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.
February 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
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
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
- 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.
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 necessary.
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