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US FDA hands Pfizer its second complete response letter for its proposed biosimilar to Epogen/Procrit, citing manufacturing compliance concerns at a legacy Hospira manufacturing facility in Kansas that was the target of a February warning letter. Issue “is not directly related to EPO itself,” Pfizer’s Salomon Azoulay says.


Pfizer Inc. is working to resolve lingering compliance issues at a legacy Hospira Inc. manufacturing facility that have blocked its bid to bring the first biosimilar version of epoetin alfa (Amgen Inc.’s Epogen/Johnson & Johnson’s Procrit) to the US market.



On June 22, Pfizer announced receipt of an FDA complete response letter a day earlier for its epoetin alfa biosimilar (proposed trade name Retacrit). The regulatory action marks the second time FDA has declined to approve the 351(k) application that Pfizer inherited through its acquisition of Hospira in September 2015.


The current letter “relates to matters noted” in a Feb. 14 warning letter for a Hospira drug manufacturing facility in McPherson, KS, where the biosimilar was to be manufactured, Pfizer said.


“It is “unfortunate that we have an issue at a manufacturing plant,” Pfizer’s Azoulay said, “but this issue is not directly related to EPO itself.”


The issues noted in the warning letter do not relate specifically to the manufacture of epoetin alfa,” Pfizer said in a release. “No additional clinical data was requested in the CRL at this time to support a future approval.”


In an interview with the Pink Sheet, Salomon Azoulay, senior vice president, chief medical officer and acting R&D head of Pfizer Essential Health, stressed that the regulatory delay did not involve issues with the biosimilar itself, and FDA’s letter contains no mention about any deficiencies in the application.


It is “unfortunate that we have an issue at a manufacturing plant,” Azoulay said, “but this issue is not directly related to EPO itself.”


Nevertheless, the issue is one that will delay the biosimilar’s approval for an unknown length of time.



Easy ODAC Suggested Clear Path Ahead…


Just a month ago, Pfizer’s epoetin biosimilar looked like it was headed for a quick approval despite a rocky first-cycle review.


Just a month after acquiring Hospira, Pfizer announced receipt of a complete response letter for the epoetin biosimilar application. Pfizer did not disclose details about that initial complete response letter except to say that further clinical trials likely would not be needed. (Also see "Biosimilar Denied: Hospira's Retacrit Could Head Back To FDA In First Half 2016" - Pink Sheet, 27 Oct, 2015.)


“The reasons Pfizer received a CRL from the FDA in 2015 are different from the recent CRL, which is related to manufacturing,” a company spokeswoman said.


Although the company said it expected to resubmit the BLA in the first half of 2016, the submission was delayed until December 2016.


The application’s second pass through FDA appeared to be going smoothly, at least based on the public advisory committee review.


On May 25, FDA’s Oncologic Drugs Advisory Committee voted 14-1 that the totality of evidence supports licensure as a biosimilar for all indications on the Epogen labeling. (Also see "Biosimilar Advisory Committees Getting Smoother, Even As Worries Stay The Same" - Pink Sheet, 25 May, 2017.)


The panel’s recommendation reinforced the views of FDA staff. In briefing documents released ahead of the meeting, FDA said there were no clinically meaningful differences between the Pfizer/Hospira product and Epogen, and the products were highly similar despite minor differences in clinically inactive components.


Those documents noted that FDA required Pfizer to change its manufacturing process after finding that the lots used for its clinical studies contained a higher erythropoietin content than US-licensed Epogen. Pfizer agreed to adjust the erythropoietin content to more closely match the reference product and to tighten the commercial product acceptance criteria. (Also see "Hospira's Epogen Biosimilar Appears Poised For Quick Advisory Cmte. OK" - Pink Sheet, 23 May, 2017.)


FDA’s briefing document also noted good clinical practice violations at several trial sites but concluded these violations did not alter the efficacy and safety conclusions from the studies.


Some advisory committee members were irked that postmarketing data for the biosimilar in Europe, where it is marketed as Retacrit, were not available for consideration. Even though the proposed US biosimilar product has same cell line and drug product formulation as EU-approved Retacrit, Pfizer did not bridge to it in its US biosimilar application. (Also see "Pfizer Excludes EU Biosimilar Experience From US Epoetin Application" - Pink Sheet, 4 Jun, 2017.).


… But Troubles Lurked At McPherson Site


While much information about an application is disclosed publicly as part of the advisory committee process, details about the facilities at which products are going to be manufactured and any related compliance concerns are generally not brought to the external experts’ attention.


However, FDA’s concerns about the site at which Pfizer’s biosimilar was to be manufactured were already well known.


On Feb. 14, the agency issued a warning letter stemming from an inspection of the McPherson, KS facility in May and June 2016. The warning letter cited the company’s failure to adequately address the presence of visible particulates in products despite multiple complaint investigations, saying this represented “a significant loss of control” in the manufacturing process. (Also see "Pfizer Suffered 'Significant Loss Of Control' At McPherson Plant, US FDA Warning Letter Says" - Pink Sheet, 28 Feb, 2017.)


“Until these violations are corrected, we may withhold approval of pending drug applications listing your facility.” – FDA’s Feb. 14 warning letter


The letter also noted that the violations are similar to those cited in four other warning letters issued to Hospira over the past six years concerning other manufacturing sites.



“Until these violations are corrected, we may withhold approval of pending drug applications listing your facility,” the warning letter states. “We may re-inspect to verify that you have completed your corrective actions. We may also refuse your requests for export certificates.”



Several days after the warning letter’s issuance, Momenta Pharmaceuticals Inc. announced that approval of its Sandoz Inc.-partnered ANDA for Glatopa (glatiramer) 40 mg, a generic of Teva Pharmaceutical Industries Ltd.’s multiple sclerosis drug Copaxone, was likely to be delayed by the compliance issues at the McPherson plant, where the product was to be manufactured. (Also see "Pfizer Warning Letter Trips Up Sandoz/Momenta’s Expected Glatopa Launch" - Pink Sheet, 23 Feb, 2017.)



Meanwhile, quality problems at the Hospira business also have led to shortages and recalls of critical drugs.



Pfizer attributes ongoing shortages of five injectable drugs to manufacturing, distribution and third-party delays. The products – sodium bicarbonate, dextrose 50%, epinephrine, calcium chloride and atropine sulfate – all have roles in emergency medicine.



Hospira also is recalling 42 lots of one of the shortage drugs, 8.4% sodium bicarbonate injection 50 ml vials, due to concerns about possible microbiological contamination.



Preparing For Facility Re-inspection


Pfizer’s epoetin biosimilar now becomes the second new product known to have fallen victim to the McPherson site’s compliance troubles.



In its release, Pfizer said it submitted a corrective and preventative action plan to FDA in March and has been working diligently to address the items raised in the warning letter. “Pfizer provides regular updates to FDA on the status of its action plan and remains dedicated to addressing all of FDA’s concerns with the McPherson, KS site,” the company said.



Azoulay said the company is “taking every corrective action” and “working very closely with the FDA” to get ready for a re-inspection of the facility. However, he could not provide a timeline for when the re-inspection would take place or when the biosimilar might be approved.



When asked whether the McPherson issues have delayed approval of any other Pfizer products, Azoulay said “not at this time.” The compliance issues have had not impacted Pfizer’s currently marketed products, he said.



When asked whether Pfizer has considered moving the epoetin biosimilar’s manufacturing to another facility, Azoulay said the company is focused on addressing the agency’s concerns about the McPherson plant.



Despite the regulatory delays in getting its version of epoetin to market, Pfizer reaffirmed its commitment to the biosimilars market in general as a means for increasing patient access to important medicines, and to biosimilar epoetin in particular.



“The company is committed to making this important treatment option available to patients and physicians as quickly as possible,” Pfizer said in its release.



In addition to epoetin alfa, the company’s website lists five other biosimilars in registration or Phase III development that reference the following products: AbbVie Inc.’s Humira (adalimumab), Genentech Inc.’s Avastin (bevacizumab) and Herceptin (trastuzumab), Janssen Biotech Inc.’s Remicade (infliximab) and Genentech and Biogen’s Rituxan (rituximab).



Pfizer markets Celltrion Inc.’s Inflectra (infliximab-dyyb), a biosimilar to Remicade, in the US and overseas. The biosimilars Retacrit (epoetin zeta) and Nivestim (filgrastim), which references Amgen’s Neupogen, are marketed overseas.

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