Pfizer Withdraws Subpart H Drug MYLOTARG From the Market

By Kurt R. Karst –   

Earlier this week, FDA announced Pfizer’s voluntarily withdrawal (at least insofar as a voluntary withdrawal is truly voluntary when FDA requests it) of MYLOTARG (gemtuzumab ozogamicin for Injection) from the market after a required postmarketing study failed to demonstrate clinical benefit.  FDA approved MYLOTARG in May 2000 under the Agency’s Subpart H (“accelerated approval”) regulations as a single agent for patients with CD33 positive Acute Myeloid Leukemia (“AML”) in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.  Pfizer announced that the company will withdraw the MYLOTARG NDA effective October 15, 2010. 

In December 1992, FDA promulgated final regulations under which the Agency will accelerate the approval of certain new drugs and biologics for serious or life-threatening illnesses, and when such products provide a meaningful therapeutic benefit to patients over existing treatments.  These accelerated approval regulations are located in Subpart H (21 C.F.R. Part 314) of FDA’s drug regulations, and in Subpart E (21 C.F.R. Part 601) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based on a demonstrated effect on a surrogate endpoint reasonably likely to predict clinical benefit and a sponsor’s commitment to complete with due diligence the required postmarketing studies to confirm the product’s clinical benefits.  A surrogate endpoint is an alternative measurement of the symptoms of a disease or condition that is substituted for measurements of observable clinical symptoms.  Importantly, FDA may expedite the withdrawal of approval of an application approved under the accelerated approval regulations if “[a] postmarketing clinical study fails to verify clinical benefit” or if a sponsor “fails to perform the required postmarketing study with due diligence.”

FDA approved MYLOTARG based on the surrogate endpoint of response rate observed in 142 patients with AML across three clinical trials and required the applicant to conduct a postmarketing study designed to determine whether adding MYLOTARG to standard chemotherapy demonstrated an improvement in overall survival time (i.e., clinical benefit) of AML patients.  The required postmarketing study was initiated in 2004, but was stopped early when no clinical benefit was observed.  In addition, according to FDA, the study was also stopped “after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone.” 

The MYLOTARG withdrawal appears to be the first instance in which a product granted accelerated approval has been withdrawn from the market – either because a postmarketing study failed to verify clinical benefit or because of a sponsor’s failure to complete a required postmarketing study with due diligence.  Although FDA could have pursued withdrawing approval of IRESSA (gefitinib) when the sponsor’s postmarketing study failed to verify clinical benefit, FDA instead approved new labeling that limits IRESSA use to patients with cancer who are currently benefiting, or have previously benefited, from IRESSA treatment.