Table 2

Summary of the 2008 FDA guidance on CVOTs (1)

To adequately evaluate the CV safety of type 2 diabetes drugs in development, future development programs should include:
 • Phase 2 and 3 trials that include patients at higher risk for CV events, are of sufficient size and duration to enable enough CV events to allow for a meaningful evaluation of CV risk, and are designed to facilitate later meta-analysis; the CV events should include CV mortality, MI, and stroke and can also include hospitalization for ACS, urgent revascularization procedures, and other end points such as HF hospitalization*
 • Independent adjudication of CV events
 • Meta-analysis of the phase 2 and 3 trials to be conducted at the end of the research program, following a protocol developed in advance that prespecifies the end points to be assessed and the statistical methods to be employed
 • Analysis of premarketing data comparing the CV events occurring with the agent to those occurring with the control group and demonstrating that the upper limit of a two-sided 95% CI of the estimated risk ratio is <1.8; if this cannot be done through the meta-analysis described above, it should be accomplished in a separate, large CV safety trial
 • For agents whose 95% CI upper limit falls between 1.3 and 1.8 in premarketing analysis, completion of a postmarketing trial or continuation of a premarketing trial after approval may be needed to conclusively show that the upper limit of the two-sided 95% CI is <1.3 with a “reassuring” point estimate of overall CV risk
  • *The FDA has gained valuable experience from CVOTs and CV risk assessments intended to meet the December 2008 guidance. The FDA has acknowledged that allowing MACE+ (a composite of CV death, nonfatal MI, or nonfatal stroke plus the less-specific end point of unstable angina requiring either hospitalization or revascularization) in the premarket CV risk assessment to exclude a 95% CI upper limit ≥1.8 is acceptable because it allows for a more reasonable sample size for evaluation. Provided no countervailing safety finding is observed, MACE+ in the premarket risk assessment strikes an appropriate balance of safety assessment without an undue burden to companies bringing new therapies to market. However, to provide longer-term, more reassuring CV safety data in the postmarketing setting, the exclusion of a 95% CI upper limit ≥1.3 should rely on the MACE composite (CV death, nonfatal MI, and nonfatal stroke). Furthermore, these data should come from a dedicated CV trial and not from the meta-analysis of multiple phase 2 or 3 trials (41).