Erythematosus
International Collaborating Clinics/
