Proteinuria as a Surrogate in Chronic Kidney Disease

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Proteinuria as a Surrogate in Chronic Kidney
Disease A Regulatory Perspective Aliza
Thompson, MD, MS Medical Officer Division of
Cardiovascular and Renal Products FDA
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Disclaimer

• The views expressed in this talk represent my
  opinions and do not necessarily represent the
  views of the FDA.

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Outline

• Efficacy and surrogates
• Proteinuria as a biomarker and surrogate
• Future directions

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Efficacy from a Regulatory Perspective

• Substantial evidence and Adequate and
  well-controlled 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

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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.
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Surrogates as a Substitute

• Benefits- earlier and easier detection, faster
  and cheaper drug development
• The Critical Path
• Initiative and surrogates

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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

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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.
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Proteinuria as a biomarker and surrogate
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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 dose-ranging
  studies)

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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 wont be lost
  but also helps weigh risks vs. benefits of drug)

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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

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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!)

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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.

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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
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Subpart H Use

• Last Cardio-Renal approval was Remodulin (PAH) in
  2002.
• Ensuring phase 4 study completion is big problem.
  Previous approval was 1996still waiting!
• Ideal is phase 4 follow-up of fully enrolled study

CDER Approvals
Year N
2003 5
2004 3
2005 4
2006 2
Based on post-hoc combination of two indices of
clinical benefit
Slide borrowed from Dr. Norman Stockbridge
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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

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Future

• More Data- what well 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?

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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.