Welcome back! This information has been provided by board-certified cardiologist, Dr. Robert Kleiman.
Each of you reading today most likely knows someone who is personally affected by Diabetes, as Diabetes is increasing at a disturbing rate in the US, Europe and in China. There are approximately 2801 million people with diabetes mellitus worldwide; 90% of these have type 2 (non-insulin dependent) diabetes. In the US alone there are currently 24 million diabetics with approximately 4,000 people being diagnosed with Type 2 diabetes each day.
The effects of diabetes are severe and often fatal. Diabetes is currently the leading cause of blindness, kidney failure, limb amputation, and is a major contributor to myocardial infarction and stroke. Approximately 70% of diabetes mellitus related deaths occur as a result of cardiovascular disease. Diabetes now accounts for a substantial proportion of health care expenditure and with the rate of cardiovascular complications remaining high in diabetics, the continued development of safe and effective new agents for the treatment and prevention of diabetes continues to be a high priority.
In recognition of this alarming growth and the ongoing research and development of both preventive and palliative diabetes treatment, in December, 2008 the FDA released Guidance for Industry – Diabetes Mellitus – Evaluating Cardiovascular Risk in New Anti-diabetic Therapies to Treat Type 2 Diabetes’2 . This guidance provides nonbinding recommendations for sponsors to demonstrate that new anti-diabetic therapies for the treatment of Type 2 diabetes are not associated with increased cardiovascular risk and are effective at treating elevated blood sugar. This article will discuss the implications of the FDA guidance recommendations and how sponsors can respond in order to ensure compliance.
Part of the assessment of a new drug’s short and long-term cardiovascular effects can be assessed by performing serial electrocardiograms (ECGs). However, the quality of the data generated by a test is only as good as the quality of the interpretation of the test itself. In order to ensure the value of ECG data for evaluating cardiovascular safety, sponsors are encouraged to use a centralized approach to their ECG program in order to achieve a standardized and consistent database.
When a decentralized model is employed, ECGs are performed at the investigator sites using local ECG machines, which may be of many different makes and models. As a result, the automated measurements and interpretations may be very inconsistent due to different types of instruments using a variety of different computer algorithms for calculations. In contrast, a centralized approach overcomes this issue of inconsistency by digitally collecting high quality data in a standardized format for assessment, with the use of consistent and validated systems. All interval duration measurements (IDMs) are assessed by a qualified individual and every ECG is evaluated by a qualified cardiologist who is trained to follow standardized procedures which are continually validated through a quality control program. As a consequence, more consistent and cleaner data will be generated. Additionally, centralization facilitates proactive data monitoring and tracking, with demography and missing visits noted automatically, thereby enabling the collection of valuable data as studies progress.
Accurate and comprehensive capture of cardiovascular events requires an instrument that can detect even the most inconspicuous of indicators. For example, myocardial infarction (MI) does not always have a classic presentation, as many as 40% of MIs are “silent”, and are associated with either no symptoms at all, or with atypical symptoms which are not recognized by the patient. These “silent” MIs may be detected on the serial ECGs collected during the trial. The capture of these otherwise unrecognized events may help to reduce the duration and cost of these large cardiovascular safety trials. However, the capture of this data requires that ECGs be evaluated in a consistent manner such that analysis of the database can reliably identify these subjects for adjudication by the cardiovascular events committee. Decentralized ECG reading, with interpretations generated by ECG machines or by a wide variety of non-cardiologist physicians may yield databases with so much noise that new events cannot be reliably resolved.
Another advantage to the use of a centralized cardiac safety core lab is the enhanced availability of ECG data for review by the sponsor and cardiovascular review committee. When ECGs are analyzed locally, the paper ECG remains at the site. In contrast, a centralized core lab stores all of the ECG data in a central repository, and can provide online access to ECG data via a centralized portal. The ability to evaluate data across a specific patient and across all patients globally may be invaluable.
Upon its initial release, the FDA Guidance on the development of treatment for Type 2 diabetes produced some controversy. The recommendations for extended trial periods with higher numbers of subjects translate into increased expense for sponsors. The use of a centralized cardiac safety core lab will improve the quality of ECG data generated, but is often thought to be more costly than use of decentralized ECG reading. In reality, however, the use of a core lab may actually be more cost-effective than having multiple individual sites perform ECG evaluations. Contracting with a core lab reduces fees paid to each site for technical support and ECG reading (often by unskilled readers). Additionally, by eliminating errors in collection and transcription of ECG data, sponsors can minimize the amount of retesting that must be carried out. In addition, recent technological innovations have led to the introduction of new, highly compact ECG instrumentation, providing the same industry-leading performance of conventional systems at a lower cost and making a centralized approach easier to implement. The Tufts Center for the Study of Drug Development published an analysis regarding the industry adoption of Centralized Cardiac Safety, perceptions from stakeholders and a comparison of cost. It was effectively shown that the use of centralized ECG provides an overall cost reduction of 34.6%.3
To comply with the recommendations of the FDA Guidance and to avoid inconsistency, inaccuracy and unnecessary extra cost, the use of centralized ECGs is crucial. As a result of centralized ECG collection and evaluation, data management quality and consistency is improved. With improved quality, greater consistency and ultimately more accurate data, false positive and negative ECG findings can be avoided. The overall duration, size and cost of the drug development program can be decreased, while still ensuring compliance with the new, more stringent regulatory requirements.
Please feel free to leave any questions or comments regarding this topic for Dr. Kleiman or ERT and we will ensure a prompt response. Thank you for being a part of the ERT community!
Robert B Kleiman is a board certified cardiologist and cardiac electrophysiologist who has performed research in both basic cellular electrophysiology as well as clinical electrophysiology. Following completion of his training at the University of Pennsylvania, he was a member of a busy cardiology practice for 12 years.
1: International Diabetes Federation, http://www.idf.org/node/1363?unode=013B84FE-189A-4A80-84F8-C994CAFB17E6
2: Guidance for Industry – Diabetes Mellitus – Evaluating Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, U.S. Department of Health and Human Services, Food and Drug Administration, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf3:
3. “Mapping Adoption of Centralized Cardiac Safety Assessment”, Tufts Center for the Study of Drug Development: Feb 2010, http://www.ert.com/knowledge-series/