How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?

Abstract

Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post-approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing 'Cardiovascular Toxicity of Medicines'. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: • Fully characterize the incidence, prevalence and impact of drug-induced cardiovascular issues at all stages of the drug development process. • Ascertain the predictive value of existing non-clinical models and assays towards the clinical outcome. • Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. • Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. • Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers.

Figure 1

Reasons for drug attrition in 1991 and 2000. PK, pharmacokinetics; T, toxicology; CS, clinical safety. Modified from Kola and Landis (2004). Over the 10 year period safety, combining non-clinical toxicology and clinical, has remained a major cause of drug attrition accounting for approximately 30% of all drug discontinuation; during the same period attrition due to pharmacokinetics and bioavailability reasons has been reduced significantly, probably reflecting in part the effort placed on front-loading Drug Metabolism and Pharmacokinetics activities in the early discovery phases.

Figure 2

Evidence, prevalence and occurrence of safety liabilities relating to the cardiovascular and hepatic systems. Information was collated from published articles (Sibille et al., 1998; Olson et al., 2000; Fung et al., 2001; Budnitz et al., 2006; Car, 2006; Stevens and Baker, 2009) and from the commercially available database BioPrint® (Krejsa et al., 2003) to provide a guide to the prevalence of adverse drug reactions (ADRs) and their impact in terms of attrition, across the cardiovascular and hepatic systems. Some datasets relate to frequency (i.e. percentage) of candidate drugs or marketed drugs associated with the toxicity; others contain data on prevalence of the ADRs in volunteer subjects or patients. Cardiovascular data do not include haematological related attrition, withdrawal or ADRs. The data were collected over different time periods, so that there is no analysis of trends over time. Attrition has a greater financial impact than ADRs per se, and the further advanced a candidate drug (CD) or drug is in clinical development, the greater the financial impact. Therefore, cardiovascular toxicity has a greater impact than hepatotoxicity in terms of its contribution to drugs withdrawn from sale and CD attrition during clinical preclinical or clinical development. Some of the adverse events (AEs) contributing to the data are functional in nature, and so would be predictable from primary, secondary or safety pharmacology studies, whereas others are pathological in nature, so would be predictable from toxicology studies (histopathological end-points). Some AEs might be indicative of idiosyncratic reactions not identified during preclinical or clinical development (e.g. hepatotoxicity-related attrition observed in late clinical development or post-approval). The difference in incidence of cardiovascular-related attrition post-approval noted between Fung et al. (2001) and Stevens and Baker (2009) may reflect the increased cardiovascular-related attrition over the last ∼15 years particularly in relation to arrhythmias. Modify from Redfern et al. (2010).

Figure 3

Cumulative cardiac and vascular adverse events (AEs) reported to the US Food and Drug Administration Adverse Event Reporting System (AERS) since 1969; the documents compiled in PharmaPendium (https://www.pharmapendium.com) refer to the Spontaneous Reporting System prior to 2000 and to the AERS from 2000 onwards, so the reports prior to that are more sporadic and less detailed. The annual number of AERS reports that exist in PharmaPendium has more than doubled over the last decade from a value of ∼200 000 in 2000. The data represent the cumulative number of cardiac (top panel) or vascular (bottom panel) AEs reported over that period of time. Within each category, the AEs are ranked by decreasing order of incidence. Such AEs data should be taken with caution, as the linkages with drugs are not always demonstrated. Overall there are six main AE categories of cardiac and vascular side effects, for which over 10 000 reports are available. Note the very large number of AERS reports related to arrhythmias probably reflects the increased scrutiny around drug-induced QT prolongation and Torsades de Pointes over the last decade. NEC, not elsewhere classified.