In response to cardiovascular (CV) safety concerns with rosiglitazone (Avandia) and other drug
used to treat type-2 diabetes the Food and Drug Administration (FDA) convened a public advisory
committee meeting in early July 2008 to review the role of CV risk assessment in the pre-approval
and post approval phases for new drugs and biologics being developed for the treatment of type-2
The advisory committee recommended by a vote of 14 to 2 that manufacturers should
provide evidence to rule out unacceptable CV risk with new type-2 diabetes drugs.
2008 the FDA issued a "Guidance for Industry - Diabetes Mellitus: Developing Drugs and
Therapeutic Biologics for Treatment and Prevention." A guidance is the FDA's current thinking
on a topic and does not carry the weight of a regulation.
In this guidance, FDA reaffirmed
that HbA1c, a surrogate endpoint, remains an acceptable primary efficacy endpoint for approval of
drugs seeking an indication for glycemic control. However, FDA acknowledged that diabetes is
associated with an elevated risk of CV disease that is the leading cause of morbidity and mortality
in this patient population. The FDA stated 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 CV risk may not be practical.
However, for type 2 diabetes, the FDA
noted that the wider range of treatments available before insulin therapy is considered for
controlling hyperglycemia allows for an opportunity to evaluate the effect of these therapies on
cardiovascular risk, enabling a more informed decision on the management of type-2 diabetes.
The guidance asks manufacturers to demonstrate that new treatments for type-2 diabetes do not
result in an unacceptable increase in CV. The guidance does not address CV assessment of
already-approved treatments for type-2 diabetes, which will be addressed in a future guidance.
Specifically, this guidance asks sponsors to do the following during the planning stage of their
drug development programs for therapies for type 2 diabetes:
- Establish an
independent CV endpoints committee to prospectively and blindly adjudicate major CV events, for
example, CV death, myocardial infarction, and stroke) during phase 2 and 3 clinical trials.
- Ensure that the phase 2 and 3 clinical trials are appropriately designed so that a pre-specified
meta-analysis of major CV events can reliably be performed. The manufacturer should provide a
protocol describing the statistical methods for the proposed meta-analysis of all placebo-controlled
trials, add-on trials, and active-comparator trials. The guidance states that it is likely that the
controlled trials will need to last longer than the typical 3 to 6 months duration to obtain a
sufficient number of events and to provide data on longer-term CV risk (e.g., minimum 2 years) for
these chronically used therapies.
- To enroll patients at increased cardiovascular risk,
such as elderly patients and those with renal impairment.
The guidance states that to
support approvability from a CV standpoint, the manufacturer should compare the incidence of major
CV events with the investigational drug to the incidence of the same types of events occurring with
the control group and show that the upper bound of the two-sided 95 percent confidence interval (95%
CI) for the estimated risk ratio is less than 1.8 with a reassuring point estimate. If this upper
bound of this 95% CI is between 1.3 and 1.8 and the overall risk-benefit analysis supports approval
then a postmarketing CV trial generally will be needed to definitively show that this upper bound is
less than 1.3. If the premarketing data show that this upper bound is less than 1.3 and the overall
risk-benefit analysis supports approval then a postmarketing CV trial generally may not be
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