Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease (2010) / Chapter Skim
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4 Case Studies
4 Case Studies
Pages 131-196
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From page 131... ...
cholesterol, which highlights how even biomarkers frequently used as surrogate endpoints need to be carefully evaluated prior to each use. Finally, the fifth case study is on beta-carotene, which contains lessons for each step of the qualification framework.
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TABLE 4-1 Brief Summary of the Results of the Case Studies Utilization: Utilization: Surrogate Biomarker Analytical Validity Qualification Possible Uses Endpoint Use Tumor Size No Numerous trials exist Data needed to Current data do not support with inconsistent findings improve analytical use as a surrogate endpoint on tumor shrinkage and validity of one or clinical benefit more test CRP High-sensitivity tests RCTs and observational Risk prediction; Current data does not support available studies available; limited potential expansion use as a surrogate endpoint data on CRP's biological of statin treatment to role in disease progression specific populations Troponin Validated tests are Extensive data for acute Safety uses Current data does not support available for many troponin, limited data on use as a surrogate endpoint uses. More sensitive chronic troponin; data tests are also being collection is ongoing developed
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More accurate fully understood tests are also being developed. Beta-carotene Validated measures Extensive RCTs and Uses include a Current data does not support of blood serum beta- observational trials are biomarker of use as a surrogate endpoint carotene levels are available intake of fruits and available for many vegetables and an uses effective intervention to address vitamin A deficiency NOTE: CRP = C-reactive protein; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; RCT = randomized controlled trial.
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Readers of these case studies may wonder what lessons can be gained toward prospective evaluation of biomarkers. For a newly discovered biomarker, it is likely that very little data will be available for review in the analytical validation and qualification steps of the evaluation framework.
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added a requirement that a clinical survival benefit or qualityof-life benefit should be demonstrated. Because long trials are usually needed to demonstrate significant survival benefit and the demand for new anticancer drugs is always urgent, in 1996 the FDA extended Accelerated Approval under subpart H of the New Drug Application for drugs that are effective against serious or life-threatening diseases as measured by surrogate endpoints to anticancer drugs (HHS, 1996)
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whereas the remaining 16 were not converted to regular approvals; all these agents remain on the market." While the outcome measured in phase III cancer trials is often overall survival, surrogate endpoints play a large role in evaluation of new therapeutic agents in phase II clinical trials (Ratain et al., 1993; Sargent et al., 2009; Scher et al., 2008; Seibert et al., 2007)
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orthogonal views and using an elliptoid model to estimate tumor volume. A growing body of literature is advocating for the use of elliptoid modeling of tumor volume as the most meaningful representation of tumor size in terms of its accurate reflection of changes in tumor bulk confirmed by other volumetric mea surements, such as water displacement and its correlation to clinical end points.
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Given the contributions of these and other factors, the biological plausibility of using tumor size as a surrogate endpoint for evaluating disease progression and therapeutic efficacy in cancer is not entirely obvious. Smaller tumors tend to grow faster, so major shrinkage of tumor mass does not necessarily translate to prolonged survival (Citron, 2004; Hudis, 2005)
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From page 139... ...
LDL, for example, is hypothesized to have a causal role in the atherosclerotic disease process, and while this has not been conclusively proven, LDL is measured as a biomarker of atherosclerotic cardiovascular disease and targeted pharmaceutically. Clearly tumor size is a different brand of surrogate endpoint from most molecular biomarkers in that increasing tumor size is viewed as a result of disease progression, not a causative factor.
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In this example Gleevec is thought to have both cytotoxic and cytostatic effects, and GIST cells are replaced by myxoid degeneration following cell death, both reasons why tumor size as a surrogate endpoint correlates poorly with clinical endpoints (Benjamin et al., 2007; Choi, 2005)
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. Even so, use of tumor size as a surrogate endpoint for regulatory approvals is decreasing and is being replaced by other, better qualified surrogate endpoints.
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Traditionally, the prevention of cardiovascular disease has occurred through lowering risk factors associated with the development of CVD (Krumholz and Lee, 2008)
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In addition, many individuals with multiple risk factors never develop cardiovascular disease; Greenland et al. found that exposure to one or more of the traditional risk factors was highly prevalent among individuals who did not develop clinical CHD (Greenland et al., 2003)
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.7, fixed image Figure In the early 1990s, it was observed that individuals with active coronary syndromes and individuals with AMI who were tested prior to the acute-phase response to infarction were shown to have higher levels of CRP. The observation of the role of inflammation in cardiovascular disease and studies that revealed CRP predicted future coronary events began the current interest of CRP and cardiovascular disease (Pepys, 2005; Ridker et al., 1997)
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From page 145... ...
Lifestyle factors that impact CRP levels include exercise, smoking, measures of adiposity, alcohol, anti-inflammatory drugs, and estrogen replacement therapy. Despite these sources for variation in CRP concentration and measurement, CRP has proved to be a clinically useful measurement because it is an independent predictor of cardiovascular risk (Ridker, 2007)
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. Reprinted with permission, Copyright 2003 by the American Heart Association.
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Although research indicates that CRP is an independent predictor of cardiovascular risk, it is not known whether CRP plays a causal role in cardiovascular disease, which creates uncertainty about its use as a potential therapeutic target and surrogate endpoint. Although inflammation is clearly involved in the development of atherosclerosis, researchers have not definitively ascertained whether CRP plays an active role in the disease process.
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From page 148... ...
LDL cholesterol and CRP reductions were only weakly correlated with each other in this analysis. Although the JUPITER trial did not show that lowering CRP levels reduced cardiovascular risk, the trial does indi cate that those patients with LDL levels of less than 130 mg per deciliter and CRP levels of greater than 2 mg per liter are at higher absolute risk and that rosuvastatin therapy resulted in a significant benefit in lowering cardiovascular events.
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and low predictive ability for genes related to biomarkers. Although the biological role of CRP in cardiovascular disease remains uncertain, CRP has been shown to be an independent predic tor of cardiovascular risk; at least 30 population cohorts (Shah and deLemos, 2009)
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(2004) found that CRP is a relatively moderate predictor of coronary heart disease in comparison with traditional risk factors (such as higher LDL levels and cigarette smoking)
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. The complexity of cardiovascular disease, including the nature of competing risks within the general population, may favor the use of CRP in risk prediction because inflammation may be an important risk factor for different subpopulations, such as non-HDL cholesterol measurement is for those with familial hypercholesterolemia.
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Current research indicates that CRP may have utility in risk prediction, especially for those at intermedi ate risk of cardiovascular disease. For use in primary prevention, aside from the JUPITER trial, there is limited information to assess the benefit of intervening with statin therapy in individuals with high CRP levels, but normal LDL cholesterol levels.
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Therefore, while CRP may be a useful biomarker for risk prediction, more evidence needs to be accumulated to establish further uses of CRP, both within clinical practice and regulatory decision making. TROPONIN Acute myocardial infarction is diagnosed through use of biomarkers, and cardiac troponin (cTn)
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While troponin levels are different in different patient populations based on a variety of biological factors such as age, posture, and more, biological variation is generally not considered when troponin levels are measured, due to inadequate sensitivity of the assays. In addition, the reference populations for these measurements are variable and determined from convenience samples composed of various ages, and include individuals without cardiovascular disease, but with high concentrations of cTn for other reasons (Apple, 2009)
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cTnT elevation was associated with congestive heart failure, left ventricular hypertrophy, diabetes mellitus, and end-stage renal disease (Wallace et al., 2006) , though the higher cTnT levels did not appear to mark acute events.
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This list will increase as more sensitive and more precise assays evolve. Box 4-1 highlights conditions associated with elevated cTn in the absence of overt ischemic heart disease.
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through interventions improves mortality risk. As these clinical trials indicate, patients with even small elevations in cTn can be identified as having higher risk (Hamm and Braunwald, 2000; Heidenreich et al., 2001)
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cTnT is more frequently elevated for reasons that are unclear at present because, in general, cTnT and cTnI are otherwise generally equivalent clinically. Additionally, in patients with end-stage renal dis ease, changes in cTn elevation may be indicative of adverse prognoses, including coronary heart disease and death (Apple et al., 2002; DeFilippi et al., 2003)
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The problem arises from the conflation of risk factors with biomarkers for benefit of intervention (i.e., surrogate endpoints)
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, HDLC has not yet qualified as a surrogate endpoint for cardiovascular risk because there is no evidence that HDL-raising interventions can improve outcomes. The FDA's Center for Food Safety and Nutrition also considers LDL-C as a qualified surrogate endpoint, so authorized health claims for cardiovascular disease risk reduction can be approved for foods containing ingredients that have been shown to lower LDL-C, with few restrictions on what other ingredients the food may contain and in the absence of information about the effect of the food on the clinical outcomes of those who consume it.
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, small LDL particle concentration, non-HDL cholesterol, and apolipoprotein B (apoB) may have stronger associations with CVD risk than LDL-C (Contois et al., 2009; Cromwell et al., 2007; El Harchaoui et al., 2007; Jiang et al., 2004; Sniderman, 2002)
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holds promise for measuring the correlation between HDL and CVD risk (Knopp et al., 2008)
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. Epidemiologic studies describe increasing CVD risk with increasing LDL-C even when other risk factors are present (Knopp et al., 2008)
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, one biomarker is unlikely to ever be a perfect surrogate endpoint for use in CVD clinical trials. Studies exist in which LDL-C was robustly decreased yet cardiac events were not reduced: specifically, estrogen replacement does result in lower LDL-C levels (Herrington et al., 2000; Hulley et al., 1998)
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, raising questions about whether raising HDL is an effective strategy for preventing CVD. A recent meta-analysis concluded that increasing HDL levels alone does not reduce risk of coronary heart disease events or deaths (Briel et al., 2009)
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. LDL and HDL: utilization An often-cited article published nearly three decades ago listed 243 coronary risk factors (Hopkins and Williams, 1981)
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, showing that even for qualified biomarkers, developing standard measures is an ongoing process. The strength of LDL as a surrogate endpoint is not absolute due to the heterogeneity of cardiovascular disease processes, the heterogeneity of LDL-lowering drug effects, and the heterogeneity of LDL particles themselves.
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High-density lipoprotein does not qualify as a surrogate endpoint for cardiovascular disease risk because these characteristics, particularly the latter, introduce high levels of variability. BETA-CAROTENE Beta-carotene (b-carotene)
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. Therefore, researchers were surprised when supplemental sources of b-carotene used in several clinical trials were associated with higher risk of lung cancer in participants who were smokers or former smokers (IOM, 2000b)
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and cancer, cardiovascular disease, and retinal degeneration, research was directed to addressing the putative biologic mechanism of antioxidant activity. These measures endeavored to assess the potential to counteract oxidative damage occurring within nucleic acid or macromolecules resulting from the presence of free oxygen radicals in cells.
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Operating under one or more notions of b-carotene as a risk biomarker, a surrogate endpoint, and a beneficial intervention, several large-scale randomized clinical trials were funded and designed to evalu ate whether increasing b-carotene intake might lower the risk of cancer, CVD, and eye disease. Three primary prevention clinical trials (mentioned below)
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. The Physicians Health Study I, consisting of a randomized two-bytwo factorial trial of b-carotene to prevent cancer and aspirin to prevent coronary heart disease, enlisted 22,071 male physicians, some of whom were smokers.
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To date, increasing b-carotene serum levels has no demonstrated value in predicting the development of cancer or CVD. Neither the subjects in control cohorts of the large clinical trials who had baseline levels of b-carotene nor those who had elevated b-carotene were necessarily protected from a neoplasm or a cardiac event.
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. In the same trial, nearly equal numbers of men given b-carotene and those not given the supplement died from a cardiovascular disease that was not ischemic heart disease, hemorrhagic stroke, or ischemic stroke (Albanes et al., 1996)
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2004. Raised cardiac troponins: Causes ex tend beyond acute coronary syndromes.
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2003. Axillary lymph node status, but not tumor size, predicts locoregional recurrence and overall survival after mastectomy for breast cancer.
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2009. C-reactive protein as a risk factor for coronary heart disease: A systematic review and meta-analyses for the U.S.
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1996. Lipids, risk factors and ischaemic heart disease.
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2009. Apolipoprotein B and cardiovascular disease risk: Position state ment from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices.
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2008b. Lipoprotein-associated phospholipase A2 is an independent predictor of incident coronary heart disease in an apparently healthy older population.
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Safety of treat ment, changes in risk factors, and incidence of coronary heart disease. New England Journal of Medicine 317(20)
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2003. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events.
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1998. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
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2007. Design of phase II cancer trials using a continuous endpoint of change in tumor size: Application to a study of sorafenib and erlotinib in non small-cell lung cancer.
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2003. Prevalence of conventional risk factors in patients with coronary heart disease.
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2009. Heart disease and stroke statistics 2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcomittee.
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1992. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study.
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2007. National Academy of Clinical Biochemistry Laboratory Medicine practice guidelines: Use of cardiac troponin and B-type natriuretic peptide or N-termi nal proB-type natriuretic peptide for etiologies other than acute coronary syndromes and heart failure.
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2007. The prevention of cardiovascular disease: Have we really made progress?
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1997. Inflam mation, aspirin, and the risk of cardiovascular disease in apparently healthy men.
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1999. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.
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2009. Critical appraisal of CRP measurement for the prediction of coronary heart disease events: New data and systematic review of 31 prospective cohorts.
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2008. Re: Design of phase II cancer trials using a continuous endpoint of change in tumor size: Application to a study of sorafenib and erlotinib in non-small cell lung cancer.
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2006. Heart disease and stroke statistics -- 2006 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
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1995. Serum total cholesterol and long-term coronary heart disease mortality in different cultures: Twenty-five-year follow-up of the seven coun tries study.
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2006. Troponin I as a predictor of coronary heart disease and mortality in 70-year-old men: A community-based cohort study.
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