Cardiac repolarisation and drug regulation: assessing cardiac safety 10 years after the CPMP guidance.

December 2007 marks the 10-year anniversary of the first regulatory guidance for evaluation of drug-induced QT interval prolongation. A decade on, it seems surprising that this document, which was released by the Committee on Proprietary Medicinal Products, caused such acrimony in the industry. Sponsors now routinely evaluate their new drugs for an effect on cardiac electrophysiology in preclinical studies, in addition to obtaining ECGs in all phases of drug development and conducting a formal thorough QT study in humans.However, concurrently, new concerns have also emerged on broader issues related to the cardiovascular safety of drugs because of their potential to shorten the QT interval as well as to induce proischaemic, profibrotic or prothrombotic effects. Drugs may also have an indirect effect by adversely affecting one or more of the cardiovascular risk factors (e.g. through fluid retention or induction of dyslipidaemia). In addition to peroxisome proliferator-activated receptor agonists and cyclo-oxygenase 2 selective inhibitors, three other drugs, darbepoetin alfa, pergolide and tegaserod, provide a more contemporary regulatory stance on tolerance of cardiovascular risk of drugs and their benefit-risk assessment. This recent, more assertive, risk-averse stance has significant implications for future drug development. These include the routine evaluation of cardiovascular safety for certain classes of drugs. Drugs that are intended for long-term use will almost certainly require long-term clinical evaluation in studies that enrol populations that most closely resemble the ultimate target population. Novel mechanisms of action and biomarkers by themselves are no guarantee of improved safety or benefits. Even some traditional biomarkers have come to be viewed with scepticism. Requirements for more extensive and earlier postmarketing assessment of clinical benefits and rare, but serious risks associated with new medicinal products should create a new standard of evidence for industry and regulators and almost certainly result in better assessment of benefit/risk, more effective and balanced regulatory actions and better care for patients.