Cardiovascular safety evaluations

Vargas HM, Bass AS, Breidenbach A, Feldman HS, Gintant GA, Harmer AR, Heath B, Hoffmann P, Lagrutta A, Leishman D, McMahon N, Mittelstadt S, Polonchuk L, Pugsley MK, Salata JJ, Valentin JP (2008). Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologies. 7 Pharmacol Toxicol Methods 58(2) 72-76. 

Vargas HM, Bass AS, Breidenbach A et al (2008) Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologies. J Pharmacol Toxicol Methods 58 72-76... 

Hanson, L.A., Bass, A.S., Gintant, G., Mittelstadt, S., Rampe, D. and Thomas, K. (2006) ILSI-HESI cardiovascular safety subcommittee initiative evaluation of three non-clinical models of QT prolongation. Journal of Pharmacological and Toxicological Methods, 54, 116—129. 

Regulatory guidance for non-clinical cardiovascular safety pharmacology testing is given in the ICH S7A and B.25,42 The effects of an NCE on blood pressure, heart rate, and the ECG should be evaluated. Furthermore, in vivo, in vitro, and ex vivo evaluations, including methods for (assessing) repolarization and conductance abnormalities, should... 

Committee for Proprietary Medicinal Products (EU). Points to Consider The assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products 1997 ICH S6 Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals, July 1997... 

Markert M, Klumpp A, Trautmann T, Guth BD (2004) A novel propellant-free inhalation drug delivery system for cardiovascular safety pharmacology evaluations in dogs. Journal of Pharmacological and toxicological Methods 50 109-119... 

For safety evaluation, the absence of cardiovascular side effects is important (Vizi et al. 2003). 

Nonclinical safety pharmacology studies submitted to regulatory agencies are outlined in ICH Guidance S7A (2001), and the basic package includes evaluation of a drug candidate s effects on the central nervous system, respiration, and the cardiovascular system. Cardiovascular system evaluation includes assessment of cardiac function and cardiac electrophysiological activity. 

The objective of preclinical cardiovascular safety testing is to identify either (1) EKG/ECG signals of potential TdP hazard, or (2) a change in heart rate (pulse) and blood pressure indicators for purposes of evaluating the potential risk to the first humans to be exposed to a new drug, and for... 

Studies in Lists A and B became de facto international blueprints for general/safety pharmacology evaluations until issue of ICH S7A. "Normally, anesthetized animals are used" hence, anesthetized animal preparation (and particularly the barbiturate-anesthetized dog) became the standard for cardiovascular-respiratory evaluations [p.l28]. 

Although the studies did demonstrate that Vioxx was safer on the digestive track than Naproxen, they also again unexpectedly found that the COX-2 inhibitor doubled the risk of cardiovascular problems. In April 2002, the FDA required that Merck note a possible link to heart attacks and strokes on Vioxx s label. But it never ordered Merck to conduct a trial comparing Vioxx with a placebo to determine whether a link existed. In April 2000 the FDA recommended that Merck conduct an animal study with Vioxx to evaluate cardiovascular safety, but no such study was ever conducted. 

Covers several Bayesian approaches, including a meta-experimental design for evaluating cardiovascular risk, adaptive trials for drug safety, and network meta-analysis for safety evaluation... 

Development of knowledge and strategies intended to improve the evaluative sciences in relation to cardiovascular safety and product development. 

Findings during Phase n development often determine the clinical safety monitoring needs for stedies in Phase HI development. In this case, they may identify what (if any) additional cardiovascular/hanodynamic evaluations or substudies might be informatively conducted during Phase HI development. 

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