Accelerating the Development of Biomarkers for Drug Safety Workshop Summary (2009) / Chapter Skim
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3 Cardiac Safety Biomarkers
3 Cardiac Safety Biomarkers
Pages 17-28
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From page 17... ...
. Among its strengths are that the technology needed to measure it is established and nearly universally available; a great deal is known about the molecular mechanisms of the ion channels that affect ventricular repolarization; a number of well-established in vitro and in vivo models exist; there is substantial clinical experience with patients who have a congenital prolonged 1 This chapter is derived from a white paper prepared by Daniel Bloomfield, Executive Director of Cardiovascular Clinical Research and Chair of the Cardiac Safety Board for Merck Research Laboratories, and Norman Stockbridge, Director of the Division of Cardiovascular and Renal Products for the FDA, with additional input from workshop discussions.
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From page 18... ...
Specifically, clinical epidemiology data have not been collected that would define the probability of an episode of the ventricular tachycardia known as torsade de pointes based on the QTc interval. It should be noted that, while many biomarkers are used to understand a wide range of cardiovascular conditions -- such as hyperlipidemia, inflammation, and ischemia -- the scope of the discussion in this session of the workshop was limited to biomarkers of electrophysiologic toxicity, in particular, those related to QT interval prolongation.
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From page 19... ...
As the regulatory response was being crafted, the FDA made a public appeal for the development of standards for digital ECG data. This action was based on the idea that it will be critical to review the ECGs from TQT studies.
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From page 20... ...
First, E14 specified that every systemically available small molecule would require a clinical TQT study even if the results of the extensive preclinical studies related to ventricular repolarization outlined in S7B were completely normal. Second, E14 set an extremely high bar for declaring that a compound posed no QTc risk: at supratherapeutic exposures, a compound had to demonstrate an increase in QTc of less than 5 milliseconds (ms)
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From page 21... ...
With regard to drug development, the ultimate success of the E14 and S7B guidance documents will be realized when there is a shared understanding between pharmaceutical companies and regulatory agencies of the clinical significance of a small increase in QTc interval in the context of the possible benefits of a new molecular entity. Excessive focus on this biomarker in the absence of true clinical risk could stifle innovation and lead to an unfortunate decision to discontinue the development of a drug that could offer patients benefits outweighing the actual risk.
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From page 22... ...
Since the toxicity associated with anthracyclines varies considerably among individuals, the use of cardiac troponin has been suggested as potentially important in planning and monitoring treatment to allow maximum anthracycline dosages
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From page 23... ...
, the FDA, and the CSRC hosted an open think tank forum on October 6–7, 2008, titled "Integrating Preclinical and Clinical Issues in Cardiac Safety: Translational Medicine Meets the Critical Path." Experts from academia, industry, and the FDA gathered to discuss key topics in cardiac safety assessment, with
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From page 24... ...
THE CARDIAC SAFETy RESEARCH CONSORTIuM As the ECG warehouse was coming online, the FDA and the Duke Clinical Research Institute initiated the CSRC, a public–private partnership, to "advance scientific knowledge on cardiac safety for new and existing medical products by building a collaborative environment based upon the principles of the FDA's Critical Path Initiative as well as other public health priorities."3 This initiative brought together pharmaceutical companies, clinical research organizations, and academic partners in an effort to leverage the ECG warehouse and associated clinical data for mutual benefit. The implementation of the CSRC has faced many challenges related to governance, infrastructure, resources (both funds and staff time)
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From page 25... ...
The CSRC also hopes to foster collaborations among industry, academia, and regulatory agencies to further the development of new cardiac safety biomarkers. These advances in biomarker development will require investments in basic science to better elucidate the molecular mechanisms of cardiac toxicity and in preclinical models and clinical data to allow evaluation of the use of biomarkers.
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From page 26... ...
The effort to develop a digital ECG data standard, which involved a team of people from pharmaceutical companies, clinical research organizations, device manufacturers, and academia, was initiated and managed by Scott Getzin of Eli Lilly. The CSRC came into being largely through the efforts of Christopher Cabell, then at the Duke Clinical Research Institute.
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From page 27... ...
One option would be to convene a standing group including representatives of the National Heart, Lung, and Blood Institute, the FDA, industry, and academia to identify and prioritize high-impact opportunities in terms of public health and to recommend specific targets for research funding. Topics that NIH should consider include technology and animal model development aimed at translation to human studies; development of biomarkers through detailed studies of human
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From page 28... ...
2005a. International conference harmonization guidance for industry: E clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non antiarrhythmic drugs.
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