FDA review red-flags AstraZeneca's case for ovarian cancer drug olaparib

AZ CEO Pascal Soriot

AstraZeneca's ($AZN) reconstructed case for the cancer drug olaparib is built on the fundamental premise that the new management team at the pharma giant is a whole lot smarter than the old crew. After a retrospective analysis found a subgroup response in the data for ovarian cancer, CEO Pascal Soriot not only ordered the team to renew its pursuit of an approval, he later assigned a $2 billion peak sales value to the program.

Inside investigators at the FDA, though, have raised some serious criticism of the data that were submitted with the application to market the drug as a maintenance therapy for patients with an hereditary BRCA mutation. Two days ahead of an external panel review, the FDA review questions whether the conclusions AstraZeneca reached could have been skewed by a very small group of patients delivering signs of a false benefit due to an "underperforming" control arm in the study. And given the potential side effects, the agency wants the reviewers to consider whether AstraZeneca should wait on more definitive data before marketing a drug that could just be adding to patients' woes.

"The small sample size of gBRCAm patients and the retrospective identification of this patient population call into question the reliability of the estimation of treatment effect," states the review. "The retrospective identification of the gBRCAm population did not appear to result in gross imbalances of known prognostic factors that could account for the treatment effect seen in Study 19, but it is important to note that the loss of randomization and the selection of a convenient sample of patients who had available whole blood sample for retrospective testing may have led inadvertently to an unequal distribution of unknown factors that may have affected the study results. The hazard ratio of 0.17 certainly suggests that most patients will have some degree of prolongation of PFS from treatment, but the data demonstrating that the placebo-treated gBRCAm performed more poorly in terms of PFS when compared to the placebo-treated gBRCAwt/vus raise the concern that the median improvement of seven months may be due in part to an "underperforming" control arm. The analysis of overall survival suggests no detriment as a result of therapy, but no survival difference was seen between treatment arms."

A setback here would raise more questions about the judgment of AstraZeneca's management group, which badly needs to demonstrate that it can efficiently develop important new drugs. Olaparib had been a significant part of Soriot's case against Pfizer's failed $120 billion takeover bid, offering proof of the bright future that lies ahead of the pharma giant now that an R&D turnaround has taken place. And the CEO has expressed supreme confidence that AstraZeneca made the right decision in reviving hopes for this drug.  

"When I saw olaparib, for me, it was a clear reflection of good science and poor management ...," Soriot told Forbes' Matthew Herper recently. "Essentially, the commercial teams were under-excited." 

A positive vote this week will help Soriot. But a thumb's down may remind investors of AstraZeneca's woeful past and revive speculation that a new Pfizer ($PFE) bid may yet be in the offing.

- here's the review (PDF)