J&J Eprex EU Label Changed; FDA Investigating Manufacturing Fraud

Johnson & Johnson is recommending intravenous administration of Eprex (epoetin alfa) over subcutaneous administration in chronic renal failure patients in order to decrease the incidence of pure red blood cell aplasia in a July 17 "Dear Doctor" letter to physicians in the EU.

The company sent "Dear Doctor" letters with similar recommendations in Canada and Switzerland June 25 and May 21, respectively. The Canadian letter followed up on an earlier letter to physicians there dated Nov. 26, 2001.

The letters recommend that "while the company continues further investigation of the multiple aspects contributing to antibody formation/PRCA in patients, the product should be administered by intravenous route in [chronic renal failure] patients where feasible. If I.V. access is not feasible in a patient with CRF, the risk/benefit of subcutaneous administration should be considered for each patient."

The EU letter also notifies physicians of revised EU labeling for Eprex. The revisions remove statements that subcutaneous administration is preferred to I.V., and that I.V. administration requires 20%-30% more of the product.

The revised label recommends I.V. administration of Eprex for hemodialysis patients and includes information for use in other chronic renal failure patient types, recommending I.V. administration when feasible and, when not feasible, that the risk/benefit of subcutaneous administration be considered on a case by case basis.

The "Dear Doctor" letters note that most of the 141 PRCA reports have been in chronic renal failure patients receiving Eprex via subcutaneous administration. "Cases of PRCA have been reported with epoetin products marketed in the EU, the majority of which relate to Eprex administered mainly by the subcutaneous route and only in patients with CRF," the letter states.

During J&J's quarterly analyst call July 16, VP-Investor Relations Helen Short noted that the affected patient population comprises a small portion of total sales. "This patient subset represents less than 20% of our Procrit/Eprex sales," Short said.

J&J markets epoetin alfa in the U.S. as Procrit , where it is manufactured by Amgen. J&J obtained the rights to market epoetin alfa in the U.S. for non-dialysis markets via a 1985 deal with Amgen. J&J currently markets Procrit for anemia associated with chemotherapy or chronic renal failure in non-dialysis patients.

The agreement gave Amgen exclusive U.S. rights to epoetin alfa for dialysis markets. Amgen is seeking to invalidate J&J's license in the U.S. through arbitration, arguing that the company intentionally sold Procrit in Amgen's exclusive dialysis market (¹ (Also see "Amgen Effort To Reclaim Procrit Rights From J&J Moving To Trial Phase" - Pink Sheet, 20 Mar, 2000.), p. 19).

J&J's Ortho Biologics division manufactures Eprex for distribution outside of the U.S., where it is marketed for the full range of indications.

Amgen markets epoetin alfa as Epogen in the U.S. for the treatment of anemia associated with hemodialysis. The company does not have international marketing rights to epoetin alfa, but manufactures and sells its EPO follow-on product Aranesp (darbepoetin alfa) worldwide.

Amgen maintains that PRCA is unique to Eprex and is not associated with Procrit (which it manufactures), Epogen or Aranesp. The company says that there have been no PRCA cases associated with Aranesp and only two reports in Epogen patients.

Amgen attributes PRCA reports to J&J's formulation and manufacturing of Eprex.

"Amgen licenses the cell line and the technical information to manufacture epoetin alfa. However, Ortho Biologics is not obligated to implement Amgen manufacturing processes," the company said in a statement responding to the PRCA reports. "Over time, Ortho Biologics has independently made formulation and manufacturing process changes to Eprex. The result is that Eprex is not equivalent to Amgen's Epogen/Procrit."

Potential differences between Epogen/Procrit (manufactured by Amgen) and Eprex (manufactured by J&J) that may cause PRCA could strengthen arguments against generic biologics. The Biotechnology Industry Organization maintains that different versions of a multisource biotech product will "inevitably differ in certain respects" (² (Also see "BIO Generic Biologics Position: All Products Need "Rigorous" Clinical Trials" - Pink Sheet, 6 Aug, 2001.), p. 22).

In 1998, Ortho Biologics removed human serum albumin from Eprex, but J&J says that this is not a cause of the PRCA cases. "We don't think it is any way related to the manufacturing technique," J&J Exec VP-Finance Robert Darretta said during the conference call.

FDA is conducting a fraud investigation at J&J's Manati, Puerto Rico facility, where Eprex is manufactured.

The investigation is related to a whistleblower lawsuit by a former employee at the plant who claims he was pressured to falsify documents at various times between 1996 and 1998, and was then suspended prior to an interview with FDA inspectors.

J&J says that the employee was a utilities worker "with no responsibility for manufacturing," and was fired in 1999 for failing to complete equipment records.

FDA's Office of Criminal Investigation sought a stay of the lawsuit in April and began investigating the plaintiff's allegation regarding false documentation at the manufacturing facility.

In response, J&J conducted an investigation of the facility, the company said. "A review of documents disclosed no suspect patterns for falsification (e.g. penmanship, consistent passing results). The review also disclosed that out of specification parameters are routinely documented and not hidden. [Standard operating procedures] around [good manufacturing practice] compliance evolved as the company gained experience," a J&J statement says.

"Based on the investigation, there is no connection between the allegations of the former employee and the occurrence of PRCA."

FDA conducted a two-week inspection of the Ortho Biologics plant in October 2001 "related to cases of immunogenicity associated with Eprex," J&J said. "That inspection resulted in only minor observations."

While J&J maintains that PRCA is a class effect of epoetin products administered subcutaneously in patients with chronic renal failure, Amgen disagrees that PRCA is related to subcutaneous administration.

"Eprex was administered safely by the SC route for many years prior" to these incidences, and other drugs within the same class "continue to demonstrate an excellent safety profile regardless of the route of administration," Amgen said.

Prior to the EU revision, Eprex labeling recommended subcutaneous administration over intravenous. U.S. labeling for Procrit and Epogen recommends either route of administration, but notes that "in patients on hemodialysis, Procrit has usually been administered as an I.V. bolus."

In addition to maintaining that PRCA is a class effect, J&J says that the condition is likely to occur with subcutaneous injection of any biologic, not just epoetin alfa.

"There tends to be, when you inject sub-q - I'm going to use the lay term for it - a clumping that occurs under the skin that apparently happens with all biologicals," Short said during the conference call. "In general, biologics are better when they are administered intravenously instead of subcutaneously. Of course we are still studying this and we are still looking for the root cause of the problem."