95% confidence interval for the risk ratio is greater than 1.8, the guidance states that there
would be inadequate evidence of cardiovascular safety to support marketing. If the upper
bound falls less than 1.8 and there are no other approvability issues, the drug would be
able to be approved but the drug may need a post-marketing required cardiovascular trial
to definitively address cardiovascular safety. The cut point for this decision is 1.3. If the
upper bound of the risk ratio is between 1.3 and 1.8 post-marketing cardiovascular trials
would be needed to show definitively that the upper bound is less than 1.3. If the upper
bound for this risk ratio is less than 1.3 and the drug can otherwise be approved, post-
marketing cardiovascular trials generally will not be necessary. These upper bounds of
1.3 and 1.8 assume a reassuring point estimate.
the upper bound represents the “worst case” potential for increased cardiovascular risk
based on a combined analysis across studies, and we set some criterion as to what that
upper bound should be. The numbers, we will talk about in a moment, are 1.3 and 1.8.
For example, an upper bound of 1.8 says that the estimated increased risk of
cardiovascular events with an investigational drug is no worse than 1.8 times the risk
of the applicants. Initially Bristol-Myers Squibb and Novo Nordisk were asked to
conduct cardiovascular analyses and they use different approaches and different
methodologies to analyze cardiovascular events. To create a more uniform approach
Let’s take a closer look at these two numbers, if the upper bound of this
I would now like to turn to the cardiovascular analyses that FDA requested
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compute the point estimate for the risk ratio comparing investigational drug to
comparator and also the 95% confidence interval for this risk ratio.
We then turn to the upper bound of this 95% confidence interval because