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The holy grail of the pharma industry is FDA approval, but the final clue may be positive top-line (Phase III) results. However, it is not out of the question that a Phase III study can meet its efficacy endpoint, yet still be rejected by the FDA. This may especially be true in cancer treatment, where deaths of the participants in the clinical trial are usually common and approval hinges on as little a difference as whether 95 instead of 100 patients died in the group receiving the investigational new drug.

In such a scenario, many deaths can be due to adverse events, which can be fatal when the patients are fragile and terminal with little functional status to survive organ failure or infections. Thus, if any adverse event appears at a higher rate than seen in the placebo group, it can be the basis of an FDA rejection, even if the overall survival improved in the treated group.

That’s what happened to Diiachi Sankyo’s drug receptor tyrosine kinase inhibitor drug, quizartinib, which was being tested as an acute myeloid leukemia (AML) drug. The drug targets the cell-surface receptor tyrosine kinase Flt3, which is upregulated or mutated to constitutive activation in AML. This seemed like a pretty safe bet since similar drugs from Astellas and Novartis were already approved by the FDA, thereby establishing the biological mechanism in AML. Indeed, the Phase III study reached its efficacy endpoint of improved survival for the patients receiving the drug, but the effect was small.

Surprisingly (or not) the FDA voted not to approve the drug due to a large number of cardiac adverse events in the patients receiving the drug. Such a decision was not without controversy, of course. Nevertheless, the whole discussion could have been avoided if there had been suspicion of cardiac events prior to the trial, so that the trial design could have been adjusted to mitigate that risk, for example by stratifying for patients with cardiac risk. Fortunately, there are now user-friendly tools available to raise such suspicions, even at the beginning of the drug discovery process.

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