Cardiovascular safety remains a leading cause of drug attrition during preclinical and clinical development, accounting for discontinuation of approximately one third of marketed drugs.
These liabilities, which pertain to both cardiovascular- and non-cardiovascular-targeted drugs, can be identified during early development by addressing cardiovascular safety endpoints prior to the selection of a drug candidate, a process known as ‘frontloading’. Although not mandated by the key regulatory guidance for safety pharmacology (ICH S7A; US FDA, 2001), an increasing number of companies choose to conduct early non-GLP cardiovascular safety studies in support of decisions on the progression of their compounds.
As an increasing number of companies partner with CROs such as Covance for the conduct of studies spanning various segments of the drug development process, an increasing responsibility is placed on the CRO partner to participate in cross-industry efforts to define early cardiovascular safety testing. The CRO involved in frontloading has the unique opportunity to integrate its scientific and technical base to support the understanding of key cardiovascular liabilities and the development of strategies for their detection.
These liabilities – including pro-arrhythmic potential (QT prolongation), hypo/hypertension, myocardial ischaemia, and heart failure – can be identified in the lead optimization or candidate selection phases. While testing earlier in the drug development process can increase the efficiency of lead candidate selection and possibly address mechanisms of adverse effects (on- or off-target), the optimal strategy for decisions on when and what to run remains in the domain of drug developers, who are in the best position to develop decision or learning maps.
While the CRO may not be in a position to offer a flow chart or a “one size fits all” model of cardiovascular derisking, they are positioned to support the process through a focus on assay sensitivity, cost reduction, and implementation of technological advances. An important factor in mapping a strategy between pharma and CRO is the conversation between experts on both sides offering complementary experiences and views. As safety questions are ultimately answered by clinical studies, the CRO scientist has the added responsibility of considering the extent of preclinical cardiovascular safety pharmacology necessary in the context of the sponsor’s resources.
Cardiovascular safety models are appropriate for use in early derisking only if they can balance a fast answer to relevant questions with low cost, are customizable, and provide high sensitivity data predictive of GLP results. Proarrhythmic potential, hypo/hypertension and ventricular contractility are cardiovascular liabilities frequently investigated early in development, especially when the target is expressed in the cardiac tissue. Telemetry, both implanted and external, is the most sensitive method for the detection of such risk. A variety of large and small animal models can be used based on the target investigated.
A significant improvement in the detection of proarrhythmic potential occurred with the advent of technological advances in preclinical ECG collection via telemetry and the streamlining of ion channel testing such as the hERG assay. Both assays focus on the risk of QT prolongation, an ECG interval biomarker of a drug’s potential cardiac safety risk. QT prolongation is accepted as a surrogate marker of Torsades de Pointes (TdPs), a relatively rare but fatal ventricular tachycardia. Most drugs that induce TdP are associated with prolongation of the QT interval and block of the human cardiac hERG channel.
Over the past decade, a reduction was seen in the number of QT-prolonging drugs in late development, likely due to increased frontloading. Additional liabilities related to vascular disorders, myocardial ischaemia or necrosis, heart failure, etc., can be investigated with preclinical models combined with telemetry, often involving the addition of imaging such as echocardiography, or the integration of histopathology and known cardiac biomarkers. Further, pharmacokinetic and functional cardiovascular endpoints can be mapped at this stage through the use of automated blood sampling techniques in conjunction with telemetry.
As preclinical models have become more streamlined in the context of a trend towards increased outsourcing, the need for rigor and alignment with best practices has also increased. Best practices for safety pharmacology have been recently outlined by the Safety Pharmacology Society (citation, see paper attached) and encompass recommendations for the characterization and sensitivity of models, alignment between facilities, and data collection or analysis.
CROs conducting safety pharmacology studies, such as Covance, are increasingly a source of data used in the generation of such recommendations, in addition to being active participants in the scientific inquiry. The ILSI/HESI Technical Committee on Cardiac Safety, formed to share resources and expertise to improve cardiovascular safety evaluation for new drugs and chemicals, is an example of a forum where various segments of the industry participate to shape the future directions for investigation of pro-arrhythmic risk, cardiac safety biomarkers, or integrated strategies.
The development and maintenance of a large spectrum of in vivo and in vitro models, as well as their large scale integration under the umbrella of a comprehensive advisory strategy, are seen increasingly as the responsibility of the CRO. A significant advantage of large scale integration is seen especially when early frontloaded studies can be continued in the GLP arena using the same tools and methodology, or when clinical studies trigger a need to expand preclinical investigations.
The availability of integrated development both within the preclinical arena or with the clinic is often an economic incentive and can result in a better understanding of the inter-relationship between nonclinical and clinical predictors of cardiovascular risk.
In the context of the rapidly developing discipline of Safety Pharmacology, the current focus on frontloading cardiovascular safety has identified areas where collaborative efforts across industry are needed to optimize strategies and techniques for conducting frontloaded studies.
Sharing of data through publications or open databases is increasingly explored in the field and encouraged by the Safety Pharmacology Society, with the goal of creating publicly available repositories of information on target-related safety, predictive value of assays, and mechanistic understanding of cardiovascular liabilities. As the source of much of this shared information, the CRO participates in continuously informing the regulatory environment and shaping the future application of safety pharmacology with the goal of developing safer drugs.