Transcript FDA perspective on surrogates/ critical path and

Proteinuria as a Surrogate in Chronic
Kidney Disease
A Regulatory Perspective
Aliza Thompson, MD, MS
Medical Officer
Division of Cardiovascular and Renal Products
FDA
Disclaimer
The views expressed in this talk represent
my opinions and do not necessarily
represent the views of the FDA.
Outline
• Efficacy and surrogates
• Proteinuria as a biomarker and
surrogate
• Future directions
Efficacy from a Regulatory Perspective
• “Substantial evidence” and “Adequate and wellcontrolled” trials
-1962 Kefauver-Harris Drug Amendment
• Labeling must bear adequate directions for use
and may not be false or misleading
-21 CFR 201.56 (a)
• Effect must be clinically meaningful (added by
court)
- 1986 Warner-Lambert v Heckler
Efficacy from a Regulatory Perspective
Clinically meaningful endpoints
• Important Outcome- death, need for dialysis
• Symptom
• Surrogate“a laboratory measurement or physical sign that is
used in therapeutic trials as a substitute for a clinically
meaningful endpoint that is a direct measure of how a
patient feels, functions, or survives and is expected to
predict the effect of the therapy” (e.g. blood pressure
and doubling of serum creatinine)
Temple R. Are surrogate markers adequate to assess
cardiovascular disease drugs? JAMA .1999; 282 (8):790-795.
Surrogates as a Substitute
• Benefits- earlier and easier detection,
faster and cheaper drug development
• The Critical Path
Initiative and surrogates
Surrogates as a Substitute
Benefit to public health of
accelerating the development
of “treatment breakthroughs”
vs.
Risk to public health of
relying on a substitute
Surrogates as a Substitute
“Before a biomarker can be accepted as a
surrogate endpoint, however, there needs
to be a great deal of confidence that
changes in the marker reliably predict the
desired clinical endpoints…”
Critical Path Opportunities Report. March 2006.
Proteinuria as a biomarker
and surrogate
Proteinuria as a biomarker
• Biomarker- a measurable characteristic that
reflects physiological, pharmacological, or
disease process
• Proteinuria used as a biomarker in drug
development (e.g. used to predict risk/safety, as
a primary efficacy endpoint for phase 2 trials,
and/or pharmacodynamic endpoint in doseranging studies)
Establishing proteinuria as a
surrogate
• Abundant epidemiologic data AND outcome studies of
pharmacologically distinct agents/distinct interventions
showing an effect on an established clinical endpoint (
doubling of creatinine, dialysis, mortality, etc) and an
effect on proteinuria
•
Ideally, some consistency in the magnitude of the effect
(implies that the effect won’t be lost but also helps weigh
risks vs. benefits of drug)
Proteinuria as a surrogate
What we know of:
 Abundant Epidemiologic Data
 Some data from controlled outcome studies (e.g.
irbesartan, losartan)
What we need to know more about:
 Data from controlled outcome studies of
pharmacologically distinct agents/other interventions
 Data from intervention trials defining the magnitude of
the association and establishing its consistency
Proteinuria as a surrogate in a very
restricted sense
Showing change from macroalbuminuria
to normoalbuminuria and that effect
persists when hemodynamic effect is gone
(the effect should be anatomically based!)
Proteinuria as a surrogate in a very
restricted sense
Persistence of effect after drug withdrawal
is critical. It makes proteinuria into a more
direct measure of an anatomical change.
Subpart H * and proteinuria
• Accelerated approval of new drugs for serious
or life-threatening illnesses
• Effectiveness shown via a surrogate endpoint
that is “reasonably likely to predict the
effectiveness of the product”
• Phase 4 commitment to verify that the effect
on the surrogate translates into improved
clinical outcomes
*Subpart E- Biologics
Subpart H Use
CDER Approvals
Year
2003
2004
N
5
3
2005
4
2006
2
Slide borrowed from Dr. Norman
Stockbridge
• Last Cardio-Renal
approval was
Remodulin (PAH) in
2002*.
• Ensuring phase 4 study
completion is big
problem. Previous
approval was 1996—
still waiting!
• Ideal is phase 4 followup of fully enrolled
study
*Based on post-hoc combination of two
indices of clinical benefit
Subpart H and proteinuria
• With respect to proteinuria endpoint, has been
incorporated into development program at least once in
recent years
• Phase 3 study endpoint= regression of microalbuminuria
that persists after drug withdrawal ( 2 months); phase 4
study endpoint= doubling sCr, ESRD, death
• Specified that enrollment for phase 4 study should be
completed prior to NDA submission
Future
• More Data- what we’ll be hearing about
• Possible Directions
- A context limited approach- use within the
context of a specific disease and/or
specific drug class
- Focus on “dramatic changes.” Are the data
sufficient to support other definitions?
Conclusions
Proteinuria is accepted as a surrogate in
a very restricted sense.
More data are needed before proteinuria
can be accepted as a surrogate in a
broader context.