Proteinuria as a Surrogate in Chronic Kidney Disease A Regulatory Perspective Aliza Thompson, MD, MS Medical Officer

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

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

3. Outline • Efficacy and surrogates • Proteinuria as a biomarker and surrogate • Future directions

4. 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

5. 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.

6. Surrogates as a Substitute • Benefits- earlier and easier detection, faster and cheaper drug development • The Critical Path Initiative and surrogates

7. 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

8. 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.

9. Proteinuria as a biomarker and surrogate

10. 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)

11. 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)

12. 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

13. 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!)

14. 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.

15. 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

16. Subpart H Use • 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 follow-up of fully enrolled study CDER Approvals *Based on post-hoc combination of two indices of clinical benefit Slide borrowed from Dr. Norman Stockbridge

17. 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

18. 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?

19. 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.