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For pharmaceutical sponsors, the role of cardiac testing in drug development programs has changed significantly in the past 10 years. As the cardiac core lab industry begins to mature, and as regulators require increased focus on drug safety, cardiac testing is expected to continue its dynamic evolution in the years ahead.
The beginnings of modern cardiac testing can be traced to 1997 when the EMEA’s (now the EMA) Committee of Proprietary Medicinal Products released a Points to Consider document on the assessment of the potential for QT interval prolongation by non-cardiovascular medicinal products. Regulatory interest grew, gathering momentum in 2003 when the FDA acknowledged that cardiac risks had surpassed liver toxicity as the lead cause of post-marketing drug withdrawals. In the same year, Health Canada and the FDA circulated a concept paper addressing the Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Their joint publication led to a cardiac safety Guidance, commonly known as E14, that was ratified by the ICH in 2005. This regulation established the importance of Thorough QT testing, and catalyzed a new era of digital ECG acquisition and highly-skilled analysis.
In those early years, most investment experts compared the cardiac testing industry to the central lab market (centralized analysis of blood, urine, and other biological samples) which had—in the previous decade—transitioned rapidly from a fragmented to a centralized model. Recognizing that ECG centralization would generate the same standardization benefits; variability reduction; and cost controls that had been recognized through biological sample centralization, financial analysts predicted rapid growth for the cardiac core lab industry.
While their estimates of an eventual $1 billion cardiac testing market appear to have been accurate, the speed of transition from site-based, paper ECGs to centralized, digital ECGs has occurred more slowly than anticipated. According to a Tufts Center for the Study of Drug Development (CSDD) report published earlier this year, approximately one third of ECGs in clinical trials are presently being centralized. While the exact size of the current centralized market is not known, it is commonly estimated in a range between $300 and $400 million.
The Tufts report describes the market as being “at an inflection point” with the adoption of centralization beginning to accelerate. Tufts’ researchers surveyed pharmaceutical sponsors and investigative sites that are experienced in both local and centralized cardiac testing. Generally, sponsors compared core labs favorably to local ECG processors stating that centralized vendors are more “organized, accurate and standardized,” with “higher quality” results and “faster” database closures. Meanwhile, interviewees from investigative sites indicated they were “ambivalent about the differences between local and central ECG providers, and consider the decision (regarding centralization) to fall within the sponsor’s domain.”
Nearly 90% of Tufts’ respondents expect ECG centralization to expand over the next five years, driven by sponsors’ increasing decisions to employ core labs rather than local processing. And the majority of those surveyed indicated they would prefer to work with a central ECG vendor on their next clinical trial.
The nearly 600 individuals interviewed by Tufts were located mostly in North America and Europe, where the E14 Guidance is well understood. However, evidence also exists that centralization is about to accelerate in the Asia-Pacific region. In October of 2009, the Japanese Ministry of Health (PMDA) announced that all drugs seeking approval after November 1, 2010 must have undergone Thorough QT testing. Learning from the FDA’s previous experience, Japanese regulators are supporting this requirement with an internal committee modeled after the FDA’s Interdisciplinary Review Team for cardiac safety testing. This focused approach may enable progress toward centralization to transpire more rapidly in Asia than it has done in the West.
As global regulatory bodies have gradually aligned their approaches, the world’s patient populations have also become increasingly aware of cardiac and cardiovascular safety risks. Patient concerns have been elevated largely by a series of high profile drug withdrawals related to cardiotoxicity—particularly VIOXX®, Bextra® and AVANDIA®. In the wake of September’s coordinated statements by the FDA and EMA regarding AVANDIA’s cardiovascular risk profile, Senator Charles Grassley (R-Iowa) and other members of the US Congress have renewed their recommendation for the FDA to create a separate center for the study of drug safety.
While the billions of dollars in revenues and legal fees associated with blockbuster drug withdrawals attract great attention, there are also many examples of lesser known medications where cardiac risks have been acknowledged long after marketing approval was granted. Just last month, sales of MERIDIA® were voluntarily curtailed in light of data demonstrating increased potential of heart attack and stroke. As demonstrated by MERIDIA, VIOXX, Bextra and AVANDIA, cardiac effects are not only generated by drugs designed to treat cardiovascular ailments. In fact, serious cardiac issues have been identified in a wide range of therapeutic areas including anti-allergenic, central nervous system, diabetes/metabolic disease, gastroenterology, infectious disease, obesity, oncology and others.
With increased awareness of cardiovascular risks across a variety of marketed products, patients are urging regulators and developers to improve their efforts to accurately define drugs’ cardiac safety profiles during the clinical trial phase. Since some signals are difficult to detect within small clinical trial populations, standardized methods for variability reduction and high skilled data analyses may become increasingly valuable for sponsors and regulators. Their need to derive more meaningful cardiac results from clinical studies is likely to stimulate further adoption of centralized cardiac testing.
There are a number of companies providing such services to biopharmaceutical sponsors. The Tufts CSDD research, cited earlier, was sponsored by an unrestricted grant from ERT, one of the major cardiac core labs. Other leading providers of centralized cardiac testing include BioMedical Systems, Cardiocore and Quintiles. In the years since E14’s finalization, their market has seen a series of mergers, acquisitions and divestments.
In 2007, ERT acquired the Cardiac Safety Services business from Covance, a multi-national CRO. In that same year, Cardiocore acquired the assets of Gentiae, a West Coast based core lab.
After emerging from bankruptcy in August of 2007, MediFacts reorganized around its central cardiac lab, focusing primarily on ambulatory blood pressure monitoring. They acquired the core lab service arm of Spacelabs in 2009, before being acquired themselves earlier this year by RadPharm, a centralized imaging vendor. That combined entity is now known as CoreLab Partners.
In 2009, MDS Pharma divested its biomarker, cardiac, and central lab business units in a deal with Clearstone. Then, in May of this year, Clearstone announced its intention to phase out cardiac services in order to focus on its central lab business. Around the time of Clearstone’s announcement, ERT executed another transaction, acquiring CareFusion’s Research Services Division. CareFusion had spun off from Cardinal Health in 2009, and had originally built its cardiac core lab operation as part of Viasys in 2002.
These corporate activities have reduced the number of established cardiac testing vendors as the industry enters its next phase of maturity. In the years ahead, collaborations between cardiac testing providers, drug developers and international regulators are likely to deepen. This community shares responsibility for the vital relationship between cardiac safety and delivery of efficacious new medications. While honing that balance, core labs, sponsors, regulators and patients all stand to benefit if more reliable safety information is generated earlier in a new drug’s life cycle. That shared goal is expected to be an engine of industry dynamics going forward, and may be the main reason that most biopharmaceutical executives interviewed for the Tufts report predict that “one hundred percent of all cardiac safety studies will eventually be handled by centralized providers.”
Patrick Hughes is Senior Vice President, Commercial Strategy for the Clinical Consulting Division of GxP International Ltd. Patrick has been working in the clinical trial industry for over 15 years specializing in all areas of eClinical Technology such as EDC, ePRO, IVR / IWR, CTMS, Document Management and Cardiac Safety Solutions. Tel: +44 (0) 7703 532 749. Email: email@example.com