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[Appendix B] 2 Review: Evaluating and Regulating Biomarker Use
Pages 275-338

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From page 275...
... , in particular -- regarding surrogate endpoints. It will also discuss the evolution in thinking in academic and industry communities, to a lesser extent.
From page 276...
... This will be discussed further in several subsections of this chapter's sec tion on evolution of regulatory perspectives on surrogate endpoints and in Chapter 5. Second, they have been used in the formulation of clinical practice guidelines.
From page 277...
... 277 APPENDIX B TABLE 2-1 Categories of Biomarker Use Use Description Discovery Identification of biochemical, image, or other biomarkers associated with a disease, condition, or behavior of interest; biomarkers identified may be screened for many potential uses, including as a target for intervention to prevent, treat, or mitigate a disease or condition Early product development Biomarkers used for target validation, compound screening, pharmacodynamic assays, safety assessments, and subject selection for clinical trials, and as endpoints in early clinical screening (i.e., phase I and II trials) Surrogate endpoints for claim and Biomarkers used for phase III clinical testing product approvals and biomarkers used to substantiate claims for product marketing Clinical endpoints Biomarkers used as endpoints for clinical trials that measure how a patient feels, functions, or survives; for example, measures of depression, blindness, and muscle weakness are biomarkers that may be used as clinical endpoints Clinical practice Biomarkers used by clinicians for uses such as risk stratification, disease prevention, screening, diagnosis, prognosis, therapeutic monitoring, and posttreatment surveillance Clinical practice guidelines Biomarkers used to make generalized recommendations for healthcare practitioners in the areas of risk stratification, disease prevention, treatment, behavior/lifestyle modifications, and more Comparative efficacy and safety Biomarkers used in clinical studies looking at the relative efficacy, safety, and cost effectiveness of any or all interventions used for a particular disease or condition, including changes in behavior, nutrition, or lifestyle; these studies are a component of comparative effectiveness research Public health practice Biomarkers used to track public health status and make recommendations for prevention, mitigation, and treatment of diseases and conditions at the population level
From page 278...
... It is possible that more trials will measure a particular surrogate endpoint in addition to or rather than the clinical endpoint of interest. In these cases, it may be desirable to include data from trials that did not measure the clinical endpoints of interest in the systematic reviews.
From page 279...
... 279 APPENDIX B BOX 2-1 Characteristics of Comparative Effectiveness Research (CER)
From page 280...
... Finally, surrogate endpoints can be found in public health practice when there is a need to estimate the health of populations or short-term impacts of longer-term programs for prevention, treatment, or mitigation of infectious or chronic diseases when health outcomes important to patients cannot be measured. For example, reporting to stakeholders about interventions to decrease diseases and conditions of importance in the population, such as stroke or heart attack, may be done by measuring and reporting blood pressure as a surrogate for the desired improvement in health status, although measuring health outcomes important to patients such as stroke or qual ity of life would be preferable as guidance to public health interventions unless such measures were deemed impractical.
From page 281...
... It may be surprising to readers that blood pressure as a surrogate endpoint for cardiovascular disease endpoints was hotly debated for decades before reaching its current status. Still, there is no broad agree ment that blood pressure is a universal surrogate endpoint (Carter, 2002; Psaty et al., 1996)
From page 282...
... . Both placebo- and active-controlled clinical trials conducted in the past three to four decades have demonstrated that pharmacologic reductions in blood pressure reduce cardiovascular mortality and morbidity (Desai et al., 2006)
From page 283...
... . Although there is still some ambiguity about the use of differing blood pressure agents, the fact that pharmacologically distinct agents have directionally similar effects on cardiovascular outcomes has provided more support for the use of blood pressure as a surrogate endpoint for coronary heart disease and stroke.
From page 284...
... As discussed earlier, hypertension -- high blood pressure -- is recognized as a strong risk factor for cardiovascular disease. CFSAN has authorized a health claim for low-sodium foods based on the surrogate endpoint–disease-related condition relationship, stating either "diets low in sodium may reduce the risk of high blood pressure, a disease associated with many factors" or "development of hypertension or high blood pressure depends on many factors.
From page 285...
... The HIV Surrogate Marker Collaborative Group undertook a meta-analysis of clinical trials to evaluate treatment-mediated changes in HIV-1 RNA and CD4 cell count as surrogate endpoints (HIV Surrogate Marker Collaborative Group, 2000)
From page 286...
... (2006) , in a discussion of the approval of tipranavir in exactly such a context, recommended that only complete suppression of plasma HIV-1 RNA be used in such studies, and that partial suppression endpoints not be used in clinical trials.
From page 287...
... While this use of surrogate endpoints inspired the creation of the Critical Path Initiative, the process of biomarker evaluation used was not systematic and so was not easily translated into other disease areas. Nonetheless, the success of this effort to speed approvals of HIV drugs highlighted the value that a systematic biomarker evaluation process could have for drug regulation in general.
From page 288...
... Schatzkin and Gail (2002) discussed use of surrogate endpoints in cancer research in 2002; they again noted the difficult balance between strong evidence that a surrogate endpoint has predictive value for the clinical endpoint and use of surrogates to achieve new drug approvals before full clinical trials using clinical endpoints can be completed.
From page 289...
... A number of biomarkers have been proposed as rational surrogate endpoints, but have failed to demonstrate usefulness for that purpose upon further scrutiny in clinical trials. One example was the use of betacarotene and retinol as biomarkers for cancer, cardiovascular disease, and (later)
From page 290...
... It is useful to note that while serum level of beta-carotene is a biomarker for adequate intake of the nutrient and a proposed surrogate endpoint for prevention of cancer and atherosclerotic disease, supplementation of the diet with beta-carotene is an intervention to either address deficiencies or conditions for which it is used as a sur
From page 291...
... However, atherosclerotic disease, either coronary heart disease or peripheral vascular disease, did not decrease following folic acid fortification or with the administration of folic acid supplements in several large clinical trials despite important decreases in serum homocysteine levels with both interventions (Clarke et al., 2007)
From page 292...
... further noted that "a review of recent experiences with surrogates is sobering, revealing many cases for which biological markers were correlates of clinical outcomes but failed to predict the effect of treatment on the clinical outcome." The following examples related to cardiovascular disease (CVD) -- arrhythmia suppression, exercise tolerance in congestive heart failure, and lowering lipids -- were outlined by Fleming and DeMets as telling examples of failed surrogate endpoints.
From page 293...
... Scientists were so confident in this hypothesis that three drugs were approved by the FDA -- encainide, flecainide, and moricizine -- using arrhythmia sup pression as the surrogate endpoint in phase III clinical trials. To illustrate the confidence scientists had in arrhythmia suppression as a surrogate endpoint, many of them believed that randomizing patients to either one of the study drugs or a placebo would be unethical.
From page 294...
... to predict clinical endpoints "underlies much of the controversy surrounding the use of surrogate endpoints as the basis for regulatory evaluation of new therapeutic entities" (Lesko and Atkinson, 2001)
From page 295...
... Several examples of the evaluation and use of surrogate endpoints in drug development are then discussed. The last two sections address the two main directions in the discussion of biomarker evaluation: those focusing on statistical methods and those focusing on qualitative methods.
From page 296...
... Nonetheless, surrogate endpoints were used before these conversations began. One of the best examples of this is blood pressure, which is used as a surrogate endpoint for CVD clinical outcomes.
From page 297...
... HIV/AIDS was also the first example of a more systematic, prospective approach to biomarker evaluation, although its precedent was not easily translatable into general guidance. Finally, after the early 1990s, much of the literature has focused on the use of surrogate endpoints to approve oncology drugs.
From page 298...
... Statistical Approaches to Biomarker Evaluation Although randomized clinical trials with clinically meaningful end points provide the most rigorous means of assessing benefit of an intervention, such trials may be lengthy and expensive, and not always fea sible. Therefore considerable interest has been shown in development of a framework for "statistical validation" of surrogates for clinical endpoints that can reliably provide information more quickly and cheaply about medical interventions.
From page 299...
... For example, suppose that a blood pressure medication induced fatigue and therefore caused a reduction in the amount of exercise patients undertook; such an adverse consequence of treatment could affect both blood pressure and clinical events, such as time to myocardial infarction. Proce dures are available to permit assessment of surrogacy in this situation, but
From page 300...
... demonstrated that the change in CD4 count was associated with clinical endpoints (time to new AIDS definition or death)
From page 301...
... From these models, decision makers can then choose the most appropriate course of action or identify areas where more information is needed. Miksad outlined important questions that can be addressed using decision analysis for biomarker evaluation (Miksad, 2009)
From page 302...
... Decision theory can be useful as a way to formalize the biomarker evaluation framework. While each biomarker evaluation would require a unique decision analysis, these analyses would provide stakeholders with a transparent accounting of the assumptions and subjective judgments that were needed for making specific decisions.
From page 303...
... In contrast, the ROC curve for a test with 100 percent accuracy will trace the y-axis up at a false-positive fraction of zero and follow along the top of the graph at a true-positive fraction of one. The area under such a curve would be 1.0 and represent a perfect test.
From page 304...
... The paper subsequently received attention from FDA staff at a conference entitled "2008 Cardiovascular Biomarkers and Surrogate Endpoints Symposium: Building a Framework for Biomarker Application." Briefly, the evaluation method proposed involves use of a committee to make decisions based on data and non-quantitative factors, such as public tol erability of the proposed decision. The first step in the process is for the committee to define and agree on a purpose and context of use for the biomarker.
From page 305...
... . A representative from CDER commented on their paper in the same issue, providing important examples of how biomarkers can be used to speed drug development without being used as surrogate endpoints (Gobburu, 2009)
From page 306...
... (2008) Proposed Evidence Map for Biomarker Qualification Evidence Type Grade D Grade D+/C- Grade C Theory on Observed Theory, indirect As for lower grade biological association only evidence of but evidence is direct plausibility relevance of the biomarker from animals Interaction with Biomarker pharmacologic identifies target in target in vitro binding Pharmacologic In vitro evidence In vitro evidence In vivo evidence mechanistic that the drug that multiple that this drug affects response affects the members of this biomarker in animals biomarker drug class affects the biomarker Linkage to Biomarker Biomarker associated clinical outcome epidemiologically with change in of a disease or associated with outcome from toxicity outcome without intervention in any intervention another drug class Mathematics An algorithm replication, is required to confirmation interpret the biomarker and was developed from the dataset Accuracy and precision (analytic validation)
From page 307...
... Clinical Pharmacology and Therapeutics 83(2) :368–371, Copyright 2007.
From page 308...
... 314.510 Accelerated approval: drugs. "Surrogate - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity."a 21 C.F.R.
From page 309...
... , or there are important limitations and uncertainties associated with an endpoint." Guidance for industry: Clinical data The document states that "For influenza needed to support the licensure vaccines, the immune response elicited of seasonal inactivated influenza following receipt of the vaccine may vaccines (CBER, 2007) serve as a surrogate endpoint that is likely to predict clinical benefit, that is, prevention of influenza illness and its complications." Guidance for industry: Clinical trial The document describes current and endpoints for the approval of cancer past thought on use of non-survival drugs and biologics (FDA, 2007)
From page 310...
... elevated blood sugar concentrations and insulin resistance for type 2 diabetes." However, it also stipulates that biomarkers not on the biological pathway of a particular nutrient–disease risk link may not be used as surrogate endpoints for development of health claims. NOTE: a http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDeveloped andApproved/DrugandBiologicApprovalReports/ucm121606.htm.
From page 311...
... The com mittee meets four times a year. In 2009, the committee discussed topics such as • Risk communication research needs, • Quality of consumer drug information, • Communicating about food recalls and food-borne illness, • Communicating about tobacco and health, • Clinical trials database, and • Use of social media as surveillance tools.
From page 312...
... : the qualification process as it would be applied to several problems such as how efficacy biomarkers can help in large, expensive drug trials where the clinical endpoint is rare and delayed, how safety biomarkers contrib ute when there is late discovery of toxicity resulting in late abandonment of the drug development program, and how safety biomarkers contrib ute when there are no sensitive methods to detect observed preclinical toxicities.
From page 313...
... , as part of the Critical Path Institute's efforts in the area of biomarker evaluation, assembled a panel of scien tists to evaluate potential safety biomarkers of acute kidney injury. These biomarkers are needed for use in "early diagnosis, to monitor severity and progression of disease, predict an outcome without an intervention, better stratify patients for clinical trials, predict who will respond to an intervention, [determine whether]
From page 314...
... that relate a food substance to reduced risk of disease are considered health claims. Implied health claims are statements, symbols, vignettes, and other forms of communication that suggest a relationship between a substance and a disease or health-related condition.5 Health claims consist of two parts, a substance (specific food or component of food, including a dietary supplement)
From page 315...
... In 2009, CFSAN completed a guidance for industry that outlined the agency's current thinking on the process for evaluating scientific evidence for a health claim, the meaning of the SSA standard, and credible scientific evidence to support qualified health claims (CFSAN, 2009a)
From page 316...
... . In the scientific review of evidence for health claims, "Surrogate endpoints of disease risk" considered valid by the FDA's Center for Food Safety and Applied Nutrition include serum LDL cholesterol, total serum cholesterol, and blood pressure for cardiovascular disease; bone mineral density for osteoporosis; adenomatous colon polyps for colon cancer; and elevated blood sugar concentrations and insulin resistance for type 2 diabetes (CFSAN, 2009a)
From page 317...
... [This TABLE 2-4 Health Claims Based on Surrogate Endpoints Surrogate Nutrient Disease Endpoint Type of Claim Phytosterols, Coronary LDL and Phytosterols: Authorized soy protein, heart disease total Soy protein: Authorized corn oil, canola cholesterol Corn oil: Qualified oil, and olive oil Canola oil: Qualified Olive oil: Qualified Chromium Type 2 Insulin Qualified picolinate diabetes resistance Calcium and Hypertension Systolic Calcium: Qualified sodium and Sodium: Authorized diastolic blood pressure Calcium and Osteoporosis Bone Authorized vitamin D mineral density Calcium Colorectal Colorectal Qualified cancer polyps NOTE: LDL = low-density lipoprotein. SOURCE: Trumbo and Ellwood (2009)
From page 318...
... can be part of a low sodium, low salt diet that might reduce the risk of hypertension or high blood pressure."10 Health claims based on authoritative statements The Food and Drug Administration Modernization Act of 1997 specified that the FDA's scientific review process could be circumvented if other scientific bodies of the U.S. government or the National Academy of Sciences 11 had issued authoritative statements about the substance/disease relationship.
From page 319...
... . Qualified health claims Litigation over the SSA standard for dietary supplements resulted in an FDA process to approve claims with lesser evidence, given additional qualifying language (qualified health claims)
From page 320...
... . On the FDA's website, the denied petitions for qualified health claims are also listed, and include lycopene and cancer, green tea and reduced risk of cardiovascular disease, vitamin E and heart disease, among others (a total of 15 letters of denial have been produced, with one petition -- soy protein and cancer -- withdrawn)
From page 321...
... As compared to health claims, dietary guidance statements make reference to either a food sub stance or a disease, but do not relate these two components in the claim. For example, a dietary guidance statement may say "carrots are good for your health" or "calcium is good for you." Unlike health claims, truthful, non-misleading dietary guidance statements may be used on food labels without premarket review by the FDA (CFSAN, 2008)
From page 322...
... . As the primary agency in charge of the safety of foods and drugs, the FDA uses and provides access to a great deal of information on the safety of food, supplements, drugs, biologics, and devices, and on the strength of evidence supporting certain types of health claims on foods and supplements.
From page 323...
... Schwartz and Woloshin noted that the FDA has recognized these problems and has begun to address them. The Risk Communication Advisory Committee was initiated at the FDA in 2008 (see Box 2-4)
From page 324...
... Professional societies can help health care providers obtain skills in how to communicate with their patients about the probabilistic nature of health-related evidence and decisions. Professional societies have an important role to play in helping physicians, consumers, dietitians, other healthcare workers, and individuals in the pharmaceuticals, biologics, medical devices, supplements, and food industries to understand the consequences of innumeracy, evidence gaps, and the insufficiency of evidence to predict all outcomes when evidence is based on surrogate endpoints, other biomarkers, short-term clinical trials, or observational studies alone rather than clinical endpoints.
From page 325...
... . Numeracy is important to the successful adoption of the biomarker evaluation framework recommended in this report.
From page 326...
... Second, changes in a biomarker caused by a particular drug, food, or other health intervention do not always predict changes in the clinical outcome of interest. Use of surrogate biomarkers, short-term clinical trials, or observational studies alone cannot adequately predict clinical benefit or harm, and in some
From page 327...
... Without information about an intervention's effect on clinical endpoints, it is impossible to have complete information about the efficacy and safety of the intervention. Humans tend to oversimplify or ignore evidence gaps in order to make decisions, and are often unaware of evidence gaps.
From page 328...
... . An example of insensitivity to probability bias, also known as neglect of probability bias, is when a person chooses to eat a nutrient or other substance that has been shown in observational studies to be associated with a reduced risk of disease, while ignoring the fact that this research alone does not confirm a sub stance's causal connection to a reduced risk of disease.
From page 329...
... Paper presented at 2008 Cardiovascular Biomarkers and Surrogate Endpoints Symposium: Building a Framework for Biomarker Application, Bethesda, MD, September 12. Boissel, J
From page 330...
... 2004. Qualified health claims: Letter of enforcement discretion -- walnuts and coronary heart disease (accessed March 17, 2009)
From page 331...
... 1989. Surrogate endpoints in clinical trials: Cancer.
From page 332...
... Paper presented at 2008 Cardiovascular Biomarkers and Surrogate Endpoints Symposium: Building a Framework for Biomarker Application, Bethesda, MD, September 12. Goodsaid, F
From page 333...
... 1998. CD4 cell count as a surrogate endpoint in HIV clinical trials: A meta-analysis of studies of the AIDS Clinical Trials Group.
From page 334...
... 2001. Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: Criteria, validation, strategies.
From page 335...
... 1990. Blood pressure, stroke, and coronary heart disease.
From page 336...
... 2009. Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials.
From page 337...
... 1989. Surrogate endpoints in clinical trials: Cardio vascular diseases.


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