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1 Introduction Biomarkers are biological substances, characteristics, or images that provide an indication of the biological state of an organism.1 Biomarkers can include physiological indicators, such as blood pressure; molecular markers, such as liver enzymes and prostate-specific antigen; and imaging biomarkers, such as those derived from magnetic resonance imaging and angiography. In the research context, biomarkers can provide indications of both the potential effectiveness and the potential hazards associated with a therapeutic intervention. They can be used to understand the mechanism by which a drug works, to make decisions about whether to develop a drug, to screen compounds for toxicity before they enter clinical trials, to monitor the development of toxicity during clinical trials, and to forecast adverse events resulting from wider exposure. Thus biomarkers can potentially reduce the costs of developing drugs, enhance the safety of drugs, and speed the movement of drugs to market. The use of biomarkers in drug development raises a number of issues. As a measure of biological function, a biomarker can help unravel a mecha- nism or biological pathway, or it can serve as a predictor of the future course of health or disease. As biomedical science evolves and becomes increasingly computational and probabilistic, the tools for understanding the predictive value of biomarkers are changing, as are the criteria used 1A National Institutes of Health (NIH) working group has defined a biological marker or biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to thera- peutic intervention” (Biomarkers Definitions Working Group, 2001). 

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 DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY for assessing them—for example, sensitivity, specificity, reliability, and dis- crimination. Since biomarkers typically quantify physiological states or therapeutic responses, choosing the values in decision rules—for example, “cutoff points”—becomes very important and difficult, as different values can yield quite different perspectives. In the familiar examples of creatinine for kidney injury, troponin for cardiac injury, and alanine aminotransferase (ALT) for liver injury, the higher is the value, the higher is the probability of true injury, yet low values may signal the early phase of damage. The use of biomarkers often involves a trade-off between sensitivity, or the proportion of positive responses that a biomarker correctly identifies as positive, and specificity, or the proportion of negative responses that a biomarker correctly identifies as negative. Different degrees of sensitivity and specificity are needed in different circumstances, and will be dependent upon the intended use of the biomarker. Individual biomarkers differ in the extent to which they reflect a known biological mechanism. Greater understanding of mechanism can be extremely helpful in such tasks as comparing the action of related drugs or gauging the relevance of animal findings to humans. However, biomarkers can provide useful information even when a detailed understanding of mechanism is lacking. No one biomarker is likely to have all of the characteristics necessary to provide a robust understanding of response As a result, future use of combinations of multiple biomarkers to enable improved prediction of drug efficacy and safety is likely. Yet the use of such combinations of biomarkers may introduce its own challenges, including technical issues of how to combine results, how to control quality, and how to interpret results in different clinical contexts. The improper use or interpretation of biomarkers can be detrimental in both clinical and research settings by misdirecting therapy or research activities. If biomarkers are to be used properly, there needs to be an understanding of their sensitivity and specificity, how and in what contexts to use them, how to interpret them in those various contexts, and how to properly validate them. WORkSHOP PuRPOSE, SCOPE, AND ObJECTIvES To better understand the current state of the art in the development of biomarkers, consider the issues involved in their development and use, and discuss their future development, the Institute of Medicine’s (IOM’s) Forum on Drug Discovery, Development, and Translation held a 1-day workshop on October 24, 2008, on “Assessing and Accelerating the Development of Biomarkers for Drug Safety.” Participants included experts from academia, government, and industry. To ensure a manageable range of content, the

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 INTRODUCTION workshop was limited in two ways. First, it focused on biomarkers used to determine safety; biomarkers used to determine efficacy were not con- sidered. Second, consideration of safety biomarkers was limited to those associated with three organ systems: cardiac, kidney, and liver. These three were chosen because they represent a large proportion of toxicity problems related to drug development, they include a diverse range of biomarker types, and they are associated with varying degrees of success in biomarker development. The workshop had three main objectives: 1. To assess the current state of the art for screening technologies to find off-target effects early in drug development 2. To compile a list of questions to address remaining obstacles to the development of biomarkers for drug safety 3. To discuss how to accelerate the development of biomarkers through public and private means The workshop benefited from three white papers on the state of bio- marker development and use for the above three organ systems. Using these papers as a starting point, three breakout groups each focused on one of these systems, producing a host of observations and insights relevant to the three objectives of the workshop. CROSSCuTTING ISSuES During the course of the workshop, three major issues emerged that affect the development and use of biomarkers to detect toxicity across the three organ systems. Incentives The development of needed information about biomarkers is thought by most to be beyond the scope of an individual company or academic insti- tution. Furthermore, the Food and Drug Administration (FDA) is neither equipped nor funded to conduct such research. Accordingly, incentives are needed to encourage research groups to overcome traditional barriers of secrecy and protection of intellectual property. Incentives could be help- ful in translating the results of basic research into biomarker applications that have an impact on health care. In particular, incentives that promote collaboration among industry, the FDA, the National Institutes of Health (NIH), and academic researchers could yield much more rapid progress in the development of biomarkers. Clear agreement on the data that need to be submitted to regulatory authorities would reduce industry-perceived

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 DEVELOPMENT OF BIOMARKERS FOR DRUG SAFETY constraints on generating some forms of data. Collaborations also could lead to the establishment of standards for submission databases, review databases, and electronic medical records. Successful partnerships depend on finding common ground among partners and taking into account the varying interests of different groups. understanding Mechanisms of Action Although a biomarker can provide predictive information based solely on the association between its intensity and organ toxicity or other out- comes, biomarkers have their greatest value when they unveil a mechanism that can be understood so the drug can be altered to avoid the toxicity. The same is true when biomarkers reveal mechanisms of benefit. Yet regardless of whether such mechanistic insights are gained, reliable information that can distinguish who is at risk and who will benefit is valuable. And the discovery of a predictive biomarker can lead to further research on the association between that biomarker and an outcome. benefit/Risk balance Ultimately, the goal of drug development is to optimize the balance of benefit and risk when a drug is used, and then to provide accurate infor- mation for patients, physicians, payers, and ultimately society about the balance that will be observed when that drug is used by patients. In the past, these estimates of benefit/risk balance have come from projections from mechanistic reasoning, often without empirical data, or from average population outcomes from clinical trials. The identification of biomarkers that can distinguish patients particularly susceptible to risk or suggest an enhanced likelihood of benefit could make these calculations more accu- rate, and enable decisions to be tailored to the characteristics of individual patients. This capability forms the basis for the concept of personalized medicine, which employs biomarkers to stratify populations into smaller groups according to such differences in benefit and risk. Realizing this capability is one potential outcome of the “learning healthcare system” that has been described by IOM (2007). In such a system, patients will be more likely to participate actively in research programs, knowing that their participation will contribute to a broader understanding not only of their condition, but also of the particular risks and benefits they face as individuals.

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 INTRODUCTION ORGANIZATION OF THE REPORT The remainder of this report provides a comprehensive summary of the presentations and discussions that occurred during the workshop. Chapter 2 provides an overview of key issues in the use of biomarkers in drug development. Chapters 3, 4, and 5 present final versions of the white papers prepared for the workshop on cardiac, kidney, and liver safety bio- markers, respectively. In addition, the final section of each of those chapters summarizes the discussions that occurred during breakout sessions that followed the presentations in these areas. Chapter 6 summarizes future actions suggested by workshop participants to further the use of biomarkers in drug development. It should be noted that while the IOM Forum on Drug Discovery, Development, and Translation introduced the idea for this workshop, its planning was the responsibility of an independently appointed committee. That committee’s role was limited to advance planning; this summary was prepared by an independent rapporteur, with the assistance of forum staff, as a factual summary of what occurred at the workshop. REFERENCES Biomarkers Definitions Working Group. 2001. Biomarkers and surrogate endpoints: Pre- ferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics 69(3):89–95. IOM (Institute of Medicine). 2007. The learning healthcare system: Workshop summary. Washington, DC: The National Academies Press.