Murglitazar, a drug for diabetes that activates both alpha- and gamma-peroxisome proliferator-activated receptors, was reviewed by FDA for approval during the committee’s work. In the preapproval trials, compared with the other arms of the trials (some compared the drug with a placebo, others with another diabetes medicine), murglitazar improved sensitivity to insulin and the control of blood lipids in patients with type 2 diabetes. Those efficacy outcomes are examples of surrogate endpoints because they are expected to predict the occurrence of cardiovascular events. In the same preapproval trials, however, patients randomized to murglitazar had a significantly higher incidence of the combined outcomes of death, heart attack, stroke, and heart failure. The reason for the discrepancy between surrogate endpoints and health outcomes is not clear, but the case of murglitazar illustrates the importance of verifying the assumed health benefits of new drugs and of conducting more complete risk-benefit analyses (Nissen et al., 2005).

As described in Chapters 2 and 3, OND clinical reviewers are primarily responsible for assessing the safety information in an NDA, and interactions and involvement of the Office of Drug Safety/Office of Surveillance and Epidemiology (ODS/OSE)1 staff vary among OND offices. A recent time-accounting exercise by CDER reports that OND devotes 51 percent of total scientific and technical staff effort on safety-related activities (FDA, 2005a). Despite that large investment of time and effort, the safety profile of a drug at the time of NDA review is necessarily uncertain at the time of approval. The only certainty at the time of approval is that the CDER official who signed the approval letter has not identified safety problems that in his or her best judgment outweigh the potential benefit of the drug for the specific indication and population studied. However, to expect that premarket studies or FDA review of these studies can reveal all the information about the risks and benefits of new drugs that is needed to make optimal treatment decisions would occasion unreasonable delay in approval.

Reducing Uncertainty About Risk and Benefit After Approval

As described in other sections of this report, important new information about a drug’s effectiveness2 accumulates after approval, although effectiveness is extremely diffcult to assess outside the context of a randomized trial. The committee has chosen to describe the major components essential to as-


In May 2006, CDER renamed the Office of Drug Safety (ODS) the Office of Surveillance and Epidemiology (OSE). The committee will refer to this office as ODS/OSE in the report in recognition that some statements refer to actions of the office in the past and some statements refer to the present.


Efficacy refers to effects in controlled clinical trials; effectiveness refers to effects in the “real world.”

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