Several first-to-file ANDAs are on the line for Ranbaxy as it tries to resolve data integrity issues at its Paonta Sahib facility with FDA.

On Feb. 25, agency officials announced they had halted scientific review of Ranbaxy drug applications that include information generated at the Indian plant, citing "evidence of falsified data."

The agency instead is assessing the validity of information in all applications, whether pending or approved, based on Paonta Sahib data.

In working with FDA, "no effort or action will be spared to timely protect key ANDAs from Paonta Sahib, which include some first-to-file applications," a company spokesperson said. He declined to elaborate on which drugs are covered by the ANDAs in question.

Among the possibilities is atorvastatin. In June 2008, Ranbaxy settled its Lipitor patent dispute with Pfizer by agreeing to delay introduction of its generic version of the blockbuster statin. The Indian firm was the first to file an ANDA for generic Lipitor and said the clock on its 180-day marketing exclusivity would begin running on Nov. 30, 2011 (¹ Also see "Pfizer Settlement With Ranbaxy Delays Generic Lipitor Entry" - Pink Sheet, 23 June, 2008., p. 22).

New Application Needed For Replacement Data

CDER has determined that Ranbaxy "submitted untrue statements of material fact in abbreviated and new drug applications," center Director Janet Woodcock advised Ranbaxy in a ² letter explaining agency findings and plans.

The problematic data largely involve information from stability tests. Examples take up four pages of the letter, and Woodcock concludes: "These and other findings indicate a pattern and practice of submitting untrue statements of material fact and other wrongful conduct."

If FDA finds information in an application to be unreliable, "the agency intends ordinarily to exercise its authority" to refuse to approve a pending application or to withdraw approval for an approved application. This action would be taken "regardless of whether the applicant attempts to replace the unreliable data with a new submission in the form of an amendment or supplement," she pointed out.

"If the applicant wishes to replace the false data with a new submission, the new submission should be in the form of a new application."

First-to-file status would appear to be forfeited with rejection of an ANDA, even if a new application is filed, since the filing date of the new application would supercede that of the original.

If Ranbaxy does file a new application, a company executive would have to take responsibility for its veracity. The truthfulness and accuracy of a new application would have to be certified by the company's president, CEO or "other official most responsible for the applicant's operations," Woodcock stated.

The company has been given 10 days from the Feb. 25 date of Woodcock's letter to tell the agency whether it intends, for each affected application, to address data validity issues or request withdrawal.

Problems with Ranbaxy's data surfaced last summer when it became known that the Department of Justice was looking into whether the firm had fabricated bioequivalence and stability data (³ Also see "Ranbaxy’s Ripples: Generic Drug Integrity Returns As Focus For Congress, FDA" - Pink Sheet, 21 July, 2008., p. 9).

Violations of good manufacturing practices subsequently prompted a Sept. 16 FDA import alert for 33 finished products produced at the Paonta Sahib and Dewas plants (⁴ Also see "Ranbaxy May Face Third-Party Oversight Of Ganciclovir Manufacturing" - Pink Sheet, 22 September, 2008., p. 4).

The current action is being taken under FDA's Application Integrity Policy, a procedure created during the generic drug scandal of the late 1980s when many firms were charged with submitting fraudulent applications.

The AIP is invoked "when there is a pattern or practice of wrongful conduct by a company that raises significant questions about the reliability of the data and information contained in an application," CDER Office of Compliance Director Deborah Autor explained to reporters during a press briefing.

FDA Finds No Reason For Recalls

Drugs produced at Paonta Sahib already are barred from the U.S. market by the import alert. Medicines approved in the affected applications but made elsewhere are not being recalled.

FDA has analyzed at least 80 samples of finished drug products covered by the affected applications and found them to meet specifications, and is continuing to collect samples and conduct testing, Autor said.

"We have no evidence of problems with the safety or efficacy of any Ranbaxy drugs on the U.S. market."

Rep. Bart Stupak, D-Mich., has questioned FDA's initial handling of Ranbaxy's problems, including the decision not to initiate a recall, and the agency's latest move will likely help build congressional momentum for legislative action on manufacturing oversight (see ⁵ Also see "Citizen Petition Changes In FDAAA Force Firms To Reconsider Timing Strategy" - Pink Sheet, 2 March, 2009.).

FDA officials noted that two cholesterol-lowering drugs - simvastatin and pravastatin - and the antihistamine loratadine do not appear to be affected, but the agency will review their applications "out of an abundance of caution."

The drugs originally were intended for production at the Paonta Sahib facility but were switched to manufacturing at Ranbaxy's OHM plant in New Jersey. When that change was made, extensive testing was done at the New Jersey site, so very little, if any, data in their applications were generated at Paonta Sahib, FDA says.

Ranbaxy cooperation in FDA's efforts to examine data integrity and reliability would include implementation of a Corrective Action Operating Plan, the agency says. A CAOP involves, but is not limited to, a third-party independent audit of the affected applications.

Five companies currently are listed by CDER or CBER as subject to the AIP. The agency believes that three of them - Biopharmaceutics, Superpharm and Sclavo - are out of business. The other two are Ranbaxy and Solopak Pharmaceuticals.

Companies that were previously on the list but resolved their data reliability issues include Biochimica Opos, Gilatech and Solvay Pharmaceuticals. FDA is not certain of all companies that have been subject to the AIP because the list predates the Internet and the revision history is not readily available.

Among those that FDA had placed on the list but didn't make the trip to the Web: Warner-Lambert (⁶ Also see "WARNER-LAMBERT FAJARDO, P.R. PLANT TO BE TAKEN OFF FDA INTEGRITY POLICY SOON, FIRM SAYS; FAILURE TO REPORT DILANTIN TEST FAILURES PROMPTS GUILTY PLEA" - Pink Sheet, 4 December, 1995., p. 3), which subsequently merged with Pfizer.

- Cathy Dombrowski (c.dombrowski@elsevier.com)

Ranbaxy’s First-To-File ANDAs At Risk In FDA Data Integrity Probe

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