FDA Issues Complete Response Letter for Epoetin Alfa Biosimilar

FDA

The FDA has rejected Hospira’s a biologics license application (BLA) for the epoetin alfa biosimilar, epoetin hospira (Retacrit), citing manufacturing concerns at the company’s fill-finish facility in McPherson, Kansas.

Pfizer announced the agency’s decision in a press release on June 22.

The FDA sent a Warning Letter to Pfizer, Hospira’s parent company, dated February 14, 2017, detailing 5 areas of concern including in-process specifications, failure to follow procedures to prevent microbiological contamination of drug products, and a lack of “scientifically sound and appropriate sampling plans for inspection and analytical activities.”

The agency argued that the company should have known the McPherson site might have problems because the FDA cited 5 other Hospira plants for similar problems from 2010 to 2015.

“These repeated failures at multiple sites demonstrate that your company’s oversight and control over the manufacture of drugs is inadequate,” the letter said.

Pfizer stressed that none of those issues specifically relate to epoetin hospira, though the McPherson plant was a potential manufacturing site. The company added that FDA did not request more data to support a further approval as it did in 2015, when the agency rejected an abbreviated BLA.

Pfizer said it submitted a corrective and preventative action plan to the FDA in March and is working to address the concerns listed in the Warning Letter.

Hospira was seeking approval for 4 indications:

• to treat anemia due to chronic kidney disease, including patients on dialysis and not on dialysis to decrease the need for red blood cell transfusion
• to treat anemia in HIV-infected patients being treated with zidovudine
• to treat chronic renal failure, specifically anemia caused by concomitant myelosuppressive chemotherapy in patients with non-myeloid malignancy
• to reduce the need for allogeneic red blood cell transfusions in patients with perioperative hemoglobin from >10 g/dL to ≤13 g/dL who are at high risk for perioperative blood loss from elective noncardiac, nonvascular surgery

This marks a rare instance of the FDA denying a drug recommended by the Oncologic Drugs Advisory Committee (ODAC). The committee voted 14-1 to approve the BLA on May 25.

ODAC staff recommended approval concluding, “The totality of the analytical similarity data supports the conclusion that epoetin hospira is highly similar to US-licensed Epogen/Procrit . . . The clinical data, including pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety and immunogenicity data, support a finding of no clinically relevant differences.”

However, even at the time of the vote, committee members had questions regarding the drug’s immunogenicity and whether it was safe for use in patients with HIV or cancer. Those patient populations were not as extensively studied when epoetin alfa was first approved in 1989.

Hospira submitted the application based on results from 2 single-center, randomized, open label studies, EPOE-12-02 and EPOE-14-01. The first was aimed to establish the PK and PD (reticulocyte count) of epoetin hospira following a single subcutaneous dose of 100 u/kg in healthy participants (N = 81). EPOE-14-01 was designed to determine the drug’s PK and PD (hemoglobin level) following multiple doses of subcutaneous 100 u/kg epoetin hospira 3 times weekly for 4 weeks in healthy participants (N = 129). Epoetin hospira was compared with epoetin alfa in both studies.

In EPOE-12-02, researchers found that epoetin hospira met the prespecified acceptance criteria for PK similarity, the geometric mean of AUC0-INF (1.06 mIU-h/mL; 90% CI, 1.01-1.11), AUC0-T (1.03 mIU-h/mL; 90% CI, 0.97-1.09), and C^MAX (1.09 mIU-h/mL; 90% CI, 1.01, 1.18). The same was true of PD for AUEC0-456 (1.01%-h; 90% CI, 0.98-1.05) and E_MAX (1.02%-h; 90% CI, 0.99-1.05).

In EPOE-14-01, epoetin hospira also met prespecified acceptance criteria for PD similarity of geometric mean of hemoglobin level AEUC 0-28d (1.00 g-h/dL; 90% CI, 0.99-1.02) and E_MAX (1.00 g/dL; 90% CI, 0.99-1.02).

Epoetin hospira has been approved in Europe for the treatment of anemia associated with chronic renal failure since 2008.

U.S. Food & Drug Administration. Warning Letter. https://www.fda.gov/iceci/enforcementactions/warningletters/2017/ucm542587.htm. Issued February 14, 2017.