Friday, February 29, 2008

Zyprexa Depot: The Real Meaning of Delayed Release

FDA’s “non-approvable” decision on Eli Lilly’s long-acting olanzapine (Zyprexa) depot reiterates the reality of the new "Safety First" climate: product labeling and educational programs simply aren’t going to cut it as a comprehensive risk minimization program--especially if there are acceptable and well-understood alternatives on the market.

Going against the recommendations of its advisory committee, FDA declined to approve the long-acting olanzapine injection yesterday, stating that it needed “more information to better understand the risk and underlying cause of excessive sedation events.” In clinical trials, 1.2% of schizophrenia patients became profoundly sedated one to three hours after administration—to the point where some slipped into a coma.

Lilly presented FDA with a risk management plan to address the excessive sedation risk, including a bolded warning in Zyprexa labeling, a recommended post-injection observational period and a patient and physician education program. The company also said it would continue to monitor sedation events via a 5,000-patient observational study.

FDA’s Psychopharmacologic Drugs Advisory Committee bought into the program, agreeing with Lilly that with the appropriate labeling around the excessive sedation events, Zyprexa depot was effective and "acceptably safe" as a schizophrenia treatment in adults.

But FDA ultimately disagreed, pointing to a case in which a patient became excessively sedated three to five hours after the injection—a significantly later onset than what had been seen earlier in clinical trials. For FDA reviewers, that event no doubt called into question whether Lilly’s proposed risk management plan could adequately protect patients.

The Zyprexa non-approvable decision provides an early look into how FDA will view risk management in light of its new drug safety authorities under the 2007 FDA Amendments Act. Under the new law, sponsors are required to submit Risk Evaluation & Mitigation Strategies for all new drugs, or provide a justification to FDA for why one is not needed.

Risk management isn’t new: drug sponsors certainly have experience with designing programs to minimize the risk associated with new products. But Zyprexa demonstrates that the old rules no longer apply—especially for a line extension of an already-approved product. FDA is raising the bar, and industry would be wise to act accordingly.

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