Table 1.

Biomarker-Surrogacy Evaluation Schema applied to albuminuria

DomainPointsCriteriaAlbuminuria
Study design criterion0Evidence from in vitro or animal studies or case reports or cross- sectional observational or retrospective observational cohorts studies evaluating the relationship between marker and target3: Two RCTs in the same drug class [RENAAL, IDNT (10,11)]
1At least one nonpopulation-based prospective observational study with collection of all covariates needed to adjust for known confounding and effect modification evaluating the relationship between marker and target
2At least one population-based prospective observational study with collection of all covariates needed to adjust for known confounding and effect modification evaluating the relationship between marker and target or one RCT of the same drug class of an intervention evaluating the relationship between marker and target
3Two RCTs of the same drug class of an intervention evaluating the relationship between marker and target
4Two RCTs in each of two drug classes and of an intervention evaluating the relationship between marker and target
5Three RCTs in each of three known drug classes of an intervention that can evaluate the relationship between marker and target or three randomized biomarker-target trials
Target outcome criterion0Target(s) is a biomarker and reversible4: ESRD
1Target(s) is a biomarker and irreversible
2Target(s) is a clinical end point of reversible mild organ morbidity or reversible mild burden of disease
3Target(s) is a clinical end point of reversible severe organ morbidity or reversible severe burden of disease or irreversible mild organ morbidity or irreversible mild burden of disease
4Target(s) is a clinical end point of irreversible severe organ morbidity or irreversible severe burden of disease
5Target(s) is death
Statistical evaluation criterion0Evidence of poor to fair prognostic validity or very poor overall surrogate statistical validityWe have not redone the analysis; for the sake of argument, we will accept the score of 4
1Evidence of good to excellent prognostic validity or poor overall surrogate statistical validity
2Fair overall surrogate statistical validity
3Good overall surrogate statistical validity
4Very good overall surrogate statistical validity
5Excellent overall surrogate statistical validity
PenaltiesBiology, epidemiology , and success in clinical trials−2: Studies have shown opposite effect [ACCOMPLISH (12)]
−1 Evidence of no surrogacy validity in at least one adequately powered RCT
−1 Evidence of one epidemiologic study that supports opposite assertion
−1 Evidence of no effect in at least one adequately powered epidemiologic study
−1 Biomarker remote from clinical end point
−1 No animal model evidence to support surrogacy validity of therapeutic response
−1 No prospective epidemiologic evidence to support surrogacy validity
−2 Evidence of one adequately powered RCT that supports opposite assertion
−2 Application of the schema used <90% of adequately powered existing trials
Generalizability−2: Has only been shown in studies of diabetic nephropathy
−2 No evidence to support surrogacy validity of therapeutic response from clinically heterogeneous study populations by age, sex, comorbidity, and disease stage
Risk-benefit−3: Studies of combination renin angiotensin system blockade show harm (3,4,13)
−3 One RCT that demonstrates use of marker confers patient harm
−3 Does not meet the threshold criterion of a rank of 3 in at least one domain if score is ≥7
  • Domains and criteria are from Lassere (7). RCT, randomized controlled trial; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; INDT, Irbesartan Diabetic Nephropathy Trial; ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension.