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Clinical Development: Antidiabetic Drugs

Living up to Expectation

Ensuring compliance to FDA guidance on cardiovascular risk is essential when creating a new treatment for Type 2 diabetes.

Diabetes is increasing at an alarming rate in the US, with approximately 4,000 people diagnosed with Type 2 diabetes each day (1).The FDA recognises the need for new therapies both for the prevention and treatment of diabetes. In December 2008, the FDA released a guidance on new antidiabetic drugs recommending that sponsors demonstrate that new antidiabetic therapies for the treatment of Type 2 diabetes are not associated with increased cardiovascular risk.

This article will discuss the implications of the FDA guidance and regulations with a specific focus on the following questions: why and how sponsors can demonstrate that their compound is not associated with increased cardiovascular risk; how ECGs and the centralisation of ECGs can play a key role in ensuring cardiac safety; and finally, what associated costs are incurred through compliance to the regulations.

Diabetes Pandemic

Type 2 diabetes has been described as an emerging global pandemic, presenting a serious public health problem on an international level.There are approximately 280 million people with diabetes mellitus worldwide; 90 per cent of these have Type 2 (non-insulin dependent) diabetes (2). In the US alone there are currently 24 million diabetics and that number is steadily increasing. This seems to mirror the rising prevalence of obesity.

The sequellae of diabetes are severe and often fatal. Diabetes is currently the leading cause of blindness, kidney failure and limb amputation, and is a major contributor to myocardial infarction and stroke. Approximately 70 per cent of diabetes mellitus related deaths occur as a result of cardiovascular disease. As a result, diabetes now accounts for a substantial proportion of healthcare expenditure.There are currently many medications used for the treatment of diabetes and these have had a great impact on many of the immediate consequences of elevated blood sugar, as well as on the development of diabetic blindness, kidney failure and peripheral neuropathy. However, the rate of cardiovascular complications remains high in diabetics, making the continued development of safe and effective new agents for the treatment and prevention of diabetes a high priority.

FDA Guidance

Concerns related to the cardiovascular risk incurred by treatment for Type 2 diabetes has heightened in recent years, as some approved drugs appear to actually increase the risk of cardiovascular events. On a broader level, regulators are becoming more stringent regarding the need to ensure the cardiovascular safety of all noncardiovascular drugs. In 2008, the FDA released the document ‘Guidance for Industry. Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes’ (3).

The FDA guidance provides nonbinding recommendations to ensure that new medications for treating diabetes are demonstrated to be safe (from a cardiovascular standpoint), as well as effective at treating elevated blood sugar levels.

The release of the FDA guidance on the treatment of Type 2 diabetes reflects the growing regulatory consensus that the lack of a preclinical signal and/or of cardiovascular events in early trials are not sufficient evidence to demonstrate the cardiovascular safety of a new agent. As such, the guidance recommends that Phase 2/3 trials must be adequately designed in order to demonstrate cardiovascular safety when compared with current therapies. As assessment of cardiovascular safety has become such a priority, the FDA recommends that pharmaceutical companies should establish an independent cardiovascular endpoints committee to prospectively adjudicate, in a blinded fashion, cardiovascular events during all Phase 2 and Phase 3 trials.

Further, it is recommended that “to obtain sufficient endpoints to allow a meaningful estimate of risk, the Phase 2 and Phase 3 programmes should include patients at higher risk of cardiovascular events, such as patients with relatively advanced disease, elderly patients and patients with some degree of renal impairment.”The FDA guidance document makes explicit recommendations about the statistical tests which will be required to demonstrate cardiovascular safety, and has provided estimates of the number of subjects required for these safety studies. It is estimated that the late phase trials to demonstrate cardiovascular safety will require upwards of 2,500 subjects; between 1,300 to 1,500 subjects should be exposed to the investigational product for one year or more, and a minimum of 300 subjects exposed for at least 18 months.This is a marked contrast to the far smaller size and shorter duration of previous trials for new antidiabetic agents.

Centralisation of ECGs

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 its interpretation. Further, the document states,“to obtain sufficient endpoints to allow a meaningful estimate of risk, the Phase 2 and Phase 3 programmes should include patients at higher risk of cardiovascular events, such as patients with relatively advanced disease, elderly patients, and patients with some degree of renal impairment.” In order to ensure the value of ECG data for evaluating cardiovascular safety, sponsors are encouraged to use a centralised approach to their ECG programme in order to achieve a standardised and consistent database.

When a decentralised 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 centralised approach overcomes this issue of inconsistency by digitally collecting high quality data in a standardised 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 standardised procedures which are continually validated through a quality control programme. As a consequence, more consistent and cleaner data will be generated. Additionally, centralisation 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 per cent of MIs are ‘silent’, and are associated with either no symptoms at all, or with atypical symptoms not recognised by the patient.These ‘silent’ MIs may be detected on the serial ECGs collected during the trial.The capture of these otherwise unrecognised 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, so that analysis of the database can reliably identify these subjects for adjudication by the cardiovascular events committee. Decentralised ECG reading, with interpretations generated by ECG machines or by a wide variety of noncardiologist physicians may yield databases with so much noise that new events cannot be resolved reliably.

Another advantage of using a centralised cardiac safety core lab is the enhanced availability of ECG data for review by the sponsor and cardiovascular review committee.When ECGs are analysed locally, the paper ECG remains at the site. In contrast, a centralised core lab stores all of the ECG data in a central repository and can provide online access to ECG data via a centralised portal.The ability to evaluate data from a specific patient, as well as across all patients globally,may be invaluable.

Cost-Effective Compliance

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 a higher number of subjects translates into increased expense for sponsors.The use of a centralised cardiac safety core lab will improve the quality of ECG data generated, but is often thought to be more costly than use of decentralised ECG reading. In reality, however, the use of a core lab may actually be more costeffective 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 minimise the amount of re-testing that must be carried out. 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 centralised approach easier to implement. In a recent comparison of cost compiled by a leading provider of technology services, it was shown that the use of centralised ECG provides an overall cost reduction of 34.6 per cent (4).

Conclusion

In order to comply with the FDA guidance on the development of new antidiabetic drugs, sponsors must now demonstrate that a new agent does not increase cardiovascular events. It is recommended that trial endpoints are clearly designed, independent cardiovascular endpoint committees are established, and that sponsors prepare to enrol higher risk subjects in longer and larger cardiovascular safety trials. Trial periods should be extended up to two years and trials must be adequately designed to detect the requisite number of cardiovascular events in order to satisfy the statistical requirements outlined in the FDA guidance.

To comply with these recommendations and avoid inconsistency, inaccuracy and unnecessary extra cost, the use of centralised ECGs is crucial. As a result of centralised 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 programme can be decreased, while still ensuring compliance with the new, more stringent regulatory requirements.

References

  1. Diabetes Public Health Resource, http://www.cdc.gov/diabetes/pubs/factsheet11.htm
  2. International Diabetes Federation, www.idf.org/node/1363?unode=013B84FE-189A-4A80-84F8-C994CAFB17E6
  3. Guidance for Industry – Diabetes Mellitus – Evaluating Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, US Department of Health and Human Services, Food and Drug Administration, www.fda.gov/cder/guidance/index.htm
  4. Mapping Adoption of Centralized Cardiac Safety Assessment, Tufts Center for the Study of Drug Development: Feb 2010, www.ert.com/knowledge-series

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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. Robert is currently ERT’s Vice President, Global Cardiology, and is responsible for the conduct of ERT’s cardiology group as well as participating in ERT’s consulting group. Following completion of his training at the University of Pennsylvania, he was a member of a busy cardiology practice for 12 years. He began working in cardiac safety as a part-time consultant in 1995 and joined ERT full-time in 2003.
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