Satisfying the Regulatory Requirements for New Antidiabetic Drugs for Type 2 Diabetes Most Expeditiously
The regulatory landscapes for the prospective exclusion of unacceptable cardiovascular risk associated with new antidiabetic drugs for type 2 diabetes in the USA and Europe were formalized in 2008 and 2012, respectively. The FDA’s Guidance for Industry sp
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Satisfying the Regulatory Requirements for New Antidiabetic Drugs for Type 2 Diabetes Most Expeditiously There is considerable interest among many stakeholders regarding ways in which the existing regulatory requirements can be met more efficiently.
13.1
Introduction
The regulatory landscapes for the prospective exclusion of unacceptable cardiovascular risk associated with new antidiabetic drugs for type 2 diabetes in the USA and Europe were formalized in 2008 and 2012, respectively. The FDA’s Guidance for Industry specifically addressing this landscape was issued in final format (a rare occurrence) in December 2008 (FDA 2008). The EMA’s updated general guidance document addresses this topic. Following the release of a first draft in 2010 and a revised draft in 2011 (a period for public comment followed each release), the document was finalized in May 2012 and became effective in November 2012 (EMA 2012). The first section of this chapter presents the key aspects of each document. As noted in Chap. 12, at the time of writing this book, the exoneration of a drug from an unacceptable cardiovascular risk has typically involved the conduct of a large, lengthy, and extremely expensive cardiovascular safety outcome trial. There is therefore considerable interest among many stakeholders regarding ways in which the existing regulatory requirements can be met more expeditiously. In January 2015, members of the CSRC published an Expert Perspectives paper entitled “Clinical Development Approaches and Statistical Methodologies to Prospectively Assess the Cardiovascular Risk of New Antidiabetic Therapies for Type 2 Diabetes” that addressed this topic (Geiger et al. 2015). Discussions in this chapter draw from that paper and also cover recent initiatives that are similarly driven. Geiger and colleagues (2015) deliberately focused on satisfying the regulatory requirements as they are currently written: their paper did not discuss the utility of the safety margins (thresholds) of 1.8 and 1.3 as presented in the FDA Guidance for Industry, or whether every diabetes drug development program should include a cardiovascular outcome trial (see Sager et al. 2015 for related discussions).
© Springer International Publishing Switzerland 2017 J.R. Turner et al., Cardiovascular Safety in Drug Development and Therapeutic Use, DOI 10.1007/978-3-319-40347-2_13
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13.2
13 Satisfying the Regulatory Requirements
The FDA and EMA Regulatory Landscapes
Before describing these regulatory landscapes, it is important to note that both the FDA and EMA have made it clear that the requirements for prospective exclusion of unacceptable cardiovascular risk do not apply to the development of insulin drugs and insulin analogues. The FDA document notes explicitly that “the absolute deficiency of insulin in patients with type 1 diabetes dictates the need for insulin therapy as an immediate lifesaving treatment for which evaluation of long-term cardiovascular risk may not be practical” (FDA 2008).
13.2.1
The FDA Guidance for Industry
The FDA’s
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