FDA Import Alert Lifted, Apotex Says; Will Lipitor ANDA Approvals Be Far Behind?

Apotex’s announcement that FDA is lifting an import alert on products manufactured at two Canadian facilities could be interpreted as a good sign for the near-term availability of Lipitor generics, either from first-filer Ranbaxy Laboratories Ltd. or subsequent ANDA filers.

For its part, however, FDA is not confirming any plans to left the import alert.

If the alert is lifted, the agency’s action would appear to remove a major roadblock to approval or tentative approval of Apotex’s atorvastatin ANDA. The move suggests FDA is satisfied that Apotex has sufficiently addressed the good manufacturing practice issues that led to the import alert in August 2009.

It also could be seen as a move by the agency to line up later-filed atorvastatin ANDAs that are ready for approval in the event that Ranbaxy cannot be approved on or after June 28.

However, Apotex’s situation also could be viewed as a positive for Ranbaxy.

Clearly, the Indian generic drug maker’s problems are more serious than those of Apotex, as evidenced by its placement on FDA’s Application Integrity Policy list in February 2009.

But FDA faces growing congressional and public pressure to ensure that Lipitor generics are not unduly delayed. The timing of the agency’s apparent clearance of Apotex’s facilities – less than two months before the June 28 expiration of pediatric exclusivity on Pfizer’s enantiomer patent – could mean it also is working expeditiously with Ranbaxy to resolve its manufacturing issues and thereby enable ANDA approval by the first-filer.

GMP Woes Began In 2008

Apotex’s GMP problems date back to an FDA inspection of the firm’s Etobicoke site in December 2008, which resulted in a June 2009 warning letter. The agency identified similar violations during a July-August 2009 inspection of a Toronto manufacturing facility, which resulted in all finished drug products manufactured at the two sites being placed on an import alert and denied entry into the U.S.

In a March 2010 warning letter stemming from the Toronto site inspection, FDA said the GMP violations observed at both sites “demonstrated a lack of adequate process controls and raised serious questions regarding your corporation’s quality and production systems.”

The letter stated FDA would withhold approval of new ANDAs pending correction of the violations (Also see "Apotex Manufacturing Violations Could Delay Launch Of Taxotere Generic" - Pink Sheet, 19 Apr, 2010.).

In a May 11 press release, Apotex said FDA had decided to lift the import alert affecting the firm’s largest solid oral dose manufacturing facility that supplies products to the U.S., and shipments would resume soon. The company did not respond to requests for further comment.

In response to inquiries from “The Pink Sheet,” the agency said it had no comment on any plans to change Apotex’s import alert status. As of May 13, the agency’s website continued to reflect an import alert for the two Apotex facilities.

Apotex’s website states its Toronto manufacturing facility focuses on oral solid dose products. The Etobicoke site, established in 1993 to serve the U.S. market, has the same production capabilities and also makes coated pellets used in modified-release products. R&D activities supporting applications for solid dose products are conducted at Etobicoke.

Apotex is one of at least seven firms with pending ANDAs for atorvastatin, and it remains in patent litigation with Pfizer. As part of that litigation, Apotex has sought a declaratory judgment that several Lipitor patents are invalid or not infringed; such a ruling would trigger Ranbaxy’s 180-day exclusivity (Also see "Lipitor Patent Battle: Pfizer Plots New Course In Suit With Apotex" - Pink Sheet, 2 Aug, 2010.).

The 30-month stay of approval on Apotex’ ANDA appears to have expired in early May. Assuming FDA is satisfied that GMP issues have been resolved, there would be no obvious bar to tentative approval of Apotex’s ANDA.

An April 27 docket entry in the patent case in the U.S. District Court for the Northern District of Illinois indicated Pfizer and Apotex were in settlement talks. A status conference in the case is set for May 25.

Waiting For Approval

No pending atorvastatin ANDA has received tentative approval.

Ranbaxy, Teva Pharmaceutical Industries and Mylan Pharmaceuticals Inc. have settled their patent cases with Pfizer. Ranbaxy’s settlement allows it to launch on Nov. 30. Although the terms of Teva’s and Mylan’s settlements have not been disclosed, it is believed they would be able to enter the market upon expiration of Ranbaxy’s 180-day exclusivity in May 2012.

Watson Pharmaceuticals will enter the market with an authorized generic in November but could launch earlier if another generic reaches market first.

Whether Ranbaxy, which is controlled by Daiichi Sankyo, will be able to secure approval and the accompanying 180-day exclusivity remains an open question.

The Paonta Sahib, India manufacturing facility referenced in the company’s original ANDA remains subject to FDA’s AIP due to evidence of falsified data in applications generated at that site.

Ranbaxy would lose its exclusivity, opening up the market to subsequent ANDA filers, if FDA ultimately determines its ANDA cannot be approved. Mylan’s lawsuit seeking to force a decision on Ranbaxy’s eligibility for 180-day exclusivity was dismissed by a federal judge on May 2 (Also see "Lipitor Generics: Questions About Mylan's ANDA Weigh Heavily In Court's Dismissal Of Lawsuit Against FDA" - Pink Sheet, 3 May, 2011.).

Ranbaxy would have the right to request a hearing if FDA rejects its ANDA, a process that could span several months. Any possibility of exclusivity is not extinguished until the company exhausts all available appeals.

However, knowledge that such a rejection is imminent could incentivize Ranbaxy to reach a deal with other ANDA filers to relinquish its exclusivity, and its rights to any appeal, in exchange for a cut of the profits from the atorvastatin market (Also see "The Last Days Of Lipitor: Morass Of Regulatory, Legal Issues Could Mean Few Early Generics" - Pink Sheet, 14 Feb, 2011.).

For its part, Ranbaxy officials are holding firm to their public statements that negotiations with FDA are moving forward.

Ranbaxy is in “unprecedented” negotiations with FDA and DoJ.

During a May 10 earnings call, Ranbaxy Managing Director Arun Sawhney said the firm was in “unprecedented” negotiations with FDA and the Department of Justice, and that such talks have progressed in the last few months. “I do not see anything untoward happening in our negotiation process.”

When asked if the timeline for a Nov. 30 launch could be impacted by the negotiations, Sawhney said Ranbaxy has the manufacturing capabilities to produce atorvastatin on short notice following FDA approval. "Let us keep that question for the next quarter," he said.

Referring to a recent Fortune magazine report that suggested Ranbaxy may need to pay $1 billion as part of a civil and criminal settlement, Sawhney suggested that analysts should trust the regulatory agencies to determine the amount of any penalty, rather than rely on speculation from a magazine (Also see "Talk Of $1 Billion Fine On Ranbaxy By U.S. FDA Dents Stock; Analysts Divided Over Exact Penalty" - Scrip, 5 May, 2011.).

– Sue Sutter ([email protected]) and Vikas Dandekar ([email protected])