Accelerating the Development of Biomarkers for Drug Safety Workshop Summary (2009) / Chapter Skim
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2 Overview of Key Issues
2 Overview of Key Issues
Pages 6-16
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From page 6... ...
As Janet Woodcock of the FDA pointed out, they can improve the predictability of drug development, and increase the value of preventative and therapeutic interventions by targeting individuals with a high probability of benefit and screening out those at high risk of side effects. Biomarkers can be used to screen compounds for toxicity before they enter clinical trials, to inform decisions about whether to develop a drug, to monitor the development of toxicity, to forecast adverse events given wider exposure, or to understand the mechanism by which a drug works.
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From page 7... ...
Animal studies can make use of genomic and proteomic techniques, thereby increasing the probability that initial administration to humans will be safe, or help establish the relevance of animal findings to humans. Biomarker findings in clinical trials and postmarket data also can provide information about mechanisms of drug toxicity or benefit and suggest the need for additional nonclinical studies to fully elucidate the relevant mechanisms.
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From page 8... ...
Or a bridging biomarker might predict toxicity very early in humans -- before harm occurs -- and at very low doses. As the FDA white paper Innovation or Stagnation: Challenges and Opportunity on the Critical Path to New Medical Projects states, "A new product development toolkit -- containing powerful new scien tific and technical methods such as animal or computer-based predictive models, biomarkers for safety and effectiveness, and new clinical evalua tion techniques -- is urgently needed to improve predictability and efficiency along the critical path from laboratory concept to commercial product" (FDA, 2005, p.
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From page 9... ...
One of the greatest challenges to the application of biomarkers in drug development is that numerous and conflicting arguments can be made for placing greater emphasis on specificity than sensitivity or vice versa. For example, one could argue that a biomarker that yields a high number of false negatives may fail in preclinical studies to detect problems with drugs that go on to produce toxicity in clinical studies.
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From page 10... ...
Explicit study designs are needed to answer safety questions, such as when to stop enrolling patients who test positive or to discontinue treatment in those with an elevated biomarker. It is critical to obtain definitive answers about safety while keeping participants in a trial as safe as possible.
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From page 11... ...
Drug developers may not know what preclinical signals of toxicity to look for until clinical toxicity has been observed late in drug development or even in clinical use. For example, many kinase inhibitors now used clinically in oncology produce cardiac toxicity, perhaps because they inhibit a specific kinase in the heart.
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From page 12... ...
4) , a valid biomarker is "a biomarker that is measured in an analytical test system with well-established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic, or clinical significance of test results." For in vitro diagnostics requiring a PMA, clinical utility must be demonstrated along with validity.
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From page 13... ...
As there is no way of preventing every drug that proves to have a toxic effect from proceeding into clinical trials, however, definitions and measures of safety must be established. An unintended consequence of biomarker development may be a decrease in the number of available drugs.
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From page 14... ...
Much of the publicity regarding drug safety has focused on the detection of events that are rare, such as acute hepatic failure, which recently was a cause for concern with the drug troglitazone. But a bigger problem, according to Wood, is the drug that produces an increased incidence of a frequent event, such as the Cox-2 inhibitors, which caused an increase in myocardial infarctions.
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From page 15... ...
A key problem has been predicting adverse effects in patients treated with psychiatric drugs. In a study involving 1,742 patients, 120 developed suicidal ideation while receiving antidepressants.
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From page 16... ...
Perhaps by combining a better understanding of brain circuitry from imaging with genetic and proteomic data, a panel of diverse biomarkers could be developed that would predict responses. NIH supports research to discover potential biomarkers using a variety of approaches.
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